(British Approved Name, US Adopted Name, rINN)
(British Approved Name Modified, rINNM)
Pharmacopoeias. In China, Europe, Japan, and US.
European Pharmacopoeia, 6th ed. (Ranitidine Hydrochloride). A white or pale yellow, crystalline powder. It exhibits polymorphism. Freely soluble in water sparingly soluble or slightly soluble in dehydrated alcohol very slightly soluble in dichloromethane. A 1% solution in water has a pH of 4.5 to 6.0. Store in airtight containers. Protect from light.
The United States Pharmacopeia 31, 2008 (Ranitidine Hydrochloride). A white to pale yellow, practically odourless, crystalline powder. It is sensitive to light and to moisture. Very soluble in water sparingly soluble in alcohol. A 1% solution in water has a pH of 4.5 to 6.0. Store in airtight containers. Protect from light.
As for Cimetidine. Unlike cimetidine, ranitidine has little or no anti-androgenic effect, despite isolated reports of gynaecomastia and impotence.
Carcinogenicity. For a discussion of the possible association between histamine H2-antagonists and cancer, including mention of a study with ranitidine, see Cimetidine.
Effects on the blood. For a discussion of the adverse haematological effects of H2-antagonists, see Cimetidine.
Effects on the cardiovascular system. Similarly to cimetidine, bradycardia, AV block, and cardiac arrest have been reported rarely during ranitidine therapy. A positive inotropic effect, without significant changes in heart rate or blood pressure, has also been reported in healthy subj ects and pretreatment with ranitidine has blocked the cardiac depressant effects seen in some subjects given famotidine or nizatidine. Although studies in critically ill patients and healthy subjects have found no adverse haemodynamic effects associated with ranitidine, it is likely that a small proportion of patients are more susceptible to the cardiovascular effects of ranitidine. Caution is recommended when ranitidine is given intravenously, particularly in patients with cardiovascular disease.
Effects on the endocrine system. Unlike cimetidine, ranitidine does not bind to androgen receptors and has little, if any, anti-androgenic effect. Studies in men taking ranitidine for the management of duodenal ulcer reported no significant changes in the plasma concentrations of testosterone, luteinising hormone, follicle-stimulating hormone, or prolactin after up to 2 years of treatment no significant changes in sperm concentration, motility, or morphology were noted. There have been isolated reports of gynaecomastia, loss of libido, and impotence associated with ranitidine, but in 9 patients with cimetidine-induced breast changes and impotence, transfer to ranitidine resulted in resolution of these symptoms.
Effects on the eyes. For a report of an increase in intra-ocular pressure associated with ranitidine, see under Cimetidine. A cohort study involving 140 128 patients receiving anti-ulcer therapy, 70 389 of whom received ranitidine, found no evidence that any of the drugs studied were associated with a major increased risk of vascular or inflammatory disorders of the eye.
For reference to loss of colour vision in a child receiving ranitidine see under Effects on the Nervous System, below.
Effects on the kidneys. For reference to interstitial nephritis associated with H2-antagonists including ranitidine, see under Cimetidine.
Effects on the liver. There have been some case reports of ranitidine hepatotoxicity. The increase in relative risk seen in a large cohort study involving 108 891 patients receiving antisecretory therapy was less for ranitidine (1.7:1) than for cimetidine.
Effects on the nervous system. Ranitidine has been associated with adverse neurological effects including confusion, loss of colour vision, aggressiveness, lethargy, somnolence, disorientation, depression, hallucinations, and severe headache. As with cimetidine these reactions occur mainly in the elderly, the severely ill, or patients with renal or hepatic impairment. Single-dose studies in young healthy subjects have found no adverse changes in performance, CNS function, or subjective assessment of mood after oral doses of ranitidine 150 or 300 mg.
Effects on the skin. A report of vasculitic rash occurring in 3 patients undergoing ranitidine therapy. In each case the rash cleared after withdrawal of the drug.
See also under Hypersensitivity, below, and also Cimetidine.
Fever. A report of pyrexia associated with ranitidine. Apart from raised temperature the patient was otherwise well fever resolved on stopping ranitidine and recurred on rechallenge.
Hypersensitivity. Respiratory stridor and an urticarial rash occurred in a patient shortly after taking the first dose of ranitidine the symptoms responded to adrenaline subcutaneously.
Meningitis. A 30-year-old man developed aseptic meningitis on 3 occasions after use of ranitidine. In each case symptoms resolved rapidly on withdrawal of the drug.
As for Cimetidine.
Helicobacter pylori testing. For reference to the effect of ranitidine on the urea breath test for Helicobacter pylori.
Hepatic impairment. Sixteen of 27 patients with cirrhosis of the liver and indications for treatment with an H2-antagonist (peptic ulcer, gastritis, or reflux oesophagitis) failed to respond to ranitidine 300 mg compared with 6 failures from 32 patients without cirrhosis. Famotidine 40 mg was given to 10 of the cirrhotic nonresponders and 8 still had no response 7 of these patients were given cimetidine 800 mg and only 1 responded. In the control group, all 3 patients given famotidine did not respond and only 1 responded when given cimetidine. It was concluded that the incidence of non-response to H2-antagonists is increased in patients with liver cirrhosis but no explanation could be given for this effect. Interestingly there is an earlier report of patients with cirrhosis demonstrating increased bioavailability and decreased clearance of ranitidine.
Porphyria. Ranitidine is considered to be unsafe in patients with porphyria although there is conflicting experimental evidence of porphyrinogenicity.
Renal impairment. For evidence of reduced clearance of ranitidine in patients with renal impairment see Administration in Renal Impairment, below.
Unlike cimetidine, ranitidine does not seem to affect cytochrome P450 to any great extent, and therefore is considered to have little effect on the metabolism of other drugs. However, as with other H2-antagonists, its effects on gastric pH may alter the absorption of some other drugs.
A review comparing the drug interactions of ranitidine with those of cimetidine.
Cisapride. Peak plasma concentrations of ranitidine were achieved more rapidly in 12 healthy subjects who also took cisapride. The clinical significance is questionable and such combinations have been used clinically, although the use of cisapride is now restricted in most countries.
Ranitidine is readily absorbed from the gastrointestinal tract with peak concentrations in plasma occurring about 2 to 3 hours after oral doses. Food does not significantly impair absorption. The bioavailability of ranitidine after oral doses is about 50%. Ranitidine is rapidly absorbed on intramuscular injection, with peak plasma concentrations occurring in about 15 minutes. It is weakly bound, about 15%, to plasma proteins. The elimination half-life is about 2 to 3 hours and is increased in renal impairment. A small proportion of ranitidine is metabolised in the liver to the N-oxide, the N-oxide, and desmethylranitidine the S-oxide is the major metabolite but accounts for only about 4 to 6% of a dose. About 30% of an oral dose and 70% of an intravenous dose is excreted unchanged in the urine in 24 hours, primarily by active tubular secretion there is some excretion in the faeces. Ranitidine crosses the placental barrier and is distributed into breast milk.
Distribution into breast milk. A study in a mother given multiple doses of ranitidine showed higher concentrations in breast milk than in serum the minimum milk concentration occurred between 1 and 2 hours after a dose and the highest concentration was towards the end of the 12-hour dosing interval. The amount that would be ingested by the infant could not be reliably estimated because of the variable milk to serum ratio.
Enterohepatic recycling. Some individuals have a second peak in the plasma concentration of ranitidine, which could be due to enterohepatic recirculation. However, only 0.7 to 2.6% and 0.3 to 1.0% of a dose of ranitidine was excreted into the bile of 3 patients in 24 hours after 50 mg given intravenously or 300 mg by mouth respectively, indicating that significant recirculation did not occur.
Neonates. Renal function is limited in the first month of life, and reduced clearance of ranitidine would be expected. Blood samples taken from 27 full-term neonates given a single intravenous dose of ranitidine 2.4mg/kg revealed the following pharmacokinetic data: elimination half-life, 3.45 hours total volume of distribution, 1.52 litres/kg total plasma clearance, 5.02 mL/kg per minute. None of the infants had renal or hepatic impairment. In another study, an elimination half-life of 6.61 hours was found in 13 full-term neonates given ranitidine 2 mg/kg. See also Administration in Children, below.
Uses and Administration
Ranitidine is a histamine H2-antagonist with actions and uses similar to those of cimetidine. Ranitidine may be given orally or parenterally by the intravenous or intramuscular routes. Although most preparations contain ranitidine hydrochloride, strengths and doses are expressed in terms of the base. Ranitidine hydrochloride 111.6 mg is equivalent to about 100 mg of ranitidine.
In the management of benign gastric and duodenal ulceration a single daily oral dose of 300 mg at bedtime or 150 mg twice daily (in the morning and at bedtime) is given initially for at least 4 weeks. A dose of 300 mg twice daily may also be used in duodenal ulcer. Where appropriate a maintenance dose of 150 mg daily may be given at bedtime. Ranitidine 150 mg twice daily may be given during therapy with NSAIDs for prophylaxis against duodenal ulceration. A suggested dose for the treatment of peptic ulcer in children is 2 to 4 mg/kg twice daily to a maximum of 300 mg in 24 hours a maintenance dose of 2 to 4 mg/kg once daily may be used, to a maximum of 150 mg daily.
For duodenal ulcer associated with Helicobacterpylori infection, ranitidine in a usual oral dose of 300 mg once daily or 150 mg twice daily may be given as part of triple therapy with amoxicillin 750 mg and metron-idazole 500 mg, both three times daily, for 2 weeks. Therapy with ranitidine should then be continued for a further 2 weeks.
In gastro-oesophageal reflux disease the oral dose is 150 mg twice daily or 300 mg at bedtime for up to 8 weeks or, if required, 12 weeks. This may be increased to 150 mg four times daily for up to 12 weeks in severe cases. In the maintenance of healing erosive oesophagitis, a dose of 150 mg twice daily may be used. Although there is limited data on the use of ranitidine for gastro-oesophageal reflux disease and erosive oesophagitis in children, a dose of 5 to 10 mg/kg daily, usually given in 2 divided doses, has been used. In pathological hypersecretory conditions, such as the Zollinger-Ellison syndrome, the initial oral dose is usually 150 mg twice or three times daily and may be increased if necessary doses of up to 6 g daily have been used. Alternatively, an intravenous infusion may be given, initially at a rate of 1 mg/kg per hour the rate may be increased by increments of 500 micrograms/kg per hour, beginning after 4 hours, if required.
For the management of patients at risk from stress ulceration of the upper gastrointestinal tract, parenteral therapy may be given as a slow intravenous injection of a 50-mg priming dose followed by a continuous intravenous infusion of 125 to 250 micrograms/kg per hour. Oral doses of 150 mg twice daily may be given once oral feeding is resumed.
In patients at risk of developing the acid aspiration syndrome during general anaesthesia, an oral dose of 150 mg may be given 2 hours before the induction of anaesthesia and preferably also 150 mg the previous evening. Alternatively, a dose of 50 mg may be given by intramuscular or slow intravenous injection 45 to 60 minutes before the induction of anaesthesia. In obstetric patients, at the start of labour an oral dose of 150 mg may be given and may be repeated at intervals of 6 hours if required.
In patients with chronic episodic dyspepsia, a dose of 150 mg twice daily orally for up to 6 weeks may be given. For the short-term symptomatic relief of dyspepsia a dose of 75 mg, repeated if necessary up to a maximum of 4 doses daily, may be taken. Treatment should be restricted to a maximum of 2 weeks of continuous use at one time.
The usual dose of ranitidine by intramuscular or intravenous injection is 50 mg, which may be repeated every 6 to 8 hours the intravenous injection should be given slowly over not less than 2 minutes and should be diluted to contain 50 mg in 20 mL. For an intermittent intravenous infusion the recommended dose in the UK is 25 mg/hour given for 2 hours which may be repeated every 6 to 8 hours. A rate of 6.25 mg/hour has been suggested for continuous intravenous infusion although higher rates may be used for conditions such as Zollinger-Ellison syndrome or in patients at risk from stress ulceration (see above).
Dosage In Renal Impairment
For dosage in renal impairment, see below.
Administration in children. The disposition of ranitidine in children is not significantly different from that in young adults and an oral dose of 2 mg/kg (about equal to an adult dose of 150 mg) has been used for the prevention of acid aspiration in children undergoing surgery.A study in premature infants being treated with dexamethasone for bronchopulmonary dysplasia found that infusion of ranitidine 62.5 micrograms/kg per hour was sufficient to raise and maintain gastric pH above 4 to help protect against gastrointestinal bleeding and perforation. Another study found 500 micrograms/kg twice daily to be sufficientfor preterm infants, but that 1.5 mg/kg three times daily was needed for full-term infants. A minimum dosage of 3 mg/kg daily was suggested for stress ulcer prophylaxis in older infants and children.
Administration in renal impairment. A study in patients with varying degrees of renal impairment found that the mean terminal half-life of ranitidine was increased from 2.09 hours in subjects with normal renal function to between 4.23 and 8.45 hours in patients with renal impairment, the degree of prolongation being proportional to the degree of impairment as measured by glomerular filtration rate. As a result of these findings it was recommended that the dose of ranitidine should be halved in patients with a glomerular filtration rate of 20 mL/minute or less. Licensed drug information therefore recommends that dosage of ranitidine be reduced in patients with severe renal impairment. For patients with a creatinine clearance of less than 50 mL/minute, an oral dose of 150 mg daily is recommended, which may be cautiously increased to 150 mg every 12 hours if needed.
For intravenous use, licensed recommendations vary between countries. In the UK, individual doses may be reduced to 25 mg, while the frequency is adjusted in the USA to give a recommended usual dose of 50 mg every 18 to 24 hours, which may be cautiously increased to every 12 hours or more often if necessary. Ranitidine 150 mg daily provided adequate serum concentrations without excessive accumulation in 20 patients undergoing regular haemodialysis. The serum-ranitidine concentrations fell by about 50% during a 4-hour haemodialysis session but less than 3% of the dose was removed and supplemental doses after dialysis were considered unnecessary.
Cystic fibrosis. A comparative study involving 29 patients with cystic fibrosis found that ranitidine was more effective than cisapride in improving dyspeptic symptoms and gastric emptying and distension. Antisecretory drugs are also used in this condition to decrease the inactivation of oral pancreatic enzyme therapy.
Immunomodulation. Like cimetidine, ranitidine has been proposed to have immunoregulatory effects. However, ranitidine 300 mg twice daily had no effect on absolute CD4 cell counts or plasma HIV RNA in patients with HIV infection in a placebo-controlled study. Similarly, ranitidine had no significant benefit in patients with gastric cancer (see Malignant Neoplasms).
Skin disorders. As with cimetidine, ranitidine has been tried in various skin disorders. Ranitidine 300 mg twice daily by mouth has been reported to be of benefit as an adjuvant to local treatment with corticosteroids and a moisturising ointment in patients with atopic dermatitis. There are reports of improvements in psoriasis after use of ranitidine, although this is a field that is notoriously difficult to evaluate because of the chronic relapsing and remitting nature of the disease, and others have failed to show benefit.
British Pharmacopoeia 2008: Ranitidine Injection; Ranitidine Oral Solution; Ranitidine Tablets
The United States Pharmacopeia 31, 2008: Ranitidine in Sodium Chloride Injection; Ranitidine Injection; Ranitidine Oral Solution; Ranitidine Tablets
The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.
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