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Nimotop (Nimodipine) - Warnings and Precautions

 
 



DO NOT ADMINISTER NIMOTOP INTRAVENOUSLY OR BY OTHER PARENTERAL ROUTES. DEATHS AND SERIOUS, LIFE THREATENING ADVERSE EVENTS HAVE OCCURRED WHEN THE CONTENTS OF NIMOTOP CAPSULES HAVE BEEN INJECTED PARENTERALLY (See WARNINGS and DOSAGE AND ADMINISTRATION).

 

WARNINGS

DEATH DUE TO INADVERTENT INTRAVENOUS ADMINISTRATION:

DO NOT ADMINISTER NIMOTOP INTRAVENOUSLY OR BY OTHER PARENTERAL ROUTES. DEATHS AND SERIOUS, LIFE THREATENING ADVERSE EVENTS, INCLUDING CARDIAC ARREST, CARDIOVASCULAR COLLAPSE, HYPOTENSION, AND BRADYCARDIA, HAVE OCCURRED WHEN THE CONTENTS OF NIMOTOP CAPSULES HAVE BEEN INJECTED PARENTERALLY (SEE DOSAGE AND ADMINISTRATION).

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)

PRECAUTIONS

General:

 Blood Pressure: Nimodipine has the hemodynamic effects expected of a calcium channel blocker, although they are generally not marked. However, intravenous administration of the contents of Nimotop Capsules has resulted in serious adverse consequences including death, cardiac arrest, cardiovascular collapse, hypotension, and bradycardia. In patients with subarachnoid hemorrhage given Nimotop in clinical studies, about 5% were reported to have had lowering of the blood pressure and about 1% left the study because of this (not all could be attributed to nimodipine). Nevertheless, blood pressure should be carefully monitored during treatment with Nimotop  based on its known pharmacology and the known effects of calcium channel blockers. (see WARNINGS and DOSAGE AND ADMINISTRATION)

Hepatic Disease:

The metabolism of Nimotop is decreased in patients with impaired hepatic function. Such patients should have their blood pressure and pulse rate monitored closely and should be given a lower dose (see DOSAGE AND ADMINISTRATION).

Intestinal pseudo-obstruction and ileus have been reported rarely in patients treated with nimodipine. A causal relationship has not been established. The condition has responded to conservative management.

Laboratory Test Interactions:

None known.

Drug Interactions:

 It is possible that the cardiovascular action of other calcium channel blockers could be enhanced by the addition of Nimotop.

In Europe, Nimotop was observed to occasionally intensify the effect of antihypertensive compounds taken concomitantly by patients suffering from hypertension; this phenomenon was not observed in North American clinical trials.

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.

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.

Drugs that affect nimodipine:

The extent as well the duration of interactions should be taken into account when administering nimodipine together with the following drugs:

Rifampin 

From the experience with other calcium antagonists it has to be expected that rifampin accelerates the metabolism of nimodipine due to enzyme induction. Thus, efficacy of nimodipine could be significantly reduced when concomitantly administered with rifampin. The use of nimodipine in combination with rifampin 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 adjustment in the nimodipine dose should be considered (see DOSAGE AND 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, Drug Interactions).

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. 

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.

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.

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.

Cimetidine

The simultaneous administration of the H2-antagonist cimetidine can lead to an increase in the plasma nimodipine concentration.

A study in eight healthy volunteers has shown a 50% increase in mean peak nimodipine plasma concentrations and a 90% increase in mean area under the curve, after a one-week course of cimetidine at 1,000 mg/day and nimodipine at 90 mg/day. This effect may be mediated by the known inhibition of hepatic cytochrome P-450 by cimetidine, which could decrease first-pass metabolism of nimodipine.

Valproic acid

The simultaneous administration of the anticonvulsant valproic acid can lead to an increase in the plasma nimodipine concentration.

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 administered 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.

Zidovudine

In a monkey study simultaneous administration of the anti-HIV drug zidovudine i.v. and nimodipine bolus i.v. resulted in significantly higher AUC of zidovudine, 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

 In a two-year study, higher incidences of adenocarcinoma of the uterus and Leydig-cell adenoma of the testes were observed in rats given a diet containing 1800 ppm nimodipine (equivalent to 91 to 121 mg/kg/day nimodipine) than in placebo controls. The differences were not statistically significant, however, and the higher rates were well within historical control range for these tumors in the Wistar strain. Nimodipine was found not to be carcinogenic in a 91-week mouse study but the high dose of 1800 ppm nimodipine-in-feed (546 to 774 mg/kg/day) shortened the life expectancy of the animals. Mutagenicity studies, including the Ames, micronucleus and dominant lethal tests were negative.

Nimodipine did not impair the fertility and general reproductive performance of male and female Wistar rats following oral doses of up to 30 mg/kg/day when administered daily for more than 10 weeks in the males and 3 weeks in the females prior to mating and continued to day 7 of pregnancy. This dose in a rat is about 4 times the equivalent clinical dose of 60 mg q4h in a 50 kg patient.

Pregnancy:

Pregnancy Category C.

Nimodipine has been shown to have a teratogenic effect in Himalayan rabbits. Incidences of malformations and stunted fetuses 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 fetuses was seen at 1.0 mg/kg/day but not at higher doses. Nimodipine was embryotoxic, causing resorption and stunted growth of fetuses, 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 fetuses 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.

Lactation:

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.

In-vitro fertilization:

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.

Pediatric Use:

Safety and effectiveness in children have not been established.

Geriatric Use:

Clinical studies of nimodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dosing in elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

EFFECT ON ABILITY TO DRIVE AND USE MACHINES

In principle the ability to drive and use machines can be impaired in connection with the possible occurrence of dizziness.

Page last updated: 2008-04-10

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