Valsartan - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS • Hypotension: Correct volume depletion prior to initiation • Increased angina and/or myocardial infarction • Monitor renal function and potassium in susceptible patients ( 5.4 , 5.5 ) • Exacerbation or activation of systemic lupus erythematosus • Observe for signs of fluid or electrolyte imbalance • Acute angle-closure glaucoma 5.1 Fetal Toxicity Valsartan Amlodipine, valsartan and hydrochlorothiazide tablets can cause fetal harm when administered to a pregnant woman.

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

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 amlodipine, valsartan and hydrochlorothiazide tablets as soon as possible [see Use in Specific Populations ].

Hydrochlorothiazide 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.

5.2 Hypotension in Volume- or Salt-Depleted Patients Excessive hypotension, including orthostatic hypotension, was seen in 1.7% of patients treated with the maximum dose of amlodipine, valsartan and hydrochlorothiazide tablets (10/320/25 mg) compared to 1.8% of valsartan/HCTZ (320/25 mg) patients, 0.4% of amlodipine/valsartan (10/320 mg) patients, and 0.2% of HCTZ/amlodipine (25/10 mg) patients in a controlled trial in patients with moderate to severe uncomplicated hypertension.

In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving angiotensin receptor blockers.

Correct this condition prior to administration of amlodipine, valsartan and hydrochlorothiazide tablets.

Amlodipine, valsartan and hydrochlorothiazide tablets have not been studied in patients with heart failure, recent myocardial infarction, or in patients undergoing surgery or dialysis.

Patients with heart failure or post-myocardial infarction patients given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed.

In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients.

In the Valsartan in Acute Myocardial Infarction Trial (VALIANT), hypotension in post-myocardial infarction patients led to permanent discontinuation of therapy in 1.4% of valsartan-treated patients and 0.8% of captopril-treated patients.

Since the vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration.

Do not initiate treatment with Amlodipine, valsartan and hydrochlorothiazide tablets in patients with aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.

If excessive hypotension occurs with amlodipine, valsartan and hydrochlorothiazide tablets, place the patient in a 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 Increased Angina and/or Myocardial Infarction Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease.

5.4 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 reninangiotensin 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 amlodipine, 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 amlodipine, valsartan and hydrochlorothiazide tablets [see Drug Interactions ] .

5.5 Potassium Abnormalities In the controlled trial of amlodipine, valsartan and hydrochlorothiazide tablets in moderate to severe hypertensive patients, the incidence of hypokalemia (serum potassium <3.5 mEq/L) at any time post-baseline with the maximum dose of amlodipine, valsartan and hydrochlorothiazide tablets (10/320/25 mg) was 10% compared to 25% with HCTZ/amlodipine (25/10 mg), 7% with valsartan/HCTZ (320/25 mg), and 3% with amlodipine/valsartan (10/320 mg).

One patient (0.2%) discontinued therapy due to an adverse event of hypokalemia in each of the amlodipine, valsartan and hydrochlorothiazide tablets and HCTZ/amlodipine groups.

The incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4% with amlodipine, valsartan and hydrochlorothiazide tablets compared to 0.2% to 0.7% with the dual therapies.