Each film-coated tablet contains 30mg nimodipine.
Each sterile solution contains 10 mg nimodipine in 50 ml vials of aqueous alcoholic solvent (0.02%).
Excipients/Inactive Ingredients: Tablet: Microcrystalline cellulose, maize starch, povidone, crospovidone, magnesium stearate, hypromellose, macrogol 4000, titanium dioxide E171, iron oxide yellow E172.
Infusion: Ethanol 96%, Macrogol 400, sodium citrate, citric acid, Water for Injections Ph. Eur.
ATC Code: C08 CA06.
Pharmacology: Pharmacodynamics: Nimodipine has a predilective cerebral anti-vasoconstrictive and anti-ischaemic activity. 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 eliminated by nimodipine. Nimodipine also has neuropharmacological and psychopharmacological properties.
Investigations in patients with acute cerebral blood flow disturbances have shown that nimodipine dilates the cerebral blood vessels and promotes cerebral blood flow. The increase in perfusion is as a rule greater in previously damaged or underperfused brain region than in healthy regions.
The ischemic neurological damage in patients with subarachnoid hemorrhage and the mortality rate are significantly reduced by nimodipine.
Pharmacokinetics: Absorption: The orally administered active substance nimodipine is practically completely absorbed. 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 distribution volume (Vss, 2-compartment model) for i.v. administration is calculated to be 0.9 - 1.6 l/kg body weight. The total (systemic) clearance is 0.6 - 1.9 l/h/kg.
Protein binding and distribution: Nimodipine is 97 - 99 % bound to plasma proteins.
Metabolism, elimination and excretion: Nimodipine is eliminated metabolically via the cytochrome P450 3A4 system.
Bioavailability: Attributed to the extensive first-pass metabolism (about 85 - 95 %) the absolute bioavailability is 5 - 15 %.
Toxicology: Preclinical safety data: Preclinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity, carcinogenicity and male and female fertility. In pregnant rats, doses of 30 mg/kg/day and higher inhibited foetal growth and resulted in reduced foetal weights. At 100 mg/kg/day embryolethality occurred. No evidence of teratogenicity was observed. In rabbits, no embryotoxicity and teratogenicity occurred at doses up to 10 mg/kg/day. 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.
Nimotop is indicated for the prevention (tablet) and treatment (infusion) of ischaemic neurological deficit following aneurysmal subarachnoid haemorrhage.
Tablet: Adults: Aneurysmal subarachnoid haemorrhage: Prophylactic administration: The recommended dose is two tablets at 4-hourly intervals (total daily dose 360mg) 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 previously mentioned) to complete the 21 days treatment period.
Traumatic subarachnoid haemorrhage: Not recommended as a positive benefit to risk ratio has not been established (see Precautions).
Elderly: There are no special dosage requirements for use in the elderly.
Children: Paediatric dosage has not been established.
Infusion: 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. 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 previously mentioned) 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 Precautions).
Route of administration: For administration, Nimotop solution must be drawn up into a 50ml syringe and connected to a three-way stopcock using the infusion line provided. (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, dextran 40, human albumin 5% or mannitol 10% 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 or surgical procedures.
Intracisternal instillation: 20ml of a dilute solution of Nimotop solution at a ratio of 1ml Nimotop solution to 19ml Ringer's solution. This dilution must be used immediately after preparation.
Symptoms of intoxication: Symptoms of acute overdosage to be anticipated are marked lowering of the blood pressure, tachycardia or bradycardia, and (after oral administration) gastrointestinal 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. Since no specific antidote is known, subsequent treatment for other side effects should be governed by the most prominent symptoms.
Nimodipine tablets and Nimodipine solution for infusion must not be used in cases of hypersensitivity to nimodipine or to any of the excipients.
The use of nimodipine in combination with rifampicin is contraindicated as efficacy of nimodipine tablets could be significantly reduced when concomitantly administered with rifampicin (see Interactions).
The concomitant use of oral nimodipine and the antiepileptic drugs phenobarbital, phenytoin or carbamazepine is contraindicated as efficacy of nimodipine tablets could be significantly reduced (see Interactions).
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 edema).
Caution is required in patients with hypotension (systolic blood pressure lower than 100 mm Hg).
In patients with unstable angina or within the first 4 weeks after acute myocardial infarction, physicians should consider the potential risk (e.g. reduced coronary artery perfusion and myocardial ischemia) versus the benefit (e.g. improvement of brain perfusion).
Tablet: Nimodipine is metabolized via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nimodipine (see Interactions).
Drugs, which are known inhibitors of the cytochrome P450 3A4 system and therefore may lead to increased plasma concentrations of nimodipine are, e.g.: 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 of the nimodipine dose should be considered.
Infusion: 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 Interactions).
Pregnancy: 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 weighted according to the severity of the clinical picture.
Lactation: 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.
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.
Adverse drug reactions (ADRs) 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) are listed as follows.
The frequencies of ADRs reported with nimodipine are summarized in the table as follows. 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). (See Table 1.)
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Drugs that affect nimodipine: Fluoxetine: The steady-state concomitant administration of nimodipine with the antidepressant fluoxetine led to about 50% higher nimodipine plasma concentrations. Fluoxetine exposure was markedly decreased, while its active metabolite norfluoxetine was not affected.
Nortryptyline: The steady-state concomitant administration of nimodipine and nortryptyline led to a slight decrease in nimodipine exposure with unaffected nortryptyline plasma concentrations.
Tablet: Nimodipine is metabolized via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nimodipine.
The extent as well the duration of interactions should be taken into account when administering nimodipine together with the following drugs: Rifampicin: From the experience with other calcium antagonists it has to be expected that rifampicin accelerates the metabolism of nimodipine due to enzyme induction. Thus, efficacy of nimodipine could be significantly reduced when concomitantly administered with rifampicin. The use of nimodipine in combination with rifampicin is therefore contraindicated (see Contraindications).
Cytochrome P450 3A4 system-inducing anti-epileptic drugs, such as phenobarbital, phenytoin or carbamazepine: Previous chronic administration of the antiepileptic drugs phenobarbital, phenytoin or carbamazepine markedly reduces the bioavailability of orally administered nimodipine. Therefore, the concomitant use of oral nimodipine and these antiepileptic drugs is contraindicated (see Contraindications).
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 Dosage & Administration).
Macrolide antibiotics (e.g., erythromycin): No interaction studies have been carried out between nimodipine and macrolide antibiotics. Certain macrolide antibiotics are known to inhibit the cytochrome P450 3A4 system and the potential for drug interaction cannot be ruled out at this stage. Therefore, macrolide antibiotics should not be used in combination with nimodipine (see Precautions).
Azithromycin, although structurally related to the class of macrolide antibiotic is void of CYP3A4 inhibition.
Anti-HIV protease inhibitors (e.g., ritonavir): No formal studies have been performed to investigate the potential interaction between nimodipine and anti-HIV protease inhibitors. Drugs of this class have been reported to be potent inhibitors of the cytochrome P450 3A4 system. Therefore, the potential for a marked and clinically relevant increase in nimodipine plasma concentrations upon co-administration with these protease inhibitors cannot be excluded (see Precautions).
Azole anti-mycotics (e.g., ketoconazole): A formal interaction study investigating the potential of drug interaction between nimodipine and ketoconazole has not been performed. Azole anti-mycotics are known to inhibit the cytochrome P450 3A4 system, and various interactions have been reported for other dihydropyridine calcium antagonists. Therefore, when administered together with oral nimodipine, a substantial increase in systemic bioavailability of nimodipine due to a decreased first-pass metabolism cannot be excluded (see Precautions).
Nefazodone: No formal studies have been performed to investigate the potential interaction between nimodipine and nefazodone. This antidepressant drug has been reported to be a potent inhibitor of the cytochrome P450 3A4. Therefore, the potential for an increase in nimodipine plasma concentrations upon co-administration with nefazodone cannot be excluded (see Precautions).
Quinupristin/dalfopristin: Based on experience with the calcium-antagonist nifedipine, co-administration of quinupristin/dalfopristin may lead to increased plasma concentrations of nimodipine (see Precautions).
Cimetidine: The simultaneous administration of the H2-antagonist cimetidine can lead to an increase in the plasma nimodipine concentration (see Precautions).
Valproic acid: The simultaneous administration of the anticonvulsant valproic acid can lead to an increase in the plasma nimodipine concentration (see Precautions).
Effects of nimodipine on other drugs: Blood pressure lowering drugs: Nimodipine may increase the blood pressure lowering effect of concomitantly applied anti-hypertensives, such as: diuretics, β-blockers, ACE inhibitors, A1-antagonists, other calcium antagonists, α-adrenergic blocking agents, PDE5 inhibitors, α-methyldopa.
However, if a combination of this type proves unavoidable particularly careful monitoring of the patient is necessary.
Simultaneous intravenous administration of β-blockers may lead to mutual potentiation of negative ionotropic 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 a deterioration is found discontinuation of the treatment should be considered.
Zidovudine: In a monkey study simultaneous administration of anti-HIV drug zidovudine i.v. and nimodipine bolus i.v. resulted for zidovudine in significantly higher AUC, whereas the distribution volume and clearance were significantly reduced.
Tablet: Drug-food interactions: Grapefruit juice: Grapefruit juice inhibits the cytochrome P450 3A4 system. Administration of dihydropyridine calcium antagonists together with grapefruit juice thus results in elevated plasma concentrations and prolonged action of nimodipine due to a decreased first pass metabolism or reduced clearance.
As a consequence, the blood pressure lowering effect may be increased. After intake of grapefruit juice this effect may last for at least 4 days after the last ingestion of grapefruit juice.
Ingestion of grapefruit / grapefruit juice is therefore to be avoided while taking nimodipine (see Dosage & Administration).
Infusion: Other forms of interaction: Since nimodipine infusion solution contains 23.7 % vol-% of alcohol, interactions with alcohol-incompatible drugs should be taken into consideration (see Precautions).
Tablet: Instructions for use/handling: Not applicable.
Incompatibilities: None known.
Infusion: Instructions for use, handling and disposal: Parenteral drug products should be inspected visually for particulate matter and color change prior to administration. Any residual solution should not be kept for later use.
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, lmed Ltd.). Nimotop solution is incompatible with infusion bags and any giving sets made of PVC (e.g. Viaflex, Travenol; Steriflex, Boots).
Incompatibilities: 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.
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 exceeding 30°C.
Shelf-life of the product as packaged for sale: See Table 2.
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C08CA06 - nimodipine ; Belongs to the class of dihydropyridine derivative selective calcium-channel blockers with mainly vascular effects. Used in the treatment of cardiovascular diseases.
FC tab 30 mg (yellow) x 30's. Soln for infusion (vial) 10 mg/50 mL (0.02%) (clear, yellow, sterile solution) x 5's.