Fetal/Neonatal Morbidity and Mortality

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin- converting enzyme inhibitors. There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction when pregnant women have taken valsartan. When pregnancy is detected, Diovan HCT® (valsartan and hydrochlorothiazide, USP) should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

In addition, first trimester use of ACE inhibitors, a specific class of drugs acting on the renin-angiotensin system, has been associated with a potential risk of birth defects in retrospective data. Healthcare professionals that prescribe drugs acting directly on the renin-angiotensin system should counsel women of childbearing potential about the potential risks of these agents during pregnancy.

Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment.

If oligohydramnios is observed, Diovan HCT should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

Valsartan - Hydrochlorothiazide in Animals

There was no evidence of teratogenicity in mice, rats, or rabbits treated orally with valsartan at doses up to 600, 100 and 10 mg/kg/day, respectively, in combination with hydrochlorothiazide at doses up to 188, 31 and 3 mg/kg/day. These non- teratogenic doses in mice, rats and rabbits, respectively, represent 9, 3.5 and 0.5 times the maximum recommended human dose (MRHD) of valsartan and 38, 13 and 2 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.)

Fetotoxicity was observed in association with maternal toxicity in rats and rabbits at valsartan doses of ≥ 200 and 10 mg/kg/day, respectively, in combination with hydrochlorothiazide doses of ≥ 63 and 3 mg/kg/day. Fetotoxicity in rats was considered to be related to decreased fetal weights and included fetal variations of sternebrae, vertebrae, ribs and/or renal papillae. Fetotoxicity in rabbits included increased numbers of late resorptions with resultant increases in total resorptions, postimplantation losses and decreased number of live fetuses. The no observed adverse effect doses in mice, rats and rabbits for valsartan were 600, 100 and 3 mg/kg/day, respectively, in combination with hydrochlorothiazide doses of 188, 31 and 1 mg/kg/day. These no adverse effect doses in mice, rats and rabbits, respectively, represent 9, 3 and 0.18 times the MRHD of valsartan and 38, 13 and 0.5 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 in Animals

No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. The no observed adverse effect doses of 600, 200 and 2 mg/kg/day in mice, rats and rabbits represent 9, 6 and 0.1 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 in Animals

Under the auspices of the National Toxicology Program, pregnant mice and rats that received hydrochlorothiazide via gavage at doses up to 3000 and 1000 mg/kg/day, respectively, on gestation days 6 through 15 showed no evidence of teratogenicity. These doses of hydrochlorothiazide in mice and rats represent 608 and 405 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.)

Intrauterine exposure to thiazide diuretics is associated with fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

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 Diovan HCT 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 Diovan HCT, 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.

Hydrochlorothiazide

Impaired Hepatic Function

Thiazide diuretics should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

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.

Systemic Lupus Erythematosus

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

Lithium Interaction

Lithium generally should not be given with thiazides (see PRECAUTIONS: DRUG INTERACTIONS, Hydrochlorothiazide, Lithium).

Serum Electrolytes

Valsartan - Hydrochlorothiazide

In the controlled trials of various doses of the combination of valsartan and hydrochlorothiazide 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%.

In controlled clinical trials of Diovan HCT® (valsartan and hydrochlorothiazide, USP), the average change in serum potassium was near zero in subjects who received Diovan HCT 160/12.5 mg, 320/12.5 mg or 320/25 mg but the average subject who received Diovan HCT 80/12.5 mg, 80/25 mg or 160/25 mg experienced a mild reduction in serum potassium.

In clinical trials, the opposite effects of valsartan (80, 160 or 320 mg) and hydrochlorothiazide (12.5 mg) on serum potassium approximately balanced each other in many patients. In other patients, one or the other effect may be dominant. Periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Hydrochlorothiazide

All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy.

Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

In diabetic patients dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus latent diabetes mellitus may become manifest during thiazide therapy.

The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.

If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy.

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Impaired Hepatic Function

Valsartan

As the majority of valsartan is eliminated in the bile, patients with mild-to-moderate hepatic impairment, including patients with biliary obstructive disorders, showed lower valsartan clearance (higher AUCs). Care should be exercised in administering valsartan to these patients.

Impaired Renal Function

Valsartan

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin- converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with Diovan.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. In a 4-day trial of valsartan in 12 patients with unilateral renal artery stenosis, no significant increases in serum creatinine or blood urea nitrogen were observed. There has been no long-term use of valsartan in patients with unilateral or bilateral renal artery stenosis, but an effect similar to that seen with ACE inhibitors should be anticipated.

Hydrochlorothiazide

Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.

Information for Patients

Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to drugs that act on the renin- angiotensin system. Discuss other treatment options with female patients planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.

Symptomatic Hypotension: A patient receiving Diovan HCT 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, Diovan HCT 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 Diovan HCT should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.

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 maximum recommended human dose on a mg/m² 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 maximum recommended human dose on a mg/m² 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 maximum recommended human dose on a mg/m² basis. (Calculations assume an oral dose of 25 mg/day and a 60-kg patient.)

Pregnancy Categories C (first trimester) and D (second and third trimesters)

See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

Nursing Mothers

It is not known whether valsartan is excreted in human milk, but valsartan was excreted in the milk of lactating rats. Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

In the controlled clinical trials of Diovan HCT, 764 (17.5%) of 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.

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