NIMOTOP® NIMOTOP® I.V.
Bayer
Nimodipine
Adjunct in the Management of Subarachnoid Hemorrhage – Calcium Channel Blocking Agent
Action And Clinical Pharmacology: Delayed neurologic deterioration secondary to cerebral ischemic deficits is believed to be a major determinant of outcome in patients who survive their initial subarachnoid hemorrhage (SAH). Nimodipine is a calcium channel blocker of the dihydropyridine group. It appears to have a more marked effect on the cerebral circulation than on the peripheral circulation. Since it acts on the vascular smooth muscle tone by modifying the contractile process which is dependent upon the movement of extracellular calcium into the cells during depolarization, it was tested in patients with SAH in an effort to improve the neurologic outcome in these patients. Clinical studies with nimodipine support its usefulness as an adjunct in the management of some patients with SAH from ruptured aneurysm by improving their neurologic outcome, particularly in Hunt and Hess grades 1 to 3 patients (consult the manufacturer for further information).
A prospective, multicentre, randomized, double-blind placebo-controlled study was conducted with nimodipine in patients with traumatic head injuries in which traumatic subarachnoid hemorrhage (tSAH) was confirmed by computer tomography (CT) scanning. Within 12 hours of head injury, patients received either a sequential course of i.v. nimodipine (2 mg/hour) for 7 to 10 days followed by oral nimodipine (60 mg q4h) until day 21 or matching placebo. The majority of the patients (approximately 80%) in both nimodipine and placebo groups did not receive cytochrome P450 enzyme-inducing anticonvulsants (i.e., phenytoin or carbamazepine) as a concomitant medication. The incidence of unfavorable outcomes (death, severe disability, vegetative state as defined by the Glasgow Outcome Scale) at 6 months was 25% in nimodipine treated patients (n=60) vs 46% in placebo treated patients (p=0.02, n=61). The incidence of favorable outcomes (good recovery or moderate disability) in the nimodipine group was 75% vs 54% in placebo treated patients (p=0.02) (consult the manufacturer for further information). Due to the small number of patients in this study, the results can only be considered to be preliminary.
The actual mechanism of the possible beneficial effect of nimodipine is, however, unknown. The original rationale for using nimodipine after SAH was to reduce cerebral arterial spasm, but available evidence indicates that nimodipine does not reduce the incidence or severity of cerebral spasm as seen on angiography.
Pharmacokinetics: Nimodipine is rapidly and completely absorbed after oral administration of the capsule. Because of a strong first-pass metabolism in the liver, only about 10% of the unchanged drug enters the systemic circulation. The drug is detectable in plasma 15 minutes after oral administration, and peak levels occur within 90 minutes. The earlier elimination half-life is approximately 2 hours indicating the need for frequent dosing, although the terminal elimination half-life is 8 to 9 hours. The absolute bioavailability of nimodipine capsule is approximately 13%. No change in the average maximum and minimum plasma concentration occurred after a repeated oral dosage regimen of 3 times a day for 7 days in volunteers. Nimodipine injection exhibits a terminal elimination half-life of about 1 hour and a plasma clearance of approximately 125 L/hour.
Nimodipine is metabolized through the cytochrome P450 system, mainly by the CYP 3A4 isoenzyme.
Nimodipine is 99% bound to serum proteins. Approximately 80% is excreted in the bile, and 20% by the kidney.The metabolites of nimodipine are believed to be either inactive or considerably less active than the parent compound.
Indications And Clinical Uses: Nimodipine may be useful as an adjunct to improve the neurologic outcome following subarachnoid hemorrhage (SAH) from ruptured intracranial aneurysm.
Contra-Indications: Hypersensitivity to nimodipine.
Manufacturers’ Warnings In Clinical States: Intestinal pseudo-obstruction (paralytic ileus) has been reported rarely. A causal relationship to nimodipine cannot be ruled out. In 3 cases, the condition responded to conservative management, but a fourth patient required surgical decompression of the extremely distended colon.
Management of Patients with SAH: In view of the potential usefulness of nimodipine in improving the neurologic outcome in some patients with SAH, an early decision (whenever possible within 4 days of the ictus) should be made regarding the use of the drug. Since nimodipine is an adjunct in the management of SAH, an early assessment and a complete management program for the individual patient, including the possible indication of neurosurgery, are imperative.
Blood Pressure: Nimodipine has the hemodynamic effects of a calcium channel blocker. In the course of clinical studies in patients with SAH, hypotension was reported in 6.6% of patients with Hunt and Hess grades III to V given 90 mg doses (n=91), and in 7.5% of patients with grades I and II using 30 to 60 mg doses (n=255). A fall in blood pressure requiring discontinuation of the drug was reported in 2.2% of the patients in the former group. Hypertensive patients may be more susceptible to a lowering of the blood pressure. Blood pressure should, nevertheless, always be carefully monitored during treatment with nimodipine. The use of nimodipine is, however, not generally recommended in patients taking antihypertensive drugs, including other calcium channel blockers, since it may potentiate the effects of these medications.
Simultaneous i.v. administration of beta blockers can lead to mutual potentiation of negative inotropic effects and even to decompensated heart failure.
Patients with Myocardial Infarction: Since there has not been a study of nimodipine in acute myocardial infarction reported, similar effects of nimodipine to that of immediate-release nifedipine cannot be excluded in acute myocardial infarction. Immediate-release nifedipine is contraindicated in acute myocardial infarction.
Patients with Unstable Angina: Some clinical trials have shown that treatment with the immediate-release formulation of the dihydropyridine, nifedipine, in this setting increases the risk of myocardial infarction and recurrent ischemia.
Cerebral Edema or Severely Raised Intracranial Pressure: Nimodipine should be used only with great caution under these conditions.
Pregnancy: Nimodipine has been shown to have a teratogenic effect in rabbits and to be embryotoxic, causing resorption, stunted growth, and higher incidence of skeletal variations, in rats. The safety of nimodipine with respect to adverse effects on human fetal development has not been established. Nimodipine should, therefore, not be used during pregnancy unless the potential benefits are considered to justify the potential risk to the fetus. Precautions
Precautions: Lactation: Nimodipine and/or its metabolites have been shown to appear in rat milk at concentrations much higher than those in maternal plasma although it is not known whether the drug is excreted in human milk. Nursing mothers are advised not to breast-feed their babies when taking the drug.
Children: Safety and effectiveness in children have not been established.
Hepatic Dysfunction: The metabolism of nimodipine is decreased in patients with impaired hepatic function. Such patients should be given lower doses of the drug and their blood pressure and pulse should be closely monitored.
Renal Dysfunction: There are insufficient data on patients with impaired renal function. Patients with known renal disease and/or receiving nephrotoxic drugs should have renal function closely monitored during i.v. treatment with nimodipine.
Administration with Food: A pharmacokinetic study has shown that the bioavailability of nimodipine capsule is reduced in the presence of an American standard breakfast to about two thirds of its value in the fasted condition. Patients should be advised to be consistent in the timing of nimodipine capsule administration with or without food.
Interaction with Grapefruit Juice: Published data indicate that through inhibition of cytochrome P450, grapefruit juice can increase plasma levels and augment pharmacodynamic effects of some dihydropyridine calcium channel blockers. Therefore, consumption of grapefruit juice prior to or during treatment with nimodipine should be avoided.
Drug Interactions: General: As with all drugs, care should be exercised when treating patients with multiple medications. Dihydropyridine calcium channel blockers undergo biotransformation by the cytochrome P450 system, mainly via the CYP 3A4 isoenzyme. Coadministration of nimodipine with other drugs which follow the same route of biotransformation may result in altered bioavailability.
Dosages of similarly metabolized drugs, particularly those of low therapeutic ratio, and especially in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered nimodipine to maintain optimum therapeutic blood levels.
Drugs known to be inhibitors of the cytochrome P450 system include: azole antifungals, cimetidine, cyclosporine, erythromycin, quinidine, terfenadine, warfarin.
Drugs known to be inducers of the cytochrome P450 system include: phenobarbital, phenytoin, rifampin.
Drugs known to be biotransformed via P450 include: benzodiazepines, flecainide, imipramine, propafenone, theophylline.
Cimetidine: A pharmacokinetic study has shown that concurrent administration of cimetidine and oral nimodipine results in an almost doubling of the area under the nimodipine plasma concentration curve and about a 50% increase in the peak nimodipine plasma concentration. Patients receiving the 2 drugs concomitantly should be watched carefully for the possible exaggeration of the effects of nimodipine. It may be necessary to adjust the dosage of nimodipine.
Warfarin: An interaction study with nimodipine and warfarin has shown no clinically significant interactions between these drugs.
Diazepam: An interaction study with nimodipine and diazepam has shown no clinically significant interactions between these drugs.
Antiepileptic Drugs: A pharmacokinetic study in epileptic patients receiving long-term treatment has shown that concurrent administration of oral nimodipine and antiepileptic drugs (phenobarbital, phenytoin and/or carbamazepine) reduces the bioavailability of nimodipine by about 80%. In those patients receiving sodium valproate and oral nimodipine, the bioavailability of the nimodipine increased by about 50%. Therefore, the concomitant use of oral nimodipine and these antiepileptic drugs requires close monitoring and appropriate adjustment of the dosage of nimodipine.
Rifampin: From experience with the calcium antagonist nifedipine it is to be expected that rifampin accelerates the metabolism of nimodipine capsules due to enzyme induction. Thus, efficacy of nimodipine capsules could be reduced when concomitantly administered with rifampin.
Ethanol: Since ethanol is a solvent in nimodipine for injection, interactions with alcohol-incompatible drugs may occur.
Adverse Reactions: Capsules: The most commonly reported adverse events in double-blind clinical studies for patients receiving 60 or 90 mg every 4 hours (n=666) were decreased blood pressure (5.0%), nausea (1.1%), bradycardia (0.9%), rash (0.8%), edema (0.6%), and diarrhea (0.5%). Adverse events reported with a frequency greater than 1% are shown in Table I (by dose).
Adverse events for the 60 and 90 mg q4h doses with an incidence of less than 1% at all dosages were hepatitis, itching, diaphoresis, gastrointestinal hemorrhage, vomiting, thrombocytopenia, anemia, jaundice, hematoma, hyponatremia, decreased platelet count, disseminated intravascular coagulation, deep vein thrombosis, palpitation, hypertension, congestive heart failure, light headedness, dizziness, rebound vasospasm, neurological deterioration, wheezing, and phenytoin toxicity.
In severely ill patients, there was overall increased mortality in the nimodipine group using the 90 mg q4h dose as compared to placebo.
Laboratory Values: Isolated cases of nonfasting elevated serum glucose levels (0.8%), elevated LDH levels (0.4%), decreased platelet counts (0.3%), elevated BUN (0.3%), elevated alkaline phosphatase levels (0.2%) and elevated ALT levels (0.2%) have been reported.
I.V.: The most commonly reported adverse events in patients receiving nimodipine injection (n=1 306) classified as possibly/probably related to the drug were predominantly mild to moderate decreases in blood pressure (3.4%), abnormal liver function test (1.9%), headache (1.2%), and extrasystoles (0.6%). Discontinuation of therapy was required in 21 patients (1.6%) because of adverse events.
Other adverse events reported were hypertension (0.3%), hyperglycemia (0.3%), diaphoresis (0.2%), thrombophlebitis (0.2%), and vomiting (0.2%). Adverse events with an incidence of less than 0.1% were agitation, hypernatremia, hypokalemia, injection site pain, paraesthesia, vasodilation, anxiety, asthma, depression, diabetes mellitus, dizziness, atrial fibrillation, heart arrest, laboratory test abnormalities (increased AST and ALT), liver damage, abdominal pain, phlebitis, and rash. Electrocardiographic (ECG) abnormalities, such as bradycardia (1.5%), extrasystoles (0.8%), tachycardia (0.6%), and arrhythmias (0.2%), were reported in 39/1 306 patients (3.0%). Since the association of ECG abnormalities with SAH is well known, it is likely that some or all of these abnormalities occurred as a result of the natural course of the disease due to stimulation of the parasympathetic/sympathetic system by hemorrhage.
In one study, there were more deaths caused by re-bleeding in the nimodipine group (8 patients) compared to 4 deaths in the placebo group.
Adverse events known to be associated with calcium channel blockers should be appropriately monitored.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: There have been no reports of overdosage from the administration of nimodipine. Symptoms of overdosage would be expected to be related to cardiovascular effects and the patients may experience peripheral vasodilation with flushing, headache, and marked systemic hypotension.
Clinically significant hypotension due to overdosage may require active cardiovascular support and should include close monitoring of cardiac and respiratory function. Since nimodipine is 99% bound to serum protein, dialysis is not likely to be of benefit.
Dosage And Administration: For the management of neurological deficits following subarachnoid hemorrhage (SAH), nimodipine therapy should commence as soon as possible or within 4 days of the diagnosis of SAH. Sequential administration (see below) provides an opportunity to obtain therapeutic concentrations as rapidly as possible and/or to provide the drug to patients unable to swallow.
Sequential Administration: Nimodipine injection must be administered by co-infusion via 3-way stop cock to the central catheter. The initial dosage is 5 mL i.v. (equivalent to 1 mg nimodipine)/hour infused continuously for the first 2 hours; this is approximately 15 g/kg body weight/hour. Co-infusion solution must be administered at a rate of 20 mL/hour with this initial dosage. If this dosage is tolerated, particularly if there is no severe reduction in blood pressure, the dosage should then be increased to 10 mL i.v. solution/hour with a corresponding increase in rate of co-infusion solution to 40 mL/hour. Infusion should continue for 7 to 10 days after diagnosis of SAH.
Rates of administration of recommended co-infusion solutions must be followed due to the possibility of crystal formation as seen in in vitro tests with nimodipine i.v. at higher dilutions.
I.V. lines must be changed every 24 hours.
Thereafter, the recommended dosage of nimodipine capsule is 60 mg (2 capsules of 30 mg) administered orally every 4 hours up to 21 days after diagnosis of SAH. Doses of up to 90 mg every 4 hours have been used in some patients, although the safety of higher doses in severely ill patients has not been well established.
Patients weighing considerably less than 70 kg or those having labile blood pressure should receive an initial dosage of 2.5 mL nimodipine i.v./hour with corresponding reduction in rate of co-infusion solution and, if at all possible, the dosage should not be raised above 5 mL i.v./hour.
Patients with hepatic insufficiency may have substantially reduced clearance and approximately doubled maximum plasma concentration; dosage should be reduced to 2.5 mL/hour and/or one 30 mg nimodipine capsule every 4 hours in these patients.
Nimodipine may be used during anaesthesia or surgical procedures. In the event of surgical intervention, administration of nimodipine should be continued, with dosages as above, for at least 5 days in the case of nimodipine i.v. to complete the 21 day period in the case of nimodipine capsules.
Due to the possibility of hydrolysis in high alkaline pH, alkaline mixtures should not be given for 2 hours before or after administering nimodipine capsules.
Drug effects should be carefully monitored in all patients, particularly if higher doses are used.
Oral Administration: The recommended dosage is 60 mg (2 capsules of 30 mg) administered orally every 4 hours for 21 consecutive days after diagnosis of SAH. Doses of up to 90 mg every 4 hours have been used in some patients, although the safety of higher doses in severely ill patients has not been well established.
If the patient is unable to swallow, the capsule contents may be aspirated into a syringe, emptied into the patients’ in-situ naso-gastric tube and washed down the tube with 30 mL normal saline.
Patients with hepatic insufficiency may have substantially reduced clearance and approximately doubled maximum plasma concentration; accordingly, dosage should be reduced to one 30 mg capsule every 4 hours in these patients.
Nimodipine may be used during anesthesia or surgical procedures. In the event of surgical intervention, administration of nimodipine should be continued, with dosages as above, to complete the 21 day period.
Due to the possibility of hydrolysis in high alkaline pH, alkaline mixtures should not be given for 2 hours before or after administering nimodipine capsules.
Drug effects should be carefully monitored in all patients, particularly if higher doses are used.
Parenteral Products: Continuous I.V. Infusion: Should be administered by means of an infusion pump in the bypass together with the recommended infusion solution via 3-way stop cock to the central catheter.
The ratio of nimodipine solution to concomitant infusion solution should be maintained at 1 to 4 by volume to ensure appropriate dilution of nimodipine i.v. This avoids the possibility of precipitating nimodipine with resulting crystal formation seen in in vitro tests at higher dilutions.
The following i.v. infusion fluids were found to be compatible at recommended administration rates: glucose 5%, Ringer’s Lactate, dextran 40, saline.
Other common infusion solutions must not be used.
I.V. lines must be changed every 24 hours.
Since the nimodipine is absorbed by polyvinylchloride (PVC) only polyethylene (PE) infusion tubing, and polyethylene (PE) or polypropylene (PPE) extensions, taps, connectors may be used.
Nimodipine is slightly light-sensitive such that its use in direct sunlight should be avoided. No special protective measures need to be taken for up to 10 hours if nimodipine i.v. is being administered in diffuse daylight or in artificial light.
The simultaneous use of nimodipine with other calcium antagonists, beta-receptor-blockers or methyldopa should be avoided, especially during continuous i.v. infusion of the drug.
Nimodipine i.v. contains 20% ethanol and 17% polyethylene glycol 400; this should be taken into account during treatment.
Nimodipine i.v. must not be added to an infusion bag or bottle.
Nimodipine capsules and nimodipine i.v. may be used during anaesthesia or surgical procedures.
Availability And Storage: Capsules: Each ivory-colored, soft gelatin capsule, imprinted with the word NIMOTOP, contains: nimodipine 30 mg. Nonmedicinal ingredients: gelatin, glycerin, peppermint oil, polyethylene glycol and titanium dioxide. Individually packed in foil strips, cartons of 100.
I.V.: Each mL of solution contains: nimodipine 0.2 mg. Nonmedicinal ingredients: citric acid, ethanol, polyethylene glycol and sodium citrate. Brown glass bottles of 250 mL, packages of 1.
Nimodipine is light sensitive and therefore the i.v. solution and capsule should be stored only in the manufacturer’s light-protective container below 25°C. Protect from freezing. (Shown in Product Recognition Section)
NIMOTOP® NIMOTOP® I.V. Bayer Nimodipine Adjunct in the Management of Subarachnoid Hemorrhage – Calcium Channel Blocking Agent
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