FDA label a824287d-64f8-e894-e053-2995a90a4626

WARNING:FETAL TOXICITY WARNING: FETAL TOXICITY • When pregnancy is detected, discontinue valsartan and hydrochlorothiazide 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 valsartan and hydrochlorothiazide 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 • Hypotension: Correct volume depletion prior to initiation ( 5.2 ) • Observe for signs of fluid or electrolyte imbalance ( 5.9 ) • Monitor renal function and potassium in susceptible patients ( 5.3 , 5.7 ) • Exacerbation or activation of systemic lupus erythematosus ( 5.5 ) • Acute angle-closure glaucoma ( 5.8 ) 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 Valsartan and hydrochlorothiazide tablets as soon as possible [see Use in Specific Populations (8.1) ]. Intrauterine exposure to thiazide diuretics is associated with fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults 5.2 Hypotension in Volume- and/or Salt-Depleted Patients Excessive reduction of blood pressure was rarely seen (0.7%) in patients with uncomplicated hypertension treated with valsartan and hydrochlorothiazide tablets in controlled trials. 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. This condition should be corrected prior to administration of valsartan and hydrochlorothiazide tablets, or the treatment should start under close medical supervision. If hypotension occurs, 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 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 valsartan and hydrochlorothiazide tablets. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan and hydrochlorothiazide tablets [See Drug Interactions ( 7 )]. 5.4 Hypersensitivity Reaction Hydrochlorothiazide: Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. 5.5 Systemic Lupus Erythematosus Hydrochlorothiazide: Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. 5.6 Lithium Interaction Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of valsartan or thiazide diuretics. Monitor lithium levels in patients receiving valsartan HCT and lithium. [See Drug Interactions ( 7 )]. 5.7 Potassium Abnormalities Valsartan – Hydrochlorothiazide: In the controlled trials of various doses of valsartan and hydrochlorothiazide tablets the incidence of hypertensive patients who developed hypokalemia (serum potassium <3.5 mEq/L) was 3.0%; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4%. Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically. If hypokalemia is accompanied by clinical signs (e.g. muscular weakness, paresis, or ECG alterations), valsartan and hydrochlorothiazide tablets should be discontinued. Correction of hypokalemia and any coexisting hypomagnesemia is recommended prior to the initiation of thiazides. 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 the diuretic and/or valsartan may be required [see Adverse Reactions ( 6.1 )]. 5.8 Acute Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy. 5.9 Metabolic Disturbances Hydrochlorothiazide Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium. Monitor calcium levels in patients with hypercalcemia receiving valsartan and hydrochlorothiazide tablets.

6 ADVERSE REACTIONS The most common reasons for discontinuation of therapy with valsartan and hydrochlorothiazide were headache and dizziness. The only adverse experience that occurred in ≥2% of patients treated with valsartan and hydrochlorothiazide and at a higher incidence than placebo was nasopharyngitis (2.4% vs. 1.9%) ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc., at 1-888-943-3210 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reactions 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. 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. Hypertension Valsartan and hydrochlorothiazide tablets, USP have been evaluated for safety in more than 5,700 patients, including over 990 treated for over 6 months, and over 370 for over 1 year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall incidence of adverse reactions with valsartan and hydrochlorothiazide tablets was comparable to placebo. The overall frequency of adverse reactions was neither dose-related nor related to gender, age, or race. In controlled clinical trials, discontinuation of therapy due to side effects was required in 2.3% of valsartan-hydrochlorothiazide patients and 3.1% of placebo patients. The most common reasons for discontinuation of therapy with valsartan and hydrochlorothiazide tablets were headache and dizziness. The only adverse reaction that occurred in controlled clinical trials in at least 2% of patients treated with valsartan and hydrochlorothiazide tablets and at a higher incidence in valsartan-hydrochlorothiazide (n=4372) than placebo (n=262) patients was nasopharyngitis (2.4% vs. 1.9%). Dose-related orthostatic effects were seen in fewer than 1% of patients. In individual trials, a dose-related increase in the incidence of dizziness was observed in patients treated with valsartan and hydrochlorothiazide tablets. Other adverse reactions that have been reported with valsartan-hydrochlorothiazide (>0.2% of valsartan-hydrochlorothiazide patients in controlled clinical trials) without regard to causality, are listed below: Cardiovascular: Palpitations and tachycardia Ear and Labyrinth: Tinnitus and vertigo Gastrointestinal: Dyspepsia, diarrhea, flatulence, dry mouth, nausea, abdominal pain, abdominal pain upper, and vomiting General and Administration Site Conditions: Asthenia, chest pain, fatigue, peripheral edema and pyrexia Infections and Infestations: Bronchitis, bronchitis acute, influenza, gastroenteritis, sinusitis, upper respiratory tract infection and urinary tract infection Investigations: Blood urea increased Musculoskeletal: Arthralgia, back pain, muscle cramps, myalgia, and pain in extremity Nervous System: Dizziness postural, paresthesia, and somnolence Psychiatric: Anxiety and insomnia Renal and Urinary: Pollakiuria Reproductive System: Erectile dysfunction Respiratory, Thoracic and Mediastinal: Dyspnea, cough, nasal congestion, pharyngolaryngeal pain and sinus congestion Skin and Subcutaneous Tissue: Hyperhidrosis and rash Vascular: Hypotension Other reported reactions seen less frequently in clinical trials included abnormal vision, anaphylaxis, bronchospasm, constipation, depression, dehydration, decreased libido, dysuria, epistaxis, flushing, gout, increased appetite, muscle weakness, pharyngitis, pruritus, sunburn, syncope, and viral infection. Initial Therapy - Hypertension In a clinical study in patients with severe hypertension (diastolic blood pressure ≥110 mmHg and systolic blood pressure ≥140 mmHg), the overall pattern of adverse reactions reported through 6 weeks of follow-up was similar in patients treated with valsartan and hydrochlorothiazide tablets as initial therapy and in patients treated with valsartan as initial therapy. Comparing the groups treated with valsartan and hydrochlorothiazide tablets (force-titrated to 320/25 mg) and valsartan (force-titrated to 320 mg), dizziness was observed in 6% and 2% of patients, respectively. Hypotension was observed in 1% of those patients receiving valsartan and hydrochlorothiazide tablets and 0% of patients receiving valsartan. There were no reported cases of syncope in either treatment group. Laboratory changes with valsartan and hydrochlorothiazide tablets as initial therapy in patients with severe hypertension were similar to those reported with valsartan and hydrochlorothiazide tablets in patients with less severe hypertension [ see Clinical Studies ( 14.2 ) and Drug Interactions ( 7 )]. Valsartan: 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%, 69% respectively (p <0.001). Other reported reactions seen less frequently in clinical trials included chest pain, syncope, anorexia, vomiting, and angioedema. Hydrochlorothiazide: Other adverse reactions not listed above that have been reported with hydrochlorothiazide, without regard to causality, are listed below: Body As A Whole: weakness Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions Metabolic: hyperglycemia, glycosuria, hyperuricemia Musculoskeletal: muscle spasm Nervous System/Psychiatric: restlessness Renal: renal failure, renal dysfunction, interstitial nephritis Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis Special Senses: transient blurred vision, xanthopsia Clinical Laboratory Test Findings In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of valsartan and hydrochlorothiazide tablets. Creatinine/Blood Urea Nitrogen (BUN): Minor elevations in creatinine and BUN occurred in 2% and 15% respectively, of patients taking valsartan and hydrochlorothiazide tablets and 0.4% and 6% respectively, given placebo in controlled clinical trials. Hemoglobin and Hematocrit: Greater than 20% decreases in hemoglobin and hematocrit were observed in less than 0.1% of valsartan and hydrochlorothiazide tablets patients, compared with 0% in placebo-treated patients. Liver Function Tests: Occasional elevations (greater than 150%) of liver chemistries occurred in valsartan and hydrochlorothiazide tablets -treated patients. Neutropenia: Neutropenia was observed in 0.1% of patients treated with valsartan and hydrochlorothiazide tablets and 0.4% of patients treated with placebo. 6.2 Postmarketing Experience The following additional adverse reactions have been reported in valsartan or valsartan/ hydrochlorothiazide postmarketing 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. Hypersensitivity: There are rare reports of angioedema. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Valsartan and hydrochlorothiazide tablets should not be re-adminitered to patients who have had angioedema. Digestive: Elevated liver enzymes and very rare reports of hepatitis Renal: Impaired renal function Clinical Laboratory Tests: Hyperkalemia Dermatologic: Alopecia, bullous dermatitis Vascular: Vasculitis Nervous System: Syncope Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers. Hydrochlorothiazide: The following additional adverse reactions have been reported in post-marketing experience with hydrochlorothiazide: Acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle spasm, asthenia, acute angle-closure glaucoma, bone marrow failure, worsening of diabetes control, hypokalemia, blood lipids increased, hyponatremia, hypomagnesemia, hypercalcemia, hypochloremic alkalosis, impotence, and visual impairment. Pathological changes in the parathyroid gland of patients with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. If hypercalcemia occurs, further diagnostic evaluation is necessary.