For the use of a Registered Medical Practitioner or a Hospital or a Institution only.
NIMODIPINE TABLETS B.P. is a dihydropyridine calcium channel blocker. Chemically, Nimodipine is 2-Methoxyethyl 1-methylethyl (4RS)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate. Its molecular formula is C21H26N2O7 and molecular weight is 418.4.
STRUCTURAL FORMULA :
Its structural formula is :
NIMODIPINE TABLETS B.P. are orange coloured, round film coated tablets.
Each film coated tablet contains :
Nimodipine B.P. 30 mg
Colours : Titanium Dioxide B.P., Tartrazine, Sunset Yellow
Nimodipine is a calcium channel blocker of the dihydropyridine group with preferential activity on cerebral vessels. 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 Nimodipine 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. 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 %). 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. 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. Effects on liver enzymes by induction or inhibition are unknown. In humans the metabolites are excreted about 50 % renally and 30 % in the bile. 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.
NIMODIPINE TABLETS B.P. is indicated for prevention and treatment of ischaemic neurological deficits following aneurysmal subarachnoid haemorrhage.
For Oral Use
In general, the NIMODIPINE TABLETS B.P. 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.
Prevention, by mouth, 60 mg every 4 hours, starting within 4 days of aneurysmal subarachnoid haemorrhage and continued for 21 days.
Child 1 month – 18 years :
0.9 – 1.2 mg/kg (maximum 60 mg) 6 times daily, starting within 4 days of haemorrhage and continued for 21 days.
Known hypersensitivity to NIMODIPINE TABLETS B.P. or any of the excipients. Nimodipine should not be administered to patients during or within one month of a myocardial infarction or an episode of unstable angina or acute porphyria. The use of Nimodipine in combination with rifampicin or the antiepileptic drugs, phenobarbital, phenytoin or carbamazepine is contraindicated as the efficacy of NIMODIPINE TABLETS B.P. could be significantly reduced when concomitantly administered.
Although treatment with Nimodipine 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 (generalized 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 NIMODIPINE TABLETS B.P. and, therefore, close monitoring of blood pressure is recommended in these patients.
NIMODIPINE TABLETS B.P. contains lactose which is contra-indicated in patients with galactosaemia, the glucose-galactose malabsorption syndrome, or lactase deficiency. NIMODIPINE TABLETS contains “tartrazine” colour which may cause allergic reactions, including bronchial asthma, especially in patients who are allergic to the acetyl salicylic acid .
Cerebral oedema or severely raised intracranial pressure; hypotension; avoid concomitant administration of NIMODIPINE TABLETS B.P. and infusion, other calcium-channel blockers, or beta-blockers; concomitant nephrotoxic drugs; hepatic impairment; renal impairment; pregnancy.
Laboratory Test Interactions :
Pregnancy : Pregnancy Category C
NIMODIPINE TABLETS B.P. has been shown to have a teratogenic effect in Himalayan rabbits. Incidences of malformations and stunted foetuses were increased at oral doses of 1 and 10 mg/kg/day administered (by gavage) from day 6 through day 18 of pregnancy but not at 3.0 mg/kg/day in one of two identical rabbit studies. In the second study an increased incidence of stunted foetuses was seen at 1.0 mg/kg/day but not at higher doses. Nimodipine was embryotoxic, causing resorption and stunted growth of foetuses, in Long Evans rats at 100 mg/kg/day administered by gavage from day 6 through day 15 of pregnancy. In two other rat studies, doses of 30 mg/kg/day nimodipine administered by gavage from day 16 of gestation and continued until sacrifice (day 20 of pregnancy or day 21 post partum) were associated with higher incidences of skeletal variation, stunted foetuses and stillbirths but no malformations. There are no adequate and well controlled studies in pregnant women. If nimodipine 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.
Nimodipine and/or its metabolites have been shown to appear in rat milk at concentrations much higher than in maternal plasma. Nimodipine and its metabolites have been shown to appear in human milk at concentrations of the same order of magnitude as corresponding maternal plasma concentrations. Nursing mothers are advised not to breastfeed their babies when taking the drug.
Paediatric Use :
Safety and effectiveness in children have not been established.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES :
In principle the ability to drive and use machines can be impaired with the possible with the indication occurrence of dizziness. In using Nimodipine infusion solution this will generally not be importance.
NIMODIPINE TABLETS B.P. should not be administered concomitantly with NIMODIPINE 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. 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. The efficacy of NIMODIPINE TABLETS B.P. could be reduced if these drugs are administered concomitantly. Concurrent three times daily administration of 30 mg nimodipine and three times daily administration of 10 mg 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 :
- macrolide antibiotics (e.g. erythromycin)
- anti-HIV protease inhibitors (e.g. ritonavir)
- azole anti-mycotics (e.g. ketoconazole)
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. Azithromycin, although structurally related to the class of macrolide antibiotics, is void of CYP3A4 inhibition. Concurrent twice daily administration of 30 mg nimodipine and daily administration of 20 mg 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. 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. Based on experience with the calcium-antagonist nifedipine, co-administration of quinupristin/dalfopristin may lead to increased plasma concentrations of nimodipine.
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 antihypertensive, such as :
- ACE inhibitors,
- other calcium antagonists,
- alpha-adrenergic blocking agents,
- PDE5 inhibitors
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 90 mg 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.
SIDE EFFECTS :
The following events have been mainly reported in clinical trials. The following definitions of frequencies are used :
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 Lymphatic System Disorders :
Thrombocytopenia is uncommon.
Immune System Disorders :
Acute hypersensitivity reactions include uncommonly occurring mild to moderate allergic reactions.
Associated clinical symptoms related to skin (uncommon rash).
Nervous System Disorders :
Unspecific cerebrovascular symptoms include uncommonly occurring headache.
Cardiac Disorders :
Unspecific cardiac arrhythmias: tachycardia is uncommon and bradycardia is rare.
Vascular Disorders :
Unspecific cardiovascular symptoms such as hypotension and vasodilatation (sweating, flushing and feeling of warmth) are uncommon.
Gastrointestinal Disorders :
Unspecific gastrointestinal and abdominal symptoms include uncommonly occurring nausea. Rarely ileus has been reported.
Haepatobiliary Disorders :
Liver reactions include a rarely occurring transient increase in liver enzymes (including an increase in transaminases, alkaline phosphatase and γ-GT). General Disorders and Administration Site
Infusion and injection site reactions are rare (including infusion site (thrombo-) phlebitis).
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 OVERDOSAGE :
In the event of acute overdosage, treatment with NIMODIPINE TABLETS B.P. 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.
Store below 30°C (86°F), protected from moisture and light.
Do not refrigerate.
SHELF LIFE :
24 months from the date of manufacture.
NIMODIPINE TABLETS B.P. contains Nimodipine B.P. 30 mg.
3 strips of 10 Tablets per Box .
Disclaimer : For the use of a Registered Medical Practitioner or a Hospital or a Institution only. Also it is not intended to be used by healthcare professionals or patients for the purpose of prescribing or administering these products. Questions regarding the complete and current content of product labeling / specification / presentation should be directed to SGPharma.