SIDE-EFFECTS OF RANITIDINE

Ranitidine was first marketed in 1981; since then many patients have been treated such that much experience has been accumulated on the safety of this histamine H2-receptor antagonist in the treatment of gastroduodenal disease. A wide array of ranitidine-associated side effects has been described, but infrequently. As so much information is now available, the aim of this review is to assess the weight of evidence for a causal link between ranitidine and the reported side effects. Overall, ranitidine is well tolerated. The incidence of general side effects at less than 2% is very similar to placebo. Headaches, tiredness, dizziness and mild gastrointestinal disturbance (e.g. diarrhoea, constipation and nausea) are among the most frequent complaints, but have very seldom resulted in stopping treatment. Cardiovascular side effects are extremely rare and unpredictable with the usual doses of oral ranitidine (at most 1 in 1 million patients). They mostly comprise sinusal bradycardia and atrioventricular blockade, especially after rapid intravenous administration, receding after cessation of the drug. Clinical studies, however, have not shown a significant pharmacological effect of ranitidine on the cardiovascular system via H2-receptors, even though individual sensitivities cannot be ruled out in a few isolated reports. Ranitidine is unlikely to be directly hepatotoxic: a transient change in liver function tests has been noted in only 1 in 100 to 1 in 1000 patients. Several cases of mixed hepatitis have been reported, but very few were fully documented. The incidence of ranitidine-associated acute hepatitis has been estimated to be less than 1 in 100 000 patients. Neuropsychiatric complications may be less common and clinically quite similar to those reported with cimetidine, i.e. confusion, disorientation, hallucinations, delirium. These side effects have occurred especially in critically ill and multiple-therapy patients, or patients with chronic renal or hepatic failure, so that the direct causal link with ranitidine treatment was often difficult to ascertain. Even though an H2-receptor-mediated effect is an attractive hypothesis (since similar complications were noted with other H2-receptor antagonists), other mechanisms have been suggested to play a role, e.g. cholinergic or histaminic effects. The overall incidence of neuropsychiatric complications is probably markedly less than 1%. White cell injury (i.e. agranulocytosis) appears to be the most frequent haematological complication, even though case reports are very few and poorly documented. The mechanism is unknown but ranitidine is unlikely to be markedly haematotoxic. Anecdotal reports of thrombocytopenia and anaemia have been published. In disagreement with a few poorly documented case reports and in contrast to cimetidine, clinical studies have shown that ranitidine has no side effects on endocrine functions, in particular androgenic function or prolactin secretion. Among other side effects associated with ranitidine treatment, cutaneous effects include nonspecific skin reactions as well as urticaria, contact dermatitis and vasculitis. In contrast to cimetidine, ranitidine failed to enhance the immune responsiveness both in animals and in humans. Drug interactions with ranitidine have been controversial. Although it can be loosely bound to cytochrome P450 components, there is no conclusive clinical evidence that interactions may occur with many drugs such as oral anticoagulants, anticonvulsants, beta-blocking drugs, calcium antagonists, lidocaine (lignocaine), benzodiazepines, tricyclic antidepressants or oral hypoglycaemic drugs. A few clinical case reports suggest that ranitidine may interfere with theophylline, although all human pharmacokinetic studies have been negative.