"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)./"...
Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue TEVETEN as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the reninangiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examination to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue TEVETEN, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to TEVETEN for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use).
Eprosartan mesylate has been shown to produce maternal and fetal toxicities (maternal and fetal mortality, low maternal body weight and food consumption, resorptions, abortions and litter loss) in pregnant rabbits given oral doses as low as 10 mg eprosartan/kg/day. No maternal or fetal adverse effects were observed at 3 mg/kg/day; this oral dose yielded a systemic exposure (AUC) to unbound eprosartan 0.8 times that achieved in humans given 400 mg b.i.d. No adverse effects on in utero or postnatal development and maturation of offspring were observed when eprosartan mesylate was administered to pregnant rats at oral doses up to 1000 mg eprosartan/kg/day (the 1000 mg eprosartan/kg/day dose in non-pregnant rats yielded systemic exposure to unbound eprosartan approximately 0.6 times the exposure achieved in humans given 400 mg b.i.d.).
Hypotension In Volume- And/Or Salt-Depleted Patients
In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with diuretics), symptomatic hypotension may occur. These conditions should be corrected prior to administration of TEVETEN®, or the treatment should start under close medical supervision. If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
Risk Of Renal Impairment
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been reported in susceptible individuals treated with angiotensin II antagonists; in some patients, these changes in renal function were reversible upon discontinuation of therapy. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. TEVETEN® would be expected to behave similarly.
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or BUN have been reported. Similar effects have been reported with angiotensin II antagonists; in some patients, these effects were reversible upon discontinuation of therapy.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Eprosartan mesylate was not carcinogenic in dietary restricted rats or ad libitum fed mice dosed at 600 mg and 2000 mg eprosartan/kg/day, respectively, for up to 2 years. In male and female rats, the systemic exposure (AUC) to unbound eprosartan at the dose evaluated was only approximately 20% of the exposure achieved in humans given 400 mg b.i.d. In mice, the systemic exposure (AUC) to unbound eprosartan was approximately 25 times the exposure achieved in humans given 400 mg b.i.d.
Eprosartan mesylate was not mutagenic in vitro in bacteria or mammalian cells (mouse lymphoma assay). Eprosartan mesylate also did not cause structural chromosomal damage in vivo (mouse micronucleus assay). In human peripheral lymphocytes in vitro, eprosartan mesylate was equivocal for clastogenicity with metabolic activation, and was negative without metabolic activation. In the same assay, eprosartan mesylate was positive for polyploidy with metabolic activation and equivocal for polyploidy without metabolic activation.
Eprosartan mesylate had no adverse effects on the reproductive performance of male or female rats at oral doses up to 1000 mg eprosartan/kg/day. This dose provided systemic exposure (AUC) to unbound eprosartan approximately 0.6 times the exposure achieved in humans given 400 mg b.i.d.
Eprosartan is excreted in animal milk; it is not known whether eprosartan is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from eprosartan, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Neonates With A History Of In Utero Exposure to TEVETEN
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
Safety and effectiveness in pediatric patients have not been established.
Of the total number of patients receiving TEVETEN® in clinical studies, 29% (681 of 2,334) were 65 years and over, while 5% (124 of 2,334) were 75 years and over. Based on the pooled data from randomized trials, the decrease in diastolic blood pressure and systolic blood pressure with TEVETEN® was slightly less in patients ≥ 65 years of age compared to younger patients. In a study of only patients over the age of 65, TEVETEN® at 200 mg twice daily (and increased optionally up to 300 mg twice daily) decreased diastolic blood pressure on average by 3 mmHg (placebo corrected). Adverse experiences were similar in younger and older patients.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 1/19/2016
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