Azilsartan medoxomil

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue azilsartan medoxomil tablets as soon as possible [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )] . Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.1 )] . WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning. When pregnancy is detected, discontinue azilsartan medoxomil tablets as soon as possible. ( 5.1 , 8.1 ) Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. ( 5.1 , 8.1 )

5 WARNINGS AND PRECAUTIONS Correct volume or salt depletion prior to administration of azilsartan medoxomil tablets. ( 5.2 ) Monitor for worsening renal function in patients with renal impairment. ( 5.3 ) 5.1 Fetal Toxicity Azilsartan medoxomil tablets can cause fetal harm when administered to a pregnant woman. 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 azilsartan medoxomil tablets as soon as possible [see Use in Specific Populations ( 8.1 )]. 5.2 Hypotension in Volume- 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 high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with azilsartan medoxomil tablets. Correct volume or salt depletion prior to administration of azilsartan medoxomil tablets or start treatment at 40 mg. If hypotension does occur, 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. 5.3 Impaired Renal Function As a consequence of inhibiting the renin-angiotensin system, changes in renal function may be anticipated in susceptible individuals treated with azilsartan medoxomil tablets. In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g., patients with severe congestive heart failure, renal artery stenosis or volume depletion), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. Similar results may be anticipated in patients treated with azilsartan medoxomil tablets [see Drug Interactions ( 7 ), Use in Specific Populations ( 8.6 ) 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 have been reported. There has been no long-term use of azilsartan medoxomil tablets in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.

6 ADVERSE REACTIONS The most common adverse reaction in adults was diarrhea (2%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 4814 patients were evaluated for safety when treated with azilsartan medoxomil tablets at doses of 20, 40 or 80 mg in clinical trials. This includes 1704 patients treated for at least six months; of these, 588 were treated for at least one year. Treatment with azilsartan medoxomil tablets was well-tolerated with an overall incidence of adverse reactions similar to placebo. The rate of withdrawals due to adverse events in placebo-controlled monotherapy and combination therapy trials was 2.4% (19/801) for placebo, 2.2% (24/1072) for azilsartan medoxomil tablets 40 mg and 2.7% (29/1074) for azilsartan medoxomil tablets 80 mg. The most common adverse event leading to discontinuation, hypotension/orthostatic hypotension, was reported by 0.4% (8/2146) patients randomized to azilsartan medoxomil tablets 40 mg or 80 mg compared to 0% (0/801) patients randomized to placebo. Generally, adverse reactions were mild, not dose related and similar regardless of age, gender and race. In placebo-controlled monotherapy trials, diarrhea was reported up to 2% in patients treated with azilsartan medoxomil tablets 80 mg daily compared with 0.5% of patients on placebo. Other adverse reactions with a plausible relationship to treatment that have been reported with an incidence of > 0.3% and greater than placebo in more than 3300 patients treated with azilsartan medoxomil tablets in controlled trials are listed below: Gastrointestinal Disorders: nausea General Disorders and Administration Site Conditions: asthenia, fatigue Musculoskeletal and Connective Tissue Disorders: muscle spasm Nervous System Disorders: dizziness, dizziness postural Respiratory, Thoracic and Mediastinal Disorders: cough 6.2 Postmarketing Experience The following adverse reactions have been identified during the postmarketing use of azilsartan medoxomil tablets. 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. Rash Pruritus Angioedema