Isradipine Drug Information

Hypertension Isradipine capsules are indicated in the management of hypertension. It may be used alone or concurrently with thiazide-type diuretics.

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 to 3 hours.

Maximal response may require 2 to 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 to 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.

Dizziness 7.3 8 5.3 3.4 4.4 8.2 Edema 7.2 3.5 8.7 8.5

3

Palpitations 4 1 4.7 5.1 1.4 1.5 Fatigue 3.9 2.5 2 8.5

0.3

Flushing 2.6 3 2 5.1 0 1.2 Chest Pain 2.4 2.5 2.7

1.7 2.4

Nausea 1.8 1 2.7 5.1 1.7 3.1 Dyspnea 1.8 0.5 2.7 3.4

1

Abdominal Discomfort 1.7 0 3.3 1.7 1.7 3.9 Tachycardia 1.5 1 1.3

3.4 0.3

Rash 1.5 1.5 2 1.7 0.3 0.7 Pollakiuria 1.5 2 1.3 3.4

0 <1 Weakness 1.2 0 0.7 0 0

Vomiting 1.1 1 1.3 0 0.3 0.2 Diarrhea 1.1 0 2.7 3.4

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 6.5 6.1 5.2 5.2 5.8

Dizziness 1.6 1.9 1.7 2.2 2.3 2 Edema 1.2 2.5 3.2 3.2

5.3

Palpitations 1.2 1.3 1.4 1.9 2.1 1.4 Fatigue 0.4 1 1.4 1.2

1.2

Flushing 1.2 1.3 2 1.4 2.1 1.4 Week N 7 153 8

377 9 261 10 362 11 107 12 105 Adverse Reaction Headache 2 2.7 1.9 2.8 2.8

Dizziness 2 1.9 2.3 3.9 4.7 3.8 Edema 5.9 5 4.6 4.7

3.8

Palpitations 1.3 0.8 0.8 1.7 1.9 2.9 Fatigue 2 2.7 1.5 1.4

0.9

Flushing 3.3 1.3 1.1 0.8 0 0 Edema, palpitations, fatigue, and flushing

appear to be dose-related, especially at the higher doses of 15 to 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 adverse experiences were reported in 0.5% to 1% of the isradipine-treated patients in hypertension studies, or are rare. More serious events from this and other data sources, including postmarketing exposure, are shown in italics. The relationship of these adverse events to isradipine administration is uncertain.

Skin: pruritus, urticaria Musculoskeletal: cramps of legs/feet Respiratory: cough Cardiovascular: shortness of breath, hypotension, atrial fibrillation, ventricular fibrillation, myocardial infarction, heart failure Gastrointestinal: abdominal discomfort, constipation, diarrhea Urogenital: nocturia Nervous System: drowsiness, insomnia, lethargy, nervousness, impotence, decreased libido, depression, syncope, paresthesia (which includes numbness and tingling), transient ischemic attack, stroke Autonomic: hyperhidrosis, visual disturbance, dry mouth, numbness Miscellaneous: throat discomfort, leukopenia, elevated liver function tests

• 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 occur.

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.

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

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

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.