Dynacirc

Overdose

Minimal empirical data are available on DynaCirc® (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 DynaCirc® (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.

Contraindications

DynaCirc® (isradipine) is contraindicated in individuals who have shown hypersensitivity to any of the ingredients in the formulation.

Undesirable effects

In multiple dose U.S. studies in hypertension, 1228 patients received DynaCirc® (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 DynaCirc® (isradipine) in U.S. studies of conditions other than hypertension, and 1321 patients received DynaCirc® (isradipine) in non-U.S. studies. About 500 patients received DynaCirc® (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 DynaCirc® (isradipine), including foreign marketing experience.

Most adverse reactions were mild and related to the vasodilatory effects of DynaCirc (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 DynaCirc® (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 DynaCirc® (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 5.0 mg b.i.d.

DynaCirc® (isradipine)

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 DynaCirc (isradipine) (All Doses) by Week (%)

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 adverse experiences were reported in 0.5%-1.0% 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 ischemicattack, stroke

Autonomic: hyperhidrosis, visual disturbance, dry mouth, numbness

Miscellaneous: throat discomfort, leukopenia, elevated liver function tests

Therapeutic indications

DynaCirc® (isradipine) is indicated in the management of hypertension. It may be used alone or concurrently with thiazide-type diuretics.

Name of the medicinal product

Fertility, pregnancy and lactation

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 DynaCirc® (isradipine) during pregnancy should only be considered if the potential benefit outweighs potential risks.

Qualitative and quantitative composition

DynaCirc® (isradipine) Capsules

White, imprinted twice with the DynaCirc (isradipine) ® logo and "DynaCirc (isradipine) " on one end, and "Reliant" and "2.5" on the other, twice.

Bottles of 100 capsules (NDC 65726-226-25)
Bottles of 60 capsules (NDC 65726-226-15)

Light pink, imprinted twice with the DynaCirc (isradipine) ® logo and "DynaCirc (isradipine) " on one end, and "Reliant" and "5"on the other, twice.

Bottles of 100 capsules (NDC 65726-227-25)
Bottles of 60 capsules (NDC 65726-227-15)

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-89°F) and dispense in a tight, light-resistant container.

Distributed by: Reliant Pharmaceuticals. Liberty Corner, New Jersey 07938.

Special warnings and precautions for use

None

Because DynaCirc® (isradipine) decreases peripheral resistance, like other calcium blockers DynaCirc® (isradipine) may occasionally produce symptomatic hypotension. However, symptoms like syncope and severe dizziness have rarely been reported in hypertensive patients administered DynaCirc® (isradipine), particularly at the initial recommended doses (see DOSAGE AND ADMINISTRATION).

Although acute hemodynamic studies in patients with congestive heart failure have shown that DynaCirc® (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.

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.

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 DynaCirc® (isradipine) during pregnancy should only be considered if the potential benefit outweighs potential risks.

It is not known whether DynaCirc® (isradipine) is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for adverse effects of DynaCirc® (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.

Safety and effectiveness in pediatric patients have not been established.

Dosage (Posology) and method of administration

The dosage of DynaCirc® (isradipine) should be individualized. The recommended initial dose of DynaCirc® (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 DynaCirc (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.

Interaction with other medicinal products and other forms of interaction

In multiple dose U.S. studies in hypertension, 1228 patients received DynaCirc® (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 DynaCirc® (isradipine) in U.S. studies of conditions other than hypertension, and 1321 patients received DynaCirc® (isradipine) in non-U.S. studies. About 500 patients received DynaCirc® (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 DynaCirc® (isradipine), including foreign marketing experience.

Most adverse reactions were mild and related to the vasodilatory effects of DynaCirc (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 DynaCirc® (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 DynaCirc® (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 5.0 mg b.i.d.

DynaCirc® (isradipine)

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 DynaCirc (isradipine) (All Doses) by Week (%)

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 adverse experiences were reported in 0.5%-1.0% 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 ischemicattack, stroke

Autonomic: hyperhidrosis, visual disturbance, dry mouth, numbness

Miscellaneous: throat discomfort, leukopenia, elevated liver function tests

Nitroglycerin: DynaCirc® (isradipine) has been safely coadministered with nitroglycerin.

Hydrochlorothiazide: A study in normal healthy volunteers has shown that concomitant administration of DynaCirc® (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 administrationof 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 DynaCirc® (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 DynaCirc® (isradipine), an increased volume of circulating fluids might be required if such an interaction were to occur.