DESCRIPTION SECTION

11 DESCRIPTION

Valsartan, USP is a nonpeptide, orally active, and specific angiotensin II receptor blocker acting on the AT 1 receptor subtype.

Valsartan, USP is chemically described as N-(1-oxopentyl)- N-[[2'-(1 H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]methyl]-L­-valine. Its empirical formula is C 24H 29N 5O 3, its molecular weight is 435.5, and its structural formula is:

Valsartan, USP is off white to white powder. It is soluble in methanol, freely soluble in anhydrous ethanol, sparingly soluble in methylene chloride, practically insoluble in water.

Valsartan, USP is available as tablets for oral administration, containing 40 mg, 80 mg, 160 mg or 320 mg of valsartan. The inactive ingredients of the tablets are colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, lactose monohydrate, sodium lauryl sulfate, microcrystalline cellulose, macrogol, iron oxides (yellow, black and red), and titanium dioxide.

---

INDICATIONS & USAGE SECTION

Highlight: Valsartan is an angiotensin II receptor blocker (ARB) indicated for:

• Hypertension, to lower blood pressure in adults and children 6 years and older. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions ( 1.1)
• Heart failure (NYHA class II-IV), to reduce hospitalization for heart failure in adults ( 1.2)
• Post-myocardial infarction, for the reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction in adults ( 1.3)

1 INDICATIONS AND USAGE

1.1 Hypertension

Valsartan tablets are indicated for the treatment of hypertension, to lower blood pressure in adults and pediatric patients six years of age and older. 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 tablets.

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.

Valsartan tablets may be used alone or in combination with other antihypertensive agents.

Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's Diovan (valsartan) tablets. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

1.2 Heart Failure

Valsartan tablets are indicated to reduce the risk of hospitalization for heart failure in adult patients with heart failure (NYHA class II-IV). There is no evidence that valsartan provides added benefits when it is used with an adequate dose of an angiotensin converting enzyme (ACE) inhibitor [see Clinical Studies (14.2)].

1.3 Post-Myocardial Infarction

In clinically stable adult patients with left ventricular failure or left ventricular dysfunction following myocardial infarction, valsartan is indicated to reduce the risk of cardiovascular mortality [see Clinical Studies (14.3)].

DOSAGE & ADMINISTRATION SECTION

Highlight:

As tolerated by patient
Indication	Starting Dose	Dose Range*****
Hypertension Adults ( 2.2)	80 mg to 160 mg once daily	80 mg to 320 mg once daily
6 to 16 years ( 2.3)	1 mg/kg once daily Up to 40 mg daily	1 mg/kg to 4 mg/kg once daily Up to 160 mg daily
Heart Failure ( 2.4)	40 mg twice daily	40mg to 160 mg twice daily
Post-Myocardial Infarction ( 2.5)	20 mg twice daily	20 mg to160 mg twice daily

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Preparation Information

Valsartan tablets and oral suspension are not substitutable on a milligram- per-milligram basis. Do not combine two dosage forms to achieve the total dose. The systemic exposure to valsartan (AUC) is 60% higher with the suspension compared to tablets [see Clinical Pharmacology (12.3)] .

Use of the oral suspension is recommended:

• in patients ≥ 6 years of age who cannot swallow tablets and
• in pediatric patients for whom the calculated dose (mg/kg) does not correspond to the available tablet strengths of valsartan.

When switching between suspension and tablets, the dose of valsartan may need to be adjusted.

Preparation of Suspension (for 160 mL of a 4 mg/mL suspension)

• Add 80 mL of Ora-Plus ®* oral suspending vehicle to an amber glass bottle containing 8 valsartan 80 mg tablets and shake for a minimum of 2 minutes.
• Allow the suspension to stand for a minimum of 1 hour.
• After the standing time, shake the suspension for a minimum of 1 additional minute.
• Add 80 mL of Ora-Sweet SF ®* oral sweetening vehicle to the bottle and shake the suspension for at least 10 seconds to disperse the ingredients.
• The suspension is homogenous and can be stored for either up to 30 days at room temperature (below 30°C/86°F) or up to 75 days at refrigerated conditions (2°C to 8°C/35°F to 46°F) in the glass bottle with a child-resistant screw-cap closure.
• Shake the bottle well (at least 10 seconds) prior to dispensing the suspension.

*Ora-Sweet SF ® and Ora-Plus ® are registered trademarks of Paddock Laboratories, Inc.

Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's Diovan (valsartan) tablets. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

2.2 Adult Hypertension

The recommended starting dose of valsartan tablets is 80 mg or 160 mg once daily when used as monotherapy in patients who are not volume-depleted. Patients requiring greater reductions may be started at the higher dose. Valsartan tablets may be used over a dose range of 80 mg to 320 mg daily, administered once a day.

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 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.

Valsartan tablets may be administered with other antihypertensive agents.

2.3 Pediatric Hypertension 6 to 16 Years of Age

The usual recommended starting dose is 1 mg/kg once daily (up to 40 mg total). A higher starting dose of 2 mg/kg may be considered in selected cases when a greater reduction of blood pressure is needed. The dosage should be adjusted according to blood pressure response and tolerability, up to a maximum dose of 4 mg/kg once daily (maximum daily dose 160 mg).

No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate <30 mL/min/1.73 m 2 [see Use in Specific Populations (8.4)].

Use of valsartan tablets are not recommended in children less than 1 year of age [see Adverse Reactions (6.1), Pediatric Use in Specific Populations (8.4), Nonclinical Toxicology (13.2)].

Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's Diovan (valsartan) tablets. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

2.4 Heart Failure

The recommended starting dose of valsartan tablets is 40 mg twice daily. Uptitrate to 80 mg and 160 mg twice daily or to the highest dose 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

Valsartan tablets may be initiated as early as 12 hours after a myocardial infarction. The recommended starting dose of valsartan tablets is 20 mg twice daily. Patients may be uptitrated 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. Valsartan tablets may be given with other standard post-myocardial infarction treatment, including thrombolytics, aspirin, beta-blockers, and statins.

2.6 Missed Dose

If a dose of valsartan tablet 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.

---

DRUG INTERACTIONS SECTION

Highlight: * Potassium-sparing diuretics, potassium supplements or salt substitutes may lead to increases in serum potassium, and in heart failure patients, increases in serum creatinine ( 7.1)

• Non-Steroidal Anti-Inflammatory Drug (NSAID) use may lead to increased risk of renal impairment and loss of antihypertensive effect ( 7.2)
• Dual inhibition of the Renin-Angiotensin System (RAS): Increased risk of renal impairment, hypotension, and hyperkalemia ( 7.3)
• Lithium: Increases in serum lithium level and lithium toxicity ( 7.4)

7 DRUG INTERACTIONS

7.1 Agents Increasing Serum Potassium

Concomitant use of valsartan with other agents that block the renin- angiotensin system, potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium or other drugs that may increase potassium levels (e.g., heparin) may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine. If co-medication is considered necessary, monitoring of serum potassium is advisable.

7.2 Non-Steroidal Anti-Inflammatory Agents Including Selective

Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including valsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving valsartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including valsartan, may be attenuated by NSAIDs including selective COX-2 inhibitors.

7.3 Dual Blockade of the Renin-Angiotensin System (RAS)

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy [see Clinical Studies (14.3)] . In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on valsartan tablets and other agents that affect the RAS.

Do not coadminister aliskiren with valsartan in patients with diabetes. Avoid use of aliskiren with valsartan in patients with renal impairment (GFR <60 mL/min).

7.4 Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use.

---

USE IN SPECIFIC POPULATIONS SECTION

Highlight: Lactation: Breastfeeding is not recommended ( 8.2)

Pediatrics: Use of valsartan tablets is not recommended in children less than 1 year of age ( 6.1, 8.4, 13.2)

Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's Diovan (valsartan) tablets. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

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. 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 ( see Clinical Considerations).

When pregnancy is detected, consider alternative drug treatment and discontinue valsartan 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 valsartan tablets 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 valsartan for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to valsartan, 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/m 2 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 mg/kg/day and 10 mg/kg/day, fetotoxicity was observed.

8.2 Lactation

Risk Summary

There is no information regarding the presence of valsartan 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 serious adverse reactions in breastfed infants from exposure to valsartan, advise a nursing woman that breastfeeding is not recommended during treatment with valsartan.

Data

Valsartan was detected in the milk of lactating rats 15 minutes after oral administration of a 3 mg/kg dose.

8.4 Pediatric Use

The antihypertensive effects of valsartan tablets have been evaluated in a clinical study in pediatric patients from 6 to 16 years of age [see Clinical Studies (14.1)] . The pharmacokinetics of valsartan tablets have been evaluated in pediatric patients 1 to 16 years of age [see Clinical Pharmacology (12.3)] . The adverse experience profile of valsartan tablets was similar to that described for adults [see Adverse Reactions (6.1)] .

In children and adolescents with hypertension where underlying renal abnormalities may be more common, renal function and serum potassium should be closely monitored as clinically indicated.

Use of valsartan tablets is not recommended in children less than 1 year of age. [see Nonclinical Toxicology (13.2)] . It is not known whether post-natal use of valsartan, before maturation of renal function is complete, has a long term deleterious effect on the kidney.

No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate less than 30 mL/min/1.73 m 2.

Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's Diovan (valsartan) tablets. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

8.5 Geriatric Use

In the controlled clinical trials of valsartan, 1,214 (36.2%) hypertensive patients treated with valsartan were ≥ 65 years and 265 (7.9%) were ≥ 75 years. No overall difference in the efficacy or safety of valsartan was observed in this patient population, but greater sensitivity of some older individuals cannot be ruled out. Exposure [measured by area under the curve (AUC)] to valsartan is higher by 70% in the elderly than in the young, however no dosage adjustment is necessary [see Clinical Pharmacology (12.3)] .

Of the 2,511 patients with heart failure randomized to valsartan in the Valsartan Heart Failure Trial, 45% (1,141) were 65 years of age or older. In the VALsartan In Acute myocardial iNfarcTion trial (VALIANT), 53% (2,596) of the 4,909 patients treated with valsartan and 51% (2,515) of the 4,885 patients treated with valsartan + captopril were 65 years of age or older. There were no notable differences in efficacy or safety between older and younger patients in either trial.

8.6 Renal Impairment

Safety and effectiveness of valsartan tablets in patients with severe renal impairment (glomerular filtration rate less than 30 mL/min/1.73 m 2) have not been established. No dose adjustment is required in patients with mild (glomerular filtration rate 60 to 90 mL/min/1.73 m 2) or moderate (glomerular filtration rate 30 to 60 mL/min/1.73 m 2) renal impairment.

8.7 Hepatic Impairment

No dose adjustment is necessary for patients with mild-to-moderate liver disease. No dosing recommendations can be provided for patients with severe liver disease.

---

ADVERSE REACTIONS SECTION

Highlight: 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 ScieGen Pharmaceuticals Inc at 1-855-724-3436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6 ADVERSE REACTIONS

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 mg to 160 mg (2% to 4%).

Pediatric Hypertension

Valsartan has been evaluated for safety in 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 with underlying chronic kidney disease (CKD).

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 tablets 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)] .

Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's Diovan (valsartan) tablets. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

6.2 Postmarketing Experience

The following additional adverse reactions have been reported in postmarketing use of valsartan 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.

Hypersensitivity: Angioedema has been reported. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Valsartan tablets 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

---

NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at doses up to 160 mg/kg/day and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.6 and 6 times, respectively, the MRHD on a mg/m 2 basis (Calculations assume an oral dose of 320 mg/day and a 60-kg patient).

Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella (Ames) and E coli; a gene mutation test with Chinese hamster V79 cells; a cytogenetic test with Chinese hamster ovary cells; and a rat micronucleus test.

Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is 6 times the MRHD on a mg/m 2 basis (Calculations assume an oral dose of 320 mg/day and a 60-kg patient).

13.2 Animal Toxicology and/or Pharmacology

Daily oral dosing of neonatal/juvenile rats with valsartan at doses as low as 1 mg/kg/day (about 10% of the maximum recommended pediatric dose on a mg/m 2 basis) from postnatal day 7 to postnatal day 70 produced persistent, irreversible kidney damage. These kidney effects in neonatal rats represent expected exaggerated pharmacological effects that are observed if rats are treated during the first 13 days of life. This period coincides with 36 weeks of gestation in humans, which could occasionally extend up to 44 weeks after conception in humans. In humans, nephrogenesis is thought to be complete around birth; however, maturation of other aspects of kidney function (such as glomerular filtration and tubular function) may continue until approximately 2 years of age. It is unknown whether post-natal use of valsartan before maturation of renal function is complete has long-term deleterious effects on the kidney [see Use in Specific Populations (8.4)] .

---

SPL PATIENT PACKAGE INSERT SECTION

PATIENT INFORMATION

---

** Valsartan Tablets**

---

** (val sar’ tan)**

What is the most important information I should know about valsartan tablets?

Valsartan tablets can cause harm or death to an unborn baby.

• Talk to your healthcare provider about other ways to lower your blood pressure if you plan to become pregnant.
• If you become pregnant during treatment with valsartan tablets, stop taking valsartan tablets and tell your healthcare provider right away.

What are valsartan tablets?

Valsartan tablets are prescription medicine used in:

• adults and children 6 years of age and older to lower high blood pressure (hypertension). Valsartan tablets may be used alone or in combination with other blood pressure medicines.
• adults to treat heart failure. Valsartan tablets may help decrease your need for hospitalization that happens with heart failure.
• adults with certain types of heart failure, to increase the chance of living longer after a heart attack (myocardial infarction).

Valsartan tablets should not be used to treat high blood pressure in children less than 1 year of age. It is not known if valsartan tablets are safe and effective in children with certain kidney problems.

Do not take Valsartan tablets if you:

• are allergic to any of the ingredients in valsartan tablets. See the end of this leaflet for a complete list of ingredients in valsartan tablets.
• have diabetes and are also taking aliskiren. Talk to your healthcare provider if you are not sure.

Before taking valsartan tablets, tell your healthcare provider about all of your medical conditions including, if you:

• have heart problems
• have kidney problems *are pregnant or plan to become pregnant.See“What is the most important information I should know about valsartan tablets?”
• are breastfeeding or plan to breastfeed. It is not known if valsartan tablets passes into your breast milk. You should not breastfeed during treatment with valsartan tablets. Talk with your healthcare provider about the best way to feed your baby during your treatment with valsartan tablets.

Tell your healthcare provider about all the medicines you takeincluding prescription and over- the-counter medicines, vitamins and herbal supplements. Valsartan tablets may affect the way other medicines work.

Especially tell your healthcare provider if you take:

• other medicines for high blood pressure or a heart problem
• water pills (also called “diuretics”)
• potassium-containing medicines, potassium supplements or salt substitutes containing potassium. Your healthcare provider may check the amount of potassium in your blood regularly.
• nonsteroidal anti-inflammatory drugs (NSAIDs)
• Lithium. Your healthcare provider will check the amount of lithium in your blood regularly.

Know the medicines you take. Keep a list of your medicines with you to show to your healthcare provider and pharmacist when a new medicine is prescribed. Talk to your healthcare provider or pharmacist before you start taking any new medicine.

How should I take valsartan tablets?

• Take valsartan tablets exactly as prescribed by your healthcare provider.

• For treatment of high blood pressure, take valsartan tablets 1 time each day ***For children:**Your pharmacist will mix valsartan tablets as a liquid suspension for your child, if:

• your child is ≥ 6 years of age and cannot swallow tablets, or

• if tablets are not available in the prescribed strength needed for your child

• If your child switches between taking the tablet and the suspension, your healthcare provider will adjust the dose as needed.

  • Shake the bottle of suspension well for at least 10 seconds before pouring the dose of medicine to give to your child.

*For adultswith heart failure or who have had a heart attack, take valsartan tablets 2 times each day. Your healthcare provider may start you on a low dose of valsartan tablets and may increase the dose during your treatment.

• Valsartan tablets can be taken with or without food.
• If you miss a dose, take it as soon as you remember. If it is close to your next dose, do not take the missed dose. Take the next dose at your regular time.

If you take too much valsartan tablets, call your healthcare provider, or go to the nearest hospital emergency room.

What are the possible side effects of valsartan tablets?

*Valsartan tablets can cause serious side effects, including: See “What is the most important information I should know about valsartan tablets?” ***Low blood pressure (hypotension).**Low blood pressure can happen with valsartan tablets, especially when you first start taking it and can cause you to feel lightheaded. Feeling lightheaded is most likely to happen if you:

take water pills are on a low-salt diet get dialysis treatments do not drink enough liquids

are dehydrated (decreased body fluids) due to vomiting and diarrhea you sweat excessively have heart problems

Lie down, if you feel lightheaded, dizzy or faint. Call your healthcare provider right away.

***Kidney problems.**Kidney problems may get worse in people that already have kidney disease or heart problems. Your doctor may do blood tests to check for this. ***Increased potassium in your blood.**Some people may develop increased potassium in the blood during treatment with valsartan tablets. Your doctor may do a blood test to check your potassium levels as needed.

The most common side effects of valsartan tablets used to treat people with high blood pressure include:

• headache
• dizziness
• flu symptoms
• tiredness
• stomach (abdominal) pain

The most common side effects of valsartan tablets used to treat people with heart failure include:

• dizziness
• low blood pressure
• diarrhea
• joint and back pain
• tiredness
• high blood potassium

The most common side effects of valsartan tablets used to treat people after a heart attack that cause them to stop taking valsartan tablets include:

• low blood pressure
• cough
• high blood creatinine (decreased kidney function)

You should not stop taking valsartan tablets without talking to your healthcare provider. These are not all of the possible side effects of valsartan tablets. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store valsartan tablets?

• Store valsartan tablets at room temperature between 68ºF to 77ºF (20ºC to 25ºC).
• Keep valsartan tablets container tightly closed and in a dry place to protect from moisture.
• Valsartan suspension is provided in a glass bottle with a child-resistant screw-cap closure.
• Store bottles of valsartan suspension at room temperature less than 86ºF (30ºC) for up to 30 days,orrefrigerate between 35ºF to 46ºF (2ºC to 8ºC) for up to 75 days.

Keep valsartan tablets and all medicines out of the reach of children.

**General information about the safe and effective use of valsartan tablets. **

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use valsartan tablets for a condition for which it was not prescribed. Do not give valsartan tablets to other people, even if they have the same symptoms you have. It may harm them.

You can ask your healthcare provider or pharmacist for information about valsartan tablets that is written for health professionals.

What are the ingredients in valsartan tablets, USP?

**Active ingredient:**valsartan, USP

Inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, lactose monohydrate, sodium lauryl sulfate, microcrystalline cellulose, macrogol, iron oxides (yellow, black and red), and titanium dioxide.

Manufactured by:

ScieGen Pharmaceuticals Inc

Hauppauge, NY 11788

USA

For more information, call 1-855-724-3436.

Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's Diovan (valsartan) tablets. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Rev. 10/2021

---

HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

Valsartan tablets, USP are available as film coated tablets containing 40 mg, 80 mg, 160 mg, or 320 mg of valsartan. All strengths are packaged in bottles as described below.

The 40 mg tablets are scored on one side and capsule shaped, biconvex film coated tablets. 80 mg, 160 mg, and 320 mg tablets are unscored and oval shaped, biconvex, film coated tablets.

Tablet	Color	Deboss	NDC –50228-xxx-xx
Side 1	Side 2	Bottle of
30	1000	500
40 mg	Yellow	S on the left side and G on the right side of bisect	135	135-30	135-10	---
80 mg	Pink	SG	134	134-30	134-10	---
160 mg	Orange	SG	133	133-30	133-10	---
320 mg	Dark Purple	SG	132	132-30	---	132-05

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

Protect from moisture.

Dispense in tight container (USP).

---