olmesartan medoxomil

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue olmesartan medoxomil tablets as soon as possible (5.1) . Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (5.1) . WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning. When pregnancy is detected, discontinue olmesartan medoxomil tablets as soon as possible (5.1) . Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (5.1) .

5 WARNINGS AND PRECAUTIONS Avoid fetal (in utero) exposure (5.1) . Children <1 year of age must not receive olmesartan medoxomil for hypertension (5.2) . Observe for signs and symptoms of hypotension in volume- or salt-depleted patients with treatment initiation (5.3) . Monitor for worsening renal function in patients with renal impairment (5.4) . Sprue-like enteropathy has been reported. Consider discontinuation of olmesartan medoxomil tablets in cases where no other etiology is found (5.5) . 5.1 Fetal Toxicity 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 olmesartan medoxomil tablets as soon as possible [ see Use in specific Populations (8.1 )] . 5.2 Morbidity in Infants Children <1 year of age must not receive olmesartan medoxomil 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 (8.4) ] . 5.3 Hypotension in Volume- or Salt-Depleted Patients In patients with an activated renin-angiotensin aldosterone system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. 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 (2.1) ] . A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. 5.4 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 olmesartan medoxomil. 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 olmesartan medoxomil [see Dosage and Administration (2.1) , Drug Interactions (7) , Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . 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 results may be expected. 5.5 Sprue-like Enteropathy 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 olmesartan medoxomil in cases where no other etiology is identified. 5.6 Electrolyte Imbalances Olmesartan medoxomil tablets contain olmesartan, a drug that inhibits the renin-angiotensin system (RAS). Drugs that inhibit the RAS can cause hyperkalemia. Monitor serum electrolytes periodically.

6 ADVERSE REACTIONS The most common adverse reaction in adults was dizziness (3%) (6.1) . To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare, Inc. at 1-866-941-7875 or www.accordhealthcare.us or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adult Hypertension Olmesartan medoxomil has been evaluated for safety in more than 3825 patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 for at least 1 year. Treatment with olmesartan medoxomil was well tolerated, with an incidence of adverse reactions similar to placebo. Events generally were mild, transient and had no relationship to the dose of olmesartan medoxomil. The overall frequency of adverse reactions was not dose-related. Analysis of gender, age and race groups demonstrated no differences between olmesartan medoxomil and placebo-treated patients. The rate of withdrawals due to adverse reactions in all trials of hypertensive patients was 2.4% (i.e., 79/3278) of patients treated with olmesartan medoxomil and 2.7% (i.e., 32/1179) of control patients. In placebo-controlled trials, the only adverse reaction that occurred in more than 1% of patients treated with olmesartan medoxomil and at a higher incidence versus placebo was dizziness (3% vs. 1%). The following adverse reactions occurred in placebo-controlled clinical trials at an incidence of more than 1% of patients treated with olmesartan medoxomil, but also occurred at about the same or greater incidence in patients receiving placebo: back pain, bronchitis, creatine phosphokinase increased, diarrhea, headache, hematuria, hyperglycemia, hypertriglyceridemia, influenza-like symptoms, pharyngitis, rhinitis and sinusitis. The incidence of cough was similar in placebo (0.7%) and olmesartan medoxomil (0.9%) patients. Other potentially important adverse reactions that have been reported with an incidence of greater than 0.5%, whether or not attributed to treatment, in the more than 3100 hypertensive patients treated with olmesartan medoxomil monotherapy in controlled or open-label trials are listed below. Body as a Whole: chest pain, peripheral edema Central and Peripheral Nervous System: vertigo Gastrointestinal: abdominal pain, dyspepsia, gastroenteritis, nausea Heart Rate and Rhythm Disorders: tachycardia Metabolic and Nutritional Disorders: hypercholesterolemia, hyperlipemia, hyperuricemia Musculoskeletal: arthralgia, arthritis, myalgia Skin and Appendages: rash Facial edema was reported in five patients receiving olmesartan medoxomil. Angioedema has been reported with angiotensin II antagonists. Laboratory Test Findings: In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of olmesartan medoxomil. Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g/dL and 0.3 volume percent, respectively) were observed. Liver Function Tests: Elevations of liver enzymes and/or serum bilirubin were observed infrequently. Five patients (0.1%) assigned to olmesartan medoxomil and one patient (0.2%) assigned to placebo in clinical trials were withdrawn because of abnormal liver chemistries (transaminases or total bilirubin). Of the five olmesartan medoxomil patients, three had elevated transaminases, which were attributed to alcohol use, and one had a single elevated bilirubin value, which normalized while treatment continued. Pediatric Hypertension No relevant differences were identified between the adverse experience profile for pediatric patients aged 1 to 16 years and that previously reported for adult patients. 6.2 Post-Marketing Experience The following adverse reactions have been reported in post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Asthenia, angioedema, anaphylactic reactions Gastrointestinal: Vomiting, sprue-like enteropathy [see Warnings and Precautions (5.5) ] Metabolic and Nutritional Disorders: Hyperkalemia Musculoskeletal: Rhabdomyolysis Urogenital System: Acute renal failure, increased blood creatinine levels Skin and Appendages: Alopecia, pruritus, urticaria Data from one controlled trial and an epidemiologic study have suggested that high-dose olmesartan may increase cardiovascular (CV) risk in diabetic patients, but the overall data are not conclusive. The randomized, placebo-controlled, double-blind ROADMAP trial (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention trial, n=4447) examined the use of olmesartan, 40 mg daily, vs. placebo in patients with type 2 diabetes mellitus, normoalbuminuria, and at least one additional risk factor for CV disease. The trial met its primary endpoint, delayed onset of microalbuminuria, but olmesartan had no beneficial effect on decline in glomerular filtration rate (GFR). There was a finding of increased CV mortality (adjudicated sudden cardiac death, fatal myocardial infarction, fatal stroke, revascularization death) in the olmesartan group compared to the placebo group (15 olmesartan vs. 3 placebo, HR 4.9, 95% confidence interval [CI], 1.4, 17), but the risk of non-fatal myocardial infarction was lower with olmesartan (HR 0.64, 95% CI 0.35, 1.18). The epidemiologic study included patients 65 years and older with overall exposure of > 300,000 patient-years. In the sub-group of diabetic patients receiving high-dose olmesartan (40 mg/d) for > 6 months, there appeared to be an increased risk of death (HR 2.0, 95% CI 1.1, 3.8) compared to similar patients taking other angiotensin receptor blockers. In contrast, high-dose olmesartan use in non-diabetic patients appeared to be associated with a decreased risk of death (HR 0.46, 95% CI 0.24, 0.86) compared to similar patients taking other angiotensin receptor blockers. No differences were observed between the groups receiving lower doses of olmesartan compared to other angiotensin blockers or those receiving therapy for < 6 months. Overall, these data raise a concern of a possible increased CV risk associated with the use of high-dose olmesartan in diabetic patients. There are, however, concerns with the credibility of the finding of increased CV risk, notably the observation in the large epidemiologic study for a survival benefit in non-diabetics of a magnitude similar to the adverse finding in diabetics.