Valsartan

7 DRUG INTERACTIONS Potassium-sparing diuretics, potassium supplements or salt substitutes may lead to increases in serum potassium, and in heart failure patients, increases in serum creatinine ( 7.1 ) Non-Steroidal Anti-Inflammatory Drug (NSAID) use may lead to increased risk of renal impairment and loss of antihypertensive effect ( 7.2 ) Dual inhibition of the Renin-Angiotensin System (RAS): Increased risk of renal impairment, hypotension, and hyperkalemia ( 7.3 ) Lithium: Increases in serum lithium level and lithium toxicity ( 7.4 ) 7.1 Agents Increasing Serum Potassium Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium or other drugs that may increase potassium levels (e.g., heparin) may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine. If co-medication is considered necessary, monitoring of serum potassium is advisable. 7.2 Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including valsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving valsartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including valsartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors. 7.3 Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy [see Clinical Studies (14.3)] . In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on Diovan and other agents that affect the RAS. Do not coadminister aliskiren with Diovan in patients with diabetes. Avoid use of aliskiren with Diovan in patients with renal impairment (GFR < 60 mL/min). 7.4 Lithium Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use.

Valsartan tablets are indicated for: - Hypertension, "to lower blood pressure in adults and children 6 years and older" - Heart failure, "to reduce hospitalization for heart failure in adults" with NYHA class II-IV - Post-myocardial infarction, "for the reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction."

2 DOSAGE AND ADMINISTRATION *As tolerated by patient Indication Starting Dose Dose Range* Hypertension Adults ( 2.2 ) 80 mg to 160 mg once daily 80 mg to 320 mg once daily 1 to 16 years ( 2.3 ) 1 mg/kg once daily Up to 40 mg daily 1 mg/kg to 4 mg/kg once daily Up to 160 mg daily Heart Failure ( 2.4 ) 40 mg twice daily 40 mg to 160 mg twice daily Post-Myocardial Infarction ( 2.5 ) 20 mg twice daily 20 mg to 160 mg twice daily 2.1 Important Dosage and Preparation Information Diovan tablets and oral suspension are not substitutable on a milligram-per-milligram basis. Do not combine two dosage forms to achieve the total dose. The systemic exposure to valsartan (AUC) is 60% higher with the suspension compared to tablets [see Clinical Pharmacology (12.3)] . Use of the oral suspension is recommended: in pediatric patients aged 1 to 5 years in patients >5 years of age who cannot swallow tablets and in pediatric patients for whom the calculated dose (mg/kg) does not correspond to the available tablet strengths of Diovan. When switching between suspension and tablets, the dose of valsartan may need to be adjusted. Preparation of Suspension (for 160 mL of a 4 mg/mL suspension) Add 80 mL of Ora-Plus ®* oral suspending vehicle to an amber glass bottle containing 8 Diovan 80 mg tablets and shake for a minimum of 2 minutes. Allow the suspension to stand for a minimum of 1 hour. After the standing time, shake the suspension for a minimum of 1 additional minute. Add 80 mL of Ora-Sweet SF ®* oral sweetening vehicle to the bottle and shake the suspension for at least 10 seconds to disperse the ingredients. The suspension is homogenous and can be stored for either up to 30 days at room temperature (below 30°C/86°F) or up to 75 days at refrigerated conditions (2°C to 8°C/35°F to 46°F) in the glass bottle with a child-resistant screw-cap closure. Shake the bottle well (at least 10 seconds) prior to dispensing the suspension. * Ora-Sweet SF ® and Ora-Plus ® are registered trademarks of Paddock Laboratories, Inc. 2.2 Adult Hypertension The recommended starting dose of Diovan is 80 mg or 160 mg once daily when used as monotherapy in patients who are not volume-depleted. Patients requiring greater reductions may be started at the higher dose. Diovan may be used over a dose range of 80 mg to 320 mg daily, administered once a day. The antihypertensive effect is substantially present within 2 weeks and maximal reduction is generally attained after 4 weeks. If additional antihypertensive effect is required over the starting dose range, the dose may be increased to a maximum of 320 mg or a diuretic may be added. Addition of a diuretic has a greater effect than dose increases beyond 80 mg. Diovan may be administered with other antihypertensive agents. 2.3 Pediatric Hypertension 1 to 16 Years of Age The usual recommended starting dose is 1 mg/kg once daily (up to 40 mg total). A higher starting dose of 2 mg/kg may be considered in selected cases when a greater reduction of blood pressure is needed. The dosage should be adjusted according to blood pressure response and tolerability, up to a maximum dose of 4 mg/kg once daily (maximum daily dose 160 mg). No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate < 30 mL/min/1.73 m 2 [see Use in Specific Populations (8.4)] . Use of Diovan is not recommended in children less than 1 year of age [see Adverse Reactions (6.1), Pediatric Use in Specific Populations (8.4), Nonclinical Toxicology (13.2)] . 2.4 Heart Failure The recommended starting dose of Diovan is 40 mg twice daily. Uptitrate to 80 mg and 160 mg twice daily or to the highest dose tolerated by the patient. Consider reducing the dose of concomitant diuretics. The maximum daily dose administered in clinical trials is 320 mg in divided doses. 2.5 Post-Myocardial Infarction Diovan may be initiated as early as 12 hours after a myocardial infarction. The recommended starting dose of Diovan is 20 mg twice daily. Patients may be uptitrated within 7 days to 40 mg twice daily, with subsequent titrations to a target maintenance dose of 160 mg twice daily, as tolerated by the patient. If symptomatic hypotension or renal dysfunction occurs, consider dosage reduction. Diovan may be given with other standard post-myocardial infarction treatment, including thrombolytics, aspirin, beta-blockers, and statins. 2.6 Missed Dose If a dose of DIOVAN is missed, it should be administered as soon as possible, unless it is almost time for the next dose. The dose should not be doubled to make up for a missed dose.

In hypertension, common reactions included "headache, dizziness, viral infection, fatigue and abdominal pain." In heart failure, "dizziness, hypotension, diarrhea, arthralgia, back pain, fatigue and hyperkalemia" were reported. In post-MI patients, "hypotension, cough and increased blood creatinine" were the primary reasons for discontinuation.