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Cimetidine


Drug Approvals

(British Approved Name, US Adopted Name, rINN)

Synonyms: Cimetidin; Cimetidina; Cimetidinas; Cimetidinum; SKF-92334; Simetidiini
BAN: Cimetidine
USAN: Cimetidine
INN: Cimetidine [rINN (en)]
INN: Cimetidina [rINN (es)]
INN: Cimétidine [rINN (fr)]
INN: Cimetidinum [rINN (la)]
INN: Циметидин [rINN (ru)]
Chemical name: 2-Cyano-1-methyl-3-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guanidine
Molecular formula: C10H16N6S =252.3
CAS: 51481-61-9
ATC code: A02BA01
Read code: y01P9

Pharmacopoeias. In China, Europe, International, Japan, US

European Pharmacopoeia, 6th ed. (Cimetidine). A white or almost white, polymorphic powder. Slightly soluble in water soluble in alcohol practically insoluble in dichloromethane. It dissolves in dilute mineral acids. Store in airtight containers. Protect from light.

The United States Pharmacopeia 31, 2008 (Cimetidine). A white to off-white crystalline powder, odourless or with a slight mercaptan odour. Slightly soluble in water and in chloroform soluble in alcohol and in macrogol 400 practically insoluble in ether sparingly soluble in isopropyl alcohol freely soluble in methyl alcohol. Store in airtight containers. Protect from light.

Cimetidine Hydrochloride

(British Approved Name Modified, US Adopted Name, rINNM)

Drug Nomenclature

Synonyms: Cimetidin-hidroklorid; Cimetidin-hydrochlorid; Cimetidina, hidrocloruro de; Cimetidinhydroklorid; Cimetidini Hydrochloridum; Cimetidino hidrochloridas; Simetidiinihydrokloridi
BAN: Cimetidine Hydrochloride [BANM]
USAN: Cimetidine Hydrochloride
INN: Cimetidine Hydrochloride [rINNM (en)]
INN: Hidrocloruro de cimetidina [rINNM (es)]
INN: Cimétidine, Chlorhydrate de [rINNM (fr)]
INN: Cimetidini Hydrochloridum [rINNM (la)]
INN: Циметидина Гидрохлорид [rINNM (ru)]
Molecular formula: C10H16N6S,HCl =288.8
CAS: 70059-30-2
ATC code: A02BA01

Pharmacopoeias. In Europe and US.

European Pharmacopoeia, 6th ed. (Cimetidine Hydrochloride). A white or almost white, crystalline powder. Freely soluble in water sparingly soluble in dehydrated alcohol. A 1% solution in water has a pH of 4.0 to 5.0. Store in airtight containers. Protect from light.

The United States Pharmacopeia 31, 2008 (Cimetidine Hydrochloride). Store in airtight containers. Protect from light.

Adverse Effects

Adverse reactions to cimetidine and other histamine H2-antagonists are generally infrequent. The commonest adverse effects reported have been diarrhoea and other gastrointestinal disturbances, dizziness, tiredness, headache, and rashes.

Altered liver function tests have occurred and there have been rare reports of hepatotoxicity. Reversible confusional states, especially in the elderly or in seriously ill patients such as those with renal failure, have occasionally occurred. Other adverse effects that have been reported rarely are hyper sensitivity reactions and fever, arthralgia and myalgia, blood disorders including agranulocytosis, leucopenia, and thrombocytopenia, acute pancreatitis, interstitial nephritis, hallucinations and depression, and cardiovascular disorders including bradycardia, tachycardia, and heart block. Rapid intravenous injection should be avoided as there have been rare associations with cardiac arrest and arrhythmias transient hypotension has also been seen. In patients such as the elderly, those with chronic lung disease, diabetes mellitus, or the immunocompro-mised, treatment with H2-antagonists may be associated with an increased risk of developing community-acquired pneumonia.

Cimetidine has a weak anti-androgenic effect and gynaecomastia and impotence have also occasionally occurred in men these are usually reversible.

Incidence of adverse effects. In a meta-analysis of 24 double-blind placebo-controlled studies, the incidence of adverse effects with cimetidine was not significantly different from placebo. The most common adverse effects reported by patients taking cimetidine who were followed up for at least one year’ were diarrhoea, headache, fatigue, skin rash or pruritus, and gynaeco-mastia. The incidence of adverse effects was dose-related and decreased with length of treatment. No fatal adverse effect of cimetidine could be found in a mortality survey involving 9928 patients taking cimetidine and 9351 controls although the mortality rate was higher in the cimetidine patients, this was explained by the presence of underlying disease (known or unknown) before starting cimetidine treatment and the use of cimetidine to counter adverse gastric effects of other drugs. Follow-up of 9377 of these cimetidine-treated patients for a further 3 years still revealed no fatal disorder attributable to cimetidine treatment and a steady fall in the excess death rate in cimetidine users was seen with increasing length of follow-up by the fourth year there was little difference between the observed and expected death rate. Cimetidine still appeared to be safe after 10 years of follow-up.

Carcinogenicity. An association between H2-antagonists and gastric cancer was proposed after individual case reports, the finding of tumours in long-term high-dose animal studies, and the possibility that nitrites and nitroso compounds may be produced, but seemed of little clinical relevance. The excess risk of gastric cancer reported in patients taking cimetidine or ranitidine decreases with time and there is no evidence for any long-term persistence of the effect. The increased risk may be explained by misdiagnosis and inappropriate cimetidine treatment of existing malignancy. An apparently protective effect has been seen for H2-antagonist use starting 10 or more years before diagnosis of gastric cancer.

The observed excess risk for cancers of the respiratory system is probably related to smoking, since this is causally related to both peptic ulcer and lung cancer and the excess risk does not decline with time.

Effects on the blood. A review in 1988 noted that leucopenia, thrombocytopenia, and pancytopenia have all been reported with cimetidine and ranitidine, with neutropenia and agranulocytosis occurring most often. There were also isolated reports of haemolytic anaemia and leucocytosis associated with cimetidine therapy. The overall incidence of cimetidine-associated blood cytopenia was estimated as 2.3 per 100 000 treated patients the incidence for ranitidine was less and although there were reports with famotidine the incidence had not been determined. A subsequent case-control study, concluded that the risk of hospitali-sation due to neutropenia in patients receiving a 6-week course of cimetidine was no more than 1 in 116 000, while agranulocytosis did not occur in more than 1 in 573 000 patients. A review of the safety profile of famotidine noted that as of May 1992 there had been 60 reports of serious blood dy scrasias in patients receiving famotidine, of which 22 were considered possibly related to drug therapy (6 cases of pancytopenia or bone marrow depression, 5 of thrombocytopenia, 4 of leucopenia, 3 of combined leucopenia and thrombocytopenia, and 3 of agranulocytosis).

Effects on the cardiovascular system. Bradycardia, AV block, tachycardia, and hypotension have been reported during cimetidine treatment given by mouth and by intravenous injection or infusion. Although there are studies in patients and healthy subjects that have found no significant cardiovascular effects associated with cimetidine treatment, it is likely that a small proportion of patients are more susceptible to the cardiovascular effects of cimetidine. Caution is recommended if the drug is given intravenously to patients with cardiovascular disease (see Precautions). See also under Overdosage.

Effects on the endocrine system. Cimetidine has dose-related mild anti-androgenic properties and reduced sperm counts and raised serum-prolactin concentrations have been reported in men during cimetidine treatment as have gynaecomastia, breast tenderness, and impotence. Those symptoms resolved after withdrawal of cimetidine, reduction of the dose, or transfer to ranitidine.

A study by the Boston Collaborative Drug Surveillance Program, using data from 81 535 men in the UK, found that cimetidine was associated with an incidence of 3.29 cases of gynaecomastia per 1000 person years, representing a relative risk 7.2 times greater than that of non-users. The period at highest risk seemed to be between the seventh and twelfth month after starting treatment, and the occurrence was related to dose, with most of the risk associated with doses over 1 g daily. This large study found no significant risk of gynaecomastia with ranitidine or omeprazole. However, there have been isolated reports of gynaecomastia or impotence with ranitidine, nizatidine, and famotidine.

Effects on the eyes. Ocular pain, blurred vision, and a rise in intra-ocular pressure occurred in a patient with chronic glaucoma during treatment with cimetidine ocular symptoms associated with raised intra-ocular pressure subsequently developed during ranitidine treatment. However, a study suggested that cimetidine had no effect on intra-ocular pressure. A cohort study involving 140 128 patients receiving anti-ulcer therapy, 68 504 of whom received cimetidine, found no evidence that any of the drugs were associated with a major increased risk of vascular or inflammatory disorders of the eye.

Effects on the kidneys. A review of the nephrotoxicity and hepatotoxicity of H2-antagonists noted that mild elevation of se-rum-creatinine was relatively common after use of cimetidine but appeared to have no clinical significance. However, the authors found 25 published reports of acute interstitial nephritis associated with this class of drug (20 with cimetidine, 4 with ranitidine, and 1 with famotidine) and 16 cases reported to the Australian Drug Reaction Advisory Committee (ADRAC) between 1972 and 1999 (11 with cimetidine, 4 with ranitidine, and 1 with famotidine). Symptoms were mostly non-specific, and did not seem to be associated with the rash, arthralgia, and flank pain that may be seen in nephritis induced by other drugs. Nephritis invariably resolved when the drug was withdrawn in 6 cases, rechal-lenge resulted in prompt return of clinical features, although there was some evidence that patients who developed nephrotoxicity with one H2-antagonist might be able to tolerate substitution with another. The effect was rare (an earlier analysis estimated an incidence of around 1 in 100 000 treated patients) but with the increasing availability of over-the-counter H2-antagonist formulations it was important to be aware of the risk.

Effects on the liver. A cohort study involving 108 891 patients given cimetidine, ranitidine, famotidine, or omeprazole between 1990 and 1993, found 33 cases meeting the authors’ definition of clinically serious liver injury (cholestatic in 8 cases, hepatocellular in 15 and mixed in 10), most of whom presented with jaundice. Of these cases of liver injury, 12 were among current users of cimetidine, compared with 5 among users of ranitidine and 1 omeprazole user. It was estimated that the incidence of hepatotoxicity among patients using cimetidine was 2.3 cases per 10 000 users, and the adjusted relative risk was 5.5 times that of non-users. The relative risk for use of ranitidine or omeprazole was calculated at 1.7 and 2.1 respectively. The risk with cimetidine was greatest at high doses (800 mg daily or above) and at the beginning of therapy. For reports of liver damage with famotidine and cimetidine.

Effects on the nervous system. Cimetidine has been associated with a number of adverse neurological effects including confusion, bizarre behaviour, reversible brain stem syndrome (with ataxia, dysarthria, visual impairment, deafness, and paraesthesia), coma, convulsions, encephalopathy, visual hallucinations, paranoia, chorea, myopathy, and neuropathy. These reactions occur mainly in patients who are elderly, critically ill, or with impaired renal or hepatic function, in whom there may be increased penetration of the blood-brain barrier by cimetidine. Single-dose studies in young healthy subjects have found no adverse changes in performance, central nervous function, or subjective assessment of mood after oral cimetidine 200 or 400 mg.

There is no clear evidence that cimetidine is a more frequent cause of CNS reactions than ranitidine, famotidine, or nizatidine.

Effects on the skin. Widespread erythrosis-like lesions in a 36-year-old man were probably induced by cimetidine. There has been a report of a skin eruption clinically consistent with erythema annulare centrifugum developing in a patient after 6 months of treatment with cimetidine the eruption resolved after withdrawal of cimetidine and reappeared on rechallenge. The condition had not recurred during therapy with ranitidine. Erythema multiforme eruptions occurred after both cimetidine and famotidine in one patient. There have been reports of the Stevens-Johnson syndrome during cimetidine treatment in patients with a history of hypersensitivity to penicillin or sulfon-amides, and a report of toxic epidermal necrolysis. Urticarial vasculitis and alopecia have also been associated with cimetidine treatment.

Fever. There are reports of febrile reactions associated with cimetidine. Fever has also been reported with famotidine and ranitidine.

Hypersensitivity. Facial oedema, laryngospasm, pruritus, rash, angioedema and anaphylaxis have been reported in patients receiving cimetidine by mouth or intravenously. See also under Effects on the Skin.

Infection. Treatment with H2-antagonists may predispose patients to salmonella infection, probably because the decrease in gastric acidity reduces the gastric killing of ingested organisms. The greatest increase in risk was seen in patients over 65 years of age.

There are conflicting data on whether the use of H2-antagonists for prophylaxis of stress ulcers in critically ill patients increases the risk for pneumonia (see under Peptic Ulcer Disease). However, a case-control study in a large cohort of patients in primary care suggested that the risk of developing pneumonia in these less-severely ill patients was increased by antisecretory drugs: the relative risk was 1.63 in patients receiving ^-antagonists, and 1.89 in those prescribed a proton pump inhibitor there was also some evidence of a dose-response relationship in the latter group.

Data from case-control studies suggest that gastric acid suppression by H2-antagonists may also be a risk factor for Clostridium difficile-assodated disease. A case-control study in very low birth-weight infants found that use of H2-antagonists was associated with an increased incidence of necrotising enterocolitis. The authors postulate that this could be due to bacterial overgrowth in a less acidic gastric environment.

Mai absorption. Vitamin B12 deficiency has been reported in association with acid-suppressive therapy, including H2-antagonists. The deficiency was thought to result from impaired release of vitamin B12 from food protein, which requires gastric acid and pepsin.

Overdosage. No serious toxic effects were noted in reports of overdosage in patients who took cimetidine 5.2 to 20 g (including one patient who took about 12 g daily for 5 days). Resultant plasma concentrations had been up to 57micrograms/mL compared with a usual peak plasma concentration of 1 microgram/mL after a 200-mg dose. However, an overdose of about 12 g produced high pulse rate, dilated pupils, speech disturbances, agitation and disorientation in one patient and respiratory depression in another patient who had chronic schizophrenia and was also taking trifluoperazine and hydroxyzine. Also, fatal bradycardia has been reported after overdosage with an unknown amount of cimetidine and diazepam. In a review of 881 cases of cimetidine overdose, excluding cases where several drugs were taken, it was concluded that the toxicity of cimetidine after acute overdose was very low. No symptoms were observed in 79% of cases, which included ingestions of up to 15 g of cimetidine, and only 3 patients had moderate clinical manifestations (dizziness and bradycardia CNS depression vomiting). No patients had major medical outcomes and there were no fatalities. Gastric emptying was performed in 34% of cases but supportive measures and symptomatic treatment alone may be adequate. Forced diuresis does not appear to enhance the excretion of cimetidine from the body, and is not recommended.

Precautions

Before giving cimetidine or other histamine H2-antagonists to patients with gastric ulcers the possibility of malignancy should be considered since these drugs may mask symptoms and delay diagnosis. They should be given in reduced dosage to patients with renal impairment.

Intravenous injections of cimetidine should be given slowly and intravenous infusion is preferred, particularly for high doses and in patients with cardiovascular impairment.

Breast feeding. In the UK, manufacturers advise that mothers receiving cimetidine avoid breast feeding. Cimetidine is reported to be actively transported into breast milk, resulting in a milk:se-rum ratio 5.5 times higher than that expected with passive diffusion. In one case, where cimetidine was detected in the milk of a nursing mother in concentrations higher than in her plasma, it was calculated that the maximum amount of cimetidine that an infant could ingest assuming an intake of about 1 litre of milk daily and fed at the time of peak concentrations would be about 6 mg. However, the Committee on Drugs of the American Academy of Pediatrics has pointed out that there was no evidence of signs or symptoms attributable to the drug in the infant in this case, despite 6 months of breast feeding, and cimetidine has been classified by that body as usually compatible with breast feeding

Burns. The clearance of cimetidine has been reported to be increased in burn patients, with the increase correlating to the size of the burn. Despite another study that reported a decreased renal clearance (but an increased non-renal clearance) early in the evolution of burn injury, it has been recommended that the dosage of cimetidine be increased in patients with burns, depending on the extent of injury. A requirement for increased dosage has also been noted in paediatric burns patients.

Helicobacter pylori testing. In one study, 2 of 11 patients with Helicobacter pylori infection had false-negative urea breath tests while receiving high dose ranitidine (600 mg daily). The breath test became positive again within 5 days of stopping therapy. The manufacturers of the breath test recommend it should not be performed for at least 2 weeks after stopping antisecretory drug therapy.

Hepatic impairment. An increased resistance to H2-receptor antagonists has been reported in patients with cirrhosis, see Ranitidine. For a suggestion that dosage reduction of cimetidine may be required in patients with portal systemic encepha-lopathy, see Administration in Hepatic Impairment.

Porphyria. Cimetidine is considered to be unsafe in patients with porphyria although there is conflicting experimental evidence of porphyrinogenicity.

For reference to clinical and biochemical improvement in porphyric patients receiving cimetidine, see below.

Renal impairment. The clearance of cimetidine is reduced in renal impairment and dosage reduction is recommended (see under Administration in Renal Impairment).

Interactions

Cimetidine and other H2-antagonists can reduce the absorption of drugs such as dasatinib, ketoconazole, and possibly itraconazole, whose absorption is dependent on an acid gastric pH. For the effect of itraconazole on cimetidine see Antifungals, below. Cimetidine may inhibit the hepatic metabolism of many drugs by binding to cytochrome P450 isoenzymes, notably CYP1A2, CYP2C9, CYP2D6, and CYP3A4. Although many such interactions may occur, only a few are considered clinically significant, notably those with phenytoin, theophylline, lidocaine, and oral anticoagulants. Avoidance of the combination, or a reduction in the dosage of these drugs may be required.

Cimetidine can affect a wide range of drugs” but these interactions are of clinical significance for only a few, particularly those that have a narrow therapeutic index where the risk of toxicity may necessitate adjustment of dosage. The majority of interactions are due to binding of cimetidine to cytochrome P450 isoenzymes in the liver with subsequent inhibition of microsom-al oxidative metabolism and increased bioavailability or plasma concentrations of drugs metabolised by these enzymes. A few interactions are due to competition for renal tubular secretion. Other mechanisms of interaction such as changes in hepatic blood flow play only a minor role.

Significant or potentially significant interactions have occurred with

• antiepileptics such as phenytoin and carbamazepine

• biguanide antidiabetics

• lidocaine

• nifedipine

• opioid analgesics

• procainamide

• theophylline

• tricyclic antidepressants such as amitriptyline

• warfarin and other oral anticoagulants

• zalcitabine

• zolmitriptan

Combinations of these drugs and cimetidine should be avoided or used with caution, with monitoring of effects or plasma-drug concentrations and reductions in dosage as appropriate. Famotidine, nizatidine, and ranitidine do not inhibit cytochrome P450, and the potential for drug interactions is therefore reduced.

Alcohol. Any interaction between H2-antagonists and alcohol is generally thought unlikely to be clinically significant.

Antacids. Single-dose studies of the interaction between cimetidine and antacids have shown reduced bioavailability of cimetidine as well as no interaction. The neutralising capacity of the antacid appears to be a factor in determining whether an interaction occurs and a dose with less than 50 mmol neutralising capacity will have little, if any, effect on cimetidine absorption. There is no evidence that the therapeutic efficacy of cimetidine is reduced and with long-term use of the combination the bioavailability of cimetidine is unlikely to be reduced.

Antifungals. Itraconazole increased the area under the concentration-time curve of cimetidine, and reduced the total plasma clearance and renal tubular secretory clearance of cimetidine in a pharmacokinetic study in 8 healthy subjects. The authors proposed that this was due to inhibition of P-glycoprotein-mediated renal tubular secretion.

Antimuscarinics. The antimuscarinic propantheline delays gastric emptying and reduces intestinal motility and has been reported to reduce the bioavailability of cimetidine.

Prokinetic drugs. Metoclopramide may reduce the bioavailability of cimetidine possibly due to reduction of gastrointestinal transit time. A similar interaction has been reported between cimetidine and the prokinetic drug cisapride The clinical significance of this interaction is questionable since such combinations may be clinically effective, although the use of cisapride is now restricted in many countries.

Sucralfate. Licensed product information for the mucosal pro-tectant sucralfate states that it has been shown to reduce the bioavailability of cimetidine and other H2 antagonists, presumably due to binding in the gastrointestinal tract. The effect can be avoided by separating doses of the two drugs by 2 hours, but it is not clear whether the interaction has a clinical significance.

Pharmacokinetics

Cimetidine is readily absorbed from the gastrointestinal tract and peak plasma concentrations are obtained after about an hour when given on an empty stomach a second peak may be seen after about 3 hours. Food delays the rate and may slightly decrease the extent of absorption, with the peak plasma concentration occurring after about 2 hours.

The bioavailability of cimetidine after oral doses is about 60 to 70%. Cimetidine is widely distributed and has a volume of distribution of about 1 litre/kg and is weakly bound, about 20%, to plasma proteins. The elimination half-life from plasma is about 2 hours and is increased in renal impairment. Cimetidine is partially metabolised in the liver to the sulfoxide and to hydroxymethylcimetidine. About 50% of an oral dose, and 75% of an intravenous dose, is excreted unchanged in the urine in 24 hours. Cimetidine crosses the placental barrier and is distributed into breast milk.

Children. Renal function is limited in the first few months of life and half-lives of 1.1 to 3.7 hours have been reported for cimetidine in neonates._ A dosage regimen for neonates based on renal function has been suggested with 15 to 20 mg/kg daily for full-term neonates, but with lower doses for premature neonates and those with renal dysfunction. However, single doses of 5 to 7 mg/kg may be sufficient to suppress gastric acid secretion in neonates.

In older infants and children maturation of renal function is complete and the clearance of cimetidine is increased compared with that in adults while younger children show higher clearance values than older children. A Typical dosage regimen for children is 30 mg/kg daily, in 3 or 4 divided doses However, even this dose might not produce optimal control of gastric acid.

Uses and Administration

Cimetidine is a histamine H2-antagonist and inhibits actions of histamine mediated by H2-receptors such as gastric acid secretion and pepsin output. It is used where inhibition of gastric acid secretion may be beneficial, as in peptic ulcer disease, including stress ulceration, gastro-oesophageal reflux disease, selected cases of persistent dyspepsia, pathological hypersecretory states such as the Zollinger-Ellison syndrome, and in patients at risk of acid aspiration during general anaesthesia or child birth. Cimetidine may also be used to reduce malabsorption and fluid loss in patients with the short bowel syndrome and to reduce the degradation of enzyme supplements given to patients with pancreatic insufficiency.

Cimetidine may be given orally, by the nasogastric route, or parenterally by the intravenous or intramuscular routes the total daily dose by any route should not normally exceed 2.4 g. Although some formulations are prepared as the hydrochloride, strengths and doses are expressed in terms of the base. Cimetidine 100 mg is equivalent to about 114.4 mg of cimetidine hydro-chloride. Doses should be reduced in renal impairment and may also need to be reduced in hepatic impairment.

Specific Disease Doses

In the management of benign gastric and duodenal ulceration a single daily oral dose of 800 mg at bedtime is recommended, which should be given for at least 4 weeks in the case of duodenal, and for at least 6 weeks in the case of gastric, ulcers. Where appropriate a maintenance dose of 400 mg may then be given once daily at bedtime, or twice daily in the morning and at bedtime. Other regimens have also been used for treatment and maintenance.

In gastro-oesophageal reflux disease the recommended oral dose is 400 mg four times daily (with meals and at bedtime), or 800 mg twice daily, for 4 to 8 weeks. In pathological hypersecretory conditions, such as the Zollinger-Ellison syndrome, an oral dose of 300 or 400 mg four times daily is normally used, although sometimes higher doses may be necessary. Doses of 200 to 400 mg orally, by nasogastric tube, or parenterally (200 mg only for direct intravenous injection) every 4 to 6 hours are recommended for the management of patients at risk from stress ulceration of the upper gastrointestinal tract. In patients at risk of developing the acid aspiration syndrome, an oral dose of 400 mg may be given 90 to 120 minutes before the induction of anaesthesia, or at the start of labour (in obstetric practice), and doses of up to 400 mg (by the parenteral route if appropriate, see below) may be repeated at intervals of 4 hours if required. Doses of up to 200 mg four times daily have been taken for non-ulcer dyspepsia 100 mg at night has been used in the prophylaxis of nocturnal heartburn. To reduce the degradation of pancreatic enzyme supplements, patients with pancreatic insufficiency, as in cystic fibrosis, may be given oral cimetidine 800 to 1600 mg daily in 4 divided doses, 60 to 90 minutes before meals.

Parenteral Administration

In the UK, the usual dose of cimetidine by intravenous injection is 200 mg, which should be given slowly over at least 5 minutes and may be repeated every 4 to 6 hours. If a larger dose is required, or if the patient has cardiovascular impairment, intravenous infusion is recommended. For an intermittent intravenous infusion the recommended dose is 200 to 400 mg every 4 to 6 hours if necessary. For a continuous intravenous infusion the recommended rate is 50 to 100 mg/hour. The usual intramuscular dose is 200 mg which may be repeated at intervals of 4 to 6 hours. In the USA, parenteral dosage recommendations are 300 mg every 6 to 8 hours by intramuscular injection or by slow intravenous injection over at least 5 minutes. The same dosage may be given by intermittent intravenous infusion over 15 to 20 minutes for continuous intravenous infusion the recommended rate is 37.5 mg/hour, which may be preceded by 150 mg as an intravenous loading dose. However, a rate of 50 mg/hour is recommended for prevention of stress ulceration.

Children’s Doses

For children over one year of age 25 to 30 mg/kg daily may be given in divided doses, by mouth or parenterally. Under 1 year of age, 20 mg/kg daily in divided doses has been used (see also Children, under Pharmacokinetics).

Administration in hepatic impairment. The bioavailabili-ty of cimetidine may be increased in patients with cirrhosis’ and a dosage reduction of up to 40% has been suggested in patients with portal systemic encephalopathy. However, UK and US licensed drug information does not include recommendations for dosage adjustment in hepatic impairment.

Administration in renal impairment. The dosage of cimetidine should be reduced in patients with renal impairment suggested doses according to creatinine clearance (CC) are:

• CC over 50 mL/minute: normal dosage

• CC 30 to 50 mL/minute: 200 mg four times daily

• CC 15 to 30 mL/minute: 200 mg three times daily

• CC 0 to 15 mL/minute: 200 mg twice daily

Cimetidine is removed by haemodialysis, but not significantly removed by peritoneal dialysis.

Bladder disorders. Cimetidine effectively relieved symptoms in patients with painful bladder disease (encompassing conditions including cystitis, painful bladder syndrome, and urethral syndrome), especially suprapubic pain and nocturia, despite no apparent histological change in the bladder mucosa after treatment.

Dapsone toxicity. Cimetidine might reduce the haemolysis and methaemoglobinaemia associated with dapsone. For references supporting this suggestion, see Effects on the Blood, under Dapsone.

Diagnostic use. Cimetidine blocks renal tubular secretion of creatinine and has been used experimentally to improve the accuracy of estimations of glomerular filtration rate from creatinine clearance in patients with renal disease. Best results were achieved with a bolus dose of 1.2 g and the use of such a high dose was questioned.

Echinococcosis. Cimetidine has been given with albendazole to increase its effect (by inhibiting its metabolism) in the treatment of echinococcosis.

Immunomodulation. Studies in mice and humans have shown that H2-antagonists have an immunoregulatory effect. T-lymphocyte suppressor cells have histamine H2 receptors and cimetidine has been reported to reduce activity of these cells, thus enhancing immune response. There is also some evidence that it enhances cellular immunity, notably natural killer cell activity. This discovery has led to the investigation of cimetidine in a number of disorders associated with alteration of the immune response including eosinophilic fasciitis, herpesvirus infections, mucocutaneous candidiasis, hypogammaglobulinae-mia, and various malignancies.

EOSINOPHILIC FASCIITIS. Eosinophilic fasciitis is a scleroderma-like syndrome of inflammation of the muscle fascia and associated eosinophilia and hypergammaglobulinaemia. A1-though it responds well to corticosteroid therapy in most cases, cimetidine has also been tried. The effect of cimetidine on eosinophilic fasciitis is unpredictable with both remission and lack of response having been reported in a few patients.

HERPESVIRUS AND PAPILLOMAVIRUS INFECTIONS. Although there have been numerous isolated and anecdotal reports of a beneficial response to cimetidine in patients with infections due to various herpesviruses, including genital herpes simplex, infectious mononucleosis, and herpes zoster” some of these reports have been criticised’ mainly on the grounds that the majority of cases of herpes zoster will resolve within 2 to 3 weeks whether any treatment is given or not. Also, a double-blind placebo-controlled study involving 63 patients with herpes zoster found no evidence that cimetidine relieved the pain or accelerated the rate of healing of lesions.

There are reports of benefit from the use of cimetidine in patients with viral warts, but controlled studies have failed to show significant benefit.

MALIGNANT NEOPLASMS. Because of its immunomodulatory effects cimetidine has been tried, with some reported benefit, as an adjuvant in the management of a variety of malignant neoplasms such as those of the gastrointestinal tract. However, a large randomised study failed to show any benefit for cimetidine compared with placebo in gastric cancer. A similar study with ranitidine also failed to show any significant benefit.

Mastocytosis. Cimetidine, alone or with an antihistamine (histamine H1 antagonist), has been reported to relieve gastrointestinal symptoms, pruritus, and urticaria’ in patients with mastocytosis.

Paracetamol toxicity. It has been suggested that cimetidine might be of use in the treatment of paracetamol poisoning because of its inhibition of the cytochrome P450 system. However, there appears to be no evidence to support the claims of benefit made in some anecdotal reports.

Porphyria. There are reports of patients with acute intermittent porphyria showing clinical and biochemical improvement during treatment with cimetidine. Cimetidine is, however, considered to be unsafe in patients with porphyria (see under Precautions).

Skin disorders. Cimetidine has been used alone or with an antihistamine (H1-antagonist) in various skin disorders. H2-antagonists such as cimetidine and ranitidine have produced improvement in certain types of urticaria, especially those associated with cold or angioedema. Their routine use in urticaria is controversial, but in practice their addition to conventional treatment can be tried in resistant cases. Little additional benefit has been found with combination therapy in dermographic urticaria. Although they may act by antagonism of H2-recep-tors on cutaneous bloodvessels, other mechanisms of action may be involved. Patients with pruritus of various causes may also respond to H1-antagonists, but studies in larger groups of patients have demonstrated no benefit.

Preparations

British Pharmacopoeia 2008: Cimetidine Injection Cimetidine Oral Solution Cimetidine Oral Suspension Cimetidine Tablets

The United States Pharmacopeia 31, 2008: Cimetidine in Sodium Chloride Injection Cimetidine Injection Cimetidine Tablets.

Proprietary Preparations

Argentina: Tagamet Ulcerfen

Australia: Cimehexal Magicul Sigmetadinel Tagamet

Austria: Acidex Cimetag Neutromed Neutronorm Sodexx Cimetidine Ulcometin Ulcostad

Belgium: Doccimeti Nuardin Tagamet

Brazil: Cigamete Cimetetax Cimetidan Cimetil Cimetilab Cimetin Cimetinab Cimetinax Cimetival Cintidina Cinton Climatidine Duomet Eti-dine Gastidirr|- Laveranf Novacimet Pristonal Prometidine Stomakon Tagaliv Tagamet Tranimet Ulcedine Ulcenon Ulcerac Ulceracid Ulcimet Ulcinax Ulcitag Ulcitrat

Canada: Gaviscon Prevent Novo-Cimetine Nu-Cimet Tagamet

Czech Republic: CimLich Lock-2 Primamet

Denmark: Aciloc Acinil Cimecodan Hocimin Novamet

France: Stomedine Tagamet

Germany: Azucimet Cime Cimebeta Cimehexal Cimet CimLich duraH2 Gastroprotect H2 Blocker Sigacimet Tagamet

Greece: Alkastorrr Besidin Cimeton Gastrolene Tagamet Tamper

Hong Kong: Cementin Cimedine Cimeta Cimulcen Citidine Gastab Gastidine Maritidine Simaglen Syncomet Tagadine Tagamet Ulcomet

Hungary: Histodil

India: Cimet

Indonesia: Cimexol Corsamet Licomet Nulcer Sanmetidin Tagamet Ulcedine Ulcumet Ulcusan Ulsikur Xepamet

Ireland: Cedine Cimagen Cimeldine Dyspamet Galenamet Geramet Pinamet Tagamet

Israel: Cemidin Cimetag Cimi Tagamet

Italy: Biomag Brumetidina Dinaf Etideme Notulf Stomet Tagamet Temic Ulcedin Ulcodina Ulcomedina Ulis

Malaysia: Cimulcer Shintamet Tagamet Ulcidine Xepamet

Mexico: Alcatex Antil Cimebec Cimedul Cimeffer Cimetase Colimet Columina Gastrodina Metidisol Procimeti Sercim Sinegastrin Tagamet Ulcedine Ulmarin Ulserral

The Netherlands: Tagamet

Norway: Cimal Tagamet

New Zealand: Cytine

Philippines: Antag Ciclem Cimecid Cimulcer Duogastril Montidin Tagamet Ulcenon

Poland: Altramet Cimegast

Portugal: Cim Evicer Tagamet Ulceridine

Russia: Histodil

South Africa: Aci-Med Cimlok Cinadine Cymi Hexamet Lenamet Secadine Tagamet Ulcim

Singapore: Cementin Cimulcer Citidine Gastromet Himetin Shintamet Tagamet Xepamet

Spain: Ali Veg Fremet Mansal Tagamet

Sweden: Acinil Tagamet

Switzerland: Malimed Tagamet

Thailand: Aidar Alserine Cencamet Cidine Cigamet Gimiet-P Cimetine Cimidine Citidine Clinimet Duotric Gastrodin Iwamet Manomet Med-Gastramet Milamet Peptica Promet Rinadine Sertidine Siamidine Simaglen Simex Tagamet Ulcedine Ulcemet Ulcimet Umamett

United Arab Emirates: Cimetag

UK: Acitak Dyspamet Galenamet Peptimax Tagamet Ultec Zita

USA: Tagamet

Venezuela: Cavimet Cimetix Gadol Iscaten Mempotal

Multi-ingredient

The Netherlands: Aciflux

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