Valsartan

WARNING: FETAL TOXICITY • When pregnancy is detected, discontinue 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 ) WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning. • When pregnancy is detected, discontinue 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 )

5 WARNINGS AND PRECAUTIONS • Observe for signs and symptoms of hypotension ( 5.2 ) • Monitor renal function and potassium in susceptible patients ( 5.3 , 5.4 ) 5.1 Fetal Toxicity Valsartan 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 valsartan as soon as possible [see Use in Specific Populations (8.1) ]. 5.2 Hypotension Excessive hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with valsartan alone. 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, or the treatment should start under close medical supervision. 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. If excessive hypotension occurs, place the patient in the supine position and, if necessary, give intravenous 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. 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 [see Drug Interactions (7) ]. 5.4 Hyperkalemia Some patients with heart failure have developed increases in potassium. 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 valsartan may be required [see Adverse Reactions (6.1) ].

6 ADVERSE REACTIONS Hypertension : Most common adverse reactions are headache, dizziness, viral infection, fatigue and abdominal pain ( 6.1 ) Heart Failure : Most common adverse reactions are dizziness, hypotension, diarrhea, arthralgia, back pain, fatigue and hyperkalemia ( 6.1 ) Post-Myocardial Infarction : Most common adverse reactions which caused patients to discontinue therapy are hypotension, cough and increased blood creatinine ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Laurus Generics Inc. at 1-833-3-LAURUS (1-833-352-8787) 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 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 Valsartan has been evaluated for safety in more than 4,000 patients, including over 400 treated for over 6 months, and more than 160 for over 1 year. Adverse reactions have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall incidence of adverse reactions with valsartan was similar to placebo. The overall frequency of adverse reactions was neither dose-related nor related to gender, age, race, or regimen. Discontinuation of therapy due to side effects was required in 2.3% of valsartan patients and 2.0% of placebo patients. The most common reasons for discontinuation of therapy with valsartan were headache and dizziness. The adverse reactions that occurred in placebo-controlled clinical trials in at least 1% of patients treated with valsartan and at a higher incidence in valsartan (n=2,316) than placebo (n=888) patients included viral infection (3% vs. 2%), fatigue (2% vs. 1%), and abdominal pain (2% vs. 1%). 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, HCTZ, or lisinopril were 20%, 19%, and 69% respectively (p < 0.001). Dose-related orthostatic effects were seen in less than 1% of patients. An increase in the incidence of dizziness was observed in patients treated with valsartan 320 mg (8%) compared to 10 to 160 mg (2% to 4%). Pediatric Hypertension Valsartan has been evaluated for safety in 290 pediatric patients aged 1 to less than 6 years and over 400 patients aged 6 to 17 years. No relevant differences were identified between the adverse experience profile for pediatric patients and that previously reported for adult patients. Hyperkalemia was more frequently observed in pediatric patients aged 1 to 17 years with underlying chronic kidney disease (CKD). Cases of elevated ALT and/or AST have been reported in pediatric patients 1 to less than 6 years of age. These events occurred in a study population which frequently had significant comorbidities; hence, a causal relationship to valsartan could not be established. Heart Failure In the Valsartan Heart Failure Trial (Val-HeFT), comparing valsartan in total daily doses up to 320 mg (n=2,506) to placebo (n=2,494), 10% of valsartan patients discontinued for adverse reactions vs. 7% of placebo patients. The table shows adverse reactions in double-blind short-term heart failure trials, including the first 4 months of the Valsartan Heart Failure Trial, with an incidence of at least 2% that were more frequent in valsartan-treated patients than in placebo-treated patients. All patients received standard drug therapy for heart failure, frequently as multiple medications, which could include diuretics, digitalis, beta-blockers. About 93% of patients received concomitant ACE inhibitors. Valsartan (n=3,282) Placebo (n=2,740) Dizziness 17% 9% Hypotension 7% 2% Diarrhea 5% 4% Arthralgia 3% 2% Fatigue 3% 2% Back Pain 3% 2% Dizziness, postural 2% 1% Hyperkalemia 2% 1% Hypotension, postural 2% 1% Discontinuations occurred in 0.5% of valsartan-treated patients and 0.1% of placebo patients for each of the following: elevations in creatinine and elevations in potassium. Other adverse reactions with an incidence greater than 1% and greater than placebo included headache, nausea, renal impairment, syncope, blurred vision, upper abdominal pain and vertigo. From the long-term data in the Valsartan Heart Failure Trial, there did not appear to be any significant adverse reactions not previously identified. Post-Myocardial Infarction The table shows the percentage of patients discontinued in the valsartan and captopril-treated groups in the VALsartan In Acute myocardial iNfarcTion trial (VALIANT) with a rate of at least 0.5% in either of the treatment groups. Discontinuations due to renal dysfunction occurred in 1.1% of valsartan-treated patients and 0.8% of captopril-treated patients. Valsartan (n=4,885) Captopril (n=4,879) Discontinuation for adverse reaction 5.8% 7.7% Adverse reactions Hypotension NOS 1.4% 0.8% Cough 0.6% 2.5% Blood creatinine increased 0.6% 0.4% Rash NOS 0.2% 0.6% Clinical Laboratory Test Findings Creatinine : In heart failure trials, 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. Neutropenia: Neutropenia was observed in 1.9% of patients treated with valsartan and 0.8% of patients treated with placebo. Blood Urea Nitrogen (BUN): In heart failure trials, greater than 50% increases in BUN were observed in 16.6% of valsartan-treated patients compared to 6.3% of placebo-treated patients [see Warnings and Precautions (5.3) ]. 6.2 Postmarketing Experience The following additional adverse reactions have been reported in postmarketing use of valsartan. 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: Angioedema has been reported. Some of these patients previously experienced angioedema with other drugs, including ACE inhibitors. Valsartan should not be re-administered to patients who have had angioedema. Digestive: Elevated liver enzymes and very rare reports of hepatitis Musculoskeletal : Rhabdomyolysis Renal: Impaired renal function, renal failure Dermatologic: Alopecia, bullous dermatitis Blood and Lymphatic: Thrombocytopenia Vascular: Vasculitis

<table cellspacing="0" cellpadding="0" border="0"><colgroup><col width="30%"/><col width="32.88%"/><col width="37.12%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" valign="middle"> <content styleCode="bold"> Valsartan (n=3,282)</content> </td><td styleCode="Rrule" valign="top"> <content styleCode="bold">Placebo (n=2,740)</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Dizziness </td><td styleCode="Rrule" valign="top"> 17% </td><td styleCode="Rrule" valign="top"> 9% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Hypotension </td><td styleCode="Rrule" valign="top"> 7% </td><td styleCode="Rrule" valign="top"> 2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Diarrhea </td><td styleCode="Rrule" valign="top"> 5% </td><td styleCode="Rrule" valign="top"> 4% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Arthralgia </td><td styleCode="Rrule" valign="top"> 3% </td><td styleCode="Rrule" valign="top"> 2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Fatigue </td><td styleCode="Rrule" valign="top"> 3% </td><td styleCode="Rrule" valign="top"> 2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Back Pain </td><td styleCode="Rrule" valign="top"> 3% </td><td styleCode="Rrule" valign="top"> 2% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Dizziness, postural </td><td styleCode="Rrule" valign="top"> 2% </td><td styleCode="Rrule" valign="top"> 1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Hyperkalemia </td><td styleCode="Rrule" valign="top"> 2% </td><td styleCode="Rrule" valign="top"> 1% </td></tr><tr><td styleCode="Lrule Rrule" valign="top"> Hypotension, postural </td><td styleCode="Rrule" valign="top"> 2% </td><td styleCode="Rrule" valign="top"> 1% </td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0" width="100%"><colgroup><col width="35.52%"/><col width="31.04%"/><col width="33.44%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> </td><td styleCode="Rrule" valign="top"> <content styleCode="bold">Valsartan (n=4,885)</content> </td><td styleCode="Rrule" valign="top"> <content styleCode="bold">Captopril (n=4,879)</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Discontinuation for adverse reaction </td><td styleCode="Rrule" valign="top"> 5.8% </td><td styleCode="Rrule" valign="top"> 7.7% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Adverse reactions </td><td styleCode="Rrule" valign="top"> </td><td styleCode="Rrule" valign="top"> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Hypotension NOS </td><td styleCode="Rrule" valign="top"> 1.4% </td><td styleCode="Rrule" valign="top"> 0.8% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Cough </td><td styleCode="Rrule" valign="top"> 0.6% </td><td styleCode="Rrule" valign="top"> 2.5% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Blood creatinine increased </td><td styleCode="Rrule" valign="top"> 0.6% </td><td styleCode="Rrule" valign="top"> 0.4% </td></tr><tr><td styleCode="Lrule Rrule" valign="top"> Rash NOS </td><td styleCode="Rrule" valign="top"> 0.2% </td><td styleCode="Rrule" valign="top"> 0.6% </td></tr></tbody></table>