Duoval/Duoval Max

Valsartan is chemically described as N-(1-oxopenty)-N-1[[2- (1H-tetrazol-5 -yl) [1,1-biphenyl]-4-yl] methyl] L-valine. Its empirical formula is C24 H29 N5O3 and its molecular weight is 435.5. Valsartan is a white to partially white fine powder, it is soluble in ethanol and slightly soluble in water. Hydrochlorothiazide is a white, or partially white, practically odourless, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in n-butylamine, and in methylformamide; sparingly soluble in methanol and insoluble in ether, in chloroform, and in dilute mineral acids. Hydrochlorothiazide is chemically described as 6-chloro-3, 4-hydrochlorothiazide. Its empirical formula is C7H8CIN3O4S2 and its molecular weight is 297.73. Valsartan is non-peptide orally active specific angiotensin II antagonist acting on the AT1 receptor subtype and hydrochlorothiazide is a thiazide diuretic.
FORMULATION: Duoval: Each film-coated tablet contains: Valsartan 80 mg, Hydrochlorothiazide 12.5 mg.
Duoval Max: Each film-coated tablet contains: Valsartan 160 mg, Hydrochlorothiazide 12.5 mg.

Clinical Pharmacology: Pharmacodynamics: Mechanism of Action: Angiotensin II is formed from Angiotensin I in a reaction catalyzed by Angiotensin-Converting Enzyme (ACE, Kininase II). Angiotensin I is the principle 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 adrenal gland. Its action is therefore independent of the pathway for Angiotensin II. 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 increase in plasma renin activity and increases in urinary potassium. The renin-aldosterone link is mediated by Angiotensin II receptor antagonist and tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazide is unknown.
Pharmacodynamics and clinical effects: Valsartan inhibits the pressor effect of Angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. No information on the effect of a larger dose available. Removal of the negative feed back of Angiotensin II causes 2 to 3-fold rise in plasma renin and consequent rise in Angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan; very little effect on serum potassium was observed. In most patients, after administration of a single dose, onset of antihypertensive activity occurs at approximately 2 hours, and maximum reduction of blood pressure is achieved within 6 hours. The antihypertensive effect persists for 24 hours after dosing, but there is a decrease from peak effect at lower dose (40 mg) presumably reflecting loss of inhibition of Angiotensin II. At higher dose, however (160 mg), there is little difference in peak and trough effect. During the repeated dosing, the reduction in blood pressure with any dose is substantially present within 2 weeks, and maximal reduction is generally attained after 4 weeks. In long term follow up studies (without placebo control) the effect of valsartan appeared to be maintained for up to two years. The antihypertensive effect is independent of age, gender or race. The latter finding regarding race is based on pooled data and should be viewed with caution, because antihypertensive drugs that affect the renin-angiotensin system (that is, ACE inhibitors and angiotensin II blockers) have generally been found to be less effective in low-renin hypertensives (frequently blacks) than in higher-renin hypertensives (frequently whites). Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure.
Hydrochlorothiazide: After an oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.
Pharmacokinetics: Valsartan: Valsartan peak plasma concentration is reached 2 to 4 hours after dosing. Valsartan shows bi-exponential decay kinetics following intravenous administration, with an average elimination half-life of about 6 hours. Absolute bioavailability for Valsartan is about 24% (range 10%-35%). Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (C max) by about 50%. AUC and C max values of valsartan increase approximately linearly with increasing dose over the clinical dosing range. Valsartan does not accumulate appreciably in plasma following repeated administration.
Metabolism and Elimination: Valsartan, when administered as an oral dose is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, which only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. The enzyme(s) responsible for valsartan metabolism have not been identified but do not seem to be CYP 450 isozymes.
Hydrochlorothiazide: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated as unchanged drug within 24 hours. The elimination half life is between 5.8 and 18.9 hours.
Distribution: Valsartan: Valsartan does not distribute into tissue extensively. Valsartan is highly bound to serum proteins (95%) mainly serum albumin.
Hydrochlorothiazide: Hydrochlorothiazide crosses the placenta but not the serum albumin 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 half-life is longer by 35% in the elderly than in the young.
Gender: The 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 AUC) to valsartan in patients with different degree of renal impairment. 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 value) to valsartan of healthy volunteers (match by age, sex and weight).

(Valsartan + hydrochlorothiazide) Duoval film-coated tablets are indicated for the treatment of hypertension.

The recommended starting dosage of valsartan is 80 mg once daily when used as monotherapy in patients who are not volume depleted. Patients requiring greater reduction may be increased to a dose of 160 mg daily. The antihypertensive effect is substantially present within 2 weeks and maximal reduction is generally attained after 4 weeks. If an additional antihypertensive effect is required over the starting dose range, the dose may be increased to a maximum of 320 mg or a diuretic may be added. Addition of a diuretic has a greater effect than dose increases beyond 80 mg. Care should be exercised with dosing of (Valsartan + hydrochlorothiazide) Duoval in patients with hepatic or severe renal impairment. Valsartan + hydrochlorothiazide may be administered with other antihypertensive agents. Valsartan + hydrochlorothiazide may be administered with or without food. Hydrochlorothiazide is effective in a dose of 12.5 to 25 mg once daily, and can be given a dose of 12.5 mg to 25 mg as (Valsartan and hydrochlorothiazide) Duoval. To minimize dose-independent adverse effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. The adverse effects 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, Stevens-Johnson Syndrome), the former much more common than the latter. Therapy with any combination of valsartan and hydrochlorothiazide will be associated with both sets of adverse effects.
Heart failure: The recommended starting dosage of (Valsartan + hydrochlorothiazide) Duoval is 40 mg twice daily. Up titration to 80 mg and 160 mg twice daily should be done to the highest dose, as tolerated by the patients, consideration should be given to reducing the dose of concomitant diuretics. The maximum daily dose administered in clinical trials is 320 mg in divided doses. Concomitant use with an ACE inhibitor and beta blockers is not recommended. Or as prescribed by the physician.

Related to overdosage in humans, limited data are available. The most likely manifestation of overdosage would hypotension and tachycardia from parasympathetic (vagal) stimulation. 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 electrolytic depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate arrhythmias.

(Valsartan + hydrochlorothiazide) Duoval is contraindicated in patients who are sensitive 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.

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.
Valsartan must not be given to pregnant women or woman of child-bearing age with no intention to use contraception.
Hypotension in volume- and/or salt-depleted patients: Excessive reduction of blood pressure was seen (0.5%) in patients with uncomplicated hypertension treated with valsartan and hydrochlorothiazide. In a patient with an activated renin-angiotensin system, such as a volume- and/or salt-depleted patient receiving high dose of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to administration of (Valsartan + hydrochlorothiazide) Duoval, or the treatment should start under close medical supervision.
Hydrochlorothiazide: Impaired Hepatic Function: Thiazide diuretics should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alteration of fluid and electrolyte balance may precipitate hepatic coma.
Hypersensitivity Reaction: Hypersensitivity reaction 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.

Serum Electrolytes: Valsartan-Hydrochlorothiazide: In 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 0.3%.
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 determination are particularly important when the patients is vomiting excessively or receiving parenteral fluids.
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 + hydrochlorothiazide) Duoval to these patients.
Impaired Renal Function - Heart Failure: 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). Treatments with Angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists have been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. (Valsartan + hydrochlorothiazide) Duoval would be expected to behave similarly.
Hydrochlorothiazide: Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may be precipitate azotemia. Cumulative effects of the drug may develop in a patient with impaired renal function.
INFORMATION FOR THE PATIENT: Pregnancy: Female patients of childbearing age should be told about the consequences of second and third trimester exposure to drug that act on the renin-angiotensin system and they should be told that these consequences do not appears to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physician as soon as possible.

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.
Valsartan must not be given to pregnant women or woman of child-bearing age with no intention to use contraception.
Pregnancy: Female patients of childbearing age should be told about the consequences of second and third trimester exposure to drug that act on the renin-angiotensin system and they should be told that these consequences do not appears to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physician as soon as possible.

Headache, upper respiratory infection, sinusitis, back pain and chest pain occurred at a more than 2% rate but at about the same incidence in placebo and valsartan-hydrochlorothiazide patients. Dose related orthostatic effects were seen in less than 1% of patients. A dose related increase in the incidence of dizziness was observed in patients treated with (Valsartan + hydrochlorothiazide) Duoval from 80/12.5 mg (6%) to 160/25 mg (16%). Other adverse experiences that have been reported with valsartan-hydrochlorothiazide (>0.2% of valsartan-hydrochlorothiazide patients in controlled trials) without regard to causality are listed as follows: Body as a whole: Allergic reaction, anaphylaxis, asthenia, and dependent edema.
Cardiovascular: Palpitations, syncope, and tachycardia.
Dermatologic: Flushing, rash, sunburn and increased sweating.
Digestive: Increased appetite, constipation, dyspepsia, flatulence, dry mouth, nausea abdominal pain, and vomiting.
Metabolic: Dehydration and gout.
Musculoskeletal: Arthralgia, muscle cramps, muscle weakness, arm pain, and leg pain.
Neurologic and Psychiatric: Anxiety, depression, insomnia, decreased libido, paresthesia, and somnolence.
Respiratory: Bronchospasm, dyspnea, and epistaxis.
Urogenital: Dysuria, impotence, micturition frequency, and urinary tract infection.

Valsartan: No clinically significant pharmacokinetic interactions were observed when valsartan was co-administered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glibenclamide, hydrochlorothiazide, or indometacin. The valsartan-atenolol combination was more antihypertensive than either agent given alone.
Hydrochlorothiazide: When administered concurrently the following drugs may interact with thiazide diuretics: Potentiation of Alcohol, Barbiturates, or narcotics-potentiation of orthostatic hypotension may occur. Antidiabetic drugs (oral agents and insulin)-Dosage adjustment of the antidiabetic drug may be required.

Store at temperatures not exceeding 30°C. Protect from heat and moisture.

Angiotensin II Antagonists / Diuretics

C09DA03 - valsartan and diuretics ; Belongs to the class of angiotensin II receptor blockers (ARBs) in combination with diuretics. Used in the treatment of cardiovascular disease.

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