"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 Azor as soon as possible [See Use In Specific Populations] .
Hypotension In Volume-Or Salt-Depleted Patients
Symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. Patients with an activated renin-angiotensin system, such as volume-and/or salt-depleted patients (e.g., those being treated with high doses of diuretics) may be particularly vulnerable. Initiate treatment with Azor 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. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
Since the vasodilation attributable to amlodipine in Azor is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, exercise caution, as with any other peripheral vasodilator, when administering Azor, particularly in patients with severe aortic stenosis.
Patients With Severe Obstructive Coronary Artery Disease
Patients, particularly those with severe obstructive coronary artery disease, may develop increased frequency, duration, 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 elucidated.
Patients With Congestive Heart Failure
Amlodipine (5–10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). Amlodipine has been compared to placebo in four 8–12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsening of heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF.
Patients With Impaired Renal Function
There are no studies of Azor in patients with renal impairment.
Changes in renal function may be anticipated in susceptible individuals treated with olmesartan medoxomil as a consequence of inhibiting the renin-angiotensin-aldosterone system. 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 inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and (rarely) with acute renal failure and/or death. Similar effects may occur in patients treated with Azor because of the olmesartan medoxomil component [See DRUG INTERACTIONS 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 olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar effects would be expected with olmesartan medoxomil and Azor.
Patients With Hepatic Impairment
Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t½) is 56 hours in patients with severely impaired hepatic function, exercise caution when administering Azor to patients with severe hepatic impairment.
Patients with hepatic impairment have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in hepatically impaired patients is recommended. The lowest dose of Azor is 5/20 mg; therefore, initial therapy with Azor is not recommended in hepatically impaired patients [See Use in Specific Populations].
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 Azor in cases where no other etiology is identified.
In post-marketing experience, hepatic enzyme elevations have been reported.
In post-marketing experience, increased blood creatinine levels and hyperkalemia have been reported.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of amlodipine 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m² basis, similar to the maximum recommended human dose (MRHD) of amlodipine 10 mg/day. For the rat, the highest dose was, on a mg/m² basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.)
Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome level.
There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of amlodipine up to 10 mg/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m² basis).
Olmesartan 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. 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 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 Azor 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 intraamniotic environment. If oligohydramnios is observed, discontinue Azor, 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 Azor for hypotension, oliguria, and hyperkalemia [See Use In Specific Populations].
No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose (MRHD) on a mg/m² basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m² basis; higher doses could not be evaluated for effects on fetal development as they were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were observed at doses ≥ 1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricular, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ≥ 8 mg/kg/day. The no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day.
No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively about 10 and 20 times the maximum recommended human dose of 10 mg amlodipine on a mg/m² basis) during their respective periods of major organogenesis. (Calculations based on a patient weight of 60 kg). However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestational period and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known whether the amlodipine or olmesartan medoxomil components of Azor are 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 Azor
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 safety and effectiveness of Azor in pediatric patients have not been established.
The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.
Safety and effectiveness of olmesartan medoxomil in pediatric patients have not been established.
Of the total number of subjects in the double-blind clinical study of Azor, 20% (384/1940) were 65 years of age or older and 3% (62/1940) were 75 years or older. No overall differences in safety or effectiveness were observed between subjects 65 years of age or older and younger subjects.
Elderly patients have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in patients ≥ 75 years old is recommended. The lowest dose of Azor is 5/20 mg; therefore, initial therapy with Azor is not recommended in patients ≥ 75 years old.
Reported clinical experience has not identified differences in responses between the elderly and younger patients. 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. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40% to 60%, and a lower initial dose may be required.
Of the total number of hypertensive patients receiving olmesartan medoxomil 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.
There are no studies of Azor in patients with hepatic insufficiency, but both amlodipine and olmesartan medoxomil show moderate increases in exposure in patients with hepatic impairment. Use caution when administering Azor to patients with severe hepatic impairment.
Patients with hepatic impairment have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in patients with hepatic impairment is recommended. The lowest dose of Azor is 5/20 mg; therefore, initial therapy with Azor is not recommended in hepatically impaired patients.
There are no studies of Azor in patients with renal impairment.
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
Patients with renal insufficiency have elevated serum concentrations of olmesartan compared with patients with normal renal function. After repeated dosing, 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).
Of the total number of subjects in the double-blind clinical study of Azor, 25% (481/1940) were black patients. Azor was effective in treating black patients (usually a low-renin population), and the magnitude of blood pressure reduction in black patients approached that observed for non-black patients.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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