Summary of Product Characteristics Updated 10-Oct-2017 | Bayer plc
Aneurysmal subarachnoid haemorrhage:
Prophylactic administration - AdultsThe 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)
Patients with hepatic impairmentSeverely 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).
ElderlyThere are no special dosage requirements for use in the elderly.
Paediatric populationThe safety and efficacy of Nimotop in patients under 18 years of age have not been established.
Method of administrationIn 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).
Drugs that affect nimodipineNimodipine 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 drugsAnimal 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 interactionBlood 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 existA 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.
PregnancyThere 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-feedingNimodipine 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.
FertilityIn 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.
|System Organ Class (MedDRA)||Uncommon||Rare|
|Blood and the lymphatic system disorders||Thrombocytopenia|
|Immune system disorders||Allergic reaction Rash|
|Nervous system disorders||Headache|
|Vascular disorders||Hypotension Vasodilatation|
|Hepatobiliary disorders||Transient increase in liver enzymes|
Symptoms of intoxicationSymptoms 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 intoxicationIn 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.
AbsorptionAfter 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 %).
DistributionThe 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.
BiotransformationThe 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.
EliminationEffects 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-linearityFor 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.
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31 August 2017