VALSARTAN (Page 4 of 5)

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 and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.6 and 6 times, respectively, the maximum recommended human dose 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 maximum recommended human dose 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

Reproductive Toxicology Studies

No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. The no observed adverse effect doses of 600, 200 and 2 mg/kg/day in mice, rats and rabbits represent 9, 6, and 0.1 times, respectively, the maximum recommended human dose on a mg/m 2 basis. Calculations assume an oral dose of 320 mg/day and a 60 kg patient.

CLINICAL STUDIES

14.1 Hypertension

Adult Hypertension

The antihypertensive effects of valsartan were demonstrated principally in 7 placebo-controlled, 4- to 12-week trials (one in patients over 65) of dosages from 10 to 320 mg/day in patients with baseline diastolic blood pressures of 95 to 115. The studies allowed comparison of once-daily and twice-daily regimens of 160 mg/day; comparison of peak and trough effects; comparison (in pooled data) of response by gender, age, and race; and evaluation of incremental effects of hydrochlorothiazide.

Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic and diastolic blood pressure, usually with little or no orthostatic change.

In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs at approximately 2 hours, and maximum reduction of blood pressure is achieved within 6 hours. The antihypertensive effect persists for 24 hours after dosing, but there is a decrease from peak effect at lower doses (40 mg) presumably reflecting loss of inhibition of angiotensin II. At higher doses, however (160 mg), there is little difference in peak and trough effect. During repeated dosing, the reduction in blood pressure with any dose is substantially present within 2 weeks, and maximal reduction is generally attained after 4 weeks. In long-term follow-up studies (without placebo control), the effect of valsartan appeared to be maintained for up to 2 years. The antihypertensive effect is independent of age, gender or race. The latter finding regarding race is based on pooled data and should be viewed with caution, because antihypertensive drugs that affect the renin-angiotensin system (that is, ACE inhibitors and angiotensin-II blockers) have generally been found to be less effective in low-renin hypertensives (frequently blacks) than in high-renin hypertensives (frequently whites). In pooled, randomized, controlled trials of valsartan that included a total of 140 blacks and 830 whites, valsartan and an ACE-inhibitor control were generally at least as effective in blacks as whites. The explanation for this difference from previous findings is unclear.

Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure.

The blood pressure lowering effect of valsartan and thiazide-type diuretics are approximately additive.

The 7 studies of valsartan monotherapy included over 2,000 patients randomized to various doses of valsartan and about 800 patients randomized to placebo. Doses below 80 mg were not consistently distinguished from those of placebo at trough, but doses of 80, 160 and 320 mg produced dose-related decreases in systolic and diastolic blood pressure, with the difference from placebo of approximately 6 to 9/3 to 5 mmHg at 80 to 160 mg and 9/6 mmHg at 320 mg. In a controlled trial the addition of HCTZ to valsartan 80 mg resulted in additional lowering of systolic and diastolic blood pressure by approximately 6/3 and 12/5 mmHg for 12.5 and 25 mg of HCTZ, respectively, compared to valsartan 80 mg alone.

Patients with an inadequate response to 80 mg once daily were titrated to either 160 mg once daily or 80 mg twice daily, which resulted in a comparable response in both groups.

In controlled trials, the antihypertensive effect of once-daily valsartan 80 mg was similar to that of once-daily enalapril 20 mg or once-daily lisinopril 10 mg.

There are no trials of valsartan demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.

There was essentially no change in heart rate in valsartan-treated patients in controlled trials.

Pediatric Hypertension

The antihypertensive effects of valsartan were evaluated in two randomized, double-blind clinical studies.

In a clinical study involving 261 hypertensive pediatric patients 6 to 16 years of age, patients who weighed < 35 kg received 10, 40 or 80 mg of valsartan daily (low, medium and high doses), and patients who weighed ≥ 35 kg received 20, 80, and 160 mg of valsartan daily (low, medium and high doses). Renal and urinary disorders, and essential hypertension with or without obesity were the most common underlying causes of hypertension in children enrolled in this study. At the end of 2 weeks, valsartan reduced both systolic and diastolic blood pressure in a dose-dependent manner. Overall, the three dose levels of valsartan (low, medium and high) significantly reduced systolic blood pressure by -8, -10, -12 mmHg from the baseline, respectively. Patients were re-randomized to either continue receiving the same dose of valsartan or were switched to placebo. In patients who continued to receive the medium and high doses of valsartan, systolic blood pressure at trough was -4 and -7 mmHg lower than patients who received the placebo treatment. In patients receiving the low dose of valsartan, systolic blood pressure at trough was similar to that of patients who received the placebo treatment. Overall, the dose-dependent antihypertensive effect of valsartan was consistent across all the demographic subgroups.

In a clinical study involving 90 hypertensive pediatric patients 1 to 5 years of age with a similar study design, there was some evidence of effectiveness, but safety findings for which a relationship to treatment could not be excluded mitigate against recommending use in this age group [see Adverse Reactions (6.1)].

14.2 Heart Failure

The Valsartan Heart Failure Trial (Val-HeFT) was a multinational, double-blind study in which 5,010 patients with NYHA class II (62%) to IV (2%) heart failure and LVEF < 40%, on baseline therapy chosen by their physicians, were randomized to placebo or valsartan (titrated from 40 mg twice daily to the highest tolerated dose or 160 mg twice daily) and followed for a mean of about 2 years. Although Val-HeFT’s primary goal was to examine the effect of valsartan when added to an ACE inhibitor, about 7% were not receiving an ACE inhibitor. Other background therapy included diuretics (86%), digoxin (67%), and beta-blockers (36%). The population studied was 80% male, 46% 65 years or older and 89% Caucasian. At the end of the trial, patients in the valsartan group had a blood pressure that was 4 mmHg systolic and 2 mmHg diastolic lower than the placebo group. There were two primary end points, both assessed as time to first event: all-cause mortality and heart failure morbidity, the latter defined as all-cause mortality, sudden death with resuscitation, hospitalization for heart failure, and the need for intravenous inotropic or vasodilatory drugs for at least 4 hours.

PLEASE VIEW THE MANUFACTURER’S COMPLETE DRUG INFORMATION INCLUDING THE VALSARTAN HEART FAILURE TRIAL RESULTS HERE:

http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ab5e0e5a-5bdf-4cfc-9d18-57ea4d642f65

In patients not receiving an ACE inhibitor, valsartan-treated patients had an increase in ejection fraction and reduction in left ventricular internal diastolic diameter (LVIDD).

Effects were generally consistent across subgroups defined by age and gender for the population of patients not receiving an ACE inhibitor. The number of black patients was small and does not permit a meaningful assessment in this subset of patients.

INFORMATION FOR PATIENTS

Information for Patients

Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to valsartan during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.

VALSARTAN TABLETS, USP

Rx only

Read the Patient Information that comes with valsartan tablets, USP before you take it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about valsartan tablets, USP, ask your doctor or pharmacist.

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

Valsartan tablets, USP 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 valsartan tablets, USP, tell your doctor right away.

What are valsartan tablets, USP?

Valsartan tablets, USP are prescription medicine called an angiotensin receptor blocker (ARB). It is used in adults to:

• lower high blood pressure (hypertension) in adults and children, 6 to 16 years of age.

• treat heart failure in adults. In these patients, valsartan tablets, USP may lower the need for hospitalization that happens from heart failure.

Valsartan tablets, USP are not for children under 6 years of age or children with certain kidney problems.

High Blood Pressure (Hypertension). Blood pressure is the force in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. Valsartan tablets, USP can help your blood vessels relax so your blood pressure is lower. Medicines that lower your blood pressure lower your chance of having a stroke or heart attack.

High blood pressure makes the heart work harder to pump blood throughout the body and causes damage to the blood vessels. If high blood pressure is not treated, it can lead to stroke, heart attack, heart failure, kidney failure and vision problems.

Heart Failure occurs when the heart is weak and cannot pump enough blood to your lungs and the rest of your body. Just walking or moving can make you short of breath, so you may have to rest a lot.

What should I tell my doctor before taking valsartan tablets, USP?

Tell your doctor about all your medical conditions including whether you:

• have any allergies. See the end of this leaflet for a complete list of ingredients in valsartan tablets, USP.

• have a heart condition

• have liver problems

• have kidney problems

• are pregnant or planning to become pregnant. See “What is the most important information I should know about valsartan tablets, USP?”

• are breast-feeding. It is not known if valsartan passes into your breast milk. You and your doctor should decide if you will take valsartan tablets, USP or breast-feed, but not both. Talk with your doctor about the best way to feed your baby if you take valsartan tablets, USP.

• have ever had a reaction called angioedema, to another blood pressure medicine. Angioedema causes swelling of the face, lips, tongue and/or throat, and may cause difficulty breathing.

Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements. Especially tell your doctor if you take:

• other medicines for high blood pressure or a heart problem

• water pills (also called “diuretics”)

• potassium supplements. Your doctor may check the amount of potassium in your blood periodically

• a salt substitute. Your doctor may check the amount of potassium in your blood periodically

• Nonsteroidal anti-inflammatory drugs (like ibuprofen or naproxen)

• certain antibiotics (rifamycin group), a drug used to protect against transplant rejection (cyclosporin) or an antiretroviral drug used to treat HIV/AIDS infection (ritonavir). These drugs may increase the effect of valsartan.

• Lithium, a medicine used in some types of depression

Know the medicines you take. Keep a list of your medicines with you to show to your doctor and pharmacist when a new medicine is prescribed. Talk to your doctor or pharmacist before you start taking any new medicine. Your doctor or pharmacist will know what medicines are safe to take together.

How should I take valsartan tablets, USP?

• Take valsartan tablets, USP exactly as prescribed by your doctor.

• For treatment of high blood pressure, take valsartan tablet, USP one time each day, at the same time each day.

• If your child cannot swallow tablets, or if tablets are not available in the prescribed strength, your pharmacist will mix valsartan tablets, USP as a liquid suspension for your child. If your child switches between taking the tablet and the suspension, your doctor 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 adult patients with heart failure, take valsartan tablets, USP two times each day, at the same time each day. Your doctor may start you on a low dose of valsartan tablets, USP and may increase the dose during your treatment.

• Valsartan tablets, USP 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, USP, call your doctor or Poison Control Center, or go to the nearest hospital emergency room.

What are the possible side effects of valsartan tablets, USP?

Valsartan tablets, USP may cause the following serious side effects:

Injury or death to an unborn baby. See “What is the most important information I should know about valsartan tablets, USP?”

Low Blood Pressure (Hypotension). Low blood pressure is most likely to happen if you also take water pills, are on a low-salt diet, get dialysis treatments, have heart problems, or get sick with vomiting or diarrhea. Lie down, if you feel faint or dizzy. Call your doctor right away.

Kidney problems. Kidney problems may get worse if you already have kidney disease. Some patients will have changes on blood tests for kidney function and may need a lower dose of valsartan tablets, USP. Call your doctor if you get swelling in your feet, ankles, or hands, or unexplained weight gain. If you have heart failure, your doctor should check your kidney function before prescribing valsartan tablets, USP.

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

• headache

• dizziness

• flu symptoms

• tiredness

• stomach (abdominal) pain

Side effects were generally mild and brief. They generally have not caused patients to stop taking valsartan tablets, USP.

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

• dizziness

• low blood pressure

• diarrhea

• joint and back pain

• tiredness

• high blood potassium

Tell your doctor if you get any side effect that bothers you or that does not go away.

These are not all the possible side effects of valsartan tablets, USP. For a complete list, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How do I store valsartan tablets, USP?

• Store valsartan tablets, USP at room temperature between 68º — 77º F (20º — 25º C).

• Keep valsartan tablets, USP in a closed container in a dry place.

• Store bottles of valsartan suspension at room temperature less than 86ºF (30ºC) for up to 30 days, or refrigerate between 35ºF — 46ºF (2ºC — 8ºC) for up to 75 days.

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

General information about valsartan tablets, USP

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use valsartan tablets, USP for a condition for which it was not prescribed. Do not give valsartan tablets, USP to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about valsartan tablets, USP. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about valsartan tablets, USP that is written for health professionals.

For more information about valsartan tablets, USP, ask your pharmacist or doctor, or call 1-888-726-2299.

What are the ingredients in valsartan tablets, USP?

Active ingredient: valsartan, USP

Inactive ingredients: colloidal silicon dioxide, crospovidone, hypromellose, ferric oxide black (in 160 mg and 320 mg strength), ferric oxide red (in 80 mg, 160 mg, and 320 mg strength), ferric oxide yellow (in 40 mg, 80 mg, and 320 mg strength), magnesium stearate, microcrystalline cellulose, pregelatinized starch, polyethylene glycol, talc, and titanium dioxide.

Distributed by:

Ohm Laboratories Inc.

North Brunswick, NJ 08902 USA

March 2014 FDA-02

Repackaged by Northwind Pharmacaeuticals

Indianapolis, IN 46256

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