Isradipine

Description

DESCRIPTION Isradipine is a calcium antagonist available for oral administration in capsules containing 2.5 mg or 5 mg. The structural formula of isradipine is: Chemically, isradipine is 3,5-Pyridinedicarboxylic acid, 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-, methyl 1-methylethyl ester. Isradipine is a yellow, fine crystalline powder which is odorless or has a faint characteristic odor. Isradipine is practically insoluble in water (<10 mg/L at 37ºC), but is soluble in ethanol and freely soluble in acetone, chloroform and methylene chloride. Active Ingredient: isradipine Inactive Ingredients: colloidal silicon dioxide, red iron oxide (2.5 mg capsule only), yellow iron oxide, gelatin, anhydrous lactose, magnesium stearate, sodium lauryl sulfate, starch (corn), titanium dioxide, black ink: black iron oxide, shellac and potassium hydroxide. structural formula of isradipine

What Is Isradipine Used For?

INDICATIONS AND USAGE Hypertension Isradipine is indicated in the management of hypertension. It may be used alone or concurrently with thiazide-type diuretics.

Dosage and Administration

DOSAGE AND ADMINISTRATION The dosage of isradipine should be individualized. The recommended initial dose of isradipine is 2.5 mg b.i.d. alone or in combination with a thiazide diuretic. An antihypertensive response usually occurs within 2-3 hours. Maximal response may require 2-4 weeks. If a satisfactory reduction in blood pressure does not occur after this period, the dose may be adjusted in increments of 5 mg/day at 2-4 week intervals up to a maximum of 20 mg/day. Most patients, however, show no additional response to doses above 10 mg/day, and adverse effects are increased in frequency above 10 mg/day. The bioavailability of isradipine (increased AUC) is increased in elderly patients (above 65 years of age), patients with hepatic functional impairment, and patients with mild renal impairment. Ordinarily, the starting dose should still be 2.5 mg b.i.d. in these patients.

Side Effects (Adverse Reactions)

ADVERSE REACTIONS In multiple dose U.S. studies in hypertension, 1228 patients received isradipine alone or in combination with other agents, principally a thiazide diuretic, 934 of them in controlled comparisons with placebo or active agents. An additional 652 patients (which includes 374 normal volunteers) received isradipine in U.S. studies of conditions other than hypertension, and 1321 patients received isradipine in non-U.S. studies. About 500 patients received isradipine in long-term hypertension studies, 410 of them for at least 6 months. The adverse reaction rates given below are principally based on controlled hypertension studies, but rarer serious events are derived from all exposures to isradipine, including foreign marketing experience. Most adverse reactions were mild and related to the vasodilatory effects of isradipine (dizziness, edema, palpitations, flushing, tachycardia), and many were transient. About 5% of isradipine patients left studies prematurely because of adverse reactions (vs. 3% of placebo patients and 6% of active control patients), principally due to headache, edema, dizziness, palpitations, and gastrointestinal disturbances. The following table shows the most common adverse reactions, volunteered or elicited, considered by the investigator to be at least possibly drug related. The results for the isradipine treated patients are presented for all doses pooled together (reported by 1% or greater of patients receiving any dose of isradipine), and also for the two treatment regimens most applicable to the treatment of hypertension with isradipine: (1) initial and maintenance dose of 2.5 mg b.i.d., and (2) initial dose of 2.5 mg b.i.d. followed by maintenance dose of 5 mg b.i.d. Isradipine Adverse Experience All Doses N=934 % 2.5 mg b.i.d. 199 % 5 mg b.i.d.† 150 % 10 mg b.i.d.†† 59 % Placebo % Active Controls* 414 % Headache Dizziness Edema Palpitations 13.7 7.3 7.2 4.0 12.6 8.0 3.5 1.0 10.7 5.3 8.7 4.7 22.0 3.4 8.5 5.1 14.1 4.4 3.0 1.4 9.4 8.2 2.9 1.5 Fatigue Flushing Chest Pain Nausea 3.9 2.6 2.4 1.8 2.5 3.0 2.5 1.0 2.0 2.0 2.7 2.7 8.5 5.1 1.7 5.1 0.3 0.0 2.4 1.7 6.3 1.2 2.9 3.1 Dyspnea Abdominal Discomfort Tachycardia Rash 1.8 1.7 1.5 1.5 0.5 0.0 1.0 1.5 2.7 3.3 1.3 2.0 3.4 1.7 3.4 1.7 1.0 1.7 0.3 0.3 2.2 3.9 0.5 0.7 Pollakiuria Weakness Vomiting Diarrhea 1.5 1.2 1.1 1.1 2.0 0.0 1.0 0.0 1.3 0.7 1.3 2.7 3.4 0.0 0.0 3.4 0.0 0.0 0.3 2.0 <1.0 1.2 0.2 1.9 †Initial dose of 2.5 mg b.i.d. followed by maintenance dose of 5 mg b.i.d. †† Initial dose of 2.5 mg b.i.d. followed by sequential titration to 5 mg b.i.d., 7.5 mg b.i.d., and maintenance dose of 10 mg b.i.d. *Propranolol, prazosin, hydrochlorothiazide, enalapril, captopril. Except for headache, which is not clearly drug-related (see previous table), the more frequent adverse reactions listed show little change, or increase slightly, in frequency over time, as shown in the following table: Incidence Rates for Isradipine (All Doses) by Week (%) Week N 1 694 2 906 3 649 4 847 5 432 6 494 Adverse Reaction Headache Dizziness Edema Palpitations Fatigue Flushing 6.5 1.6 1.2 1.2 0.4 1.2 6.1 1.9 2.5 1.3 1.0 1.3 5.2 1.7 3.2 1.4 1.4 2.0 5.2 2.2 3.2 1.9 1.2 1.4 5.8 2.3 5.3 2.1 1.2 2.1 4.5 2.0 5.5 1.4 1.6 1.4 Week N 7 153 8 377 9 261 10 362 11 107 12 105 Adverse Reaction Headache Dizziness Edema Palpitations Fatigue Flushing 2.0 2.0 5.9 1.3 2.0 3.3 2.7 1.9 5.0 0.8 2.7 1.3 1.9 2.3 4.6 0.8 1.5 1.1 2.8 3.9 4.7 1.7 1.4 0.8 2.8 4.7 3.8 1.9 0.9 0.0 3.8 3.8 3.8 2.9 1.9 0.0 Edema, palpitations, fatigue, and flushing appear to be dose-related, especially at the higher doses of 15-20 mg/day. In open-label, long-term studies of up to two years in duration, the adverse events reported were generally the same as those reported in the short-term controlled trials. The overall frequencies of these adverse events were slightly higher in the long-term than in the controlled studies, but as in the controlled trials most adverse reactions were mild and transient. The following...

Drug Interactions

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 C max (58%) and decreases in t max (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 C max 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...

Contraindications

CONTRAINDICATIONS Isradipine is contraindicated in individuals who have shown hypersensitivity to any of the ingredients in the formulation.

Pregnancy and Breastfeeding

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.

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.

Overdosage

OVERDOSAGE Minimal empirical data are available on isradipine overdosage. Three individual suicide attempts with dosages of isradipine reported to be from 20 mg up to 100 mg resulted in lethargy, sinus tachycardia and, in the case of the person ingesting 100 mg, transient hypotension which responded to fluid therapy. A foreign report of the ingestion of 200 mg of isradipine with ethanol resulted only in flushing, tachycardia with ST depression on ECG, and hypotension, all of which were reversible. The ingestion of 5 mg of isradipine by a 22-month old child and the accidental ingestion of 100 mg of isradipine by a 58-year old female did not result in any sequelae. Available data suggest that, as with other dihydropyridines, overdosage with isradipine might result in excessive peripheral vasodilatation with subsequent marked and probably prolonged systemic hypotension, and tachycardia. Emesis, gastric lavage, administration of activated charcoal followed in 30 minutes by a saline cathartic would be reasonable therapy. Isradipine is highly protein-bound and not removed by hemodialysis. Overdosage characterized by clinically significant hypotension should be treated with active cardiovascular support including monitoring of cardiac and respiratory function, elevation of lower extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor (such as epinephrine, norepinephrine, or levarterenol) may be helpful in restoring a normotensive state, provided that there is no contraindication to its use. Refractory hypotension or AV conduction disturbances may be treated with intravenous calcium salts, or glucagon. Cimetidine should be withheld in such instances due to the risk of further increasing plasma isradipine levels. Significant lethality was observed in mice given oral doses of over 200 mg/kg and rabbits given about 50 mg/kg of isradipine. Rats tolerated doses of over 2000 mg/kg without effects on survival.

How Supplied

HOW SUPPLIED Isradipine Capsules, USP 2.5 mg Brown opaque, imprinted with “ ” IS 2.5. Bottles of 100 capsules (NDC 42291-062-01) 5 mg Caramel opaque, imprinted with “ ” IS 5. Store and Dispense Store at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature] and dispense in a tight, light-resistant container Rx Only Manufactured for: AvKARE Pulaski, TN 38478 Mfg. Rev. 06/17 AV 05/23 (P) Cobalt symbol Cobalt symbol