Continuing Education Activity

Nimodipine is a second-generation 1,4-dihydropyridine calcium channel blocker that was originally approved by the FDA to manage hypertension. Today, nimodipine is predominantly used to manage vasospasm subsequent to subarachnoid hemorrhage, in addition to off-label applications. Nimodipine is available in various formulations, including oral tablets, solutions, and intravenous infusions. This discussion will primarily focus on this medication's administration methods and associated considerations. Equally important are the indications, mechanisms of action, adverse effects, contraindications, and monitoring associated with nimodipine administration. Healthcare professionals must have a deep comprehension of this medication in order to use it effectively. This informed decision-making not only optimizes dosage regimens but also mitigates adverse reactions, facilitating enhanced patient outcomes in subarachnoid hemorrhage scenarios treated with nimodipine.

Objectives:

• Identify the mechanism of action of nimodipine.

• Differentiate between the FDA-approved indications and the off-label indications of nimodipine.

• Identify the contraindications of nimodipine.

• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from nimodipine treatment.

Indications

Nimodipine (C₂₁H₂₆N₂O₇) is a second-generation 1,4-dihydropyridine calcium channel blocker initially developed to manage systemic hypertension. The FDA approved its use in 1988. However, its current use is restricted primarily to managing vasospasm following subarachnoid hemorrhage.

FDA-Approved Indication

• Prevention and treatment of cerebral vasospasm following subarachnoid hemorrhage. Nimodipine is indicated to improve neurological outcomes by reducing the incidence and severity of ischemic deficits regardless of their post-ictus neurological condition.[1]

 Off-Label Uses

• Diffuse brain injury along with hyperbaric oxygen therapy [2]
• Assisting recovery after cranial nerve injury [3]
• Migraine prevention [4]
• Peripheral vertigo and Ménière disease [5]
• Reducing the development of postoperative delirium in older patients under general anesthesia [6]
• Drug-resistant epilepsy [7]
• Orgasmic and bath-related headaches [8][9]
• Potential for glaucoma management as an ophthalmic formulation [10]

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

• One recent study reports that a considerable risk of mortality and morbidity is associated with SAH; nearly half of survivors experience significant cognitive dysfunction that affects their functional status and quality of life. Besides the severity of the initial hemorrhage, secondary brain injury resulting from early brain injury and delayed cerebral ischemia significantly impacts outcomes for patients with SAH. Although numerous strategies to address secondary brain injury have been explored, only nimodipine has demonstrated effectiveness in improving long-term functional outcomes.[11]
• Current evidence suggests nimodipine may reduce the risk of death or vegetative state related to delayed cerebral ischemia (DCI). However, some studies also indicate that fixed-dose regimens may decrease mortality and infarction rates. Further research is needed to determine nimodipine's broader benefits and the optimal dosing strategy for contemporary practice.[12]
• Reducing nimodipine doses must be performed cautiously in patients with high vasopressor demand after an aneurysmal subarachnoid hemorrhage (aSAH). One study examined risks during days 5 to 10 post-hemorrhage. Among 205 patients, 53% had reduced dosage ('reduction group'). This group had worse World Federation of Neurosurgical Societies (WFNS) and Fisher grades and more delayed cerebral ischemia (DCI), cerebral vasospasm (CVS), DCI-related infarction, and other unfavorable outcomes. Multivariable analysis identified 'reduced nimodipine dose' as the sole predictor for DCI and CVS. 'Poor WFNS grade' and 'reduced nimodipine dose' were linked to DCI-related infarction, while 'older age,' 'poor WFNS grade,' and 'reduced nimodipine dose' correlated with unfavorable outcomes at 3 months. This study concludes that reducing nimodipine dosage during days 5 to 10 post-hemorrhage might negate its benefits and should be carefully considered.[13]
• Nimodipine should be given to patients with no neurological deficits after subarachnoid hemorrhage to reduce the risk of new neurological deficits due to vasospasm.[1]
• Oral nimodipine 60 mg every 4 hours was well tolerated, reduced cerebral infarction, and improved outcomes after a subarachnoid hemorrhage.[14]
• There is no statistically proven benefit of nimodipine in head injury patients.[15]
• Nimodipine has no role in improving the functional outcome of acute ischemic hemispheric stroke.[16]
• There is no benefit of nimodipine in the treatment of head injury patients.[17]
• Nimodipine has a minimal role in the prevention of migraine without aura.[18]
• Researchers noted a beneficial effect of nimodipine in acute cerebral ischemia.[19]
• Nimodipine may be effective in patients with small vessel subcortical vascular dementia.[20]
• Early supplementation of nimodipine in stroke patients does not have any beneficial effect.[21]
• Oral and intravenous nimodipine are equally efficient in preventing vasospasm following subarachnoid hemorrhage.[22]
• Nimodipine has a potential neuroprotective effect by preventing calcium overload in ischemic neurons. However, this is outweighed by its harmful hemodynamic effects in the ischemic area in treating acute ischemic stroke.
• One Phase III randomized trial compared the efficacy and safety of single intraventricular administration nimodipine microparticles to the standard 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.[23][24]
• A recent innovative formulation has connected nimodipine with pH-sensitive chitosan nanoparticles. The objective of using this technique is to maintain systemic administration of nimodipine but restrict the release of the drug to tissues in the ischemic penumbra with a lower pH.[25]

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 and keep them in their inactive conformation, preventing vasoconstriction. Nimodipine preferentially acts on cerebral blood vessels because it is lipophilic and can cross the blood-brain barrier.[26] Proposed mechanisms leading to a beneficial effect include decreased angiographic vasospasm, increased fibrinolytic activity, and enhanced neuroprotection.[25]

Pharmacokinetics

Absorption: Nimodipine is rapidly absorbed after oral administration, and peak concentration is achieved within 1.5 hours. Due to an elevated first-pass metabolism, the bioavailability of nimodipine is approximately 13% after oral administration. Taking nimodipine with meals results in a decreased peak plasma concentration and lower bioavailability compared to fasting.

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 α-acid glycoprotein. Accordingly, the concentration of α-acid glycoprotein can influence the distribution of nimodipine.

Metabolism: Nimodipine is 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 to 2 hours); frequent (every 4 hours) dosing is necessary. Nimodipine is excreted primarily via the kidney, and less than 1% of the parent drug is recovered unchanged in the urine. Pharmacokinetic studies have documented the variability of nimodipine concentrations in patients with subarachnoid hemorrhage.[27]

Administration

Available Dosage Forms

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 unavailable in the U.S. 

Nimodipine is available as a 30 mg oral capsule and an oral solution (6 mg/mL).

The Neurocritical Care Society guidelines suggest that all patients with aneurysmal subarachnoid hemorrhage should receive oral nimodipine 60 mg every 4 hours for 21 days after an SAH occurs.[28] 

Oral Administration

• Nimodipine is available as liquid-filled oral capsules (30 mg) and oral solution (6 mg/mL and 30 mg/10 mL strength [unit-dose prefilled syringe and 8 oz container]). This drug must be administered at least 1 hour before or 2 hours after meals.
• Nimodipine should be administered as early as possible but must be administered within 96 hours of a diagnosis of subarachnoid hemorrhage. The recommended dose for adults is 60 mg (as 2 30 mg capsules) every 4 hours for 21 consecutive days.
• If the patient is not conscious enough to swallow the nimodipine capsule, the contents can be extracted into a syringe, fed through a nasogastric tube, and washed down with 30 mL of normal saline (0.9%).

Intravenous Administration

• Parental administration is strongly discouraged (see USFDA boxed warning). The following parenteral techniques are described for educational purposes only. Nimodipine can be given intravenously via a central venous catheter at a starting dose of 1 mg/h (15 μg/kg/h, equivalent to 5 mL/h) for the first 2 hours. If the patient tolerates the drug well without hypotension, the dose can increase to 2 mg/h (30 μg/kg/h, equivalent to 10 mL/h) after the first 2 hours.
• If the patient has hypotension or a body weight of less than 70 kg, nimodipine should be started at 0.5 mg/h (2.5 mL of solution per hour) or less, if necessary.

Intraventricular Administration

• The outcome, dosage, and duration of intraventricular nimodipine administration were assessed in the NEWTON trial. The results of this trial indicated no significant benefit for intraventricular nimodipine compared with the standard of care.[23][29]

Aneurysmal Subarachnoid Hemorrhage Treatment Duration

• Intravenous administration 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 requires surgical intervention, nimodipine should be administered at a steady dose for at least 5 days.
• Intravenous nimodipine administration can begin 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 21 days.
• Nimodipine should not be administered intravenously for more than 14 days. Patients should not be administered intravenous and oral nimodipine concomitantly.
• During a surgical procedure, a 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 administered intracisternally. This diluted solution must be used immediately after preparation.

Specific Patient Population [28]

Hepatic impairment: Bioavailability increases in patients with cirrhosis, making it necessary to reduce the dose in patients with this condition. The recommended dosage for patients with cirrhosis is 30 mg every 4 hours. 

Renal impairment: No information is available on the manufacturer's label concerning nimodipine dosing for patients with impaired renal function.

Pregnancy considerations: Nimodipine is a former U.S. FDA pregnancy category C medicine, and alternative agents are preferred.

Breastfeeding considerations: Based on the available data, nimodipine is present in human milk; relative infant exposure is less and is not expected to cause adverse effects in breastfed infants. However, the decision to breastfeed during an episode of SAH merits a risk-benefit evaluation.[30]

Pediatric patients: Nimodipine is not FDA-approved for pediatric patients. Research indicates that administering oral nimodipine to children following subarachnoid hemorrhage does not eliminate vasospasm, infarction, or rebleeding. Nimodipine is also associated with significant hypotension. Further investigation, including dose titration, is necessary before administration to pediatric patients can be advised.[31]

Older patients: In older patients, clinicians should be cautious when dosing nimodipine for patients with reduced cardiac, hepatic, or renal function. One case report suggests that adverse effects like hypotension and AV block from nimodipine can be more pronounced in older patients who have a "poor metabolizer" CYP3A5 genotype.[32]

Adverse Effects

Nimodipine is usually well-tolerated orally, but its use correlates with some side effects related to its use as a vasodilator. The most common adverse effects of this medication include headache, vertigo, flushing, nausea, diarrhea, pedal edema, rash, and palpitations.

Acute colonic pseudo-obstruction (Ogilvie syndrome) has been documented in patients administered oral nimodipine.[33] Internal carotid and middle cerebral artery narrowing leading to cerebral infarction have been reported 5 months after intraventricular administration of sustained-release nimodipine.[29]

Drug-Drug Interactions

Nimodipine is metabolized by the cytochrome P450 3A4 system. Drugs that inhibit this enzyme can cause elevated plasma concentrations of nimodipine. These drugs include macrolide antibiotics (eg, erythromycin, clarithromycin, and telithromycin), protease inhibitors (eg, ritonavir, indinavir, nelfinavir, and saquinavir), "-azole" antimycotics (eg, ketoconazole, voriconazole, itraconazole), antidepressants (eg, nefazodone, fluoxetine), quinupristin/dalfopristin, cimetidine, and valproic acid. Grapefruit juice also inhibits this cytochrome system and should be avoided by any patient taking nimodipine.[32]

Medications including carbamazepine, phenobarbital (phenobarbitone), and phenytoin are CYP3A4 inducers. Concomitant administration of any of these medications enhances nimodipine's metabolism. This process reduces nimodipine's serum concentration and increases the likelihood of treatment failure.[34]

Contraindications

The following are contraindications to nimodipine administration:

• A history of hypersensitivity reaction to nimodipine is an absolute contraindication.
• Liver failure and hypotension are relative contraindications for administering nimodipine.
• Concomitant administration with potent CYP3A4 inhibitors is also a relative contraindication.[34]
• Nimodipine is not entirely safe for pregnancy (Category C under the former FDA system), and patients who are pregnant should only use it if a strong benefit-risk ratio has been determined. Breastfeeding is contraindicated while taking the drug due to the chance of harmful effects on the baby. Current research has not yet fully established safety for pediatric patients.[35][30]

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 is injected parenterally. The IV formulation of nimodipine is currently available in Europe but is not FDA-approved, so it is not available in the U.S.[25]

Monitoring

Blood pressure monitoring is necessary for patients administered nimodipine as it can cause hypotension. The risk of hypotension is elevated in the following scenarios:[36]

• The plasma concentration of nimodipine is elevated by medications that moderately or weakly inhibit CYP3A4. Therefore, the patient's blood pressure must be closely monitored if nimodipine is administered concomitantly with CYP3A4 inhibitors; reducing the nimodipine dose may be necessary.
• Nimodipine may augment the blood pressure reduction of concomitantly administered antihypertensives (eg, diuretics, β-blockers, ACE inhibitors, calcium antagonists, α-blockers, PDE5 inhibitors, α-methyldopa). Reducing the nimodipine dosage to prevent hypotension may be required.
• Patients with SAH should be monitored for hyponatremia, seizures, and vasospasm, especially during the 4 to 14-day "vasospasm window."[37] 
• Patients prescribed nimodipine are at risk for elevated intracranial pressure and rebleeding.[38]
• Patients with SAH must be monitored with comprehensive neurological examinations and grading scales (eg, Fisher grading scale).[39]
• Patients' global disability and recovery should be monitored using the Glasgow Outcome Scale-Extended (GOSE).[40]

Toxicity

Signs and Symptoms of Overdose

Acute toxicity due to overdose can cause significant hypotension, cardiac arrhythmia, nausea, and vomiting. Refractory, nimodipine-induced vasoplegia may occur.

Management of Overdose

No specific antidote is available. Overdoses are managed initially by discontinuing nimodipine and treating symptoms. Gastric lavage may be considered if the toxicity is due to oral intake, and charcoal can be administered in emergencies. Hypotension is managed with inotropes, and arrhythmias are managed by cardiologists and emergency department staff. Since nimodipine is highly protein-bound, dialysis is unlikely to be beneficial.[41][42] Recent case reports suggest hydroxocobalamin as a potential rescue therapy for nimodipine-induced refractory vasoplegia.[43]

Enhancing Healthcare Team Outcomes

Management of aneurysmal subarachnoid hemorrhage with nimodipine is best carried out by an interprofessional healthcare team. A cardiologist or internal medicine specialist frequently initiates this treatment. Nurses 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 SAH cases. Before initiating nimodipine therapy, a pharmacist should be consulted on dosing and drug interactions. Interprofessional coordination of effort permits the healthcare team to obtain optimal outcomes with minimal adverse events. One study has demonstrated that early and aggressive care of SAH leads to a significant improvement in survival and favorable outcomes.[44]

When administering nimodipine, providers must be aware of hypotension as an adverse effect. After administration, careful blood pressure monitoring is necessary, especially in patients concomitantly receiving CYP3A4 inhibitors and antihypertensives. Administration of nimodipine is possible by pushing the tablet contents through a nasogastric tube. In these cases, oral nimodipine should be labeled and kept separate to avoid its administration intravenously. An interprofessional team approach and open communication between clinicians (MDs, DOs, NPs, PAs), pharmacists, nurses, and specialists are necessary to optimize patient outcomes with nimodipine therapy.