Nimotop

Nimotop

nimodipine

Manufacturer:

Bayer

Distributor:

Zuellig
Full Prescribing Info
Contents
Nimodipine.
Description
Tab: Each tablet contains: Nimodipine 30 mg.
Excipients/Inactive Ingredients: Poly(1-vinyl-2-pyrrolidone) 25, microcrystalline cellulose, corn starch, crospovidone, magnesium stearate, hydroxypropyl methylcellulose, macrogol 4000, titanium dioxide (E 171), iron oxide yellow (E 172).
Soln for infusion: Each glass bottle with 50ml for infusion contains: Nimodipine 10mg.
Excipients/Inactive Ingredients: Each 50 ml bottle contains: Ethanol 96%, macrogol 400, sodium citrate dihydrate (0.1 g = 1.0 mmol sodium), anhydrous citric acid, water for injection.
Action
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.
Indications/Uses
Prophylaxis and treatment of ischemic neurological deficits caused by cerebral vasospasms following subarachnoid hemorrhage of aneurysmal origin. Nimodipine (Nimotop) tablets are indicated subsequently to Nimodipine (Nimotop) infusion solution.
Dosage/Direction for Use
Tab: Administration of Nimodipine (Nimotop) tablets is recommended for about 7 days after the end of the 5-14 days infusion therapy with Nimodipine (Nimotop) infusion solution.
In general, the tablets should be swallowed whole with a little liquid, independent of meal time.
Grapefruit juice is to be avoided (see Interactions). The interval between successive doses must not be less than 4 hours.
Dosage regimen: The recommended procedure is administration of Nimodipine (Nimotop) infusion solution for 5 - 14 days, followed by a daily dose of 6 x 2 Nimodipine (Nimotop) tablets (6 x 60 mg nimodipine).
In patients who develop adverse reactions the dose should be reduced as necessary or the treatment discontinued.
Upon co-administration with CYP 3A4 inhibitors or CYP 3A4 inducers a dose-adaptation may be necessary (see Interactions). Prophylactic Use: After the end of the infusion therapy, it is advisable to continue with oral administration of 6 x 60 mg Nimodipine (Nimotop) tablets daily at four-hourly intervals for about further 7 days.
Therapeutic Use: After intravenous application, oral administration of 6 x 60 mg Nimodipine (Nimotop) tablet per day at four-hourly intervals for 7 days is recommended.
Patients with hepatic impairment: Severely disturbed liver function, particularly liver cirrhosis, may result in an increased bioavailability of Nimodipine (Nimotop) 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 or, if necessary, discontinuation of the treatment should be considered.
Soln for IV infusion: Method of administration: Nimodipine (Nimotop) solution for infusion is administered as a continuous i.v. infusion via a central catheter using an infusion pump. It should be given via a three-way stopcock together with either glucose 5%, sodium chloride 0.9%, lactated Ringer's solution, lactated Ringer's solution with magnesium, dextran 40 solution or HAES (poly(O-2-hydroxyethyl) starch 6% in a ratio of about 1:4 (nimodipine: co-infusion). Also mannitol, human albumin or blood are suitable for co-infusion.
The three-way stopcock should be used to connect the nimodipine polyethylene tube with the co-infusion line and the central catheter.
Nimodipine (Nimotop) solution for infusion must not added to an infusion bag or bottle and must not be mixed with other drugs.
Administration of nimodipine (Nimotop) solution for infusion should be continued during anesthesia, surgery and angiography.
Dosage regimen: Intravenous infusion: At the beginning of treatment 1 mg/h nimodipine (=5 ml nimodipine (Nimotop) solution for infusion/h) for 2 h (about 15 µg/kg body weight/h). If this is well tolerated, and particularly if there is no marked reduction in blood pressure, the dose is increased after 2 h to 2 mg/h nimodipine (= 10 ml nimodipine (Nimotop) solution for infusion/h) (about 30 µg/kg body weight/h).
Patients whose body weight is appreciably below 70 kg or who have labile blood pressure should be started with a dose of 0.5 mg/h nimodipine (= 2.5 ml nimodipine (Nimotop) solution for infusion/h).
Intracisternal Installation: During surgery a freshly prepared dilute solution of nimodipine (1 ml nimodipine (Nimotop) solution for infusion and 19 ml Ringer's solution) warmed up to blood temperature may be instilled intracisternally.
This dilute solution of nimodipine (Nimotop) solution for infusionmust be used immediately after preparation.
Duration of use: Prophylactic Use: Intravenous therapy should be started no later than 4 days after the hemorrhage, and be continued during the period of maximum risk of vasospasm, i.e. up to 10-14 days after the hemorrhage.
If during prophylactic administration of nimodipine (Nimotop) solution for infusion, the source of the hemorrhage is treated surgically, intravenous treatment with nimodipine (Nimotop) solution for infusion should be continued post-operatively for at least 5 days.
After the end of the infusion therapy, it is advisable to continue with oral administration of 6 x 60 mg nimodipine daily at four-hourly intervals for about a further 7 days.
Therapeutic Use: If ischemic neurological disturbances caused by vasospasm after aneurysmal subarachnoid hemorrhage are already present, treatment should be started as early as possible and be continued for at least 5 days up to a maximum of 14 days. Thereafter, oral administration of 6 x 60 mg nimodipine per day at four-hourly intervals for 7 days is recommended.
If during therapeutic administration of nimodipine (Nimotop) solution for infusion, the source of the hemorrhage is treated surgically, intravenous treatment with nimodipine (Nimotop) solution for infusion should be continued post-operatively for at least 5 days.
Overdosage
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 tablet 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. Since no specific antidote is known, subsequent treatment for other side effects should be governed by the most prominent symptoms.
Contraindications
Nimodipine (Nimotop) tablets must not be used in cases of hypersensitivity to nimodipine or to any of the excipients.
Tab: The use of nimodipine in combination with rifampicin is contraindicated as efficacy of Nimodipine (Nimotop) 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 (Nimotop) tablets could be significantly reduced (see Interactions).
Special Precautions
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).
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).
Tab: 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.
Use In Pregnancy & Lactation
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 Reactions
Tabulated list of adverse reactions: 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. (See table.) 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).

Click on icon to see table/diagram/image
Drug Interactions
Tab: 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 coadministration 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).
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.
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).
Further drug interaction: Nortryptyline: The steady-state concomitant administration of nimodipine and nortryptyline led to a slight decrease in nimodipine exposure with unaffected nortryptyline plasma concentrations.
Effects of nimodipine on other drugs: Blood pressure lowering drugs: Nimodipine may increase the blood pressure lowering effect of concomitantly applied antihypertensives, 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.
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.
Drug-food interactions: Grapefruit juice: Grapefruit juice inhibits the cytochrome P450 3A4 system. Administration of dyhydropyridine 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).
Soln for IV infusion: 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 administrationof nimodipine and nortryptyline led to a slight decrease in nimodipine exposure with unaffected nortryptyilne plasma concentrations. Effects of nimodipine on other drugs: Blood pressure lowering drugs: Nimodipine may increase the blood pressure lowering effect of concomitant 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.
Other forms of interaction: Since nimodipine (Nimotop) solution for infusion contain 23.7% vol-% of alcohol, interactions with alcohol-incompatible drugs should be taken into consideration (see Precautions).
Caution For Usage
Incompatibilities: Tab: None.
Soln for IV infusion: Since the active substance of nimodipine (Nimotop) solution for infusion is absorbed by polyvinyl-chloride (PVC), only polyethylene (PE) infusion tubing may be used.
The active substance of nimodipine (Nimotop) solution for infusion is slightly light-sensitive such that its use in direct sunlight should be avoided. If direct exposure to sunlight is unavoidable during an infusion, black, brown, yellow or red glass syringes and connecting tubing should be used, or the infusion pump and the tubing be protected by opaque wrappings. However, no special protective measures need be taken for up to 10 h if nimodipine (Nimotop) solution for infusion is being given in diffuse daylight or in artificial light.
Instructions for use/handling: Tab: Do not use after expiration date.
Soln for IV infusion: 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.
Storage
Tab: Store at temperatures not exceeding 30°C.
Soln for IV infusion: Store below 25°C. Protect from light.
ATC Classification
C08CA06 - nimodipine ; Belongs to the class of dihydropyridine derivative selective calcium-channel blockers with mainly vascular effects. Used in the treatment of cardiovascular diseases.
Presentation/Packing
Tab 30 mg x 50's. Soln for IV infusion (clear) 10 mg/50 mL x 1's.
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