Although there is no well documented experience with DynaCirc® (isradipine) overdosage,available data suggest that, as with other dihydropyridines, gross overdosage would result in excessive peripheral vasodilation with subsequent marked and probably prolonged systemic hypotension. Clinically significant hypotension overdosage calls for 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 vascular tone and blood pressure,provided that there is no contraindication to its use.Since isradipine is highly protein bound, dialysis is not likely to be of benefit.
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.
Dilatol Sro® (isradipine) is contraindicated in individuals who have shown hypersensitivity to any of the ingredients in the formulation.
In a controlled clinical trial with Dilatol Sro® (isradipine), dose-related edema occurred at an incidence of approximately 9% at 5 mg; 13% at 10 mg; 16% at 15 mg; and 36% at the highest dose studied (20 mg), was mild to moderate in severity,and was not related to age or gender.
The incidences of elicited or volunteered adverse reactions (excluding non-drug related) in the following tables are based on 6-week multicenter, placebo-controlled, double-blind hypertension studies. Less than 1% of Dilatol Sro® (isradipine) or placebo-treated patients discontinued from these studies due to adverse reactions.
The most common adverse experiences ( ≥ 1.0%) reported with Dilatol Sro® (isradipine) in a dose-response study are shown in the following table.There were no discontinuations of patients treated with Dilatol Sro® (isradipine) in this study due to these common side effects.
Most Frequently Reported Newly-Occurring Adverse Reactions in Dose-Response Study
| Adverse Reactions (Excluding Non-Drug Related) | Dilatol Sro® (isradipine) | ||||
| 5 mg (N=79) | 10 mg (N=79) | 15 mg (N=82) | 20 mg (N=78) | Placebo Group (N=83) | |
| Headache | 13.9% | 12.7% | 18.3% | 10.3% | 15.7% |
| Edema | 8.9% | 12.7% | 15.9% | 35.9% | 3.6% |
| Dizziness | 5.1% | 6.3% | 3.7% | 6.4% | 2.4% |
| Constipation | 3.8% | 1.3% | 1.2% | 2.6% | 0.0% |
| Fatigue | 2.5% | 7.6% | 3.7% | 3.8% | 2.4% |
| Flushing | 2.5% | 3.8% | 1.2% | 1.3% | 1.2% |
| Abdominal Discomfort | 1.3% | 5.1% | 3.7% | 5.1% | 1.2% |
| Rash | 1.3% | 1.3% | 0.0% | 2.6% | 0.0% |
The table below shows elicited or volunteered adverse experiences for Dilatol Sro® (isradipine) treated patients in two 6-week, placebo-controlled, multicenter studies, at doses from 5-20 mg, and considered by the investigator to be at least possibly drug related.The results for Dilatol Sro® (isradipine) treated patients are presented for all doses pooled together (reported by at least 1.0% of active drug treated patients).The incidence of adverse reactions are listed below:
| Adverse Reactions (Excluding Non-Drug Related) | Treatment Group | |
| Dilatol Sro®(isradipine) (N=422) | Placebo (N=186) | |
| Edema | 15.2% | 2.2% |
| Headache | 13.0% | 12.4% |
| Dizziness | 4.7% | 2.7% |
| Fatigue | 4.3% | 2.2% |
| Abdominal Discomfort | 2.8% | 0.5% |
| Flushing | 1.9% | 0.5% |
| Constipation | 1.7% | 0.0% |
| Palpitations | 1.2% | 0.0% |
| Nausea | 1.2% | 1.6% |
| Abdominal Distention | 1.2% | 0.0% |
The following adverse experiences were reported in 0.5%-1.0% or less of Dilatol Sro® (isradipine) or immediate-release DynaCirc® (isradipine) treated patients in hypertensive studies,or were noted in postmarketing experience with immediate-release DynaCirc® (isradipine) Capsules. More serious events are shown in italics. The relationship of these adverse experiences to isradipine administration is uncertain.
SKIN:Pruritus, urticaria, angioedema.
MUSCULOSKELETAL: Backache/pain, joint pain,neck pain/sore/stiff,legs ache/pain,cramps of legs/feet.
RESPIRATORY: Dyspnea, nasal congestion,cough.
CARDIOVASCULAR: Epistaxis,tachycardia,chest pain,shortness of breath,hypotension, syncope,atrial or ventricular fibrillation,myocardial infarction,heart failure.
GASTROINTESTINAL:Diarrhea,vomiting,appetite increased or decreased.
UROGENITAL: Pollakiuria,impotence,dysuria,nocturia.
CENTRAL NERVOUS: Drowsiness, insomnia, lethargy,nervousness, libido decrease/frigidity,impotence, depression, paresthesia (which includes numbness and tingling), transient ischemic attack,stroke.
AUTONOMIC: Dry mouth,hyperhidrosis,visual disturbance.
MISCELLANEOUS: Weight gain, throat discomfort, drug fever, leukopenia, elevated liver function tests.
No gastrointestinal bleeding has been reported in clinical trials with Dilatol Sro® (isradipine) Controlled Release Tablets.
In a long-term (one-year) Dilatol Sro® (isradipine) open-label, hypertension trial, the adverse events reported were generally the same as those seen in the short-term placebo-controlled studies. About 6% of Dilatol Sro® (isradipine) treated patients discontinued the long-term trial due to adverse reactions.
With immediate-release DynaCirc® (isradipine) Capsules, most of the adverse experiences were transient, mild, and related to vasodilatory effects.The following table shows the most common adverse events reported in U.S.clinical tri-als for immediate-release DynaCirc® (isradipine) Capsules, volunteered or elicited, and considered by the investigator to be at least possibly drug related.
| Adverse Experience | DynaCirc® (isradipine) | Placebo (N=297) % | ActiveControls* (N=414) % | |||
| All Doses | 2.5 mg b.i.d. | 5 mg b.i.d.† | 10 mg b.i.d.†† | |||
| Headache | 13.7 | 12.6 | 10.7 | 22.0 | 14.1 | 9.4 |
| Dizziness | 7.3 | 8.0 | 5.3 | 3.4 | 4.4 | 8.2 |
| Edema | 7.2 | 3.5 | 8.7 | 8.5 | 3.0 | 2.9 |
| Palpitations | 4.0 | 1.0 | 4.7 | 5.1 | 1.4 | 1.5 |
| Fatigue | 3.9 | 2.5 | 2.0 | 8.5 | 0.3 | 6.3 |
| Flushing | 2.6 | 3.0 | 2.0 | 5.1 | 0.0 | 1.2 |
| Chest Pain | 2.4 | 2.5 | 2.7 | 1.7 | 2.4 | 2.9 |
| Nausea | 1.8 | 1.0 | 2.7 | 5.1 | 1.7 | 3.1 |
| Dyspnea | 1.8 | 0.5 | 2.7 | 3.4 | 1.0 | 2.2 |
| Abdominal Discomfort | 1.7 | 0.0 | 3.3 | 1.7 | 1.7 | 3.9 |
| Tachycardia | 1.5 | 1.0 | 1.3 | 3.4 | 0.3 | 0.5 |
| Rash | 1.5 | 1.5 | 2.0 | 1.7 | 0.3 | 0.7 |
| Pollakiuria | 1.5 | 2.0 | 1.3 | 3.4 | 0.0 | 1.0 |
| Weakness | 1.2 | 0.0 | 0.7 | 0.0 | 0.0 | 1.2 |
| Vomiting | 1.1 | 1.0 | 1.3 | 0.0 | 0.3 | 0.2 |
| Diarrhea | 1.1 | 0.0 | 2.7 | 3.4 | 2.0 | 1.9 |
| †Initial dose of 2.5 mg b.i.d.followed by maintenance dose of 5.0 mg b.i.d. ††Initial dose of 2.5 mg b.i.d.followed by sequential titration to 5.0 mg b.i.d.,7.5 mg b.i.d.,and maintenance dose of 10.0 mg b.i.d. *Propranolol,prazosin,hydrochlorothiazide,enalapril,captopril. |
In open-label,long-term studies of up to two years in duration with immediate-release DynaCirc® (isradipine) Capsules, the adverse experiences 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 in the controlled studies most adverse reactions were mild and transient.
Dilatol Sro® (isradipine) is indicated in the management of hypertension. It may be used alone or concurrently with thiazide-type diuretics.
None
PRECAUTIONS GeneralBlood Pressure: Because Dilatol Sro® (isradipine) decreases peripheral resistance, like other calcium blockers Dilatol Sro® (isradipine) may occasionally produce symptomatic hypotension. However, symptoms like syncope and severe dizziness have rarely been reported in hypertensive patients administered Dilatol Sro® (isradipine), particularly at the initial recommended doses (see DOSAGE AND ADMINISTRATION).
Use in Patients with Congestive Heart Failure: Although acute hemodynamic studies in patients with congestive heart failure have shown that immediate-release 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 Dilatol Sro® (isradipine) in congestive heart failure patients, particularly in combination with a beta-blocker.
Peripheral Edema: Peripheral edema, when it occurs, is usually mild to moderate in severity. It is a localized phenomenon thought to be associated with vasodilation of arterioles and other small blood vessels,and not due to left ventricular dysfunction or generalized fluid retention. Peripheral edema is dose-related with an incidence ranging from approximately 9% at 5 mg; 13% at 10 mg; 16% at 15 mg; and 36% at the highest dose studied (20 mg once-daily). With patients whose hypertension is complicated by congestive heart failure, care should be taken to differentiate this edema from the effects of decreasing left ventricular function. Although the frequency of edema is correlated with dose, no Dilatol Sro® (isradipine) treated patients discontinued the short-term (6 weeks or less), placebo-controlled hypertension studies as a result of edema. Less than 5% of Dilatol Sro® (isradipine) treated patients in long-term studies discontinued due to edema.
Other: As with any other non-deformable material, caution should be used when administering Dilatol Sro® (isradipine) in patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic).There have been reports of obstructive symptoms in patients with known strictures associated with ingestion of other GITS products.
Carcinogenesis, Mutagenesis,Impairment of FertilityTreatment 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 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.
PregnancyPregnancy 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 ofpregnant rabbits with doses of 1,3,or 10mg/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 Dilatol Sro® (isradipine) during pregnancy should only be considered if the potential benefit outweighs potential risks.
Nursing MothersIt 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.
Pediatric UseSafety and effectiveness have not been established in children.
Geriatric UseClinical studies of Dilatol Sro® (isradipine) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Elderly patients have deceased clearance of DynaCirc® (isradipine) with a higher average AUC and Cmax (see Pharmacokinetics and Metabolism).The larger extent of bioavailability may be a result of a reduced clearance and/or reduced first-pass metabolism of the drug. In general, dose selection for an elderly patient should be cautious,reflecting the greater frequency of decreased hepatic, renal,or cardiac function,and of concomitant disease or other drug therapy (see DOSAGE AND ADMINISTRATION).
The dosage of Dilatol Sro® (isradipine) Controlled Release Tablets should be individualized.The recommended initial dose of Dilatol Sro® (isradipine) is 5 mg once-daily as monotherapy or in combination with a thiazide diuretic. An antihypertensive response usually occurs within 2 hours,with the peak antihypertensive response occurring 8-10hours post-dose; blood pressure reduction is maintained for at least 24 hours following drug administration.If necessary,the dose may be adjusted in increments of 5 mg at 2-4 week intervals up to a maximum dose of 20 mg/day. Adverse experiences are increased in frequency above 10 mg/day.
Dilatol Sro® (isradipine) Controlled Release Tablets should be swallowed whole and should not be bitten or divided.
The bioavailability (increased AUC) of immediate-release DynaCirc® (isradipine) is increased in elderly patients (above 65 years of age), patients with hepatic functional impairment, and patients with mild renal impairment. Ordinarily, a starting dose of Dilatol Sro® (isradipine) 5 mg once-daily should be used in these patients.
