"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 Benicar as soon as possible [see Use In Specific Populations].
Morbidity in Infants
Children < 1 year of age must not receive Benicar for hypertension. Drugs that act directly on the renin-angiotensin aldosterone system (RAAS) can have effects on the development of immature kidneys [see Use in Specific Populations] .
Hypotension In Volume-Or Salt-Depleted Patients
In patients with an activated renin-angiotensin aldosterone system, such as volumeand/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may be anticipated after initiation of treatment with Benicar. Initiate treatment under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline [see DOSAGE AND ADMINISTRATION] . A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
Impaired Renal Function
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals treated with Benicar. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. Similar results may be anticipated in patients treated with Benicar [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS, Use In Specific Populations and CLINICAL PHARMACOLOGY] .
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of Benicar in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.
Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider discontinuation of Benicar in cases where no other etiology is identified.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Olmesartan medoxomil was not carcinogenic when administered by dietary administration to rats for up to 2 years. The highest dose tested (2000 mg/kg/day) was, on a mg/m² basis, about 480 times the maximum recommended human dose (MRHD) of 40 mg/day. Two carcinogenicity studies conducted in mice, a 6-month gavage study in the p53 knockout mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of a carcinogenic effect of olmesartan medoxomil.
Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (olmesartan not tested).
Fertility of rats was unaffected by administration of olmesartan medoxomil at dose levels as high as 1000 mg/kg/day (240 times the MRHD) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating.
Use In Specific Populations
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 Benicar 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 renin-angiotensin 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 examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Benicar, 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 Benicar for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations] .
It is not known whether olmesartan is excreted in human milk, but olmesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Neonates with a history of in utero exposure to Benicar: 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.
The antihypertensive effects of Benicar were evaluated in one randomized, double-blind clinical study in pediatric patients 1 to 16 years of age [see Clinical Studies] . The pharmacokinetics of Benicar were evaluated in pediatric patients 1 to 16 years of age [see CLINICAL PHARMACOLOGY] . Benicar was generally well tolerated in pediatric patients, and the adverse experience profile was similar to that described for adults.
Benicar has not been shown to be effective for hypertension in children < 6 years of age.
Children < 1 year of age must not receive Benicar for hypertension [see WARNINGS AND PRECAUTIONS] . The renin-angiotensin aldosterone system (RAAS) plays a critical role in kidney development. RAAS blockade has been shown to lead to abnormal kidney development in very young mice. Administering drugs that act directly on the reninangiotensin aldosterone system (RAAS) can alter normal renal development.
Of the total number of hypertensive patients receiving Benicar in clinical studies, more than 20% were 65 years of age and over, while more than 5% were 75 years of age and older. No overall differences in effectiveness or safety were observed between elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY] .
Increases in AUC0-∞ and Cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%. No initial dosage adjustment is recommended for patients with moderate to marked hepatic dysfunction [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY] .
Patients with renal insufficiency have elevated serum concentrations of olmesartan compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance < 20 mL/min). No initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance < 40 mL/min) [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY] .
The antihypertensive effect of Benicar was smaller in black patients (usually a low-renin population), as has been seen with ACE inhibitors, beta-blockers and other angiotensin receptor blockers.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 6/27/2014
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