Prexxartan

1 INDICATIONS AND USAGE PREXXARTAN™ is an angiotensin II receptor blocker (ARB) indicated for: • Hypertension in adults and children six years and older, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions • Heart failure (NYHA class II-IV); PREXXARTAN™ significantly reduces hospitalization for heart failure in patients who are unable to swallow valsartan tablets • Post-myocardial infarction , stable left ventricular failure or left ventricular dysfunction following myocardial infarction; PREXXARTAN™ reduces cardiovascular mortality in patients who are unable to swallow valsartan tablets

1.1Hypertension PREXXARTAN™

is indicated for the treatment of hypertension in adults and children six years and older, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including the class to which valsartan principally belongs.

There are no controlled trials in hypertensive patients demonstrating risk reduction with valsartan. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals.

For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (e.g., patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).

These considerations may guide selection of therapy. PREXXARTAN™ may be used alone or in combination with other antihypertensive agents.

1.2Heart Failure PREXXARTAN™

is indicated for the treatment of heart failure (NYHA class II-IV) to reduce the risk of hospitalization for heart failure in patients who are unable to swallow valsartan tablets. There is no evidence that valsartan provides added benefits when it is used with an adequate dose of an angiotensin converting enzyme (ACE) inhibitor .

1.3Post-Myocardial Infarction PREXXARTAN™

is indicated to reduce the risk of cardiovascular death in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction who are unable to swallow valsartan tablets .

Indication Starting Dose Dose Range Target Maintenance Dose* Hypertension - adults 40 or 80 mg twice daily 40 -160 mg twice daily --- Hypertension—age 6 to16 years 0.65 mg/kg twice daily (up to 40 mg total) 0.65-1.35 mg/kg twice daily (up to 40 mg-160 mg total) --- Heart Failure 40 mg twice daily 40 mg-160 mg twice daily 160 mg twice daily Post-Myocardial Infarction 20 mg twice daily 20 mg-160 mg twice daily 160 mg twice daily * As tolerated by patient

2.1General Considerations PREXXARTAN™

is not therapeutically equivalent to the tablet formulation of Diovan. The peak concentration of valsartan with PREXXARTAN™ is higher than with Diovan . Follow dosing instructions given here.

2.2Adult Hypertension The

recommended starting dose of PREXXARTAN™ is 40 mg or 80 mg twice daily when used as monotherapy in patients who are not volume-depleted. Patients requiring greater reductions in blood pressure may be started at 80 mg administered twice a day. PREXXARTAN™ may be used over a total daily dose range of 80 mg to 320 mg.

The antihypertensive effect is substantially present within 2 weeks and maximal reduction is generally attained after 4 weeks. If additional antihypertensive effect is required over the starting dose range, the total daily dose may be increased to a maximum of 320 mg or a diuretic may be added. Addition of a diuretic has a greater effect than dose increases beyond 80 mg.

PREXXARTAN™ may be administered with other antihypertensive agents.

2.3Pediatric Hypertension

6 to 16 Years of Age The recommended starting dose is 0.65 mg/kg twice daily (up to 40 mg total daily dose). The dosage should be adjusted according to blood pressure response. Doses higher than 1.35 mg/kg twice daily (or >160 mg total daily dose) have not been studied in pediatric patients 6 to 16 years old.

No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate <30 mL/min/1.73 m 2 . Use of PREXXARTAN™ is not recommended for patients under 6 years of age .

2.4Heart Failure The

recommended starting dose of PREXXARTAN TM is 40 mg twice daily. Titrate to 80 mg and 160 mg twice daily, as tolerated by the patient. Consider reducing the dose of concomitant diuretics. The maximum daily dose administered in clinical trials is 320 mg in divided doses. 2. 5 Post-Myocardial Infarction PREXXARTAN TM may be initiated as early as 12 hours after a myocardial infarction.

The recommended starting dose of PREXXARTAN TM is 20 mg twice daily. Patients may be up titrated within 7 days to 40 mg twice daily, with subsequent titrations to a target maintenance dose of 160 mg twice daily, as tolerated by the patient. If symptomatic hypotension or renal dysfunction occurs, consider dosage reduction.

PREXXARTAN TM may be given with other standard post-myocardial infarction treatment, including thrombolytics, aspirin, beta-blockers, and statins.

2.6Missed Dose If a

dose of PREXXARTAN™ is missed, it should be administered as soon as possible, unless it is almost time for the next dose. The dose should not be doubled to make up for a missed dose.

2.6Missed Dose If a

dose of PREXXARTAN™ is missed, it should be administered as soon as possible, unless it is almost time for the next dose. The dose should not be doubled to make up for a missed dose.

Observe for signs and symptoms of hypotension Monitor renal function and potassium in susceptible patients ( 5.3 , 5.4 )

5.1Fetal Toxicity PREXXARTAN™

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 PREXXARTAN™ as soon as possible .

5.2Hypotension 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. Peak plasma concentrations of valsartan are higher following administration of PREXXARTAN™ and may result in increased risk of hypotension as compared to administration of valsartan tablets . Patients with heart failure or post-myocardial infarction patients given valsartan tablets in clinical trials commonly had some reduction in blood pressure.

Only use PREXXARTAN™ in heart failure or post-myocardial infarction patients who are unable to swallow valsartan tablets. In clinical trials of valsartan tablets, discontinuation of therapy because of continuing symptomatic hypotension usually was not necessary. In controlled trials in heart failure patients, the incidence of hypotension in valsartantreated 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 symptomatic hypotension occurs, place the patient in the supine position and, if necessary, give 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.

5.3Impaired 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 .

5.4Hyperkalemia 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 PREXXARTAN™ may be required .

Do not use in patients with known hypersensitivity to any component. Do not coadminister aliskiren with PREXXARTAN™ in patients with diabetes . Known hypersensitivity Patients with diabetes on aliskiren

8.1Pregnancy Risk Summary PREXXARTAN™

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. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.

Published reports include cases of anhydramnios and oligohydramnios in pregnant women treated with valsartan . Studies in rats and rabbits with valsartan showed fetotoxicity only at maternally toxic doses . When pregnancy is detected, consider alternative drug treatment and discontinue PREXXARTAN™ as soon as possible. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4%, and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.

Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension and death. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.

In patients taking PREXXARTAN™ during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

If oligohydramnios is observed, consider alternative drug treatment. Closely observe neonates with histories of in utero exposure to PREXXARTAN™ for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to PREXXARTAN™, if oliguria or hypotension occurs, support blood pressure and renal perfusion.

Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function. Data Animal Data No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses of up to 600 mg/kg/day (9 and 18 times the maximum recommended human dose (MRHD) on a mg/m2 basis) and to pregnant rabbits at oral doses of up to 10 mg/kg/day. In rats, oral valsartan administered at maternally toxic doses (600 mg/kg/day) during organogenesis or late gestation and lactation, resulted in decreased fetal and pup weight, pup survival and delayed developmental milestones.

In rabbits administered maternally toxic doses of 5 and 10 mg/kg/day, fetotoxicity was observed.

8.2Lactation Risk Summary There

are no data on the presence of PREXXARTAN™ in human milk, the effects on the breastfed infant, or the effects on milk production. Valsartan is present in rat milk . Because of the potential for valsartan to affect postnatal renal development in nursing infants, advise a nursing woman not to breastfeed during treatment with PREXXARTAN™. Data Valsartan was detected in the milk of lactating rats 15 minutes after oral administration of a 3 mg/kg dose.

Hypertension: Most common adverse reactions are headache, dizziness, fatigue and abdominal pain Heart Failure: Most common adverse reactions are dizziness, hypotension, diarrhea, arthralgia, back pain, fatigue and hyperkalemia Post-Myocardial Infarction: Most common adverse reactions which caused patients to discontinue therapy are hypotension, cough and increased blood creatinine To report SUSPECTED ADVERSE REACTIONS, contact Carmel Biosciences, Inc. at 1-855-462-3186 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Studies 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 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 over 400 pediatric patients aged 6 to 17 years and more than 160 pediatric patients aged 6 months to 5 years. No relevant differences were identified between the adverse experience profile for pediatric patients aged 6 to 16 years and that previously reported for adult patients. Headache and hyperkalemia were the most common adverse events suspected to be study drug-related in older children (6 to 17 years old) and younger children (6 months to 5 years old), respectively.

Hyperkalemia was mainly observed in children with underlying renal disease. Neurocognitive and developmental assessment of pediatric patients aged 6 to 16 years revealed no overall clinically relevant adverse impact after treatment with valsartan for up to 1 year. Valsartan is not recommended for pediatric patients under 6 years of age.

In a study (n=90) of pediatric patients (1 to 5 years), two deaths and three cases of on-treatment transaminase elevations were seen in the one-year open-label extension phase. These 5 events occurred in a study population in which patients frequently had significant co-morbidities. A causal relationship to valsartan has not been established.

In a second study of 6-months duration in 75 children aged 1 to 5 years, there were no deaths; one case of marked liver transaminase elevations occurred following 6 months of treatment. 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 .

6.2Postm

arketing 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