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用药速查|对乙酰氨基酚如何安全用药?一文理清 - 丁香园

用药速查|对乙酰氨基酚如何安全用药?一文理清 - 丁香园

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用药速查|对乙酰氨基酚如何安全用药?一文理清

2022-12-13 11:37

来源:丁香园

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对乙酰氨基酚(Acetaminophen、Paracetamol) ,又称醋氨酚、扑热息痛,Panadol、Tylenol、Fortolin 等都是这类药物,为苯胺类解热镇痛药。在 12 月 8 日,国家卫健委发布的《新冠病毒感染者居家治疗常用药参考表》(图 1)中,对乙酰氨基酚是治疗发热症状的推荐常用药物之一。本文将总结国内外说明书、指南,围绕适应症、用法用量、特殊人群用药、相互作用和配伍禁忌等对对乙酰氨基酚进行介绍。                                                                                                                     症状常用药物适用人群及用法、用量发热对乙酰氨基酚、布洛芬、阿司匹林、金花清感颗粒、连花清瘟颗粒/胶囊、宣肺败毒颗粒、清肺排毒颗粒、疏风解毒胶囊等须按药品说明书服用或咨询医生 咽干咽痛地喹氯铵、六神丸、清咽滴丸、疏风解毒胶囊等咳嗽咳痰溴己新、氨溴索、愈创甘油醚、乙酰半胱氨基酸等干咳无痰福尔可定、右美沙芬等流鼻涕氯苯那敏、氯雷他定、西替利嗪等鼻塞赛洛唑啉滴鼻剂等恶心/呕吐桂利嗪、藿香正气水/胶囊等图 1:《新冠病毒感染者居家治疗常用药参照表》>>>左右滑动查看>>一、国内批准适应症、用法用量适应症1、普通感冒或流行性感冒引起的发热。2、缓解轻至中度疼痛,如头痛、关节痛、偏头痛、牙痛、肌肉痛、神经痛、痛经、癌性痛和术后止痛。用法用量1、口服:(1)片剂、泡腾片:成人一次 1 片(500 mg),若持续发热或疼痛,每 4~6 小时重复用药一次,24 小时内不得超过 4 次。(2)缓释片:成人一次 1 片(650 mg),若持续发热或疼痛,每 8 小时重复用药一次,24 小时内不得超过 3 次。(3)咀嚼片:成人一次 2~3 片(320~480 mg),若持续发热或疼痛,每 4~6 小时重复用药一次,24 小时内不得超过 4 次。(4)糖浆、口服溶液:成人一次 15~25 mL(360~600 mg),若持续发热或疼痛,每 4~6 小时重复用药一次,24 小时内不得超过 80 mL(1920 mg)。(5)胶囊:成人一次 1~2 粒(300~600 mg),若持续发热或疼痛,每 4~6 小时重复用药一次,24 小时内不得超过 4 次。2、肌内注射:成人一次 150~250 mg。退热疗程一般不超过 3 天,镇痛疗程一般不宜超过 10 天。二、特殊人群用药、禁忌症老年用药在对乙酰氨基酚注射液的临床研究中,15% 的受试者年龄为 65 岁及以上,而 5% 为 75 岁及以上。在这些受试者和年轻受试者之间没有观察到安全性或有效性的总体差异,其他报道的临床经验也没有发现老年人和年轻病人之间的反应差异,但不能排除一些老年人对对乙酰氨基酚的敏感性更强。儿童用药口服:1、滴剂(1.5 g/15 mL 规格):(1)1~2 岁儿童,10~12 kg:0.5~1 mL/ 次;(2)2~3 岁儿童,12~14 kg:1~1.5 mL/ 次;(3)4~6 岁儿童,16~22 kg:1.5~2 mL/ 次;(4)7~9 岁儿童,22~28 kg:2~2.5 mL/ 次;(5)10~12 岁儿童,28~32 kg:2.5~3 mL/ 次;(6)若持续发热或疼痛,可间隔  4~6  小时重复给药 1 次,24 小时内不得超过 4 次;(7)直接滴于口中服用或溶于 20 倍的水中服用。2、混悬液(3.2 g/100 mL 规格):(1)1~3 岁儿童,12~15 kg:3 mL/ 次;(2)4~6 岁儿童,16~21 kg:5 mL/ 次;(3)7~9 岁儿童,22~27 kg:8 mL/ 次;(4)10~12 岁儿童,28~32 kg:10 mL/ 次;(5)若持续发热或疼痛,可间隔 4~6 小时重复给药 1 次,24 小时内不得超过 4 次。3、糖浆( 2.40 g/100 mL 规格):(1)1~2 岁儿童,10~15 kg:5~8 mL/ 次;(2)3~6 岁儿童,16~21 kg:8~10 mL/ 次;(3)7~9 岁儿童,22~27 kg:10~12 mL/ 次;(4)10~12 岁儿童,28~32 kg:12~15 mL/ 次;(5)若持续发热或疼痛,可间隔 4~6 小时重复给药 1 次,24 小时内不得超过 4 次。4、片剂:(1)6~12 岁儿童:250 mg 每次;(2)12 岁以上儿童:500 mg 每次;(3)若持续发热或疼痛,可间隔 4~6 小时重复给药 1 次,24 小时内不得超过 4 次。5、缓释片:(1)12 岁以上儿童:650 mg 每次;(2)若持续发热或疼痛,可间隔 8 小时重复给药 1 次,24 小时内不得超过 3 次。6、咀嚼片:(1)1~3 岁儿童,10~15 kg:80~160 mg 每次;(2)4~6 岁儿童,16~21 kg:160~240 mg 每次;(3)7~9 岁儿童,22~27 kg:240~320 mg 每次;(4)10~12 岁儿童,28~32 kg:320 mg 每次;(5)若持续发热或疼痛,可间隔 4~6 小时重复给药 1 次,24 小时内不得超过 4 次。哺乳期用药1. 大量哺乳期妇女用药研究证明安全。此外,该药并不明显增加婴儿的副作用,这类药物可能对哺乳婴儿的危害甚微。2. 应同时考虑到母乳喂养对婴儿益处、母亲对乙酰氨基酚的临床需要,以及对乙酰氨基酚对母体状况及母乳喂养婴儿的任何潜在不利影响。妊娠期用药1、在 FDA 分级中,对乙酰氨基酚属于 B 级。2、从给药方式上看,当以口服形式或直肠给药时,分级为 B 。当以肠道外或静脉形式给药时,分级为 C 。3、对乙酰氨基酚不影响血小板功能,分娩期应用不增加出血危险,而且早产儿颅内出血率也无增加,但不能长时间使用 [1]。长期服用对乙酰氨基酚可增强抗凝药的抗凝作用.禁忌症1、对任何形式的对乙酰氨基酚或药剂中含有的任一成分过敏的患者禁用。2、患有严重肝功能损害或严重活动性肝病的患者禁用三、药物相互作用、配伍禁忌1、对乙酰胺基粉的相互作用, 见表 1。                                  表 1:用药助手 APP-合理用药-对乙酰氨基酚表 2:作用程度分级2、对乙酰氨基酚的配伍禁忌,见表 3。表 3:用药助手 APP-合理用药-对乙酰氨基酚四、关于肝脏毒性的风险1. 对乙酰氨基酚已与与急性肝衰竭的病例有关,有时会导致肝脏坏死和死亡。2. 大多数肝脏损伤的案例都与过量使用对乙酰氨基酚有关,并且往往涉及同时服用多种对乙酰氨基酚药品。五、药物过量过量表现:1、在急性对乙酰氨基酚过量的情况下,剂量依赖性的、可能致命的肝脏坏死是最严重的不良反应。肾小管坏死、低血糖昏迷和血小板减少也可能发生。2、口服后 4 小时内,血浆中的对乙酰氨基酚水平如果超过 300 mg/mL,那么 90% 的患者可能会造成肝损伤。90% 的患者会有肝脏损害;如果摄入对乙酰氨基酚4小时后的血药浓度低于 150 µg/mL 或 12 小时后的血药浓度低于 37.5 µ/mL,则预计肝脏损害会很小。3、导致潜在肝中毒的药物过量的早期症状包括:恶心、呕吐、腹泻和全身不适。肝脏毒性的临床和实验室证据可能在服药后 48~72 h 才会显现。过量处理:1、如果怀疑是对乙酰氨基酚过量,应尽快进行血清中对乙酰氨基酚浓度的检测,但应在服药 4 小时后进行。2、尽快获得肝功能报告,并且需要每 24 小时重复检测。一旦发现潜在肝毒性,使用解毒剂 N -乙酰半胱氨酸(NAC)。3、对乙酰氨基酚过量处理指导:可将对乙酰氨基酚血药浓度与服药后时间绘制成一个诺莫图(Rumack-Matthew)。诺莫图上判断药物过量的下线为服药后 4 小时 150 µg/m或 12 小时后 37.5 µg/mL。如果血药浓度高于下线,则进行的 NAC 治疗,如果对乙酰氨基酚水平低于下线,则暂停 NAC 治疗。相关阅读:用哪些药物不能与对乙酰氨基酚同服?参考文献:[1]  焦秀兰 . 妊娠期用药安全的药物分析 [J]. 中国现代药物应用,2010,4 ( 23) : 170.编辑|圆脸大侠题图 | 站酷海洛 

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ETHICS Paracetamol 500mg — Kiwi Chemist

ETHICS Paracetamol 500mg — Kiwi Chemist

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What does it do? Paracetamol is used to treat and prevent mild to moderate pain, and reduce fever.

Dosing Adults & children over 12 years: 1-2 tablets repeated every 4-6 hours if necessary.Children 6-12 years: ½ -1 tablet repeated every 4-6 hours if necessary.Maximum of 4 doses in any 24 hours. Do not exceed stated dose

Caution Do not take more than the stated dose. For adults this is usually up to a maximum of 8 tablets/capsules (500 mg) in 24 hours. Do not take other medicines that also contain paracetamol, unless you discuss this with a health professional. For Adults: Do not use for more than a few days at a time, except on medical advice. For children ages 7-17: Do not use for more than 48 hours, except on medical advice. Do not exceed the stated dose.

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Vitamins and minerals are supplementary to and not a replacement for a balanced diet. Always read the label, use only as directed. If symptoms persist, see your healthcare professional. Weight management products should be used with a balanced diet and exercise.

Pharmacist only products - your pharmacist will advise you whether this preparation is suitable for your condition. The pharmacist reserves the right not to supply when contrary to our professional and ethical obligation.

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Paracetamol (Acetaminophen) - Pharmaceutical Drugs - NCBI Bookshelf

Paracetamol (Acetaminophen) - Pharmaceutical Drugs - NCBI Bookshelf

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NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Pharmaceutical Drugs. Lyon (FR): International Agency for Research on Cancer; 1990. (IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans, No. 50.)Pharmaceutical Drugs.Show detailsIARC Monographs on the Evaluation of the Carcinogenic Risks to Humans, No. 50.IARC Working Group on the Evaluation of Carcinogenic Risks to Humans.Lyon (FR): International Agency for Research on Cancer; 1990.ContentsSearch term < PrevNext >

Paracetamol (Acetaminophen)1. Chemical and Physical Data1.1. Synonyms and trade namesChem. Abstr. Services Reg. No.: 103-90-2Chem. Abstr. Name: Acetamide, N-(4-hydroxyphenyl)-Synonyms: 4′-Hydroxy-acetanilide; para-acetaminophenol; acetophenum; para-acetylamidophenol; N-acetyl-para-aminophenol; para-acetylaminophenol; para-hydroxyacetanilide; N-para-hydroxyphenylacetamideA large number of fixed combinations containing paracetamol are available.1.2. Structural and molecular formula and molecular weight

1.3. Chemical and

physical properties of the pure

substanceFrom Fairbrother, (1974) and

El-Obeid

and Al-Badr, (1985)Description:

White odourless crystalline powder; large

monoclinic prisms from

waterMelting-point:

169–170.5

°CSolubility:

Soluble in water (1:70, 1:20 at 100°C), ethanol

(1:7), acetone (1:13), chloroform (1:50), glycerol

(1:40), methanol (1:10), propylene glycol (1:9)

and solutions of alkali hydroxides; insoluble in

diethyl ether. A saturated aqueous solution has a

pH of

~6.Spectroscopy

data: Infrared, ultraviolet, nuclear

magnetic resonance, fluorescence and mass spectra

have been

reported.Stability: Dry, pure paracetamol is stable to 45°C. Contamination with traces of para-aminophenol, and humid conditions that cause hydrolysis to para-aminophenol, result in further degradation and discoloration. Slightly light-sensitive in solution, and degradation is catalysed by acids or bases.Dissociation constant: pKa = 9.0–9.5Partition coefficient: Pc = 6.237 (octanol: pH 7.2 buffer)1.4. Technical products and impuritiesParacetamol is available in pure form as numerous trade-name preparations for oral use. It is also found combined in over 200 preparations with other drugs.Trade names: Abensanil; Acamol; Acephen; Acetalgin; Acetamol; Aferadol; Alba-Temp; Alpiny; Alvedon; Amadil; Anacin-3; Anaflon; Anhiba; Anuphen; Apamide; APAP; Atasol; Ben-u-ron; Bickie-mol; Bramcetamol; Calip; Calpol; Calpon; Campain; Capital; Captin; Ceetamol; Cetadol; Cetamol; Cetapon; Claradol; Claratal; Custodial; Dafalgan; Datril; Dial-a-gesix; Dirox; Disprol Paediatric; Dolamin; Dolanex; Doliprane; Doloral; Dolorol; Dolprone; Dorcol Children's Fever and Pain Reducer; Doregrippin; Dymadon; Efferalgan; Enelfa; Eneril; Ennagesic; Eu-Med; Exdol; Fanalgic; Febrigesic; Febrilix; Fendon; Fevamol; Finimal; Fonafor; Gelocatil; Glenpar; Gynospasmine; Hedex; Homoolan; Kinderfinimal; Kinder-Finiweh; Korum; Liquiprin; Lyteca; Malgis; Melabon; Momentum; Napamol; Naprinol; Nebs; Neuridal; Nevral; Nina 120; Nobedon; Ophinal; Oraphen; Pacemo; Pacemol; Painamol; Painaway; Paldesic; Pamol; Panado; Panadol; Panaleve; Panamax; Panasorb; Panets; Panex; Panodil; Panofen; Pantalgin; Paracet; Paracetamolum; Paraclear; Paralgin; Parapain; Paraprom; Parasin; Paraspen; Paratol; Parmol; Pasolind; Phendex; Pinex; Placemol; Praecimed; Proval; Puernol; Pyragesic; Pyralen; Reliv; Repamol; Resolve; Robigesic; Rounox; Salzone; Schmerzex; Sedapyren; Servigesic; Setamol; SK-APAP; Summadol; Tabalgin; Tachipirina; Tapar; Temlo; Tempra; Tenasfen; Ticelgesic; Tralgon; Treupel; Treuphadol; Tricocetamol; Tylenol; Tymol; Valadol; ZolbenParacetamol is available as 325-mg or 500-mg tablets, which may include calcium stearate or magnesium stearate, cellulose, docusate sodium and sodium benzoate or sodium lauryl sulfate, starch, hydroxypropyl methylcellulose, propylene glycol, sodium starch glycolate, polyethylene glycol and Red #40.It is also available as 500-mg gelatin capsules and as a mint-flavoured liquid containing 500 mg/15 ml solution, which can include 7% ethanol, citric acid, glycerine, polyethylene glycol, sodium benzoate, sorbitol, sucrose, Yellow #6, #10 and Blue #1. For children, drops (80 mg/0.8 ml), chewable tablets (80 mg), elixir (160 mg/5 ml) and coated capsules (160 mg/capsule) are available (Barnhart, 1989).Characteristic impurities may include para-nitrophenol, para-aminophenol, para-chloroaniline, ortho-acetyl paracetamol, azobenzene (see IARC, 1975), azoxybenzene, quinone (see IARC, 1977), quinonimine, inorganic chloride, inorganic sulfate, inorganic sulfide and water (Fairbrother, 1974).2. Production, Occurrence, Use and Analysis2.1. Production and occurrenceParacetamol may be made by acetylation of para-aminophenol (obtained by reduction of para-nitrophenol) with acetic acid or acetic anhydride. A number of other synthetic routes have been described (Fairbrother, 1974).Paracetamol is synthesized in Argentina, Brazil, China, Colombia, France, the Federal Republic of Germany, India, Japan, Mexico, Poland, Republic of Korea, Romania, Taiwan, Turkey, the UK and the USA (Chemical Information Services Ltd, 1989–90).In Sweden, paracetamol sales in 1988 were 20.02 defined daily doses per 1000 inhabitants (Apoteksbolaget, 1988, 1989).Paracetamol is not known to occur naturally, but it is the major metabolite of phenacetin (see IARC, 1980, 1987).2.2. UseParacetamol is used as an analgesic and antipyretic drug. It is the preferred alternative analgesic-antipyretic to aspirin (acetylsalicylic acid), particularly in patients with coagulation disorders, individuals with a history of peptic ulcer or who cannot tolerate aspirin, as well as in children (American Medical Association, 1986). Paracetamol was first used in clinical medicine in 1893. Following initial use as a prescription product in the USA in 1951, it subsequently became available without prescription in 1955 (Ameer & Greenblatt, 1977). In many countries, it is widely available without prescription.The conventional oral dose for adults is 500–1000 mg. Dosing may be repeated every 4 h as necessary, but the total daily dose should not exceed 4000 mg. For children, the recommended dose is 10–15 mg/kg bw; no more than five doses should be administered over 24 h. Prolonged use (for more than ten days) and use for young children is not recommended (Flower et al., 1985).The usual dose for rectal administration is equal to that for oral administration (American Medical Association, 1986).2.3. AnalysisMethods for the analysis of paracetamol have been reviewed (El-Obeid and Al-Badr, 1985).Paracetamol and its metabolites can be analysed in biological fluids by high-performance liquid chromatography (HPLC; Manno et al., 1981; Kinney & Kelly, 1987; Aguilar et al., 1988; Meatherall & Ford, 1988), HPLC-mass spectrometry (Betowski et al., 1987) and fluorescence polarization immunoassay (Koizumi et al., 1988). It can be analysed in pharmaceutical preparations by HPLC (Biemer, 1987) and spectrophotometric (US Pharmacopeial Convention, Inc., 1989) methods.3. Biological Data Relevant to the Evaluation of Carcinogenic Risk to Humans3.1. Carcinogenicity studies in animalsSince paracetamol is a metabolite of phenacetin (Reynolds, 1989), carcinogenicity studies of phenacetin result in exposure of animals to paracetamol. For the results of studies on phenacetin, see IARC (1987).(a) Oral administrationMouse: Groups of 60 male and 60 female young adult IF strain mice were fed paracetamol (> 98% pure; dissolved in acetone then evaporated) at 5000 or 10 000 mg/kg of diet for 18 months (approximate daily intake, 250 or 500 mg/kg bw, respectively). A group of 52 males and 52 females fed basal diet served as controls. Shortly after the beginning of treatment, 33 males and seven females in the higher-dose group died from liver necrosis. Subsequent survival in all groups was high. All survivors were killed at 18 months after the beginning of the experiment, and complete necropsy was carried out with histological examination of the liver, lungs, pancreas, kidneys, spleen, bladder and adrenal glands. The effective numbers of animals were 50 male and 48 female controls, 54 males and 57 females in the lower-dose group and 23 males and 47 females in the higher-dose group. The incidences of large, often multiple liver neoplasms (adenomas and carcinomas combined) were 20/23 (87%: 15 adenomas, 5 carcinomas) in higher-dose males, 9/47 (7 adenomas, 2 carcinomas) in higher-dose females, 1/54 (adenoma) in lower-dose males, 0/57 in lower-dose females, 1/50 (adenoma) in control males and 0/48 in control females (Flaks & Flaks, 1983). [The Working Group noted that the high dose produced early lethal hepatotoxicity in half the males.]Groups of 50 and 55 male or female (C57Bl/6 × C3H/He)Fl (B6C3F1) mice, eight to nine weeks of age, were fed paracetamol (> 98% pure) at 3000 and 6000 mg/kg of diet, respectively. The total intake of paracetamol in the high-dose groups was 863 g/kg bw for males and 675 g/kg bw for females. Two groups of 50 males and females were maintained on basal diet. All survivors were killed at 134 weeks. Survival among males was 43/50 (controls), 39/50 (low-dose) and 45/55 (high-dose), and that among females was 49/50 (controls), 46/50 (low-dose) and 50/55 (high-dose). The numbers of mice scored for tumours were 27/43 control males, 32/49 control females, 21/39 low-dose males, 33/46 low-dose females, 23/45 high-dose males and 33/50 high-dose females. No difference was found in the incidence of tumours at any site between treated and control mice (Arno & Matsuyama, 1985).Groups of 60 and 120 male B6C3F1 mice, six weeks of age, received paracetamol at 5000 or 10 000 mg/kg of diet, respectively, for up to 70 weeks, at which time the remaining animals were killed. A group of 30 mice served as controls. Survival in the high-dose group was less than 50% at 24 weeks and 16% at 72 weeks; in the low-dose group, the survival was greater than 90%. Severe hepatotoxicity was a common finding in mice that died. No increased incidence of neoplasms was observed (Hagiwara & Ward, 1986). [The Working Group noted the poor survival in the high-dose group.]Rat: Groups of 30 male SPF Sprague-Dawley rats, six weeks of age, were fed paracetamol (99.5–99.7% pure) at 0 or 5350 mg/kg of diet for 117 weeks (total paracetamol intake, 86.5 g per rat). All animals were necropsied, and kidneys, urinary bladder, adrenal glands, liver, stomach, spleen, lungs, heart and any grossly abnormal organs or tissues were examined histologically. No significant difference in survival rates was observed. In the treated group, 4/30 rats developed bladder papillomatosis or tumours versus 2/30 controls (Johansson, 1981). [The Working Group noted the relatively small number of animals used in the study.]Groups of 50 male and 50 female Fischer 344/DuCrj rats, five weeks of age were fed pharmacopoeial-grade paracetamol at 0, 4500 or 9000 mg/kg (males) and 0, 6500 or 13 000 mg/kg (females) of diet for 104 weeks and were then observed for a further 26 weeks (average daily intakes: lower-dose males, 195 mg/kg bw; lower-dose females, 336 mg/kg bw; higher-dose males, 402 mg/kg bw; higher-dose females, 688 mg/kg bw), at which time all survivors were killed. Survival rates at 104 weeks varied between 86 and 90% in males and 80 and 82% in females, with no significant difference between treated and control rats. All rats were necropsied, and major organs, tissues and gross abnormalities were examined histologically. No difference was seen in tumour incidence between the groups (Hiraga & Fujii, 1985).Groups of 50 male and 50 female young adult Leeds inbred rats were fed paracetamol (> 98% pure) at 5000 or 10 000 mg/kg of diet for up to 18 months (mean daily intake, 300 and 600 mg/kg bw, respectively), at which time all survivors were killed. A group of 40 males and 40 females fed basal diet alone served as controls. Survival was high: male controls, 40/40; female controls, 40/40; lower-dose males, 48/50; lower-dose females, 49/50; higher-dose males, 45/50; and higher-dose females, 49/50. All animals were necropsied, and samples from each liver lobe, lungs, kidneys, pancreas, mammary glands, spleen, adrenal glands and from grossly visible lesions were examined histologically. No tumour was observed among controls. In treated animals, no hepatocellular carcinoma was observed, but hepatocellular neoplastic nodules occurred in 0/40, 1/48 and 9/45 control, lower-dose and higher-dose males and 0/40, 0/49 and 10/49 control, lower-dose and higher-dose females; and 20–25% of rats in each treated group developed hyperplasia of the bladder epithelium. Bladder calculi were present in about 30% of all treated male animals and in 6% of females; no clear association was seen between hyperplasia and the presence of bladder calculi. Bladder papillomas were observed in 5/49 higher-dose males and bladder carcinomas in 1/49 higher-dose males; the total bladder tumour incidence was significantly higher [p = 0.02, Fisher's exact test] among high-dose males. In the low-dose group, 4/49 females developed bladder papillomas and 1/49 females developed bladder carcinoma. Total bladder tumour incidence was significantly higher in low-dose female rats [p = 0.045, Fisher's exact test] (Flaks et al., 1985). [The Working Group noted that there were increased incidences of calculi, hyperplasia and tumours of the bladder in treated animals but there was no relationship between the presence of calculi and the presence of either hyperplasia or tumours.](b) Administration with known carcinogensMouse: Groups of 30 and 60 male B6C3F1 mice, six weeks of age, received paracetamol at 5000 or 10 000 mg/kg of diet, respectively, continuously for up to 70 weeks following a single intraperitoneal injection of 40 mg/kg bw N-nitrosodiethylamine at four weeks of age. A group of 30 mice that received N-nitrosodiethylamine alone served as controls. Mice were sacrified at either 24 or 72 weeks after injection of the nitrosamine. Survival in the higher-dose group was very poor; severe hepatotoxicity was a common finding in mice that died. No increased incidence of neoplasms was found (Hagiwara & Ward, 1986).Rat: Two groups of 25 or 30 male Fisher 344 rats weighing 150 g were administered N-nitrosoethyl-N-hydroxyethylamine (NEHEA) at 0 or 0.1% (v/v) in drinking-water for two weeks and one week later were fed diets containing paracetamol [purity unspecified] at 1.3% for 29 weeks. One group of 25 rats received NEHEA in the drinking-water followed by no further treatment. All animals were killed at the end of week 32, and samples from liver, kidneys and other organs with gross abnormalities were examined histologically. γ-Glutamyltranspeptidase foci, hyperplastic nodules, hepatocellular carcinomas, renal-cell carcinomas, as well as ‘atypical cell foci’ and adenomas were measured. Paracetamol inhibited the formation of NEHEA-induced γ-glutamyltranspeptidase foci, hyperplastic nodules and carcinomas in comparison with animals treated with NEHEA only. No liver lesion was found in any animal treated with paracetamol only. In contrast, the incidence and multiplicity of preneoplastic renal lesions and renal-cell adenomas were significantly increased in NEHEA-initiated animals treated with paracetamol in comparison with animals treated with NEHEA only. No such renal lesion was observed in groups treated with paracetamol alone (Tsuda et al., 1984). [The Working Group noted that the progression of the lesions described as preneoplastic to neoplasms was not documented.]Groups of 25 male Fischer 344 rats, seven weeks old, were administered N-nitrosobutyl-N-(4-hydroxybutyl)amine at 0 or 0.05% (v/v) in the drinking-water for four weeks to initiate bladder carcinogenesis and were then fed paracetamol [purity unspecified] at 13 000 mg/kg of diet for a further 32 weeks, at which time all rats were killed. One group received treatment with the nitrosamine only. Urinary bladders, livers and kidneys were examined histologically. No significant difference in the incidence of bladder tumours was observed between the groups (Kurata et al., 1986).Groups of male Fischer 344 rats [numbers unspecified], six weeks of age, were subjected to a two-thirds partial hepatectomy and 24 h later received either intragastric intubations of paracetamol (purity, >99%) at 0 or 1000 mg/kg bw in 0.2% tragacanth gum twice a week for five weeks, or a single intragastric instillation of paracetamol at 500 mg/kg bw. Two weeks after the end of paracetamol treatment, the animals were administered phenobarbital (pharmacopoeial grade) at 0 or 1 mg/ml drinking-water for 12 weeks. The experiment was terminated at the end of phenobarbital treatment (weeks 13 and 18). Livers, kidneys, thyroid glands and any gross lesions were examined histologically. The tumour-initiating activity of paracetamol was evaluated by the formation of placental-type glutathione S-transferase-positive foci in liver cells; treatment with paracetamol did not result in the induction of such foci (Hasegawa et al., 1988). [The Working Group noted that the rate of absorption of paracetamol from the tragacanth suspension was not measured, and the limited reporting of the experiment.]To examine possible interference with the activation of 2-acetylaminofluorene, groups of 20 female SPF CD rats were given diets containing acetylaminofluorene at 250 mg/kg alone or with paracetamol at 11 000 mg/kg for 20 weeks and were observed for an additional ten weeks. Mammary tumours were seen in 14/20 females given acetylaminofluorene and in 7/20 (p = 0.028, Fisher's exact test) animals given acetylaminofluorene and paracetamol (Weisburger et al., 1973).Hamster. Groups of 30 male and 30 female Syrian golden hamsters, six weeks old, were given N-hydroxyacetylaminofluorene at 430 mg/kg alone or with paracetamol at 11000 mg/kg of diet for 39 weeks. The experiment was terminated at 47 weeks. The incidences of liver cholangiomas in animals treated with N-hydroxy-acetylaminofluorene were 13/26 in males and 22/25 in females; in the group treated with N-hydroxyacetylaminofluorene and paracetamol, no liver tumour was seen in 24 males but two occurred in 24 females. Similar results were found in groups given acetylaminofluorene at 400 mg/kg alone or with paracetamol at 11000 mg/kg: with acetylaminofluorene, the incidence of liver cholangiomas was 6/30 males and 28/30 females; in the group treated with acetylaminofluorene and paracetamol, the incidence was 0/29 males (p = 0.013, Fisher's exact test) and 4/28 females (p < 0.001, Fisher's exact test) (Weisburger et al., 1973).3.2. Other relevant data(a) Experimental systems(i) Absorption, distribution, excretion and metabolismDogs receiving a single oral administration of a wide range of doses of paracetamol excreted about 85% of the administered dose within the first 24 h (Savides et al., 1984).A summary of the proposed metabolic pathways of paracetamol is shown in Figure 1. The major urinary metabolites (the glucuronide, sulfate and 3-mercapto derivatives) are observed in most species, although there is much species variation regarding the percentages of these conjugates excreted in the urine (Davis et al., 1976). Each of the other metabolites shown in Figure 1 has been identified in one species (see Gemborys & Mudge, 1981, for details). In rats, biliary excretion of the various metabolites of paracetamol increased from 20 to 49% as doses were increased from 37.5 to 600 mg/kg bw. The glucuronide conjugate was the major metabolite recovered in the bile at all doses (Hjelle & Klaassen, 1984). The putative reactive intermediates are not known but are thought to include benzoquinone (Hinson et al., 1977).Fig. 1Summary or metabolism of paracetamol based on data for different speciesa A minor but important metabolic pathway involves the conversion of paracetamol to a reactive metabolite by the hepatic cytochrome P450-dependent mixed-function oxidase system (Mitchell et al., 1973; Potter et al., 1973). The reactive metabolite is thought to be either N-acetyl-para-benzoquinoneimine (Corcoran et al., 1980) or the corresponding semiquinone free radical (De Vries, 1981; Nelson et al., 1981). With low doses of paracetamol, a conjugate of reduced glutathione with the reactive metabolite is further transformed to cysteine and mercapturic acid conjugates, which are excreted. As the dose of paracetamol increases, hepatic glutathione stores are diminished and the glucuronidation and sulfation pathways become saturated (Galinsky & Levy, 1981). A correlation has been demonstrated between species sensitivity to the hepatotoxicity of paracetamol and the balance between two pathways: (i) formation of glutathione conjugates and the corresponding hydrolysis products (indicative of the ‘toxic’ pathway) and (ii) metabolism via formation of glucuronide and sulfate esters (the ‘detoxification pathway’) (Gregus et al., 1988). Paracetamol-induced liver toxicity and depletion of glutathione may be partially prevented by provision of dietary methionine (Reicks et al., 1988; McLean et al., 1989). At sufficiently high doses of paracetamol, glutathione is depleted and the reactive metabolite binds covalently to cell macromolecules. It has also been noted that paracetamol and N-acetyl-para-benzoquinoneimine may exert their cytotoxic effects via disruption of Ca2+ homeostasis secondary to the depletion of soluble and protein-bound thiols (Moore et al., 1985). These data indicate that oxidative or free-radical reactions initiated by paracetamol have a role in the hepatotoxicity of this drug (Birge et al., 1988).Radiolabel was bound covalently to hepatocellular proteins following incubation of mouse, rat, hamster, rabbit or guinea-pig liver microsomes with 3H-paracetamol; the degree of binding was correlated with the susceptibility of the species to hepatotoxicity in vivo (Davis et al., 1974). Similar covalent binding of radiolabel to liver proteins of rats 48 h after administration of [ring-14C]-paracetamol was proportional to the extent of liver damage (Davis et al., 1976). Covalent binding of radiolabel to liver plasma membranes and microsomes was demonstrated 2.5 h after oral administration of 3H-paracetamol at 2.5 g/kg bw to rats (Tsokos-Kuhn et al., 1988).Paracetamol is activated in the kidney by an NADPH-dependent cytochrome P450 mechanism to an arylating agent which can bind covalently to cellular macromolecules (McMurty et al., 1978). Studies in several species have suggested that formation of para-aminophenol may be of importance with respect to paracetamol nephrotoxicity. prara-Aminophenol was identified as a urinary metabolite in hamsters (Gemborys & Mudge, 1981); the deacetylation of paracetamol to para-aminophenol has also been demonstrated in mouse renal cortical slices (Carpenter & Mudge, 1981). In comparison to acetyl-labelled paracetamol, ring-labelled paracetamol was preferentially bound to renal macromolecules in Fischer rats, which are sensitive to paracetamol nephrotoxicity, whereas binding of ring- and acetyl-labelled paracetamol to renal macromolecules was similar in non-susceptible Sprague-Dawley rats (Newton et al., 1985). This suggests that para-aminophenol may be responsible for paracetamol-induced renal necrosis in Fischer 344 rats (Newton et al., 1982).(ii) Toxic effectsThe single-dose oral LD50 of paracetamol in male rats was 3.7 g/kg bw (Boyd & Bereczky, 1966); the 100-day LD50 in rats was 400 mg per day (Boyd & Hogan, 1968).Hepatic necrosis following administration of paracetamol was first reported in rats (Boyd & Bereczky, 1966). The main signs are hydropic vacuolation, centrilobular necrosis, macrophage infiltration and regenerative activity (Dixon et al., 1971). Paracetamol-induced hepatotoxicity varies considerably among species: hamsters and mice are most sensitive, whereas rats, rabbits and guinea-pigs are resistant to paracetamol-induced liver injury (Davis et al., 1974; Siegers et al., 1978). Toxic effects in dogs and cats given a single oral dose of paracetamol (maximal doses, 500 and 120 mg/kg bw, respectively) included hepatic centrilobular pathology in dogs, while cats, which do not glucuronidate exogenous compounds, had more diffuse liver pathological changes (Savides et al., 1984).The hepatotoxic effects of paracetamol administered in the diet to mice have been examined histologically. After continuous exposure at 10 000 mg/kg diet for 72 weeks (Hagiwara & Ward, 1986), severe chronic hepatotoxicity was observed, with centrilobular hepatocytomegaly, cirrhosis, lipofuscin deposition and hepatocyte necrosis varying from focal to massive. With the same dose, Ham and Calder (1984) observed macroscopically and microscopically deformed livers with extensive lobular collapse, foci of hepatic necrosis and lymphoid aggregation in portal tracts after 32 weeks. At a lower dose (5000 mg/kg bw) and a shorter exposure time (24 weeks), histological changes were mild. Ultrastructural changes in the livers of rats administered paracetamol at 10 000 mg/kg diet for up to 18 months have been described (Flaks et al., 1985).Histopathological review of liver sections from B6C3F1 mice of each sex fed paracetamol at 3000, 6000 or 12 500 mg/kg diet for 41 weeks and from NIH general-purpose mice of each sex fed paracetamol at 11000 mg/kg diet for 48 weeks indicated severe liver injury, characterized by centrilobular necrosis in animals receiving more than 10 000 mg/kg diet (Maruyama & Williams, 1988).A single subcutaneous dose of paracetamol at 750 mg/kg bw to male Fischer 344 rats produced renal tubular necrosis restricted to the upper part of the proximal tubule (McMurty et al., 1978). Chronic cortical and medullary damage has been produced in uninephrectomized homozygous Gunn rats by single doses of various analgesic preparations containing paracetamol (Henry & Tange, 1984).In fasted adult male mice given paracetamol at 600 mg/kg bw orally and killed within 48 h after treatment, degenerative and necrotic changes were detected in the bronchial epithelium and in testicular and lymphoid tissue, in addition to renal and hepatic effects (Placke et al., 1987).When male rats were given paracetamol at 500 mg/kg bw per day orally for 70 days, a significant decrease in testicular weight was observed (Jacqueson et al., 1984).(iii) Effects on reproduction and prenatal toxicityIn Sprague-Dawley rats administered paracetamol at 250 mg/kg bw orally on days 8 through 19 of gestation, embryo- and fetotoxic effects were not seen (Lubawy & Burriss Garret, 1977).(iv) Genetic and related effectsParacetamol was not mutagenic to Salmonella typhimurium at concentrations of up to 50 mg/plate in the presence or absence of an exogenous metabolic system (King et al., 1979; Wirth et al., 1980; Imamura et al., 1983; Dybing et al., 1984; Oldham et al., 1986; Jasiewicz & Richardson, 1987). It did not induce mutations in a liquid pre-incubation test with Escherichia coli in the presence or absence of an exogenous metabolic system (King et al., 1979). As reported in an abstract, paracetamol exhibited mutagenic activity towards S. typhimurium TA100 in the presence of an exogenous metabolic system (Tamura et al., 1980).Feeding of male Drosophila melanogaster with a 40-mM solution of paracetamol did not induce sex-linked recessive mutations (King et al., 1979).Treatment of Chinese hamster V79 cells with low concentrations (0.1–3.0 mM) of paracetamol inhibited DNA synthesis (Holme et al., 1988; Hongslo et al., 1988). Paracetamol at 10 mM had no effect on Reuber H4-II-E rat hepatoma cell DNA, as assayed by alkaline elution, but the toxic metabolite of paracetamol, N-acetyl-para-benzoquinoneimine, induced DNA strand breaks (Dybing et al., 1984). Treatment of Chinese hamster V79 cells induced DNA strand breaks at 3 and 10 mM but not at 1 mM (Hongslo et al., 1988). Analogous results were obtained with Chinese hamster ovary cells (Sasaki, 1986). Species specificity was observed in assays for unscheduled DNA synthesis in vitro. No unscheduled DNA synthesis was detected in Chinese hamster V79 cells (Hongslo et al., 1988), in Syrian hamster or guinea-pig primary hepatocytes (Holme & Soderlund, 1986) or in rat hepatocytes (Milam & Byard, 1985; Sasaki, 1986; Williams et al., 1989); however, a small but significant increase in unscheduled DNA synthesis was seen in rat primary hepatocytes and a marked increase in unscheduled DNA synthesis was observed in mouse hepatocytes (Holme & Soderlund, 1986).Paracetamol did not induce mutations to ouabain-resistance in C3H/10T½ clone 8 mouse embryo cells (Patierno et al., 1989). It was reported in an abstract that paracetamol did not induce mutations at the hprt locus in Chinese hamster V79 cells (Sawada et al., 1985). It induced sister chromatid exchange in Chinese hamster V79 (Holme et al., 1988; Hongslo et al., 1988) and CHO cells (Sasaki, 1986). Micronuclei were induced by paracetamol in a rat kidney cell line (NRK-49F) at concentrations above 10 mM (Dunn et al., 1987). Paracetamol induced chromosomal aberrations in three different Chinese hamster cell lines (Sasaki et al., 1980; Sasaki, 1986; Ishidate, 1988) and in human lymphocytes (Watanabe, 1982). It weakly transformed C3H/10T½ clone 8 mouse embryo cells (Patierno et al., 1989).Paracetamol given twice at a dose of 3 mM (450 mg/kg bw) either intraperitoneally or orally to NMRI mice did not induce micronuclei (King et al., 1979). Oral treatment of female Sprague-Dawley rats with paracetamol at 500 and 1000 mg/kg bw induced aneuploidy in 12-day embryos (Tsuruzaki et al., 1982). Oral treatment of Swiss mice with single or three consecutive daily doses of aqueous solutions of up to 2.5 mg/0.5 ml did not lead to chromatid breaks in bone-marrow cells (Reddy, 1984) or meiotic cells of male Swiss mice (Reddy & Subramanyam, 1985). [The Working Group noted that the description of the doses used in the two last studies was unclear.](b) Humans(i) PharmacokineticsFollowing an oral dose, paracetamol is absorbed rapidly from the small intestine. The rate of absorption depends on the rate of gastric emptying (Clements et al., 1978). First-pass metabolism of paracetamol is dose-dependent: systemic availability ranges from 90% (with 1–2 g) to 68% (with 0.5 g). Plasma concentrations of paracetamol in fasting healthy subjects peaked within 1 h after treatment with 0.5 or 1.0 g but continued to rise up to 2 h after treatment with 2.0 g (Rawlings et al., 1977).Paracetamol is rapidly and relatively uniformly distributed throughout the body fluids (Gwilt et al., 1963). Binding to plasma proteins is considered insignificant (Gazzard et al., 1973). The apparent volume of distribution of paracetamol in man is about 0.9 1/kg bw (Forrest et al., 1982). The decrease in paracetamol concentrations in plasma is multiphasic both after intravenous injections and after oral dosing with 500 and 1000 mg. When the data from six healthy volunteers were interpreted according to a two-compartment open model, the half-time of the first exponential ranged from 0.15 to 0.53 h and that of the second exponential from 2.24 to 3.30 h. The latter value was in agreement with that found after oral dosing. Mean clearance (± SEM) after intravenous administration of 1000 mg was 352 (± 40) ml/min (Rawlings et al., 1977). Renal excretion of paracetamol involves glomerular filtration and passive reabsorption, and the sulfate conjugate is subject to active renal tubular secretion (Morris & Levy, 1984). Both these metabolites have been shown to accumulate in plasma in patients with renal failure who are taking paracetamol (Lowenthal et al., 1976).Paracetamol crosses the placenta in unconjugated form, and excretion in the urine of an exposed neonate was similar to that of a two- to three-day-old infant (Collins, 1981).Paracetamol passes rapidly into milk, and the milk:plasma concentration ratio ranges from 0.7 to 1.1 (Berlin et al., 1980; Notarianni et al., 1987).Paracetamol is metabolized predominantly to the glucuronide and sulfate conjugates in the human liver. A minor fraction is converted by cytochrome P450-dependent hepatic mixed-function oxidase to a highly reactive arylating metabolite, which is postulated to be N-acetyl-para-benzoquinoneimine (Miner & Kissenger, 1979). This metabolite is rapidly inactivated by conjugation with reduced glutathione and eventually excreted in the urine as acetyl cysteine and mercapturic acid conjugates. Large doses of paracetamol can deplete glutathione stores, and the excess of highly reactive intermediate binds covalently with vital cell elements, which may result in acute hepatic necrosis (Mitchell et al., 1973, 1974). Only 2–5% of a therapeutic dose was excreted unchanged in the urine. In young healthy subjects, about 55, 30, 4 and 4% of a therapeutic dose was excreted after hepatic conjugation with glucuronic acid, sulfuric acid, cysteine and mercapturic acid, respectively (Forrest et al., 1982).The fractional recovery of mercapturic acid and cysteine conjugates after ingestion of paracetamol at 1500 mg was 9.3% in Caucasians compared with only 4.4–5.2% in Africans (Critchley et al., 1986). This may reflect different susceptibility to paracetamol hepatotoxicity.(ii) Adverse effectsThe toxic effects of paracetamol have been reviewed (Flower et al., 1985).Reports on the acute toxicity, and in particular hepatotoxicity, of paracetamol have continued to appear since the reporting of the first two cases in 1966 (Davidson & Eastham, 1966). Initial symptoms of overdose are nausea, vomiting, diarrhoea and abdominal pain. Clinical indications of hepatic damage become manifest within two to four days after ingestion of toxic doses; in adults, a single dose of 10–15 g (200–250 mg/kg bw) is toxic. Serum transaminases, lactic dehydrogenase and bilirubin concentrations are elevated, and prothrombin time is prolonged (Koch-Weser, 1976). The severity of hepatic injury increases with the ingested dose and with previous consumption of other drugs that induce liver cytochrome P450 enzymes (Wright & Prescott, 1973). Biopsy of the liver reveals centrilobular necrosis with sparing of the periportal area (James et al., 1975). In nonfatal cases, the hepatic lesions are reversible over a period of months, without development of cirrhosis (Hamlyn et al., 1977).Heavy alcohol consumption has been stated in several case reports to be related to more severe paracetamol hepatotoxicity than in non- or moderate drinkers (for review, see Black, 1984). Five cases of combined hepatocellular injury and renal tubular necrosis have been reported among patients with a history of chronic alcohol use who were receiving therapeutic doses of paracetamol (Kaysen et al., 1985).(iii) Effects on reproduction and prenatal toxicityNo association of paracetamol use with congenital abnormalities or stillbirths was observed in a study on drug use in approximately 10 000 pregnancies in the UK (Crombie et al., 1970). In a case-control study of 458 mothers of malformed babies and 911 controls, there was no association of abnormalities with use of paracetamol during the first trimester (Nelson & Forfar, 1971). In the Collaborative Perinatal Project, in which drug intake and pregnancy outcome were studied in a series of 50 282 women in 1959–65, 226 women had been exposed to paracetamol during the first trimester of pregnancy. There were 17 malformed children in the exposed group, giving a nonsignificant standardized relative risk (RR) of 1.05 (Heinonen et al., 1977).In a study of 280 000 women belonging to a prepaid health plan in Seattle, WA (USA), all drug prescriptions and all pregnancy outcomes were monitored between July 1977 and December 1979. Among the liveborn babies of 6837 women, 80(1.2%) had major congenital malformations. Three of the infants born to 493 women for whom paracetamol had been prescribed in the first trimester had major malformations (types not specified), giving a prevalence of 6 per 1000, which was not significantly different from the overall prevalence in the total population studied (12 per 1000). A second group of 328 women were exposed to paracetamol with codeine in the first trimester. Five of these had malformed babies, giving a prevalence of 15 per 1000, which was not significantly different from that in controls (Jick et al., 1981).In a second study of the same population, covering the period January 1980 to June 1982, 6509 women had pregnancies ending in livebirths; 105 (1.5%) of the infants had major congenital malformations. Two of the infants born to 350 women for whom paracetamol had been prescribed in the first trimester had major malformations (types not specified), giving a prevalence of 6 per 1000 compared with an overall prevalence in the entire group of 16 per 1000. Three of 347 women exposed to paracetamol with codeine had malformed babies, giving a prevalence of 9 per 1000 (not significant) (Aselton et al., 1985).(iv) Genetic and related effectsEleven healthy volunteers were given paracetamol at 1000 mg three times over a period of 8 h. The frequency of chromatid breaks in peripheral blood lymphocytes was significantly increased after one day but returned to normal one week later (Kocisova et al., 1988).3.3. Case reports and epidemiological studies of carcinogenicity to humansThe Working Group considered only studies in which paracetamol was taken directly, either alone or in mixtures. Paracetamol may be taken by analgesic users who previously took phenacetin. Analgesic mixtures containing phenacetin are carcinogenic to humans; and phenacetin is probably carcinogenic to humans (IARC, 1980, 1987).A population-based case-control study was conducted in Minnesota, USA, involving 495 cases of cancer of the renal parenchyma and 74 cases of cancer of the renal pelvis, diagnosed in 1974–79, and 697 controls (McLaughlin et al., 1983, 1984, 1985). An association between cancer of the renal pelvis and intensity and duration of use of paracetamol-containing drugs was seen in women (p for trend, < 0.05; RR in the highest exposure category, based on three exposed cases and eight exposed controls, 5.8; 95% confidence interval (CI), 0.8–40). [The Working Group noted that the trend test included unexposed cases and controls; if the unexposed are excluded, the trend is not statistically significant.] No other significant association was observed. Four of the five cases in the highest exposure category (two men, three women) who developed renal pelvic cancer had also taken phenacetin-containing analgesics; in the entire study, only two cases of cancer of the renal pelvis and seven controls had taken paracetamol alone.Another population-based case control study was conducted among women aged 20–49 years in the state of New York (USA) involving 173 cases of bladder cancer diagnosed in 1975–79 and an equal number of controls matched for age and telephone area code (Piper et al., 1985). A history of regular use of analgesics containing paracetamol (and not phenacetin) at least one year before diagnosis yielded a smoking-adjusted RR of 1.5 (95% CI, 0.4–7.2). In contrast, the risk for regular users of phenacetin-containing analgesics was significantly elevated whether they also regularly took paracetamol (RR, 3.8; 95% CI, 1.4–13.0) or not (RR, 6.5; 95% CI, 1.5–59.2).A series of population-based case-control studies of urinary-tract cancer were conducted in New South Wales, Australia, involving cases identified in 1977–82 (McCredie et al., 1983a,b, 1988; McCredie & Stewart, 1988). Ultimately, there were 360 cases of renal parenchymal cancer, 73 cases of renal pelvic cancer, 55 cases of ureteral cancer and 162 cases (women only) of bladder cancer. Controls (985 for renal parenchymal cancer and 689 for the other sites) were derived from electoral rolls. The only significant increase in risk for regular use of paracetamol (cumulative consumption of at least 0.1 kg) was with ureteral cancer (RR, 2.5; 95% CI, 1.1–5.9); this association was not further elevated in the subgroup with higher exposure (at least 1 kg; RR, 2.0; 95% CI, 0.8–4.5). The RR for cancer of the renal pelvis was 1.2 (95% CI, 0.6–2.3). These analyses were adjusted for cigarette smoking and the presence of urological disease.A further population-based case-control study was conducted in Los Angeles County, USA, based on 187 cases of cancer of the renal pelvis or ureter diagnosed in 1978–82 and an equal number of neighbourhood controls (Ross et al., 1989). An association was found with use of nonprescription analgesics in general. The risks for use of analgesics containing paracetamol were nonsignificantly elevated, at 1.3 for use more than 30 days/year (p = 0.34) and 2.0 for use more than 30 consecutive days/year (p = 0.08). The analyses were controlled for cigarette smoking and history of urinary-tract stones. The authors noted that it was difficult to distinguish the effects of individual compounds in this study.In a hypothesis-generating cohort study designed to screen a large number of drugs for possible carcinogenicity (described in detail in the monograph on ampicillin), 3238 persons to whom at least one prescription for paracetamol alone and 2612 to whom at least one prescription for paracetamol with codeine had been dispensed during 1969–73 were followed up for up to 15 years (Selby et al., 1989). No significant association with cancer at any site was seen for use of paracetamol with codeine. For paracetamol alone, a positive association was noted for melanoma (seven cases observed, 1.7 expected; RR, 4.1; 95% CI, 1.7–8.5), and negative associations for cancer of the colon (four observed, 12.1 expected; RR, 0.33; 95% CI, 0.1–0.85) and cancer of the uterine corpus (one observed, 6.5 expected; RR, 0.15; 95% CI, 0–0.86); but no association was seen for any cancer of the urinary tract or for all cancers combined (Friedman & Ury, 1980, 1983; Selby et al., 1989). [The Working Group noted that there was no information on non-prescription dispensing of paracetamol, which is the most common way that it is obtained. Since, as also noted by the authors, some 12 000 comparisons were made in this study, the associations should be verified independently. Data on duration of use were not provided.]4. Summary of Data Reported and Evaluation4.1. Exposure dataParacetamol has been used extensively as an analgesic and antipyretic since 1946.4.2. Experimental carcinogenicity dataParacetamol was tested for carcinogenicity by oral administration in mice and rats. In one strain of mice, a significant increase in the incidence of multiple liver carcinomas and adenomas was observed in animals of each sex at a markedly toxic dose; in two studies on another strain, no increase in the incidence of any tumour was observed at a well-tolerated dose that was approximately half that in the preceding study. Administration of paracetamol to two different strains of rats did not increase tumour incidence. In a further strain of rats, the incidence of neoplastic liver nodules was increased in animals of each sex given the higher dose; the combined incidence of bladder papillomas and carcinomas (mostly papillomas) was significantly greater in high-dose male and in low-dose female rats. Although treatment increased the incidence of bladder calculi in treated rats, there was no relationship between the presence of calculi and of either hyperplasia or tumours in the bladder.Oral administration of paracetamol to rats enhanced the incidence of renal adenomas induced by N-nitrosoethyl-N-hydroxyethylamine.4.3. Human carcinogenicity dataA positive association between use of paracetamol and cancer of the ureter (but not of other sites in the urinary tract) was observed in an Australian case-control study. None of three other population-based case-control studies showed an association between paracetamol use and cancer in the urinary tract.4.4. Other relevant dataOne study provided no evidence that use of paracetamol in the first trimester of pregnancy is associated with an increase in the incidence of malformations. Paracetamol induced testicular atrophy in rats.Hepatotoxicity has been reported repeatedly in people taking high doses of paracetamol; chronic alcohol users are particularly sensitive. Paracetamol is metabolized in humans and animals to reactive intermediates that bind to proteins. It is hepatotoxic to experimental animals and causes renal tubular necrosis in rats.Paracetamol induced chromatid breaks in peripheral human lymphocytes in vivo. It induced aneuploidy in rat embryos treated transplacentally. It gave negative results in the micronucleus test in mice in vivo. It did not induce chromosomal aberrations in bone-marrow cells or spermatocytes of mice.Paracetamol induced sister chromatid exchange and chromosomal aberrations in Chinese hamster cells, micronuclei in rat kidney cells and chromosomal aberrations in human lymphocytes in vitro. It did not induce point mutations in mouse or Chinese hamster cells. 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[PubMed: 6142774]Tsuruzaki T., Yamamoto M., Watanabe G. Maternal consumption of antipyretic analgesics produces chromosome anomalies in F1 rat embryos. Teratology. 1982;26:42A.US Pharmacopeial Convention, Inc. (1989) US Pharmacopeia, 22nd rev., Easton, PA, pp. 12–15.Watanabe M. The cytogenetic effects of aspirin and acetaminophen on in vitro human lymphocytes. Jpn. J. Hyg. 1982;37:673–685.Weisburger J.H., Weisburger E.K., Madison R.M., Wenk M.L., Klein D.S. Effect of acetanilide and p-hydroxy-acetanilide on the carcinogenicity of N-2-fluoronylacetamide and N-hydroxy-N-2-fluorenylacetamide in mice, hamsters and female rats. J. natl Cancer Inst. 1973;51:235–240. [PubMed: 4720874]Williams G.M., Mori H., McQueen C.A. Structure-activity relationship in the rat hepatocyte DNA repair test for 300 chemicals. Mutat. Res. 1989;221:263–286. [PubMed: 2682231]Wirth P.J., Dybing E., von Bahr C., Thorgeirsson S.S. Mechanism of N-hydroxyacetylarylamine mutagenicity in the Salmonella test system: metabolic activation of N-hydroxyphenacetin by liver and kidney fractions from rat, mouse, hamster, and man. Mol. Pharmacol. 1980;18:117–127. [PubMed: 6997726]Wong L.T., Solomonraj G., Thomas B.H. Metabolism of [14C]paracetamol and its interactions with aspirin in hamsters. Xenobiotica. 1976;6:575–584. [PubMed: 983128]Wright N., Prescott L.F. Potentiation by previous drug therapy of hepatotoxicity following paracetamol overdosage. Scott. med. J. 1973;18:56–58. [PubMed: 4699828]Footnotes1For description of the italicized terms, see Preamble, pp. 26–29.

©International Agency for Research on Cancer, 1990.Bookshelf ID: NBK526213Contents< PrevNext >

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ViewsPubReaderPrint ViewCite this PageIARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Pharmaceutical Drugs. Lyon (FR): International Agency for Research on Cancer; 1990. (IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans, No. 50.) Paracetamol (Acetaminophen)PDF version of this title (25M)In this PageChemical and Physical DataProduction, Occurrence, Use and AnalysisBiological Data Relevant to the Evaluation of Carcinogenic Risk to HumansSummary of Data Reported and EvaluationReferencesOther titles in this collectionIARC Monographs on the Evaluation of the Carcinogenic Risks to HumansRelated informationPMCPubMed Central citationsPubMedLinks to PubMedSimilar articles in PubMedReview International Commission for Protection against Environmental Mutagens and Carcinogens. An evaluation of the genetic toxicity of paracetamol.[Mutat Res. 1995]Review International Commission for Protection against Environmental Mutagens and Carcinogens. An evaluation of the genetic toxicity of paracetamol.Rannug U, Holme JA, Hongslo JK, Srám R. Mutat Res. 1995 Mar; 327(1-2):179-200. Review Series: current issues in mutagenesis and carcinogenesis, No. 65. The genotoxicity and carcinogenicity of paracetamol: a regulatory (re)view.[Mutat Res. 1996]Review Series: current issues in mutagenesis and carcinogenesis, No. 65. The genotoxicity and carcinogenicity of paracetamol: a regulatory (re)view.Bergman K, Müller L, Teigen SW. Mutat Res. 1996 Feb 1; 349(2):263-88. Additional effect of acetaminophen on the mutagenicity and clastogenicity of N-methyl-N'-nitro-N-nitrosoguanidine in cultured Chinese hamster CHO-Kl cells.[Mutat Res. 1983]Additional effect of acetaminophen on the mutagenicity and clastogenicity of N-methyl-N'-nitro-N-nitrosoguanidine in cultured Chinese hamster CHO-Kl cells.Sasaki M, Yoshida S, Hiraga K. Mutat Res. 1983 Dec; 122(3-4):367-72. Aniline Is Rapidly Converted Into Paracetamol Impairing Male Reproductive Development.[Toxicol Sci. 2015]Aniline Is Rapidly Converted Into Paracetamol Impairing Male Reproductive Development.Holm JB, Chalmey C, Modick H, Jensen LS, Dierkes G, Weiss T, Jensen BA, Nørregård MM, Borkowski K, Styrishave B, et al. Toxicol Sci. 2015 Nov; 148(1):288-98. Epub 2015 Aug 10.Review Hydrochlorothiazide.[IARC Monogr Eval Carcinog Risk...]Review Hydrochlorothiazide.. IARC Monogr Eval Carcinog Risks Hum. 1990; 50:293-305. See reviews...See all...Recent ActivityClearTurn OffTurn OnParacetamol (Acetaminophen) - Pharmaceutical DrugsParacetamol (Acetaminophen) - Pharmaceutical DrugsYour browsing activity is empty.Activity recording is turned off.Turn recording back onSee more...

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Paracetamol 500mg Caplets BP (PL 43461/0078) - Summary of Product Characteristics (SmPC) - (emc)

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Paracetamol 500mg Caplets BP (PL 43461/0078)

Active Ingredient:

paracetamol

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Flamingo Pharma (UK) Ltd

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Last updated on emc: 14 Oct 2022

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Undesirable Effects

Pharmacological Properties

Interactions

Posology

Contraindications

Excipients

Storage precautions

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1. Name of the medicinal product

Paracetamol 500mg Tablets BP.

PocketPak Paracetamol 500 mg Caplets

2. Qualitative and quantitative composition

Paracetamol 500mg.

For excipients, see 6.1.

3. Pharmaceutical form

Tablet.

White, capsule shaped tablet with a break-line on one face.

4. Clinical particulars

4.1 Therapeutic indications

For the treatment of mild to moderate pain including headache, migraine, neuralgia, toothache, sore throat, period pain, aches and pains.

Symptomatic relief of rheumatic aches and pains.

Symptomatic relief of influenza, feverishness, feverish colds.

4.2 Posology and method of administration

Posology

Adults, the elderly and children 16 years and over: One or two tablets to be taken up to four times daily. Maximum dose of 8 tablets in 24 hours.

Children 10 to 15 years of age: One tablet to be taken for every 4-6 hours when necessary to a maximum of 4 doses in 24 hours.

Children under 10 years of age: Not recommended. Alternative presentations of paracetamol are recommended for paediatric usage in order to obtain suitable doses of less than 500mg.

The dose should not be repeated more frequently than every 4 hours, and not more than 4 doses should be taken in any 24 hour period.

Dosage should not be continued for more than 3 days without consulting a doctor.

Method of administration

For oral administration.

4.3 Contraindications

Hypersensitivity to paracetamol or any of the other ingredients.

4.4 Special warnings and precautions for use

Where analgesics are used long-term (>3 months) with administration every two days or more frequently, headache may develop or worsen. Headache induced by overuse of analgesics (MOH medication-overuse headache) should not be treated by dose increase. In such cases, the use of analgesics should be discontinued in consultation with the doctor.

Care is advised in the administration of paracetamol to patients with alcohol dependency (see section 4.9), severe renal or severe hepatic impairment. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease.

Patients should be advised to consult their doctor if their headaches become persistent.

Patients should be advised to consult a doctor if they suffer from non-serious arthritis and need to take painkillers every day.

Do not exceed the recommended dose.

If symptoms persist, consult your doctor.

Keep out of the sight and reach of children.

May rarely cause severe hypersensitivity reactions and bronchospasm as this medicine contains sodium metabisulphite.

The label will state the following warnings:

Do not take more medicine than the label tells you to. If you do not get better, talk to your doctor. Do not take anything else containing paracetamol while taking this medicine. Talk to a doctor at once if you take too much of this medicine, even if you feel well.

The leaflet will state the following warnings:

Do not take more medicine than the label tells you to. If you do not get better, talk to your doctor. Do not take anything else containing paracetamol while taking this medicine.

Talk to a doctor at once if you take too much of this medicine, even if you feel well. This is because too much paracetamol can cause delayed, serious liver damage.

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol reduces liver capacity to deal with paracetamol.

The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged, regular use of paracetamol, with increased risk of bleeding; occasional doses have no significant effect.

Colestyramine reduces absorption if given within one hour of paracetamol; and Metoclopramide and Domperidone accelerate absorption of paracetamol. May interact with chloramphenicol causing increased plasma levels.

Imatinib - restriction or avoidance of concomitant regular paracetamol use should be taken with imatinib.

4.6 Fertility, pregnancy and lactation

A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published literature do not contraindicate breast-feeding.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

Adverse effects of paracetamol are rare but hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia, neutropenia, pancytopenia, leukopenia and agranulocytosis, but these were not necessarily causally related to paracetamol.

Adverse events of paracetamol from historical clinical trial data are both infrequent and from small patient exposure. Accordingly, events reported from extensive post-marketing experience at therapeutic/labelled dose and considered attributable are tabulated below by system class. Due to limited clinical trial data, the frequency of these adverse events is not known (cannot be estimated from available data), but post-marketing experience indicates that adverse reactions to paracetamol are rare and serious reactions are very rare.

Post marketing data:

Skin and subcutaneous disorders: Very rare cases of serious skin reactions have been reported.

Blood and lymphatic system disorders: Thrombocytopenia, agranulocytosis.

Immune system disorders: Anaphylaxis. Cutaneous hypersensitivity reactions including skin rashes, angioedema and Stevens Johnson syndrome/toxic epidermal necrolysis.

Respiratory, thoracic and mediastinal disorders: Bronchospasm*.

*There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.

Hepatobiliary disorders: Hepatic dysfunction.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Liver damage is possible in adults who have taken 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk factors:-

If the patient

• Is on long term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.

• Regularly consumes ethanol in excess of recommended amounts.

• Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N–acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24 hours from ingestion should be discussed with the NPIS or a liver unit.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Paracetamol is an effective analgesic and antipyretic agent but has only weak anti-inflammatory properties. Its mechanism of action is not fully understood, as it is only a weak inhibitor of prostaglandin bio-synthesis, but it has been suggested that it is more effective against enzymes in the CNS than those in the periphery. The drug has no effect on the cardiovascular and respiratory systems, and it does not cause gastric irritation or bleeding like salicylates.

5.2 Pharmacokinetic properties

Paracetamol is readily absorbed from the gastro-intestinal tract with peak plasma concentrations occurring 10 to 60 minutes after ingestion. It is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted unchanged as paracetamol. It is distributed in most body tissues. Paracetamol crosses the placenta and is present in breast milk. Plasma protein binding is negligible at usual therapeutic concentrations but increases with increasing concentration.

The elimination half life varies from about 1 to 4 hours.

A minor hydroxylated metabolite which is usually produced in very small amounts by mixed function oxidases in the liver and which is usually detoxified by conjugation with liver glutathione may accumulate following paracetamol overdosage and cause liver damage.

5.3 Preclinical safety data

Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.

6. Pharmaceutical particulars

6.1 List of excipients

Pregelatinised Maize Starch

Sodium Metabisulphite

Magnesium Stearate

6.2 Incompatibilities

Not Applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

Blister strips: Do not store above 25°C. Store in the original package.

Tablet containers: Do not store above 25°C. Keep the container tightly closed. Store in the original container.

6.5 Nature and contents of container

Al/PVC blister strips (child resistant) enclosed in an outer carton containing 8, 12 or 16

Al/PVC blister (child resistant) containing 12 tablets, enclosed in an outer carton – 'PocketPak' format.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

None applicable.

7. Marketing authorisation holder

Flamingo Pharma UK Ltd.

1st floor, Kirkland House,

11-15 Peterborough Road,

Harrow, Middlesex,

HA12AX, United Kingdom.

8. Marketing authorisation number(s)

PL 43461/0078

9. Date of first authorisation/renewal of the authorisation

18/05/2009

10. Date of revision of the text

09/02/2021

Flamingo Pharma (UK) Ltd

Address

The BLOC, 38 Springfield Way, Kingston Upon Hull, HU10 6RJ, UK

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http://www.flamingopharma.co.uk

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+44 (0) 7784240228

Medical Information Direct Line

00 800 890 13370

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J Clin Med. 2021 Aug; 10(15): 3420. Published online 2021 Jul 31. doi: 10.3390/jcm10153420PMCID: PMC8347233PMID: 34362203Paracetamol: A Review of Guideline RecommendationsUlderico Freo,1,* Chiara Ruocco,2 Alessandra Valerio,3 Irene Scagnol,1 and Enzo Nisoli2Ulderico Freo1Anesthesiology and Intensive Care, Department of Medicine—DIMED, University of Padua, 35122 Padua, Italy; moc.liamg@3.longacs.eneriFind articles by Ulderico FreoChiara Ruocco2Center for the Study and Research on Obesity, Department of Biomedical Technology and Translational Medicine, University of Milan, 20129 Milan, Italy; moc.liamg@occouraraihc (C.R.); ti.iminu@ilosin.ozne (E.N.)Find articles by Chiara RuoccoAlessandra Valerio3Department of Molecular and Translational Medicine, University of Brescia, 25100 Brescia, Italy; ti.sbinu@oirelav.ardnasselaFind articles by Alessandra ValerioIrene Scagnol1Anesthesiology and Intensive Care, Department of Medicine—DIMED, University of Padua, 35122 Padua, Italy; moc.liamg@3.longacs.eneriFind articles by Irene ScagnolEnzo Nisoli2Center for the Study and Research on Obesity, Department of Biomedical Technology and Translational Medicine, University of Milan, 20129 Milan, Italy; moc.liamg@occouraraihc (C.R.); ti.iminu@ilosin.ozne (E.N.)Find articles by Enzo NisoliAndrea D. Furlan, Academic Editor and Laura Murphy, Academic EditorAuthor information Article notes Copyright and License information PMC Disclaimer1Anesthesiology and Intensive Care, Department of Medicine—DIMED, University of Padua, 35122 Padua, Italy; moc.liamg@3.longacs.eneri2Center for the Study and Research on Obesity, Department of Biomedical Technology and Translational Medicine, University of Milan, 20129 Milan, Italy; moc.liamg@occouraraihc (C.R.); ti.iminu@ilosin.ozne (E.N.)3Department of Molecular and Translational Medicine, University of Brescia, 25100 Brescia, Italy; ti.sbinu@oirelav.ardnassela*Correspondence: ti.dpinu@oerf.ociredlu; Tel.: +39-049-821-3090Received 2021 May 29; Accepted 2021 Jul 28.Copyright © 2021 by the authors.Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).Associated DataData Availability StatementNot applicable.AbstractMusculoskeletal pain conditions are age-related, leading contributors to chronic pain and pain-related disability, which are expected to rise with the rapid global population aging. Current medical treatments provide only partial relief. Furthermore, non-steroidal anti-inflammatory drugs (NSAIDs) and opioids are effective in young and otherwise healthy individuals but are often contraindicated in elderly and frail patients. As a result of its favorable safety and tolerability record, paracetamol has long been the most common drug for treating pain. Strikingly, recent reports questioned its therapeutic value and safety. This review aims to present guideline recommendations. Paracetamol has been assessed in different conditions and demonstrated therapeutic efficacy on both acute and chronic pain. It is active as a single agent and is additive or synergistic with NSAIDs and opioids, improving their efficacy and safety. However, a lack of significant efficacy and hepatic toxicity have also been reported. Fast dissolving formulations of paracetamol provide superior and more extended pain relief that is similar to intravenous paracetamol. A dose reduction is recommended in patients with liver disease or malnourished. Genotyping may improve efficacy and safety. Within the current trend toward the minimization of opioid analgesia, it is consistently included in multimodal, non-opioid, or opioid-sparing therapies. Paracetamol is being recommended by guidelines as a first or second-line drug for acute pain and chronic pain, especially for patients with limited therapeutic options and for the elderly.Keywords: pain, musculoskeletal, cancer, headache, elderly, paracetamol, guidelines1. IntroductionMusculoskeletal pain (MSP) conditions are the main contributors of years lived with disability worldwide [1,2,3]. They include back and neck pain, hip, and knee osteoarthritis (OA), rheumatoid arthritis, gout, and a heterogeneous group of autoimmune, inflammatory, and degenerative disorders of joints, tendons, and muscles. Acute and chronic pain, stiffness, and impairment of personal and social activities and of quality of life are unifying features [1,2,3].Most MSP conditions increase with age. As a result of the rapid aging of the world population, the global impact of MSP and of related disability will steadily and markedly increase in the near future [1,3]. Available pharmacological treatments with non-steroidal anti-inflammatory drugs (NSAIDs) with or without opioids improve MSP in young and/or otherwise healthy people; however, these drugs are often useless in the elderly, frail, or sick patients because of comorbidities and contraindications. NSAIDs are commonly prescribed in the setting of acute MSP. Medical societies, including the American Geriatric Society, the American College of Rheumatology, and the European League Against Rheumatism, recommend extreme caution when giving NSAIDs to the elderly and limit their use to the lowest effective dose and the shortest duration [4]. Since even a short course with NSAIDs has been associated with severe adverse events, gastro-intestinal, renal, and cardiovascular side effects should be routinely monitored [4,5]. As NSAIDs are not indicated for chronic use, opioids have been the mainstay for the long-term treatment of chronic MSP [6,7,8]. However, in contrast to positive reports in young patients, there is a lack of well-designed specific studies on the efficacy and safety of opioids in the elderly patients [6,7,8]. Furthermore, when opioids are used in the elderly, the age-related physiological decline of hepatic and renal functions require a slow titration and frequent monitoring for potential adverse events [6,7,8]. Cardiovascular and respiratory disorders with the risk of respiratory depression are further complications that require careful dosing and often prevent achieving an adequate analgesia in a substantial percentage of patients [6,7,8]. In addition, the abuse and misuse of opioids have caused enormous economic and social costs of the so-called opioid epidemic and led to the revision of guidelines and recommendations against their use in MSP [9,10]. Finally, the development of new drugs for pain has been plagued by failures in advanced human trials, leaving clinicians with few therapeutic options to treat pain.Paracetamol is one of the most used drugs both over the counter and on prescription for pain and fever [11]. It has a unique clinical pharmacological profile that includes potent analgesic and antipyretic effects and no or little anti-inflammatory activity as well as minor gastrointestinal, renal, and vascular side effects (Table 1). For a long time, paracetamol has been recommended as a first-line drug in pain management guidelines. Recently it underwent intense investigations with reports showing that its analgesic efficacy may be lower than previously thought. Pharmacoepidemiology and pharmacovigilance studies report the occurrence of acute liver injury in association with paracetamol utilization.Table 1Clinical pharmacological activities of paracetamol.analgesichigh activityantipyretichigh activityanti-inflammatorylow activityantiplateletlow activityantidepressantanecdotalcognitive-enhanceranecdotalOpen in a separate windowHowever, because of its good safety record, paracetamol remains a recommended analgesic, especially for aged and frail patients. Furthermore, its efficacy is enhanced in fast-dissolving formulations, and it has a useful opioid-sparing activity that reduces adverse events and risks from high doses of opioids. The objective of this paper is to conduct a scoping literature to summarize the evidence and the guideline recommendations on paracetamol for pain.2. MethodsThis is a scoping review aiming to provide an overview of the current guidelines on paracetamol for the management of most common pain conditions. The review was guided by the methodological framework devised by Arksey and O’Malley and subsequently modified by the Johanna Briggs Institute [12]. The PRISMA Extension for Scoping Reviews (PRISMA-ScR) was followed to summarize the screening methods of the review (Figure 1) [13].Open in a separate windowFigure 1Flowchart of study screening, eligibility and inclusion.Relevant reports of guidelines were identified by searching the CINAHL, Cochrane EMBASE, and Medline databases utilizing the following strategy. The words “paracetamol/acetaminophen” were explored with the words “pain”, “randomized controlled trial” (RCT), “review”, “meta-analysis”, and “guidelines”. Two authors (UF and IS) independently screened abstracts and papers; in case of disagreement, a third author was consulted (EN). The criteria for including studies into this review were as follows: to be claimed as guidelines; to be authored by a specific health organization or medical society; to report a detailed methodology including the definition of the target population, data selection, methods for decision making, and the specific aims of the guidelines; to deal with one of the following pain conditions: MSP, cancer pain, and headache; to be published between 2000 and 2021. Exclusion criteria were as follows: studies not conducted to develop guidelines; guidelines dealing with other pain conditions (i.e., dysmenorrhea, dental pain, ear pain, eye pain, and pain in the neonatal or pediatric population); guidelines written in a language other than English.The AGREE II instrument [14] was used to determine the methodological quality of the included guidelines in six domains: scope and purpose, stakeholder involvement, rigor of development, clarity and presentation, applicability, editorial independence, and an overall assessment. The 23-item AGREE II instrument uses a 7-point agreement scale from 1 (strongly disagree) to 7 (strongly agree). Each guideline was independently scored by two authors (UF and IS). In case of a significant discrepancy, a third author was consulted (EN). Each item was scored, and a total quality score was calculated for each domain by summing the score of each item. The mean domain scores between the two raters was used to standardize the domain score as a percentage.3. Paracetamol3.1. Acetaminophen or ParacetamolAcetaminophen (paracetamol; N-acetyl-p-aminophenol) is the active metabolite of phenacetin. Unlike phenacetin, paracetamol is not carcinogenic. It is available on prescription and over-the-counter as a widely used reliever of fever and pain [11,15,16,17,18,19]. Paracetamol is well-tolerated and safe, without several of the side effects typically observed with aspirin. During the middle- and late-19th century, pharmacologists isolated salicin and salicylic acid. The French chemist Charles Frederic Gerhardt (Strasburg, 1816–1856) and the Bayer chemist Felix Hoffmann (Ludwigsburg, 1868–Switzerland, 1946) developed the synthesis methods to produce acetylsalicylic acid. In the 1880s, the cinchona tree became limited, and production alternatives were sought. Acetanilide was synthesized in 1886, and phenacetin was synthesized in 1887. In 1878, Harmon Northrop Morse (1848–1920) synthesized paracetamol by reducing p-nitrophenol with tin in glacial acetic acid. Still, this substance only became widely used as a drug after Morse’s death. Interestingly, paracetamol was found in the urine of subjects consuming phenacetin, and it was discovered as a metabolite of acetanilide in 1899, yet the finding was still ignored at the time. In 1946, Bernard Brodie (Liverpool, 1907–Charlottesville, 1989) and Julius Axelrod (New York, 1912–Rockville, 2004) investigated why non-aspirin agents were related to the development of methemoglobinemia, which is a disease that decreased the oxygen-carrying capacity of blood and that was potentially lethal. In 1948, Brodie and Axelrod explained that acetanilide caused methemoglobinemia. Then, they determined that acetanilide’s analgesic effect was due to its active metabolite paracetamol and that paracetamol had no toxic effects on acetanilide [15,16,17,18,19].The product was first sold in 1955 by McNeil Laboratories as a pain and fever reliever for children, under the brand name Tylenol Children’s Elixir. Paracetamol 500 mg tablets went on sale in the United Kingdom (Panadol) in 1956 and were initially available only by prescription, and it was marketed for the treatment of pain and fever. In contrast to other analgesic agents containing aspirin, paracetamol was not a stomach irritant. Paracetamol was added to the British Pharmacopoeia in 1963 and has gained popularity since then as an analgesic agent with few side effects and little interaction with other pharmaceutical agents.3.2. ChemistryParacetamol is constituted by a benzene ring core substituted by one hydroxyl group and the nitrogen atom of an amide group (acetamide) in the para (1,4) pattern (Figure 2).Open in a separate windowFigure 2Molecular structure of paracetamol (acetaminophen).The molecule is extensively conjugated: the lone pair on the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the p orbital on the carbonyl carbon, and the lone pair on the carbonyl oxygen are all conjugated. The benzene ring is highly reactive toward electrophilic aromatic substitution by the presence of two activating groups. This conjugation markedly diminishes the basic value of oxygen and nitrogen atoms, while making acid the hydroxyl group through delocalization of the charge developed on the phenoxide anion.3.3. Mechanisms of Actions The mechanisms of the analgesic activity of paracetamol are not fully understood and may involve Peripheral and Central Nervous System sites of action [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30]. It is widely accepted that paracetamol decreases the tissue concentrations of prostaglandins and pro-inflammatory mediators, whose synthesis is also inhibited by aspirin (acetylsalicylic acid). However, unlike aspirin, paracetamol is not featured by a significant anti-inflammatory activity and does not inhibit the synthesis of pro-clotting thromboxanes. Although it can inhibit cyclooxygenase (COX) enzymes, paracetamol may act via two major alternative molecular pathways [15,16,17,18,19,20]. The prostaglandin G/H synthase enzymes, also known as the COXs, function as essential enzymes for metabolism of the arachidonic acid metabolism to prostaglandin G/H, which is an unstable molecule quickly converted to other pro-inflammatory derivatives. NSAIDs selectively block this step. There are two COX forms, COX-1 and COX-2. Inhibition of COX-2 is thought to mediate the antipyretic, analgesic, and anti-inflammatory actions of NSAIDs. Aspirin is a non-competitive, irreversible inhibitor because it acetylates the isozymes in the aspirin-binding channel. Paracetamol acts as a non-competitive reversible inhibitor by reducing the peroxide site of the enzymes [16,19].Paracetamol can affect the central neurotransmission of pain in different ways [18,20,21,22,23,24,25,26,27,28,29,30]. In particular, the drug is metabolized to N-arachidonoylaminophenol (AM404), which is a compound with multiple potential analgesic activities, including the blockade of neuronal uptake of anandamide and of neuronal sodium channels [20,23,26].Cholinergic, noradrenergic, opioid, and serotoninergic (5-HT) mechanisms are thought to be involved in the complex “central”, spinal and supraspinal, actions of paracetamol [18]. In experiment animals, the blockade of the 5-HT neurotransmission by the neurotoxic lesion of descending 5-HT pathways, inhibition of 5-HT synthesis, or antagonism of 5-HT3 receptors reverses paracetamol antinociception in rodents [18]. Ondansetron and tropisetron, two 5-HT3 antagonists, abolish paracetamol analgesia in humans [23,24]. Naloxone and naltrexone, two μ-opioid receptor antagonists, reduce or abo-lish paracetamol analgesia in different animal pain models [25,26].Pickering et al. investigated the central antinociceptive effects of paracetamol in humans [27,28]. Using the blood oxygenation level-dependent signal of the functional Magnetic Resonance Imaging, they measured the cerebral blood flow responses to a thermal stimulus of moderate-to-severe intensity (i.e., pain Numerical Rating Scale (NRS) 6/10) in healthy volunteers receiving placebo or paracetamol in randomized, double-blind, crossover design sessions. Compared to the placebo sessions, in the paracetamol sessions, the pain-induced increases of cerebral blood flow were significantly attenuated in the prefrontal cortices, insula, thalamus, anterior cingulate cortex, and periaqueductal gray matter [27]. The findings suggest that paracetamol negatively modulates the ascending spinothalamic projection to supraspinal cortical areas.Although, opioids do not alter cognition in chronic pain patients when given at stable doses, their potential cognitive impact is a concern, especially in the elderly population [6,7]. In contrast, Pickering et al. also showed that paracetamol positively affects cognition in decision making and working memory domains [28]. Cognitive performances were measured in 40 healthy volunteers 1 week apart with a set of cognitive tests (i.e., information sampling task for pre-decisional processing, Stockings of Cambridge for spatial memory, reaction time, delayed matching of a sample, and pattern recognition memory) before and after random oral administration of placebo or 2 g paracetamol. Treatment with paracetamol improved tasks of information sampling, spatial planning, and working memory [28]. The implications are twofold: firstly, the findings confirmed the clinically relevant effects paracetamol has on the Central Nervous System; secondly, paracetamol has positive effects on cognition [28].3.4. PharmacokineticsOral paracetamol has excellent bioavailability with peak plasma concentrations occurring within 30–60 min after ingestion; the plasma t1/2 is about 120 min. Its binds to plasma proteins less than NSAIDs and diffuses throughout most body fluids. The kidneys excrete glucuronide conjugates. Some 90–100% of the drug may be recovered in the urine within the first day at therapeutic dosing [18,19]. Paracetamol is principally transformed into inactive compounds through the conjugation with sulfate and glucuronide, and a small portion is oxidized via the cytochrome P450 enzyme system (its CYP2E1 and CYP1A2 isoenzymes). The CYP2E1 and CYP1A2 convert paracetamol into the alkylating metabolite (N-acetyl-p-benzoquinone imine, NAPQI), which may be responsible for paracetamol liver toxicity (see also Section 6. Safety and Toxicity). Based on the levels of CYP2D6 expression, individuals can be classified into “extensive”, “ultrarapid”, and “poor metabolizers” [30].3.5. Oral vs. Intravenous FormulationsParacetamol is available in tablets, suppositories, and oral and injectable solutions. The standard adult dose is 500 to 1000 mg, while adult’s recommended maximum daily dose is 3 to 4 g. In the last two decades, intravenous and oral rapidly dissolving preparations, granules, or tablets became widely available. They provide faster Tmax and higher Cmax than tablets with the oral solution achieving higher bioavailability than intravenous formulation [31]. Intravenous paracetamol produces peak plasma concentrations in approximately 15 min compared to 45–50 min following oral administration, resulting, theoretically, in a faster onset of the analgesic effect (5 min) [31,32]. However, several studies, demonstrate similar analgesic efficacy of intravenous and oral preparations [31,32,33,34,35,36]. In a double-blind RCT, a heterogeneous group of 87 patients of the Emergency Department with moderate-to-severe pain (median age of 45 years, 60% females) were randomized to receive 1 g of paracetamol either intravenously or orally; the changes in Visual Analogue Score (VAS) for pain from baseline (67.9 ± 16.0 mm) to 30 min post-administration outcome did not differ between groups (−16.0 ± 19.1 mm in the intravenous group and −14.6 ± 26.4 in the oral group, p = 0.79) [33]. Secondary outcomes including the length of stay, patient satisfaction, and need for rescue analgesia did not differ between groups [33]. The authors concluded that intravenous and oral paracetamol produced a small but clinically significant decrease in pain [33]. In an RCT comparing intravenous and oral paracetamol in 120 patients undergoing hip and knee arthroplasty, 1 g of intravenous or oral paracetamol was administered preoperatively and then every 6 h for 24 h. The 24 h average pain VAS and 24 h hydromorphone rescue analgesia did not differ between the two groups, except for a lower pain VAS in the intravenous group at the postoperative 0–4 h interval [32]. In a double-blind RCT, 154 patients undergoing a total hip arthroplasty procedure received either intravenous or oral 1 g of paracetamol as part of a postoperative opioid-sparing, multimodal analgesia (i.e., 15–30 mg intravenous ketorolac every 8 h, for a total of 6 doses, and then oral meloxicam 7.5–15 mg until postoperative day three or discharge; upon request, tramadol 50–100 mg for mild–moderate pain or oxycodone 5 mg for severe pain; intravenous 2 mg hydromorphone as rescue analgesia for severe pain). Paracetamol was administered 30 min after admission to the post-anesthesia care unit and then every 6 h for three days or to discharge [34]. The pain NRS during physical therapy on postoperative day 1 was similar in the intravenous and oral treatment group (3.9 ± 2.4 and 3.6 ± 2.4); the cumulative doses of oral morphine equivalent were also similar between groups [34]. The authors concluded that patients in both groups had low pain scores and limited opioid usage [34]. Much alike, Johnson et al. found that a single preoperative administration of 1 g of oral paracetamol produced postoperative analgesia similar to 1 g of intravenous paracetamol in patients undergoing laparoscopic cholecystectomy [32]. Fenlon et al. studied 130 patients treated with oral or intravenous paracetamol and oral or intravenous placebo for third molar extraction; there was no difference in the analgesic outcome of satisfactory analgesia at 1 postoperative h [35]. In a meta-analysis of six RCTs comparing intravenous versus oral administration, Jibril et al. found no evidence indicating that the increased bioavailability of the intravenous preparations produces a superior analgesia [31]. In a recent systematic review of 14 trials with 1695 participants on postoperative pain, there was no significant difference between intravenous and oral paracetamol in terms of pain intensity up to >24 postoperative h [36].4. PainPain is a health problem of epidemic proportions with 15% and 25% of people reporting to suffer from pain most or every day over the last 3 to 6 months; pain increases with age and with low socioeconomic status [1,2,3,4]. Persistent, intense pain can impair a person’s mental and physical well-being. For these reasons, in 1995 James Campbell, in his Presidential Address to the American Pain Society, proposed that pain should be measured as a fifth vital sign, along with blood pressure, temperature, heart rate, and respiratory rate. While the initiative was intended to improve pain care, the lack of long-term safe treatments of pain led to increased opioid prescriptions that eventually contributed to the opioid crisis [37]. As a result of the large numbers of deaths from overdose of prescribed opioids, in 2016, the American Medical Association voted to stop considering pain as the fifth vital sign, to reduce opioid prescription, and to shift to non-opioid therapies to manage pain [38].Acute and chronic pain are different clinical entities. Acute pain is viewed as a physiological, time-limited, protective response to a specific injury that resolves with healing. In contrast, chronic pain may be considered a ‘disease state in its own right’ according to the European Pain Federation. It outlasts the expected time of healing from a disease or injury, has no biological purpose and, often, no recognizable cause. OA is the most frequent cause of chronic pain with a prevalence varying markedly depending on age range considered, gender and geographic distribution, genetics and lifestyles, and the method has defined. Lumbar spine OA is the single leading cause of disability, with estimates ranging from 40% to 85% [39,40]. Large joint OA is most common in the knee, followed by the hand and hip, affecting 10% of men and 13% of women aged 60 years or older [40]. Radiographic investigations reveal an earlier and larger prevalence for asymptomatic radiographic OA than for symptomatic OA [40].Genetic factors and female sex represent 40% to 80% of cases in hand and hip OA cases while accounting for somewhat less in knee OA. Obesity is a risk factor for knee OA and joint deformity is a risk factor for hip OA. The several environmental risk factors for lower limb OA include joint injury from high-impact sports and heavy work activities involving lifting, cumulative physical loads, full-body vibration, and bending/kneeling/squatting [41]. However, the most relevant risk factor of OA is aging because of age-related cumulative exposure to risk factors and degenerative changes in joint structures. Prevalence of knee and hand OA rises more rapidly in women than in men after the age of 50 years, peaking at the age of 75 years. MSP from multiple joint sites is a common occurrence [42]. According to the Osteoarthritis Foundation, currently, 300 million mostly older people may suffer from OA worldwide; these numbers are expected to rise because of the rapid aging and the increasing obesity in the global population.OA is primarily a degenerative joint disease characterized by cartilage damage and remodeling and inflammation of joint structures [43]. In the elderly, OA is almost constantly associated with sarcopenia and tendinopathies that both worsen joint stability and pathology [44]. OA pain is mostly a nociceptive pain that arises from peripheral nociceptors stimulated by movement and/or inflammatory reactions; then, it is transmitted through myelinated Aβ and Aδ fibers and unmyelinated and C fibers to the spinal cord and then through the spinothalamic tracts to supraspinal, pain-processing cortical regions. The cartilage is physiologically aneural and cannot directly cause pain; however, it can become pathologically innervated and, along with densely innervated subchondral bone, synovium, and joint structure, can generate intense pain [43]. A neuropathic pain component resulting from the pathological innervation of cartilage and/or central sensitization is a common occurrence in OA [43]. OA causes a considerable socioeconomic burden as it leads to loss of productive days and years in adulthood and to loss of Quality of Life during aging. Furthermore, lower limb OA has been positively associated also with increased cardiovascular mortality probably, in part, via unrefreshing sleep, depression, and reduced activity [45,46]. However, OA-related pain and disability are often underdiagnosed and undertreated, especially in the elderly; for example, 72% of hip fracture patients receive no prehospital treatment for pain [47]. Patients and their caregivers often regard pain as a common natural occurrence of aging or because elderly patients are thought to feel less pain, be cognitively impaired, or be reluctant to report pain for stoicism [47,48,49]. A negative attitude toward treating pain in the elderly is favored by a lack of studies on the efficacy and safety of pharmacological treatments of OA pain in the elderly [50,51,52,53,54,55,56]. In a review of 83 clinical studies involving >10,000 subjects treated with analgesics, only 2.3% of people were over 65 years [50]. Furthermore, aging is the most critical risk factor for cardiovascular disease, and elderly OA patients have one of the highest multimorbidity rates in general practice [52,53,54]. In Australian studies, older patients with OA also had hypertension (>50%), cardiovascular disease (20%), dyslipidemia (19%), diabetes (14%), and mental health disorders (12%), many of which are contraindications to NSAIDs and opioids practice [55]. In diabetic patients, although it is under prescribed, the prevalence of NSAIDs contraindicating antiplatelet therapy is >50% [56]. Side effects are common and may lead to treatment discontinuation.Cancer is a leading cause of morbidity and mortality, with more than 18 million new cases and 9 million deaths in 2018 globally [57]. Pain is frequent in cancer, affecting approximately 55% of patients undergoing anticancer treatment, and 66% of patients with advanced or terminal disease [57]. Pain can be nociceptive arising from direct tissue invasion and/or from a perilesional inflammatory reaction; neuropathic pain is caused by nerve involvement from cancer- or therapy-related nerve injury. Treatment can be challenging because patients are often older, frail, highly comorbid, or with multiple and/or end-stage organ failure [57,58]. However, in cancer patients, early pain therapy is critical not only to reduce pain discomfort but slow the disease progression and improve survival [58].5. Clinical GuidelinesMedical institutions and societies develop clinical practice guidelines to ensure the best treatment to patients. Expert panels draw them up with regarding the pertinent literature and a consensus opinion is reached. Panelists grade the quality of evidence in a rather standard fashion, most frequently from I to V with I indicating high-quality evidence from properly designed RCTs and meta-analysis and V indicating lower quality evidence from case reports and expert opinions. The strength of treatment recommendations is graded on the basis of quantity and quality of the evidence most frequently from A to D (A: high quality of evidence; effective. B: mode-rate quality of evidence; probably effective. C: low quality of evidence; probably ineffective. D: very low quality of evidence; not effective). The GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach is frequently used [59]. However, the panelists take into account not only the clinical research findings collated through systematic reviews and meta-analyses on treatment efficacy but also the specific definitions of clinical conditions, the benefit/harm balance, the economic costs, the epidemiological context, the availability of alternative treatments, the patient acceptability, and their own clinical experience. The agreement of panelists is obtained in different ways. As a consequence, the analyses of the same evidence may lead to different recommendations by different committees. Clinical guidelines are updated periodically to keep up with new scientific discoveries, new treatments, and emerging pharmacoepidemiological data. The efficacy of paracetamol has been determined in RCTs as well as real-life studies to show its superiority versus placebo or other pain drugs [33,34,35,36,60,61,62,63,64,65,66,67,68,69,70]. However, recently, paracetamol failed to show superiority over placebo, and questions have been raised about its safety [70]. However, at the same time, severe concerns have been raised about the organ toxicity by NSAIDs particularly in the elderly and the risk of abuse and overdose of opioids [4,5,9,10]. The opioid epidemic is still underway. As a consequence, paracetamol is still maintained or included in clinical guidelines.The search strategy identified 716 publications with 109 duplicates. After screening and review, 17 documents containing 18 guidelines were included in the review (Figure 1 shows the PRISMA flow chart).The AGREE II domain scores for each guideline are displayed in Table 2. The mean scores for each domain were (range ± SD): scope and purpose 96.1 ± 4.6; stakeholder involvement 73.5 ± 14.8; rigor of development 64.5 ± 17.0; clarity of presentation 90.6 ± 9.4; applicability 26.1 ± 21.4; editorial independence 65.8 ± 22.6. On the overall assessment, 10 guidelines were judged as recommended since their quality scores was 5 to 7, representing high- or good-quality guidelines; 7 guidelines were recommended after modification (quality scores 3 and 4); 1 guideline was scored 2 and not recommended.Table 2Guideline assessment according to the AGREE II instrument.Organization/SocietyConditionAGREE II Domain Score (%)Scope and PurposeStakeholder InvolvementRigor of DevelopmentClarity of PresentationApplicabilityEditorial IndependenceOverallASAS-EULARaxSpA97656791305868OPTIMaLBP100777386146770NICELBP100928968429080EBMLBP97494694352157ACROA97896489276261AAOS/ASRAOA8942346905251ESCEOOA1006664100244767NICEOA1009983100868793OARSIOA100775493409276ACP/ASIMMSP1008678971210079AGSMSP8757349414856BGS, BPSMSP100716094163363AHSHA94716994129272EFNSHA89693910055059NICEHA89897386429078ASCOCP1008086100517582ESMOCP9471838665459Open in a separate windowAbbreviations: ACP-ASIM: American College of Physicians–American Society of Internal Medicine; ACR: American College of Rheumathology; AAOS: American Association of Orthopedic Surgeons; AGS: American Geriatric Society AHS: American Headache Society; ASAS-EULAR: Assessment of SpondyloArthritis international Society; ASCO: American Society of Clinical Oncology; ASRA: American Society of Regional Anesthesia and Pain Medicine; axSpA: axial spondyloarthritis; BGS: British Geriatric Society; BPS: British Pain Society; CP: cancer pain; EBM: Evidence-Based Medicine; EFNS: European Federation of Neurological Societies; ESCEO: European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases; ESMO: European Society of Medical Oncology; EULAR: European League Against Rheumatism; HA, headache; LBP: low back pain; MSP: musculoskeletal pain; OA: osteoarthritis; NICE: National Institute for Health and Care Excellence; OARSI: Osteoarthritis Research Society International; OPTIMa: Ontario Protocol for Traffic Injury Management.5.1. Acute PainAcute pain requires an analgesic with a fast onset of action. Fast dissolving tablets and intravenous and oral solutions of paracetamol have been developed for this purpose. Paracetamol can be administered alone to treat mild-to-moderate pain [33,34]. Paracetamol is often co-administered with NSAIDs or opioids with remarkable drug-sparing effects in subjects with severe pain [33,34,65].Hung et al. randomized 783 patients, with a soft tissue injury, to receive either paracetamol 1000 mg or ibuprofen 400 mg or paracetamol 1000 mg and ibuprofen 400 mg. The pain intensity on the 0–100 mm VAS pain scale declined by 12, 12, and 13 mm, respectively, in the paracetamol, ibuprofen, and in the combined paracetamol and ibuprofen groups. The authors concluded that the treatments were clinically effective without significant differences between groups [60].Paracetamol was not inferior to diclofenac or indomethacin in the management of acute MSP [61,62,63]. A Cochrane review on nine studies with 991 patients, comparing paracetamol with NSAIDs for acute soft tissue injury, found no clinically relevant differences (low-to-moderate quality evidence) between patients treated with paracetamol or with NSAIDs in pain-attenuating effects at day 1–7, swelling, and return to function at day 7; gastrointestinal adverse events were more common in patients treated with NSAIDs [64]. In a qualitative review of RCTs comparing paracetamol with NSAIDs, Hyllested et al. found that while it was less effective than NSAIDs in dental surgery, paracetamol was equally effective to NSAIDs in major surgery and orthopedic surgery; also, paracetamol enhanced analgesia when added to a NSAID, compared with NSAIDs alone [65]. The authors concluded that paracetamol is a viable alternative to NSAIDs because of the low incidence of adverse effects, and it should be the preferred analgesia in high-risk patients [65]. Although less active on the severe hip or knee OA, paracetamol was equally effective than diclofenac/misoprostol in mild OA [66].A large RCT involving 1644 adult patients with acute renal colic compared the anal-gesic efficacy of 1000 mg intravenous paracetamol, 75 mg intramuscular diclofenac, or 0.1 mg/kg intravenous morphine intravenously [67]. The primary analgesic outcome of 50% pain reduction at 30 min post-administration was achieved by 66%, 68%, and 61% with no differences among groups [67]. In a prospective cohort study in 116 patients presented to the Emergency Department of a level one trauma center because of fractures, strains, or sprains receiving opioids in the ambulance or during their stay in the Emergency Department, paracetamol did not modify morphine requirement in the acute phase or after discharge [68]. In a recent systematic review, paracetamol was found to be as effective as NSAIDs in treating acute MSP in patients with minor musculoskeletal injuries in terms of analgesic efficacy need for additional analgesia and adverse events (low quality of evidence) [69].Multimodal analgesia is recommended for severe postoperative or trauma pain [71]; it is based on the premise that the combined use of different analgesic drugs and technique primarily non-opioid analgesics that can have additive or synergistic effects that provide superior analgesia while reducing opioid dosing and related adverse effects. Paracetamol has a role in the multimodal approach [71]. Miranda et al. used isobolographic analysis to calculate the effects of paracetamol on the ED50 of different NSAIDs in mice; they demonstrate that all the combinations were synergistic, the experimental ED50s being significantly smaller than the theoretically calculated ED50s [72]. Zeidan et al. formally determined the median ED50s of paracetamol and morphine alone and paracetamol and morphine combination using the Dixon and Mood up-and-down method in three groups of 30 patients undergoing moderately painful surgery; initial doses were 1.5 g and 5 mg in the paracetamol and morphine groups, and they were 1.5 g and 3 mg in the paracetamol–morphine combination group [73]. The median ED50s of paracetamol and morphine alone were 2.1 g and 5 mg in paracetamol and morphine groups, respectively, and they were 1.3 g for paracetamol and 2.7 mg for morphine in the combination treatment group. The results demonstrated that paracetamol and morphine share, at least, additive analgesic effects [73]. In elderly painful conditions, the non-opioid analgesics such as paracetamol should be continued to facilitate “opioid-sparing” dosing [74]. A systematic review of the peer-reviewed literature confirmed that the combined use of paracetamol and NSAIDs could significantly enhance the analgesic effects of either drug alone [75,76]. Furthermore, in patients with rheumatoid arthritis, the co-administration of a fish oil containing the n-3 fatty acid, eicosapentaenoic acid enhanced the inhibition of COX-2 generated prostaglandin E2 [77].Paracetamol has been used for a long time for the treatment of headache and migraine. Using the American Academy of Neurology criteria to develop guidelines, the American Headache Society considered oral paracetamol effective with a level of evidence A (established as effective) when it is used alone or in combination with aspirin for non-incapacitating attacks of migraine (effective), with a level B (probably effective) when is used in combination with codeine or tramadol, and with a level C (possibly effective) when used in combination with butalbital [78]. In an RCT, 1 g of oral paracetamol was superior to placebo in terms of 2 h headache relief (i.e., responder percent after paracetamol or placebo 51% vs. 27%, P = 0.008) and of associated symptoms such as functional disability, photophobia, and phonophobia [79]. Not all studies were positive. In fact, in contrast to previous reports, intravenous 1 g of paracetamol for treating an acute migraine attack failed to demonstrate significant differences over placebo in terms of headache freedom and relief at two and at 24 h (31% vs. 33% placebo; P = not significant) [80]. However, paracetamol is recommended for the treatment of migraine by most national and international societies including the American Headache Society, the American Academy of Fa-mily Physicians and the American College of Physicians–American Society of Internal Medicine, and the Ad Hoc Committee of the Italian Society for the Study of Headaches for the Guidelines of Primary Headaches in adults (Table 3) [78,81,82]. The European Federation of Neurological Societies supports paracetamol as first-line treatment a high degree of evidence (level A) for tension-type headache [83].Table 3Guideline recommendations for pain treatment with paracetamol.Organization/SocietyFirst Author, YearConditionRecommendationComments

ASAS-EULAR

van der Heijde, 2016axSpARto be considered after NSAIDs failed

OPTIMa

Wong, 2016LBPRrecommended in acute LBP

NICE

NICE 2020LBPCRnot recommended alone, recommended in association with opioids

EBM

EBM 2019LBPRrecommended for acute and chronic LBP

ACR

Kolasinski, 2020OACRrecommended for patients intolerant to NSAIDs, monitor liver function

AAOS/ASRA

Fillingham, 2020OAR

ESCEO

Bruyere, 2014OARfirst line for short-term treatment (<3 g/day); not for long-term treatment

NICE

NICE 2020OARto be considered ahead of NSAIDs

OARSI

Bannuru, 2019OACNR

ACP/AAFP

Qasem, 2020MSPCR

AGS

AGS Panel, 2009MSPRcontraindicated in liver failure; not exceed max 4 g/day dose

BGS, BPS

Abdulla, 2013MSPRelderly population; not to exceed max 4 g/day dose

AHS

Marmura, 2018HAR

EFNS

Bendtsen, 2010HAR1 g for acute therapy

NICE

NICE, 2021HARindicated for migraine and tension headache

ASCO

Paice, 2016CPRavoid drug interaction

ESMO

Fallon, 2018CPNR

WHO

WHO, 2019painR

Open in a separate windowRecommendations by medical societies for pain management with paracetamol in different clinical conditions. Each society followed specific criteria to grade quality evidence and recommendations that should be consulted. Abbreviations: same as in Table 1. Recommendations: light red-CNR: conditionally not recommended (probably ineffective); light green-CR: conditionally recommended (effective in some patients); yellow-NR: no recommendation (not enough reason to support or refute its use); green-R: strongly recommended or recommended (effective or probably effective).5.2. Chronic PainThe management of recurrent and chronic pain requires a stepwise approach with an initial recommended treatment in guidelines with paracetamol and topical agents [9,84]. In recent years, several studies and meta-analyses have compared the analgesic efficacy and safety of paracetamol versus placebo or NSAIDs for chronic pain. Some evidence of reduced efficacy of paracetamol has changed some opinions and guidelines. Nevertheless, paracetamol continues to be used, clinically tested, and recommended by several clinical practice guidelines that were based on expert opinions and structured reviews of the literature (Table 2).Five hundred and seventy-one patients with hip or knee OA were randomly treated for 6 or 12 months with 4 g/day paracetamol or naproxen 750 mg/day. Paracetamol improved the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores similarly to naproxen. In paracetamol-treated patients, the mean changes from baseline to outcome in WOMAC pain, stiffness, and physical function scores were −21.6, −20.6, and −18.9 points, respectively [85]. In a Cochrane review of 15 RCTs involving 5986 participants, paracetamol was superior to placebo in five out of seven RCTs with a 5% relative improvement from baseline and a number-needed-to-treat of four to 16 to achieve a pain improvement; treatment with paracetamol did not modify WOMAC outcome [86].The group of interest of the Italian Society of Anesthesia, Reanimation, and Intensive Care supported the use of paracetamol for chronic non-cancer pain [87]. In a meta-analysis of 15 RCTs, including 5133 patients of whom 3275 received an NSAID and 1858 paracetamol, paracetamol seemed slightly less effective than NSAIDs when larger numbers of patients with hip OA were included [88]. However, paracetamol was consistently associated with a better gastrointestinal safety profile than NSAIDs [88].In his first meta-analysis of 10 RCTs, including 1712 young patients suffering from knee or knee and hip OA, Zhang et al. reported a significant pain reduction by paracetamol [89]. If initial treatment with paracetamol was favorable, paracetamol was recommended for continued long-term use for OA and lower back pain (LBP) [90,91]. For the management of knee OA, the European League against Rheumatism (EULAR) recommended paracetamol as the first and preferred long-term oral analgesic (Table 2) [92]. The European League of Associations of Rheumatology recommended paracetamol as the first-line treatment for mild-to-moderate OA pain because of its safety and effectiveness. NSAIDs should be considered in patients not responding to paracetamol and should be prescribed at the lowest effective dose and for the shortest duration [93]. The American College of Rheumatology for the treatment of hip and knee OA proposes a treatment with paracetamol before NSAIDs [94]. In its 2014 Osteoarthritis Care and Management Clinical Guideline, the National Institute for Health and Care Excellent (NICE) acknowledges a reduced effectiveness of paracetamol. NICE recommends that paracetamol be considered for pain relief and core treatments ahead of oral NSAIDs [95]. After having critically reviewed 1287 publications yielding 17 publications representing the best available evidence for analysis on the efficacy and safety of paracetamol for total joint arthroplasty, the American Association of Hip and Knee Surgeons, American Academy of Orthopedic Surgeons (AAOS), Hip Society, Knee Society, and American Society of Regional Anesthesia and Pain Managements supports with strong evidence the perioperative use of oral and intravenous paracetamol as a non-opioid adjunct for pain management of patients undergoing primary total joint arthroplasty both during hospitalization and following discharge [96].In a subsequent analysis of 64 systematic reviews and 266 RCTs, Zhang et al. found that the analgesic effect size (i.e., mean effect of paracetamol group-mean effect of placebo group/standard deviation) of paracetamol was reduced not significantly from 0.21 to 0.14; however, the effect size was 0.1 and no longer significant when analyzing only high-quality-graded trials [97]. Therefore, in the recently updated of the Osteoarthritis Research Society International (OARSI) guidelines for non-surgical management of OA, paracetamol was conditionally not recommended; oral and transdermal opioids were strongly not recommended as well, and oral NSAIDs were not endorsed for cardiovascular or frail patients [98]. A recent Cochrane systematic review of 10 placebo-controlled RCTs involving 3541 patients stated that paracetamol alone provided only small clinical benefits at 3 weeks to 3 month follow-up and no increased risk of adverse events overall [99]. Nevertheless, the recent guidelines of the American College of Rheumatology/Arthritis conditionally recommend paracetamol for hand, hip, or knee OA at a maximum dose of 3 g/day, especially for patients with reduced therapeutic options because of contraindications to NSAIDs [100].However, guideline reviews primarily focus on the analgesic efficacy in young patients and pay less attention to potential adverse events especially in the much less studied older patient population [101]. Nevertheless, when potential benefits and risks of harm are considered, paracetamol continues to be investigated and recommended as a first-line analgesic for older adults with mild-to-moderate pain [84,101]. In a systematic review of recommendations and guidelines for managing OA pain, the Chronic Osteoarthritis Management Initiative of the U.S. Bone and Joint Initiative, paracetamol was the first-line treatment across guidelines [90]. Although it reports findings questioning its efficacy, the NICE eventually recommended that paracetamol and/or topical NSAIDs to be kept in the NICE 2014 guidelines for OA and to be considered before oral NSAIDs, COX-2 inhibitors, or opioids [102]. The British Royal College of General Practitioners, the Primary Care Rheumatology Society, and the British Society for Rheumatology raised concerns about removing paracetamol from the recommended analgesics could result in unforeseen consequences from increased use of NSAIDs and opiates [102]. Makris et al. carried out a clinical review based on graded evidence from 92 studies on pharmacological and nonpharmacologic interventions, which were mostly primarily focused on older adults with OA. Given the scarcity of RCTs on older adults, the authors included reviews, guidelines, and consensus statements and concluded supporting a stepwise approach with paracetamol as first-line therapy for pain in the elderly [103]. The American Geriatric Society recommends extreme caution in the use of NSAIDs in the elderly because of frequent adverse events on the gastrointestinal, cardiovascular, and renal systems and the increased risk of hospitalization, renal toxicity, myocardial infarction, stroke, and death [104]; they recommend paracetamol as initial pharmacological therapy in the treatment of persistent pain, particularly MSP, because of its efficacy and safety profile (high quality of evidence; strong recommendation) [105]. They considered a liver failure as an absolute contraindication (high quality of evidence, strong recommendation) and hepatic insufficiency, chronic alcohol abuse, or dependence as relative contraindications (moderate quality of evidence, strong recommendation) [105]. The British Geriatric Society and British Pain Society indicate in the first UK guideline paracetamol as first-line treatment in older patients, particularly for MSP [106]. The American Geriatric Society recommends paracetamol as a first-line treatment for persistent pain with a 50–75% dose reduction in patients with liver failure [105]. Using a modified Delphi technique (two-round), a Brazilian expert panel suggested paracetamol as a possible alternative medication for pain in the elderly [107].Interestingly, paracetamol is considered and commonly prescribed as first-line treatment for pain also in patients with dementia [108,109,110,111]. In observational studies, paracetamol improved pain and behavioral symptoms, enabling a reduction in psychotropic drugs in patients with dementia; in an RCT, paracetamol improved social engagement but did not affect behavioral symptoms [110]. These benefits were confirmed in an RCT on nursing home patients with mild-to-moderate dementia; using a stepwise approach, pain treatment with paracetamol improved daily living [111]. In a 6-month study by the Mount Sinai Visiting Doctors who provide home-based primary and palliative care to home-bound patients >80 years, the prescription for patients with moderate-to-severe pain of opiates and paracetamol increased from baseline to the end of the study from 48% to 57% and 52% to 91%, respectively [112].Increasing or maintaining motor activity may be protective against OA progression and the excess mortality associated with OA [46]. Aging entails a progressive loss of muscle volume and function that impacts joint stability and motility and favors cartilage degeneration [113]. In this regard, paracetamol may be particularly useful. Carroll et al. have demonstrated that a 3-month resistance training and treatment with paracetamol 4 g/day versus placebo increased the cross-sectional area, deformation, and strain of the patellar tendon and decreased stiffness and modulus [114]. In a second RCT in older adults (mean ages 67 ± 2 and 64 ± 1 years), in comparison to the placebo, paracetamol 4 g/day or ibuprofen 1.2 g/day given during a 12-week knee extensor resistance training increases muscle and strength without altering muscle concentrations of muscle proteins, water, myosin heavy chain, and COX-1 and -2 [115].Chronic low back pain (LBP) has a special place in pain-related disability; it is a complex syndrome resulting part from spinal OA and part from abnormalities of intervertebral discs and other structures [116,117]. Approximately 90% of all patients with LBP have non-specific LBP, which is a diagnosis based on the exclusion of specific causes including lumbar disc herniation, facet joint syndrome, lumbar spinal stenosis, spondylolisthesis, cancer, and infection. LBP is the first cause of disability worldwide [70,116,117,118,119]. Although paracetamol has long been recommended as the first-line treatment, recent systematic reviews found insufficient evidence to support its use in LBP [70,116,117,118,119]. Most recent guidelines advise against its use in chronic LBP (Table 2). Still, Morlion et al. recommend paracetamol as a first-line treatment for LBP in patients of advanced age or with gastrointestinal, cardiovascular, or renal comorbidities [117]. Koes et al. rightfully pointed out that analyzing the same evidence, paracetamol was recommended in three out of eight and was not recommended in four out of eight national guidelines for LBP [116]. Due to its safety, the Evidence-Based Medicine guidelines indicate paracetamol as a first-line analgesic for LBP [119].The 2016 ASAS-EULAR guidelines recommend paracetamol for patients with axial spondylarthritis, an autoimmune disease of the spine, and who present failure, contraindications, or poor tolerance to first-line recommended treatments [120].5.3. Cancer PainThe World Health Organization developed a three-step analgesic ladder in 1986, specifically for cancer pain. Paracetamol and NSAIDs have been included in the first step of the ladder and the World Health Organization Model List of Essential Medicines [121]. Although paracetamol is rarely sufficient to control severe pain when administered in monotherapy, it is useful in the initial phase of treatment of cancer pain. According to Portenoy and Ahmed, paracetamol is “a reasonable alternative to a low dose of a strong opioid alone for opioid-naïve patients with moderate to severe cancer pain” [122]; these authors also suggest to use a fixed-dose of paracetamol in patients who began opioid therapy and are sensitive to their side effects. In the setting of multimodal analgesia, paracetamol has been administered with different opioids (i.e., codeine, hydromorphone, hydrocodone) and has consistently demonstrated an opioid-sparing effect on the postoperative pain [123]. Finally, in combination with weak or strong opioids, paracetamol provided clinically meaningful relief in patients with moderate or severe cancer pain [122,123]. Nevertheless, a 2017 Cochrane review of three RCTs comparing paracetamol alone with placebo or paracetamol plus an opioid with the same dose of opioid alone concluded that there was a high risk of bias and no high-quality evidence to support or refute the use of paracetamol in patients with cancer pain of any intensity [124]. Therefore, the European Society of Medical Oncology stated that there is no reason to recommend or refute paracetamol for mild-to-moderate cancer pain [125]. Conversely, a 2019 network meta-analysis of analgesic drugs for chronic cancer pain concluded that the top-ranking drug classes for global efficacy were non-opioid analgesics, including paracetamol, as well as NSAIDs and opioids [126]. It is considered the first-choice drug for mild-to-moderate pain in older patients with cancer naïve to opioids [127].The American Society of Clinical Oncology (ASCO) indicates that paracetamol may be prescribed to relieve chronic pain and improve function in cancer survivors in whom there are no contraindications including dangerous drug–drug interaction (evidence quality: intermediate; strength of recommendation: moderate) [128]. The Spanish Oncological Society recommends paracetamol for pain management in cancer patients regardless of pain intensity and provided it is not contraindicated (level of evidence I, degree of recommendation A) [129]. The combination of paracetamol with strong opioids improves pain management and the sense of well-being [129].6. Safety and Toxicity6.1. Pharmacoepidemiology Oral formulations of paracetamol have been used for over 140 years with no clinically relevant adverse effects being usually apparent with recommended doses (i.e., up to 4 g per day) [130]. Almost all RCTs and meta-analyses reported numbers of adverse events from paracetamol that were inferior to those of NSAIDs and comparable to those of placebo. However, reviews on long-term observational data reported increased cardiovascular, gastrointestinal, and renal adverse events during therapy with paracetamol, especially in the high dose range; cases of acute liver failure have been reported after accidental and unintentional overdose of paracetamol [10,131,132,133,134,135,136,137,138,139,140,141,142,143,144]. Acute liver failure is infrequent with an approximate incidence for all causes of 1/million/year and is declining [134]. In recent Canadian reports, the numbers of paracetamol ingestions reporting to the Emergency Department declined from April 2011 to February 2019 [134]. Despite its rarity, acute liver failure generates interest and study by multiple disciplines because it affects all organ systems and requires substantial resource use [134]. Thusius et al. reported that the vast majority of patients survived and recovered without lasting medical sequelae. The liver transplant rate was 1.5% and the death rate <1%; the majority of both intentional and unintentional overdose patients underwent inpatient medical and psychiatric treatment [135]. Furthermore, drug-induced liver injury is a diagnosis of exclusion that has been ascribed almost only to paracetamol [143]. However, a recent review indicates that a drug-induced liver injury is idiosyncratic, unpredictable, and related to herbal and dietary supplements and to a number of many potentially toxic drugs to the liver [144].In the patients enrolled in the US NIH registry of the Liver Failure Study Group between 2007 and 2013, acute liver toxicity from paracetamol overdosing was mostly related to psychiatric comorbidity including depression, frequent substance abuse, and increased impulsivity [132]. Psychiatric patients may require special monitoring of paracetamol consumption as they do with any medication. Patients who are fasting, consuming excessive alcohol drink, or suffering from liver diseases (i.e., non-alcoholic fatty liver diseases) may present a higher risk of toxic liver damage [132]. A cautious dose reduction to 2 g/24 h is advised for malnourished patients (weight < 50 kg) when paracetamol is used regularly in these patients. Not all initial safety warnings are being confirmed. For example, it has been suggested that paracetamol may alter the therapeutic response to conventional antidepressants [133]. A recent investigation in bipolar disorders indicated instead that paracetamol has no detrimental effect on affective disorder treatment; more specifically, it does not modify the lithium- or quetiapine-based bipolar disorder mood-stabilizing treatment outcomes [133].6.2. Potential Mechanisms of Paracetamol ToxicityParacetamol overdose can cause liver damage and failure for which different mechanisms have been suggested [136,137,138]. At therapeutic doses, paracetamol is metabolized in the liver primarily by glucuronidation (50–60%) and sulfonation pathways (25–30%) and less by oxidation by cytochrome P450 2E1 (<10%). The latter produces only small amounts of the toxic metabolite NAPQI, which is detoxified by glutathione conjugation [137]. In paracetamol overdose or when sulfate availability and/or activity of sulfotransferases are low, NAPQI is formed in excess [135]. It binds to mitochondrial proteins, forming cytotoxic adducts, leading to mitochondrial dysfunction and severe hepatocellular necrosis [137]. Following the direct hepatotoxic effects of NAPQI, the inflammatory reaction and other critical events contribute to the evolution toward liver regeneration or liver irreversible damage. They include oxidative stress, reactive nitrogen formation, and JNK activation [138]. A key role is played by platelets that recruit macrophages and neutrophils; it has recently been shown that blocking the platelets C-type lectin-like receptor improves liver regeneration [136].6.3. Treatments of Paracetamol ToxicityN-acetyl cysteine has been widely used as a glutathione regenerator to treat paracetamol overdoses, and several other molecules are under investigation to treat paracetamol-induced liver damage [139,140,141].Guidelines for paracetamol overdose include charcoal for patients that can be treated early after ingestion and intravenous N-acetyl cysteine for patients at risk of hepatotoxicity [141]. In a RCT on 24 healthy volunteers given paracetamol (1 g × 4 daily × 4 days) with N-acetyl cysteine or with placebo, N-acetyl cysteine prevented glutathione depletion without interfering with paracetamol analgesia [141].7. Recent Findings and Future DirectionsThe numbers of studies, systemic reviews, and meta-analyses on paracetamol is high and growing. However, large, authoritative clinical trials are costly, and it is unclear whether they will be done [145,146].Recently, Abdel Shaheed analyzed data from 36 publications and reported that paracetamol produced modest pain relief in hip and knee osteoarthritis, tension headache, and post-craniotomy pain and that it was ineffective in other conditions [145]; the authors concluded with the need for large, high-quality trials to reduce uncertainty about the efficacy of paracetamol in common pain conditions. In the last few months, new published studies report the safe use of paracetamol in patients with chronic kidney disease [147], the significant efficacy of paracetamol for post-arthroplasty pain [148], the lesser efficacy of paracetamol than ibuprofen for post-laminectomy pain [149], the opioid-sparing effects of paracetamol in the Emergency Department [150], the recommendations against paracetamol in lumbar spinal stenosis with neurogenic claudication [151], and the recommendations in favor of paracetamol for postcesarean pain [152] and for migraine [153,154].RCTs and other evidence should be analyzed critically by experts before adopting (or refusing) the results to daily clinical practice [155]. Clinical guidelines fill the gap between scientific evidence and its application in clinical practice. They have the advantage of being more comprehensive because they are generated from the consolidated medical and because they consider a number several economical, epidemiological, research, and therapeutic factors including, for example, the availability of alternative treatments. In our opinion, practice guidelines are essential tools in managing the complexity of decision-making processes.8. ConclusionsParacetamol has been one of the most recognizable drugs, both on- and off-prescription, and it is likely to remain so in the future. As a result of the global aging, painful and disabling conditions are increasing. Paracetamol has a favorable safety profile that will be of utmost importance across all ages and especially in the elderly. Liver toxicity is a concern, but it is questionable at doses up to 4 g/day. Although it underwent intense scrutiny of its efficacy and safety, paracetamol is recommended by guidelines for the treatment in diverse acute and chronic pain.Finally, the safety and tolerability record and the safety advantages of paracetamol over other classes of NSAIDs and opioid analgesics have been among the reasons for its maintenance or inclusion in pain treatment guidelines by expert panels.Notably, several reports support the equivalent safety and efficacy profile of both oral and intravenous administrations. This conclusion is particularly relevant, suggesting that paracetamol may be used equally through both administration routes in several clinical cases in the emergency setting in chronic pain conditions.Author ContributionsAll authors have contributed, read, and agreed the manuscript. All authors have read and agreed to the published version of the manuscript.FundingThis work was supported by Department funds (UF, IS), by the Fondazione Umberto Veronesi (C.R.), and by the Cariplo Foundation (E.N., A.V; grant 2016-1006).Institutional Review Board StatementNot applicable.Informed Consent StatementNot applicable.Data Availability StatementNot applicable.Conflicts of InterestThe authors declare no conflict of interest.FootnotesPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.References1. Blyth F.M., Briggs A.M., Schneider C.H., Hoy D.G., March L.M. The Global Burden of Musculoskeletal Pain-Where to From Here? Am. J. Public Health. 2019;109:35–40. doi: 10.2105/AJPH.2018.304747. [PMC free article] [PubMed] [CrossRef] [Google Scholar]2. Sprangers M.A., de Regt E.B., Andries F., van Agt H.M., Bijl R.V., de Boer J.B., Foets M., Hoeymans N., Jacobs A.E., Kempen I.J.M., et al. 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Br J Clin Pharmacol. 2018 Oct; 84(10): 2218–2230. Published online 2018 Jul 20. doi: 10.1111/bcp.13656PMCID: PMC6138494PMID: 29863746Long‐term adverse effects of paracetamol – a reviewJ. C. McCrae,

1

E. E. Morrison,

1

I. M. MacIntyre,

1

J. W. Dear,

1

and D. J. Webb

1

J. C. McCrae

1

BHF Centre of Research Excellence (CoRE),

Queen's Medical Research Institute, Pharmacology, Toxicology & Therapeutics,

Edinburgh,

UK

Find articles by J. C. McCraeE. E. Morrison

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BHF Centre of Research Excellence (CoRE),

Queen's Medical Research Institute, Pharmacology, Toxicology & Therapeutics,

Edinburgh,

UK

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BHF Centre of Research Excellence (CoRE),

Queen's Medical Research Institute, Pharmacology, Toxicology & Therapeutics,

Edinburgh,

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1

BHF Centre of Research Excellence (CoRE),

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Find articles by J. W. DearD. J. Webb

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BHF Centre of Research Excellence (CoRE),

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BHF Centre of Research Excellence (CoRE),

Queen's Medical Research Institute, Pharmacology, Toxicology & Therapeutics,

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J. C. McCrae, Email: moc.liamg@earccmcj.Corresponding author.*

Correspondence

Dr Jame C McCrae, BHF Centre of Research Excellence (CoRE), Queen's Medical Research Institute, Pharmacology, Toxicology & Therapeutics, Edinburgh, UK. E‐mail: moc.liamg@earccmcj, Received 2018 Jan 14; Revised 2018 May 16; Accepted 2018 May 24.Copyright © 2018 The British Pharmacological SocietyAbstractParacetamol (acetaminophen) is the most commonly used drug in the world, with a long record of use in acute and chronic pain. In recent years, the benefits of paracetamol use in chronic conditions has been questioned, notably in the areas of osteoarthritis and lower back pain. Over the same period, concerns over the long‐term adverse effects of paracetamol use have increased, initially in the field of hypertension, but more recently in other areas as well. The evidence base for the adverse effects of chronic paracetamol use consists of many cohort and observational studies, with few randomized controlled trials, many of which contradict each other, so these studies must be interpreted with caution. Nevertheless, there are some areas where the evidence for harm is more robust, and if a clinician is starting paracetamol with the expectation of chronic use it might be advisable to discuss these side effects with patients beforehand. In particular, an increased risk of gastrointestinal bleeding and a small (~4 mmHg) increase in systolic blood pressure are adverse effects for which the evidence is particularly strong, and which show a degree of dose dependence. As our estimation of the benefits decreases, an accurate assessment of the harms is ever more important. The present review summarizes the current evidence on the harms associated with chronic paracetamol use, focusing on cardiovascular disease, asthma and renal injury, and the effects of in utero exposure.Keywords: acetaminophen, adverse effects, asthma, gastrointestinal bleeding, hypertension, kidney diseaseIntroduction

http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5239 (acetaminophen) was first synthesized in 1878 1, from its precursor http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7402. Its use was not widespread initially, due to early reports of a link to methaemoglobinaemia 2, 3. After this association was discredited, it was marketed in the 1950s as a safer alternative to phenacetin, which by then had been found to be nephrotoxic and potentially carcinogenic 4. In the early 1980s, paracetamol overtook http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4139 as the most widely used over‐the‐counter (OTC) analgesic in the UK 5. It is now the most commonly used analgesic in the world 6, and the first step of the World Health Organization (WHO) analgesic ladder for the treatment of cancer pain 7.Paracetamol is currently marketed as an analgesic and antipyretic, to be used for no more than 3 days without consulting a doctor 8. However, due in part to its inclusion in the WHO analgesic ladder, as well as decades of clinical experience, it is also prescribed in chronic conditions such as osteoarthritis and lower back pain. Recently, meta‐analyses of the randomized controlled trials (RCTs) covering these conditions have shown the effect sizes to be modest, although still statistically significant, compared with placebo (averaging a 4–5% reduction in pain) 9, 10, 11, 12. Despite this, paracetamol continues to be recommended as first‐line treatment in UK guidelines 13, and attempts to remove it as a recommendation from the UK's National Institute for Health and Care Excellence (NICE) guidance on osteoarthritis raised considerable concerns among medicines regulators and various specialist societies 14, particularly as this would leave opioids as the major alternative. Given the current opioid addiction epidemic ongoing in several US states 15, and a desire not to repeat this in the UK 16, 17, the introduction of opioids earlier in the pain management pathway is unlikely to be viewed favourably.Paracetamol has less of an analgesic effect in chronic use than previously thought; there needs to be greater emphasis on accurately determining the harms of long‐term use at therapeutic doses. This helps clinicians to balance harms against likely benefits for individual patients and allows regulators to make recommendations on its availability in OTC preparations. The acute effects of paracetamol ingestion in overdose are well known 18. Harms with long‐term therapeutic use are less clear. Concerns have been raised over the effects on the cardiovascular, respiratory, renal, gastrointestinal and central nervous systems, as well as potential effects in the offspring of pregnant women ingesting paracetamol.The present review summarizes our understanding of the evidence on the adverse effects of paracetamol in long‐term therapeutic use, informs clinicians of the risks and provides a clearer picture of the underpinning evidence base. This will, in turn, allow clinicians to discuss with their patients the relative benefits and harms of long‐term paracetamol use.Mechanism of actionThe mechanism of action of paracetamol is not completely understood but is likely to involve http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1376 (COX‐2) inhibition. Traditional nonsteroidal anti‐inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes, preventing the metabolism of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391 to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5245. COX enzymes also have a separate peroxidase function, and metabolize PGG2 to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4483, which, in turn, is converted to several different PGs by local tissues according to their individual needs 2, 19, 20. Unlike the closely related NSAIDs, paracetamol interferes with the peroxidase activity of COX isoenzymes, predominantly COX‐2, particularly when the cellular environment is low in arachidonic acid and peroxides 2, 19, 20. This explains paracetamol's apparent ‘central’ effect in earlier studies (as COX‐2 is constitutively expressed in neural tissue) 19, 21, and why it appears to be ineffective in inflamed tissues (where peroxide and arachidonic acid are abundant), seen in conditions such as rheumatoid arthritis. A proposed COX‐3 isoenzyme (an exon splice variant of COX‐1 seen in insects and rodents) has not been found in humans, and further studies suggest that paracetamol has no clinically significant effects on the COX‐1 exon splice variants found so far in humans 19, 21. Other possible mechanisms of action include the inhibition of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2364 reuptake (and subsequent cannabinoid receptor http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=56 stimulation) by paracetamol metabolite N‐arachidonoylphenolamine (AM404), which is produced by the conjugation of arachidonic acid and deacetylated paracetamol 22, and direct activation by this metabolite of the capsaicin receptor transient receptor potential cation channel subfamily V member 1 (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=507) 23. Transient receptor potential cation channel, subfamily A, member 1 (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=485) activation by paracetamol metabolites has also been suggested 24, 25.Paracetamol is mostly metabolized by the formation of conjugates (with glucuronide and sulphate), and subsequently excreted in urine. In therapeutic dosing, around 10% of paracetamol is metabolized by http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=242 (CYP) enzymes to form http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6299 (NAPQI), which is subsequently conjugated with intracellular http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6737, and ultimately excreted as cysteine and mercapturic acid conjugates. Less than 5% is excreted unchanged 26.Search strategyWe conducted a literature search of PubMed, searching the years 1980 to 2016. An initial Pubmed review of ʻparacetamol [Title] OR acetaminophen [Title]ʼ with ʻside effects OR adverse effectsʼ revealed several key interest areas, which were subsequently searched for specifically as follows: we combined ʻparacetamol [Title] OR acetaminophen [Title]ʼ with: ʻhypertension OR blood pressureʼ; ʻmyocardial infarction OR cardiac OR cardiovascularʼ; ʻstroke OR CVA OR cerebrovascular accidentʼ; ʻliver OR hepatic OR transaminase OR aminotransferaseʼ; ʻgastrointestinal OR bleeding OR anaemiaʼ; ʻrenal OR kidney OR CKD OR chronic kidney diseaseʼ; ʻrespiratory OR asthma OR chestʼ; ʻreproductive OR maternal OR ADHD OR attention deficitʼ. Papers were selected uisng the following criteria: (i) human subjects; and (ii) meta‐analyses, reviews, RCTs, prospective studies and cohort studies. English language was not included as a filter but this would not have excluded any papers from review. Titles and abstracts were then reviewed, and relevant articles reviewed in full. Key papers identified in references were also reviewed by the authors, when considered relevant (see Figure 1 for our search strategy).Open in a separate windowFigure 1Outline of search strategyCardiovascular diseaseStudies examining the effect of paracetamol on the incidence of cardiovascular disease are relatively sparse when compared to those on NSAIDs 27. Early studies focused on hypertension (which we have reviewed previously 28), owing to the known association of NSAIDs with hypertension, and the similar mechanism of action of paracetamol 29. One such study was a placebo‐controlled crossover study of 20 treated hypertensive patients, in whom a 4 mmHg rise in blood pressure (BP) was found when paracetamol was administered 30. Given that a 2 mmHg rise in systolic BP is associated with a 7% increase in the risk of ischaemic heart disease and a 10% increased risk of stroke 31, this apparently small increase in BP could have serious population‐based consequences.However, observational and interventional studies examining the effect of paracetamol on hypertension have produced conflicting results 28. To date, most 32, 33, 34, but not all 35, 36, observational studies suggest that long‐term paracetamol use increases the risk of developing hypertension. The Nurses' Health Study II, which included 80 020 participants, found that regular NSAID or paracetamol use was associated with an increased risk of developing hypertension 33: the relative risk (RR) of developing hypertension on NSAIDS was 1.86 [95% confidence interval (CI) 1.51 to 2.28) and on paracetamol was 2.00 (95% CI 1.52 to 2.62). It also seems that there is some evidence for a dose–response relationship between daily paracetamol dose and the risk of incident hypertension. This was observed not only in the Nurses’ Health Studies I and II 37, but also by Roberts et al. 6 for overall cardiovascular risk in their systematic review of paracetamol‐related adverse effects.By contrast, a retrospective observational study by Dawson et al. 36, with propensity matching, found no impact of paracetamol on BP in a cohort of 2754 participants with treated hypertension. Although observational studies may find an association between paracetamol use and hypertension, underlying confounders (such as chronic inflammatory conditions) need to be considered. Unfortunately, to date, interventional studies examining the impact of paracetamol on BP have been limited by study design and small sample size. One recent study, by Sudano et al. 38, randomized 33 patients with established coronary artery disease to paracetamol 1 g three times per day or placebo in a double‐blinded crossover study. Two weeks of treatment with paracetamol significantly increased mean systolic ambulatory BP (from 122 ± 12 mmHg to 125 ± 12 mmHg; P = 0.02) and diastolic ambulatory BP (from 73 ± 7 mmHg to 75 ± 8 mmHg; P = 0.02). Although this difference is unlikely to have a significant effect on an individual patient's cardiovascular outcomes, it may explain the finding that self‐reported frequent paracetamol use in women is associated with an increase in cardiovascular events similar to that seen with frequent NSAID use 27. Fulton et al. 39 showed no increased risk of myocardial infarction or stroke in a hypertensive cohort of 4000 subjects, and no change in BP, which suggests that any increase in risk may be driven by BP alone. Further research in this area is clearly required, and there is currently a suitably powered double‐blind, placebo‐controlled, crossover trial from our centre examining the effects of 2 weeks of paracetamol use on BP in hypertensive patients (https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT01997112","term_id":"NCT01997112"}}NCT01997112), which should report soon.Respiratory effectsAfter aspirin was recognized to cause the rare but serious complication of Reye's syndrome, its use was banned in children under 12 years of age 40, 41. As aspirin use as an antipyretic waned in developed countries and paracetamol use became more common 42, concerns over paracetamol's association with asthma were raised 43. Observational and cross‐sectional studies demonstrated a connection between paracetamol use and asthma diagnoses or exacerbations 44, 45, 46, 47, 48, 49, 50, 51. However, as for BP, almost all of these studies suffer from confounding by indication: recurrent symptomatic respiratory infections and febrile illnesses are more common in asthmatic patients and contribute to the onset of asthma in childhood 52, 53, 54. In some studies, an increase in the risk/odds for developing asthma with increasing paracetamol use becomes nonsignificant when adjusted for recurrent respiratory tract infection 55, 56, 57, although this is not universal 50. Meta‐analyses of these observational studies tend to show only a small effect [e.g. odds ratio (OR) 1.15 for use in infancy], and suffer from considerable heterogeneity 44, 52.A link between paracetamol use and asthma is biologically plausible. Paracetamol metabolism involves the antioxidant glutathione, which is depleted when large doses of paracetamol are taken. There are papers describing glutathione depletion at therapeutic doses of paracetamol 58, 59, and increased oxidative stress could contribute towards either the development of asthma or inflammatory exacerbations in asthmatics 60, 61, 62, 63, 64. Glutathione depletion may also change T helper (Th) physiology towards a Th2 phenotype, which is associated with atopic disease 46. Paracetamol may also cause an imbalance in lipoxygenase activity, brought about by COX inhibition, resulting in increased http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=272 and decreased http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1883 production 60, 61, 65. This latter mechanism has support from studies carried out in patients with aspirin‐associated asthma, in which decreases in forced expiratory volume in 1 s (FEV1) following paracetamol administration were observed 66. In one such study, 34% of aspirin‐sensitive participants showed cross‐reactivity to paracetamol 67, and in patients with aspirin‐associated asthma it is recommended to use the lowest effective dose of paracetamol for analgesia 68, 69. It should be noted that a later double‐blind RCT in non‐aspirin‐sensitive subjects (n = 85) taking paracetamol 1 g twice daily or placebo for 12 weeks showed no differences in bronchial hyperresponsiveness 70.A few researchers have attempted to study the effects of paracetamol on asthmatic patients (adult and paediatric) in RCTs. Ioannides et al. 70 randomized adults with mild‐to‐moderate asthma to placebo or paracetamol 4 g d–1 for 12 weeks, then submitted them to a http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7438 challenge test. Airway hyperresponsiveness was similar in both groups (amount of methacholine required to reduce FEV1 by 20%, paracetamol group – placebo was −0.48 mg ml–1, 95% CI –1.28 to – 0.32) but this study was notably underpowered (n = 94; recommended sample size 650) 70. More recently, Sheehan et al. 71 conducted an RCT in which they randomized children aged 0.5–5 years to receive either paracetamol or http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2713 for analgesia/antipyresis over the following 48 weeks. Participants received a mean of 5.5 doses (range 1–15), with no between‐group differences. The RR for asthma exacerbations was similar between the two groups, and there were no significant differences in secondary outcomes (asthma‐controlled days, unscheduled care, use of rescue medication), indicating that, at least in mild‐to‐moderately asthmatic children, paracetamol was as safe to use as ibuprofen 71.Overall, there is evidence of a weak association of paracetamol use with asthma, but causation cannot be established. RCTs are limited, but seem to provide reassurance that paracetamol is safe to use in patients with established asthma 70, 71, 72.Gastrointestinal (GI) effectsThe acute effects on the liver of paracetamol in overdose have been well documented 73, 74, 75. However, the effect of chronic therapeutic‐dose paracetamol use on the liver and GI system in general is less clear. Concerns are generally focused around GI blood loss and chronic hepatotoxicity.GI bleedingParacetamol has long been considered the ‘safe’ analgesic alternative to NSAIDs in patients prone to GI bleeding. Indeed, in studies of the analgesic effects of NSAIDS it is commonly used as a comparator, owing to the ethical issues of withholding analgesia 76, 77, 78. There is some evidence to support the safety of paracetamol. Examining adverse events reported in the Spanish drug monitoring system, Carvajal et al. 79 found that paracetamol use was associated with nausea (3.3% of all reported adverse events) and dyspepsia (4.2%), but not GI bleeding. Furthermore, a meta‐analysis of individual patient data from three case–control studies, looking at the risk of GI bleeding with individual NSAIDs, included paracetamol as a comparator and found no increased risk of GI bleeding with increasing daily doses of paracetamol 80.However, recent epidemiological studies have identified a potential increased risk of upper GI bleeding with doses of paracetamol ≥2–3 g d–1. In 2001, a case–control study was conducted using the UK's General Practice Research Database (GPRD) 81. Adults aged 40–79 years with no history of prior GI disease or alcohol misuse (n = 13 605) were followed up between 1993 and 1998. The incidence of upper GI complications was documented, as was the prescription of paracetamol and potentially confounding medications. Compared with nonusers of paracetamol, users of ≤2 g d–1 did not have a significant increase in GI complications. However, use of >2 g d–1 had an adjusted RR (95% CI) of 3.6 (2.6 to 5.1). When this analysis was confined to those patients with no prior NSAID prescription or antecedents of GI disorders (e.g. dyspepsia), the adjusted RR was 5.7 (2.0 to 16.4). When combined with NSAID, the risk increased to 13.2 (9.2 to 18.9), indicating a substantial interaction. It is important to recognize the potential influence of channelling bias in this instance (NSAIDS are not prescribed to those at risk of upper GI bleeding unless necessary, so high‐risk patients may be disproportionately prescribed paracetamol). The authors tried to compensate for this by excluding a history of Mallory–Weiss tear, cancer, oesophageal varices, coagulopathy or alcohol‐related disease, and adjusting the RR for age, smoking, upper GI risk factors and concomitant medications, but this (they admitted) cannot exclude all bias. Additionally, the study was of prescriptions, not ‘real‐world’ use. The authors had no data on OTC use of paracetamol by patients, and the daily dose was calculated from prescription frequencies, both of which have the potential to confound the results (although would not explain the apparent dose–response relationship found). The same group later published a follow‐up examination of the link between GI complications and paracetamol in the GPRD 82, and found a pooled RR of 1.3 (1.1 to 1.5). Furthermore, in users of ≥2 g d–1, the RR was 3.6 (2.6 5.1). They did not detect evidence of heterogeneity or publication bias.In 2008, a study of GI‐related hospitalisation in elderly patients in Quebec examined the effect of NSAIDs, paracetamol ≤3 g d–1, paracetamol >3 g d–1, and proton pump inhibitors (PPI) 83. Using paracetamol ≤3 g d–1 as the reference population, they found hazard ratios (HRs) for GI‐related hospitalization of 1.2 (95% CI 1.03 to 1.40) for paracetamol >3 g d–1, 1.63 (95% CI 1.44 to 1.85) for NSAID, and 2.55 (95% CI 1.98 to 3.28) for combined usage. With the use of a PPI, the hazards became nonsignificant except in the combined usage group [HR 2.15 (95% CI 1.35 to 3.40)]. These data would suggest that elderly patients taking paracetamol with or without concomitant NSAID are at risk of GI‐related hospitalization. The authors hypothesize that the additional, weak, nonspecific COX inhibition from paracetamol could have an additive effect to that of NSAIDs, creating an increased risk of gastric mucosal injury when used together.Early RCTs in this area appeared to give reassuring results. One crossover study examining the effects of 7 days of paracetamol, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4795 or placebo on endoscopic appearances found no acute effects of paracetamol on the GI mucosa 84. However, more recent RCTs have been less reassuring. In 2011, Doherty et al. 76 examined the effects of paracetamol (3 g d–1), ibuprofen (1200 mg d–1) and a combination of the two (ibuprofen 600 mg/paracetamol 1.5 g daily, or twice this dose) for chronic knee pain in a parallel‐group RCT of 892 patients. Although the study was powered to detect differences in analgesic effect [a 5.5‐point reduction in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale], they also collected data on adverse events. After 13 weeks, they examined the proportion of the groups that had a decrease in haemoglobin of ≥1 g dl–1. This was 19.6% in the ibuprofen group, 20.3% for paracetamol, 24.1% for the low‐dose combination and 38.4% for the high‐dose combination, which was significantly different to the other three groups. As there was also a small but significant drop in platelet count, and an increase in mean cell volume, the authors suggested that the haemoglobin decrease was likely to be due to occult GI blood loss. They concluded that paracetamol 3 g d–1 and ibuprofen 1200 mg d–1 were associated with similar amounts of occult blood loss, and that there was an additive effect in the higher‐dose combination. More recently, in 2016, the authors of the PERFORM trial (Prevention of cerebrovascular and cardiovascular Events of ischaemic origin with teRutroban in patients with a history oF ischaemic strOke or tRansient ischaeMic attack) examined the effects of paracetamol and ibuprofen on cardiovascular effects and bleeding using a nested case–control study within their cohort of 19 120 participants with recent ischaemic stroke 85. A total of 800 cases were paired with 1600 controls, and the incidence of bleeding (in general, but including intracerebral haemorrhage or intraocular bleed) was recorded. They found that the use of ≥3 g d–1 was associated with bleeding events [OR 3.72 (95% CI 1.58 to 8.75)]. Doses of ≤3 g d–1 were not associated with significant risk, but the trend test was significant (P = 0.02), indicating a dose–response relationship.Based on these data, it seems that when taken regularly at doses of >2–3 g d–1 (i.e. at daily doses normally seen in chronic use), there is a significant risk of GI bleeding with paracetamol. The dose–response relationship seen in some of the studies would indicate that something in the mechanism of action of paracetamol can cause GI bleeding as an adverse effect, and that this effect is additive when combined with NSAIDs.HepatotoxicityOver the past few decades, there have been several case reports and small studies implying a connection between the ingestion of therapeutic doses of paracetamol and liver injury 86. It has been known for many years that therapeutic paracetamol use (≤4 g d–1) has been associated with subclinical rises in liver injury markers 74. However, transient rises in alanine aminotransferase (ALT) can be secondary to many factors, such as exercise, vitamin intake, congestive heart failure, diabetes and medications such as aspirin, heparins and statins 87, 88. Whether such an enzyme rise results in clinically significant liver injury is less clear. Heard et al. 89 looked at this issue with healthy volunteers in an RCT of long‐term paracetamol ingestion (dose 4 g d–1). They found that ~50% of the paracetamol group experienced no ALT rise, ~25% had a transient rise, which was gone by day 16, and ~25% had ALT normalize by day 40 89. These findings are consistent with those from Dart and Bailey's review of observational data in >40 000 patients, showing a low incidence of transaminitis (0.4–1.0%) and no progression to hepatotoxicity 90.Of those case reports of liver injury in patients taking therapeutic doses, additional factors such as alcohol abuse, nutritional deficiency or concurrent febrile illness are usually present 91. As the toxic metabolite of paracetamol NAPQI is produced via CYP metabolism (predominantly the http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1330 isoenzyme), clinicians have hypothesized that induction of these enzymes through alcohol misuse might predispose patients to liver injury. This appeared to be supported by animal studies showing that CYP2E1 was induced by ethanol in rodents, and that levels of NAPQI and hepatotoxicity were increased when paracetamol was administered 86. However, researchers have failed to replicate this finding in humans, and have found evidence of the opposite: CYP2E1 appears to increase only modestly with short‐term alcohol use, reversing soon after abstinence 86, and one examination of cirrhotic livers found them to have 59% less CYP2E1 than control samples 92. In addition, NAPQI levels are not increased in chronic alcoholics taking paracetamol and, although the drug's half‐life is prolonged in chronic liver disease, this does not significantly affect metabolism or lead to NAPQI accumulation/hepatotoxicity 86, 93. Similarly, taking CYP‐inducing medication (such as rifampicin and CYP‐inducing anticonvulsants) does not seem to lead to an increased production of NAPQI when paracetamol is taken at therapeutic doses 94. This has led some researchers to hypothesize that glutathione depletion may be the causal factor in those few cases where therapeutic‐dose paracetamol has resulted in liver injury 91. Glutathione must be >70% deplete before NAPQI starts to accumulate, but in a starvation state (such as that seen in some alcoholics) this could occur. Indeed, it is known that chronic alcohol misuse is associated with glutathione deficiency 95. Despite these concerns, owing to its lack of a direct effect on coagulation (although there is evidence that a dose of 4 g day–1 taken for 2 weeks raises the international normalized ratio of patients taking warfarin by ~0.8 96) and (apparent) GI safety profile, paracetamol remains the first‐line analgesic of choice for patient with chronic liver disease 97. There does not seem to be evidence for therapeutic paracetamol treatment causing hepatotoxicity, either in healthy individuals or chronic liver disease patients, with the exception of those in a poor nutritional state 98, 99.Hepatotoxicity in childrenChildren metabolize paracetamol differently to adults 100, and there is some concern that they may also suffer as a result of ingestion of therapeutic doses of paracetamol. This prompted Lavonas et al. 87 to perform a systematic review in 2010, examining 62 studies and >32 000 children receiving therapeutic‐dose paracetamol (≤75 mg kg–1 d–1, up to a maximum of 4 g d–1) for an average of 3–5 days. The range of settings (inpatient, outpatient, primary care, developed and developing world) and indications for paracetamol (infective illness, postoperative pain) was comprehensive. In their analysis, no child showed symptoms of liver disease, and only 10 showed any hepatic adverse events at all (incidence 0.031%, 95% CI 0.015 to 0.057%). They concluded that short‐term, therapeutic dose paracetamol is not associated with significant hepatotoxicity.Renal effectsAcute kidney injury is said to occur in 1–2% of patients in paracetamol overdose 101 and most commonly occurs in the setting of severe paracetamol‐induced hepatotoxicity 102. Renal biopsy, while not often performed, shows evidence of acute tubular necrosis, particularly of the proximal tubule 101. While the explanation for hepatotoxicity is well known 18, the causes of renal toxicity are less clear: possible reasons include the local generation of NAPQI or other toxic metabolites from paracetamol by CYP or COX enzymes 103. Administration of N‐acetylcysteine has no effect on peak creatinine concentration, suggesting that the depletion of glutathione stores is not the sole cause of renal toxicity 104, 105. The clinical outcome from paracetamol‐induced nephrotoxicity in the absence of concomitant liver failure is good, with only 1% of patients needing temporizing dialysis and most patients returning to baseline renal function within 1 month 101.Analgesic nephropathy is characterized by interstitial nephritis and progressive reduction in renal size due to repeated episodes of papillary necrosis. The association between the analgesic phenacetin and nephropathy was first described in 1953 106, and by the 1970s analgesic nephropathy was reported to be responsible for at least 10–20% of cases of chronic renal failure in the UK and Australia 106. Despite phenacetin's withdrawal from sale in the 1980s, analgesic nephropathy has not been eradicated, suggesting that other agents may also be responsible 107, 108. As the major active metabolite of phenacetin is paracetamol 109, some questioned whether chronic paracetamol use might also cause chronic kidney disease. In 1994, Perneger et al. 110 studied 716 subjects with end‐stage renal disease (ESRD) and found that this was associated with an increase in paracetamol use in a dose‐dependent fashion, with ~10% of the overall incidence of ESRD attributable to paracetamol use. The study unfortunately failed to adjust for possible previous use of phenacetin and NSAIDs, bringing its results into question. A large review in 2000, requested by the regulatory authorities of Germany, Switzerland and Austria, examined all published data on nonphenacetin analgesic nephropathy 111. Overall, its findings were that there was insufficient evidence to claim that nonphenacetin‐containing analgesics were causally associated with nephropathy, suggesting that further research was required 111.PregnancyParacetamol is administered to pregnant women as an antipyretic agent and for the management of mild‐to‐moderate pain. The presumed safety of this agent has resulted in paracetamol becoming one of the most common prescriptions in pregnancy: ~50–60% of pregnant women in North and Western Europe self‐report using this medication 112. Its popularity is mainly due to the recommendation of paracetamol over other analgesics, with NSAIDs having a less favourable risk profile in pregnant women, and use of aspirin limited due to concerns over its effect on the fetus 113, 114.In recent years, the safety of paracetamol in pregnancy has come under increasing scrutiny. Paracetamol and its metabolites cross the placenta 115 and undergo different pharmacokinetic/pharmacodynamic processes in neonates than in adults; an immature glucuronide conjugation system makes the sulphation pathway the major route of metabolism in neonates 116. Paracetamol has been postulated to cause a diverse range of embryo–fetal and neonatal adverse effects, dependent on dose, duration of treatment and the trimester of exposure. However, large cohort studies have not found an association between maternal paracetamol use in the first trimester and either adverse pregnancy outcomes or congenital malformations 117, 118. Nevertheless, there is some evidence of increased risk with paracetamol use in pregnancy and neurodevelopmental disorders, respiratory illness and reproductive toxicity.Neurodevelopmental effectsThe association between paracetamol exposure in utero and the risk of long‐term neurological disorders has been the focus of several controversial pharmaco‐epidemiological studies. Brandlistuen et al. 119 suggested that maternal paracetamol use for >28 days during pregnancy was associated with problems in gross motor development, communication, externalizing and internalizing behaviour, and higher activity levels, when compared with controls. These data were obtained from a Norwegian sibling‐controlled study (n = 2919) and based on parental reports of child behaviour at 18 months and 36 months. Notably, the group also reviewed ibuprofen exposure, to control for possible confounders arising from paracetamol indication, and concluded that ibuprofen exposure was not associated with adverse neurodevelopmental outcomes. There was no relationship between trimester of exposure to paracetamol and any of the above outcomes.Maternal paracetamol use was later linked to a neurodevelopmental clinical outcome in the Danish National Cohort Study. Liew et al. 120 suggested that maternal paracetamol use during pregnancy was associated with a higher risk of receiving a hospital diagnosis of hyperkinetic disorder (HR 1.37, 95% CI 1.19 to 1.59), use of attention‐deficit/hyperactivity disorder (ADHD) medications (HR 1.29, 95% CI 1.15 to 1.44) or having ADHD‐like behaviours at age 7 years (HR 1.13, 95% CI 1.01 to 1.27). The strengths of this flagship study lie in its large sample size (n = 64 322) and adjustment for a large number of potential confounders. Notably, these associations were stronger with increased frequency of paracetamol use and were not confounded by maternal inflammation or infection during pregnancy. Using hospital outcome coding data in the same patient cohort, the group later identified an association between prenatal paracetamol use and an increased risk of autistic spectrum disorder (ASD) accompanied by hyperkinetic symptoms (HR 1.51, 95% CI 1.19 to 1.92), but not with other ASD cases 121; other studies have suggested an association with ASD symptoms in male offspring only, with associations dependent on the frequency of exposure 122.The mechanism by which paracetamol and its metabolites may affect neurological development is poorly understood. Animal studies have reported behavioural and cognitive changes in mice given paracetamol during neonatal brain development – specifically, locomotor activity and attainment of spatial learning 123. Levels of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4872 (BDNF) in the neonatal brain were affected (significantly increased in the frontal, and decreased in the parietal, cortices), postulating that this may be the mechanism of action. The role of BDNF in development and brain maturation has been extensively reviewed elsewhere 124.In conclusion, on the basis of these studies, only weak associations between paracetamol exposure and neurodevelopmental issues have been identified, and no causal link can be inferred. The epidemiological studies that support a link are subject to confounding by unmeasured environmental factors, recall bias, diagnostic inaccuracy (most rely on coding data or parental recall for their outcomes) and differences in drop‐out rates. Notably, few studies confirm the effect of duration and timing of paracetamol exposure, details that are critical in the assessment of toxicological risk in pregnancy.AsthmaThe potential mechanisms by which paracetamol may contribute to the development/exacerbation of asthma have been described earlier. How paracetamol exposure in utero could cause asthma is less clear, unless glutathione levels are lowered sufficiently in the fetus to affect lung development. Some support for maternal intake of paracetamol affecting offspring comes from mouse studies, where adult mice exposed to paracetamol in utero underwent an allergic airway challenge 125. Increased airway infiltration by leukocytes (notably eosinophils) was observed, suggesting an increased susceptibility to asthma, but this finding has not been consistently reproduced 126.The Avon Longitudinal Study of Parents and Children was one of the first epidemiological studies to examine the causal link between paracetamol exposure during pregnancy and childhood asthma 127. Frequent paracetamol use in late pregnancy (20–32 weeks) was associated with an increased risk of wheezing in the offspring at 30–42 months (adjusted OR 2.10, 95% CI 1.30 to 3.41), particularly if wheezing started before 6 months (termed ‘persistent wheezers’ – OR 2.34, 95% CI 1.24 to 4.40). Two further cohort studies suggested that paracetamol use during any time of pregnancy was associated with a small increased risk of asthma or bronchitis among children at 18 months (RR 1.17, 95% CI 1.13 to 1.23) and 7 years (RR 1.15, 95% CI 1.02 to 1.29) 128, 129. Interestingly, maternal pain showed a positive association with asthma development without the use of paracetamol 129.However, maternal infections, including respiratory infections, have already been associated with an increase in childhood asthma 130, 131. Paracetamol use may simply be a surrogate for these disease states. Notably, maternal paracetamol use for non‐infectious disorders revealed no increased risk of wheezing in children 132. Further studies expanded on this theme of confounding by paracetamol indication and have highlighted that the increased risk of asthma diagnosis in children exposed to paracetamol prenatally (unadjusted OR 1.36, 95% CI 1.14 to 1.61) drops significantly (OR 1.26, 95% CI 1.02 to 1.58) when adjusted for potential confounders 133. For an in‐depth review of paracetamol exposure and asthma in children, and the issue of confounding, see elsewhere 60. Further clarification of this issue will be difficult, as RCTs would be both unethical and impractical 52.Endocrine and reproductive toxicityThe incidence of cryptorchidism is reportedly increasing, which is particularly concerning given its association with early adulthood disorders such as low sperm count and testicular germ cell cancers 134. When considered together, these conditions represent a testicular dysgenesis syndrome, a disorder related to androgen disruption during the fetal programming window 135. Experimental data have shown reduced testicular PG and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2858 production and reduced ano–genital distance (a marker for androgen action) in rats prenatally exposed to paracetamol 136. Prenatal paracetamol exposure is likely to result in a reduction in key steroidogenic enzymes (http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1358, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1361), implicated in the reduced fetal plasma testosterone (45% reduction; P = 0.025) and seminal vesicle weight (18% reduction; P = 0.005) 137. These changes were noted in castrated host mice bearing human fetal testis xenografts following exposure to therapeutic doses of paracetamol for 7 days. Notably, however, exposure for 1 day had no effect 137. Another recent study has linked reduced germ cell development in human fetal testes and ovary xenografts when exposed to paracetamol; this effect was linked to PGE2‐mediated alterations in epigenetic regulatory genes, indicating that the effect of paracetamol on the fetus may affect the genetics of subsequent generations 138.Several clinical studies associate paracetamol exposure during pregnancy with increased occurrence of cryptorchidism, particularly when used in for >2 weeks in the second trimester 136, 139, 140. Few of these studies considered indication for paracetamol use in their analyses, and, latterly, reanalysis of these data sets showed slightly lower HRs for paracetamol exposure during weeks 8–14 among women who did not report an illness that would trigger weak analgesic use 141. This is an interesting paradoxical observation, given that this time frame represents the human fetal programming window, disruption of which has previously been linked to reduced male infant ano–genital distance 135, 142. However, we should also note that several large cohort studies have not identified any association between paracetamol and cryptorchidism 117, 143, 144, 145. Indeed, the use of paracetamol may decrease the risk of selected congenital abnormalities when used for febrile illness 144.The continuing search for evidence that paracetamol causes harm in pregnancy clearly highlights the difficulty in implying causation from pharmaco‐epidemiological studies. Extrapolation of preclinical toxicology data to humans may suggest associations with asthma, ADHD and androgen disruption but the small associations seen in clinical cohort studies may be explained by various confounders and biases inherent in the study designs. Confidently teasing apart these issues would require RCTs, which would be difficult to perform ethically in pregnant populations. Carefully designed, long‐term, sibling‐ and sex‐matched cohort studies are more ethically acceptable, and would further our understanding of the risks. While the evidence base is uncertain, care should be taken to avoid raising poorly founded concerns among pregnant women because of the risk of switching to other analgesic/antipyretic drugs with less favourable risk profiles 113. Untreated febrile illness is associated with severe harm to both mother and child, posing a far greater risk than that postulated for paracetamol exposure 130, 146, 147, 148. Practical advice would be to avoid the protracted use of paracetamol for nonfebrile illness, a view shared by many study authors 137, 149.DiscussionClearly, there remains considerable uncertainty regarding the chronic adverse effects of paracetamol use. The evidence base in each of the above sections relies mostly on observational and cohort studies, and so is prone to inherent biases. The positive associations found in these studies are generally weak, and often contradictory. Few RCTs have been performed but, when undertaken, usually give reassuring results. Further studies are required in many areas, but RCTs may be difficult to perform, either because they would need to be very large to detect the modest increases in risk seen in the observational studies, or because of the significant ethical issues of using placebo in patients in pain, as well as of conducting trials in children and pregnant women.The two areas in which the evidence is most convincing are hypertension and GI bleeding. A small BP rise of 4 mmHg would be clinically important at the population level, and the outcome of ongoing RCTs should clarify the reliability of this estimate. This may be particularly important in patients with angina or pre‐existing hypertension. The fairly consistent evidence for GI bleeding associated with paracetamol use, along with its additive effect when combined with NSAIDs, may be less well known but similarly important. When considering prescribing paracetamol in the chronic setting it would seem wise to consider these adverse effects, based on current data, and discuss them with the patient.Whether paracetamol use in the chronic setting should be restricted is doubtful, given that the alternatives are NSAIDs and opioids. Indeed, in patients intolerant of NSAIDs, their next option would be opioid medication, which comes with risks of addiction, drowsiness and fatal accidental overdose.In summary, the average therapeutic effect for chronic pain syndromes is small, but there is accumulating evidence of clinically significant adverse effects in chronic use. Despite this, for patients who derive clear symptomatic benefit, or only take occasional therapeutic doses, the risks are probably very small. For this reason, paracetamol can be seen as the ‘least‐worst’ option – which probably means that it will remain, for now at least, the first‐line analgesic of choice.ConclusionThe present review is designed to provide an objective summary of the evidence base for chronic adverse effects of paracetamol use. We hope that by highlighting the key epidemiological studies, RCTs, meta‐analyses and reviews, we have provided a valuable summary of knowledge in this field. We hope this work will help clinicians and their patients to make an evidence‐based, informed decision regarding their chronic pain management, based on the likelihood of clinically relevant adverse effects.Nomenclature of targets and ligandsKey protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 150, and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 151, 152, 153.Competing InterestsThere are no competing interests to declare.Notes

McCrae, J. C.

,

Morrison, E. E.

,

MacIntyre, I. M.

,

Dear, J. W.

, and

Webb, D. J.

(2018) Long‐term adverse effects of paracetamol – a review. Br J Clin Pharmacol, 84: 2218–2230. 10.1111/bcp.13656. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

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Paracetamol Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD

Paracetamol Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD

Skip to main content Home Conditions Back Conditions View All ADD/ADHDAllergiesArthritisAtrial fibrillationBreast CancerCancerCrohn's DiseaseDepressionDiabetesDVTEczemaEye HealthHeart DiseaseHIV & AIDSLung DiseaseLupusMental HealthMultiple SclerosisMigrainePain ManagementPsoriasisPsoriatic ArthritisRheumatoid ArthritisSexual ConditionsSkin ProblemsSleep DisordersUlcerative Colitis View All Drugs & Supplements Back Drugs & SupplementsDrugsSupplementsPill IdentifierInteraction CheckerWell-Being Back Well-Being View All Aging WellBabyBirth ControlChildren's HealthDiet & Weight ManagementFitness & ExerciseFood & RecipesHealthy BeautyMen's HealthParentingPet HealthPregnancySex & RelationshipsTeen HealthWomen's Health View All Symptom CheckerFind a DoctorMore Back MoreNewsBlogsPodcastsWebinarsNewslettersWebMD MagazineBest HospitalsSupport GroupsOrthopedics Privacy & More Subscribe Log In Search Subscribe MENU DRUGS AND MEDICATIONS CENTERFind a DrugMy MedicinePill IdentifierInteraction CheckerFind a VitaminFind a PharmacyVITAMINS & SUPPLEMENTS CENTERFind a Vitamin or SupplementVitamin Lifestyle GuideAssess Your Vitamin NeedsFIRST AID RESOURCESFirst Aid HomeFirst Aid Kit & Wound CareFirst Aid Mobile Drugs & Medications Paracetamol TabletParacetamol Tablet - Uses, Side Effects, and More Generic Name(S): acetaminophenUsesSide EffectsWarningsPrecautionsInteractionsOverdoseImages Reviews (17) Uses This drug is used to treat mild to moderate pain (from headaches, menstrual periods, toothaches, backaches, osteoarthritis, or cold/flu aches and pains) and to reduce fever. How to use Paracetamol TabletTake this product by mouth as directed. Follow all directions on the product package. If you have any questions, ask your doctor or pharmacist.There are many brands and forms of acetaminophen available. Read the dosing instructions carefully for each product because the amount of acetaminophen may be different between products. Do not take more acetaminophen than recommended. (See also Warning section.)If you are giving acetaminophen to a child, be sure you use a product that is meant for children. Use your child's weight to find the right dose on the product package. If you don't know your child's weight, you can use their age.For suspensions, shake the medication well before each dose. Some liquids do not need to be shaken before use. Follow all directions on the product package. Measure the liquid medication with the provided dose-measuring spoon/dropper/syringe to make sure you have the correct dose. Do not use a household spoon.For rapidly-dissolving tablets, chew or allow to dissolve on the tongue, then swallow with or without water. For chewable tablets, chew thoroughly before swallowing.Do not crush or chew extended-release tablets. Doing so can release all of the drug at once, increasing the risk of side effects. Swallow the tablets whole.For effervescent tablets, dissolve the dose in the recommended amount of water, then drink.Pain medications work best if they are used as the first signs of pain occur. If you wait until the symptoms have worsened, the medication may not work as well.Do not take this medication for fever for more than 3 days unless directed by your doctor. For adults, do not take this product for pain for more than 10 days (5 days in children) unless directed by your doctor. If the child has a sore throat (especially with high fever, headache, or nausea/vomiting), consult the doctor promptly.Tell your doctor if your condition lasts or gets worse or if you develop new symptoms. If you think you may have a serious medical problem, get medical help right away. Side Effects See also Warning section.This drug usually has no side effects. If you have any unusual effects, contact your doctor or pharmacist promptly.If your doctor has directed you to use this medication, remember that your doctor has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345. Warnings Taking too much acetaminophen may cause serious (possibly fatal) liver disease. Adults should not take more than 4000 milligrams (4 grams) of acetaminophen a day. People with liver problems and children should take less acetaminophen. Ask your doctor or pharmacist how much acetaminophen is safe to take.Do not use with any other drug containing acetaminophen without asking your doctor or pharmacist first. Acetaminophen is in many nonprescription and prescription medications (such as pain/fever drugs or cough-and-cold products). Check the labels on all your medicines to see if they contain acetaminophen, and ask your pharmacist if you are unsure.Get medical help right away if you take too much acetaminophen (overdose), even if you feel well. Overdose symptoms may include nausea, vomiting, loss of appetite, sweating, stomach/abdominal pain, extreme tiredness, yellowing eyes/skin, and dark urine.Daily alcohol use, especially when combined with acetaminophen, may damage your liver. Avoid alcohol. Precautions See also Warning section.Before taking acetaminophen, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this product, tell your doctor or pharmacist your medical history, especially of: liver disease, regular use/abuse of alcohol.Liquid products, chewable tablets, or dissolving/effervescent tablets and powders may contain sugar or aspartame. Caution is advised if you have diabetes, phenylketonuria (PKU), or any other condition that requires you to limit/avoid these substances in your diet. If you have any of these conditions, ask your doctor or pharmacist about using these products safely.Tell your doctor if you are pregnant before using this medication.Acetaminophen passes into breast milk. Consult your doctor before breast-feeding. Interactions See also Warning section.Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.Some products that may interact with this drug are: ketoconazole, levoketoconazole.This medication may interfere with certain lab tests, possibly causing false test results. Make sure lab personnel and all your doctors know you use this drug. Does Paracetamol Tablet interact with other drugs you are taking? Enter your medication into the WebMD interaction checker Check Interaction Overdose If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: nausea, vomiting, loss of appetite, sweating, stomach/abdominal pain, extreme tiredness, yellowing eyes/skin, dark urine.Notes Notes Acetaminophen does not cause the stomach and intestinal ulcers that NSAIDs such as aspirin, ibuprofen, and naproxen may cause. However, acetaminophen does not reduce swelling (inflammation) like the NSAIDs do. Consult your doctor for more details and to see which medication might be right for you.Missed Dose Missed Dose If you are taking this medication on a regular schedule and miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.Storage Storage Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company. Images NextYou Might Also LikeTake Control of Your Migraine, NowPainkillers and Opioid Use DisorderBotox Injections for MigrainesWhat to Know About CBD Oils, Gummies, & MoreTreating Psoriatic Arthritis With Ixekizumab: What to KnowPain During a Sickle Cell Crisis: An Advocate Explains Side Effects From aHUS TreatmentExplore Medicare Advantage & Prescription Drug Coverage Search Drugs Related Drugs Common Searches AdderallCelexaCiproCymbaltaFlexerilHydrocodonePrilosecProzacSeroquelSynthroidTramadolTrazodoneLexaproLisinoprilMobicNaproxenNeurontinPradaxaPrednisoneVicodinWarfarinWellbutrinXanaxZocorZoloft Show More Show Less Select a condition to view a list of medication options paina toothachepain with menstruationheadachepain associated with arthritisbackachemuscle painfever Drug Survey Have you ever purchased Paracetamol Tablet? Yes, In the past 3 monthsYes, In the past 6 monthsYes, In the past yearHaven't purchased but consideringDon't plan to purchase This survey is being conducted by the WebMD marketing sciences department. Selected from data included with permission and copyrighted by First Databank, Inc. This copyrighted material has been downloaded from a licensed data provider and is not for distribution, except as may be authorized by the applicable terms of use. CONDITIONS OF USE: The information in this database is intended to supplement, not substitute for, the expertise and judgment of healthcare professionals. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for you or anyone else. A healthcare professional should be consulted before taking any drug, changing any diet or commencing or discontinuing any course of treatment. More on Drugs & MedicationsDrug Recalls: What Do They Mean?Choosing an OTC Pain Reliever: What to ConsiderIs Your Medication Making You Tired?More About Drugs and MedicationsPill IdentifierInteraction CheckerDrugs and Medications A-ZDrugs and Medical ConditionsFDA Labeling for Paracetamol oral on RxListLatest Drug NewsFind a Pharmacy Find a Vitamin PoliciesPrivacy PolicyCookie PolicyEditorial PolicyAdvertising PolicyCorrection PolicyTerms of UseAboutContact UsAbout WebMDCareersNewsletterCorporateWebMD Health ServicesSite MapAccessibilityOur AppsWebMD MobileWebMD AppPregnancyBabyAllergyFor AdvertisersAdvertise with UsAdvertising Policy © 2005 - 2024 WebMD LLC, an Internet Brands company. All rights reserved. WebMD does not provide medical advice, diagnosis or treatment. See additional information.

Drug Office - Paracetamol

Drug Office - Paracetamol

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News & Information > Health and Drug Education > Knowledge on Medicines > Tips for Using Medicines Containing Paracetamol

Tips for Using Medicines Containing Paracetamol

Paracetamol (or acetaminophen) is a common medicine ingredient used for symptomatic relief of fever and pain. There are also multiple ingredients preparations containing paracetamol and other medicine ingredients for symptomatic relief of cold and flu. Although oral preparations and suppositories containing paracetamol are generally over-the-counter medicines, which could be purchased without a doctor’s prescription, members of the public should seek advice from healthcare professionals before taking any medicines. To assist members of the public to differentiate these registered products containing paracetamol, a list of these products has been posted in the website of the Drug Office, DH:

https://www.drugoffice.gov.hk/eps/do/en/doc/List_of_registered_pharmaceutical_products_containing_paracetamol.pdf

Members of the public should take note of the following when taking any medicines containing paracetamol.

Medicines containing Paracetamol

Medicines containing paracetamol are generally supplied for oral use in tablets, capsules, solutions and powder for oral solution.

Oral solid preparations, e.g. tablets or capsules, have different quantities and are generally for adults and children over 12.

Oral liquid preparations, e.g. solutions or powder for oral solution, are generally for children 12 or below. It is important to note that the dose of paracetamol for children is dependent on their body weight and the concentration of liquid preparation. Parents should measure the right amount using oral syringe or dosing spoon according to instructions as stated in the product package or insert.

Medicines containing paracetamol are also available as suppositories, mainly for infants.

Members of the public should read the instructions as stated in the product package or insert, and to seek advice from healthcare professionals, before using paracetamol-containing medicines.

Precautions

People who are allergic to paracetamol should not take medicines containing paracetamol.

People with kidney disease, liver disease or taking anticoagulants (e.g. Warfarin) are advised to consult healthcare professionals before using medicines containing paracetamol.

Overdose of paracetamol may cause serious liver injury, therefore, a normal adult should not consume more than 4,000mg of paracetamol within 24 hours (for a tablet containing 500mg paracetamol, the maximum daily intake for a normal adult is 8 tablets). Children or persons with certain disease conditions should take a lower dose either in accordance with product package or insert and/or advice from healthcare professionals. People who are underweight or malnourished should consult a doctor before using medicines containing paracetamol.

Members of the public should monitor their health condition and seek advice from healthcare professionals if fever persists for more than 3 days after taking paracetamol.

Do not take with other products containing paracetamol unless advised by healthcare professionals.

Drug Office

Department of Health

Dec 2023

What’s the point of paracetamol? | University of Oxford

What’s the point of paracetamol? | University of Oxford

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HomeResearchWhat’s the point of paracetamol?

What’s the point of paracetamol?

Andrew Moore, Honorary Senior Research Fellow, University of OxfordParacetamol has been around for over 50 years. It’s safe and many guidelines recommend it as the go-to treatment. At least, that’s the conventional view of the drug. It’s a view so ingrained that it’s rarely questioned. The trouble is that the conventional view is probably wrong.Huge amounts of paracetamol are used to treat pain, measured not in how many tablets are used but in the thousands of tons. For the UK, an estimate of the amount of paracetamol sold is just under 6,300 tonnes a year. That’s 35 tonnes per million of population: 35 grams or 70 paracetamol tablets each, every year.But does it work?The evidence is that it probably does not work at all for chronic pain. Large, good and independent clinical trials and reviews from the Cochrane Library show paracetamol to be no better than placebo for chronic back pain or arthritis. This is at the maximum daily dose in trials lasting for three months, so it has been pretty thoroughly tested.Acute pains are sudden in onset and go away after a while (headache or pain after an operation, for instance). For these, reviews from the Cochrane Library show that paracetamol can provide pain relief, but only for a small number of people. For postoperative pain, perhaps one in four people benefit; for headache perhaps one in ten. This evidence comes from systematic reviews, often of large numbers of good clinical trials.These are robust and trustworthy results. If paracetamol works for you, that’s great. But for most, it won’t.Is it safe?Safety boils down to examining really bad things happening to a very small number of people who take a drug. Unless the rate of the very bad thing is vanishingly small, the authorities won’t let us buy the drug from a petrol station. If we want to study those rare events, then we need study large numbers of people. Partly because paracetamol is such an old drug these studies have largely not been done until recently.Those we have tell us that paracetamol use is associated with increased rates of death, heart attack, stomach bleeding and kidney failure. Paracetamol is known to cause liver failure in overdose, but it also causes liver failure in people taking standard doses for pain relief. The risk is only about one in a million, but it is a risk. All these different risks stack up.Are we competent to take analgesics?

Half of a sample of Americans didn’t know that Tylenol contained paracetamol.(Credit: dcwcreations/Shutterstock.com)

There are some scary facts about how much we, as ordinary members of the public, know about painkillers. Here are a few.Many people don’t know what is in their analgesics. A study in a London emergency department found that half of the patients thought ibuprofen contained paracetamol. In the US, half of a similar group did not know that the popular brand of paracetamol, Tylenol, actually contained paracetamol.Most people have no idea of the maximum daily dose of paracetamol. In the UK about one in four people frequently exceed the maximum daily dose (it’s 4,000mg, or eight tablets, by the way). In the US, half did not know the maximum daily dose, and one in 20 thought it as high as 10,000mg.Paracetamol is not just in paracetamol, but all sorts of cold and flu medicines as well, and headache tablets. Around 200m packs of paracetamol are sold without prescription in the UK every year, though sales fell after pack size restriction. In the US it could be one billion (but different pack sizes and tablet doses).The conundrum is what to do with this information for a drug with limited effect but dangerous in overdose. It’s a headache for regulators and licensing authorities, not to mention organisations like NICE trying to help doctors make sensible treatment decisions. Nor is there a simple alternative. Non-pharmacological methods of treating pain are largely without good evidence. Other drugs may work better, but they have side effects too.Let’s not rush to judgement here and dismiss paracetamol entirely. But a rethink is surely timely.This article was originally published on The Conversation. Read the original article.

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Paracetamol (Acetaminophen) - Pharmaceutical Drugs - NCBI Bookshelf

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NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Pharmaceutical Drugs. Lyon (FR): International Agency for Research on Cancer; 1990. (IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans, No. 50.)Pharmaceutical Drugs.Show detailsIARC Monographs on the Evaluation of the Carcinogenic Risks to Humans, No. 50.IARC Working Group on the Evaluation of Carcinogenic Risks to Humans.Lyon (FR): International Agency for Research on Cancer; 1990.ContentsSearch term < PrevNext >

Paracetamol (Acetaminophen)1. Chemical and Physical Data1.1. Synonyms and trade namesChem. Abstr. Services Reg. No.: 103-90-2Chem. Abstr. Name: Acetamide, N-(4-hydroxyphenyl)-Synonyms: 4′-Hydroxy-acetanilide; para-acetaminophenol; acetophenum; para-acetylamidophenol; N-acetyl-para-aminophenol; para-acetylaminophenol; para-hydroxyacetanilide; N-para-hydroxyphenylacetamideA large number of fixed combinations containing paracetamol are available.1.2. Structural and molecular formula and molecular weight

1.3. Chemical and

physical properties of the pure

substanceFrom Fairbrother, (1974) and

El-Obeid

and Al-Badr, (1985)Description:

White odourless crystalline powder; large

monoclinic prisms from

waterMelting-point:

169–170.5

°CSolubility:

Soluble in water (1:70, 1:20 at 100°C), ethanol

(1:7), acetone (1:13), chloroform (1:50), glycerol

(1:40), methanol (1:10), propylene glycol (1:9)

and solutions of alkali hydroxides; insoluble in

diethyl ether. A saturated aqueous solution has a

pH of

~6.Spectroscopy

data: Infrared, ultraviolet, nuclear

magnetic resonance, fluorescence and mass spectra

have been

reported.Stability: Dry, pure paracetamol is stable to 45°C. Contamination with traces of para-aminophenol, and humid conditions that cause hydrolysis to para-aminophenol, result in further degradation and discoloration. Slightly light-sensitive in solution, and degradation is catalysed by acids or bases.Dissociation constant: pKa = 9.0–9.5Partition coefficient: Pc = 6.237 (octanol: pH 7.2 buffer)1.4. Technical products and impuritiesParacetamol is available in pure form as numerous trade-name preparations for oral use. It is also found combined in over 200 preparations with other drugs.Trade names: Abensanil; Acamol; Acephen; Acetalgin; Acetamol; Aferadol; Alba-Temp; Alpiny; Alvedon; Amadil; Anacin-3; Anaflon; Anhiba; Anuphen; Apamide; APAP; Atasol; Ben-u-ron; Bickie-mol; Bramcetamol; Calip; Calpol; Calpon; Campain; Capital; Captin; Ceetamol; Cetadol; Cetamol; Cetapon; Claradol; Claratal; Custodial; Dafalgan; Datril; Dial-a-gesix; Dirox; Disprol Paediatric; Dolamin; Dolanex; Doliprane; Doloral; Dolorol; Dolprone; Dorcol Children's Fever and Pain Reducer; Doregrippin; Dymadon; Efferalgan; Enelfa; Eneril; Ennagesic; Eu-Med; Exdol; Fanalgic; Febrigesic; Febrilix; Fendon; Fevamol; Finimal; Fonafor; Gelocatil; Glenpar; Gynospasmine; Hedex; Homoolan; Kinderfinimal; Kinder-Finiweh; Korum; Liquiprin; Lyteca; Malgis; Melabon; Momentum; Napamol; Naprinol; Nebs; Neuridal; Nevral; Nina 120; Nobedon; Ophinal; Oraphen; Pacemo; Pacemol; Painamol; Painaway; Paldesic; Pamol; Panado; Panadol; Panaleve; Panamax; Panasorb; Panets; Panex; Panodil; Panofen; Pantalgin; Paracet; Paracetamolum; Paraclear; Paralgin; Parapain; Paraprom; Parasin; Paraspen; Paratol; Parmol; Pasolind; Phendex; Pinex; Placemol; Praecimed; Proval; Puernol; Pyragesic; Pyralen; Reliv; Repamol; Resolve; Robigesic; Rounox; Salzone; Schmerzex; Sedapyren; Servigesic; Setamol; SK-APAP; Summadol; Tabalgin; Tachipirina; Tapar; Temlo; Tempra; Tenasfen; Ticelgesic; Tralgon; Treupel; Treuphadol; Tricocetamol; Tylenol; Tymol; Valadol; ZolbenParacetamol is available as 325-mg or 500-mg tablets, which may include calcium stearate or magnesium stearate, cellulose, docusate sodium and sodium benzoate or sodium lauryl sulfate, starch, hydroxypropyl methylcellulose, propylene glycol, sodium starch glycolate, polyethylene glycol and Red #40.It is also available as 500-mg gelatin capsules and as a mint-flavoured liquid containing 500 mg/15 ml solution, which can include 7% ethanol, citric acid, glycerine, polyethylene glycol, sodium benzoate, sorbitol, sucrose, Yellow #6, #10 and Blue #1. For children, drops (80 mg/0.8 ml), chewable tablets (80 mg), elixir (160 mg/5 ml) and coated capsules (160 mg/capsule) are available (Barnhart, 1989).Characteristic impurities may include para-nitrophenol, para-aminophenol, para-chloroaniline, ortho-acetyl paracetamol, azobenzene (see IARC, 1975), azoxybenzene, quinone (see IARC, 1977), quinonimine, inorganic chloride, inorganic sulfate, inorganic sulfide and water (Fairbrother, 1974).2. Production, Occurrence, Use and Analysis2.1. Production and occurrenceParacetamol may be made by acetylation of para-aminophenol (obtained by reduction of para-nitrophenol) with acetic acid or acetic anhydride. A number of other synthetic routes have been described (Fairbrother, 1974).Paracetamol is synthesized in Argentina, Brazil, China, Colombia, France, the Federal Republic of Germany, India, Japan, Mexico, Poland, Republic of Korea, Romania, Taiwan, Turkey, the UK and the USA (Chemical Information Services Ltd, 1989–90).In Sweden, paracetamol sales in 1988 were 20.02 defined daily doses per 1000 inhabitants (Apoteksbolaget, 1988, 1989).Paracetamol is not known to occur naturally, but it is the major metabolite of phenacetin (see IARC, 1980, 1987).2.2. UseParacetamol is used as an analgesic and antipyretic drug. It is the preferred alternative analgesic-antipyretic to aspirin (acetylsalicylic acid), particularly in patients with coagulation disorders, individuals with a history of peptic ulcer or who cannot tolerate aspirin, as well as in children (American Medical Association, 1986). Paracetamol was first used in clinical medicine in 1893. Following initial use as a prescription product in the USA in 1951, it subsequently became available without prescription in 1955 (Ameer & Greenblatt, 1977). In many countries, it is widely available without prescription.The conventional oral dose for adults is 500–1000 mg. Dosing may be repeated every 4 h as necessary, but the total daily dose should not exceed 4000 mg. For children, the recommended dose is 10–15 mg/kg bw; no more than five doses should be administered over 24 h. Prolonged use (for more than ten days) and use for young children is not recommended (Flower et al., 1985).The usual dose for rectal administration is equal to that for oral administration (American Medical Association, 1986).2.3. AnalysisMethods for the analysis of paracetamol have been reviewed (El-Obeid and Al-Badr, 1985).Paracetamol and its metabolites can be analysed in biological fluids by high-performance liquid chromatography (HPLC; Manno et al., 1981; Kinney & Kelly, 1987; Aguilar et al., 1988; Meatherall & Ford, 1988), HPLC-mass spectrometry (Betowski et al., 1987) and fluorescence polarization immunoassay (Koizumi et al., 1988). It can be analysed in pharmaceutical preparations by HPLC (Biemer, 1987) and spectrophotometric (US Pharmacopeial Convention, Inc., 1989) methods.3. Biological Data Relevant to the Evaluation of Carcinogenic Risk to Humans3.1. Carcinogenicity studies in animalsSince paracetamol is a metabolite of phenacetin (Reynolds, 1989), carcinogenicity studies of phenacetin result in exposure of animals to paracetamol. For the results of studies on phenacetin, see IARC (1987).(a) Oral administrationMouse: Groups of 60 male and 60 female young adult IF strain mice were fed paracetamol (> 98% pure; dissolved in acetone then evaporated) at 5000 or 10 000 mg/kg of diet for 18 months (approximate daily intake, 250 or 500 mg/kg bw, respectively). A group of 52 males and 52 females fed basal diet served as controls. Shortly after the beginning of treatment, 33 males and seven females in the higher-dose group died from liver necrosis. Subsequent survival in all groups was high. All survivors were killed at 18 months after the beginning of the experiment, and complete necropsy was carried out with histological examination of the liver, lungs, pancreas, kidneys, spleen, bladder and adrenal glands. The effective numbers of animals were 50 male and 48 female controls, 54 males and 57 females in the lower-dose group and 23 males and 47 females in the higher-dose group. The incidences of large, often multiple liver neoplasms (adenomas and carcinomas combined) were 20/23 (87%: 15 adenomas, 5 carcinomas) in higher-dose males, 9/47 (7 adenomas, 2 carcinomas) in higher-dose females, 1/54 (adenoma) in lower-dose males, 0/57 in lower-dose females, 1/50 (adenoma) in control males and 0/48 in control females (Flaks & Flaks, 1983). [The Working Group noted that the high dose produced early lethal hepatotoxicity in half the males.]Groups of 50 and 55 male or female (C57Bl/6 × C3H/He)Fl (B6C3F1) mice, eight to nine weeks of age, were fed paracetamol (> 98% pure) at 3000 and 6000 mg/kg of diet, respectively. The total intake of paracetamol in the high-dose groups was 863 g/kg bw for males and 675 g/kg bw for females. Two groups of 50 males and females were maintained on basal diet. All survivors were killed at 134 weeks. Survival among males was 43/50 (controls), 39/50 (low-dose) and 45/55 (high-dose), and that among females was 49/50 (controls), 46/50 (low-dose) and 50/55 (high-dose). The numbers of mice scored for tumours were 27/43 control males, 32/49 control females, 21/39 low-dose males, 33/46 low-dose females, 23/45 high-dose males and 33/50 high-dose females. No difference was found in the incidence of tumours at any site between treated and control mice (Arno & Matsuyama, 1985).Groups of 60 and 120 male B6C3F1 mice, six weeks of age, received paracetamol at 5000 or 10 000 mg/kg of diet, respectively, for up to 70 weeks, at which time the remaining animals were killed. A group of 30 mice served as controls. Survival in the high-dose group was less than 50% at 24 weeks and 16% at 72 weeks; in the low-dose group, the survival was greater than 90%. Severe hepatotoxicity was a common finding in mice that died. No increased incidence of neoplasms was observed (Hagiwara & Ward, 1986). [The Working Group noted the poor survival in the high-dose group.]Rat: Groups of 30 male SPF Sprague-Dawley rats, six weeks of age, were fed paracetamol (99.5–99.7% pure) at 0 or 5350 mg/kg of diet for 117 weeks (total paracetamol intake, 86.5 g per rat). All animals were necropsied, and kidneys, urinary bladder, adrenal glands, liver, stomach, spleen, lungs, heart and any grossly abnormal organs or tissues were examined histologically. No significant difference in survival rates was observed. In the treated group, 4/30 rats developed bladder papillomatosis or tumours versus 2/30 controls (Johansson, 1981). [The Working Group noted the relatively small number of animals used in the study.]Groups of 50 male and 50 female Fischer 344/DuCrj rats, five weeks of age were fed pharmacopoeial-grade paracetamol at 0, 4500 or 9000 mg/kg (males) and 0, 6500 or 13 000 mg/kg (females) of diet for 104 weeks and were then observed for a further 26 weeks (average daily intakes: lower-dose males, 195 mg/kg bw; lower-dose females, 336 mg/kg bw; higher-dose males, 402 mg/kg bw; higher-dose females, 688 mg/kg bw), at which time all survivors were killed. Survival rates at 104 weeks varied between 86 and 90% in males and 80 and 82% in females, with no significant difference between treated and control rats. All rats were necropsied, and major organs, tissues and gross abnormalities were examined histologically. No difference was seen in tumour incidence between the groups (Hiraga & Fujii, 1985).Groups of 50 male and 50 female young adult Leeds inbred rats were fed paracetamol (> 98% pure) at 5000 or 10 000 mg/kg of diet for up to 18 months (mean daily intake, 300 and 600 mg/kg bw, respectively), at which time all survivors were killed. A group of 40 males and 40 females fed basal diet alone served as controls. Survival was high: male controls, 40/40; female controls, 40/40; lower-dose males, 48/50; lower-dose females, 49/50; higher-dose males, 45/50; and higher-dose females, 49/50. All animals were necropsied, and samples from each liver lobe, lungs, kidneys, pancreas, mammary glands, spleen, adrenal glands and from grossly visible lesions were examined histologically. No tumour was observed among controls. In treated animals, no hepatocellular carcinoma was observed, but hepatocellular neoplastic nodules occurred in 0/40, 1/48 and 9/45 control, lower-dose and higher-dose males and 0/40, 0/49 and 10/49 control, lower-dose and higher-dose females; and 20–25% of rats in each treated group developed hyperplasia of the bladder epithelium. Bladder calculi were present in about 30% of all treated male animals and in 6% of females; no clear association was seen between hyperplasia and the presence of bladder calculi. Bladder papillomas were observed in 5/49 higher-dose males and bladder carcinomas in 1/49 higher-dose males; the total bladder tumour incidence was significantly higher [p = 0.02, Fisher's exact test] among high-dose males. In the low-dose group, 4/49 females developed bladder papillomas and 1/49 females developed bladder carcinoma. Total bladder tumour incidence was significantly higher in low-dose female rats [p = 0.045, Fisher's exact test] (Flaks et al., 1985). [The Working Group noted that there were increased incidences of calculi, hyperplasia and tumours of the bladder in treated animals but there was no relationship between the presence of calculi and the presence of either hyperplasia or tumours.](b) Administration with known carcinogensMouse: Groups of 30 and 60 male B6C3F1 mice, six weeks of age, received paracetamol at 5000 or 10 000 mg/kg of diet, respectively, continuously for up to 70 weeks following a single intraperitoneal injection of 40 mg/kg bw N-nitrosodiethylamine at four weeks of age. A group of 30 mice that received N-nitrosodiethylamine alone served as controls. Mice were sacrified at either 24 or 72 weeks after injection of the nitrosamine. Survival in the higher-dose group was very poor; severe hepatotoxicity was a common finding in mice that died. No increased incidence of neoplasms was found (Hagiwara & Ward, 1986).Rat: Two groups of 25 or 30 male Fisher 344 rats weighing 150 g were administered N-nitrosoethyl-N-hydroxyethylamine (NEHEA) at 0 or 0.1% (v/v) in drinking-water for two weeks and one week later were fed diets containing paracetamol [purity unspecified] at 1.3% for 29 weeks. One group of 25 rats received NEHEA in the drinking-water followed by no further treatment. All animals were killed at the end of week 32, and samples from liver, kidneys and other organs with gross abnormalities were examined histologically. γ-Glutamyltranspeptidase foci, hyperplastic nodules, hepatocellular carcinomas, renal-cell carcinomas, as well as ‘atypical cell foci’ and adenomas were measured. Paracetamol inhibited the formation of NEHEA-induced γ-glutamyltranspeptidase foci, hyperplastic nodules and carcinomas in comparison with animals treated with NEHEA only. No liver lesion was found in any animal treated with paracetamol only. In contrast, the incidence and multiplicity of preneoplastic renal lesions and renal-cell adenomas were significantly increased in NEHEA-initiated animals treated with paracetamol in comparison with animals treated with NEHEA only. No such renal lesion was observed in groups treated with paracetamol alone (Tsuda et al., 1984). [The Working Group noted that the progression of the lesions described as preneoplastic to neoplasms was not documented.]Groups of 25 male Fischer 344 rats, seven weeks old, were administered N-nitrosobutyl-N-(4-hydroxybutyl)amine at 0 or 0.05% (v/v) in the drinking-water for four weeks to initiate bladder carcinogenesis and were then fed paracetamol [purity unspecified] at 13 000 mg/kg of diet for a further 32 weeks, at which time all rats were killed. One group received treatment with the nitrosamine only. Urinary bladders, livers and kidneys were examined histologically. No significant difference in the incidence of bladder tumours was observed between the groups (Kurata et al., 1986).Groups of male Fischer 344 rats [numbers unspecified], six weeks of age, were subjected to a two-thirds partial hepatectomy and 24 h later received either intragastric intubations of paracetamol (purity, >99%) at 0 or 1000 mg/kg bw in 0.2% tragacanth gum twice a week for five weeks, or a single intragastric instillation of paracetamol at 500 mg/kg bw. Two weeks after the end of paracetamol treatment, the animals were administered phenobarbital (pharmacopoeial grade) at 0 or 1 mg/ml drinking-water for 12 weeks. The experiment was terminated at the end of phenobarbital treatment (weeks 13 and 18). Livers, kidneys, thyroid glands and any gross lesions were examined histologically. The tumour-initiating activity of paracetamol was evaluated by the formation of placental-type glutathione S-transferase-positive foci in liver cells; treatment with paracetamol did not result in the induction of such foci (Hasegawa et al., 1988). [The Working Group noted that the rate of absorption of paracetamol from the tragacanth suspension was not measured, and the limited reporting of the experiment.]To examine possible interference with the activation of 2-acetylaminofluorene, groups of 20 female SPF CD rats were given diets containing acetylaminofluorene at 250 mg/kg alone or with paracetamol at 11 000 mg/kg for 20 weeks and were observed for an additional ten weeks. Mammary tumours were seen in 14/20 females given acetylaminofluorene and in 7/20 (p = 0.028, Fisher's exact test) animals given acetylaminofluorene and paracetamol (Weisburger et al., 1973).Hamster. Groups of 30 male and 30 female Syrian golden hamsters, six weeks old, were given N-hydroxyacetylaminofluorene at 430 mg/kg alone or with paracetamol at 11000 mg/kg of diet for 39 weeks. The experiment was terminated at 47 weeks. The incidences of liver cholangiomas in animals treated with N-hydroxy-acetylaminofluorene were 13/26 in males and 22/25 in females; in the group treated with N-hydroxyacetylaminofluorene and paracetamol, no liver tumour was seen in 24 males but two occurred in 24 females. Similar results were found in groups given acetylaminofluorene at 400 mg/kg alone or with paracetamol at 11000 mg/kg: with acetylaminofluorene, the incidence of liver cholangiomas was 6/30 males and 28/30 females; in the group treated with acetylaminofluorene and paracetamol, the incidence was 0/29 males (p = 0.013, Fisher's exact test) and 4/28 females (p < 0.001, Fisher's exact test) (Weisburger et al., 1973).3.2. Other relevant data(a) Experimental systems(i) Absorption, distribution, excretion and metabolismDogs receiving a single oral administration of a wide range of doses of paracetamol excreted about 85% of the administered dose within the first 24 h (Savides et al., 1984).A summary of the proposed metabolic pathways of paracetamol is shown in Figure 1. The major urinary metabolites (the glucuronide, sulfate and 3-mercapto derivatives) are observed in most species, although there is much species variation regarding the percentages of these conjugates excreted in the urine (Davis et al., 1976). Each of the other metabolites shown in Figure 1 has been identified in one species (see Gemborys & Mudge, 1981, for details). In rats, biliary excretion of the various metabolites of paracetamol increased from 20 to 49% as doses were increased from 37.5 to 600 mg/kg bw. The glucuronide conjugate was the major metabolite recovered in the bile at all doses (Hjelle & Klaassen, 1984). The putative reactive intermediates are not known but are thought to include benzoquinone (Hinson et al., 1977).Fig. 1Summary or metabolism of paracetamol based on data for different speciesa A minor but important metabolic pathway involves the conversion of paracetamol to a reactive metabolite by the hepatic cytochrome P450-dependent mixed-function oxidase system (Mitchell et al., 1973; Potter et al., 1973). The reactive metabolite is thought to be either N-acetyl-para-benzoquinoneimine (Corcoran et al., 1980) or the corresponding semiquinone free radical (De Vries, 1981; Nelson et al., 1981). With low doses of paracetamol, a conjugate of reduced glutathione with the reactive metabolite is further transformed to cysteine and mercapturic acid conjugates, which are excreted. As the dose of paracetamol increases, hepatic glutathione stores are diminished and the glucuronidation and sulfation pathways become saturated (Galinsky & Levy, 1981). A correlation has been demonstrated between species sensitivity to the hepatotoxicity of paracetamol and the balance between two pathways: (i) formation of glutathione conjugates and the corresponding hydrolysis products (indicative of the ‘toxic’ pathway) and (ii) metabolism via formation of glucuronide and sulfate esters (the ‘detoxification pathway’) (Gregus et al., 1988). Paracetamol-induced liver toxicity and depletion of glutathione may be partially prevented by provision of dietary methionine (Reicks et al., 1988; McLean et al., 1989). At sufficiently high doses of paracetamol, glutathione is depleted and the reactive metabolite binds covalently to cell macromolecules. It has also been noted that paracetamol and N-acetyl-para-benzoquinoneimine may exert their cytotoxic effects via disruption of Ca2+ homeostasis secondary to the depletion of soluble and protein-bound thiols (Moore et al., 1985). These data indicate that oxidative or free-radical reactions initiated by paracetamol have a role in the hepatotoxicity of this drug (Birge et al., 1988).Radiolabel was bound covalently to hepatocellular proteins following incubation of mouse, rat, hamster, rabbit or guinea-pig liver microsomes with 3H-paracetamol; the degree of binding was correlated with the susceptibility of the species to hepatotoxicity in vivo (Davis et al., 1974). Similar covalent binding of radiolabel to liver proteins of rats 48 h after administration of [ring-14C]-paracetamol was proportional to the extent of liver damage (Davis et al., 1976). Covalent binding of radiolabel to liver plasma membranes and microsomes was demonstrated 2.5 h after oral administration of 3H-paracetamol at 2.5 g/kg bw to rats (Tsokos-Kuhn et al., 1988).Paracetamol is activated in the kidney by an NADPH-dependent cytochrome P450 mechanism to an arylating agent which can bind covalently to cellular macromolecules (McMurty et al., 1978). Studies in several species have suggested that formation of para-aminophenol may be of importance with respect to paracetamol nephrotoxicity. prara-Aminophenol was identified as a urinary metabolite in hamsters (Gemborys & Mudge, 1981); the deacetylation of paracetamol to para-aminophenol has also been demonstrated in mouse renal cortical slices (Carpenter & Mudge, 1981). In comparison to acetyl-labelled paracetamol, ring-labelled paracetamol was preferentially bound to renal macromolecules in Fischer rats, which are sensitive to paracetamol nephrotoxicity, whereas binding of ring- and acetyl-labelled paracetamol to renal macromolecules was similar in non-susceptible Sprague-Dawley rats (Newton et al., 1985). This suggests that para-aminophenol may be responsible for paracetamol-induced renal necrosis in Fischer 344 rats (Newton et al., 1982).(ii) Toxic effectsThe single-dose oral LD50 of paracetamol in male rats was 3.7 g/kg bw (Boyd & Bereczky, 1966); the 100-day LD50 in rats was 400 mg per day (Boyd & Hogan, 1968).Hepatic necrosis following administration of paracetamol was first reported in rats (Boyd & Bereczky, 1966). The main signs are hydropic vacuolation, centrilobular necrosis, macrophage infiltration and regenerative activity (Dixon et al., 1971). Paracetamol-induced hepatotoxicity varies considerably among species: hamsters and mice are most sensitive, whereas rats, rabbits and guinea-pigs are resistant to paracetamol-induced liver injury (Davis et al., 1974; Siegers et al., 1978). Toxic effects in dogs and cats given a single oral dose of paracetamol (maximal doses, 500 and 120 mg/kg bw, respectively) included hepatic centrilobular pathology in dogs, while cats, which do not glucuronidate exogenous compounds, had more diffuse liver pathological changes (Savides et al., 1984).The hepatotoxic effects of paracetamol administered in the diet to mice have been examined histologically. After continuous exposure at 10 000 mg/kg diet for 72 weeks (Hagiwara & Ward, 1986), severe chronic hepatotoxicity was observed, with centrilobular hepatocytomegaly, cirrhosis, lipofuscin deposition and hepatocyte necrosis varying from focal to massive. With the same dose, Ham and Calder (1984) observed macroscopically and microscopically deformed livers with extensive lobular collapse, foci of hepatic necrosis and lymphoid aggregation in portal tracts after 32 weeks. At a lower dose (5000 mg/kg bw) and a shorter exposure time (24 weeks), histological changes were mild. Ultrastructural changes in the livers of rats administered paracetamol at 10 000 mg/kg diet for up to 18 months have been described (Flaks et al., 1985).Histopathological review of liver sections from B6C3F1 mice of each sex fed paracetamol at 3000, 6000 or 12 500 mg/kg diet for 41 weeks and from NIH general-purpose mice of each sex fed paracetamol at 11000 mg/kg diet for 48 weeks indicated severe liver injury, characterized by centrilobular necrosis in animals receiving more than 10 000 mg/kg diet (Maruyama & Williams, 1988).A single subcutaneous dose of paracetamol at 750 mg/kg bw to male Fischer 344 rats produced renal tubular necrosis restricted to the upper part of the proximal tubule (McMurty et al., 1978). Chronic cortical and medullary damage has been produced in uninephrectomized homozygous Gunn rats by single doses of various analgesic preparations containing paracetamol (Henry & Tange, 1984).In fasted adult male mice given paracetamol at 600 mg/kg bw orally and killed within 48 h after treatment, degenerative and necrotic changes were detected in the bronchial epithelium and in testicular and lymphoid tissue, in addition to renal and hepatic effects (Placke et al., 1987).When male rats were given paracetamol at 500 mg/kg bw per day orally for 70 days, a significant decrease in testicular weight was observed (Jacqueson et al., 1984).(iii) Effects on reproduction and prenatal toxicityIn Sprague-Dawley rats administered paracetamol at 250 mg/kg bw orally on days 8 through 19 of gestation, embryo- and fetotoxic effects were not seen (Lubawy & Burriss Garret, 1977).(iv) Genetic and related effectsParacetamol was not mutagenic to Salmonella typhimurium at concentrations of up to 50 mg/plate in the presence or absence of an exogenous metabolic system (King et al., 1979; Wirth et al., 1980; Imamura et al., 1983; Dybing et al., 1984; Oldham et al., 1986; Jasiewicz & Richardson, 1987). It did not induce mutations in a liquid pre-incubation test with Escherichia coli in the presence or absence of an exogenous metabolic system (King et al., 1979). As reported in an abstract, paracetamol exhibited mutagenic activity towards S. typhimurium TA100 in the presence of an exogenous metabolic system (Tamura et al., 1980).Feeding of male Drosophila melanogaster with a 40-mM solution of paracetamol did not induce sex-linked recessive mutations (King et al., 1979).Treatment of Chinese hamster V79 cells with low concentrations (0.1–3.0 mM) of paracetamol inhibited DNA synthesis (Holme et al., 1988; Hongslo et al., 1988). Paracetamol at 10 mM had no effect on Reuber H4-II-E rat hepatoma cell DNA, as assayed by alkaline elution, but the toxic metabolite of paracetamol, N-acetyl-para-benzoquinoneimine, induced DNA strand breaks (Dybing et al., 1984). Treatment of Chinese hamster V79 cells induced DNA strand breaks at 3 and 10 mM but not at 1 mM (Hongslo et al., 1988). Analogous results were obtained with Chinese hamster ovary cells (Sasaki, 1986). Species specificity was observed in assays for unscheduled DNA synthesis in vitro. No unscheduled DNA synthesis was detected in Chinese hamster V79 cells (Hongslo et al., 1988), in Syrian hamster or guinea-pig primary hepatocytes (Holme & Soderlund, 1986) or in rat hepatocytes (Milam & Byard, 1985; Sasaki, 1986; Williams et al., 1989); however, a small but significant increase in unscheduled DNA synthesis was seen in rat primary hepatocytes and a marked increase in unscheduled DNA synthesis was observed in mouse hepatocytes (Holme & Soderlund, 1986).Paracetamol did not induce mutations to ouabain-resistance in C3H/10T½ clone 8 mouse embryo cells (Patierno et al., 1989). It was reported in an abstract that paracetamol did not induce mutations at the hprt locus in Chinese hamster V79 cells (Sawada et al., 1985). It induced sister chromatid exchange in Chinese hamster V79 (Holme et al., 1988; Hongslo et al., 1988) and CHO cells (Sasaki, 1986). Micronuclei were induced by paracetamol in a rat kidney cell line (NRK-49F) at concentrations above 10 mM (Dunn et al., 1987). Paracetamol induced chromosomal aberrations in three different Chinese hamster cell lines (Sasaki et al., 1980; Sasaki, 1986; Ishidate, 1988) and in human lymphocytes (Watanabe, 1982). It weakly transformed C3H/10T½ clone 8 mouse embryo cells (Patierno et al., 1989).Paracetamol given twice at a dose of 3 mM (450 mg/kg bw) either intraperitoneally or orally to NMRI mice did not induce micronuclei (King et al., 1979). Oral treatment of female Sprague-Dawley rats with paracetamol at 500 and 1000 mg/kg bw induced aneuploidy in 12-day embryos (Tsuruzaki et al., 1982). Oral treatment of Swiss mice with single or three consecutive daily doses of aqueous solutions of up to 2.5 mg/0.5 ml did not lead to chromatid breaks in bone-marrow cells (Reddy, 1984) or meiotic cells of male Swiss mice (Reddy & Subramanyam, 1985). [The Working Group noted that the description of the doses used in the two last studies was unclear.](b) Humans(i) PharmacokineticsFollowing an oral dose, paracetamol is absorbed rapidly from the small intestine. The rate of absorption depends on the rate of gastric emptying (Clements et al., 1978). First-pass metabolism of paracetamol is dose-dependent: systemic availability ranges from 90% (with 1–2 g) to 68% (with 0.5 g). Plasma concentrations of paracetamol in fasting healthy subjects peaked within 1 h after treatment with 0.5 or 1.0 g but continued to rise up to 2 h after treatment with 2.0 g (Rawlings et al., 1977).Paracetamol is rapidly and relatively uniformly distributed throughout the body fluids (Gwilt et al., 1963). Binding to plasma proteins is considered insignificant (Gazzard et al., 1973). The apparent volume of distribution of paracetamol in man is about 0.9 1/kg bw (Forrest et al., 1982). The decrease in paracetamol concentrations in plasma is multiphasic both after intravenous injections and after oral dosing with 500 and 1000 mg. When the data from six healthy volunteers were interpreted according to a two-compartment open model, the half-time of the first exponential ranged from 0.15 to 0.53 h and that of the second exponential from 2.24 to 3.30 h. The latter value was in agreement with that found after oral dosing. Mean clearance (± SEM) after intravenous administration of 1000 mg was 352 (± 40) ml/min (Rawlings et al., 1977). Renal excretion of paracetamol involves glomerular filtration and passive reabsorption, and the sulfate conjugate is subject to active renal tubular secretion (Morris & Levy, 1984). Both these metabolites have been shown to accumulate in plasma in patients with renal failure who are taking paracetamol (Lowenthal et al., 1976).Paracetamol crosses the placenta in unconjugated form, and excretion in the urine of an exposed neonate was similar to that of a two- to three-day-old infant (Collins, 1981).Paracetamol passes rapidly into milk, and the milk:plasma concentration ratio ranges from 0.7 to 1.1 (Berlin et al., 1980; Notarianni et al., 1987).Paracetamol is metabolized predominantly to the glucuronide and sulfate conjugates in the human liver. A minor fraction is converted by cytochrome P450-dependent hepatic mixed-function oxidase to a highly reactive arylating metabolite, which is postulated to be N-acetyl-para-benzoquinoneimine (Miner & Kissenger, 1979). This metabolite is rapidly inactivated by conjugation with reduced glutathione and eventually excreted in the urine as acetyl cysteine and mercapturic acid conjugates. Large doses of paracetamol can deplete glutathione stores, and the excess of highly reactive intermediate binds covalently with vital cell elements, which may result in acute hepatic necrosis (Mitchell et al., 1973, 1974). Only 2–5% of a therapeutic dose was excreted unchanged in the urine. In young healthy subjects, about 55, 30, 4 and 4% of a therapeutic dose was excreted after hepatic conjugation with glucuronic acid, sulfuric acid, cysteine and mercapturic acid, respectively (Forrest et al., 1982).The fractional recovery of mercapturic acid and cysteine conjugates after ingestion of paracetamol at 1500 mg was 9.3% in Caucasians compared with only 4.4–5.2% in Africans (Critchley et al., 1986). This may reflect different susceptibility to paracetamol hepatotoxicity.(ii) Adverse effectsThe toxic effects of paracetamol have been reviewed (Flower et al., 1985).Reports on the acute toxicity, and in particular hepatotoxicity, of paracetamol have continued to appear since the reporting of the first two cases in 1966 (Davidson & Eastham, 1966). Initial symptoms of overdose are nausea, vomiting, diarrhoea and abdominal pain. Clinical indications of hepatic damage become manifest within two to four days after ingestion of toxic doses; in adults, a single dose of 10–15 g (200–250 mg/kg bw) is toxic. Serum transaminases, lactic dehydrogenase and bilirubin concentrations are elevated, and prothrombin time is prolonged (Koch-Weser, 1976). The severity of hepatic injury increases with the ingested dose and with previous consumption of other drugs that induce liver cytochrome P450 enzymes (Wright & Prescott, 1973). Biopsy of the liver reveals centrilobular necrosis with sparing of the periportal area (James et al., 1975). In nonfatal cases, the hepatic lesions are reversible over a period of months, without development of cirrhosis (Hamlyn et al., 1977).Heavy alcohol consumption has been stated in several case reports to be related to more severe paracetamol hepatotoxicity than in non- or moderate drinkers (for review, see Black, 1984). Five cases of combined hepatocellular injury and renal tubular necrosis have been reported among patients with a history of chronic alcohol use who were receiving therapeutic doses of paracetamol (Kaysen et al., 1985).(iii) Effects on reproduction and prenatal toxicityNo association of paracetamol use with congenital abnormalities or stillbirths was observed in a study on drug use in approximately 10 000 pregnancies in the UK (Crombie et al., 1970). In a case-control study of 458 mothers of malformed babies and 911 controls, there was no association of abnormalities with use of paracetamol during the first trimester (Nelson & Forfar, 1971). In the Collaborative Perinatal Project, in which drug intake and pregnancy outcome were studied in a series of 50 282 women in 1959–65, 226 women had been exposed to paracetamol during the first trimester of pregnancy. There were 17 malformed children in the exposed group, giving a nonsignificant standardized relative risk (RR) of 1.05 (Heinonen et al., 1977).In a study of 280 000 women belonging to a prepaid health plan in Seattle, WA (USA), all drug prescriptions and all pregnancy outcomes were monitored between July 1977 and December 1979. Among the liveborn babies of 6837 women, 80(1.2%) had major congenital malformations. Three of the infants born to 493 women for whom paracetamol had been prescribed in the first trimester had major malformations (types not specified), giving a prevalence of 6 per 1000, which was not significantly different from the overall prevalence in the total population studied (12 per 1000). A second group of 328 women were exposed to paracetamol with codeine in the first trimester. Five of these had malformed babies, giving a prevalence of 15 per 1000, which was not significantly different from that in controls (Jick et al., 1981).In a second study of the same population, covering the period January 1980 to June 1982, 6509 women had pregnancies ending in livebirths; 105 (1.5%) of the infants had major congenital malformations. Two of the infants born to 350 women for whom paracetamol had been prescribed in the first trimester had major malformations (types not specified), giving a prevalence of 6 per 1000 compared with an overall prevalence in the entire group of 16 per 1000. Three of 347 women exposed to paracetamol with codeine had malformed babies, giving a prevalence of 9 per 1000 (not significant) (Aselton et al., 1985).(iv) Genetic and related effectsEleven healthy volunteers were given paracetamol at 1000 mg three times over a period of 8 h. The frequency of chromatid breaks in peripheral blood lymphocytes was significantly increased after one day but returned to normal one week later (Kocisova et al., 1988).3.3. Case reports and epidemiological studies of carcinogenicity to humansThe Working Group considered only studies in which paracetamol was taken directly, either alone or in mixtures. Paracetamol may be taken by analgesic users who previously took phenacetin. Analgesic mixtures containing phenacetin are carcinogenic to humans; and phenacetin is probably carcinogenic to humans (IARC, 1980, 1987).A population-based case-control study was conducted in Minnesota, USA, involving 495 cases of cancer of the renal parenchyma and 74 cases of cancer of the renal pelvis, diagnosed in 1974–79, and 697 controls (McLaughlin et al., 1983, 1984, 1985). An association between cancer of the renal pelvis and intensity and duration of use of paracetamol-containing drugs was seen in women (p for trend, < 0.05; RR in the highest exposure category, based on three exposed cases and eight exposed controls, 5.8; 95% confidence interval (CI), 0.8–40). [The Working Group noted that the trend test included unexposed cases and controls; if the unexposed are excluded, the trend is not statistically significant.] No other significant association was observed. Four of the five cases in the highest exposure category (two men, three women) who developed renal pelvic cancer had also taken phenacetin-containing analgesics; in the entire study, only two cases of cancer of the renal pelvis and seven controls had taken paracetamol alone.Another population-based case control study was conducted among women aged 20–49 years in the state of New York (USA) involving 173 cases of bladder cancer diagnosed in 1975–79 and an equal number of controls matched for age and telephone area code (Piper et al., 1985). A history of regular use of analgesics containing paracetamol (and not phenacetin) at least one year before diagnosis yielded a smoking-adjusted RR of 1.5 (95% CI, 0.4–7.2). In contrast, the risk for regular users of phenacetin-containing analgesics was significantly elevated whether they also regularly took paracetamol (RR, 3.8; 95% CI, 1.4–13.0) or not (RR, 6.5; 95% CI, 1.5–59.2).A series of population-based case-control studies of urinary-tract cancer were conducted in New South Wales, Australia, involving cases identified in 1977–82 (McCredie et al., 1983a,b, 1988; McCredie & Stewart, 1988). Ultimately, there were 360 cases of renal parenchymal cancer, 73 cases of renal pelvic cancer, 55 cases of ureteral cancer and 162 cases (women only) of bladder cancer. Controls (985 for renal parenchymal cancer and 689 for the other sites) were derived from electoral rolls. The only significant increase in risk for regular use of paracetamol (cumulative consumption of at least 0.1 kg) was with ureteral cancer (RR, 2.5; 95% CI, 1.1–5.9); this association was not further elevated in the subgroup with higher exposure (at least 1 kg; RR, 2.0; 95% CI, 0.8–4.5). The RR for cancer of the renal pelvis was 1.2 (95% CI, 0.6–2.3). These analyses were adjusted for cigarette smoking and the presence of urological disease.A further population-based case-control study was conducted in Los Angeles County, USA, based on 187 cases of cancer of the renal pelvis or ureter diagnosed in 1978–82 and an equal number of neighbourhood controls (Ross et al., 1989). An association was found with use of nonprescription analgesics in general. The risks for use of analgesics containing paracetamol were nonsignificantly elevated, at 1.3 for use more than 30 days/year (p = 0.34) and 2.0 for use more than 30 consecutive days/year (p = 0.08). The analyses were controlled for cigarette smoking and history of urinary-tract stones. The authors noted that it was difficult to distinguish the effects of individual compounds in this study.In a hypothesis-generating cohort study designed to screen a large number of drugs for possible carcinogenicity (described in detail in the monograph on ampicillin), 3238 persons to whom at least one prescription for paracetamol alone and 2612 to whom at least one prescription for paracetamol with codeine had been dispensed during 1969–73 were followed up for up to 15 years (Selby et al., 1989). No significant association with cancer at any site was seen for use of paracetamol with codeine. For paracetamol alone, a positive association was noted for melanoma (seven cases observed, 1.7 expected; RR, 4.1; 95% CI, 1.7–8.5), and negative associations for cancer of the colon (four observed, 12.1 expected; RR, 0.33; 95% CI, 0.1–0.85) and cancer of the uterine corpus (one observed, 6.5 expected; RR, 0.15; 95% CI, 0–0.86); but no association was seen for any cancer of the urinary tract or for all cancers combined (Friedman & Ury, 1980, 1983; Selby et al., 1989). [The Working Group noted that there was no information on non-prescription dispensing of paracetamol, which is the most common way that it is obtained. Since, as also noted by the authors, some 12 000 comparisons were made in this study, the associations should be verified independently. Data on duration of use were not provided.]4. Summary of Data Reported and Evaluation4.1. Exposure dataParacetamol has been used extensively as an analgesic and antipyretic since 1946.4.2. Experimental carcinogenicity dataParacetamol was tested for carcinogenicity by oral administration in mice and rats. In one strain of mice, a significant increase in the incidence of multiple liver carcinomas and adenomas was observed in animals of each sex at a markedly toxic dose; in two studies on another strain, no increase in the incidence of any tumour was observed at a well-tolerated dose that was approximately half that in the preceding study. Administration of paracetamol to two different strains of rats did not increase tumour incidence. In a further strain of rats, the incidence of neoplastic liver nodules was increased in animals of each sex given the higher dose; the combined incidence of bladder papillomas and carcinomas (mostly papillomas) was significantly greater in high-dose male and in low-dose female rats. Although treatment increased the incidence of bladder calculi in treated rats, there was no relationship between the presence of calculi and of either hyperplasia or tumours in the bladder.Oral administration of paracetamol to rats enhanced the incidence of renal adenomas induced by N-nitrosoethyl-N-hydroxyethylamine.4.3. Human carcinogenicity dataA positive association between use of paracetamol and cancer of the ureter (but not of other sites in the urinary tract) was observed in an Australian case-control study. None of three other population-based case-control studies showed an association between paracetamol use and cancer in the urinary tract.4.4. Other relevant dataOne study provided no evidence that use of paracetamol in the first trimester of pregnancy is associated with an increase in the incidence of malformations. Paracetamol induced testicular atrophy in rats.Hepatotoxicity has been reported repeatedly in people taking high doses of paracetamol; chronic alcohol users are particularly sensitive. Paracetamol is metabolized in humans and animals to reactive intermediates that bind to proteins. It is hepatotoxic to experimental animals and causes renal tubular necrosis in rats.Paracetamol induced chromatid breaks in peripheral human lymphocytes in vivo. It induced aneuploidy in rat embryos treated transplacentally. It gave negative results in the micronucleus test in mice in vivo. It did not induce chromosomal aberrations in bone-marrow cells or spermatocytes of mice.Paracetamol induced sister chromatid exchange and chromosomal aberrations in Chinese hamster cells, micronuclei in rat kidney cells and chromosomal aberrations in human lymphocytes in vitro. It did not induce point mutations in mouse or Chinese hamster cells. 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ViewsPubReaderPrint ViewCite this PageIARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Pharmaceutical Drugs. Lyon (FR): International Agency for Research on Cancer; 1990. (IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans, No. 50.) Paracetamol (Acetaminophen)PDF version of this title (25M)In this PageChemical and Physical DataProduction, Occurrence, Use and AnalysisBiological Data Relevant to the Evaluation of Carcinogenic Risk to HumansSummary of Data Reported and EvaluationReferencesOther titles in this collectionIARC Monographs on the Evaluation of the Carcinogenic Risks to HumansRelated informationPMCPubMed Central citationsPubMedLinks to PubMedSimilar articles in PubMedReview International Commission for Protection against Environmental Mutagens and Carcinogens. An evaluation of the genetic toxicity of paracetamol.[Mutat Res. 1995]Review International Commission for Protection against Environmental Mutagens and Carcinogens. An evaluation of the genetic toxicity of paracetamol.Rannug U, Holme JA, Hongslo JK, Srám R. Mutat Res. 1995 Mar; 327(1-2):179-200. Review Series: current issues in mutagenesis and carcinogenesis, No. 65. The genotoxicity and carcinogenicity of paracetamol: a regulatory (re)view.[Mutat Res. 1996]Review Series: current issues in mutagenesis and carcinogenesis, No. 65. The genotoxicity and carcinogenicity of paracetamol: a regulatory (re)view.Bergman K, Müller L, Teigen SW. Mutat Res. 1996 Feb 1; 349(2):263-88. Additional effect of acetaminophen on the mutagenicity and clastogenicity of N-methyl-N'-nitro-N-nitrosoguanidine in cultured Chinese hamster CHO-Kl cells.[Mutat Res. 1983]Additional effect of acetaminophen on the mutagenicity and clastogenicity of N-methyl-N'-nitro-N-nitrosoguanidine in cultured Chinese hamster CHO-Kl cells.Sasaki M, Yoshida S, Hiraga K. Mutat Res. 1983 Dec; 122(3-4):367-72. Aniline Is Rapidly Converted Into Paracetamol Impairing Male Reproductive Development.[Toxicol Sci. 2015]Aniline Is Rapidly Converted Into Paracetamol Impairing Male Reproductive Development.Holm JB, Chalmey C, Modick H, Jensen LS, Dierkes G, Weiss T, Jensen BA, Nørregård MM, Borkowski K, Styrishave B, et al. Toxicol Sci. 2015 Nov; 148(1):288-98. Epub 2015 Aug 10.Review Hydrochlorothiazide.[IARC Monogr Eval Carcinog Risk...]Review Hydrochlorothiazide.. IARC Monogr Eval Carcinog Risks Hum. 1990; 50:293-305. See reviews...See all...Recent ActivityClearTurn OffTurn OnParacetamol (Acetaminophen) - Pharmaceutical DrugsParacetamol (Acetaminophen) - Pharmaceutical DrugsYour browsing activity is empty.Activity recording is turned off.Turn recording back onSee more...

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What does it do? Paracetamol is used to treat and prevent mild to moderate pain, and reduce fever.

Dosing Adults & children over 12 years: 1-2 tablets repeated every 4-6 hours if necessary.Children 6-12 years: ½ -1 tablet repeated every 4-6 hours if necessary.Maximum of 4 doses in any 24 hours. Do not exceed stated dose

Caution Do not take more than the stated dose. For adults this is usually up to a maximum of 8 tablets/capsules (500 mg) in 24 hours. Do not take other medicines that also contain paracetamol, unless you discuss this with a health professional. For Adults: Do not use for more than a few days at a time, except on medical advice. For children ages 7-17: Do not use for more than 48 hours, except on medical advice. Do not exceed the stated dose.

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What’s the point of paracetamol? | University of Oxford

What’s the point of paracetamol? | University of Oxford

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HomeResearchWhat’s the point of paracetamol?

What’s the point of paracetamol?

Andrew Moore, Honorary Senior Research Fellow, University of OxfordParacetamol has been around for over 50 years. It’s safe and many guidelines recommend it as the go-to treatment. At least, that’s the conventional view of the drug. It’s a view so ingrained that it’s rarely questioned. The trouble is that the conventional view is probably wrong.Huge amounts of paracetamol are used to treat pain, measured not in how many tablets are used but in the thousands of tons. For the UK, an estimate of the amount of paracetamol sold is just under 6,300 tonnes a year. That’s 35 tonnes per million of population: 35 grams or 70 paracetamol tablets each, every year.But does it work?The evidence is that it probably does not work at all for chronic pain. Large, good and independent clinical trials and reviews from the Cochrane Library show paracetamol to be no better than placebo for chronic back pain or arthritis. This is at the maximum daily dose in trials lasting for three months, so it has been pretty thoroughly tested.Acute pains are sudden in onset and go away after a while (headache or pain after an operation, for instance). For these, reviews from the Cochrane Library show that paracetamol can provide pain relief, but only for a small number of people. For postoperative pain, perhaps one in four people benefit; for headache perhaps one in ten. This evidence comes from systematic reviews, often of large numbers of good clinical trials.These are robust and trustworthy results. If paracetamol works for you, that’s great. But for most, it won’t.Is it safe?Safety boils down to examining really bad things happening to a very small number of people who take a drug. Unless the rate of the very bad thing is vanishingly small, the authorities won’t let us buy the drug from a petrol station. If we want to study those rare events, then we need study large numbers of people. Partly because paracetamol is such an old drug these studies have largely not been done until recently.Those we have tell us that paracetamol use is associated with increased rates of death, heart attack, stomach bleeding and kidney failure. Paracetamol is known to cause liver failure in overdose, but it also causes liver failure in people taking standard doses for pain relief. The risk is only about one in a million, but it is a risk. All these different risks stack up.Are we competent to take analgesics?

Half of a sample of Americans didn’t know that Tylenol contained paracetamol.(Credit: dcwcreations/Shutterstock.com)

There are some scary facts about how much we, as ordinary members of the public, know about painkillers. Here are a few.Many people don’t know what is in their analgesics. A study in a London emergency department found that half of the patients thought ibuprofen contained paracetamol. In the US, half of a similar group did not know that the popular brand of paracetamol, Tylenol, actually contained paracetamol.Most people have no idea of the maximum daily dose of paracetamol. In the UK about one in four people frequently exceed the maximum daily dose (it’s 4,000mg, or eight tablets, by the way). In the US, half did not know the maximum daily dose, and one in 20 thought it as high as 10,000mg.Paracetamol is not just in paracetamol, but all sorts of cold and flu medicines as well, and headache tablets. Around 200m packs of paracetamol are sold without prescription in the UK every year, though sales fell after pack size restriction. In the US it could be one billion (but different pack sizes and tablet doses).The conundrum is what to do with this information for a drug with limited effect but dangerous in overdose. It’s a headache for regulators and licensing authorities, not to mention organisations like NICE trying to help doctors make sensible treatment decisions. Nor is there a simple alternative. Non-pharmacological methods of treating pain are largely without good evidence. Other drugs may work better, but they have side effects too.Let’s not rush to judgement here and dismiss paracetamol entirely. But a rethink is surely timely.This article was originally published on The Conversation. Read the original article.

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Paracetamol 500mg Caplets BP (PL 43461/0078) - Summary of Product Characteristics (SmPC) - (emc)

Paracetamol 500mg Caplets BP (PL 43461/0078) - Summary of Product Characteristics (SmPC) - (emc)

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Paracetamol 500mg Caplets BP (PL 43461/0078)

Active Ingredient:

paracetamol

Company:  

Flamingo Pharma (UK) Ltd

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Healthcare Professionals (SmPC)

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This information is for use by healthcare professionals

Last updated on emc: 14 Oct 2022

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Undesirable Effects

Pharmacological Properties

Interactions

Posology

Contraindications

Excipients

Storage precautions

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1. Name of the medicinal product

Paracetamol 500mg Tablets BP.

PocketPak Paracetamol 500 mg Caplets

2. Qualitative and quantitative composition

Paracetamol 500mg.

For excipients, see 6.1.

3. Pharmaceutical form

Tablet.

White, capsule shaped tablet with a break-line on one face.

4. Clinical particulars

4.1 Therapeutic indications

For the treatment of mild to moderate pain including headache, migraine, neuralgia, toothache, sore throat, period pain, aches and pains.

Symptomatic relief of rheumatic aches and pains.

Symptomatic relief of influenza, feverishness, feverish colds.

4.2 Posology and method of administration

Posology

Adults, the elderly and children 16 years and over: One or two tablets to be taken up to four times daily. Maximum dose of 8 tablets in 24 hours.

Children 10 to 15 years of age: One tablet to be taken for every 4-6 hours when necessary to a maximum of 4 doses in 24 hours.

Children under 10 years of age: Not recommended. Alternative presentations of paracetamol are recommended for paediatric usage in order to obtain suitable doses of less than 500mg.

The dose should not be repeated more frequently than every 4 hours, and not more than 4 doses should be taken in any 24 hour period.

Dosage should not be continued for more than 3 days without consulting a doctor.

Method of administration

For oral administration.

4.3 Contraindications

Hypersensitivity to paracetamol or any of the other ingredients.

4.4 Special warnings and precautions for use

Where analgesics are used long-term (>3 months) with administration every two days or more frequently, headache may develop or worsen. Headache induced by overuse of analgesics (MOH medication-overuse headache) should not be treated by dose increase. In such cases, the use of analgesics should be discontinued in consultation with the doctor.

Care is advised in the administration of paracetamol to patients with alcohol dependency (see section 4.9), severe renal or severe hepatic impairment. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease.

Patients should be advised to consult their doctor if their headaches become persistent.

Patients should be advised to consult a doctor if they suffer from non-serious arthritis and need to take painkillers every day.

Do not exceed the recommended dose.

If symptoms persist, consult your doctor.

Keep out of the sight and reach of children.

May rarely cause severe hypersensitivity reactions and bronchospasm as this medicine contains sodium metabisulphite.

The label will state the following warnings:

Do not take more medicine than the label tells you to. If you do not get better, talk to your doctor. Do not take anything else containing paracetamol while taking this medicine. Talk to a doctor at once if you take too much of this medicine, even if you feel well.

The leaflet will state the following warnings:

Do not take more medicine than the label tells you to. If you do not get better, talk to your doctor. Do not take anything else containing paracetamol while taking this medicine.

Talk to a doctor at once if you take too much of this medicine, even if you feel well. This is because too much paracetamol can cause delayed, serious liver damage.

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol reduces liver capacity to deal with paracetamol.

The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged, regular use of paracetamol, with increased risk of bleeding; occasional doses have no significant effect.

Colestyramine reduces absorption if given within one hour of paracetamol; and Metoclopramide and Domperidone accelerate absorption of paracetamol. May interact with chloramphenicol causing increased plasma levels.

Imatinib - restriction or avoidance of concomitant regular paracetamol use should be taken with imatinib.

4.6 Fertility, pregnancy and lactation

A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published literature do not contraindicate breast-feeding.

4.7 Effects on ability to drive and use machines

None known.

4.8 Undesirable effects

Adverse effects of paracetamol are rare but hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia, neutropenia, pancytopenia, leukopenia and agranulocytosis, but these were not necessarily causally related to paracetamol.

Adverse events of paracetamol from historical clinical trial data are both infrequent and from small patient exposure. Accordingly, events reported from extensive post-marketing experience at therapeutic/labelled dose and considered attributable are tabulated below by system class. Due to limited clinical trial data, the frequency of these adverse events is not known (cannot be estimated from available data), but post-marketing experience indicates that adverse reactions to paracetamol are rare and serious reactions are very rare.

Post marketing data:

Skin and subcutaneous disorders: Very rare cases of serious skin reactions have been reported.

Blood and lymphatic system disorders: Thrombocytopenia, agranulocytosis.

Immune system disorders: Anaphylaxis. Cutaneous hypersensitivity reactions including skin rashes, angioedema and Stevens Johnson syndrome/toxic epidermal necrolysis.

Respiratory, thoracic and mediastinal disorders: Bronchospasm*.

*There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.

Hepatobiliary disorders: Hepatic dysfunction.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Liver damage is possible in adults who have taken 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).

Risk factors:-

If the patient

• Is on long term treatment with carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes.

• Regularly consumes ethanol in excess of recommended amounts.

• Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.

Symptoms

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N–acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24 hours from ingestion should be discussed with the NPIS or a liver unit.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Paracetamol is an effective analgesic and antipyretic agent but has only weak anti-inflammatory properties. Its mechanism of action is not fully understood, as it is only a weak inhibitor of prostaglandin bio-synthesis, but it has been suggested that it is more effective against enzymes in the CNS than those in the periphery. The drug has no effect on the cardiovascular and respiratory systems, and it does not cause gastric irritation or bleeding like salicylates.

5.2 Pharmacokinetic properties

Paracetamol is readily absorbed from the gastro-intestinal tract with peak plasma concentrations occurring 10 to 60 minutes after ingestion. It is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted unchanged as paracetamol. It is distributed in most body tissues. Paracetamol crosses the placenta and is present in breast milk. Plasma protein binding is negligible at usual therapeutic concentrations but increases with increasing concentration.

The elimination half life varies from about 1 to 4 hours.

A minor hydroxylated metabolite which is usually produced in very small amounts by mixed function oxidases in the liver and which is usually detoxified by conjugation with liver glutathione may accumulate following paracetamol overdosage and cause liver damage.

5.3 Preclinical safety data

Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.

6. Pharmaceutical particulars

6.1 List of excipients

Pregelatinised Maize Starch

Sodium Metabisulphite

Magnesium Stearate

6.2 Incompatibilities

Not Applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

Blister strips: Do not store above 25°C. Store in the original package.

Tablet containers: Do not store above 25°C. Keep the container tightly closed. Store in the original container.

6.5 Nature and contents of container

Al/PVC blister strips (child resistant) enclosed in an outer carton containing 8, 12 or 16

Al/PVC blister (child resistant) containing 12 tablets, enclosed in an outer carton – 'PocketPak' format.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

None applicable.

7. Marketing authorisation holder

Flamingo Pharma UK Ltd.

1st floor, Kirkland House,

11-15 Peterborough Road,

Harrow, Middlesex,

HA12AX, United Kingdom.

8. Marketing authorisation number(s)

PL 43461/0078

9. Date of first authorisation/renewal of the authorisation

18/05/2009

10. Date of revision of the text

09/02/2021

Flamingo Pharma (UK) Ltd

Address

The BLOC, 38 Springfield Way, Kingston Upon Hull, HU10 6RJ, UK

WWW

http://www.flamingopharma.co.uk

Telephone

+44 (0) 7784240228

Medical Information Direct Line

00 800 890 13370

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[email protected]

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