VA Class:CV200
Nimodipine is a 1,4-dihydropyridine-derivative calcium-channel blocking agent that affects the CNS preferentially.1, 4, 5, 13, 22, 96, 245
Nimodipine is used for the improvement in neurologic outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage resulting from ruptured intracranial berry aneurysms regardless of the patient's postictal neurologic condition (e.g., Hunt and Hess grades I-V).1, 2, 4, 5, 8, 20, 21, 22, 23, 69, 95, 109, 230, 231, 246 Although nimodipine does not appear to reduce substantially the incidence of angiographically documented delayed cerebral vasospasm,1, 2, 4, 115 which frequently accompanies subarachnoid hemorrhage,44, 82, 95, 102, 132 the drug has been shown to decrease the severity and incidence of associated delayed ischemic neurologic deficits.1, 2, 5, 20, 21, 22, 23, 40, 82, 95, 231 Some evidence also suggests that nimodipine therapy may reduce the incidence of cerebral infarction20 and mortality20, 69, 95 in patients with subarachnoid hemorrhage,4 but additional study and experience are necessary to further evaluate the effects of nimodipine on these outcomes.4, 95, 230
The principal goals of therapy for patients with subarachnoid hemorrhage are prevention of aneurysm rerupture and prevention and treatment of delayed ischemic neurologic deficits associated with cerebral vasospasm.44, 83, 230, 231 If the patient's clinical condition permits, surgical repair of the aneurysm is the optimal method for eliminating the threat of aneurysm rerupture, but surgery does not prevent and may even aggravate cerebral vasospasm.4, 44, 83, 95, 115, 230, 231 While further clinical experience is required to determine optimum patient selection and timing of nimodipine therapy relative to surgical repair of the aneurysm,4, 95 the limited therapeutic options for treatment of subarachnoid hemorrhage4, 14, 44, 83 and the relatively low incidence of adverse effects associated with nimodipine therapy suggest that such therapy has a favorable benefit-to-risk ratio in most patients with this condition.4, 95, 230, 231
Subarachnoid hemorrhage resulting from rupture of saccular arterial aneurysms at the base of the brain frequently leads to clot formation in the basal subarachnoid cisterns and subsequent cerebral vasospasm.44, 82, 95, 102 Delayed cerebral vasospasm with neurologic deficits occurs in approximately 30% of patients with subarachnoid hemorrhage.44, 82, 83, 146, 214 Manifestations of cerebral vasospasm usually are apparent within 3-4 days after subarachnoid hemorrhage,14, 22, 40, 44, 82, 83, 84 with a peak incidence 6-10 days after the initial hemorrhage.20, 40, 44, 82, 83, 84, 144, 145 Nimodipine therapy should be initiated as soon as possible following subarachnoid hemorrhage,1, 4, 20 preferably within 96 hours of ictus.1, 230, 231
Much of the information on the use of nimodipine in patients with subarachnoid hemorrhage is from uncontrolled, noncomparative studies in which the drug was administered IV† (IV dosage form currently not commercially available in the US), orally, and/or, occasionally, intracisternally†.40, 67, 84, 92, 93, 95, 96, 102, 105, 106, 110, 116, 117, 118, 119, 120, 214 However, several randomized, placebo-controlled studies in which orally administered nimodipine alone was initiated within 72-96 hours of subarachnoid hemorrhage and given in dosages of 20-90 mg (usually 60 mg)20, 21, 69 every 4 hours for 16-21 days demonstrate a reduction in the incidence and severity of delayed ischemic neurologic deficits associated with cerebral vasospasm in subarachnoid hemorrhage.1, 2, 5, 20, 21, 22, 23, 69 In a large, placebo-controlled study in patients (principally Hunt and Hess grades I-III) with subarachnoid hemorrhage conducted in England, the incidence of poor outcome (i.e., death, vegetative state, or severe neurologic disability) and cerebral infarction were reduced by 40 and 34%, respectively, with oral nimodipine therapy.1, 20 The effect of the presence or absence of cerebral vasospasm on therapeutic response was not determined, but benefit was apparent in all clinical grades of patients regardless of time of initiation of nimodipine (i.e., either before or after surgery) within a 96-hour period after subarachnoid hemorrhage.20
The efficacy of orally administered nimodipine in reducing mortality from subarachnoid hemorrhage has not been fully established.1, 95 Mortality in evaluable patients in at least one study was substantially reduced,69 and a trend toward reduced mortality was noted in another study.20 However, in a placebo-controlled study in seriously ill (Hunt and Hess grades III-V) patients in Canada who received nimodipine 90 mg orally every 4 hours for 21 days,1, 23 mortality was increased somewhat (not statistically significant) compared with placebo despite a reduction in delayed ischemic neurologic deficits in nimodipine-treated patients.23 While most deaths in this study appeared to be related to subarachnoid hemorrhage, the possibility that the drug might have contributed to mortality could not be excluded.23 In some studies, detailed information on neurologic outcome was provided only for patients who were considered to have vasospasm-related neurologic deficits,21, 22 making it difficult to evaluate the effect of nimodipine on overall outcome in patients with subarachnoid hemorrhage.4, 95, 107, 108 Several studies have demonstrated that the incidence of poor response, generally defined as death or severe disability after subarachnoid hemorrhage, is reduced by nimodipine therapy.20, 21, 22 However, analysis of pooled data from the British and Canadian placebo-controlled studies showed that the incidence of good recovery in patients with subarachnoid hemorrhage was increased with nimodipine therapy; in addition, fewer patients receiving nimodipine had severe disability or vegetative survival.1
Some clinicians suggest that oral administration of nimodipine in conjunction with early (i.e., within 72 hours) surgical repair of the aneurysm in selected good-condition patients (i.e., Hunt and Hess grades I-III) may produce optimal results in patients with subarachnoid hemorrhage.67, 95, 110, 116, 117, 118, 119, 120, 230, 231 IV nimodipine also has been used in conjunction with surgical repair of the aneurysm in selected good-condition patients; however, an IV dosage form currently is not commercially available in the US.67, 95, 110, 116, 117, 118, 119, 120 The contents of nimodipine capsules must not be administered by IV injection or any other parenteral route because serious, life-threatening adverse effects have occurred with such administration.1, 245, 246, 248, 249, 250 (See Cautions: Cardiovascular Effects.)
Limited evidence suggests that nimodipine may improve neurologic recovery and reduce mortality compared with plasma volume expansion therapy or placebo in some patients with acute ischemic stroke†.4, 10, 76, 77, 220, 240, 241, 247 In 2 randomized, controlled studies, patients receiving nimodipine 120 mg daily for 28 days in addition to IV low-molecular-weight dextran demonstrated an improved level of consciousness early in treatment and/or reduced disability as assessed by the Mathew9 scale.76, 77 In a study in which nimodipine therapy was initiated within 24 hours of onset of stroke symptoms, patients with moderate to severe deficits showed the greatest neurologic benefit; overall mortality at 6 months was 29% in nimodipine-treated patients versus 17% in patients given IV dextran, but this difference in survival was attributable solely to fewer deaths in males.77 Analysis of pooled data from 5 placebo-controlled studies also revealed evidence of reduced neurologic impairment and mortality in patients receiving 120 mg of nimodipine daily for 21 or 28 days.242 Further study and experience are needed to establish the efficacy and safety of nimodipine therapy in patients with acute ischemic stroke.206, 220, 221, 222, 224, 230, 231, 240, 241, 247
In a few randomized, controlled studies of approximately 8- to 16-weeks' duration, oral nimodipine 120 mg daily in divided doses reduced the frequency and possibly the severity and duration of migraine attacks in patients with classic or common migraine†;4, 8, 11, 12, 78, 79, 80, 90, 101, 114, 206, 244 benefit generally was observed within 1-2 months of initiating therapy.11, 78, 80, 90, 185, 206 However, another randomized, controlled study of 24-weeks' duration found no substantial benefit of nimodipine 120 mg daily in patients with common or classic migraine.233, 244 Nimodipine also has been used in a few patients with cluster headache.90, 100, 114 Additional studies are needed to determine the role of nimodipine relative to that of other therapies used in the management of migraine headaches78, 79, 80, 206, 230, 231 and to determine whether tolerance to the prophylactic effects of the drug develops during chronic therapy.206 For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.
Nimodipine has been used with some success in patients with severe non-migraine vascular headache associated with chronic cerebral ischemia.113 The drug also has been used in a few patients with chronic focal epilepsy† (epilepsia partialis continua)112 and is undergoing clinical study in patients with age-associated memory disorders† (e.g., dementia of the Alzheimer's type).5, 230 Further studies are needed to determine the potential usefulness of nimodipine in these conditions.230, 231
The contents of nimodipine capsules must not be administered by IV injection or any other parenteral route; deaths and serious, life-threatening adverse effects such as cardiac arrest, cardiovascular collapse, hypotension, and bradycardia have occurred with such administration .1, 245, 246, 248, 249, 250(See Cautions: Cardiovascular Effects.)
Because presence of food in the GI tract can substantially decrease the extent of oral absorption of nimodipine, the drug should be administered at least 1 hour before or 2 hours after meals.1
Nimodipine capsules are for oral administration only .1, 245, 246, 248, 249, 250 If the oral capsule cannot be swallowed (e.g., when administered at the time of surgery or to an unconscious patient), the liquid-filled capsule may be punctured at both ends with an 18-gauge needle and the contents emptied into a syringe,1, 245, 246, 249, 250 preferably using a syringe designed for nasogastric or percutaneous endoscopic gastrostomy administration (e.g., Toomey syringe).246, 250 To help minimize administration errors, the syringe should be labeled for oral use only; not for IV use .1, 245, 246, 248, 249, 250 The contents of the capsule should then be administered via the patient's nasogastric tube.1, 245, 246, 249, 250 Following administration, the tubing should be flushed with 30 mL of 0.9% sodium chloride solution.1, 245, 246, 249 The contents of the nimodipine capsule should not be admixed with any solution prior to oral administration because of the possibility of drug decomposition.230
Awareness among health-care professionals of potential medical errors that may result in the inadvertent injection of syringe contents into an IV line or via other parenteral routes should be reinforced.246, 248, 249, 250
If inadvertent IV administration of contents of nimodipine capsules occurs, cardiovascular support with vasopressor agents may be required for clinically important hypotension and specific treatments for overdosage associated with calcium-channel blocking agents should be promptly administered.1, 246
Nimodipine also has been administered by IV infusion† (IV dosage form currently not commercially available in the US) in patients with subarachnoid hemorrhage, often in conjunction with intracisternal† application during surgery67, 117, 119, 120, 214 and usually followed by oral therapy.5, 67, 93, 116, 117, 118, 119, 120, 214 However, the manufacturer states that the contents of nimodipine capsules must not be administered IV or by any other parenteral route.1, 245, 246
Various dosages of nimodipine (20-90 mg but usually 60 mg daily) have been used for prevention of delayed ischemic neurologic deficits in patients with subarachnoid hemorrhage.1, 2, 5, 20, 21, 22, 23, 69 A study comparing oral nimodipine dosages of 30, 60, or 90 mg every 4 hours reportedly found that response, in terms of the rate of neurologic deficits, in patients with subarachnoid hemorrhage was not related substantially to dosage.1, 230 However, because mortality in nimodipine-treated patients in a study23 in seriously ill patients (Hunt and Hess grades III-V) was higher than in the placebo group and an adverse effect of the drug on mortality could not be ruled out,1 a dosage of 90 mg every 4 hours is not recommended.1, 230, 231 (See Cautions: Precautions and Contraindications.)
Based on current evidence, the manufacturer recommends an oral nimodipine dosage of 60 mg every 4 hours for 21 consecutive days for the management of subarachnoid hemorrhage.1, 5 Therapy with the drug should begin as soon as possible after the occurrence of subarachnoid hemorrhage, preferably within 96 hours.1, 5, 230, 231 Some clinicians suggest that, while the drug should be continued for a full 21-day course in most patients, discontinuance may be possible after 14 consecutive days (but not earlier) in some uncomplicated cases in which early aneurysm surgery is performed.231 In patients in whom surgical repair of the aneurysm is performed relatively late (e.g., day 20), some clinicians suggest that nimodipine be continued for at least 5 days after the procedure to minimize the possibility of postoperative vasospasm.4, 231 In addition, some clinicians suggest that therapy in patients with unstable blood pressure be initiated with a lower dosage of nimodipine (e.g., 30 mg every 4 hours orally) and with frequent monitoring of blood pressure and heart rate;4, 231 however, the manufacturer states that the usual adult dosage should be used in such patients.230
For the improvement in neurologic outcome in patients with acute ischemic stroke†, an oral nimodipine dosage of 120 mg daily given in divided doses for 21 or 28 days has been used.76, 77, 242, 247
For prevention of migraine headache†, an oral nimodipine dosage of 120 mg daily given in divided doses has been used.4, 8, 11, 12, 78, 79, 80, 101, 114, 206 Response to therapy is delayed,11, 78, 80, 185, 206 but usually is apparent within 1-2 months after initiating prophylactic treatment with the drug.11, 78, 80, 206
Dosage in Renal and Hepatic Impairment
Patients with hepatic failure (e.g., cirrhosis) may have substantially reduced clearance of nimodipine, and peak plasma concentrations achieved in these patients may be substantially higher than those in patients with normal hepatic function.1, 89 (See Pharmacokinetics: Absorption.) Therefore, dosage of nimodipine should be reduced in patients with impaired hepatic function.1, 5 The initial dosage of nimodipine in such patients should be reduced to 30 mg every 4 hours1, 5, 89 and blood pressure and heart rate monitored closely;1, 89 if necessary, pharmacologic support of blood pressure (e.g., vasopressors such as norepinephrine or dopamine) may be used.230, 231
Reduced clearance of nimodipine also has been reported in patients with renal impairment, although concomitant age-related hepatic impairment may have contributed to the reported reduction in clearance.88
Nimodipine generally is well tolerated following oral administration.2, 4, 20, 21, 22, 69, 84, 96, 110, 154, 160, 162 Adverse effects reportedly occurred in about 11% of patients receiving oral nimodipine dosages of 0.35 mg/kg or 30-120 (principally 60) mg every 4 hours for the management of subarachnoid hemorrhage.1 The most common adverse effect of nimodipine is decreased blood pressure,1, 4, 112 which may be dose-related1, 122 and occasionally requires discontinuance of the drug.1, 5 The manufacturer states that only decreased blood pressure, edema, and headache have been attributed directly to oral nimodipine therapy in patients with subarachnoid hemorrhage based on an occurrence substantially more often than with placebo or evidence of a dose relationship to the drug.1, 23, 230, 231 However, because patients with subarachnoid hemorrhage frequently may have alterations in consciousness, the actual incidence of adverse effects in these patients may be higher than reported.1 In addition, other adverse effects typically associated with calcium-channel blocking agents (e.g., flushing, headache) have been reported in healthy individuals154 and in patients receiving nimodipine for conditions other than subarachnoid hemorrhage,1, 8 and the possibility that the drug may produce such effects should be considered.1
IV administration of the contents of nimodipine capsules† has resulted in deaths and serious, life-threatening adverse effects, including cardiac arrest, cardiovascular collapse, hypotension, and bradycardia; the contents of nimodipine capsules must not be administered by IV or any other parenteral routes.1, 245, 246, 248, 249, 250 (See Cautions: Precautions and Contraindications.)
Although the hemodynamic effects of nimodipine are qualitatively similar to those of other 1,4-dihydropyridine calcium-channel blockers,1, 7, 128, 230, 231 the effect of orally administered nimodipine on systemic blood pressure generally is not marked at usual therapeutic dosages.1, 2, 6, 7, 20, 21, 22, 23, 54, 69, 246 The manufacturer states that decreased blood pressure has been reported in approximately 5% of patients with subarachnoid hemorrhage receiving oral nimodipine in clinical studies,1, 246 requiring discontinuance of the drug in approximately 1%.1, 246 However, in clinical studies of patients with subarachnoid hemorrhage receiving either 0.35 mg/kg (approximately 25 mg in a 70-kg patient) or 60 mg of nimodipine orally every 4 hours, decreased blood pressure was uncommon.20, 21, 22, 69, 151 In a study in more seriously ill (Hunt and Hess grades III-V) patients with subarachnoid hemorrhage, hypotension was reported in about 7% of patients receiving 90 mg of nimodipine orally or via nasogastric tube every 4 hours23 (dosage not currently recommended),230, 231 requiring temporary or permanent drug discontinuance in half of the patients exhibiting this adverse effect.23 Patients with hepatic disease (e.g., cirrhosis) may have decreased clearance of nimodipine (see Pharmacokinetics: Elimination) and therefore may be more likely to experience hypotension during therapy with the drug.1, 4, 89, 230, 231
Adverse cardiovascular effects reported in less than 1% of patients with subarachnoid hemorrhage1, 230 receiving oral nimodipine were dyspnea1 and edema,1 which may be dose-related.1 ECG abnormalities,1, 69, 93 including tachycardia1, 69, 93, 106 and bradycardia,1, 5, 69, 93 also have been reported in less than 1% of patients with subarachnoid hemorrhage receiving oral nimodipine;1, 230 however, these abnormalities also occur frequently after subarachnoid hemorrhage in patients not receiving the drug.44, 83, 93 While not reported to date with nimodipine, the possibility that the drug may produce other cardiac effects associated with calcium-channel blocker therapy (e.g., AV-conduction disturbances) should be considered.1 Adverse cardiovascular effects reported in less than 1% of patients with subarachnoid hemorrhage receiving oral nimodipine1 include palpitations,1 flushing,1, 20 rebound vasospasm,1 and hypertension.1, 20 In addition, congestive heart failure,1, 23 pulmonary edema23 and ventriculitis23 have been reported in less than 1% of patients receiving an oral nimodipine dosage of 90 mg every 4 hours.1
Flushing1, 8 and fluid retention1 have been reported in approximately 2% and in less than 1%, respectively, of patients receiving nimodipine for conditions other than subarachnoid hemorrhage.1, 8
Left ventricular papillary muscle lesions have developed in dogs given oral nimodipine dosages of 10 mg/kg daily for 3 months.128 These lesions also have been reported in animals164, 165, 166 but not in humans167 after administration of other vasodilating agents (e.g., minoxidil) and apparently are related to myocardial hypoxia resulting from hypotension and subsequent reflex tachycardia following nimodipine administration.128, 165, 166
Thrombocytopenia1, 23 and anemia1 have been reported in less than 1% of patients with subarachnoid hemorrhage receiving oral nimodipine.1 In addition, disseminated intravascular coagulation,1, 23 deep-vein thrombosis,1, 23 decreased platelet count,1 and pulmonary embolism23 have been reported in less than 1% of patients with subarachnoid hemorrhage receiving an oral nimodipine dosage of 90 mg every 4 hours.1
Rash,1, 4, 23 requiring discontinuance of the drug in at least one case,23 and acne1 have been reported in less than 1% of patients with subarachnoid hemorrhage receiving oral nimodipine.1, 230 Pruritus,1 diaphoresis,1 and hematoma1 also have been reported in less than 1% of such patients.1
GI symptoms have been reported in less than 1% of patients with subarachnoid hemorrhage receiving oral nimodipine.1, 230 Lower abdominal discomfort or cramps11, 76, 78 and constipation127, 234, 235 have been reported in patients receiving oral nimodipine for prolonged periods (e.g., for migraine headache). Intestinal pseudo-obstruction and ileus, which responded to conservative management, has been reported rarely.1, 127 It has been suggested that abdominal discomfort and constipation may result from the relaxant effect of nimodipine on intestinal smooth muscle.11, 76 Constipation is commonly associated with other calcium-channel blockers, particularly verapamil;155, 156, 157, 158, 159, 160, 186 the mechanism of this effect appears to involve voltage-dependent calcium channels that produce contraction of intestinal smooth muscles when stimulated.155, 186 Diarrhea1, 23 also has been reported in less than 1% of patients with subarachnoid hemorrhage receiving nimodipine.1, 230 Vomiting1 and GI hemorrhage 1 have been reported less frequently.1
Elevations in one or more liver function test result, including elevated serum concentrations of LDH,1 alkaline phosphatase,1, 93 or ALT (SGPT),1, 93 have been reported in less than 1% of patients with subarachnoid hemorrhage receiving oral nimodipine.1, 230 Reversible4, 76, 84, 92, 93, 96 increases in creatine kinase (CK, creatine phosphokinase, CPK),76 AST (SGOT),4, 76, 84, 92, 93, 163 ALT,4, 76, 84, 92, 93, 163γ-glutamyl transferase (GGT, γ-glutamyltranspeptidase, GGTP),4, 76, 84, 92, 93, 96 bilirubin,163 and amylase163 also have been reported in patients receiving nimodipine.2, 4, 84, 92, 93, 96
Adverse hepatic effects reported in less than 1% of patients with subarachnoid hemorrhage receiving oral nimodipine include hepatitis1 and jaundice.1, 69
Adverse CNS effects reported in less than 1%1, 230 of patients with subarachnoid hemorrhage receiving oral nimodipine include mental depression,1 headache,1, 5, 20 lightheadedness,1 and dizziness.1 Neurologic deterioration1, 23 and hydrocephalus23 have been reported in less than 1% of patients with subarachnoid hemorrhage receiving an oral nimodipine dosage of 90 mg every 4 hours (dosage not currently recommended).1, 230, 231 Confusion with psychosis4, 76 and exacerbation of insomnia78 each have been reported in at least one patient receiving the drug orally. Drowsiness, sleepiness, tiredness, and relaxation have been reported in healthy individuals receiving single doses of nimodipine up to 60 mg orally.154
Muscle pain1 or cramp1 has been reported in less than 1% of patients with subarachnoid hemorrhage receiving oral nimodipine.1, 230 Other adverse effects reported in less than 1% of patients with subarachnoid hemorrhage receiving the drug orally include wheezing1 and, at an oral nimodipine dosage of 90 mg every 4 hours, hyponatremia.1 Elevated serum concentrations of glucose (non-fasting)1 and/or hyperglycemia23 have been reported rarely in patients receiving nimodipine.1, 23 Other adverse effects reported in patients with subarachnoid hemorrhage receiving oral nimodipine include pneumonia23 and wound infection.23
No cases of drug abuse or dependence have been reported with nimodipine to date.1
Precautions and Contraindications
The contents of nimodipine oral capsules must not be administered IV or by any other parenteral routes. 1, 245, 246, 248, 249, 250Death and serious life-threatening adverse effects (e.g., cardiac arrest, cardiovascular collapse, hypotension, bradycardia) have occurred following parenteral injection of the contents of nimodipine capsules. 1, 245, 246, 248, 249, 250
According to the US Food and Drug Administration (FDA), cases of IV nimodipine use, with serious and sometimes fatal outcomes, continue to be reported despite revisions to the drug's labeling (including addition of a boxed warning) that warn against such use.248, 249, 250 Factors identified by FDA as contributing to the occurrence of this medication error include the use of IV syringes to administer the drug by nasogastric tube to patients who cannot swallow the capsules (IV syringes sometimes are used to remove the liquid contents from the capsules since a standard needle will not fit an oral syringe) and the fact that most patients receiving the drug are in critical care settings and are receiving other IV therapy.249, 250
A total of 31 medication errors involving nimodipine use were reported between 1989 and 2009; 25 of these reports involved erroneous IV nimodipine prescribing or administration.249, 250 Among the 25 patients who received IV nimodipine, 4 patients died, 5 were described as having near-death events, and one patient was considered to have suffered permanent harm.249, 250 Health care providers are encouraged to report adverse events or medication errors involving nimodipine capsules to the FDA MedWatch program.248, 250
Nimodipine shares the toxic potentials of other calcium-channel blocking agents, and the possibility that adverse effects associated with these drugs could occur with nimodipine should be considered.1 Like other calcium-channel blockers, nimodipine can reduce systemic blood pressure.1, 246 Although such reductions generally are not marked with usual oral dosages of nimodipine,1, 2, 6, 7, 20, 21, 22, 23, 54, 69, 132, 246 blood pressure should be monitored closely during therapy with the drug.1, 246 Careful monitoring of blood pressure and pulse rate is particularly important in patients with impaired hepatic function, since metabolism of the drug may be decreased in such patients; initial dosage of the drug should be reduced in these patients.1 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)
There are no known contraindications to use of nimodipine in patients with subarachnoid hemorrhage.1 However, increased overall mortality in seriously ill (Hunt and Hess grades III-V) patients receiving the drug was noted in one placebo-controlled study, although neurologic improvement also was observed with nimodipine treatment, principally in grade III and IV patients.1, 23 Although most of the deaths in this study appeared to be related to subarachnoid hemorrhage, an adverse effect of the drug on mortality could not be ruled out.1, 23 Therefore, the manufacturer states that use of an oral nimodipine dosage of 90 mg every 4 hours and treatment of Hunt and Hess grade IV or V patients currently is not recommended,1, 230 although some clinicians suggest that therapy with recommended dosages of nimodipine (i.e., 60 mg every 4 hours) can be attempted in Hunt and Hess grade IV patients with subarachnoid hemorrhage.231 (See Uses: Subarachnoid Hemorrhage.)
Safety and efficacy of nimodipine in children younger than 18 years of age have not been established.1, 230
The manufacturer states that clinical studies of nimodipine did not include a sufficient number of patients 65 years of age or older to determine whether such patients respond differently than younger individuals but that other reported clinical experience has not identified differences in response between geriatric and younger patients.1 In a pharmacokinetic study, peak plasma concentrations and area under the plasma concentration-time curve (AUC) of nimodipine were about twice as high in geriatric individuals as in younger individuals following single and multiple dosing; however, no clinically important age-related differences in response were noted.1 (See Pharmacokinetics: Absorption.) Appropriate dosage of nimodipine in geriatric patients should be selected with caution because of the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease and drug therapy in these patients.1
Mutagenicity and Carcinogenicity
Nimodipine did not exhibit mutagenic activity in several in vitro test systems, including the Ames microbial mutagen test, micronucleus test, or dominant lethal test.1, 128
In a 2-year study, Wistar rats given a diet containing 1800 ppm of nimodipine daily (91-121 mg/kg daily) had a higher incidence of adenocarcinoma of the uterus and Leydig-cell adenoma of the testes than rats given placebo.1, 128 However, these differences were not statistically significant, and the higher rates of cancer were within the historical control range for this strain of rat.1, 128 Although cellular hypertrophy of the zona glomerulosa of the adrenal cortex also was observed in these rats, this effect was attributed to functional adaptation of the adrenal cortex to nimodipine-induced compensatory effects on the renin-angiotensin-aldosterone system.128 Nimodipine was not found to be carcinogenic in a 91-week study in mice, but life expectancy was shortened in mice receiving an oral dosage of 1800 ppm daily (546-774 mg/kg daily).1
Pregnancy, Fertility, and Lactation
Although there are no adequate and controlled studies to date in humans, nimodipine at oral (gavage) dosages of 1 or 10 mg/kg daily but not at 3 mg/kg daily was associated with an increased incidence of malformations and stunted fetal growth when given from day 6 through day 18 of pregnancy in rabbits.1 In an identical study, an increased incidence of stunted fetal growth was observed at oral dosages of 1 mg/kg daily but not at the higher dosages.1 Nimodipine was embryotoxic in rats at oral dosages of 100 mg/kg daily, causing resorption or stunted fetal growth when administered by gavage from day 6 through 15 of pregnancy.1 Slight maternotoxicity was observed in one of these studies but may have been attributable to the presence of polyethylene glycol 400 in the gavage solution.128 When administered in 2 other studies to rats at oral dosages of 30 mg/kg daily from day 16 of gestation until sacrifice (at day 20 of pregnancy or day 21 postpartum), nimodipine was associated with higher incidences of skeletal variation, stunted fetal growth, and stillbirths1 but no malformations.1, 128 In addition, the drug did not impair postnatal development.128 Nimodipine should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1
When administered to Wistar rats for more than 10 weeks prior to mating in males or for 3 weeks prior to mating through day 7 of pregnancy in females, oral nimodipine dosages up to 30 mg/kg daily were not associated with impairment of fertility or general reproductive performance.1, 128 This dosage of nimodipine is approximately 4 times higher than the usual recommended oral dosage of 60 mg every 4 hours administered to a 50-kg adult.1
Nimodipine and/or its metabolites are distributed into milk in animals (rats) in concentrations much higher than those in maternal plasma.1, 91 Since it is not known whether the drug is distributed into human milk,1, 230 women should be advised not to breast-feed while taking nimodipine.1
Limited in vitro evidence in animals suggests that diltiazem, a calcium-channel blocker, potentiates the negative inotropic effect of nimodipine in a reversible, stereospecific manner.136, 155 The clinical relevance of these findings has not been determined to date, but the possibility that nimodipine could potentiate the cardiovascular effects of concurrently administered calcium-channel blocking agents should be kept in mind when considering concomitant use of these drugs;1, 230, 231 some clinicians suggest that use of such combined therapy be avoided if possible.231
Potentiation by nimodipine of the effects of concurrently administered antihypertensive drugs has been reported occasionally.1, 93 Because reduction in blood pressure or hypotension has been reported in patients receiving nimodipine alone,1, 4, 5, 11, 20, 23, 84, 92, 96, 112, 122 patients who must receive the drug concurrently with hypotensive agents should have their blood pressure carefully monitored; short-acting hypotensive agents preferably should be used, if possible,231 and a reduction in dosage or cautious discontinuance of the hypotensive agent and/or initiation of pharmacologic support of blood pressure may be required.230, 231
Increased plasma concentrations of nimodipine have been reported in one study in healthy men receiving 30 mg of nimodipine 3 times daily concomitantly with cimetidine dosages of 1 g daily for 7 days.1, 243 In this study, area under the plasma concentration-time curve (AUC) and mean peak plasma concentrations of nimodipine increased by 90 and 50%, respectively.1, 243 However, no clinically important changes, as measured by laboratory evaluations and tolerance, were reported after concomitant administration of cimetidine with nimodipine.243 Although the precise mechanism of this interaction is not known, cimetidine-induced inhibition of the cytochrome P-450 mixed-function oxidase system (the enzyme system that may be responsible for the first-pass metabolism of nimodipine) may play a role.1
Phenytoin toxicity reportedly has occurred in at least one patient with subarachnoid hemorrhage receiving nimodipine.1 However, most patients with subarachnoid hemorrhage receiving nimodipine received concomitant therapy with phenytoin or barbiturates reportedly with no apparent evidence of drug interactions.230
Phenytoin toxicity also has occurred within 4 weeks after initiating nifedipine, another 1,4-dihydropyridine calcium-channel blocker, in a patient stabilized on phenytoin.179, 180 Manifestations of phenytoin toxicity (e.g., headaches, nystagmus, tremors, slurred speech, ataxia, mental depression) resolved and plasma concentrations of the drug decreased within 2 weeks after discontinuance of nifedipine.179, 180 While the mechanism has not been elucidated, it was suggested that nifedipine may have reduced the metabolism of phenytoin.179
Pending further accumulation of data, patients and plasma phenytoin concentrations should be monitored carefully whenever therapy with a 1, 4-dihydropyridine calcium-channel blocker is initiated or withdrawn from a patient receiving phenytoin.179
Limited data suggest that nimodipine does not interfere with or potentiate the hemodynamic effects of anesthetic agents during surgery.54, 230, 231 In a study in patients receiving a 0.7-mg/kg oral loading dose of nimodipine followed by 0.35 mg/kg orally every 4 hours before aneurysm repair, the drug had minimal effects on mean blood pressure measured before and during surgery.54
Limited evidence in healthy individuals suggests that low doses (i.e., 30 mg twice daily) of orally administered nimodipine do not alter the pharmacokinetics or hemodynamic effects of digoxin.137
There is in vitro evidence that calcium-channel blocking agents, including nimodipine, can enhance the cytotoxic effects of certain antineoplastic agents,140, 141, 190, 191, 192, 193, 195 but the clinical importance of these findings remains to be established.230, 231 (See Pharmacology: Other Effects.)
The contents of nimodipine capsules must not be administered by IV injection or any other parenteral route because deaths and serious, life-threatening adverse effects have occurred with such administration.1, 245, 246, 248, 249, 250 (See Cautions: Cardiovascular Effects and Precautions and Contraindications.)
The manufacturer states that there has been no experience to date with overdosage of orally administered nimodipine in humans.1
The oral LD50 of the drug has been reported to be approximately 3.6, 6.6, 5, and 1-2 g/kg in mice, rats, rabbits, and dogs, respectively, and the IV LD50 has been reported to be approximately 33, 16, 2.5, and 4 mg/kg, respectively, in these animals.128
In general, overdosage of nimodipine may be expected to produce effects that are extensions of the drug's pharmacologic and adverse effects, principally cardiovascular effects such as excessive peripheral vasodilation and resultant marked systemic hypotension.1, 230, 231
Management of nimodipine overdosage generally would be expected to involve symptomatic and supportive care.1 Active cardiovascular support, such as administration of a vasopressor agent, may be necessary if clinically important hypotension occurs.1, 246 Specific treatments for overdosage associated with calcium-channel blocking agents should be promptly administered.1, 246 IV calcium salts also have been used for the management of hypotension and possibly some other cardiovascular disturbances associated with overdosage of calcium-channel blocking agents.168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 230, 231 Because nimodipine is extensively protein bound, dialysis is not likely to be beneficial in enhancing elimination of the drug from the body.1
Nimodipine has pharmacologic actions similar to those of other calcium-channel blocking agents;1, 3, 4, 7, 10, 49, 126, 128, 245 however, at usual dosages, nimodipine, unlike other currently available calcium-channel blockers, appears to affect the central nervous system preferentially.1, 4, 7, 8, 13, 17, 35, 42, 45, 55, 82, 155, 185, 206, 229, 230 The principal physiologic action of nimodipine is to inhibit the influx of extracellular calcium ions through voltage-dependent (membrane depolarization-induced)7, 10, 41, 48, 49, 133 and receptor-operated4, 7, 14, 35, 49, 53, 59, 133 slow calcium channels in the membranes of myocardial, vascular smooth muscle, and neuronal cells.1, 3, 4, 5, 7, 10, 132, 133, 236
The exact mechanism by which nimodipine inhibits calcium ion influx across slow calcium channels is not known, but binding of the drug to specific, high-affinity receptor sites on the cell membrane39, 48, 155, 186, 187, 188, 189, 210 in or near the calcium channel125, 155, 210 is thought to alter ion-control gating mechanisms of the channel by favoring a gating mode in which the calcium channel is unavailable for opening.47, 48, 155 These stereoselective, receptor binding sites have been referred to as 1,4-dihydropyridine ([3H]nitrendipine) receptors.39, 48, 155, 181, 182, 186, 187, 188, 189 Other receptor sites also have been described.155, 186 Limited in vitro evidence suggests that the vasodilatory action of nimodipine may be attributed in part to its effects on the activity of sodium-potassium-activated adenosinetriphosphatase (Na+-K+-ATPase), an enzyme required for active transport of sodium across cell membranes.103 In general, nimodipine and other 1,4-dihydropyridines with calcium-channel blocking activity (e.g., nifedipine) exhibit relative selectivity for vascular versus myocardial cells7, 42, 189, 206 and have greater vasodilatory effects than other calcium-channel blockers;10, 206 the 1,4-dihydropyridine calcium-channel blockers also have minimal electrophysiologic and negative inotropic effects compared with verapamil or diltiazem.7, 42, 206
Although the mechanism(s) of nimodipine's clinical benefit in patients with subarachnoid hemorrhage has not been fully elucidated,1, 4, 20, 69, 102 current evidence suggests that dilation of small cerebral resistance vessels,2, 23, 36, 102, 131 with a resultant increase in collateral circulation,4, 5, 23, 52, 67, 83, 98, 131 and/or a direct effect involving prevention of calcium overload in neurons2, 4, 5, 13, 23, 68, 69, 82, 83, 96, 102, 104, 132, 206 may be responsible.
Nimodipine exerts relatively selective pharmacologic effects on cerebral arteries compared with arteries elsewhere in the body,1, 4, 7, 8, 13, 17, 35, 42, 45, 55, 82, 185, 206, 229 which may be attributable in part to the drug's high lipid solubility and specific binding to cerebral tissue.1, 5, 8, 13, 16, 82, 132 The affinity of nimodipine for cerebral binding sites has been shown in vitro to correlate with its potency as a calcium-channel blocking agent.16, 82, 189 Compared with nifedipine, nimodipine is more lipophilic,132 a more potent cerebral vasodilator,8, 10, 17, 22, 23, 35, 55, 82, 155, 206 and is more rapidly and widely distributed in cerebral tissue.13, 45, 132
Evidence suggesting that the influx of extracellular calcium represents the principal determinant of cerebrovascular compared with peripheral vascular smooth muscle contraction may explain in part the apparent preferential effects of nimodipine on cerebrovascular tissue.6, 13, 20, 22, 41, 82, 133 Differences in tissue specificity among calcium-channel blockers also have been attributed to variations in the types of calcium channels and associated receptors present in various tissues.10, 155, 186, 189, 210, 229 Although calcium-channel blockers appear to inhibit voltage-dependent calcium channels in most blood vessels,133 inhibition of receptor-operated (agonist-induced) channels in blood vessels from different tissues varies considerably.133, 186, 229 Studies in which isolated saphenous and basilar arteries of animals were exposed to nimodipine demonstrate that the drug inhibits contractions induced by potassium (depolarization-induced) and by serotonin (agonist-induced) in both types of vessels but prevents agonist-induced contractions only in basilar arteries;15, 132, 133, 229 the mechanism of this selectivity for receptor-operated calcium channels in cerebral tissue has not been determined.133
Nimodipine has produced dilation of cerebral arterioles and increased cerebral blood flow in most studies when administered IV, intra-arterially, intraperitoneally, or intracisternally (parenteral dosage forms currently not commercially available in the US) during surgery in animals4, 50, 51, 56, 57, 58, 59, 62, 63, 226 or humans.4, 36, 40, 43, 65, 94 Clinical studies of patients with subarachnoid hemorrhage in which transcranial Doppler ultrasonography was used have demonstrated reduced cerebral vasoconstriction, particularly in high-risk patients who have large amounts of blood in the subarachnoid space.2, 92
Nifedipine and other 1,4-dihydropyridine calcium-channel blockers also may increase cerebral blood flow,7 but nimodipine generally does so at dosages that are not associated with clinically important systemic hypotension.7, 13, 18, 25, 33, 34, 63, 64, 132 In vivo evidence in animals suggests that nimodipine increases cerebral blood flow principally by opposing preexisting agonist-induced elevations in cerebrovascular resistance (such as those induced by anesthesia),4, 53, 60 although some evidence suggests that the drug also increases cerebral blood flow in the absence of agonist-induced vasoconstriction.61, 62 The increase in cerebral blood flow associated with nimodipine appears to occur in the absence of increased cerebral glucose metabolism and/or oxygen requirements.6, 13, 18, 25, 34, 62, 63, 132, 226 In addition, nimodipine may preferentially divert blood flow to ischemic tissue,2, 66, 99 while substantial diversion of blood flow from ischemic to healthy tissue (“cerebral steal”) does not appear to occur.14, 66, 224 Some evidence indicates that nimodipine disrupts autoregulation of cerebral blood flow,4, 57, 63 the inherent ability of cerebral vessels to maintain a constant blood flow over a range of cerebral perfusion pressures.10 Although inhibition of the ability of cerebral vessels to constrict in response to acute increases in systemic arterial pressure potentially could be harmful,57 the importance of such an effect in humans has not been established.230, 231
The exact mechanism(s) by which nimodipine reduces the incidence and/or severity of ischemic neurologic deficits in patients with subarachnoid hemorrhage has not been determined.1, 4, 20, 69, 102 In stroke-prone spontaneously hypertensive rats, nimodipine substantially reduced mortality and the number of cerebral ischemic lesions without decreasing systemic blood pressure, which suggests a specific protective effect of the drug on cerebral circulation.14, 70, 132 The presumed mechanism by which nimodipine would be of benefit in patients with subarachnoid hemorrhage was initially thought to be alleviation of the delayed cerebral vasospasm that often accompanies this condition;44, 82, 95, 102, 132 this assumption was consistent with the results of studies in animals showing that the drug dilates cerebral arteries and increases cerebral blood flow.40, 43, 50, 51, 53, 56, 57, 58, 59, 60, 94, 132, 226 Prevention or reversal of cerebral vasospasm in patients with subarachnoid hemorrhage has not been documented angiographically to date in controlled studies;1, 4, 5, 20, 21, 23 however, it is not known whether the angiographic methods used in such studies were adequate to detect a clinically meaningful effect, if any, on vasospasm.1 Nimodipine has improved neurologic outcome in patients regardless of the angiographic presence or absence of cerebral vasospasm prior to therapy.20, 230 Therefore, other mechanisms, such as preferential dilation of small pial resistance vessels not visible on angiography2, 23, 36, 102, 131, 132 and subsequent increases in collateral blood flow to ischemic tissues, may contribute to the drug's clinical benefit in patients with subarachnoid hemorrhage.4, 5, 23, 52, 67, 83, 98, 131 Observations of human pial blood vessels during surgery indicate that nimodipine preferentially dilates small arterioles (those having diameters of less than 70-100 µm) while having only a small effect on venules.36, 43, 50, 58, 65
A direct anti-ischemic effect of nimodipine on neurons also has been suggested.2, 4, 5, 13, 23, 24, 68, 69, 82, 83, 96, 102, 104, 132, 224 Cerebral ischemia results in a massive influx of calcium ions into the neuron and subsequent disruption of cellular calcium homeostasis, leading to cell catabolism and necrosis;75, 111, 224 nimodipine may protect against or ameliorate the effects of ischemia by blocking calcium entry into the neuron.3, 111, 224 In animals, pretreatment with nimodipine has improved neurologic outcome and/or reduced the area of ischemic tissue damage after experimentally induced cerebral artery occlusion or intracerebral hemorrhage,38, 132, 134, 135, 227, 228 although not consistently.38, 134 Other evidence in animals given nimodipine up to 6 hours after cerebral artery occlusion indicates that the drug reduced the size of the periphery of the infarcted area (ischemic “penumbra”) compared with placebo;24 similarly, there is limited evidence demonstrating increased cerebral blood flow in the penumbra but not in the central area of infarction in patients receiving nimodipine within 6 hours of acute ischemic stroke.98, 239
The mechanism of nimodipine's beneficial effects in migraine headache has not been fully elucidated.101, 185, 206, 207, 208, 209 Although various etiologies of migraine headache have been proposed, current evidence appears to favor a “hypoxic” model for migraine initially involving vasoconstriction (presumably mediated by vasoactive amines or neurotransmitters such as serotonin) and decreased cerebral blood flow, which leads to cellular ischemia and hypoxia, influx of calcium into the cell, and subsequent cellular dysfunction.101, 185, 206, 208, 209 The headache is thought to occur during cerebral vasodilation that follows the vasoconstriction.185, 206, 207, 208, 209 It has been suggested that calcium-channel blockers such as nimodipine may prevent cerebral vasoconstriction (regardless of the initiating agent) by inhibiting the cellular influx of calcium, the final common pathway controlling vascular smooth muscle contraction;101, 206, 207 with continued administration, these agents may attenuate cerebral vasodilation associated with migraine headache by depleting intracellular calcium stores.90, 185, 206
Limited evidence in animals with experimentally induced carotid artery occlusion indicates that metabolic effects of nimodipine, such as retarding decreases in cellular pH and ATP concentrations and enhancing recovery of intracellular glucose concentrations, also may contribute to the beneficial effects of the drug in cerebral ischemia.13, 26, 27, 228
Nimodipine shares the hemodynamic effects of other calcium-channel blocking agents, although these effects generally are not marked with usual therapeutic dosages of nimodipine.1, 7, 13, 18, 25, 33, 34, 63, 64, 132, 246 In clinical studies in patients with subarachnoid hemorrhage, decreases in blood pressure were uncommon,1, 21, 22, 69 reportedly occurring in approximately 5% of nimodipine-treated patients.1 Few studies in patients with subarachnoid hemorrhage have reported hemodynamic effects of orally administered nimodipine other than infrequent effects on blood pressure and heart rate;20, 151, 161, 162, 231 small (approximately 10 mm Hg) dose-dependent decreases in systolic blood pressure have been reported in patients with acute ischemic stroke receiving nimodipine 240 mg daily.152 In anesthetized animals, IV administration (IV dosage form currently not commercially available in the US) of single doses of nimodipine in dosages of 0.3-10 mcg/kg reduced systemic blood pressure, heart rate, and coronary resistance but increased coronary blood flow.132, 148 Nimodipine also prolonged AV conduction time slightly in these animals, but only at high (10-30 mcg/kg) dosages.132, 148 Oral administration of 1- or 3-mg/kg doses of nimodipine to conscious dogs produced dose-dependent reductions in mean arterial pressure that were accompanied, unlike in anesthetized animals, by compensatory increases in heart rate.147
Limited data suggest that nimodipine does not interfere with or potentiate the hemodynamic effects of anesthetic agents during surgery.54 In a study of patients receiving a 0.7-mg/kg loading dose of nimodipine followed by 0.35 mg/kg orally every 4 hours before aneurysm repair, the drug had minimal effects on mean blood pressure measured before and during surgery.54
Nimodipine appears to exert anxiolytic effects in animals,223 and EEG profiles from healthy individuals receiving nimodipine are similar to those produced by drugs having mood-elevating and anxiolytic properties (e.g., imipramine).4, 153, 212 Other evidence suggests that nimodipine produces EEG changes indicative of alterations in vigilance or alertness.4, 71, 72 In animals, nimodipine has been shown to have antiamnestic properties and to potentiate α-receptor agonist-induced antinociceptive effects and hexobarbital-induced anesthesia,13, 28, 223 and limited evidence suggests that nimodipine potentiates fentanyl analgesia in patients undergoing heart surgery.154
Although the clinical importance has not been determined to date, nimodipine has been shown to potentiate the hypothermic effects of alcohol139 and diazepam138 and to enhance alcohol-induced motor incoordination in animals.139 In rats, nimodipine prevented seizures and reduced mortality associated with withdrawal from chronic alcohol intake13, 29 and also reduced signs of opiate withdrawal in these animals.13, 30
Nimodipine has been reported to facilitate associative learning in old animals, suggesting that it may be useful for improving learning deficits in such animals.81 Nimodipine also has exhibited evidence of anticonvulsant activity in a few patients with epilepsia partialis continua (Koshevnikoff's epilepsy, chronic focal epilepsy)112 and against seizures induced by ischemia, reperfusion, or drugs in animals.13, 31, 32, 223 In addition, in vitro receptor-binding studies suggest that 1, 4-dihydropyridine ([3H]nitrendipine) receptors in the CNS181, 183, 184 may be involved in modulating paroxysmal neuronal activity,183 further supporting the anticonvulsant potential of calcium-channel blockers that are active at these receptors.181, 183, 184
In vitro, phenytoin has been shown to reduce the binding of calcium-channel blockers to brain 1,4-dihydropyridine ([3H]nitrendipine) receptors.181, 182 This effect appears to result from phenytoin-induced reductions in receptor binding affinity rather than changes in the number of binding sites.181, 182 While the clinical importance of this effect is not known, there also is evidence that this receptor may be involved in anticonvulsant activity181, 182, 183, 184 and that calcium-channel blockers and phenytoin may inhibit voltage-dependent ion-control gating mechanisms of slow calcium channels by distinct but functionally linked mechanisms.181
Some evidence suggests that nimodipine may possess hemorrheologic effects.4, 83, 211 At relatively high concentrations (1 or 5 mcg/mL) in vitro, nimodipine has decreased blood and plasma viscosity by decreasing erythrocyte rigidity;4, 83, 211 however, the drug does not appear to affect erythrocyte aggregation.4, 211
Nimodipine alone appears to have little direct effect on platelet aggregation13, 19, 74 but at high concentrations has been shown to potentiate prostacyclin-induced inhibition of platelet aggregation.4, 73, 230
Calcium-channel blocking agents,140, 141, 190, 191, 192, 193, 194 including nimodipine,141, 190, 191, 192, 193, 195 have enhanced the cytotoxicity of certain antineoplastic agents in vitro, including that in multidrug-resistant cells. The mechanism(s) of these effects have not been fully elucidated, but there is some evidence that calcium-channel blockers may enhance intracellular concentrations of such antineoplastic agents (e.g., doxorubicin, vincristine) by inhibiting their outward transport.141, 190, 191, 192 However, other mechanisms (e.g., alterations in prostaglandin leukotriene pathways) also may be involved.140, 193, 215 Current evidence suggests that the ability of calcium-channel blockers to reverse multidrug resistance is not associated with their effects on calcium transport.216, 217, 218, 219
Calcium-channel blockers also have inhibited thymidine uptake in malignant human glioma cells, which may suggest an antiproliferative effect,196 and malignant cell-induced platelet aggregation and platelet-enhanced adhesion of malignant cells, which may suggest an antimetastatic effect;197, 198, 199, 200 the relevance of these findings remains to be elucidated.230, 231
Nimodipine and other calcium-channel blockers have decreased prolactin production in normal and malignant pituitary cells,201, 202, 203, 204 but nimodipine did not alter plasma concentrations of thyrotropin or prolactin after administration of protirelin (thyrotropin releasing hormone) in healthy individuals.225 Less pronounced decreases in somatotropin (growth hormone) production have been observed.201 Calcium-channel blockers occasionally have been reported to cause gynecomastia in men receiving the drugs, but the mechanism of this effect is unknown.205
Studies evaluating the pharmacokinetics of nimodipine after oral administration have been conducted in patients receiving the drug as capsules,46, 89, 213 tablets,46, 85, 88, 213 or an oral solution;85 information on the pharmacokinetics of the commercially available dosage form, a liquid-filled, soft-gelatin capsule,1 currently is limited.4, 46, 89 The pharmacokinetics of nimodipine also have been studied after IV administration (IV dosage form currently not commercially available in the US) of the drug.46, 85, 124, 213
Nimodipine is rapidly1, 46, 85, 89, 213 and almost completely4, 5, 213 absorbed following oral administration; however, because of extensive first-pass metabolism in the liver, oral bioavailability of the drug is low and variable.1, 46, 85, 213, 230 Limited data indicate that oral bioavailability of nimodipine administered in single doses as capsules to healthy individuals averages approximately 13%;1, 46 mean bioavailability of the drug administered as tablets has ranged from approximately 3-12%46, 85, 86, 213 in healthy individuals to 16% (range: 3-30%) in patients with subarachnoid hemorrhage.124 Sublingual administration of the contents of the capsule does not appear to alter the degree of first-pass metabolism of nimodipine.89 Presence of food in the GI tract can substantially decrease the extent of oral absorption of nimodipine.1 In one study in a limited number of healthy individuals, administration of nimodipine capsules following a standard breakfast decreased peak plasma concentrations 68% and decreased bioavailability 38% compared with administration on an empty stomach.1 Limited evidence suggests that the drug may undergo enterohepatic circulation.89, 123 (See Pharmacokinetics: Elimination.)
Peak nimodipine concentrations are attained within 1 hour after oral administration of single doses of the drug as capsules,1, 46, 89, 213 tablets,46, 85, 88, 213 or a solution.85 Peak nimodipine concentrations reported following oral administration of single 60-mg doses of the drug as capsules in healthy individuals have averaged 30 ng/mL 213 or 62 ng/mL46 in plasma at 0.4 or 0.5 hours, respectively, and 80 ng/mL in serum89 at 0.7 hours.46, 89, 213 In patients with subarachnoid hemorrhage, peak plasma nimodipine concentrations after oral dosing exhibit considerable interindividual variation, but generally occur 1 hour after administration and range from 7-96 ng/mL.86, 110, 124 While limited data suggest that peak plasma concentration and area under the plasma concentration-time curve (AUC) for nimodipine are approximately linearly related to dose at oral doses up to 80 mg,4, 86, 213 no dose-response relationship was found in a dose-ranging study comparing 30, 60, and 90-mg doses of nimodipine.1
Systemic availability of nimodipine may be increased substantially in patients with hepatic disease (e.g., cirrhosis).1, 89, 230 Peak serum drug concentrations and AUCs after oral administration in patients with hepatic cirrhosis have been considerably higher than those in healthy individuals.1, 89, 230 In one study, a mean peak serum nimodipine concentration of 116 ng/mL was reported in patients with hepatic cirrhosis after oral administration of single 60-mg doses of nimodipine as capsules; this value was approximately 1.5 times that reported in age-matched healthy individuals receiving the same dose.89
In a parallel-group study, peak plasma concentration and area under the plasma concentration-time curve (AUC) following administration of nimodipine 30 mg as a single dose and at steady state (3 times daily for 6 days) were about twice as high in geriatric individuals (59-79 years of age) as in younger adults (22-40 years of age).1 However, the clinical responses associated with these age-related differences were not considered important.1
Peak plasma nimodipine concentrations measured in healthy individuals 3 minutes after rapid IV injection (IV dosage form currently not commercially available in the US) of a 30-mcg/kg dose ranged from 39-148 ng/mL.86, 213 During IV infusion at a rate of 2 mg/hour in patients with subarachnoid hemorrhage, mean plasma nimodipine concentrations ranged from 36-72 ng/mL.86
Studies in animals indicate that nimodipine is widely distributed into body tissues after oral or IV administration (IV dosage form currently not commercially available in the US).87 Following IV administration in healthy individuals, nimodipine distributes rapidly into the central compartment with a half-life of approximately 6-7 minutes;4, 46, 86, 213, 230 the volume of distribution of the central compartment averaged 0.43 L/kg.4, 86 The steady-state volume of distribution following IV administration has been reported to range from 0.94-2.3 L/kg.4, 85, 213 Plasma protein binding of unchanged nimodipine averages more than 95%1, 4, 213 and is independent of concentration over a range of 10 ng/mL to 10 mcg/mL.1
Nimodipine appears to distribute to a limited extent into CSF.4, 22, 86, 231 After oral administration of nimodipine 0.35 mg/kg every 4 hours for 3 weeks, mean CSF and plasma nimodipine concentrations were 0.77 and 6.9 ng/mL, respectively.4, 22 However, concentrations as high as 12.5 ng/mL reportedly have been detected in CSF of at least one patient230 with subarachnoid hemorrhage receiving the drug.1
Nimodipine crosses the placenta to a limited extent in animals.4, 87 Nimodipine and its metabolites are distributed into milk in animals in concentrations substantially exceeding those in maternal plasma.1, 91
Nimodipine concentrations appear to decline in a biphasic manner.46, 89, 213 Mean elimination half-lives ranging from 1.7-9 hours have been reported after oral administration of the drug in healthy individuals.1, 4, 5, 46, 85, 86, 88, 89, 213 No evidence of drug accumulation was noted in patients receiving 40 mg of nimodipine 3 times daily for 7 days.1, 86, 213
After administration of single oral doses of radiolabeled nimodipine to healthy individuals, approximately 32% of radioactivity reportedly was recovered in feces, possibly secondary to biliary excretion.4 Limited evidence in animals indicates that nimodipine and/or its metabolites undergo extensive enterohepatic circulation.123 Although evidence suggesting possible enterohepatic circulation has been reported in humans,89 additional study is needed to confirm these findings.230, 231
Nimodipine is extensively metabolized in the liver, with approximately 10% or less than 1% of an orally administered dose present in plasma or urine, respectively, as unchanged drug.1, 5, 4, 88, 89, 213 The principal metabolites of nimodipine appearing in plasma are formed by dehydrogenation of the 1,4-dihydropyridine nucleus4, 85, 126, 213 or oxidative demethylation of the methoxy group on the parent drug or the dehydrogenated metabolite;4, 85, 126, 213 it appears that demethylation followed by dehydrogenation is the major metabolic pathway in humans.4, 85, 86 Ester hydrolysis followed by hydroxylation to form carboxylic and hydroxycarboxylic acid derivatives, respectively, may then occur,85, 86, 126, 213 with subsequent glucuronide conjugation;85, 126 other metabolites identified in animals also may be present in low concentrations in urine of humans.4, 85, 126 All metabolites of nimodipine are either inactive or substantially less active than the parent drug.1, 124, 125, 213 Approximately 50% of an ly administered dose of nimodipine is excreted almost exclusively as metabolites in the urine within 4 days.4
Plasma clearance of nimodipine varies considerably, averaging 0.84 L/kg per hour (range: 0.51-1.15 L/kg per hour) in healthy individuals86 and 1.18 L/kg per hour (range: 0.57-1.77 L/kg per hour) in patients with subarachnoid hemorrhage.124 Clearance of nimodipine may be substantially decreased in patients with hepatic dysfunction.4, 89 In one study, mean clearance rates in patients with hepatic cirrhosis receiving single 60-mg doses of nimodipine ly were less than half those in healthy individuals.89 Another study indicated a substantial prolongation of nimodipine elimination half-life and a reduction in plasma clearance of the drug in patients with renal impairment compared with healthy individuals; however, these findings may have been attributable in part to age-related reductions in liver function in patients with renal impairment, who were substantially older (mean age 65.3 years) than healthy controls (mean age 25.2 years).88 Additional study and experience are needed to further elucidate the effects of renal and hepatic impairment on the pharmacokinetics of nimodipine.4, 88, 231
It is not known whether nimodipine is removed by peritoneal dialysis or hemodialysis, but the drug's extensive protein binding suggests that dialysis is not likely to be beneficial in removing nimodipine from the body.1, 230, 231
Nimodipine is a 1,4-dihydropyridine-derivative calcium-channel blocking agent1, 4, 5, 13, 22, 96 that is structurally related to nifedipine.5, 8, 148 The calcium-channel blocking activity of nimodipine appears to be attributable principally to the levorotatory, S- configuration isomer;28, 125 pharmacologic activity of 1,4-dihydropyridine calcium-channel blockers such as nimodipine also appears to be influenced by the position of substituents on the 4-aryl ring and the planarity of the 1, 4-dihydropyridine ring.48, 49 The mechanism of nimodipine's selectivity for cerebral tissue is complex and has not been fully elucidated; tissue selectivity of 1,4-dihydropyridine calcium-channel blockers may be related to differences in chemical structure, binding site characteristics, and/or calcium-channel gating behavior.47, 48, 210
Nimodipine occurs as a yellow crystalline powder.1, 230 The drug is practically insoluble in water but soluble in alcohol and in polyethylene glycol 400.1, 230 The commercially available liquid-filled, soft-gelatin capsules contain nimodipine in a vehicle of glycerin, peppermint oil, water, and polyethylene glycol 400.1
Nimodipine is light-sensitive but to a lesser degree than nifedipine.129 The degradation half-lives of nimodipine are 16 and 56 hours following exposure of aqueous solutions of the drug to UV light (360 nm wavelength, 300 lux) and daylight, respectively.129 Exposure of nimodipine in aqueous solution to bright microscopic light for up to 30 minutes following intracranial instillation during surgery does not appear to produce substantial degradation of the drug.129
Nimodipine capsules should be protected from light by storing them in the manufacturer's original unit-dose foil packaging; the capsules also should be protected from freezing and stored at 25°C but may be stored at 15-30°C.1
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
1. Bayer. Nimotop® (nimodipine) capsules prescribing information. West Haven, CT; 2005 Dec.
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