NIMOTOP 0.02% Solution for infusion Ref.[7830] 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 solution should be used with care when cerebral oedema or severely raised intracranial pressure are 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).

Nimotop solution must be used with caution in hypotensive patients (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.

This medicinal product contains 1 mmol (23 mg) sodium per 50 ml bottle or 5.1 mmol (115 mg) sodium per 250 ml bottle. To be taken into consideration by patients on a controlled sodium diet.

Patients with known renal disease and/or receiving nephrotoxic drugs should have renal function monitored closely during intravenous treatment with Nimotop solution (see section 4.5).

Nimodipine is metabolised via the cytochrome P450 3A4 system. 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 and valproic acid (see section 4.5).

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

This medicinal product contains 23.7 vol % ethanol (alcohol), i.e. up to 50 g per daily dose (250 ml). This may be harmful for those suffering from alcoholism or impaired alcohol metabolism and should be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease or epilepsy. The amount of alcohol in this medicinal product may alter the effects of other medicines (see section 4.5).

Nimotop tablets should not be administered concomitantly with Nimotop solution.

Drugs that affect nimodipine

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.

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. (See section 4.4).

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 (see section 4.2):

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

Effects of nimodipine on other drugs

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.

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 (see section 4.4).

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.

Other forms of interaction

Since Nimotop solution contains 23.7 vol % ethanol (alcohol), patients should be monitored for any possible interactions with alcohol-incompatible drugs (see Section 4.4).

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

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.

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. 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 (see section 5.3). If Nimotop 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.

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 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 Nimotop Solution.

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

Hepato-biliary disorders

Rare: Transient increase in liver enzymes

General disorders and administration site conditions

Rare: Injection and infusion site reactions, Infusion site (thrombo-) phlebitis

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.

Nimotop solution reacts with polyvinylchloride (PVC) and should not be allowed to come in contact with PVC. Nimotop solution must not be added to an infusion bag or bottle and must not be mixed with other drugs. Crystallization was observed during co-infusion of Nimotop solution with 2.5% xylite in 0.4% sodium chloride solution (Summafusin), Aminosteril (Fresenius) and Ringer’s solution DAB7.