VALSARTAN AND HYDROCHLOROTHIAZIDE - valsartan and hydrochlorothiazide tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
VALSARTAN (UNII: 80M03YXJ7I) (VALSARTAN - UNII:80M03YXJ7I), HYDROCHLOROTHIAZIDE (UNII: 0J48LPH2TH) (HYDROCHLOROTHIAZIDE - UNII:0J48LPH2TH)
Available from:
Bryant Ranch Prepack
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Valsartan and hydrochlorothiazide tablets are indicated for the treatment of hypertension, 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 hydrochlorothiazide and the ARB class to which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with valsartan and hydrochlorothiazide 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 1 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 Progra
Product summary:
Product: 63629-8142 NDC: 63629-8142-1 90 TABLET in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
63629-8142-1

VALSARTAN AND HYDROCHLOROTHIAZIDE - valsartan and hydrochlorothiazide tablet

Bryant Ranch Prepack

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use valsartan and hydrochlorothiazide tablets,

safely and effectively. See full prescribing information for valsartan and hydrochlorothiazide tablets.

VALSARTAN and HYDROCHLOROTHIAZIDE tablets, for oral use

Initial U.S. Approval: 1998

WARNING: FETAL TOXICITY

See full prescribing information for complete boxed warning.

When pregnancy is detected, discontinue valsartan and hydrochlorothiazide tablets as soon as

possible. (5.1)

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing

fetus. (5.1)

INDICATIONS AND USAGE

Valsartan and hydrochlorothiazide tablets are the combination tablet of valsartan, an angiotensin II receptor blocker (ARB)

and hydrochlorothiazide (HCTZ), a diuretic.

Valsartan and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to lower blood pressure :

In patients not adequately controlled with monotherapy (1)

As initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals (1)

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial

infarctions

DOSAGE AND ADMINISTRATION

Dose once daily. Titrate as needed to a maximum dose of 320/25mg (2)

May be used as add-on/switch therapy for patients not adequately controlled on any of the components (valsartan or

HCTZ) (2)

May be substituted for titrated components (2.3)

DOSAGE FORMS AND STRENGTHS

Tablets (valsartan/HCTZ mg): 80/12.5, 160/12.5, 160/25, 320/12.5, 320/25 (3)

CONTRAINDICATIONS

Anuria; Hypersensitivity to any sulfonamide-derived drugs or any component; Do not coadminister aliskiren with valsartan

and hydrochlorothiazide tablets in patients with diabetes (4)

WARNINGS AND PRECAUTIONS

Hypotension: Correct volume depletion prior to initiation (5.2)

Observe for signs of fluid or electrolyte imbalance (5.9)

Monitor renal function and potassium in susceptible patients (5.3,5.7)

Exacerbation or activation of systemic lupus erythematosus (5.5)

Acute angle-closure glaucoma (5.8)

ADVERSE REACTIONS

The most common reasons for discontinuation of therapy with valsartan and hydrochlorothiazide were headache and

dizziness. The only adverse experience that occurred in ≥2% of patients treated with valsartan and hydrochlorothiazide

and at a higher incidence than placebo was nasopharyngitis (2.4% vs. 1.9%) (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc., at 1-888-943-3210 or FDA

at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Antidiabetic drugs: Dosage adjustment of antidiabetic may be required (7)

Cholestyramine and colestipol: Reduced absorption of thiazides (12.3)

Lithium: Increase risk of lithium toxicity. Monitor serum lithium concentrations during concurrent use. (7)

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): May increase risk of renal impairment. Can reduce diuretic,

natriuretic and antihypertensive effects of diuretics. (7)

Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia (7)

USE IN SPECIFIC POPULATIONS

Lactation: Breastfeeding is not recommended (8.2) (8)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 8/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING:FETAL TOXICITY

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 General Considerations

2.2 Add-On Therapy

2.3 Replacement Therapy

2.4 Initial Therapy

2.5 Use with Other Antihypertensive Drugs

3 DOSAGE FORMS & STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Fetal Toxicity

5.2 Hypotension in Volume- and/or Salt-Depleted Patients

5.3 Impaired Renal Function

5.4 Hypersensitivity Reaction

5.5 Systemic Lupus Erythematosus

5.6 Lithium Interaction

5.7 Potassium Abnormalities

5.8 Acute Myopia and Secondary Angle-Closure Glaucoma

5.9 Metabolic Disturbances

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Hypertension

14.2 Initial Therapy - Hypertension

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING:FETAL TOXICITY

WARNING: FETAL TOXICITY

When pregnancy is detected, discontinue valsartan and hydrochlorothiazide tablets as

soon as possible. (5.1)

Drugs that act directly on the renin-angiotensin system can cause injury and death to the

developing fetus. (5.1)

1 INDICATIONS AND USAGE

Valsartan and hydrochlorothiazide tablets are indicated for the treatment of hypertension, 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 hydrochlorothiazide

and the ARB class to which valsartan principally belongs. There are no controlled trials demonstrating

risk reduction with valsartan and hydrochlorothiazide 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 1 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 have also 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 (for example, 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

Sections or subsections omitted from the full prescribing information are not listed.

failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Add-On Therapy

Valsartan and hydrochlorothiazide tablets may be used in patients whose blood pressure is not

adequately controlled on monotherapy.

Replacement Therapy

Valsartan and hydrochlorothiazide tablets may be substituted for the titrated components.

Initial Therapy

Valsartan and hydrochlorothiazide tablets may be used as initial therapy in patients who are likely to

need multiple drugs to achieve blood pressure goals.

The choice of valsartan and hydrochlorothiazide tablets as initial therapy for hypertension should be

based on an assessment of potential benefits and risks.

Patients with stage 2 hypertension are at a relatively high risk for cardiovascular events (such as

strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is

clinically relevant. The decision to use a combination as initial therapy should be individualized and

should be shaped by considerations such as baseline blood pressure, the target goal and the incremental

likelihood of achieving goal with a combination compared to monotherapy. Individual blood pressure

goals may vary based upon the patient's risk.

Data from the high dose multifactorial trial [see Clinical Studies (14.1)]provides estimates of the

probability of reaching a target blood pressure with valsartan and hydrochlorothiazide tablets compared

to valsartan or hydrochlorothiazide monotherapy. The figures below provide estimates of the

likelihood of achieving systolic or diastolic blood pressure control with valsartan and

hydrochlorothiazide tablets 320/25 mg, based upon baseline systolic or diastolic blood pressure. The

curve of each treatment group was estimated by logistic regression modeling. The estimated likelihood

at the right tail of each curve is less reliable due to small numbers of subjects with high baseline blood

pressures.

Figure 1: Probability of Achieving Systolic Blood Pressure <140 mmHg at Week 8

Figure 2: Probability of Achieving Diastolic Blood Pressure <90 mmHg at Week 8

Figure 3: Probability of Achieving Systolic Blood Pressure <130 mmHg at Week 8

Figure 4: Probability of Achieving Diastolic Blood Pressure <80 mmHg at Week 8

For example, a patient with a baseline blood pressure of 160/100 mmHg has about a 41% likelihood of

achieving a goal of <140 mmHg (systolic) and 60% likelihood of achieving <90 mmHg (diastolic) on

valsartan alone and the likelihood of achieving these goals on HCTZ alone is about 50% (systolic) or

57% (diastolic). The likelihood of achieving these goals on valsartan and hydrochlorothiazide

tablets rises to about 84% (systolic) or 80% (diastolic). The likelihood of achieving these goals on

placebo is about 23% (systolic) or 36% (diastolic).

2 DOSAGE AND ADMINISTRATION

2.1 General Considerations

The usual starting dose is valsartan and hydrochlorothiazide tablets 160/12.5 mg once daily. The

dosage can be increased after 1 to 2 weeks of therapy to a maximum of one 320/25 tablet once daily as

needed to control blood pressure [see Clinical Studies (14.2)]. Maximum antihypertensive effects are

attained within 2 to 4 weeks after a change in dose.

2.2 Add-On Therapy

A patient whose blood pressure is not adequately controlled with valsartan (or another ARB) alone or

hydrochlorothiazide alone may be switched to combination therapy with valsartan and

hydrochlorothiazide tablets.

A patient who experiences dose-limiting adverse reactions on either component alone may be switched

to valsartan and hydrochlorothiazide tablets containing a lower dose of that component in combination

with the other to achieve similar blood pressure reductions. The clinical response to valsartan and

hydrochlorothiazide tablets should be subsequently evaluated and if blood pressure remains

uncontrolled after 3 to 4 weeks of therapy, the dose may be titrated up to a maximum of 320/25 mg.

2.3 Replacement Therapy

Valsartan and hydrochlorothiazide tablets may be substituted for the titrated components.

2.4 Initial Therapy

Valsartan and hydrochlorothiazide tablets are not recommended as initial therapy in patients with

intravascular volume depletion [see Warnings and Precautions (5.2)].

2.5 Use with Other Antihypertensive Drugs

Valsartan and hydrochlorothiazide tablets may be administered with other antihypertensive agents.

3 DOSAGE FORMS & STRENGTHS

80/12.5 mg tablets, debossed with "L16" on side and plain on other side

160/12.5 mg tablets, debossed with "L17" on side and plain on other side

160/25 mg tablets, debossed with "L18" on side and plain on other side

320/12.5 mg tablets, debossed with "L19" on side and plain on other side

320/25 mg tablets, debossed with "L20" on side and plain on other side

4 CONTRAINDICATIONS

Valsartan and hydrochlorothiazide tablets are contraindicated in patients who are hypersensitive to any

component of this product.

Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or

hypersensitivity to other sulfonamide-derived drugs.

Do not coadminister aliskiren with valsartan and hydrochlorothiazide tablets in patients with diabetes

[See Drug Interactions (7)].

5 WARNINGS AND PRECAUTIONS

5.1 Fetal Toxicity

Valsartan and hydrochlorothiazide tablets can cause fetal harm when administered to a pregnant woman.

Use of drugs that act on the rennin-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.

Thiazides cross the placenta, and use of thiazides during pregnancy is associated with fetal or neonatal

jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

When pregnancy is detected, discontinue valsartan and hydrochlorothiazide tablets as soon as possible

[see Use in Specific Populations (8.1)].

5.2 Hypotension in Volume- and/or Salt-Depleted Patients

Excessive reduction of blood pressure was rarely seen (0.7%) in patients with uncomplicated

hypertension treated with valsartan and hydrochlorothiazide tablets in controlled trials. In patients with

an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high

doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to

administration of valsartan and hydrochlorothiazide tablets, or the treatment should start under close

medical supervision.

If hypotension occurs, 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 and hydrochlorothiazide tablets. Monitor renal function periodically in these patients.

Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease

in renal function on valsartan and hydrochlorothiazide tablets [See Drug Interactions (7)].

5.4 Hypersensitivity Reaction

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of

allergy or bronchial asthma, but are more likely in patients with such a history.

5.5 Systemic Lupus Erythematosus

Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus

erythematosus.

5.6 Lithium Interaction

Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use

of valsartan or thiazide diuretics. Monitor lithium levels in patients receiving valsartan and

hydrochlorothiazide and lithium. [See Drug Interactions (7)].

5.7 Potassium Abnormalities

In the controlled trials of various doses of valsartan and hydrochlorothiazide tablets the incidence of

hypertensive patients who developed hypokalemia (serum potassium <3.5 mEq/L) was 3.0%; the

incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4%.

Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in

hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-

angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically.

If hypokalemia is accompanied by clinical signs (e.g. muscular weakness, paresis, or ECG alterations),

valsartan and hydrochlorothiazide tablets should be discontinued. Correction of hypokalemia and any

coexisting hypomagnesemia is recommended prior to the initiation of thiazides.

Some patients with heart failure have developed increases in potassium with valsartan therapy. These

effects are usually minor and transient, and they are more likely to occur in patients with pre-existing

renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or valsartan may be

required [see Adverse Reactions (6.1)].

5.8 Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient

myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or

ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure

glaucoma can lead to permanent vision loss. The primary treatment is to discontinue

hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be

considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-

closure glaucoma may include a history of sulfonamide or penicillin allergy.

5.9 Metabolic Disturbances

Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and

triglycerides.

Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may

cause or exacerbate hyperuricemia and precipitate gout in susceptible patients.

Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium.

Monitor calcium levels in patients with hypercalcemia receiving valsartan and hydrochlorothiazide

tablets.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reactions rates

observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of

another drug and may not reflect the rates observed in practice. The adverse reaction information from

clinical trials does, however, provide a basis for identifying the adverse events that appear to be related

to drug use and for approximating rates.

Hypertens ion

Valsartan and hydrochlorothiazide tablets have been evaluated for safety in more than 5,700 patients,

including over 990 treated for over 6 months, and over 370 for over 1 year. Adverse experiences have

generally been mild and transient in nature and have only infrequently required discontinuation of

therapy. The overall incidence of adverse reactions with valsartan and hydrochlorothiazide tablets was

comparable to placebo.

The overall frequency of adverse reactions was neither dose-related nor related to gender, age, or

race. In controlled clinical trials, discontinuation of therapy due to side effects was required in 2.3% of

valsartan-hydrochlorothiazide patients and 3.1% of placebo patients. The most common reasons for

discontinuation of therapy with valsartan and hydrochlorothiazide tablets were headache and dizziness.

The only adverse reaction that occurred in controlled clinical trials in at least 2% of patients treated

with valsartan and hydrochlorothiazide tablets and at a higher incidence in valsartan-

hydrochlorothiazide (n=4372) than placebo (n=262) patients was nasopharyngitis (2.4% vs. 1.9%).

Dose-related orthostatic effects were seen in fewer than 1% of patients. In individual trials, a dose-

related increase in the incidence of dizziness was observed in patients treated with valsartan and

hydrochlorothiazide tablets.

Initial Therapy - Hypertension

In a clinical study in patients with severe hypertension (diastolic blood pressure ≥110 mmHg and

systolic blood pressure ≥140 mmHg), the overall pattern of adverse reactions reported through 6

weeks of follow-up was similar in patients treated with valsartan and hydrochlorothiazide tablets as

initial therapy and in patients treated with valsartan as initial therapy. Comparing the groups treated with

valsartan and hydrochlorothiazide tablets (force-titrated to 320/25 mg) and valsartan (force-titrated to

320 mg), dizziness was observed in 6% and 2% of patients, respectively. Hypotension was observed in

1% of those patients receiving valsartan and hydrochlorothiazide tablets and 0% of patients receiving

valsartan. There were no reported cases of syncope in either treatment group. Laboratory changes with

valsartan and hydrochlorothiazide tablets as initial therapy in patients with severe hypertension were

similar to those reported with valsartan and hydrochlorothiazide tablets in patients with less severe

hypertension [see Clinical Studies (14.2) and Drug Interactions (7)].

Valsartan: In trials in which valsartan was compared to an ACE inhibitor with or without placebo, the

incidence of dry cough was significantly greater in the ACE inhibitor group (7.9%) than in the groups

who received valsartan (2.6%) or placebo (1.5%). In a 129-patient trial limited to patients who had had

dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who

received valsartan, hydrochlorothiazide, or lisinopril were 20%, 19%, 69% respectively (p <0.001).

6.2 Postmarketing Experience

The following additional adverse reactions have been reported in valsartan or valsartan/

hydrochlorothiazide postmarketing experience. Because these reactions are reported voluntarily from a

population of uncertain size, it is not always possible to reliably estimate their frequency or establish a

causal relationship to drug exposure.

Hypersensitivity: Angioedema has been reported. Some of these patients previously experienced

angioedema with other drugs including ACE inhibitors. Valsartan and hydrochlorothiazide tablets

should not be re-adminitered to patients who have had angioedema.

Digestive: Elevated liver enzymes and reports of hepatitis

Musculoskeletal: Rhabdomyolsis

Renal: Impaired renal function

Dermatologic: Alopecia, bullous dermatitis

Vascular: Vasculitis

Nervous System: Syncope

Hydrochlorothiazide:

The following additional adverse reactions have been reported in post-marketing experience with

hydrochlorothiazide:

Acute renal failure, renal disorder, aplastic anemia, erythema multiforme, pyrexia, muscle spasm,

asthenia, acute angle-closure glaucoma, bone marrow failure, worsening of diabetes control,

hypokalemia, blood lipids increased, hyponatremia, hypomagnesemia, hypercalcemia, hypochloremic

alkalosis, impotence, and visual impairment.

Pathological changes in the parathyroid gland of patients with hypercalcemia and hypophosphatemia

have been observed in a few patients on prolonged thiazide therapy. If hypercalcemia occurs, further

diagnostic evaluation is necessary.

7 DRUG INTERACTIONS

Valsartan-Hydrochlorothiazide:

Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported during

concomitant administration of lithium with angiotensin II receptor antagonists or thiazides. Monitor

lithium levels in patients taking valsartan HCT.

Valsartan:

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.

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.

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. In general, avoid combined use of RAS inhibitors. Closely monitor blood

pressure, renal function and electrolytes in patients on valsartan 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).

Hydrochlorothiazide: When administered concurrently, the following drugs may interact with thiazide

diuretics:

Antidiabetic Drugs (oral agents and insulin) - Dosage adjustment of the antidiabetic drug may be

required.

Nonsteroidal Anti-inflammatory Drugs (NSAIDS and COX-2 selective inhibitors) - When valsartan and

hydrochlorothiazide tablets and nonsteroidal anti-inflammatory agents are used concomitantly, the patient

should be observed closely to determine if the desired effect of the diuretic is obtained.

Carbamazepine – May lead to symptomatic hyponatremia.

Ion exchange resins: Staggering the dosage of hydrochlorothiazide and ion exchange resins (e.g.,

cholestyramine, colestipol) such that hydrochlorothiazide is administered at least 4 hours before or 4-6

hours after the administration of resins would potentially minimize the interaction.

[see Clinical Pharmacology (12.3)].

Cyclosporine: Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-

type complications.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Valsartan and hydrochlorothiazide tablet can cause fetal harm when administered to a pregnant woman.

Use of drugs that act on the rennin-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 discontinue valsartan and hydrochlorothiazide tablet 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 2-4% and 1520%, 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

Valsartan

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.

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 and hydrochlorothiazide tablet for hypotension, oliguria, and

hyperkalemia. In neonates with a history of in utero exposure to valsartan and hydrochlorothiazide

tablet, 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.

Hydrochlorothiazide

Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the

maternal plasma. Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion. It

accumulates in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical

vein plasma. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or

thrombocytopenia. Since they do not prevent or alter the course of EPH (Edema, Proteinuria,

Hypertension) gestosis (pre-eclampsia), these drugs should not be used to treat hypertension in pregnant

women. The use of hydrochlorothiazide for other indications (e.g., heart disease) in pregnancy should

be avoided.

Data

Animal Data

Valsartan plus Hydrochlorothiazide

There was no evidence of teratogenicity in mice, rats, or rabbits treated orally with valsartan at doses of

up to 600, 100, and 10 mg/kg/day (9, 3.5 and 0.5 times the MRHD), respectively, in combination with

hydrochlorothiazide at doses up to 188, 31, and 3 mg/kg/day (38, 13 and 2 times the MRHD).

Fetotoxicity was observed in association with maternal toxicity in rats at valsartan/hydrochlorothiazide

doses of ≥ 200/63 mg/kg/day and in rabbits at valsartan/hydrochlorothiazide doses of 10/3 mg/kg/day.

Evidence of fetotoxicity in rats consisted of decreased fetal weight and fetal variations of sternebrae,

vertebrae, ribs, and/or renal papillae. Evidence of fetotoxicity in rabbits included increased numbers of

late resorptions with resultant increases in total resorptions, post-implantation losses, and decreased

number of live fetuses.

8.2 Lactation

Risk Summary

There is limited information regarding the presence of valsartan and hydrochlorothiazide tablet in

human milk, the effects on the breastfed infant, or the effects on milk production. Valsartan is present in

rat milk. Hydrochlorothiazide is present in human breast milk. Because of the potential for serious

adverse reactions in breastfed infants, advise a nursing woman that breastfeeding is not recommended

during treatment with valsartan and hydrochlorothiazide tablet.

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

Safety and effectiveness of valsartan and hydrochlorothiazide tablet in pediatric patients have not been

established.

8.5 Geriatric Use

In the controlled clinical trials of valsartan and hydrochlorothiazide tablets, 764 (17.5%) patients treated

with valsartan-hydrochlorothiazide were ≥65 years and 118 (2.7%) were ≥75 years. No overall

difference in the efficacy or safety of valsartan-hydrochlorothiazide was observed between these

patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment

Safety and effectiveness of valsartan and hydrochlorothiazide tablets in patients with severe renal

impairment (CrCl ≤ 30 mL/min) have not been established. No dose adjustment is required in patients

with mild (CrCl 60-90 mL/min) or moderate (CrCl 30 to 60mL/min) renal impairment.

8.7 Hepatic Impairment

Valsartan

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.

Hydrochlorothiazide

Minor alterations of fluid and electrolyte balance may precipitate hepatic coma in patients with impaired

hepatic function or progressive liver disease.

10 OVERDOSAGE

Limited data are available related to overdosage in humans. The most likely manifestations of

overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic

(vagal) stimulation. Depressed level of consciousness, circulatory collapse and shock have been

reported. If symptomatic hypotension should occur, institute supportive treatment.

Valsartan is not removed from the plasma by dialysis.

The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The

most common signs and symptoms observed in patients are those caused by electrolyte depletion

(hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If

digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

In rats and marmosets, single oral doses of valsartan up to 1524 and 762 mg/kg in combination with

hydrochlorothiazide at doses up to 476 and 238 mg/kg, respectively, did not show any adverse

treatment-related effects. These no adverse effect doses in rats and marmosets, respectively, represent

46.5 and 23 times the maximum recommended human dose (MRHD) of valsartan and 188 and 113 times

the MRHD of hydrochlorothiazide on a mg/m2 basis. (Calculations assume an oral dose of 320 mg/day

valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.)

Valsartan was without grossly observable adverse effects at single oral doses up to 2000 mg/kg in rats

and up to 1000 mg/kg in marmosets, except for salivation and diarrhea in the rat and vomiting in the

marmoset at the highest dose (60 and 31 times, respectively, the MRHD on a mg/m basis). (Calculations

assume an oral dose of 320 mg/day and a 60-kg patient.)

The oral LD of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, which represents

2027 and 4054 times, respectively, the MRHD on a mg/m2 basis. (Calculations assume an oral dose of

25 mg/day and a 60-kg patient.)

11 DESCRIPTION

Valsartan and hydrochlorothiazide tablets, USP are a combination of valsartan, an orally active, specific

angiotensin II receptor blocker (ARB) acting on the AT receptor subtype, and hydrochlorothiazide, a

diuretic.

Valsartan, a nonpeptide molecule, is chemically described as N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-

yl)[1,1′-biphenyl]-4-yl]methyl]-L-Valine. Its empirical formula is C

H N O , its molecular weight is

435.5, and its structural formula is

Valsartan is a white to practically white fine powder. It is soluble in ethanol and methanol and slightly

soluble in water.

Hydrochlorothiazide USP is a white, or practically white, practically odorless, crystalline powder. It is

slightly soluble in water; freely soluble in sodium hydroxide solution, in n-butylamine, and in

dimethylformamide; sparingly soluble in methanol; and insoluble in ether, in chloroform, and in dilute

mineral acids. Hydrochlorothiazide is chemically described as 6-chloro-3,4-dihydro-2H-1,2,4-

benzothiadiazine-7-sulfonamide 1,1-dioxide.

Hydrochlorothiazide is a thiazide diuretic. Its empirical formula is C H ClN O S , its molecular

weight is 297.73, and its structural formula is

Valsartan and hydrochlorothiazide tablets, USP, are formulated for oral administration to contain

valsartan and hydrochlorothiazide, USP 80/12.5 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg and 320/25

mg. The inactive ingredients of the tablets are colloidal silicon dioxide, crospovidone, hydroxypropyl

methylcellulose, iron oxides, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc,

and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme

(ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with

effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac

stimulation, and renal reabsorption of sodium. Valsartan blocks the vasoconstrictor and aldosterone-

secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT

receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore

independent of the pathways for angiotensin II synthesis.

There is also an AT receptor found in many tissues, but AT is not known to be associated with

cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT

receptor than for the AT receptor. The primary metabolite of valsartan is essentially inactive with an

affinity for the AT receptor about one 200th that of valsartan itself.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of

angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also

inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not

inhibit ACE (kininase II) it does not affect the response to bradykinin. Whether this difference has

clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion

channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on

renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do

not overcome the effect of valsartan on blood pressure.

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte

reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts.

Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent

increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium

loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so

coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated

with these diuretics.

The mechanism of the antihypertensive effect of thiazides is unknown.

12.2 Pharmacodynamics

Valsartan: Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg

inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24

hours. No information on the effect of larger doses is available.

Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and

consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in

plasma aldosterone were observed after administration of valsartan; very little effect on serum

potassium was observed.

Hydrochlorothiazide: After oral administration of hydrochlorothiazide, diuresis begins within 2 hours,

peaks in about 4 hours and lasts about 6 to 12 hours.

Pharmacodynamic Drug Interactions

Hydrochlorothiazide:

Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.

Skeletal muscle relaxants: Possible increased responsiveness to muscle relaxants such as curare

derivatives.

Digitalis glycosides: Thiazide-induced hypokalemia or hypomagnesemia may predispose the patient to

digoxin toxicity.

12.3 Pharmacokinetics

Valsartan: Valsartan peak plasma concentration is reached 2 to 4 hours after dosing. Valsartan shows bi-

exponential decay kinetics following intravenous administration, with an average elimination half-life of

about 6 hours. Absolute bioavailability for the capsule formulation is about 25% (range 10%-35%).

Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma

concentration (C

) by about 50%. AUC and C

values of valsartan increase approximately linearly

with increasing dose over the clinical dosing range. Valsartan does not accumulate appreciably in

plasma following repeated administration.

Hydrochlorothiazide: The estimated absolute bioavailability of hydrochlorothiazide after oral

administration is about 70%. Peak plasma hydrochlorothiazide concentrations (C

) are reached within

2 to 5 hours after oral administration. There is no clinically significant effect of food on the

bioavailability of hydrochlorothiazide.

Hydrochlorothiazide binds to albumin (40 to 70%) and distributes into erythrocytes. Following oral

administration, plasma hydrochlorothiazide concentrations decline bi-exponentially, with a mean

distribution half-life of about 2 hours and an elimination half-life of about 10 hours.

Valsartan and hydrochlorothiazide tablets: Valsartan and hydrochlorothiazide tablets may be administered

with or without food.

Distribution

Valsartan: The steady state volume of distribution of valsartan after intravenous administration is small

(17 L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to

serum proteins (95%), mainly serum albumin.

Metabolism

Valsartan: The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In

vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme

is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450

isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and

co-administered drugs are unlikely because of the low extent of metabolism.

Hydrochlorothiazide: Is not metabolized.

Excretion

Valsartan: Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83%

of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about

20% of dose recovered as metabolites.

Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal

Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal

clearance is 0.62 L/h (about 30% of total clearance).

Hydrochlorothiazide:

About 70% of an orally administered dose of hydrochlorothiazide is eliminated in the urine as

unchanged drug.

Special Populations

Geriatric: Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by

35% in the elderly than in the young. A limited amount of data suggest that the systemic clearance of

hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young

healthy volunteers.

Gender: Pharmacokinetics of valsartan does not differ significantly between males and females.

Race: Pharmacokinetic differences due to race have not been studied.

Renal Insufficiency: There is no apparent correlation between renal function (measured by creatinine

clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal

impairment. Valsartan has not been studied in patients with severe impairment of renal function

(creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by hemodialysis.

In a study in individuals with impaired renal function, the mean elimination half-life of

hydrochlorothiazide was doubled in individuals with mild/moderate renal impairment (30 < CrCl < 90

mL/min) and tripled in severe renal impairment (≤ 30 mL/min), compared to individuals with normal renal

function (CrCl > 90 mL/min)[see Use in Specific Populations (8.6)].

Hepatic Insufficiency: On average, patients with mild-to-moderate chronic liver disease have twice the

exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex, and

weight)[see Use in Specific Populations (8.7)].

Drug Interactions

Valsartan

No clinically significant pharmacokinetic interactions were observed when valsartan was

coadministered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide,

hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was more antihypertensive

than either component, but it did not lower the heart rate more than atenolol alone.

Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-

course of the anticoagulant properties of warfarin.

Transporters: The results from an in vitro study with human liver tissue indicate that valsartan is a

substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2.

Coadministration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter

(ritonavir) may increase the systemic exposure to valsartan.

Hydrochlorothiazide:

Drugs that alter gastrointestinal motility: The bioavailability of thiazide-type diuretics may be increased

by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal

motility and the stomach emptying rate. Conversely, pro-kinetic drugs may decrease the bioavailability

of thiazide diuretics.

Cholestyramine: In a dedicated drug interaction study, administration of cholestyramine 2 hours before

hydrochlorothiazide resulted in a 70% reduction in exposure to hydrochlorothiazide. Further,

administration of hydrochlorothiazide 2 hours before cholestyramine resulted in 35% reduction in

exposure to hydrochlorothiazide.

Antineoplastic agents (e.g. cyclophosphamide, methotrexate): Concomitant use of thiazide diuretics may

reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Valsartan-Hydrochlorothiazide: No carcinogenicity, mutagenicity or fertility studies have been

conducted with the combination of valsartan and hydrochlorothiazide. However, these studies have been

conducted for valsartan as well as hydrochlorothiazide alone. Based on the preclinical safety and human

pharmacokinetic studies, there is no indication of any adverse interaction between valsartan and

hydrochlorothiazide.

Valsartan: 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 MRHD on a mg/m 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 about 6 times the MRHD on a mg/m basis. (Calculations assume an

oral dose of 320 mg/day and a 60-kg patient.)

Hydrochlorothiazide: Two-year feeding studies in mice and rats conducted under the auspices of the

National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of

hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and

female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal

evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella

Typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster

Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell

chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive

lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange

(clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of

hydrochlorothiazide from 43 to 1300 mcgm/mL, and in the Aspergillus Nidulans non-disjunction assay

at an unspecified concentration.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies

wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively,

prior to mating and throughout gestation. These doses of hydrochlorothiazide in mice and rats represent

19 and 1.5 times, respectively, the MRHD on a mg/m basis. (Calculations assume an oral dose of 25

mg/day and a 60-kg patient.)

14 CLINICAL STUDIES

14.1 Hypertension

Valsartan-Hydrochlorothiazide: In controlled clinical trials including over 7600 patients, 4372

patients were exposed to valsartan (80, 160 and 320 mg) and concomitant hydrochlorothiazide (12.5 and

25 mg). Two factorial trials compared various combinations of 80/12.5 mg, 80/25 mg, 160/12.5 mg,

160/25 mg, 320/12.5 mg and 320/25 mg with their respective components and placebo. The combination

of valsartan and hydrochlorothiazide resulted in additive placebo-adjusted decreases in systolic and

diastolic blood pressure at trough of 14-21/8-11 mmHg at 80/12.5 mg to 320/25 mg, compared to 7-

10/4-5 mmHg for valsartan 80 mg to 320 mg and 5-11/2-5 mmHg for hydrochlorothiazide 12.5 mg to 25

mg, alone.

Three other controlled trials investigated the addition of hydrochlorothiazide to patients who did not

respond adequately to valsartan 80 mg to valsartan 320 mg, resulted in the additional lowering of

systolic and diastolic blood pressure by approximately 4-12/2-5 mmHg.

The maximal antihypertensive effect was attained 4 weeks after the initiation of therapy, the first time

point at which blood pressure was measured in these trials.

In long-term follow-up studies (without placebo control) the effect of the combination of valsartan and

hydrochlorothiazide appeared to be maintained for up to two years. The antihypertensive effect is

independent of age or gender. The overall response to the combination was similar for black and non-

black patients.

There was essentially no change in heart rate in patients treated with the combination of valsartan and

hydrochlorothiazide in controlled trials.

There are no trials of the valsartan and hydrochlorothiazide combination tablet demonstrating reductions

in cardiovascular risk in patients with hypertension, but the hydrochlorothiazide component and several

ARBs, which are the same pharmacological class as the valsartan component, have demonstrated such

benefits.

Valsartan: 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 95-115. 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 7 studies of valsartan monotherapy included over 2000 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

6-9/3-5 mmHg at 80-160 mg and 9/6 mmHg at 320 mg.

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 similar response in both groups.

In another 4-week study, 1876 patients randomized to valsartan 320 mg once daily had an incremental

blood pressure reduction 3/1 mmHg lower than did 1900 patients randomized to valsartan 160 mg once

daily.

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

14.2 Initial Therapy - Hypertension

The safety and efficacy of valsartan and hydrochlorothiazide tablets as initial therapy for patients with

severe hypertension (defined as a sitting diastolic blood pressure ≥110 mmHg and systolic blood

pressure ≥140 mmHg off all antihypertensive therapy) was studied in a 6-week multicenter, randomized,

double-blind study. Patients were randomized to either valsartan and hydrochlorothiazide tablets

(valsartan and hydrochlorothiazide 160/12.5 mg once daily) or to valsartan (160 mg once daily) and

followed for blood pressure response. Patients were force-titrated at 2-week intervals. Patients on

combination therapy were subsequently titrated to 160/25 mg followed by 320/25 mg

valsartan/hydrochlorothiazide. Patients on monotherapy were subsequently titrated to 320 mg valsartan

followed by a titration to 320 mg valsartan to maintain the blind.

The study randomized 608 patients, including 261 (43%) females, 147 (24%) blacks, and 75 (12%) ≥65

years of age. The mean blood pressure at baseline for the total population was 168/112 mmHg. The

mean age was 52 years. After 4 weeks of therapy, reductions in systolic and diastolic blood pressure

were 9/5 mmHg greater in the group treated with valsartan and hydrochlorothiazide tablets compared to

valsartan. Similar trends were seen when the patients were grouped according to gender, race or age.

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 63629-8142

NDC: 63629-8142-1 90 TABLET in a BOTTLE

17 PATIENT COUNSELING INFORMATION

Information for Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Pregnancy: Advise female patients of childbearing age about the consequences of exposure to valsartan

and hydrochlorothiazide tablets during pregnancy. Discuss treatment options with women planning to

become pregnant. Ask patients to report pregnancies to their physicians as soon as possible. [see

Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

Lactation: Advise women not to breastfeed during treatment with valsartan and hydrochlorothiazide

tablets [see Use in Specific Populations (8.2)].

Symptomatic Hypotension: Advise patients that lightheadedness can occur, especially during the first

days of therapy, and that it should be reported to their healthcare provider. Tell patients that if syncope

occurs, to discontinue valsartan and hydrochlorothiazide tablets until the physician has been consulted.

Caution all patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to

an excessive fall in blood pressure, with the same consequences of lightheadedness and possible

syncope [see Warnings and Precautions (5.2)].

Potassium Supplements: Advise patients not to use salt substitutes without consulting their healthcare

provider [see Drug Interactions (7)].

Manufactured for:

Macleods Pharma USA, Inc.,

Plainsboro, NJ 08536

Manufactured by:

Macleods Pharmaceutical Limited

Daman (U.T.) INDIA

Manufactured by :

Macleods Pharmaceuticals Ltd.

Baddi, Himachal Pradesh, INDIA

Revised: 07/2019

SPL PATIENT PACKAGE INSERT

FDA-Approved Patient Labeling

PATIENT INFORMATION

Valsartan and Hydrochlorothiazide Tablets

(val sar' tan and hye'' droe klor'' oh thye' a zide)

Read the Patient Information that comes with valsartan and hydrochlorothiazide tablets before you start

taking 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 condition and treatment. If you have any questions about

valsartan and hydrochlorothiazide tablets, ask your doctor or pharmacist.

What is the most important information I should know about valsartan and hydrochlorothiazide

tablets?

Valsartan and hydrochlorothiazide tablets 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 and hydrochlorothiazide tablets, tell your doctor right away.

What are Valsartan and hydrochlorothiazide tablets?

Valsartan and hydrochlorothiazide tablets contain 2 prescription medicines:

1. valsartan, an angiotensin receptor blocker (ARB)

2. hydrochlorothiazide (HCTZ), a water pill (diuretic)

Valsartan and hydrochlorothiazide tablets may be used to lower high blood pressure (hypertension) in

adults-

when 1 medicine to lower your high blood pressure is not enough

as the first medicine to lower high blood pressure if your doctor decides you are likely to need more

than 1 medicine.

Valsartan and hydrochlorothiazide tablets have not been studied in children under 18 years of age.

Who should not take valsartan and hydrochlorothiazide tablets?

Do not take valsartan and hydrochlorothiazide tablets if you:

are allergic to any of the ingredients in valsartan and hydrochlorothiazide tablets. See the end of

this leaflet for a complete list of ingredients in valsartan and hydrochlorothiazide tablets.

make less urine due to kidney problems

are allergic to medicines that contain sulfonamides

What should I tell my doctor before taking valsartan and hydrochlorothiazide tablets?

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

are pregnant or plan to become pregnant. See "What is the most important information I should

know about valsartan and hydrochlorothiazide tablets?"

are breastfeeding. Valsartan and hydrochlorothiazide passes into breast milk. It is not known if

valsartan and hydrochlorothiazide effects your breastfed baby or milk production. Do not breastfeed

while you are taking valsartan and hydrochlorothiazide tablets.

have liver problems

have kidney problems

have or had gallstones

have Lupus

have low levels of potassium (with or without symptoms such as muscle weakness, muscle spasms,

abnormal heart rhythm) or magnesium in your blood

have high levels of calcium in your blood (with or without symptoms such as nausea, vomiting,

constipation, stomach pain, frequent urination, thirst, muscle weakness and twitching).

have high levels of uric acid in the blood.

have ever had a reaction called angioedema, to another blood pressure medication. Angioedema

causes swelling of the face, lips, tongue, throat and may cause difficulty breathing.

Tell your doctor about all the medicines you take including prescription and nonprescription

medicines, vitamins and herbal supplements. Some of your other medicines and valsartan and

hydrochlorothiazide tablets could affect each other, causing serious side effects. Especially, tell your

doctor if you take:

other medicines for high blood pressure or a heart problem

water pills (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.

antidiabetic medicines including insulin

narcotic pain medicines

sleeping pills

lithium, a medicine used in some types of depression (Eskalith

, Lithobid

, Lithium Carbonate,

Lithium Citrate)

aspirin or other medicines called non-steroidal anti-inflammatory Drugs (NSAIDs), like ibuprofen or

naproxen

digoxin or other digitalis glycosides (a heart medicine)

muscle relaxants (medicines used during operations)

certain cancer medicines, like cyclophosphamide or methotrexate

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.

Ask your doctor if you are not sure if you are taking 1 of these medicines.

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 and hydrochlorothiazide tablets?

Take valsartan and hydrochlorothiazide tablets exactly as prescribed by your doctor. Your doctor may

change your dose if needed.

Take valsartan and hydrochlorothiazide tablets once each day.

Valsartan and hydrochlorothiazide 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. Just take the next dose at your regular time.

If you take too much valsartan and hydrochlorothiazide tablets, call your doctor or Poison Control

Center, or go to the nearest hospital emergency room.

What should I avoid while taking valsartan and hydrochlorothiazide tablets?

You should not take valsartan and hydrochlorothiazide tablets during pregnancy. See "What is the most

important information I should know about valsartan and hydrochlorothiazide tablets?"

What are the possible side effects of valsartan and hydrochlorothiazide tablets?

Valsartan and hydrochlorothiazide tablets may cause serious side effects including:

Harm to an unborn baby causing injury and even death. See "What is the most important

information I should know about valsartan and hydrochlorothiazide tablets?"

Low blood pressure (hypotension). Low blood pressure is most likely to happen if you:

o take water pills

o are on a low salt diet

o get dialysis treatments

o have heart problems

o get sick with vomiting or diarrhea

o drink alcohol

Lie down if you feel faint or dizzy. Call your doctor right away.

Allergic reactions. People with and without allergy problems or asthma who take valsartan and

hydrochlorothiazide tablets may get allergic reactions.

Worsening of Lupus. Hydrochlorothiazide, 1 of the medicines in valsartan and hydrochlorothiazide

tablets may cause Lupus to become active or worse.

Fluid and electrolyte (salt) problems. Tell your doctor about any of the following signs and

symptoms of fluid and electrolyte problems:

dry mouth

thirst

lack of energy (lethargic)

weakness

drowsiness

restlessness

confusion

seizures

muscle pain or cramps

muscle fatigue

very low urine output

fast heartbeat

nausea and vomiting

Kidney problems. Kidney problems may become worse in people that already have kidney disease.

Some people will have changes on blood tests for kidney function and may need a lower dose of

valsartan and hydrochlorothiazide tablets. 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 and hydrochlorothiazide tablets.

Skin rash. Call your doctor right away if you have an unusual skin rash.

Eye Problems. One of the medicines in valsartan and hydrochlorothiazide tablets can cause eye

problems that may lead to vision loss. Symptoms of eye problems can happen within hours to weeks of

starting valsartan and hydrochlorothiazide tablets. Tell your doctor right away if you have:

decrease in vision

eye pain

Other side effects were generally mild and brief. They generally have not caused patients to stop taking

valsartan and hydrochlorothiazide tablets.

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

These are not all the possible side effects of valsartan and hydrochlorothiazide tablets. 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 and hydrochlorothiazide tablets?

Store valsartan and hydrochlorothiazide tablets at room temperature between 59ºF to 86ºF (15ºC to

30ºC).

Keep valsartan and hydrochlorothiazide tablets in a closed container in a dry place.

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

General information about valsartan and hydrochlorothiazide tablets

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets.

Do not use valsartan and hydrochlorothiazide tablets for a condition for which it was not prescribed. Do

not give valsartan and hydrochlorothiazide tablets 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 and hydrochlorothiazide tablets.

If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for

information about valsartan and hydrochlorothiazide tablets that is written for health professionals. For

more information about valsartan and hydrochlorothiazide tablets, call 1-888-943-3210.

What are the ingredients in valsartan and hydrochlorothiazide tablets?

Active ingredients: Valsartan and hydrochlorothiazide

Inactive ingredients: colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron

oxides, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.

What is 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 and hydrochlorothiazide tablets can

help your blood vessels relax and reduce the amount of water in your body so your blood pressure is

lower. Medicines that lower blood pressure lower your risk 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.

Eskalith

and Lithobid

are registered trademarks of Noven Pharmaceuticals, Inc

Manufactured for:

Macleods Pharma USA, Inc.,

Plainsboro, NJ 08536

Manufactured by:

Macleods Pharmaceutical Limited

Daman (U.T.) INDIA

Manufactured by :

Macleods Pharmaceuticals Ltd.

Baddi, Himachal Pradesh, INDIA

Revised: 07/2019

VALSARTAN-HCTZ 160-12.5MG TABLET

VALSARTAN AND HYDROCHLOROTHIAZIDE

valsartan and hydrochlorothiazide tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 36 29 -8 142(NDC:33342-0 76 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

VALSARTAN (UNII: 8 0 M0 3YXJ7I) (VALSARTAN - UNII:8 0 M0 3YXJ7I)

VALSARTAN

16 0 mg

HYDRO CHLO RO THIAZIDE (UNII: 0 J48 LPH2TH) (HYDROCHLOROTHIAZIDE -

UNII:0 J48 LPH2TH)

HYDROCHLOROTHIAZIDE 25 mg

Inactive Ingredients

Ingredient Name

Stre ng th

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

CRO SPO VIDO NE ( 15 MPA.S AT 5%) (UNII: 6 8 40 19 6 0 MK)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

PO LYETHYLENE GLYCO L, UNSPECIFIED (UNII: 3WJQ0 SDW1A)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

Product Characteristics

Color

ORANGE (Bro wn Orange)

S core

no sco re

S hap e

OVAL (Bico nvex)

S iz e

17mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 36 29 -8 142-1

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/29 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 3145

0 4/19 /20 13

Labeler -

Bryant Ranch Prepack (171714327)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Bryant Ranch Prepack

Bryant Ranch Prepack

171714327

REPACK(6 36 29 -8 142) , RELABEL(6 36 29 -8 142)

Revised: 8/2019

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