"The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended the marketing of selexipag (Uptravi, Actelion Registration Ltd) for the treatment of adults with pulmonary arterial hypertension (PAH)./"...
Blood Pressure: Because DynaCirc CR® (isradipine) decreases peripheral resistance, like other calcium blockers DynaCirc CR® (isradipine) may occasionally produce symptomatic hypotension. However, symptoms like syncope and severe dizziness have rarely been reported in hypertensive patients administered DynaCirc CR® (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 DynaCirc CR® (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 DynaCirc CR® (isradipine) treated patients discontinued the short-term (6 weeks or less), placebo-controlled hypertension studies as a result of edema. Less than 5% of DynaCirc CR® (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 DynaCirc CR® (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 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 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.
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 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 DynaCirc CR® (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 have not been established in children.
Clinical studies of DynaCirc CR® (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).This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 12/30/2008
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