Continuing Education Activity

Nimodipine is a second-generation 1,4-dihydropyridine calcium channel blocker. It was initially invented for the management of systemic hypertension. FDA approved the use of nimodipine for the first time in 1988. However, its use is restricted mainly in managing vasospasm following subarachnoid hemorrhage. It also has numerous off-label uses. Nimodipine is available as oral tablets, oral solutions, and intravenous infusion solutions. This activity outlines the indications, mechanism of action, methods of administration, significant adverse effects, contraindications, monitoring, and toxicity of nimodipine, so providers can direct patient therapy successfully in instances where nimodipine provides a benefit to patient care.

Objectives:

• Identify the mechanism of action of nimodipine.
• Outline the approved indications and the off-label indications for using nimodipine.
• Review the contraindications of nimodipine.
• Describe interprofessional team strategies for improving care coordination and communication to properly use nimodipine to improve patient outcomes in the varied scenarios where it can be effective.

Indications

Nimodipine (C21H26N2O7) is a second-generation 1,4-dihydropyridine calcium channel blocker. It was initially invented for the management of systemic hypertension.

FDA approved the use of nimodipine for the first time in 1988. However, its use is restricted mainly to managing vasospasm following subarachnoid hemorrhage.

• Prevention and treatment of cerebral vasospasm following subarachnoid hemorrhage (FDA-approved use): Nimodipine is indicated to improve neurological outcomes by reducing the incidence and severity of ischemic deficits regardless of their post-ictus neurological condition (Hunt and Hess Grades I to V).[1]
• In the treatment of diffuse brain injury along with hyperbaric oxygen therapy[2]
• In assisting the recovery after cranial nerve injury[3]
• Migraine prophylaxis[4]
• Peripheral vertigo and Meniere disease[5]
• Nimodipine reduces the development of postoperative delirium in elderly patients under general anesthesia[6]
• Drug-resistant epilepsy[7]
• Orgasmic headache and bath-related headache[8][9]
• The ophthalmic formulation of nimodipine is a potential agent in the management of glaucoma[10]

The following findings are derived from various trials regarding the use of nimodipine:

• Nimodipine should be given to patients with no neurological deficits after subarachnoid hemorrhage to reduce the onset of new neurological deficits due to vasospasm. (Cerebral arterial spasm controlled trial of nimodipine in patients with subarachnoid hemorrhage, 1983)[1]
• Nimodipine 60 mg every 4 hours given orally was well tolerated and reduced cerebral infarction. It also improved the outcome after subarachnoid hemorrhage. (British aneurysm nimodipine trial, 1989)[11]
• There is no statistically-proven benefit of nimodipine in head injury patients. (The British/Finnish Co-operative Head Injury Trial Group, 1990)[12]
• Nimodipine has no role in improving the functional outcome of acute ischemic hemispheric stroke. (A randomized, double-blind, placebo-controlled trial of nimodipine in acute ischemic hemispheric stroke, 1994)[13]
• There is no benefit of nimodipine in the treatment of head injury patients. (Nimodipine in traumatic subarachnoid hemorrhage: a re-analysis of the HIT I and HIT II trials, 1996)[14]
• Nimodipine has got only a very minimal role in the prophylaxis of migraine without aura. European multicenter trial of nimodipine in the prophylaxis of common migraine (migraine without aura). Migraine-Nimodipine European Study Group (MINES), 1989.[15]
• Researchers noted a beneficial effect of nimodipine in acute cerebral ischemia. (A randomized, double-blind controlled study of nimodipine in acute cerebral ischemic stroke, 1998). [16]
• Nimodipine may be effective in patients with small vessel subcortical vascular dementia. (Efficacy and safety of nimodipine in subcortical vascular dementia: a subgroup analysis of the Scandinavian Multi-Infarct Dementia Trial, 2000)[17]
• Early supplementation of nimodipine in stroke patients does not have any beneficial effect. (Very Early Nimodipine Use in Stroke (VENUS), 2001)[18]
• Oral and intravenous nimodipine are equally efficient in preventing vasospasm following subarachnoid hemorrhage. (Nimodipine in aneurysmal subarachnoid hemorrhage: a randomized study of intravenous or peroral administration, 2009)[19]
• Nimodipine has a potential neuroprotective effect by preventing calcium overload in ischemic neurons. However, this gets outweighed by its harmful hemodynamic effects in the ischemic area in treating acute ischemic stroke. (Intravenous Nimodipine West European Stroke Trial (INWEST Trial,1994)
• A Phase III randomized trial compared the efficacy and safety of single intraventricular administration nimodipine microparticles to the standard of care of oral nimodipine in patients with SAH. The trial concluded that sustained release nimodipine administered via external ventricular drain did not significantly increase favorable outcomes compared with the standard of care.[20][21]
• A recent innovative formulation has connected nimodipine with pH-sensitive chitosan nanoparticles. The objective of using such a technique would be to maintain systemic administration of nimodipine but restrict the release of the drug to tissues with decreased pH in the ischemic penumbra.[22]

Mechanism of Action

During the depolarization of smooth muscle cells of blood vessels, there is an influx of calcium ions. The primary function of nimodipine is to block voltage-gated L-type calcium channels in their inactive conformation, avoiding this influx to prevent vasoconstriction. Nimodipine preferentially acts on cerebral blood vessels as it is lipophilic and can cross the blood-brain barrier.[23] Proposed mechanisms also include decreased angiographic vasospasm, increased fibrinolytic activity, and enhanced neuroprotection.[22]

Pharmacokinetics

• Absorption: Nimodipine is rapidly absorbed after oral administration, & peak concentrations are achieved within 0.5 to 1.5 hours. However, due to high first-pass metabolism, the bioavailability of nimodipine is approximately 13% after oral administration—simultaneous administration of breakfast results in decreased peak plasma concentration and lower bioavailability relative to fasting conditions.

• Distribution: The volume of distribution (Vd) of nimodipine varies from 0.94 L/kg to 2.46 L/kg. Nimodipine is approximately 95% bound to plasma proteins, primarily to alpha-acid glycoprotein. Accordingly, the distribution of nimodipine can be influenced by the concentration of alpha-acid glycoprotein.

• Metabolism: Nimodipine is extensively metabolized by CYP3A4 and CYP3A5. Multiple inactive or less active metabolites have been identified.

• Elimination: The terminal elimination half-life of nimodipine is approximately 8 to 9 hours, but initial elimination is rapid (equivalent to a half-life of 1-2 hours); consequently, there is a need for frequent (every 4 hours) dosing. Nimodipine is excreted primarily as metabolites via the kidney, and less than 1% parent drug is recovered in the urine as an unchanged drug. Pharmacokinetic studies have documented the variability of nimodipine concentrations in patients with subarachnoid hemorrhage.[24]

Administration

Nimodipine is available as oral tablets, oral solutions, and intravenous infusion solutions. However, the FDA has not approved the intravenous infusion solution, and this formulation is not available in the US market.

Neurocritical Care Society guidelines suggest that all patients with aneurysmal subarachnoid hemorrhage should receive oral nimodipine 60 mg every four hours for 21 days from SAH onset.[25] 

USFDA Boxed Warning: Do not administer nimodipine by parenteral routes. Serious, life-threatening adverse events, including death, cardiac arrest, hypotension, cardiovascular collapse, and bradycardia, have been reported when the drug has been injected parenterally. However, an IV formulation of nimodipine is available in Europe but is not FDA-approved.[22]

Oral Administration

• Nimodipine is available as liquid-filled oral capsules of 30 mg and oral solution of 6 mg/mL and 30 mg/10 mL strength (unit-dose prefilled syringe and 8 oz container.). It has to be given at least 1 hour before or 2 hours after meals.
• Nimodipine should start as early as possible or within 96 hours of the diagnosis of subarachnoid hemorrhage. The recommended dose for adults is 60 mg (two 30-mg capsules) every 4 hours for 21 consecutive days.
• If the patient is not conscious enough to swallow the nimodipine capsule, a hole can be made in both ends using an 18-gauge needle, and the contents get extracted into a syringe. Then it can be fed through a nasogastric tube and washed down with 30 ml of normal saline (0.9%).

Intravenous Administration

• Nimodipine can be given intravenously via a central venous catheter at a starting dose of 1 mg/hr (15 mcg/kg per hour, equivalent to 5 ml per hour) for the first 2 hours. If the patient tolerates the drug well and has no hypotension, the dose can increase to 2 mg per hour (30 mcg/kg per hour, equivalent to 10 ml per hour) after the first 2 hours.
• If the patient's body weight is less than 70 kg or has hypotension, nimodipine should be started at a dose of 0.5 mg per hour (2.5 ml of solution per hour) or less, if necessary.

Intraventricular Administration

• The outcome, dosage, and duration of intraventricular administration of nimodipine were assessed in The NEWTON trial. Results of the trial indicated no significant increase in a favorable outcome for intraventricular nimodipine compared with the standard of care.[20][26]

Aneurysmal Subarachnoid Hemorrhage Treatment Duration

• Treatment via intravenous route should be started as soon as possible after the onset of clinical vasospasm and should continue for a minimum of 5 days and a maximum of 14 days. If the condition has surgical treatment, nimodipine should continue at the same dose for a minimum of 5 days.
• The administration of intravenous nimodipine can be with or without pre-treatment with nimodipine tablets. However, if nimodipine is administered intravenously following oral administration, the total duration of treatment should not exceed a maximum of 21 days.
• Intravenous nimodipine should not be given for a period longer than 14 days. In addition, patients should not take the intravenous and oral forms of nimodipine concomitantly.
• During surgery, a freshly prepared 20 mL diluted solution of nimodipine (1 ml of nimodipine concentrated intravenous infusion solution and 19 ml of Ringer solution) warmed up to blood temperature may be instilled intracisternal. This diluted solution must be used immediately after preparation.

Use in Specific Patient Population[25]

Patients with Hepatic Impairment: Bioavailability increases in patients with cirrhosis, making it necessary to reduce the dose in such patients. Use 30 mg every 4 hours in patients with cirrhosis. 

Patients with Renal Impairment: There is no information available from the manufacturer's prescribing label.

Pregnancy Considerations: Nimodipine is a former US FDA pregnancy category C medicine, and alternative agents are preferred.

Breastfeeding Considerations: Nimodipine is present in human milk; based on the available data, relative infant exposure is less and is not expected to cause any adverse effects in breastfed infants. However, the decision to breastfeed during an episode of SAH merits a risk-benefit evaluation.[27]

Adverse Effects

Nimodipine is usually well tolerated orally, but its use correlates with some side effects related to the vasodilating property. The main adverse effects of the drug are headache, vertigo, flushing, nausea, diarrhea, pedal edema, rash, and palpitations.

Acute Colonic Pseudo-Obstruction (Ogilvie Syndrome) has been reported using oral nimodipine.[28] Internal carotid and middle cerebral artery narrowing have been reported five months after placement of intraventricular sustained release nimodipine leading to cerebral infarction.[26]

Drug-Drug Interactions

The cytochrome P450 3A4 system metabolizes nimodipine. Drugs that inhibit this enzyme can lead to increased plasma concentrations of nimodipine. Such drugs include macrolide antibiotics like erythromycin, clarithromycin, and telithromycin; protease inhibitors like ritonavir, indinavir, nelfinavir, and saquinavir; azole antimycotics like ketoconazole, voriconazole, itraconazole; antidepressants like nefazodone, fluoxetine, and quinupristin/dalfopristin, cimetidine, and valproic acid. Grapefruit juice is also an inhibitor of the cytochrome system, and a patient treated with nimodipine should avoid it.[29]

CYP3A4 Inducers carbamazepine, phenobarbital (phenobarbitone), and/or phenytoin enhance the metabolism of nimodipine and decrease the serum concentration of nimodipine. This can lead to therapeutic failure of treatment with nimodipine.[30]

Contraindications

• A previous history of a hypersensitivity reaction to nimodipine is an absolute contraindication. In addition, liver failure and hypotension are relative contraindications for administering nimodipine.
• Concomitant administration with potent CYP3A4 inhibitors is also a relative contraindication.[30]
• The drug is not entirely safe in pregnancy (Category C under the former FDA system), and pregnant patients should only use it if there is a strong benefit-risk ratio. Breastfeeding is contraindicated while taking the drug due to the chance of harmful effects on the baby. Research has not yet fully established safety in the pediatric population.[31][27]

Boxed Warning: Do not administer nimodipine by parenteral routes. Serious, life-threatening adverse events, including death, cardiac arrest, hypotension, cardiovascular collapse, and bradycardia, have been reported when the drug has been injected parenterally.[22]

Monitoring

Blood pressure requires monitoring in patients receiving nimodipine as it can cause hypotension. The risk of hypotension is higher in the following scenario.[32]

• Nimodipine plasma concentration would increase in the presence of moderate and weak CYP3A4 inhibitors. Therefore, if nimodipine is used concomitantly with CYP3A4 inhibitors, blood pressure should be monitored, and reducing the nimodipine dose may be necessary.
• Nimodipine may increase the blood pressure-lowering effect of concomitantly administered anti-hypertensives (diuretics, β-blockers, ACE inhibitors, A1-antagonists, other calcium antagonists, α-adrenergic blocking agents, PDE5 inhibitors, α-methyldopa). Therefore, closely monitoring BP and reduction in nimodipine dose may be required.
• Monitor for hyponatremia and seizures in patients with SAH.Monitor for vasospasm, especially during the 4-14 days period. (vasospasm window).[33] 
• Monitor for elevated intracranial pressure and rebleeding.[34]
• Neurological status should always be monitored by comprehensive neurological examination and scales such as the modified fisher grading scale for subarachnoid hemorrhage.[35]
• Monitor and assess global disability and recovery using Glasgow Outcome Scale-Extended (GOSE).[36]

Toxicity

Symptoms

Sudden toxicity due to overdosage can cause hypotension, cardiac arrhythmias, nausea, and sometimes vomiting. Nimodipine-induced refractory vasoplegia may be observed.

Treatment

Stop the drug as the first step. Emergency symptomatic management is necessary. Gastric lavage is an option if the toxicity is due to oral intake, and charcoal can be administered in emergency scenarios. Hypotension management is achieved with inotrope, and arrhythmias are managed by a team of cardiologists and emergency department staff. No specific antidote is available. Since nimodipine is highly protein-bound, dialysis is not likely to be of benefit.[37][38] Recent case reports suggest that in nimodipine-induced refractory vasoplegia, hydroxocobalamin can be used as a  potential rescue therapy.[39]

Enhancing Healthcare Team Outcomes

Treatment of aneurysmal subarachnoid hemorrhage with nimodipine is best carried out when under the direction of an interprofessional healthcare team. A cardiologist or internal medicine specialist will most frequently initiate the treatment. Nurses often administer and monitor nimodipine treatment in the intensive care unit (ICU) and the neurosurgical floor. Neuro-intensivists and neurosurgeons play a crucial role in managing complex cases of SAH. Before initiating nimodipine, all practitioners should consult a pharmacist on dosing and drug interactions. Interprofessional coordination of effort will permit the healthcare team to obtain optimal outcomes with minimal adverse events. [Level 5] A recent study has shown that early and aggressive care of SAH leads to substantial improvement in survival and favorable outcomes.[40]

When administering nimodipine, it is essential to be aware that it can produce hypotension. After administration, careful blood pressure monitoring is necessary, especially in patients using concomitant CYP3A4 inhibitors and antihypertensive medicines. In patients who cannot be fed orally, medication administration is possible after extracting the contents in a syringe and feeding through a nasogastric tube. It should be labeled and kept separate to avoid its administration intravenously.