Diovan HCT (Valsartan / Hydrochlorothiazide) - Drug Interactions, Contraindications, Overdosage, etc

  DRUG INTERACTIONS

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 : The enzyme(s) responsible for valsartan metabolism have not been identified but do not seem to be CYP 450 isozymes. The inhibitory or induction potential of valsartan on CYP 450 is also unknown.

Hydrochlorothiazide : When administered concurrently, the following drugs may interact with thiazide diuretics:

Alcohol, Barbiturates, or N arcotics  - Potentiation of orthostatic hypotension may occur.

Antidiabetic D rugs (oral agents and insulin) - Dosage adjustment of the antidiabetic drug may be required.

Other Antihypertensive D rugs  - Additive effect or potentiation.

Cholestyramine and Colestipol R esins  - Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43% respectively.

Corticosteroids, ACTH  - Intensified electrolyte depletion, particularly hypokalemia.

Pressor A mines (e.g., norepinephrine) - Possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal Muscle Relaxants, N ondepolarizing (e.g., tubocurarine) - Possible increased responsiveness to the muscle relaxant.

Lithium  - Should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with Diovan HCT.

Non steroidal A nti -inflammatory Drugs  - In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when Diovan HCT 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.

Clinical Laboratory Test Findings

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Diovan HCT.

Creatinine /Blood Urea N itrogen (BUN) : Minor elevations in creatinine and BUN occurred in 2% and 15% respectively, of patients taking Diovan HCT and 0.4% and 6% respectively, given placebo in controlled clinical trials.

Hemoglobin and Hematocrit : Greater than 20% decreases in hemoglobin and hematocrit were observed in less than 0.1% of Diovan HCT patients, compared with 0.0% in placebo-treated patients.

Liver Function Tests : Occasional elevations (greater than 150%) of liver chemistries occurred in Diovan HCT-treated patients.

Neutropenia : Neutropenia was observed in 0.1% of patients treated with Diovan HCT and 0.4% of patients treated with placebo.

Serum Electrolytes : [ See W arnings and Precautions   ( 5.7) ].

    OVERDOSAGE

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.)

  CONTRAINDICATIONS

Diovan HCT (valsartan and hydrochlorothiazide, USP) is 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.