ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The safety and efficacy of NYMALIZE (nimodipine oral solution) in the treatment of patients with SAH is based on adequate and well-controlled studies of nimodipine oral capsules in patients with SAH. NYMALIZE (nimodipine oral solution) has comparable bioavailability to nimodipine oral capsules.The following clinically significant adverse reaction appears in other sections of the labeling:Hypotension [see Warnings and Precautions (5.1)]. Hypotension [see Warnings and Precautions (5.1)]. Most common adverse reactions (incidence >=1% and >=1% placebo) were hypotension, headache, nausea, and bradycardia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Arbor Pharmaceuticals, LLC at 1-866-516-4950 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.In clinical trials of nimodipine oral capsules in patients with SAH, eleven percent (92 of 823) of nimodipine-treated patients reported adverse events compared to six percent (29 of 479) of placebo-treated patients. The most common adverse event was decreased blood pressure in 4.4% of nimodipine-treated patients. The events reported with frequency greater than 1% are displayed in Table by dose.Table 1: Adverse Events [n (%)] reported with frequency 1% in four clinical trials (Study 1, Study 2, Study 3, and Study 4)Placebo(n=479)Nimodipine dose every hours0.35 mg/kg(n=82)30 mg(n=71)60 mg(n=494)90 mg(n=172)120 mg(n=4)Decreased Blood Pressure6 (1.2)1 (1.2)019 (3.8)14 (8.1)2 (50.0)Edema3 (0.6)002 (0.4)2 (1.2)0Diarrhea3 (0.6)03 (4.2)03 (1.7)0Rash3 (0.6)2 (2.4)03 (0.6)2 (1.2)0Headache1 (0.2)01 (1.4)6 (1.2)00Gastrointestinal Symptoms02 (2.4)002 (1.2)0Nausea01 (1.2)1 (1.4)6 (1.2)1 (0.6)0Dyspnea01 (1.2)0000EKG Abnormalities001 (1.4)01 (0.6)0Tachycardia001 (1.4)000Bradycardia0005 (1.0)1 (0.6)0Muscle Pain/Cramp001 (1.4)1 (0.2)1 (0.6)0Acne001 (1.4)000Depression001 (1.4)000SAH is frequently accompanied by alterations in consciousness that may lead to an under-reporting of adverse experiences. As 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 in SAH trials.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn two-year study in rats, the incidences of adenocarcinoma of the uterus and Leydig cell adenoma of the testes were increased at 1800 ppm nimodipine in the diet (approximately 90-120 mg/kg/day). The increases were not statistically significant, however, and the higher rates were within the historical control range for these tumors. Nimodipine was found not to be carcinogenic in 91-week mouse study, but the high dose of 1800 ppm nimodipine in the diet (approximately 550-775 mg/kg/day) was associated with an increased mortality rate.. MutagenesisMutagenicity studies, including the Ames, micronucleus, and dominant lethal assays, were negative.. Impairment of FertilityNimodipine did not impair the fertility and general reproductive performance of male and female rats following oral doses of up to 30 mg/kg/day when administered prior to mating and continuing in females to day of pregnancy. This dose in rat is similar to clinical dose of 60 mg every hours in 60 kg patient, on body surface area (mg/m2) basis.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Nimodipine is dihydropyridine 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 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 SAH patients.The precise mechanism of action of nimodipine in reducing the incidence and severity of ischemic deficits in adult patients with SAH from ruptured intracranial berry aneurysms is unknown. Although the clinical studies demonstrate favorable effect of nimodipine on the severity of neurological deficits caused by cerebral vasospasm following SAH, there is no arteriographic evidence that nimodipine either prevents or relieves the spasm of these arteries. However, whether or not the arteriographic methodology utilized was adequate to detect clinically meaningful effect, if any, on vasospasm is unknown.. 12.3 Pharmacokinetics. After single 60 mg oral dose of NYMALIZE, mean (CV%) Cmax was 69.9 ng/mL (36.1%), AUCinf was 151 hng/mL (36.0%) and within subject variability (CV%) was 21.7% and 12.4%, respectively. There were no signs of accumulation when nimodipine was given three times day for seven days.. AbsorptionIn humans, nimodipine was absorbed with time to maximum concentration (Tmax) ranging from 0.25 to 1.05 hours following oral administration. Because of high first-pass metabolism, the bioavailability of nimodipine averages 13% after oral administration.. Effect of FoodIn study of 24 healthy male volunteers, administration of nimodipine capsules following standard breakfast resulted in 68% lower peak plasma concentration and 38% lower bioavailability relative to dosing under fasted conditions [see Dosage and Administration (2.1)].. DistributionNimodipine is over 95% bound to plasma proteins. The binding was concentration independent over the range of 10 ng/mL to 10 mcg/mL.. EliminationThe terminal elimination half-life is approximately to hours but earlier elimination rates are much more rapid, equivalent to half-life of 1-2 hours; consequence is the need for frequent (every hours) dosing.. MetabolismNumerous 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 [see Drug Interactions (7.2, 7.3)]. ExcretionNimodipine is eliminated almost exclusively in the form of metabolites and less than 1% is recovered in the urine as unchanged drug.. Specific Populations. Patients with CirrhosisThe bioavailability of nimodipine is significantly increased in patients with cirrhosis, with Cmax approximately double that in normals, which necessitates lowering the dose in this group of patients [see Dosage and Administration (2.4), Warnings and Precautions (5.2)].. Geriatric PatientsIn single parallel-group study involving 24 elderly subjects (aged 59-79 years) and 24 younger subjects (aged 22-40 years), the observed AUC and Cmax of nimodipine was approximately 2-fold higher in the elderly population compared to the younger study subjects following oral administration (given as single dose of 30 mg and dosed to steady-state with 30 mg three times daily [less than the recommended dosing regimen] for days). The clinical response to these age-related pharmacokinetic differences, however, was not considered significant [see Use in Specific Populations (8.5)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The safety and efficacy of NYMALIZE (nimodipine oral solution) in the treatment of patients with SAH is based on adequate and well-controlled studies of nimodipine oral capsules in patients with SAH. NYMALIZE (nimodipine oral solution) has comparable bioavailability to nimodipine oral capsules.Nimodipine has been shown in randomized, double-blind, placebo-controlled trials to reduce the severity of neurological deficits resulting from vasospasm in patients who have had recent SAH (Studies 1, 2, 3, and 4).The trials used doses ranging from 20-30 mg to 90 mg every hours, with drug given for 21 days in studies, and for at least 18 days in the other. Three of the four trials followed patients for 3-6 months. Three of the trials studied relatively well patients, with all or most patients in Hunt and Hess Grades - III (essentially free of focal deficits after the initial bleed). Study studied much sicker patients with Hunt and Hess Grades III V. Studies and were similar in design, with relatively unimpaired SAH patients randomized to nimodipine or placebo. In each, 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; Study showed fewer spasm-related deficits of all severities. No effect was seen on deficits not related to spasm. See Table 2.Table 2: Deficits in Patients with Hunt and Hess Grades to III in Study and Study 2StudyGradeHunt and Hess Grade TreatmentPatientsNumber AnalyzedNumber of Patients with Any Deficit Due to SpasmNumbers with Severe DeficitStudy 1I-IIINimodipine 20-30 mg every hours56131Placebo60168p=0.03 Study 2I-IIINimodipine 60 mg every hours3142Placebo391110 Study was 554-patient trial that included SAH patients with all grades of severity (89% were in Hunt and Hess Grades I-III). In Study 3, patients were treated with placebo or 60 mg of nimodipine every hours. Outcomes were not defined as spasm related or not but there was significant reduction in the overall rate of brain infarction and severely disabling neurological outcome at months (Table 3):Table 3: Degree of Recovery or Disability in Study (89% Hunt and Hess Grades I-III)NimodipinePlaceboTotal patients278276Good recovery199p 0.0444 good and moderate vs severe and dead 169Moderate disability2416Severe disability12p 0.001 severe disability 31Death43p 0.056 death 60Study enrolled much sicker patients, (Hunt and Hess Grades III-V), who had high rate of death and disability, and used dose of 90 mg every hours, but was otherwise similar to Study and Study 2. Analysis of delayed ischemic deficits, many of which result from spasm, showed significant reduction in spasm-related deficits. Among analyzed patients (72 nimodipine, 82 placebo), there were the following outcomes (Table 4).Table 4: Neurological Ischemic Deficits in Study [Hunt and Hess Grades III-V]Delayed Ischemic Deficits (DID)Permanent DeficitsNimodipine 90 mg every hoursPlaceboNimodipine 90 mg every hoursPlacebon (%)n (%)n (%)n (%)DID Spasm Alone8 (11)p 0.001, Nimodipine vs placebo 25 (31)5 (7) 22 (27)DID Spasm Contributing18 (25)21 (26)16 (22)17 (21)DID Without Spasm7 (10)8 (10)6 (8)7 (9)No DID39 (54)28 (34)45 (63)36 (44)When data were combined for Study and Study 4, 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. Table 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.Table 5: Glasgow Outcome Scale in Combined Studies and 4Glasgow Outcomep 0.045, nimodipine vs. placebo Nimodipine (n=87)Placebo (n=101)Good Recovery22 (25.3%)11 (10.9%)Moderate Disability8 (9.2%)12 (11.9%)Severe Disability6 (6.9%)15 (14.9%)Vegetative Survival4 (4.6%)9 (8.9%)Death47 (54.0%)54 (53.5%)A dose-ranging study comparing 30 mg, 60 mg, and 90 mg doses found generally low rate of spasm-related neurological deficits but no dose response relationship.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.In clinical trials of nimodipine oral capsules in patients with SAH, eleven percent (92 of 823) of nimodipine-treated patients reported adverse events compared to six percent (29 of 479) of placebo-treated patients. The most common adverse event was decreased blood pressure in 4.4% of nimodipine-treated patients. The events reported with frequency greater than 1% are displayed in Table by dose.Table 1: Adverse Events [n (%)] reported with frequency 1% in four clinical trials (Study 1, Study 2, Study 3, and Study 4)Placebo(n=479)Nimodipine dose every hours0.35 mg/kg(n=82)30 mg(n=71)60 mg(n=494)90 mg(n=172)120 mg(n=4)Decreased Blood Pressure6 (1.2)1 (1.2)019 (3.8)14 (8.1)2 (50.0)Edema3 (0.6)002 (0.4)2 (1.2)0Diarrhea3 (0.6)03 (4.2)03 (1.7)0Rash3 (0.6)2 (2.4)03 (0.6)2 (1.2)0Headache1 (0.2)01 (1.4)6 (1.2)00Gastrointestinal Symptoms02 (2.4)002 (1.2)0Nausea01 (1.2)1 (1.4)6 (1.2)1 (0.6)0Dyspnea01 (1.2)0000EKG Abnormalities001 (1.4)01 (0.6)0Tachycardia001 (1.4)000Bradycardia0005 (1.0)1 (0.6)0Muscle Pain/Cramp001 (1.4)1 (0.2)1 (0.6)0Acne001 (1.4)000Depression001 (1.4)000SAH is frequently accompanied by alterations in consciousness that may lead to an under-reporting of adverse experiences. As 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 in SAH trials.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Administer only enterally (e.g., oral, nasogastric tube, or gastric tube route). Do not administer intravenously or by other parenteral routes. (2.1)Give one hour before meal or two hours after meal. (2.1)Start dosing within 96 hours of the SAH. (2.1)Recommended dose is 10 mL (60 mg) every hours for 21 consecutive days. (2.2)Nasogastric or Gastric Tube Administration: Administer 10 mL (60 mg) every hours with supplied prefilled oral syringe. Refill syringe with 10 mL of 0.9% saline water solution; flush remaining contents from nasogastric or gastric tube into stomach. (2.3)Patients with Cirrhosis: Reduce dosage to mL (30 mg) every hours. (2.4). Administer only enterally (e.g., oral, nasogastric tube, or gastric tube route). Do not administer intravenously or by other parenteral routes. (2.1). Give one hour before meal or two hours after meal. (2.1). Start dosing within 96 hours of the SAH. (2.1). Recommended dose is 10 mL (60 mg) every hours for 21 consecutive days. (2.2). Nasogastric or Gastric Tube Administration: Administer 10 mL (60 mg) every hours with supplied prefilled oral syringe. Refill syringe with 10 mL of 0.9% saline water solution; flush remaining contents from nasogastric or gastric tube into stomach. (2.3). Patients with Cirrhosis: Reduce dosage to mL (30 mg) every hours. (2.4). 2.1 Administration Instructions. Administer only enterally (e.g., oral, nasogastric tube, or gastric tube route). Do not administer intravenously or by other parenteral routes. For all routes of administration, begin NYMALIZE within 96 hours of the onset of SAH. Administer one hour before meal or two hours after meal for all routes of administration [see Clinical Pharmacology (12.3)].. 2.2 Administration by Oral Route. The recommended oral dosage is 10 mL (60 mg) every hours for 21 consecutive days.. 2.3 Administration Via Nasogastric or Gastric Tube. Using the supplied prefilled oral syringe labeled For Oral Use Only, administer 10 mL (60 mg) every hours into nasogastric or gastric tube for 21 consecutive days. For each dose, refill the syringe with 10 mL of 0.9% saline solution and then flush any remaining contents from nasogastric or gastric tube into the stomach.. 2.4 Dosage Adjustments in Patients with Cirrhosis. In patients with cirrhosis, reduce the dosage to mL (30 mg) every hours [see Warnings and Precautions (5.2) Clinical Pharmacology (12.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Oral Solution (6 mg per mL):60 mg per 10 mL, pale yellow solution in unit-dose prefilled syringe30 mg per mL, pale yellow solution in unit-dose prefilled syringe60 mg per 10 mL (6 mg/mL), pale yellow solution in oz bottle. 60 mg per 10 mL, pale yellow solution in unit-dose prefilled syringe. 30 mg per mL, pale yellow solution in unit-dose prefilled syringe. 60 mg per 10 mL (6 mg/mL), pale yellow solution in oz bottle. Oral solution (6 mg per mL):60 mg per 10 mL in unit-dose prefilled syringe (3)30 mg per mL in unit-dose prefilled syringe (3)60 mg per 10 mL (6 mg/mL) in oz bottle (3). 60 mg per 10 mL in unit-dose prefilled syringe (3). 30 mg per mL in unit-dose prefilled syringe (3). 60 mg per 10 mL (6 mg/mL) in oz bottle (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Anti-Hypertensives: May increase risk of hypotension. Monitor blood pressure. (7.1)CYP3A4 Moderate and Weak Inhibitors: May increase risk of hypotension. Monitor blood pressure. Dose reduction of NYMALIZE may be needed. Avoid grapefruit juice. (7.2)CYP3A4 Moderate and Weak Inducers: May reduce efficacy of NYMALIZE. Dose increase may be needed. (7.3). Anti-Hypertensives: May increase risk of hypotension. Monitor blood pressure. (7.1). CYP3A4 Moderate and Weak Inhibitors: May increase risk of hypotension. Monitor blood pressure. Dose reduction of NYMALIZE may be needed. Avoid grapefruit juice. (7.2). CYP3A4 Moderate and Weak Inducers: May reduce efficacy of NYMALIZE. Dose increase may be needed. (7.3). 7.1 Blood Pressure Lowering Drugs. Nimodipine may increase the blood pressure lowering effect of concomitantly administered anti-hypertensives such as diuretics, beta-blockers, ACE inhibitors, angiotensin receptor blockers, other calcium channel blockers, -adrenergic blockers, PDE5 inhibitors, and -methyldopa. In Europe, nimodipine was observed to occasionally intensify the effect of antihypertensive drugs taken concomitantly by hypertensive patients; this phenomenon was not observed in North American clinical trials. Blood pressure should be carefully monitored, and dose adjustment of the blood pressure lowering drug(s) may be necessary.. 7.2 CYP3A4 Inhibitors. Nimodipine plasma concentration can be significantly increased when concomitantly administered with strong CYP3A4 inhibitors. As consequence, the blood pressure lowering effect may be increased. Therefore, the concomitant administration of NYMALIZE and strong CYP3A4 inhibitors should generally be avoided [see Warnings and Precautions (5.3) ]. Strong CYP3A4 inhibitors include some members of the following classes:-macrolide antibiotics (e.g., clarithromycin, telithromycin),-HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, saquinavir),-HCV protease inhibitors (e.g., boceprevir, telaprevir),-azole antimycotics (e.g., ketoconazole, itraconazole, posaconazole, voriconazole),-conivaptan, delavirdine, nefazodoneNimodipine 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 reduction of the nimodipine dose may be necessary. Moderate and weak CYP3A4 inhibitors include alprozalam, ameprenavir, amiodarone, aprepitant, atazanavir, cimetidine, cyclosporine, diltiazem, erythromycin, fluconazole, fluoxetine, isoniazid, oral contraceptives, quinuprestin/dalfopristin, valproic acid, and verapamil.A study in eight healthy volunteers has shown 50% increase in mean peak nimodipine plasma concentrations and 90% increase in mean area under the curve, after 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 (CYP) by cimetidine, which could decrease first-pass metabolism of nimodipine.Grapefruit juice inhibits CYP3A4. Ingestion of grapefruit/grapefruit juice is not recommended while taking nimodipine.. -macrolide antibiotics (e.g., clarithromycin, telithromycin),. -HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, saquinavir),. -HCV protease inhibitors (e.g., boceprevir, telaprevir),. -azole antimycotics (e.g., ketoconazole, itraconazole, posaconazole, voriconazole),. -conivaptan, delavirdine, nefazodone. 7.3 CYP3A4 Inducers. Nimodipine plasma concentration and efficacy may be significantly reduced when concomitantly administered with strong CYP3A4 inducers. Therefore, concomitant use of NYMALIZE with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin, St. Johns wort) should generally be avoided [see Warnings and Precautions (5.4)].Moderate and weak inducers of CYP3A4 may also reduce the efficacy of nimodipine. Patients on these should be closely monitored for lack of effectiveness, and nimodipine dosage increase may be required. Moderate and weak CYP3A4 inducers include, for example: amprenavir, aprepitant, armodafinil, bosentan, efavirnenz, etravirine, Echinacea, modafinil, nafcillin, pioglitazone, prednisone, rufinamide, and vemurafenib.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. NYMALIZE (nimodipine) Oral Solution mg/mL is pale yellow solution and is supplied as follows:NDC 24338-260-08: oz. bottle (237 mL) 60 mg/10 mL (6 mg/mL)NDC 24338-260-12: Carton containing 12 individually wrapped 10 mL packages. Each package contains one 60 mg/10 mL unit-dose prefilled oral syringe with purple plunger (NDC 24338-260-10). NDC 24338-230-12: Carton containing 12 individually wrapped mL packages. Each package contains one 30 mg/5 mL unit-dose prefilled oral syringe with white plunger (NDC 24338-230-05).. NDC 24338-260-08: oz. bottle (237 mL) 60 mg/10 mL (6 mg/mL). NDC 24338-260-12: Carton containing 12 individually wrapped 10 mL packages. Each package contains one 60 mg/10 mL unit-dose prefilled oral syringe with purple plunger (NDC 24338-260-10). NDC 24338-230-12: Carton containing 12 individually wrapped mL packages. Each package contains one 30 mg/5 mL unit-dose prefilled oral syringe with white plunger (NDC 24338-230-05).. Store between 20oC to 25oC (68oF to 77oF); excursions permitted to 15oC to 30oC (59oF to 86oF) [see USP Controlled Room Temperature].Protect from light.Do not refrigerate.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Inform patients that the most frequent adverse reaction associated with nimodipine is decreased blood pressure [see Warnings and Precautions (5.1) ]. Inform them that use of NYMALIZE with anti-hypertensives can cause increased drop in blood pressure [see Drug Interactions (7.1)].Patients should be aware that ingestion of grapefruit or grapefruit juice should be avoided when taking NYMALIZE due to its ability to increase nimodipine plasma concentrations and potential to increase the risk of hypotension [see Drug Interactions (7.2)].Advise patients to notify their healthcare provider if they become pregnant during treatment or plan to become pregnant during therapy [see Use in Specific Populations (8.1)].Advise female patients to notify their physicians if they intend to breastfeed or are breastfeeding an infant [see Use in Specific Populations (8.2)].

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Nimodipine is dihydropyridine 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 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 SAH patients.The precise mechanism of action of nimodipine in reducing the incidence and severity of ischemic deficits in adult patients with SAH from ruptured intracranial berry aneurysms is unknown. Although the clinical studies demonstrate favorable effect of nimodipine on the severity of neurological deficits caused by cerebral vasospasm following SAH, there is no arteriographic evidence that nimodipine either prevents or relieves the spasm of these arteries. However, whether or not the arteriographic methodology utilized was adequate to detect clinically meaningful effect, if any, on vasospasm is unknown.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn two-year study in rats, the incidences of adenocarcinoma of the uterus and Leydig cell adenoma of the testes were increased at 1800 ppm nimodipine in the diet (approximately 90-120 mg/kg/day). The increases were not statistically significant, however, and the higher rates were within the historical control range for these tumors. Nimodipine was found not to be carcinogenic in 91-week mouse study, but the high dose of 1800 ppm nimodipine in the diet (approximately 550-775 mg/kg/day) was associated with an increased mortality rate.. MutagenesisMutagenicity studies, including the Ames, micronucleus, and dominant lethal assays, were negative.. Impairment of FertilityNimodipine did not impair the fertility and general reproductive performance of male and female rats following oral doses of up to 30 mg/kg/day when administered prior to mating and continuing in females to day of pregnancy. This dose in rat is similar to clinical dose of 60 mg every hours in 60 kg patient, on body surface area (mg/m2) basis.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. After single 60 mg oral dose of NYMALIZE, mean (CV%) Cmax was 69.9 ng/mL (36.1%), AUCinf was 151 hng/mL (36.0%) and within subject variability (CV%) was 21.7% and 12.4%, respectively. There were no signs of accumulation when nimodipine was given three times day for seven days.. AbsorptionIn humans, nimodipine was absorbed with time to maximum concentration (Tmax) ranging from 0.25 to 1.05 hours following oral administration. Because of high first-pass metabolism, the bioavailability of nimodipine averages 13% after oral administration.. Effect of FoodIn study of 24 healthy male volunteers, administration of nimodipine capsules following standard breakfast resulted in 68% lower peak plasma concentration and 38% lower bioavailability relative to dosing under fasted conditions [see Dosage and Administration (2.1)].. DistributionNimodipine is over 95% bound to plasma proteins. The binding was concentration independent over the range of 10 ng/mL to 10 mcg/mL.. EliminationThe terminal elimination half-life is approximately to hours but earlier elimination rates are much more rapid, equivalent to half-life of 1-2 hours; consequence is the need for frequent (every hours) dosing.. MetabolismNumerous 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 [see Drug Interactions (7.2, 7.3)]. ExcretionNimodipine is eliminated almost exclusively in the form of metabolites and less than 1% is recovered in the urine as unchanged drug.. Specific Populations. Patients with CirrhosisThe bioavailability of nimodipine is significantly increased in patients with cirrhosis, with Cmax approximately double that in normals, which necessitates lowering the dose in this group of patients [see Dosage and Administration (2.4), Warnings and Precautions (5.2)].. Geriatric PatientsIn single parallel-group study involving 24 elderly subjects (aged 59-79 years) and 24 younger subjects (aged 22-40 years), the observed AUC and Cmax of nimodipine was approximately 2-fold higher in the elderly population compared to the younger study subjects following oral administration (given as single dose of 30 mg and dosed to steady-state with 30 mg three times daily [less than the recommended dosing regimen] for days). The clinical response to these age-related pharmacokinetic differences, however, was not considered significant [see Use in Specific Populations (8.5)].

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no adequate data on the developmental risk associated with the use of NYMALIZE in pregnant women. In animal studies, oral administration of nimodipine during pregnancy resulted in adverse effects on development (increased embryofetal mortality, increased incidences of fetal structural abnormalities, decreased fetal growth) at doses equivalent to (rat) or less than (rabbit) those used clinically [see Data].In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.. Data. Animal DataNimodipine has been shown to have teratogenic effect in two studies in rabbit. In one study, incidences of malformations and stunted fetuses were increased at oral doses of mg/kg/day and 10 mg/kg/day administered throughout organogenesis but not at mg/kg/day. In the second study, an increased incidence of stunted fetuses was seen at mg/kg/day but not at higher doses (3 mg/kg/day and 10 mg/kg/day). The lowest effect dose in rabbits (1 mg/kg/day) is less than the recommended human dose (RHD) of 360 mg/day on body surface area (mg/m2) basis.Nimodipine was embryotoxic, causing resorption and stunted growth of fetuses in rats at 100 mg/kg/day administered orally throughout organogenesis; this dose is approximately times the RHD on mg/m2 basis. In two other studies in rats, nimodipine administered orally at 30 mg/kg/day throughout organogenesis and continued until sacrifice (day 20 of pregnancy or day 21 postpartum) was associated with higher incidences of skeletal variation, stunted fetuses, and stillbirths but no malformations; this dose is similar to the RHD on mg/m2 basis.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data may cause fetal harm. (8.1). Pregnancy: Based on animal data may cause fetal harm. (8.1). 8.1 Pregnancy. Risk SummaryThere are no adequate data on the developmental risk associated with the use of NYMALIZE in pregnant women. In animal studies, oral administration of nimodipine during pregnancy resulted in adverse effects on development (increased embryofetal mortality, increased incidences of fetal structural abnormalities, decreased fetal growth) at doses equivalent to (rat) or less than (rabbit) those used clinically [see Data].In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.. Data. Animal DataNimodipine has been shown to have teratogenic effect in two studies in rabbit. In one study, incidences of malformations and stunted fetuses were increased at oral doses of mg/kg/day and 10 mg/kg/day administered throughout organogenesis but not at mg/kg/day. In the second study, an increased incidence of stunted fetuses was seen at mg/kg/day but not at higher doses (3 mg/kg/day and 10 mg/kg/day). The lowest effect dose in rabbits (1 mg/kg/day) is less than the recommended human dose (RHD) of 360 mg/day on body surface area (mg/m2) basis.Nimodipine was embryotoxic, causing resorption and stunted growth of fetuses in rats at 100 mg/kg/day administered orally throughout organogenesis; this dose is approximately times the RHD on mg/m2 basis. In two other studies in rats, nimodipine administered orally at 30 mg/kg/day throughout organogenesis and continued until sacrifice (day 20 of pregnancy or day 21 postpartum) was associated with higher incidences of skeletal variation, stunted fetuses, and stillbirths but no malformations; this dose is similar to the RHD on mg/m2 basis.. 8.2Lactation. Risk SummaryNimodipine has been detected in human milk. There are no data on the effects of nimodipine on the breastfed infant or on milk production.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for NYMALIZE and any potential adverse effects on the breastfed infant from NYMALIZE or from the underlying maternal condition.. Data. Animal Data[14C]Nimodipine and its radiolabeled metabolites were secreted in milk of orally dosed lactating rats. The milk concentration of nimodipine and/or metabolites was higher than that in plasma, with milk/plasma ratio of 0.65 to 4.7.. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. 8.5 Geriatric Use. Clinical studies of nimodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they had different clinical response than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dosing in elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypotension: Monitor blood pressure. (5.1)Patients with Cirrhosis: Higher risk of adverse reactions. Monitor blood pressure and pulse. (5.2)CYP3A4 Strong Inhibitors: May significantly increase risk of hypotension. Concomitant use with NYMALIZE should generally be avoided. (5.3)CYP3A4 Strong Inducers: May significantly reduce efficacy of nimodipine. Concomitant use with NYMALIZE should generally be avoided. (5.4). Hypotension: Monitor blood pressure. (5.1). Patients with Cirrhosis: Higher risk of adverse reactions. Monitor blood pressure and pulse. (5.2). CYP3A4 Strong Inhibitors: May significantly increase risk of hypotension. Concomitant use with NYMALIZE should generally be avoided. (5.3). CYP3A4 Strong Inducers: May significantly reduce efficacy of nimodipine. Concomitant use with NYMALIZE should generally be avoided. (5.4). 5.1 Hypotension. Blood pressure should be carefully monitored during treatment with NYMALIZE. In clinical studies of patients with subarachnoid hemorrhage, about 5% of nimodipine-treated patients compared to 1% of placebo-treated patients had hypotension and about 1% of nimodipine-treated patients left the study because of this [see Adverse Reactions (6)]. 5.2 Possible Increased Risk of Adverse Reactions in Patients with Cirrhosis. Given that the plasma levels of nimodipine are increased in patients with cirrhosis, these patients are at higher risk of adverse reactions. Therefore, monitor blood pressure and pulse rate closely and administer lower dosage [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].. 5.3 Possible Increased Risk of Hypotension with Strong CYP3A4 Inhibitors. Concomitant use of strong inhibitors of CYP3A4, such as some macrolide antibiotics (e.g., clarithromycin, telithromycin), some HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, saquinavir), some HCV protease inhibitors (e.g., boceprevir, telaprevir), some azole antimycotics (e.g., ketoconazole, itraconazole, posaconazole, voriconazole), conivaptan, delavirdine, and nefazodone with nimodipine should generally be avoided because of risk of significant hypotension [see Drug Interactions (7.2)].. 5.4 Possible Reduced Efficacy with Strong CYP3A4 Inducers. Concomitant use of strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin, St. Johns wort) and nimodipine should generally be avoided, as nimodipine plasma concentration and efficacy may be significantly reduced [see Drug Interactions (7.3)].