4.1. Therapeutic indications

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

4.2. Posology and method of administration

Posology

Recommended dose - Aneurysmal Subarachnoid Haemorrhage

For the first two hours of treatment 1 mg of nimodipine, i.e. 5 ml Nimotop solution, (about 15 µg/kg bw/h), should be infused each hour via a central catheter. If it is well tolerated, the dose should be increased after two hours to 2 mg nimodipine, i.e. 10 ml Nimotop solution per hour (about 30 µg/kg bw/h), providing no severe decrease in blood pressure is observed.

Patients of body weight less than 70 kg or with unstable blood pressure should be started on a dose of 0.5 mg nimodipine per hour (2.5 ml of Nimotop solution), or less if necessary.

Duration of treatment

Aneurysmal subarachnoid haemorrhage

Intravenous treatment should begin as early as possible after neurological deficit occurs due to arterial spasm, post subarachnoid haemorrhage. This should continue for at least five days up to a maximum of 14 days.

In the event of surgical intervention during treatment, administration of nimodipine should be continued (dose as above) for at least five days.

Nimotop solution may be used with or without pre-treatment with Nimotop tablets. In the event of Nimotop tablets and Nimotop solution being administered sequentially the total duration of treatment should not exceed 21 days. Nimotop solution should not be administered for longer than 14 days. Nimotop solution and tablets should not be used concomitantly.

Traumatic subarachnoid haemorrhage

Not recommended as a positive benefit to risk ratio has not been established (see section 4.4). Paediatric PopulationThe safety and efficacy of Nimotop in patients under 18 years of age have not been established.

Method of administration

Nimotop solution is administered as a continuous I.V. infusion via a central catheter using an infusion pump. It should be connected to a three-way stopcock using the infusion line provided. The three-way stopcock should be used to connect the Nimotop polyethylene tube with the co-infusion line and the central catheter. (The stopcock must allow for concomitant flow of the Nimotop solution and a co-infusion solution.) Nimotop solution must be administered with a co-infusion running at a rate of 40 ml/hr of either sodium chloride 0.9%, glucose 5%, Ringer's lactate solution, lactated Ringer's solution with magnesium, dextran 40, HAES® (poly[O-2-hydroxyethyl]) starch 6%, human albumin 5%, blood or mannitol 10% in a ratio of about 1:4 (Nimotop:co-infusion), which is connected to the second port of the three-way stopcock prior to its connection with the central line catheter.

Nimotop solution must not be added to an infusion bag or bottle and must not be mixed with other drugs.

Nimotop solution may be used during anaesthesia, angiography or surgical procedures.

4.3. Contraindications

Nimodipine solution for infusion must not be used in cases 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.

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 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 mm Hg).

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, equivalent to 1.15 % or 5.75 %, respectively, of the WHO recommended maximum daily intake of 2 g sodium for an adult. 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.

Nimotop contains ethanol

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).

A dose of 10 ml of this medicine administered per hour to an adult weighing 70 kg would result in exposure to 28 mg/kg/h of ethanol which may cause a rise in blood alcohol concentration (BAC) of about 4 mg/100 ml. For comparison, for an adult drinking a glass of wine or 500 ml of beer, the BAC is likely to be about 50 mg/100 ml.

Co-administration with medicines containing e.g. propylene glycol or ethanol may lead to accumulation of ethanol and induce adverse effects, in particular in young children with low or immature metabolic capacity.

Because this medicine is given slowly by continuous infusion, the effects of alcohol may be reduced.

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

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.

4.6. Fertility, pregnancy and lactation

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.

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. However, this is unlikely to be of clinical relevance in patients receiving Nimotop Solution.

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

Hepato-biliary disorders

Transient increase in liver enzymes

General disorders and administration site conditions

Injection and infusion site reactions

Infusion site (thrombo-) phlebitis

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. If the substance was ingested orally, 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.