Nimotop

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..

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.

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.

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.

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. 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)

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.

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.

Pharmacotherapeutic group: selective calcium channel blockers with mainly vascular effect, dihydropyridine derivatives, ATC Code: C08CA06

Nimodipine is a dihydropyridine calcium channel blocker with particular cerebrovascular effect. Nimodipine increases cerebral perfusion, particularly in poorly perfused areas, by arterial dilatation, an effect which is proportionately greater in smaller than in larger vessels.

Vasoconstrictions provoked in vitro by various vasoactive substances (e.g., serotonin, prostaglandins and histamine) or by blood and blood degradation products can be prevented or reduced by up to 75 % by nimodipine.

The intravenous Nimotop solution is 100% available to the tissues as the peripheral venous blood takes the drug to the lungs and heart and from there to all organs.

Absorption

After oral ingestion, absorption is rapid. Peak plasma concentrations are observed 30 to 60 minutes following oral administration. Despite high gastrointestinal absorption of nimodipine, the absolute bioavailability is 5 - 15 %, which is attributed to extensive first pass metabolism (about 85 - 95 %).

Distribution

The distribution volume (Vss, 2 compartment model) for i.v. administration is calculated to be 0.9 - 2.3 l/kg body weight. The total (systemic) clearance is 0.8 - 1.6 l/h/kg. Nimodipine is 97 - 99 % bound to plasma proteins.

Biotransformation

The cytochrome P450 3A4 system plays a major role in the metabolic elimination of nimodipine. Nimodipine is eliminated as metabolites, mainly by dehydrogenation of the dihydropyridine ring and oxidative O-demethylation. Oxidative ester cleavage, hydroxylation of the 2- and 6-methyl groups, and glucuronidation as a conjugation reaction are other important metabolic steps. The three primary metabolites occurring in plasma show no or only therapeutically negligible residual activity.

Elimination

Effects on liver enzymes by induction or inhibition are unknown. In humans the metabolites are excreted about 50 % renally and 30 % in the bile.

Linearity/non-linearity

For oral administration, the peak plasma concentration and the area under the curve increase proportionally to the dose up to the highest dose under test (90 mg). The elimination kinetics are linear. The half-life for nimodipine is between 1.1 and 1.7 hours. The terminal half-life is 5-10 hours, and is not relevant for establishing the recommended dosing interval for the medicinal product.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction. However, several preclinical findings may be of relevance to the prescribing physician. In chronic repeat dose toxicity studies in dogs, doses of 1 and 2.5 mg/kg/day were shown to be tolerated without adverse effect. However, at the higher dose of 6.25 mg/kg/day significant changes in ECGs were noted due to disturbances in myocardial blood flow, but there was no indication of histopathological damage to the heart. In pregnant rats, doses of 30 mg/kg/day and higher inhibited fetal growth and resulted in reduced fetal weights. At 100 mg/kg/day embryolethality occurred. No evidence of teratogenicity was observed. In rabbits, equivocal evidence of teratogenicity was seen in one study at doses up to 10 mg/kg/day. In two subsequent studies (one at 30 mg/kg/day), these findings were not reproduced. In one peri-postnatal study in rats, mortality and delayed physical development were observed at doses of 10 mg/kg/day and higher. The findings were not confirmed in subsequent studies.

Nimodipine 0.02% solution contains the following excipients:

Ethanol 96%, Macrogol 400, sodium citrate, citric acid, Water for Injections Ph. Eur.

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.

Shelf life of the product as packaged for sale:

A = Unopened

B = After reconstitution or when the container is opened for the first time, if appropriate.

Nimotop solution is light sensitive and therefore should be stored in the manufacturer's light-protective container within the cardboard carton at a temperature not above 25°C.

Brown glass type II infusion vials containing 50 ml of solution; with grey chlorobutyl stopper laminated with fluoropolymer.

150 cm of colorless transparent polyethylene tubing with conus connector for each vial of 50 ml of Nimotop 0.02% Solution for Infusion.

The only plastic materials suitable for use are polyethylene or polypropylene. Nimotop solution is compatible with glass infusion bottles and infusion packs made of polyethylene (e.g., Polyfusor, Boots).

The solution when in the syringe must be protected from direct sunlight during administration, but it is stable in diffuse daylight and artificial light for up to 10 hours. Nimotop solution should be infused using a glass or rigid plastic (polyethylene or polypropylene) syringe and giving set (Gillette Sabre syringe; BD plastipak syringe; Monoject disposable syringe, Sherwood Medical Ltd; Combidyn tubes, Braun; Nitrocassette giving set, Imed Ltd.). Nimotop solution is incompatible with infusion bags and any giving sets made of PVC (e.g., Viaflex, Travenol; Steriflex, Boots).

To penetrate the coated injection stoppers correctly, fine acute injection needles are recommended. DO NOT use large-core infusion needles, since this may result in cracked or bruised stoppers and the stoppers may be forced into the vial.

Bayer plc

400 South Oak Way

Reading, RG2 6AD

PL 00010/0138

21 January 1988/ 23 November 2003

31 August 2017