Valsartan and Hydrochlorothiazide (Page 2 of 8)

2.5 Use with Other Antihypertensive Drugs

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

3 DOSAGE FORMS AND STRENGTHS

  • 80 mg/12.5 mg tablets are light orange colored, ovaloid, beveled edge, biconvex film-coated tablets debossed with ‘I’ on one side and ‘61’ on other side.
  • 160 mg/12.5 mg tablets are dark red colored, ovaloid, beveled edge, biconvex film-coated tablets debossed with ‘I’ on one side and ‘62’ on other side.
  • 160 mg/25 mg tablets are brown-orange colored, ovaloid, beveled edge, biconvex film-coated tablets debossed with ‘I’ on one side and ‘63’ on other side.
  • 320 mg/12.5 mg tablets are pink colored, oval shaped, beveled edge, biconvex film-coated tablets debossed with ‘I’ on one side and ‘64’ on other side.
  • 320 mg/25 mg tablets are yellow colored, oval shaped, beveled edge, biconvex film-coated tablets debossed with ‘I’ on one side and ‘65’ 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 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.

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 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 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, 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. 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

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, the incidence of hypertensive patients who developed hypokalemia (serum potassium < 3.5 mEq/L) was 3%; 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 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.

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.

Hypertension

Valsartan and hydrochlorothiazide has been evaluated for safety in more than 5700 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 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 and hydrochlorothiazide patients and 3.1% of placebo patients. The most common reasons for discontinuation of therapy with valsartan and hydrochlorothiazide 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 and at a higher incidence in valsartan and 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.

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 as initial therapy and in patients treated with valsartan as initial therapy. Comparing the groups treated with valsartan and hydrochlorothiazide (force-titrated to 320 mg/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 and 0% of patients receiving valsartan. There were no reported cases of syncope in either treatment group. Laboratory changes with valsartan and hydrochlorothiazide as initial therapy in patients with severe hypertension were similar to those reported with valsartan and hydrochlorothiazide in patients with less severe hypertension [see Clinical Studies (14.2), 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).

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