Nimodipine

DEATH DUE TO INADVERTENT INTRAVENOUS ADMINISTRATION: DO NOT ADMINISTER NIMOTOP (nimodipine) INTRAVENOUSLY OR BY OTHER PARENTERAL ROUTES. DEATHS AND SERIOUS, LIFE THREATENING ADVERSE EVENTS, INCLUDING CARDIAC ARREST, CARDIOVASCULAR COLLAPSE, HYPOTENSION, AND BRADYCARDIA, HAVE OCCURRED WHEN THE CONTENTS OF NIMOTOP (nimodipine) CAPSULES HAVE BEEN INJECTED PARENTERALLY (SEE DOSAGE AND ADMINISTRATION).

Nimodipine is a prescription medication used to treat patients experiencing symptoms resulting from ruptured blood vessels in the brain (subarachnoid hemorrhage). A subarachnoid hemorrhage is serious, life threatening bleeding that occurs in the subarachnoid space – the area between the brain and the thin tissues that cover the brain.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Serious side effects have been reported with nimodipine including:

• hypotension. Hypotension, or low blood pressure, may cause you to feel faint or dizzy. Inadequate fluid intake, excessive sweating, diarrhea, or vomiting can lead to an excessive fall in blood pressure, too. Lie down if you feel faint or dizzy. Call your doctor right away.
• cirrhosis (scarring of the liver). People already diagnosed with cirrhosis are at an increased risk of serious side effects. Your doctor may want to monitor blood pressure and pulse rate closely and administer a lower dosage of nimodipine.

Nimodipine can cause dizziness. Do not drive or operate heavy machinery until you know how nimodipine affects you.

The recommended oral dosage is 60 mg every 4 hours for 21 consecutive days. 

For people with cirrhosis (scarring of the liver), the dose is reduced to 30 mg every 4 hours.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• a light-headed feeling, like you might pass out;

• easy bruising or bleeding;

• fast or slow heart rate; or

• swelling in your ankles or feet.

Common side effects may include:

• nausea, diarrhea, upset stomach;

• headache; or

• mild rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

A dihydropyridine-derivative calcium-channel blocking agent that affects the CNS preferentially.1 4 5 13 22 96 d

Subarachnoid Hemorrhage

Used to improve neurologic outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage resulting from ruptured intracranial berry aneurysms regardless of the patient’s postictal neurologic condition (e.g., Hunt and Hess grades I–V).1 2 4 5 8 20 21 22 23 69 95 109 230 231

Decreases severity and incidence of delayed ischemic neurologic deficits associated with subarachnoid hemorrhage.1 2 5 20 21 22 23 40 82 95 231

Efficacy in reducing mortality from subarachnoid hemorrhage after oral administration not fully established.1 20 69 95

Acute Ischemic Stroke

Limited evidence suggests that nimodipine may improve neurologic recovery and reduce mortality compared with plasma volume expansion therapy or placebo in some patients with acute ischemic stroke†.4 10 76 77 220 240 241 247

Migraine

Has been used with equivocal results for reduction of frequency and possibly severity and duration of vascular headaches (e.g., migraine attacks) in patients with classic or common migraine†.4 8 11 12 78 79 80 90 101 114 206 233 244

Also has been used in a few patients with cluster headache†.90 100 114

Additional studies are needed to determine the role of nimodipine relative to that of other therapies used in the management of migraine headaches78 79 80 206 230 231 and to determine whether tolerance to the prophylactic effects of the drug develops during chronic therapy.206

Administration

Oral Administration

Nimodipine capsules are for oral administration only.1 245 246 248 249 250 (See Boxed Warning.)

Administer orally every 4 hours, preferably at least 1 hour before or 2 hours after meals.1

If the oral capsule cannot be swallowed (e.g., when administered at the time of surgery or to an unconscious patient), puncture the capsule at both ends with an 18-gauge needle and empty the contents into a syringe,1 249 250 preferably using a syringe designed for nasogastric or percutaneous endoscopic gastrostomy administration (e.g., Toomey syringe).246 250 To help minimize administration errors, label the syringe for oral use only; not for IV use.1 245 248 249 250 The contents of the capsule should then be emptied into the patient’s nasogastric tube.1 249 250 Following administration, flush with 30 mL of 0.9% sodium chloride solution.1 245 246 249

Reinforce awareness among health-care professionals of potential medical errors that may result in inadvertent injection of syringe contents into an IV line or via other parenteral routes.246 248 249 250 (See Parenteral Administration under Cautions, see Hypotension and Other Cardiovascular Effects under Cautions, and see Boxed Warning.)

If inadvertent IV administration of contents of nimodipine capsules occurs, administer vasopressor agents for cardiovascular support if required for clinically important hypotension and promptly administer specific treatment for overdosage associated with calcium-channel blocking agents.1 246

The contents of the capsule should not be admixed with any solution prior to oral administration because of the possibility of drug decomposition.230

IV Administration

The contents of nimodipine capsules must not be administered by IV injection or any other parenteral route; serious adverse effects such as hypotension, cardiovascular collapse, and cardiac arrest have occurred with such administration.1 248 249 250 Report adverse events or medication errors involving nimodipine capsules to the FDA MedWatch program.248 250

Has been administered by IV infusion† (IV dosage form currently is not commercially available in the US)d in patients with subarachnoid hemorrhage, often in conjunction with intracisternal† application during surgery67 117 119 120 214 and usually followed by oral therapy.5 67 93 116 117 118 119 120 214

Dosage

Adults

60 mg every 4 hours for 21 consecutive days.1 5 Initiate therapy as soon as possible after the occurrence of subarachnoid hemorrhage, preferably within 96 hours.1 4 5 20 230 231

It has been suggested that the drug may be discontinued after 14 consecutive days (but not earlier) in some uncomplicated cases in which early aneurysm surgery is performed.231

In patients in whom surgical repair of the aneurysm is performed relatively late (e.g., day 20), some clinicians suggest continuation of therapy for ≥5 days after surgery to minimize the possibility of postoperative vasospasm.4 231

It has been suggested that patients with unstable BP receive a lower dosage (e.g., 30 mg every 4 hours);4 231 however, the manufacturer states that the usual adult dosage should be used in such patients.230 (See Hypotension and Other Cardiovascular Effects under Cautions.)

120 mg daily given in divided doses for 21 or 28 days has been used.76 77 242 247

120 mg daily given in divided doses has been used.4 8 11 12 78 79 80 101 114 206

Special Populations

Hepatic Impairment

Initially, 30 mg every 4 hours.1 5 89

Monitor BP and heart rate closely.1 5 89 May use pharmacologic support of BP (e.g., vasopressors such as norepinephrine or dopamine), if necessary.230 231

Renal Impairment

No specific dosage recommendations.1

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

• Inhibits transmembrane influx of extracellular calcium ions across the membranes of myocardial, vascular smooth muscle, and neuronal cells.1 4 7 10 14 41 48 49 53 126 128 132 133 236

• Appears to affect the CNS preferentially.1 4 7 8 13 17 35 42 45 55 82 155 185 206 229 230

• Mechanism of selectivity for cerebral tissue is complex and has not been fully elucidated; tissue selectivity of 1,4-dihydropyridine calcium-channel blockers may be related to differences in chemical structure, binding site characteristics, and/or calcium-channel gating behavior.47 48 210

• Mechanism(s) of clinical benefit in patients with subarachnoid hemorrhage has not been fully elucidated;1 4 20 69 102 current evidence suggests that dilation of small cerebral resistance vessels,2 23 36 102 131 with a resultant increase in collateral circulation,4 5 23 52 67 83 98 131 and/or a direct effect involving prevention of calcium overload in neurons2 4 5 13 23 68 69 82 83 96 102 104 132 206 may be responsible.

In the U.S.

• Nimotop
• Nymalize

Available Dosage Forms:

• Solution
• Capsule, Liquid Filled
• Tablet

Therapeutic Class: Cardiovascular Agent

Pharmacologic Class: Calcium Channel Blocker

Chemical Class: Dihydropyridine

General:Blood Pressure: Nimodipine has the hemodynamic effects expected of a calcium channel blocker, although they are generally not marked. However, intravenous administration of the contents of Nimodipine capsules has resulted in serious adverse consequences including death, cardiac arrest, cardiovascular collapse, hypotension, and bradycardia. In patients with subarachnoid hemorrhage given Nimodipine capsules in clinical studies, about 5% were reported to have had lowering of the blood pressure and about 1% left the study because of this (not all could be attributed to Nimodipine). Nevertheless, blood pressure should be carefully monitored during treatment with Nimodipine capsules based on its known pharmacology and the known effects of calcium channel blockers. (see WARNINGS and DOSAGE AND ADMINISTRATION).

Hepatic Disease:The metabolism of Nimodipine capsules is decreased in patients with impaired hepatic function. Such patients should have their blood pressure and pulse rate monitored closely and should be given a lower dose (see DOSAGE AND ADMINISTRATION).

Intestinal pseudo-obstruction and ileus have been reported rarely in patients treated with Nimodipine. A causal relationship has not been established. The condition has responded to conservative management.

Laboratory Test Interactions: None known.

Drug Interaction:
Nimodipine is metabolized via the cytochrome P450 3A4 system located both in the intestinal mucosa and in the liver. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of Nimodipine.

In addition, the blood pressure lowering effects of antihypertensives could be enhanced when taken concomitantly with Nimodipine.

Inducers of CYP3A4
Nimodipine plasma concentration and efficacy may be significantly reduced when concomitantly administered with strong CYP3A4 inducers. Therefore strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenobarbital, phenytoin, St. John’s Wort) should generally not be administered concomitantly with Nimodipine (see WARNINGS). Other moderate and weak inducers of CYP3A4 may also reduce the efficacy of Nimodipine, although the magnitude of decrease in Nimodipine plasma concentrations is not known. 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: amprenavir, aprepitant, armodafinil, bosentan, efavirenz, etravirine, Echinacea, modafinil, nafcillin, pioglitazone, prednisone and rufinamide.

Inhibitors of CYP3A4
Nimodipine plasma concentration can be significantly increased when concomitantly administered with strong inhibitors of the CYP3A4 system. As a consequence, the blood pressure lowering effect may be increased. Therefore strong CYP3A4 inhibitors should not be coadministered with Nimodipine (see CONTRAINDICATIONS). Strong CYP3A4 inhibitors include some members of the following classes: - macrolide antibiotics (e.g., clarithromycin, telithromycin,), - HIV protease inhibitors (e.g., delavirdine, indinavir, nelfinavir, ritonavir, saquinavir), - azole antimycotics (e.g., ketoconazole, itraconazole, voriconazole), - antidepressants (e.g., nefazodone) - grapefruit juice: after intake of grapefruit juice and Nimodipine, the blood pressure lowering effect may last for at least 4 days after the last ingestion of grapefruit juice. Ingestion of grapefruit / grapefruit juice is therefore not recommended while taking Nimodipine (see DOSAGE AND ADMINISTRATION).

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 amprenavir, aprepitant, atazanavir, amiodarone, alprozalam, cyclosporine, cimetidine, erythromycin, fluconazole, fluoxetine, isoniazid, oral contraceptives, quinuprestin/dalforpristin, and valproic acid.

Blood pressure lowering drugs
Nimodipine may increase the blood pressure lowering effect of concomitantly administered anti-hypertensives, such as:

- diuretics,                      - other calcium antagonists,
- β-blockers,                   - α-adrenergic blocking agents,
- ACE inhibitors,             - PDE5 inhibitors,
- A1-antagonists,            - α-methyldopa.

Blood pressure should be carefully monitored, and dose adjustment of the blood pressure lowering drug(s) may be necessary.

Carcinogenesis, Mutagenesis, Impairment of Fertility:
In a two-year study, higher incidences of adenocarcinoma of the uterus and Leydig-cell adenoma of the testes were observed in rats given a diet containing 1800 ppm Nimodipine (equivalent to 91 to 121 mg/kg/day Nimodipine) than in placebo controls. The differences were not statistically significant, however, and the higher rates were well within historical control range for these tumors in the Wistar strain. Nimodipine was found not to be carcinogenic in a 91-week mouse study but the high dose of 1800 ppm Nimodipine-in-feed (546 to 774 mg/kg/day) shortened the life expectancy of the animals. Mutagenicity studies, including the Ames, micronucleus and dominant lethal tests were negative.

Nimodipine did not impair the fertility and general reproductive performance of male and female Wistar rats following oral doses of up to 30 mg/kg/day when administered daily for more than 10 weeks in the males and 3 weeks in the females prior to mating and continued to day 7 of pregnancy. This dose in a rat is about 4 times the equivalent clinical dose of 60 mg q4h in a 50 kg patient.

Pregnancy: Pregnancy Category C. Nimodipine has been shown to have a teratogenic effect in Himalayan rabbits. Incidences of malformations and stunted fetuses were increased at oral doses of 1 and 10 mg/kg/day administered (by gavage) from day 6 through day 18 of pregnancy but not at 3.0 mg/kg/day in one of two identical rabbit studies. In the second study an increased incidence of stunted fetuses was seen at 1.0 mg/kg/day but not at a higher doses. Nimodipine was embryotoxic, causing resorption and stunted growth of fetuses, in Long Evans rats at 100 mg/kg/day administered by gavage from day 6 through day 15 of pregnancy. In two other rat studies, doses of 30 mg/kg/day Nimodipine administered by gavage from day 16 of gestation and continued until sacrifice (day 20 of pregnancy or day 21 post partum) were associated with higher incidences of skeletal variation, stunted fetuses and stillbirths but no malformations. There are no adequate and well controlled studies in pregnant women to directly assess the effect on human fetuses. Nimodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: Nimodipine and/or its metabolites have been shown to appear 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, nursing mothers are advised not to breast feed their babies when taking the drug.

Pediatric Use: Safety and effectiveness in children have not been established.

Geriatric Use: Clinical studies of Nimodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dosing in elderly patents should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease of other drug therapy.

Nimodipine Capsules

30 mg

30 (3 x 10) Unit-dose Capsules

• Nymalize

AUC and Cmax were approximately twofold higher in elderly patients as compared to younger patients; this response is not considered clinically significant.

US labeling:

Concomitant use with strong CYP3A4 inhibitors (eg, clarithromycin, telithromycin, delaviridine, indinavir, nelfinavir, ritonavir, saquinavir, ketoconazole, itraconazole, voriconazole, and nefazodone).

Nymalize: There are no contraindications listed in the manufacturer’s labeling.

Canadian labeling: Hypersensitivity to nimodipine or any component of the formulation; concomitant use with phenobarbital, phenytoin, carbamazepine, or rifampin

May lead to false-negative aldosterone/renin ratio (ARR) (Funder 2016)

Do not administer nimodipine intravenously (IV) or by other parenteral routes. Deaths and serious, life-threatening adverse reactions have occurred when the contents of nimodipine capsules have been injected parenterally.

Applies to nimodipine: oral capsule liquid filled, oral solution, oral tablet

Along with its needed effects, nimodipine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking nimodipine:

• Blurred vision
• chest pain or discomfort
• confusion
• difficult or labored breathing
• fast, pounding, or irregular heartbeat or pulse
• lightheadedness, dizziness, or fainting
• shortness of breath
• slow or irregular heartbeat
• sweating
• swelling
• tightness in the chest
• unusual tiredness or weakness

Some side effects of nimodipine may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Abdominal or stomach cramps, discomfort, or pain
• back pain
• blemishes on the skin
• constipation
• diarrhea
• discouragement
• feeling sad or empty
• headache
• indigestion
• irritability
• lack or loss of appetite
• loss of interest or pleasure
• muscle pain
• nausea or vomiting
• pimples
• rash
• swollen mouth and tongue
• tiredness
• trouble concentrating
• trouble sleeping
• unpleasant taste
• urge to have bowel movement