Nimodipine Information
Nimodipine ()
Nimodipine () Description
Nimodipine () belongs to the class of pharmacological agents known as calcium channel blockers. Nimodipine () is isopropyl 2 - methoxyethyl 1, 4 - dihydro - 2, 6 - dimethyl - 4 - (m - nitrophenyl) - 3, 5 – pyridinedicarboxylate. The structural formula is:
CHNO Molecular Weight: 418.5
Nimodipine () is a yellow crystalline substance, practically insoluble in water.
Nimodipine () capsules are formulated as soft gelatin capsules for oral administration. Each liquid filled capsule contains 30 mg of Nimodipine () USP in a vehicle of glycerin, peppermint oil, purified water and polyethylene glycol. The gelatin shell contains gelatin, D&C Yellow #10, glycerin, titanium dioxide and purified water. The ingredients in the edible imprinting ink contains ammonium hydroxide, black iron oxide, n-butyl alcohol, isopropyl alcohol, shellac glaze in ethanol and propylene glycol. In addition, the capsule may contain trace amounts of fractionated coconut oil.
Nimodipine () Clinical Pharmacology
Nimodipine () is a calcium channel blocker. The contractile processes of smooth muscle cells are dependent upon calcium ions, which enter these cells during depolarization as slow ionic transmembrane currents. Nimodipine () inhibits calcium ion transfer into these cells and thus inhibits contractions of vascular smooth muscle. In animal experiments, Nimodipine () had a greater effect on cerebral arteries than on arteries elsewhere in the body perhaps because it is highly lipophilic, allowing it to cross the blood-brain barrier; concentrations of Nimodipine () as high as 12.5 ng/mL have been detected in the cerebrospinal fluid of Nimodipine () -treated subarachnoid hemorrhage (SAH) patients.
The precise mechanism of action of Nimodipine () in humans is unknown. Although the clinical studies described below demonstrate a favorable effect of Nimodipine () on the severity of neurological deficits caused by cerebral vasospasm following SAH, there is no arteriographic evidence that the drug either prevents or relieves the spasm of these arteries. However, whether or not the arteriographic methodology utilized was adequate to detect a clinically meaningful effect, if any, on vasospasm is unknown.
In man, Nimodipine () is rapidly absorbed after oral administration, and peak concentrations are generally attained within one hour. The terminal elimination half-life is approximately 8 to 9 hours but earlier elimination rates are much more rapid, equivalent to a half-life of 1 to 2 hours; a consequence is the need for frequent (every 4 hours) dosing. There were no signs of accumulation when Nimodipine () was given three times a day for seven days. Nimodipine () is over 95% bound to plasma proteins. The binding was concentration independent over the range of 10 ng/mL to 10 mcg/mL. Nimodipine () is eliminated almost exclusively in the form of metabolites and less than 1% is recovered in the urine as unchanged drug. Numerous metabolites, all of which are either inactive or considerably less active than the parent compound, have been identified. Because of a high first-pass metabolism, the bioavailability of Nimodipine () averages 13% after oral administration. The bioavailability is significantly increased in patients with hepatic cirrhosis, with C approximately double that in normals which necessitates lowering the dose in this group of patients (see ). In a study of 24 healthy male volunteers, administration of Nimodipine () capsules following a standard breakfast resulted in a 68% lower peak plasma concentration and 38% lower bioavailability relative to dosing under fasted conditions.
In a single parallel-group study involving 24 elderly subjects (aged 59 to 79) and 24 younger subjects (aged 22 to 40), the observed AUC and C of Nimodipine () was approximately 2-fold higher in the elderly population compared to the younger study subjects following oral administration (given as a single dose of 30 mg and dosed to steady-state with 30 mg t.i.d. for 6 days). The clinical response to these age-related pharmacokinetic differences, however, was not considered significant (see).
Nimodipine () has been shown, in 4 randomized, double-blind, placebo-controlled trials, to reduce the severity of neurological deficits resulting from vasospasm in patients who have had a recent subarachnoid hemorrhage (SAH). The trials used doses ranging from 20 to 30 mg to 90 mg every 4 hours, with drug given for 21 days in 3 studies, and for at least 18 days in the other. Three of the four trials followed patients for 3 to 6 months. Three of the trials studied relatively well patients, with all or most patients in Hunt and Hess Grades I - III (essentially free of focal deficits after the initial bleed) the fourth studied much sicker patients, Hunt and Hess Grades III - V. Two studies, one U.S., one French, were similar in design, with relatively unimpaired SAH patients randomized to Nimodipine () or placebo. In each, a judgment was made as to whether any late-developing deficit was due to spasm or other causes, and the deficits were graded. Both studies showed significantly fewer severe deficits due to spasm in the Nimodipine () group; the second (French) study showed fewer spasm-related deficits of all severities. No effect was seen on deficits not related to spasm.
A third, large, study was performed in the United Kingdom in SAH patients with all grades of severity (but 89% were in Grades I-III). Nimodipine () was dosed 60 mg every 4 hours. Outcomes were not defined as spasm related or not but there was a significant reduction in the overall rate of infarction and severely disabling neurological outcome at 3 months:
A Canadian study entered much sicker patients, (Hunt and Hess Grades III-V), who had a high rate of death and disability, and used a dose of 90 mg every 4 hours, but was otherwise similar to the first two studies. Analysis of delayed ischemic deficits, many of which result from spasm, showed a significant reduction in spasm-related deficits. Among analyzed patients (72 Nimodipine () , 82 placebo), there were the following outcomes.
When data were combined for the Canadian and the United Kingdom studies, the treatment difference on success rate (i.e., good recovery) on the Glasgow Outcome Scale was 25.3% (Nimodipine () ) versus 10.9% (placebo) for Hunt and Hess Grades IV or V. The table below demonstrates that Nimodipine () tends to improve good recovery of SAH patients with poor neurological status post-ictus, while decreasing the numbers with severe disability and vegetative survival.
A dose-ranging study comparing 30, 60 and 90 mg doses found a generally low rate of spasm-related neurological deficits but no dose response relationship.
Nimodipine () Indications And Usage
Nimodipine () is indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition (i.e., Hunt and Hess Grades I-V).
Nimodipine () Contraindications
Nimodipine () Warnings
Nimodipine () Precautions
It is possible that the cardiovascular action of other calcium channel blockers could be enhanced by the addition of Nimodipine () .
In Europe, Nimodipine () 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.
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 () .
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 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 mg/kg/day in one of two identical rabbit studies. In the second study an increased incidence of stunted fetuses was seen at 1 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 to directly assess the effect on human fetuses. Nimodipine () should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nimodipine () Adverse Reactions
Adverse experiences were reported by 92 of 823 patients with subarachnoid hemorrhage (11.2%) who were given Nimodipine () . The most frequently reported adverse experience was decreased blood pressure in 4.4% of these patients. Twenty-nine of 479 (6.1%) placebo treated patients also reported adverse experiences. The events reported with a frequency greater than 1% are displayed below by dose.
There were no other adverse experiences reported by the patients who were given 0.35 mg/kg q4h, 30 mg q4h or 120 mg q4h. Adverse experiences with an incidence rate of less than 1% in the 60 mg q4h dose group were: hepatitis; itching; gastrointestinal hemorrhage; thrombocytopenia; anemia; palpitations; vomiting; flushing; diaphoresis; wheezing; phenytoin toxicity; lightheadedness; dizziness; rebound vasospasm; jaundice; hypertension; hematoma.
Adverse experiences with an incidence rate less than 1% in the 90 mg q4h dose group were: itching; gastrointestinal hemorrhage; thrombocytopenia; neurological deterioration; vomiting; diaphoresis; congestive heart failure; hyponatremia; decreasing platelet count; disseminated intravascular coagulation; deep vein thrombosis.
As can be seen from the table, side effects that appear related to Nimodipine () use based on increased incidence with higher dose or a higher rate compared to placebo control, included decreased blood pressure, edema and headaches which are known pharmacologic actions of calcium channel blockers. It must be noted, however, that SAH is frequently accompanied by alterations in consciousness which lead to an under reporting of adverse experiences. Patients who received Nimodipine () in clinical trials for other indications reported flushing (2.1%), headache (4.1%) and fluid retention (0.3%), typical responses to calcium channel blockers. As a calcium channel blocker, Nimodipine () may have the potential to exacerbate heart failure in susceptible patients or to interfere with A-V conduction, but these events were not observed.
No clinically significant effects on hematologic factors, renal or hepatic function or carbohydrate metabolism have been causally associated with oral Nimodipine () . Isolated cases of non-fasting elevated serum glucose levels (0.8%), elevated LDH levels (0.4%), decreased platelet counts (0.3%), elevated alkaline phosphatase levels (0.2%) and elevated SGPT levels (0.2%) have been reported rarely.
Nimodipine () Drug Abuse And Dependence
There have been no reported instances of drug abuse or dependence with Nimodipine () .
Nimodipine () Overdosage
There have been no reports of overdosage from the oral administration of Nimodipine () . Symptoms of overdosage would be expected to be related to cardiovascular effects such as excessive peripheral vasodilation with marked systemic hypotension. Clinically significant hypotension due to Nimodipine () overdosage would require active cardiovascular support with pressor agents. Specific treatments for calcium channel blocker overdose should also be given promptly. Since Nimodipine () is highly protein-bound, dialysis is not likely to be of benefit.
Nimodipine () Dosage And Administration
Nimodipine () capsules are given orally in the form of light yellow opaque, soft gelatin 30 mg capsules for subarachnoid hemorrhage.
The oral dose is 60 mg (two 30 mg capsules) every 4 hours for 21 consecutive days, preferably not less than one hour before or two hours after meals. Oral Nimodipine () capsules therapy should commence within 96 hours of the subarachnoid hemorrhage.
If the capsule cannot be swallowed, e.g., at the time of surgery, or if the patient is unconscious, a hole should be made in both ends of the capsule with an 18 gauge needle, and the contents of the capsule extracted into a syringe. To help minimize administration errors, it is recommended that the syringe be labeled “Not for IV Use”. The contents should then be emptied into the patient's naso-gastric tube and washed down the tube with 30 mL of normal saline (0.9%).
Patients with hepatic cirrhosis have substantially reduced clearance and approximately doubled C. Dosage should be reduced to 30 mg every 4 hours, with close monitoring of blood pressure and heart rate.
Nimodipine () How Supplied
Nimodipine () capsules 30 mg are clear yellow solution filled in oblong opaque light yellow softgel capsules, imprinted “135” in black ink. The capsules are available as follows:
NDC 57664-135-64 Unit Dose Blisters of 30 (6 x 5)NDC 57664-135-65 Unit Dose Blisters of 100 (4 x 25)
Storage: The capsules should be stored in manufacturer's original foil package at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
5817T02
Rev. 12/09
Nimodipine () Principal Display Panel - Bag
Nimodipine () Capsules
30 mg
10 Capsules
