Nymalize

1 INDICATIONS AND USAGE NYMALIZE 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-V). NYMALIZE 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-V). ( 1 )

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 a meal or two hours after a meal. ( 2.1 ) Start dosing within 96 hours of the SAH. ( 2.1 ) Recommended dose is 10 mL (60 mg) every 4 hours for 21 consecutive days. ( 2.2 ) Nasogastric or Gastric Tube Administration: Administer 10 mL (60 mg) every 4 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 5 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 NYMALIZE 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 10 mL (60 mg) every 4 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 4 hours into a 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 5 mL (30 mg) every 4 hours [ s ee Warnings and Precautions (5.2) , Clinical Pharmacology (12.3) ] .

4 CONTRAINDICATIONS None. None ( 4 )

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 ) 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 a 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 a 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. John's wort) and nimodipine should generally be avoided, as nimodipine plasma concentration and efficacy may be significantly reduced [see Drug Interactions (7.3) ].

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 ) 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, 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 a 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, 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 NYMALIZE 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.

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) ]. Most common adverse reactions (incidence ≥1% and ≥1% placebo) were hypotension, headache, nausea, and bradycardia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449 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.

8.1 Pregnancy Risk Summary There 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 Data Nimodipine has been shown to have a teratogenic effect in two studies in rabbit. In one study, incidences of malformations and stunted fetuses were increased at oral doses of 1 mg/kg/day and 10 mg/kg/day administered throughout organogenesis but not at 3 mg/kg/day. In the second study, an increased incidence of stunted fetuses was seen at 1 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 a body surface area (mg/m 2 ) 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 3 times the RHD on a mg/m 2 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 a mg/m 2 basis.