Nimodipine 30 mg Capsule, Liquid Filled — NDC 69452-209-13 (Billing 69452-0209-13)

WARNINGS DEATH DUE TO INADVERTENT INTRAVENOUS ADMINISTRATION: DO NOT ADMINISTER NIMODIPINE INTRAVENOUSLY OR BY OTHER PARENTERAL ROUTES. DEATHS AND SERIOUS, LIFE THREATENING ADVERSE EVENTS, INCLUDING CARDIAC ARREST, CARDIOVASCULAR COLLAPSE, HYPOTENSION, AND BRADYCARDIA, HAVE OCCURRED WHEN THE CONTENTS OF NIMODIPINE CAPSULES HAVE BEEN INJECTED PARENTERALLY (SEE DOSAGE AND ADMINISTRATION ). Reduced Efficacy with CYP3A4 Inducers: Concomitant use of strong CYP3A4 inducers (e.g. rifampin, phenobarbital, phenytoin, carbamazepine, St John’s wort) and nimodipine should generally be avoided, as nimodipine plasma concentration and efficacy may be very significantly reduced (see PRECAUTIONS, Drug Interactions ).

Moderate and weak inducers of CYP3A4 may also reduce the efficacy of nimodipine to a lesser extent. Patients on these should be closely monitored for lack of effectiveness, and a nimodipine dosage increase may be required. Moderate and weak CYP3A4 inhibitors include, for example: amprenavir, aprepitant, armodafinil, bosentan, efavirenz, etravirine, echinacea, modafinil, nafcillin, pioglitazone, prednisone and rufinamide.

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. DOSE q4h Number of Patients (%) Nimodipine Sign/Symptom 0.35 mg/kg (n=82) 30 mg (n=71) 60 mg (n=494) 90 mg (n=172) 120 mg (n=4) Placebo (n=479) Decreased Blood Pressure 1 (1.2) 0 19 (3.8) 14 (8.1) 2 (50.0) 6 (1.2) Abnormal Liver Function Test 1 (1.2) 0 2 (0.4) 1 (0.6) 0 7 (1.5) Edema 0 0 2 (0.4) 2 (1.2) 0 3 (0.6) Diarrhea 0 3 (4.2) 0 3 (1.7) 0 3 (0.6) Rash 2 (2.4) 0 3 (0.6) 2 (1.2) 0 3 (0.6) Headache 0 1 (1.4) 6 (1.2) 0 0 1 (0.2) Gastrointestinal Symptoms 2 (2.4) 0 0 2 (1.2) 0 0 Nausea 1 (1.2) 1 (1.4) 6 (1.2) 1 (0.6) 0 0 Dyspnea 1 (1.2) 0 0 0 0 0 EKG Abnormalities 0 1 (1.4) 0 1 (0.6) 0 0 Tachycardia 0 1 (1.4) 0 0 0 0 Bradycardia 0 0 5 (1.0) 1 (0.6) 0 0 Muscle Pain/Cramp 0 1 (1.4) 1 (0.2) 1 (0.6) 0 0 Acne 0 1 (1.4) 0 0 0 0 Depression 0 1 (1.4) 0 0 0 0 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.

To report SUSPECTED ADVERSE REACTIONS, contact Bionpharma Inc. at 1-888-235-BION or 1-888-235-2466 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions Nimodipine is metabolized via the cytochrome P450 3A4 system located both in the intestinal mucosa and in the liver. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nimodipine. In addition, the blood pressure lowering effects of antihypertensives could be enhanced when taken concomitantly with nimodipine.

PRECAUTIONS General Blood Pressure: Nimodipine has the hemodynamic effects expected of a calcium channel blocker, although they are generally not marked. However, intravenous administration of the contents of nimodipine capsules has resulted in serious adverse consequences including death, cardiac arrest, cardiovascular collapse, hypotension, and bradycardia. In patients with subarachnoid haemorrhage given nimodipine in clinical studies, about 5% were reported to have had lowering of the blood pressure and about 1% left the study because of this (not all could be attributed to nimodipine).

Nevertheless, blood pressure should be carefully monitored during treatment with nimodipine based on its known pharmacology and the known effects of calcium channel blockers. (see WARNINGS and DOSAGE AND ADMINISTRATION ). Hepatic Disease: The metabolism of nimodipine is decreased in patients with impaired hepatic function.

Such patients should have their blood pressure and pulse rate monitored closely and should be given a lower dose (see DOSAGE AND ADMINISTRATION ). Intestinal pseudo-obstruction and ileus have been reported rarely in patients treated with nimodipine. A causal relationship has not been established.

The condition has responded to conservative management. Laboratory Test Interactions None known. Drug Interactions Nimodipine is metabolized via the cytochrome P450 3A4 system located both in the intestinal mucosa and in the liver.

Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nimodipine. In addition, the blood pressure lowering effects of antihypertensives could be enhanced when taken concomitantly with nimodipine. Inducers of CYP3A4 Nimodipine plasma concentration and efficacy may be significantly reduced when concomitantly administered with strong CYP3A4 inducers.

Therefore strong CYP3A4 inducers (e.g. rifampin, carbamazepine, phenobarbital, phenytoin, St. John’s Wort) should generally not be administered concomitantly with nimodipine (see WARNINGS ). Other moderate and weak inducers of CYP3A4 may also reduce the efficacy of nimodipine, although the magnitude of decrease in nimodipine plasma concentrations is not known.

Patients on these should be closely monitored for lack of effectiveness, and a nimodipine dosage increase may be required. Moderate and weak CYP3A4 inducers include: amprenavir, aprepitant, armodafinil, bosentan, efavirenz, etravirine, Echinacea, modafinil, nafcillin, pioglitazone, prednisone and rufinamide. Inhibitors of CYP3A4 Nimodipine plasma concentration can be significantly increased when concomitantly administered with strong inhibitors of the CYP3A4 system.

As a consequence, the blood pressure lowering effect may be increased. Therefore strong CYP3A4 inhibitors should not be coadministered with nimodipine (See CONTRAINDICATIONS ). Strong CYP3A4 inhibitors include some members of the following classes: - macrolide antibiotics (e.g., clarithromycin, telithromycin,), - HIV protease inhibitors (e.g., delavirdine, indinavir, nelfinavir, ritonavir, saquinavir), - azole antimycotics (e.g., ketoconazole, itraconazole, voriconazole), - antidepressants (e.g. nefazodone) - grapefruit juice: after intake of grapefruit juice and nimodipine, the blood pressure lowering effect may last for at least 4 days after the last ingestion of grapefruit juice.

Ingestion of grapefruit / grapefruit juice is therefore not recommended while taking nimodipine (See DOSAGE AND ADMINISTRATION ). Nimodipine plasma concentration can also be increased in the presence of moderate and weak inhibitors of CYP3A4. If nimodipine is concomitantly administered with these drugs, blood pressure should be monitored, and a reduction of the nimodipine dose may be necessary.

Moderate and weak CYP3A4 inhibitors include amprenavir, aprepitant, atazanavir, amiodarone, alprozalam, cyclosporine, cimetidine, erythromycin, fluconazole, fluoxetine, isoniazid, oral contraceptives, q… [Excerpted — this section continues on DailyMed.]

DRUG ABUSE AND DEPENDENCE There have been no reported instances of drug abuse or dependence with nimodipine