NIMOTOP Film-coated tablet Ref.[7832] Active ingredients: Nimodipine

Nimotop 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.

Nimotop tablets should be used with care when cerebral oedema or severely raised intracranial pressure is present. Although treatment with Nimotop 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).

Caution is required in patients with hypotension (systolic blood pressure lower than 100 mmHg).

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

Nimodipine is metabolised via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or induce this enzyme system may, therefore, alter the first pass or the clearance of nimodipine (see section 4.5" and section 4.2 – “Patients with hepatic impairment”).

Drugs which are known inhibitors of the cytochrome P450 3A4 system and, therefore, may lead to increased plasma concentrations of nimodipine are:

• macrolide antibiotics (e.g. erythromycin),
• anti-HIV protease inhibitors (e.g. ritonavir),
• azole antimycotics (e.g. ketoconazole),
• the antidepressants nefazodone and fluoxetine,
• quinupristin/dalfopristin,
• cimetidine,
• valproic acid.

Upon co-administration with these drugs, the blood pressure should be monitored and, if necessary, a reduction in the nimodipine dose should be considered.

Nimotop tablets should not be administered concomitantly with Nimotop solution.

Drugs that affect nimodipine

Nimodipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Drugs that are known to either inhibit or induce this enzyme system may, therefore, alter the first pass or the clearance of nimodipine (see section 4.2 – "Patients with hepatic impairment).

The extent as well as the duration of interactions should be taken into account when administering nimodipine together with the following drugs:

The concomitant use of oral nimodipine and rifampicin or cytochrome P450 3A4 system-inducing antiepileptic drugs such as phenobarbital, phenytoin or carbamazepine is contraindicated (see section 4.3). The efficacy of Nimotop tablets could be reduced if these drugs are administered concomitantly.

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.

Upon co-administration with the following inhibitors of the cytochrome P450 3A4 system the blood pressure should be monitored and, if necessary, an adaptation in the nimodipine dose should be considered (see section 4.2):

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

Although no formal interaction studies have been performed to investigate the potential interaction between nimodipine and these drugs the potential for drug interaction and increased nimodipine plasma concentrations cannot be excluded. (See section 4.4).

Azithromycin, although structurally related to the class of macrolide antibiotics, is void of CYP3A4 inhibition.

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 (see section 4.4).

The simultaneous administration of nimodipine with the anticonvulsant valproic acid or the H2-antagonist cimetidine can lead to an increase in the plasma concentration of nimodipine (see section 4.4).

Based on experience with the calcium-antagonist nifedipine, co-administration of quinupristin/dalfopristin may lead to increased plasma concentrations of nimodipine (see section 4.4).

Effects of nimodipine on other drugs

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-effects profile of zidovudine is known to be dose-related, this interaction should be considered in patients receiving nimodipine and zidovudine concomitantly.

Other types of interaction

Blood pressure lowering drugs

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.

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. As a consequence, the blood pressure lowering effect may be increased. This effect may last for at least 4 days after the last ingestion of grapefruit juice.

Interactions shown not to exist

A study examining the effects of 90mg nimodipine (in divided doses) on elderly patients receiving haloperidol did not show evidence of potential interactions. It is unclear whether this study is relevant to use in subarachnoid haemorrhage because of the higher dose of nimodipine used.

Concomitant administration of oral nimodipine and diazepam, digoxin, glibenclamide, indometacin, ranitidine and warfarin did not reveal any potential for mutual interaction.

Pregnancy

There are no adequate and well controlled studies in pregnant women. Reproductive toxicology studies in animals using oral administration showed no teratogenic effect, although studies in animals have shown reproductive toxicity (see section 5.3). If nimodipine is to be administered during pregnancy, the benefits and potential risks must be carefully weighed according to the severity of the clinical picture.

Breast-feeding

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 are advised not to breast-feed when taking this drug.

Fertility

In single cases of in-vitro fertilisation 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.

The frequencies of ADRs reported with nimodipine summarized in the tables below are based on clinical trials with nimodipine in the indication aSAH sorted by CIOMS III categories of frequency (placebo-controlled studies: nimodipine N=703; placebo N=692; uncontrolled studies: nimodipine N=2496; status: 31 Aug 2005. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Frequencies are defined as: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to ≤1/100), Rare (≥1/10,000 to ≤1/1,000), Very rare (<1/10,000).

Blood and the lymphatic system disorders

Uncommon: Thrombocytopenia

Immune system disorders

Uncommon: Allergic reaction, Rash

Nervous system disorders

Uncommon: Headache

Cardiac disorders

Uncommon: Tachycardia

Rare: Bradycardia

Vascular disorders

Uncommon: Hypotension, Vasodilatation

Gastrointestinal disorders

Uncommon: Nausea

Rare: Ileus

Hepatobiliary disorders

Rare: Transient increase in liver enzymes

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.

None known.