Isradipine precautions

List of Precautions
General Drug Interactions Carcinogenesis, Mutagenesis, Impairment of Fertility Pregnancy Nursing Mothers Pediatric Use

General
Blood Pressure: Because Isradipine decreases peripheral resistance, like other calcium blockers Isradipine may occasionally produce symptomatic hypotension. However, symptoms like syncope and severe dizziness have rarely been reported in hypertensive patients administered Isradipine, particularly at the initial recommended doses.

Use in Patients with Congestive Heart Failure: Although acute hemodynamic studies in patients with congestive heart failure have shown that Isradipine reduced afterload without impairing myocardial contractility, it has a negative inotropic effect at high doses in vitro, and possibly in some patients. Caution should be exercised when using the drug in congestive heart failure patients, particularly in combination with a beta-blocker.

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Drug Interactions

 * Nitroglycerin: Isradipine has been safely coadministered with nitroglycerin.


 * Hydrochlorothiazide: A study in normal healthy volunteers has shown that concomitant administration of Isradipine and hydrochlorothiazide does not result in altered pharmacokinetics of either drug. In a study in hypertensive patients, addition of Isradipine to existing hydrochlorothiazide therapy did not result in any unexpected adverse effects, and Isradipine had an additional antihypertensive effect.


 * Propranolol: In a single dose study in normal volunteers, co-administration of propranolol had a small effect on the rate but no effect on the extent of Isradipine bioavailability. Significant increases in AUC (27%) and Cmax (58%) and decreases in tmax (23%) of propranolol were noted in this study. However, concomitant administration of 5 mg b.i.d. Isradipine and 40 mg b.i.d. propranolol to healthy volunteers under steady-state conditions had no relevant effect on either drug’s bioavailability. AUC and Cmax differences were <20% between Isradipine given singly and in combination with propranolol, and between propranolol given singly and in combination with Isradipine.


 * Cimetidine: In a study in healthy volunteers, a one-week course of cimetidine at 400 mg b.i.d. with a single 5 mg dose of Isradipine on the sixth day showed an increase in Isradipine mean peak plasma concentrations (36%) and significant increase in area under the curve (50%). If Isradipine therapy is initiated in a patient currently receiving cimetidine, careful monitoring for adverse reactions is advised and downward dose adjustment may be required.


 * Rifampicin: In a study in healthy volunteers, a six-day course of rifampicin at 600 mg/day followed by a single 5 mg dose of Isradipine resulted in a reduction in Isradipine levels to below detectable limits. If rifampicin therapy is required, Isradipine concentrations and therapeutic effects are likely to be markedly reduced or abolished as a consequence of increased metabolism and higher clearance of Isradipine.


 * Warfarin: In a study in healthy volunteers, no clinically relevant pharmacokinetic or pharmacodynamic interaction between Isradipine and racemic warfarin was seen when two single oral doses of warfarin (0.7 mg/kg body weight) were administered during 11 days of multiple-dose treatment with 5 mg b.i.d. Isradipine. Neither racemic warfarin nor Isradipine binding to plasma proteins in vitro was altered by the addition of the other drug.


 * Digoxin: The concomitant administration of Isradipine and digoxin in a single-dose pharmacokinetic study did not affect renal, nonrenal and total body clearance of digoxin.


 * Fentanyl Anesthesia: Severe hypotension has been reported during fentanyl anesthesia with concomitant use of a beta blocker and a calcium channel blocker. Even though such interactions have not been seen in clinical studies with Isradipine, an increased volume of circulating fluids might be required if such an interaction were to occur.

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Carcinogenesis, Mutagenesis, Impairment of Fertility
Treatment of male rats for 2 years with 2.5, 12.5, or 62.5 mg/kg/day Isradipine admixed with the diet (approximately 6, 31, and 156 times the maximum recommended daily dose based on a 50 kg man) resulted in dose dependent increases in the incidence of benign Leydig cell tumors and testicular hyperplasia relative to untreated control animals. These findings, which were replicated in a subsequent experiment, may have been indirectly related to an effect of Isradipine on circulating gonadotropin levels in the rats; a comparable endocrine effect was not evident in male patients receiving therapeutic doses of the drug on a chronic basis. Treatment of mice for two years with 2.5, 15, or 80 mg/kg/day Isradipine in the diet (approximately 6, 38, and 200 times the maximum recommended daily dose based on a 50 kg man) showed no evidence of oncogenicity. There was no evidence of mutagenic potential based on the results of a battery of mutagenic tests. No effect on fertility was observed in male and female rats treated with up to 60 mg/kg/day Isradipine.

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Pregnancy
Pregnancy Category C:

Isradipine was administered orally to rats and rabbits during organogenesis. Treatment of pregnant rats with doses of 6, 20, or 60 mg/kg/day produced a significant reduction in maternal weight gain during treatment with the highest dose (150 times the maximum recommended human daily dose) but with no lasting effects on the mother or the offspring. Treatment of pregnant rabbits with doses of 1, 3, or 10 mg/kg/day (2.5, 7.5, and 25 times the maximum recommended human daily dose) produced decrements in maternal body weight gain and increased fetal resorption at the two higher doses. There was no evidence of embryotoxicity at doses which were not maternotoxic and no evidence of teratogenicity at any dose tested. In a peri/postnatal administration study in rats, reduced maternal body weight gain during late pregnancy at oral doses of 20 and 60 mg/kg/day Isradipine was associated with reduced birth weights and decreased peri and postnatal pup survival.

There are no adequate and well controlled studies in pregnant women. The use of Isradipine during pregnancy should only be considered if the potential benefit outweighs potential risks.

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Nursing Mothers
It is not known whether Isradipine is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for adverse effects of Isradipine on nursing infants, a decision should be made as to whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

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Pediatric Use
Safety and effectiveness in pediatric patients have not been established.

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