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 to V).

DOSAGE AND ADMINISTRATION DO NOT ADMINISTER NIMODIPINE CAPSULES INTRAVENOUSLY OR BY OTHER PARENTERAL ROUTES (see WARNINGS ). If nimodipine is inadvertently administered intravenously, clinically significant hypotension may require cardiovascular support with pressor agents. Specific treatments for calcium channel blocker overdose should also be given promptly. Nimodipine is given orally in the form of soft gelatin 30 mg capsules for subarachnoid hemorrhage. The recommended oral dose is 60 mg (two 30 mg capsules) every 4 hours for 21 consecutive days. In general, the capsules should be swallowed whole with a little liquid, preferably not less than one hour before or two hours after meals. Grapefruit juice is to be avoided (see PRECAUTIONS, Drug Interactions ). Oral nimodipine therapy should commence as soon as possible within 96 hours of the onset of 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. A parenteral syringe can be used to extract the liquid inside the capsule, but the liquid should always be transferred to a syringe that cannot accept a needle and that is designed for administration orally or via a naso-gastric tube or PEG. To help minimize administration errors, it is recommended that the syringe used for administration be labeled "Not for IV Use". The contents should then be emptied into the patient's in situ naso-gastric tube and washed down the tube with 30 mL of normal saline (0.9%). Severely disturbed liver function, particularly liver cirrhosis, may result in an increased bioavailability of nimodipine due to a decreased first pass capacity and a reduced metabolic clearance. The reduction in blood pressure and other adverse effects may be more pronounced in these patients. Dosage should be reduced to one 30 mg capsule every 4 hours with close monitoring of blood pressure and heart rate; if necessary, discontinuation of the treatment should be considered. Strong inhibitors of CYP3A4 should not be administered concomitantly with nimodipine (see CONTRAINDICATIONS ). Strong inducers of CYP3A4 should generally not be administered with nimodipine (see WARNINGS ). Patients on moderate and weak inducers of CYP3A4 should be closely monitored for lack of effectiveness, and a nimodipine dose increase may be required. Patients on moderate and weak CYP3A4 inhibitors may require a nimodipine dose reduction in case of hypotension (see PRECAUTIONS, Drug Interactions ).

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 Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.