Nimodipine

Nimodipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Although no formal interaction studies have been performed to investigate the potential interaction between nimodipine and inhibitors of cytochrome P450 3A4, the potential for drug interaction and increased nimodipine plasma concentrations cannot be excluded.

Upon co-administration with the following inhibitors of the cytochrome P450 3A4 system the blood pressure should be monitored and, if necessary, an adaption in the nimodipine dose should be considered:

• macrolide antibiotics (e.g. erythromycin)
• anti-HIV protease inhibitors (e.g. ritonavir)
• azole anti-mycotics (e.g. ketoconazole)
• nefazodone.

Severely disturbed liver function, particularly liver cirrhosis, may result in an increased bioavailability of nimodipine due to a decreased first-pass capacity and a reduced metabolic clearance. The effects and side-effects, e.g. reduction in blood pressure, may be more pronounced in these patients. In such cases, the dose should be reduced (depending on the blood pressure) or, if necessary, discontinuation of the treatment should be considered.

The intake of grapefruit juice is not recommended in combination with nimodipine as it can result in increased plasma nimodipine concentrations due to the inhibition of the oxidative metabolism of dihydropyridines.

Nimodipine may increase the blood pressure lowering effect of concomitant antihypertensives, such as:

• diuretics,
• beta-blockers,
• ACE inhibitors,
• A1-antagonists,
• other calcium antagonists,
• alpha-adrenergic blocking agents,
• PDE5 inhibitors
• alpha-methyldopa.

However, if a combination of this type proves unavoidable, particularly careful monitoring of the patient is necessary.

Simultaneous intravenous administration of beta-blockers may lead to mutual potentiation of negative inotropic action going as far as decompensated heart failure.

Renal function can deteriorate if potentially nephrotoxic drugs (e.g. aminoglycosides, cephalosporins, furosemide) are given simultaneously and also in patients whose renal function is already impaired. Renal function must be monitored carefully in such cases and if deterioration is found discontinuation of the treatment should be considered

In single cases of in-vitro fertilization calcium antagonists have been associated with reversible biochemical changes in the spermatozoa’s head section that may result in impaired sperm function. The relevance of this finding in short-term treatment is unknown.

The simultaneous administration of cimetidine or sodium valproate may lead to an increase in the plasma nimodipine concentration.

Concurrent twice daily administration of 30mg nimodipine and daily administration of 20mg of the antidepressant fluoxetine to elderly patients resulted in about 50% higher nimodipine plasma levels, a marked reduction in fluoxetine levels, whilst its active metabolite norfluoxetine was not affected.

Concurrent three times daily administration of 30mg nimodipine and three times daily administration of 10mg of the antidepressant nortriptyline to elderly patients resulted in a slight decrease in nimodipine plasma levels with no effect on nortriptyline plasma levels. The daily dose used in patients with subarachnoid haemorrhage is four times the daily dose used in this trial, thus the clinical significance of this interaction in the treatment of aneurysmal subarachnoid haemorrhage (aSAH) is uncertain.

Based on experience with the calcium-antagonist nifedipine, co-administration of quinupristin/dalfopristin may lead to increased plasma concentrations of nimodipine.

Animal studies have shown that when nimodipine and zidovudine are administered concomitantly, the AUC for zidovudine was increased, and the volume of distribution and clearance rate decreased. The clinical relevance of this interaction is unknown, but since the side-effect profile of zidovudine is known to be dose related, this interaction should be considered in patients receiving nimodipine and zidovudine concomitantly.

Decreased drug clearance may occur in cirrhotic patients receiving nimodipine and, therefore, close monitoring of blood pressure is recommended in these patients.

Nimodipine solution should be used with care when cerebral oedema or severely raised intracranial pressure are present. Although treatment with nimodipine has not been shown to be associated with increases in intracranial pressure, close monitoring is recommended in these cases or when the water content of the brain tissue is elevated (generalised cerebral oedema).

Nimodipine should not be used in patients with traumatic subarachnoid haemorrhage as a positive benefit to risk ratio has not been established and the specific patient groups that might benefit cannot be identified for this indication.

Nimodipine solution must be used with caution in hypotensive patients (systolic blood pressure lower than 100 mmHg).

There are no adequate and well controlled studies in pregnant women. No reproductive toxicology studies following parenteral administration are available. Reproductive toxicology studies in animals after oral administration showed no teratogenic effect, although studies in animals have shown reproductive toxicity. If nimodipine solution is to be administered during pregnancy, the benefits and the potential risks must, therefore, be carefully weighed according to the severity of the clinical picture.

Nimodipine and its metabolites have been shown to be present in human milk at concentrations of the same order of magnitude as corresponding maternal plasma concentrations. Nursing mothers should be advised not to breast-feed when taking this drug.

Fertility

In single cases of in-vitro fertilization calcium antagonists have been associated with reversible biochemical changes in the spermatozoa’s head section that may result in impaired sperm function. The relevance of this finding in short-term treatment is unknown.

In theory, the possibility of the occurrence of the side-effect dizziness may impair the patient’s ability to drive or operate machinery. However, this is unlikely to be of clinical relevance in patients receiving nimodipine.