, aprepitant, armodafinil, bosentan, efavirenz, etravirine, echinacea, modafinil, nafcillin, pioglitazone, prednisone and rufinamide.

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 ).

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.

dence 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. pharmacokinetics and metabolism 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. the metabolism of nimodipine is mediated by cyp3a4. 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 max approximately double that in normals which necessitates lowering the dose in this group of patients (see dosage and administration ). 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 max 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 precautions: geriatric use. ) clinical trials 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 20–30 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 to iii (essentially free of focal deficits after the initial bleed) the fourth studied much sicker patients, hunt and hess grades iii to 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. * hunt and hess grade ** p=0.03 patients study dose grade* number analyzed any deficit due to spasm numbers with severe deficit u.s. 20 to 30 mg i to iii nimodipine placebo 56 60 13 16 1 8** french 60 mg i to iii nimodipine placebo 31 39 4 11 2 10** a third, large, study was performed in the united kingdom in sah patients with all grades of severity (but 89% were in grades i to 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: * p=0.0444 - good and moderate vs severe and dead ** p=0.001 - severe disability *** p=0.056 - death nimodipine placebo total patients 278 276 good recovery 199* 169 moderate disability 24 16 severe disability 12** 31 death 43*** 60 a canadian study entered much sicker patients, (hunt and hess grades iii to 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. * p = 0.001, nimodipine vs placebo delayed ischemic deficits (did) permanent deficits nimodipine n (%) placebo n (%) nimodipine n (%) placebo n (%) did spasm alone 8 (11)* 25 (31) 5 (7)* 22 (27) did spasm contributing 18 (25) 21 (26) 16 (22) 17 (21) did without spasm 7 (10) 8 (10) 6 (8) 7 (9) no did 39 (54) 28 (34) 45 (63) 36 (44) 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. * p = 0.045, nimodipine vs placebo glasgow outcome* nimodipine (n=87) placebo (n=101) good recovery 22 (25.3%) 11 (10.9%) moderate disability 8 (9.2%) 12 (11.9%) severe disability 6 (6.9%) 15 (14.9%) vegetative survival 4 (4.6%) 9 (8.9%) death 47 (54.0%) 54 (53.5%)