4.1. Therapeutic indications

Nimodipine is indicated for the prevention of ischaemic neurological deficits following aneurysmal subarachnoid haemorrhage.

4.2. Posology and method of administration

Posology

Aneurysmal subarachnoid haemorrhage:

Prophylactic administration - Adults

The recommended dose is two tablets at 4-hourly intervals (total daily dose 360 mg) to be taken with water. Prophylactic administration should commence within four days of onset of subarachnoid haemorrhage and should be continued for 21 days.

In the event of surgical intervention, administration of Nimotop tablets should be continued (dosage as above) to complete the 21 days treatment period.

In patients who develop adverse reactions the dose should be reduced as necessary or the treatment discontinued

Traumatic subarachnoid haemorrhage:

Not recommended as a positive benefit to risk ratio has not been established (see section 4.4)

Special populations:

Patients with hepatic impairment

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.

Upon co-administration with CYP 3A4 inhibitors or CYP 3A4 inducers a dose adaption may be necessary (see section 4.5).

Elderly

There are no special dosage requirements for use in the elderly.

Paediatric population

The safety and efficacy of Nimotop in patients under 18 years of age have not been established.

Method of administration

In general, the tablets should be swallowed whole with a little liquid, with or without food. The interval between successive doses must not be less than 4 hours.

Grapefruit juice is to be avoided (see section 4.5).

4.3. Contraindications

Nimodipine must not be administered in case of hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Nimodipine should not be administered to patients during or within one month of a myocardial infarction or an episode of unstable angina.

The use of nimodipine in combination with rifampicin or the antiepileptic drugs, phenobarbital, phenytoin or carbamazepine is contraindicated as the efficacy of Nimotop tablets could be significantly reduced when concomitantly administered. (See section 4.5).

4.4. Special warnings and precautions for use

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 mm Hg).

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.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

In theory, the possibility of the occurrence of the side-effect dizziness may impair the patient's ability to drive or operate machinery.

4.8. Undesirable effects

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)

Not known (cannot be estimated from the available data).

System Organ Class

(MedDRA)

Uncommon

Rare

Not known

Blood and the lymphatic system disorders

Thrombocytopenia

Immune system disorders

Allergic reaction

Rash

Nervous system disorders

Headache

Cardiac disorders

Tachycardia

Bradycardia

Vascular disorders

Hypotension

Vasodilatation

Gastrointestinal disorders

Nausea

Ileus

Hepatobiliary disorders

Transient increase in liver enzymes`

Respiratory, thoracic and mediastinal disorders

Hypoxia

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.

4.9. Overdose

Symptoms of intoxication

Symptoms of acute overdosage to be anticipated are marked lowering of the blood pressure, tachycardia, bradycardia and (after oral administration) gastro-intestinal complaints and nausea.

Treatment of intoxication

In the event of acute overdosage, treatment with Nimotop must be discontinued immediately. Emergency measures should be governed by the symptoms. Gastric lavage with addition of charcoal should be considered as an emergency therapeutic measure. If there is a marked fall in blood pressure, dopamine or noradrenaline can be administered intravenously. As no specific antidote is known, subsequent treatment for other side effects should be aimed at the most prominent symptoms