FDA label 7dcc10b8-c71f-13be-e053-2a91aa0abe91

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

What is the most important information I should know about amlodipine and valsartan tablets? Amlodipine and valsartan tablets can cause harm or death to an unborn baby. Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant. If you get pregnant while taking amlodipine and valsartan tablets, tell your doctor right away.

5 WARNINGS AND PRECAUTIONS Hypotension: Correct volume depletion prior to initiation ( 5.2 ) Increased angina and/or myocardial infarction ( 5.3 ) Monitor renal function and potassium in susceptible patients ( 5.4 , 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 amlodipine and valsartan as soon as possible [see Use in Specific Populations (8.1) ] . 5.2 Hypotension Excessive hypotension was seen in 0.4% of patients with uncomplicated hypertension treated with amlodipine and valsartan in placebo-controlled studies. In patients with an activated renin-angiotensin system, such as volume-and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving angiotensin receptor blockers. Volume depletion should be corrected prior to administration of amlodipine and valsartan. Treatment with amlodipine and valsartan should start under close medical supervision. Initiate therapy cautiously in patients with heart failure or recent myocardial infarction and in patients undergoing surgery or dialysis. Patients with heart failure or post-myocardial infarction patients given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), hypotension in post-myocardial infarction patients led to permanent discontinuation of therapy in 1.4% of valsartan-treated patients and 0.8% of captopril-treated patients. Since the vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, caution, as with any other peripheral vasodilator, should be exercised when administering amlodipine, particularly in patients with severe aortic stenosis. If excessive hypotension occurs with amlodipine and valsartan, the patient should be placed in a 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 Risk of Myocardial Infarction or Increased Angina Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease. 5.4 Impaired Renal Function Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin­-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on amlodipine and valsartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on amlodipine and valsartan [see Drug Interactions (7) ] . 5.5 Hyperkalemia Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically. Some patients with heart failure have developed increases in potassium with valsartan therapy. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of amlodipine and valsartan may be required [see Adverse Reactions (6.1) ].

6 ADVERSE REACTIONS In placebo-controlled clinical trials, discontinuation due to side effects occurred in 1.8% of patients in the amlodipine and valsartan-treated patients and 2.1% in the placebo-treated group. The most common reasons for discontinuation of therapy with amlodipine and valsartan were peripheral edema and vertigo. The adverse experiences that occurred in clinical trials (≥2% of patients) at a higher incidence than placebo included peripheral edema, nasopharyngitis, upper respiratory tract infection, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 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. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Studies with Amlodipine and Valsartan: Amlodipine and valsartan has been evaluated for safety in over 2600 patients with hypertension; over 1440 of these patients were treated for at least 6 months and over 540 of these patients were treated for at least 1 year. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The hazards [see Warnings and Precautions (5) ] of valsartan are generally independent of dose; those of amlodipine are a mixture of dose-dependent phenomena (primarily peripheral edema) and dose-independent phenomena, the former much more common than the latter. The overall frequency of adverse reactions was neither dose-related nor related to gender, age, or race. In placebo-controlled clinical trials, discontinuation due to side effects occurred in 1.8% of patients in the amlodipine and valsartan-treated patients and 2.1% in the placebo-treated group. The most common reasons for discontinuation of therapy with amlodipine and valsartan were peripheral edema (0.4%), and vertigo (0.2%). The adverse reactions that occurred in placebo-controlled clinical trials in at least 2% of patients treated with amlodipine and valsartan but at a higher incidence in amlodipine/valsartan patients (n=1437) than placebo (n=337) included peripheral edema (5.4% vs. 3%), nasopharyngitis (4.3% vs. 1.8%), upper respiratory tract infection (2.9% vs. 2.1%) and dizziness (2.1% vs. 0.9%). Orthostatic events (orthostatic hypotension and postural dizziness) were seen in less than 1% of patients. Other adverse reactions that occurred in placebo-controlled clinical trials with amlodipine and valsartan (≥0.2%) are listed below. It cannot be determined whether these events were causally related to amlodipine and valsartan. Blood and Lymphatic System Disorders: Lymphadenopathy Cardiac Disorders: Palpitations, tachycardia Ear and Labyrinth Disorders: Ear pain Gastrointestinal Disorders: Diarrhea, nausea, constipation, dyspepsia, abdominal pain, abdominal pain upper, gastritis, vomiting, abdominal discomfort, abdominal distention, dry mouth, colitis General Disorders and Administration Site Conditions: Fatigue, chest pain, asthenia, pitting edema, pyrexia, edema Immune System Disorders: Seasonal allergies Infections and Infestations: Nasopharyngitis, sinusitis, bronchitis, pharyngitis, gastroenteritis, pharyngotonsillitis, bronchitis acute, tonsillitis Injury and Poisoning : Epicondylitis, joint sprain, limb injury Metabolism and Nutrition Disorders: Gout, non-insulin-dependent diabetes mellitus, hypercholesterolemia Musculoskeletal and Connective Tissue Disorders: Arthralgia, back pain, muscle spasms, pain in extremity, myalgia, osteoarthritis, joint swelling, musculoskeletal chest pain Nervous System Disorders: Headache, sciatica, paresthesia, cervicobrachial syndrome, carpal tunnel syndrome, hypoesthesia, sinus headache, somnolence Psychiatric Disorders: Insomnia, anxiety, depression Renal and Urinary Disorders: Hematuria, nephrolithiasis, pollakiuria Reproductive System and Breast Disorders: Erectile dysfunction Respiratory, Thoracic and Mediastinal Disorders: Cough, pharyngolaryngeal pain, sinus congestion, dyspnea, epistaxis, productive cough, dysphonia, nasal congestion Skin and Subcutaneous Tissue Disorders: Pruritus, rash, hyperhidrosis, eczema, erythema Vascular Disorders: Flushing, hot flush Isolated cases of the following clinically notable adverse reactions were also observed in clinical trials: exanthema, syncope, visual disturbance, hypersensitivity, tinnitus, and hypotension. Studies with Amlodipine: Amlodipine has been evaluated for safety in more than 11000 patients in U.S. and foreign clinical trials. Other adverse events that have been reported <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain were: Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, postural hypotension, vasculitis Central and Peripheral Nervous System: neuropathy peripheral, tremor Gastrointestinal: anorexia, dysphagia, pancreatitis, gingival hyperplasia General: allergic reaction, hot flushes, malaise, rigors, weight gain, weight loss Musculoskeletal System: arthrosis, muscle cramps Psychiatric: sexual dysfunction (male and female), nervousness, abnormal dreams, depersonalization Respiratory System: dyspnea Skin and Appendages: angioedema, erythema multiforme, rash erythematous, rash maculopapular Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus Urinary System: micturition frequency, micturition disorder, nocturia Autonomic Nervous System: sweating increased Metabolic and Nutritional: hyperglycemia, thirst Hemopoietic: leukopenia, purpura, thrombocytopenia Other events reported with amlodipine at a frequency of ≤0.1% of patients include: cardiac failure, pulse irregularity, extrasystoles, skin discoloration, urticaria, skin dryness, alopecia, dermatitis, muscle weakness, twitching, ataxia, hypertonia, migraine, cold and clammy skin, apathy, agitation, amnesia, gastritis, increased appetite, loose stools, rhinitis, dysuria, polyuria, parosmia, taste perversion, abnormal visual accommodation, and xerophthalmia. Other reactions occurred sporadically and cannot be distinguished from medications or concurrent disease states such as myocardial infarction and angina. Adverse reactions reported for amlodipine for indications other than hypertension may be found in the prescribing information for amlodipine. Studies with Valsartan: Valsartan has been evaluated for safety in more than 4000 hypertensive patients in clinical trials. In trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence of dry cough was significantly greater in the ACE inhibitor group (7.9%) than in the groups who received valsartan (2.6%) or placebo (1.5%). In a 129-patient trial limited to patients who had had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, hydrochlorothiazide, or lisinopril were 20%, 19%, and 69% respectively (p<0.001). Other adverse reactions, not listed above, occurring in >0.2% of patients in controlled clinical trials with valsartan are: Body as a Whole: allergic reaction, asthenia Musculoskeletal: muscle cramps Neurologic and Psychiatric: paresthesia Respiratory: sinusitis, pharyngitis Urogenital: impotence Other reported events seen less frequently in clinical trials were: angioedema. Adverse reactions reported for valsartan for indications other than hypertension may be found in the prescribing information for valsartan. Clinical Lab Test Findings: Creatinine: In hypertensive patients, greater than 50% increases in creatinine occurred in 0.4% of patients receiving amlodipine and valsartan and 0.6% receiving placebo. In heart failure patients, greater than 50% increases in creatinine were observed in 3.9% of valsartan-treated patients compared to 0.9% of placebo-treated patients. In post-myocardial infarction patients, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients and 3.4% of captopril-treated patients. Liver Function Tests: Occasional elevations (greater than 150%) of liver chemistries occurred in amlodipine and valsartan-treated patients. Serum Potassium: In hypertensive patients, greater than 20% increases in serum potassium were observed in 2.8% of amlodipine and valsartan-treated patients compared to 3.4% of placebo-treated patients. In heart failure patients, greater than 20% increases in serum potassium were observed in 10% of valsartan-treated patients compared to 5.1% of placebo-treated patients. Blood Urea Nitrogen (BUN): In hypertensive patients, greater than 50% increases in BUN were observed in 5.5% of amlodipine and valsartan-treated patients compared to 4.7% of placebo-treated patients. In heart failure patients, greater than 50% increases in BUN were observed in 16.6% of valsartan-treated patients compared to 6.3% of placebo-treated patients. Neutropenia: Neutropenia was observed in 1.9% of patients treated with valsartan and 0.8% of patients treated with placebo. 6.2 Postmarketing Experience Amlodipine: Gynecomastia has been reported infrequently and a causal relationship is uncertain. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine. Valsartan: The following additional adverse reactions have been reported in postmarketing experience with valsartan: Blood and Lymphatic: Decrease in hemoglobin, decrease in hematocrit, neutropenia Hypersensitivity: There are rare reports of angioedema. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Amlodipine and valsartan should not be re-administered to patients who have had angioedema. Digestive: Elevated liver enzymes and very rare reports of hepatitis Renal: Impaired renal function, renal failure Clinical Laboratory Tests: Hyperkalemia Dermatologic: Alopecia, bullous dermatitis Vascular: Vasculitis Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.