"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)./"...
Increased angina and/or myocardial infarction in patients with coronary artery disease
Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed increased frequency, duration and/or severity of angina, or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been established. In controlled studies of SULAR in patients with angina this was seen about 1.5% of the time in patients given nisoldipine, compared with 0.9% in patients given placebo.
Because nisoldipine, like other vasodilators, decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of SULAR is recommended. Close observation is especially important for patients already taking medications that are known to lower blood pressure. Although in most patients the hypotensive effect of SULAR is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension. These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment.
Congestive Heart Failure
Although acute hemodynamic studies of nisoldipine in patients with NYHA Class II-IV heart failure have not demonstrated negative inotropic effects, safety of SULAR in patients with heart failure has not been established. Caution therefore should be exercised when using SULAR in patients with heart failure or compromised ventricular function, particularly in combination with a beta-blocker.
Patients With Hepatic Impairment
Because nisoldipine is extensively metabolized by the liver and, in patients with cirrhosis, it reaches blood concentrations about 5 times those in normals, SULAR should be administered cautiously in patients with severe hepatic dysfunction (see DOSAGE AND ADMINISTRATION).
SULAR is not known to interfere with the interpretation of laboratory tests.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Dietary administration of nisoldipine to male and female rats for up to 24 months (mean doses up to 82 and 111 mg/kg/day, 16 and 19 times the maximum recommended human dose [MRHD] on a mg/m² basis, respectively and female mice for up to 21 months (mean doses of up to 217 mg/kg/day, 20 times the MRHD on a mg/m² basis) revealed no evidence of tumorigenic effect of nisoldipine. In male mice receiving a mean dose of 163 mg nisoldipine/kg/day (16 times the MRHD of 60 mg/day on a mg/m² basis), an increased frequency of stomach papilloma, but still within the historical range, was observed. No evidence of stomach neoplasia was observed at lower doses (up to 58 mg/kg/day). Nisoldipine was negative when tested in a battery of genotoxicity assays including the Ames test and the CHO/HGRPT assay for mutagenicity and the in vivo mouse micronucleus test and in vitro CHO cell test for clastogenicity.
When administered to male and female rats at doses of up to 30 mg/kg/day (about 5 times the MRHD on a mg/m² basis) nisoldipine had no effect on fertility.
Pregnancy Category C
Nisoldipine was neither teratogenic nor fetotoxic at doses that were not maternally toxic. Nisoldipine was fetotoxic but not teratogenic in rats and rabbits at doses resulting in maternal toxicity (reduced maternal body weight gain). In pregnant rats, increased fetal resorption (postimplantation loss) was observed at 100 mg/kg/day and decreased fetal weight was observed at both 30 and 100 mg/kg/day. These doses are, respectively, about 5 and 16 times the MRHD when compared on a mg/m² basis. In pregnant rabbits, decreased fetal and placental weights were observed at a dose of 30 mg/kg/day, about 10 times the MRHD when compared on a mg/m² basis. In a study in which pregnant monkeys (both treated and control) had high rates of abortion and mortality, the only surviving fetus from a group exposed to a maternal dose of 100 mg nisoldipine/kg/day (about 30 times the MRHD when compared on a mg/m² basis) presented with forelimb and vertebral abnormalities not previously seen in control monkeys of the same strain. There are no adequate and well controlled studies in pregnant women. SULAR should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known whether nisoldipine is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made to discontinue nursing, or to discontinue SULAR, taking into account the importance of the drug to the mother.
Safety and effectiveness in pediatric patients have not been established.
Clinical studies of nisoldipine 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. Patients over 65 are expected to develop higher plasma concentrations of nisoldipine. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 4/19/2016
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