NIMODIPINE

Nimodipine oral solution contains nimodipine, a dihydropyridine calcium channel blocker. Nimodipine is isopropyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-( m -nitrophenyl)-3,5-pyridinedicarboxylate. It has a molecular weight of 418.45 and a molecular formula of C 21 H 26 N 2 O 7 . The structural formula is: Nimodipine USP is a light yellow or yellow, crystalline powder, freely soluble in ethyl acetate, sparingly soluble in ethanol, practically insoluble in water. Nimodipine oral solution contains 60 mg of nimodipine per 20 mL. In addition, the oral solution contains the following inactive ingredients: dibasic sodium phosphate anhydrous, ethanol 0.63% v/v, glycerin, methylparaben, monobasic sodium phosphate monohydrate, polyethylene glycol 400 and purified water. nimodipinestructure

INDICATIONS AND USE Nimodipine oral solution is indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in adult patients with subarachnoid hemorrhage (SAH) from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition (i.e., Hunt and Hess Grades I to V). Nimodipine oral solution is a dihydropyridine calcium channel blocker indicated for the improvement of neurological outcome by reducing the incidence and severity of ischemic deficits in adult patients with subarachnoid hemorrhage (SAH) from ruptured intracranial berry aneurysms regardless of their post-ictus neurological condition (i.e., Hunt and Hess Grades I to V). (1)

• 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 a meal or two hours after a meal. (2.1) • Start dosing within 96 hours of the SAH. (2.1) • Recommended dose is 20 mL (60 mg) every 4 hours for 21 consecutive days. (2.2) • Nasogastric or Gastric Tube Administration: Administer 20 mL (60 mg) every 4 hours with an oral syringe. Refill syringe with 20 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 10 mL (30 mg) every 4 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 nimodipine oral solution within 96 hours of the onset of SAH. Administer one hour before a meal or two hours after a meal for all routes of administration [see Clinical Pharmacology (12.3) ]. 2.2 Administration by Oral Route The recommended oral dosage is 60 mg/20 mL (3 mg/mL) every 4 hours for 21 consecutive days. 2.3 Administration Via Nasogastric or Gastric Tube Using the oral syringe, administer 60 mg/20 mL (3 mg/mL) every 4 hours into a nasogastric or gastric tube for 21 consecutive days. For each dose, refill the syringe with 20 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 10 mL (30 mg) every 4 hours [see Warnings and Precautions (5.2) , Clinical Pharmacology (12.3) ].

None. None (4)

The safety and efficacy of 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. 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) ]. Most common adverse reactions (incidence ≥1% and ≥1% placebo) were hypotension, headache, nausea, and bradycardia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Annora Pharma Private Limited at 1-866-495-1995 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 a 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 a frequency greater than 1% are displayed in Table 1 by dose. Table 1: Adverse Events [n (%)] reported with a frequency > 1% in four clinical trials (Study 1, Study 2, Study 3, and Study 4) Placebo (n=479) Nimodipine dose every 4 hours 0.35 mg/kg (n=82) 30 mg (n=71) 60 mg (n=494) 90 mg (n=172) 120 mg (n=4) Decreased Blood Pressure 6 (1.2) 1 (1.2) 0 19 (3.8) 14 (8.1) 2 (50.0) Edema 3 (0.6) 0 0 2 (0.4) 2 (1.2) 0 Diarrhea 3 (0.6) 0 3 (4.2) 0 3 (1.7) 0 Rash 3 (0.6) 2 (2.4) 0 3 (0.6) 2 (1.2) 0 Headache 1 (0.2) 0 1 (1.4) 6 (1.2) 0 0 Gastrointestinal Symptoms 0 2 (2.4) 0 0 2 (1.2) 0 Nausea 0 1 (1.2) 1 (1.4) 6 (1.2) 1 (0.6) 0 Dyspnea 0 1 (1.2) 0 0 0 0 EKG Abnormalities 0 0 1 (1.4) 0 1 (0.6) 0 Tachycardia 0 0 1 (1.4) 0 0 0 Bradycardia 0 0 0 5 (1.0) 1 (0.6) 0 Muscle Pain/Cramp 0 0 1 (1.4) 1 (0.2) 1 (0.6) 0 Acne 0 0 1 (1.4) 0 0 0 Depression 0 0 1 (1.4) 0 0 0 SAH is frequently accompanied by alterations in consciousness that may lead to an under-reporting of adverse experiences. 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 in SAH trials.

• 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 nimodipine may be needed. Avoid grapefruit juice. (7.2) • CYP3A4 Moderate and Weak Inducers: May reduce efficacy of nimodipine. 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, α-adrenergic blockers, PDE5 inhibitors, and α-methyldopa. In Europe, nimodipinewas 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 a consequence, the blood pressure lowering effect may be increased. Therefore, the concomitant administration of nimodipine 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, nefazodone 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 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 a 50% increase in mean peak nimodipine plasma concentrations and a 90% increase in mean area under the curve, after a 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. 7.3 CYP3A4 Inducers Nimodipine plasma concentration and efficacy may be significantly reduced when concomitantly administered with strong CYP3A4 inducers. Therefore, concomitant use of nimodipine with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampin, St. John’s 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 a 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.