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Nimodipine oral solution

Nimodipine oral solution

Description :

Nimodipine  is a dihydropyridine calcium channel blocker.

 Nimodipine is isopropyl 2methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate. 

Nimodipine is a yellow crystalline substance, practically insoluble in water.

Nimodipine Oral Solution contains 60 mg of nimodipine per 20 mL. In addition, the oral solution contains the following inactive ingredients: ethanol, glycerin, methylparaben, polyethylene glycol, sodium phosphate monobasic, sodium phosphate dibasic, and water.

Dosage forms and strengths:

      Oral Solution: 60 mg per 20 mL (3 mg/mL), pale yellow solution.

 Indications and use :

Nimodipine  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.

Dosage and administration:

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 Nimodipine 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.

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 .

Mechanism of Action:

Nimodipine is a dihydropyridine calcium channel blocker. The contractile processes of smooth muscle cells are dependent upon calcium ions, which enter these cells during depolarization as slow ionic transmembrane currents. Nimodipine inhibits calcium ion transfer into these cells and thus inhibits contractions of vascular smooth muscle. In animal experiments, nimodipine had a greater effect on cerebral arteries than on arteries elsewhere in the body perhaps because it is highly lipophilic, allowing it to cross the blood-brain barrier; concentrations of nimodipine as high as 12.5 ng/mL have been detected in the cerebrospinal fluid of nimodipine-treated SAH patients.

 

Pharmacokinetics:

In humans, nimodipine is rapidly absorbed after oral administration, and peak concentrations are generally attained within one hour. The terminal elimination half-life is approximately 8 to 9 hours but earlier elimination rates are much more rapid, equivalent to a half-life of 1-2 hours; a consequence is the need for frequent (every 4 hours) dosing. There were no signs of accumulation when nimodipine was given three times a day for seven days. Nimodipine is over 95% bound to plasma proteins. The binding was concentration independent over the range of 10 ng/mL to 10 mcg/mL. Nimodipine is eliminated almost exclusively in the form of metabolites and less than 1% is recovered in the urine as unchanged drug. Numerous metabolites, all of which are either inactive or considerably less active than the parent compound, have been identified. The metabolism of nimodipine is mediated by CYP3A4. Because of a high first-pass metabolism, the bioavailability of nimodipine averages 13% after oral administration.

Patients with Cirrhosis

The bioavailability of nimodipine is significantly increased in patients with cirrhosis, with Cmax approximately double that in normals which necessitates lowering the dose in this group of patients.

5. Warnings and precautions:

5.1 Hypotension

Blood pressure should be carefully monitored during treatment with Nimodipine.

 

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.

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, delaviridine, and nefazadone with nimodipine should generally be avoided because of a risk of significant hypotension.

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.

 

Adverse reactions:

Most common adverse reactions (incidence ≥1% and ≥1% placebo) were hypotension, headache, nausea, and bradycardia .

Drug interactions:

•         Anti-Hypertensives: May increase risk of hypotension. Monitor blood pressure .

•         CYP3A4 Moderate and Weak Inhibitors: May increase risk of hypotension. Monitor blood pressure.

•         Dose reduction of Nimodipine  may be needed.

•         Avoid grapefruit juice.

•         CYP3A4 Moderate and Weak Inducers: May reduce efficacy of Nimodipine. Dose increase may be needed.

Pregnancy:

 Based on animal data may cause fetal harm.

Overdosage :

There have been no reports of overdosage from the oral administration of nimodipine. Symptoms of overdosage would be expected to be related to cardiovascular effects such as excessive peripheral vasodilation with marked systemic hypotension. Clinically significant hypotension due to nimodipine overdosage may require active cardiovascular support with pressor agents and specific treatments for calcium channel blocker overdose. Since nimodipine is highly protein-bound, dialysis is not likely to be of benefit.

Storage:

Store at 25ºC (77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF).

Protect from light. Do not refrigerate.