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Diovan HCT®
Diovan HCT®
valsartan and hydrochlorothiazide, USP
Combination Tablets
80 mg/12.5 mg
160 mg/12.5 mg
160 mg/25 mg
320 mg/12.5 mg
320 mg/25 mg
Rx only
Prescribing Information
USE IN PREGNANCY
When used in pregnancy, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, Diovan HCT should be discontinued as soon as possible. See WARNINGS: Fetal/Neonatal Morbidity and Mortality.
DESCRIPTION
Diovan HCT® (valsartan and hydrochlorothiazide, USP) is a combination of valsartan, an orally active, specific angiotensin II antagonist acting on the AT1 receptor subtype, and hydrochlorothiazide, a diuretic.
Valsartan, a nonpeptide molecule, is chemically described as N-(1-oxopentyl)-N-
[[2´-(1H-tetrazol-5-yl)[1,1´-biphenyl]-4-yl]methyl]-L-Valine. Its empirical formula is C24H29N5O3, its molecular weight is 435.5, and its structural formula is
Valsartan is a white to practically white fine powder. It is soluble in ethanol and methanol and slightly soluble in water.
Hydrochlorothiazide USP is a white, or practically white, practically odorless, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in n-butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether, in chloroform, and in dilute mineral acids. Hydrochlorothiazide is chemically described as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7- sulfonamide 1,1-dioxide. Hydrochlorothiazide is a thiazide diuretic. Its empirical formula is C7H8ClN3O4S2, its molecular weight is 297.73, and its structural formula is
Diovan HCT tablets are formulated for oral administration to contain valsartan and hydrochlorothiazide, USP 80/12.5 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg and 320/25 mg. The inactive ingredients of the tablets are colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron oxides, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin- converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.
There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT1 receptor than for the AT2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one 200th that of valsartan itself.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II) it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.
Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.
The mechanism of the antihypertensive effect of thiazides is unknown.
Pharmacokinetics
Metabolism and Elimination
Distribution
Hydrochlorothiazide
Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
Special Populations
Pediatric: The pharmacokinetics of valsartan have not been investigated in patients <18 years of age.
Geriatric: Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. No dosage adjustment is necessary (see DOSAGE AND ADMINISTRATION).
Gender: Pharmacokinetics of valsartan does not differ significantly between males and females.
Race: Pharmacokinetic differences due to race have not been studied.
Renal Insufficiency: There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Consequently, dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been performed in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by hemodialysis. In the case of severe renal disease, exercise care with dosing of valsartan (see DOSAGE AND ADMINISTRATION).
Thiazide diuretics are eliminated by the kidney, with a terminal half-life of 5-15 hours. In a study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours.
Hepatic Insufficiency: On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex and weight). In general, no dosage adjustment is needed in patients with mild-to-moderate liver disease. Care should be exercised in patients with liver disease (see DOSAGE AND ADMINISTRATION).
Pharmacodynamics and Clinical Effects
INDICATIONS AND USAGE
Diovan HCT® (valsartan and hydrochlorothiazide, USP) is indicated for the treatment of hypertension. This fixed dose combination is not indicated for initial therapy (see DOSAGE AND ADMINISTRATION).
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.
WARNINGS
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 inadvertently 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
PRECAUTIONS
Serum Electrolytes
Impaired Hepatic Function
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.
Drug Interactions
Carcinogenesis, Mutagenesis, Impairment of Fertility
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.
ADVERSE REACTIONS
Diovan HCT® (valsartan and hydrochlorothiazide, USP) 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 experiences with Diovan HCT was comparable to placebo.
The overall frequency of adverse experiences 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-hydrochlorothiazide patients and 3.1% of placebo patients. The most common reasons for discontinuation of therapy with Diovan HCT were headache and dizziness.
The only adverse experience that occurred in controlled clinical trials in at least 2% of patients treated with Diovan HCT and at a higher incidence in valsartan- 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 Diovan HCT.
Other adverse experiences that have been reported with valsartan- hydrochlorothiazide (>0.2% of valsartan-hydrochlorothiazide patients in controlled clinical trials) without regard to causality, are uled below:
Cardiovascular: Palpitations and tachycardia.
Ear and labyrinth: Tinnitus and vertigo.
Gastrointestinal: Dyspepsia, diarrhea, flatulence, dry mouth, nausea, abdominal pain, abdominal pain upper, and vomiting.
General and administration site conditions: Asthenia, chest pain, fatigue, peripheral edema and pyrexia.
Infections and infestations: Bronchitis, bronchitis acute, influenza, gastroenteritis, sinusitis, upper respiratory tract infection and urinary tract infection.
Investigations: Blood urea increased.
Musculoskeletal: Arthralgia, back pain, muscle cramps, myalgia, and pain in extremity.
Nervous system: Dizziness postural, paraesthesia, and somnolence.
Psychiatric: Anxiety and insomnia.
Renal and urinary: Pollakiuria.
Reproductive system: Erectile dysfunction.
Respiratory, thoracic and mediastinal: Dyspnea, cough, nasal congestion, pharyngolaryngeal pain and sinus congestion.
Skin and subcutaneous tissue: Hyperhidrosis and rash.
Vascular: Hypotension.
Other reported events seen less frequently in clinical trials included abnormal vision, anaphylaxis, bronchospasm, constipation, depression, dehydration, decreased libido, dysuria, epistaxis, flushing, gout, increased appetite, muscle weakness, pharyngitis, pruritus, sunburn, syncope, and viral infection.
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).
Other reported events seen less frequently in clinical trials included chest pain, syncope, anorexia, vomiting, and angioedema.
Post-Marketing Experience
The following additional adverse reactions have been reported in post-marketing experience:
Hypersensitivity: There are rare reports of angioedema;
Digestive: Elevated liver enzymes and very rare reports of hepatitis.
Renal: Impaired Renal Function;
Clinical Laboratory Tests: Hyperkalemia;
Dermatologic: Alopecia.
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
Hydrochlorothiazide
Other adverse experiences that have been reported with hydrochlorothiazide, without regard to causality, are uled below:
Body As A Whole: weakness;
Digestive: pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation;
Hematologic: aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia;
Hypersensitivity: purpura, photosensitivity, urticaria, necrotizing angiitis (vasculitis and cutaneous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions;
Metabolic: hyperglycemia, glycosuria, hyperuricemia;
Musculoskeletal: muscle spasm;
Nervous System/Psychiatric: restlessness;
Renal: renal failure, renal dysfunction, interstitial nephritis;
Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis;
Special Senses: transient blurred vision, xanthopsia.
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 nitrogen (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 PRECAUTIONS.
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.)
DOSAGE AND ADMINISTRATION
The recommended starting dose of valsartan 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. Valsartan may be used over a dose range of 80 mg to 320 mg daily, administered once-a-day. Hydrochlorothiazide is effective in doses of 12.5 to 50 mg once daily, and can be given at doses of 12.5 mg to 25 mg as Diovan HCT® (valsartan and hydrochlorothiazide, USP).
To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.
The side effects (see WARNINGS) of valsartan are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of valsartan and hydrochlorothiazide will be associated with both sets of dose-independent side effects.
Replacement Therapy
The combination may be substituted for the titrated components.
Dose Titration by Clinical Effect
Diovan HCT tablets contain valsartan and hydrochlorothiazide, 80/12.5 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg and 320/25 mg. A patient whose blood pressure is not adequately controlled with valsartan monotherapy (see above) may add hydrochlorothiazide by switching to Diovan HCT (80/12.5 mg, 160/12.5 mg or 320/12.5 mg valsartan/hydrochlorothiazide) once daily. If blood pressure remains uncontrolled after about 3-4 weeks of therapy, either valsartan or both components may be increased depending on clinical response. There are no studies evaluating doses of valsartan greater than 320 mg in combination with hydrochlorothiazide 25 mg.
A patient whose blood pressure is inadequately controlled by 25 mg once daily of hydrochlorothiazide, or is controlled but who experiences hypokalemia with this regimen, may be switched to Diovan HCT (valsartan 80 mg/hydrochlorothiazide 12.5 mg or valsartan 160 mg/hydrochlorothiazide 12.5 mg) once daily, reducing the dose of hydrochlorothiazide without reducing the overall expected antihypertensive response. The clinical response to Diovan HCT should be subsequently evaluated and if blood pressure remains uncontrolled after 3-4 weeks of therapy, the dose may be titrated up to a maximum of valsartan 320 mg/hydrochlorothiazide 25 mg.
The maximal antihypertensive effect is attained about 4 weeks after initiation of therapy.
Patients with Renal Impairment: The usual regimens of therapy with Diovan HCT may be followed as long as the patient’s creatinine clearance is >30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so Diovan HCT is not recommended.
Patients with Hepatic Impairment: Care should be exercised with dosing of Diovan HCT in patients with hepatic impairment.
Other: No initial dosage adjustment is required for elderly patients.
Diovan HCT may be administered with other antihypertensive agents.
Diovan HCT may be administered with or without food.
HOW SUPPLIED
Diovan HCT® (valsartan and hydrochlorothiazide, USP) is available as tablets containing valsartan/hydrochlorothiazide 80/12.5 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg and 320/25 mg. All strengths are packaged in bottles of 90 tablets and unit dose buler packages.
80/12.5 mg Tablet– Light orange, ovaloid with slightly convex faces debossed CG on one side and HGH on the other side.
Bottles of 90 …………………………………………………….NDC 0078-0314-34
Unit Dose (buler pack) ………………...………………...…….NDC 0078-0314-06
Box of 100 (strips of 10)
160/12.5 mg Tablet– Dark red, ovaloid with slightly convex faces debossed CG on one side and HHH on the other side.
Bottles of 90 …………………………………………..……..…..NDC 0078-0315-34
Unit Dose (buler pack) ………………………..…….…..……..NDC 0078-0315-06
Box of 100 (strips of 10)
160/25 mg Tablet– Brown orange, ovaloid with slightly convex faces debossed NVR on one side and HXH on the other side.
Bottles of 90……………………………………………………..NDC 0078-0383-34
Unit Dose (buler pack) ……………………….………………..NDC 0078-0383-06
Box of 100 (strips of 10)
320/12.5 mg Tablet – Pink, ovaloid with beveled edge, debossed NVR on one side and HIL on the other side.
Bottles of 90 ………………………………………………….….NDC 0078-0471-34
Unit Dose (buler pack) ……………..………………….………NDC 0078-0471-06
Box of 100 (strips of 10)
320/25 mg Tablet– Yellow, ovaloid with beveled edge, debossed NVR on one side and CTI on the other side.
Bottles of 90 ………………………………….…………...……..NDC 0078-0472-34
Unit Dose (buler pack) ……………..……….………….………NDC 0078-0472-06
Box of 100 (strips of 10)
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
[see USP Controlled Room Temperature.]
Protect from moisture.
Dispense in tight container (USP).
REV: OCTOBER2006 Printed in U.S.A.
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
NDA 20-818/labelT200628+preg.doc