valsartan 320 MG / hydrochlorothiazide 25 MG Oral Tablet

Generic Name: VALSARTAN AND HYDROCHLOROTHIAZIDE
Brand Name: Valsartan and Hydrochlorothiazide
  • Substance Name(s):
  • HYDROCHLOROTHIAZIDE
  • VALSARTAN

DRUG INTERACTIONS

7. Antidiabetic drugs: Dosage adjustment of antidiabetic may be required (7) Cholestyramine and colestipol: Reduced absorption of thiazides (7) Lithium: Diuretics 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 rennin-angiotensin system: Increased risk of renal impairment, hypotension and hyperkalemia (7) 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. CYP 450 Interactions In vitro metabolism studies indicate that CYP 450 mediated drug interactions between valsartan and co-administered drugs are unlikely because of the low extent of metabolism [see CLINICAL PHARMACOLOGY (12.3)]. 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. Co-administration of inhibitors of the uptake transporter (rifampin, cyclosporine) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan. 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, coa-dministration 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. Potassium Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium sparing diuretics (e.g. spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium 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. 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. Closely monitor blood pressure, renal function and electrolytes in patients on valsartan and hydrochlorothiazide and other agents that affect the RAS. Do not co-administer aliskiren with valsartan and hydrochlorothiazide tablets in patients with diabetes. Avoid use of aliskiren with valsartan and hydrochlorothiazide tablets 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. Lithium Diuretic agents increase the risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with valsartan and hydrochlorothiazide. Monitoring of serum lithium concentrations is recommended during concurrent use. Nonsteroidal Anti-inflammatory Drugs (NSAIDS and COX-2 Selective Inhibitors) When valsartan and hydrochlorothiazide 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 to 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.

OVERDOSAGE

10. Valsartan-Hydrochlorothiazide 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, supportive treatment should be instituted. 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, were very well tolerated without any 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 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 maximum recommended human dose on a mg/m2 basis). (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.) Hydrochlorothiazide The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats, which represents 2027 and 4054 times, respectively, the maximum recommended human dose on a mg/m2 basis. (Calculations assume an oral dose of 25 mg/day and a 60-kg patient.)

DESCRIPTION

11. Valsartan and hydrochlorothiazide tablet USP is a combination of valsartan, an orally active, specific angiotensin II receptor blocker (ARB) acting on the AT1 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 C24H29N5O3, 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 C7H8ClN3O4S2, 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, 80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg and 320 mg/25 mg. The inactive ingredients of the tablets are colloidal silicon dioxide, croscarmellose sodium, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, pregelatinized starch, polyethylene glycol, titanium dioxide and additional colorants as below. 80 mg/12.5 mg: iron oxide red and iron oxide yellow 160 mg/12.5 mg: iron oxide red 160 mg/25 mg: iron oxide black, iron oxide red and iron oxide yellow 320 mg/12.5 mg: iron oxide black and iron oxide red 320 mg/25 mg: iron oxide yellow image 2 Image-3

CLINICAL STUDIES

14. 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 two 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 comparable 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 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 (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 compared to valsartan. Similar trends were seen when the patients were grouped according to gender, race or age.

HOW SUPPLIED

16. /STORAGE AND HANDLING Valsartan and hydrochlorothiazide tablets USP are available as non-scored tablets containing valsartan/hydrochlorothiazide 80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg and 320 mg/25 mg. Strengths are available as follows. 80 mg/12.5 mg Tablet – Light pink colored, capsule shaped, film-coated biconvex tablets, debossed with “LU” on one side and “P11” on the other side. Bottles of 90 NDC 68180-103-09 Bottles of 500 NDC 68180-103-02 Bottles of 1000 NDC 68180-103-03 10 X 10’ Blister Pack NDC 68180-103-13 160 mg/12.5 mg Tablet – Reddish brown colored, capsule shaped, film-coated biconvex tablets, debossed with “LU” on one side and “P12” on the other side. Bottles of 90 NDC 68180-104-09 Bottles of 500 NDC 68180-104-02 Bottles of 1000 NDC 68180-104-03 10 X 10’ Blister Pack NDC 68180-104-13 160 mg/25 mg Tablet – Light orange colored, capsule shaped, film-coated biconvex tablets, debossed with “LU” on one side and “P13” on other side. Bottles of 90 NDC 68180-105-09 Bottles of 500 NDC 68180-105-02 Bottles of 1000 NDC 68180-105-03 10 X 10’ Blister Pack NDC 68180-105-13 320 mg/12.5 mg Tablet – Pink, capsule shaped, film-coated biconvex tablets debossed with “LU” on one side and “P14” on the other side. Bottles of 90 NDC 68180-101-09 Bottles of 500 NDC 68180-101-02 10 X 10’ Blister Pack NDC 68180-101-13 320 mg/25 mg Tablet – Yellow, capsule shaped, film-coated biconvex tablets debossed with ‘LU’ on one side and ‘P15’ on the other side. Bottles of 90 NDC 68180-102-09 Bottles of 500 NDC 68180-102-02 10 X 10’ Blister Pack NDC 68180-102-13 Store at 25°C (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).

RECENT MAJOR CHANGES

Boxed Warning: Fetal Toxicity 1/2012 Indications and Usage: Benefits of lowering blood pressure (1) 12/2011 Contraindications: Dual RAS Blockade (4) 10/2012 Warnings and Precautions: Fetal Toxicity (5.1) 1/2012 Warnings and Precautions: Potassium Abnormalities (5.7) 7/2012 Drug Interactions: Dual Blockade of the Renin-Angiotensin System (7) 10/2012

GERIATRIC USE

8.5 Geriatric Use In the controlled clinical trials of valsartan and hydrochlorothiazide, 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.

DOSAGE FORMS AND STRENGTHS

3. Tablets (valsartan/HCTZ mg): 80/12.5, 160/12.5, 160/25, 320/12.5, 320/25 80 mg/12.5 mg tablets, light pink colored, capsule shaped, film-coated biconvex tablets, debossed with “LU” on one side and “P11” on the other side. 160 mg/12.5 mg tablets, reddish brown colored, capsule shaped, film-coated biconvex tablets, debossed with “LU” on one side and “P12” on the other side. 160 mg/25 mg tablets, light orange colored, capsule shaped, film-coated biconvex tablets, debossed with “LU” on one side and “P13” on other side. 320 mg/12.5 mg tablets, pink, capsule shaped, film-coated biconvex tablets debossed with ‘LU’ on one side and ‘P14’ on the other side. 320 mg/25 mg tablets, yellow, capsule shaped, film-coated biconvex tablets debossed with ‘LU’ on one side and ‘P15’ on the other side.

MECHANISM OF ACTION

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 AT1 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 AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one 200th that of valsartan itself.

INDICATIONS AND USAGE

1. Valsartan and hydrochlorothiazide tablet USP is the combination tablet of valsartan, an angiotensin II receptor blocker (ARB) and hydrochlorothiazide (HCTZ), a diuretic. Valsartan and hydrochlorothiazide tablet USP is 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. Valsartan and hydrochlorothiazide tablet USP is 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 USP. 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 (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 failure, or diabetic kidney disease). These considerations may guide selection of therapy. Add-On Therapy Valsartan and hydrochlorothiazide tablets USP may be used in patients whose blood pressure is not adequately controlled on monotherapy. Replacement Therapy Valsartan and hydrochlorothiazide tablets USP may be substituted for the titrated components. Initial Therapy Valsartan and hydrochlorothiazide tablets USP 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 USP 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 USP, 320 mg/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. 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). image 1

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness of valsartan and hydrochlorothiazide in pediatric patients have not been established. Neonates with a history of in utero exposure to valsartan and hydrochlorothiazide If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

PREGNANCY

8.1 Pregnancy Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue valsartan and hydrochlorothiazide as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. 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. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. 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. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue valsartan and hydrochlorothiazide, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to valsartan and hydrochlorothiazide for hypotension, oliguria, and hyperkalemia [see USE IN SPECIFIC POPULATIONS (8.4)] 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.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether valsartan is excreted in human milk. Valsartan was excreted into the milk of lactating rats; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Hydrochlorothiazide is excreted in human breast milk. Because many drugs are excreted into human milk and because of the potential for adverse reactions in nursing infants from valsartan and hydrochlorothiazide, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

BOXED WARNING

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) 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)

WARNING AND CAUTIONS

5. WARNINGS AND PRECAUTIONS Hypotension: Correct volume depletion prior to initiation, (5.2) Observe for signs of fluid or electrolyte imbalance (5.7) Monitor renal function and potassium in susceptible patients (5.3) Exacerbation or activation of systemic lupus erythematosus (5.5) Acute angle-closure glaucoma (5.8) 5.1 Fetal Toxicity Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue valsartan and hydrochlorothiazide as soon as possible. [see USE IN SPECIFIC POPULATIONS (8.1)]. Intrauterine exposure to thiazide diuretics is associated with fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults. 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 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, or the treatment should start under close medical supervision. If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. 5.3 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. 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 [see DRUG INTERACTIONS (7)]. 5.4 Hypersensitivity Reaction Hydrochlorothiazide 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 Hydrochlorothiazide Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. 5.6 Lithium Interaction Hydrochlorothiazide Lithium generally should not be given with thiazides [see DRUG INTERACTIONS (7)]. 5.7 Potassium Abnormalities Valsartan-Hydrochlorothiazide In the controlled trials of various doses of valsartan and hydrochlorothiazide the incidence of hypertensive patients who developed hypokalemia (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 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 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.

INFORMATION FOR PATIENTS

17. PATIENT COUNSELING INFORMATION Information for Patients Pregnancy Female patients of childbearing age should be told about the consequences of exposure to valsartan and hydrochlorothiazide tablets 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. Symptomatic Hypotension A patient receiving valsartan and hydrochlorothiazide tablets should be cautioned that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. The patients should be told that if syncope occurs, valsartan and hydrochlorothiazide tablets should be discontinued until the physician has been consulted. All patients should be cautioned 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. Potassium Supplements A patient receiving valsartan and hydrochlorothiazide tablets should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States Manufactured by: Lupin Limited Goa – 403 722 INDIA January 2013 ID#: 229952

DOSAGE AND ADMINISTRATION

2. 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) 2.1 General Considerations The usual starting dose is valsartan and hydrochlorothiazide tablets USP, 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 USP. A patient who experiences dose-limiting adverse reactions on either component alone may be switched to valsartan and hydrochlorothiazide tablets USP 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 USP 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 USP may be substituted for the titrated components. 2.4 Initial Therapy Valsartan and hydrochlorothiazide tablets USP 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 USP may be administered with other antihypertensive agents.