Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 13 April 2018

Indication(s)

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)

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None (4)
Adverse reactions
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) 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. 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.

Usage information

Dosing and administration
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 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 supplied 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 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 20 mL (60 mg) every 4 hours for 21 consecutive days. 2.3 Administration Via Nasogastric or Gastric Tube Using the supplied oral syringe labeled "ORAL USE ONLY", administer 20 mL (60 mg) 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)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data may cause fetal harm (8.1) 8.1 Pregnancy Pregnancy Category C. There are no adequate and well controlled studies in pregnant women to directly assess the effect on human fetuses. NYMALIZE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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). Nimodipine was embryotoxic, causing resorption and stunted growth of fetuses in rats at 100 mg/kg/day administered orally throughout organogenesis. In two other rat studies, doses of 30 mg/kg/day nimodipine administered orally throughout organogenesis and continued until sacrifice (day 20 of pregnancy or day 21 postpartum) were associated with higher incidences of skeletal variation, stunted fetuses, and stillbirths but no malformations. 8.3 Nursing Mothers Nimodipine and/or its metabolites have been detected in rat milk at concentrations much higher than in maternal plasma. It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from NYMALIZE, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 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 a 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)].
Pregnancy and lactation
8.3 Nursing Mothers Nimodipine and/or its metabolites have been detected in rat milk at concentrations much higher than in maternal plasma. It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from NYMALIZE, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Interactions

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/dalforpristin, 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.

More information

Category Value
Authorisation number NDA203340
Agency product number 57WA9QZ5WH
Orphan designation No
Product NDC 24338-200,24338-205
Date Last Revised 29-09-2017
Type HUMAN PRESCRIPTION DRUG
Storage and handling Store at 25ºC (77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature]. Protect from light. Do not refrigerate.
Marketing authorisation holder Arbor Pharmaceuticals