Valsartan, hydrochlorothiazide.
Each film-coated tablet contains: Valsartan, USP 80 mg, Hydrochlorothiazide 12.5 mg.
Pharmacology: Mechanism of Action: Valsartan is an angiotensin II receptor antagonist with antihypertensive activity due mainly to selective blockade of AT1 receptors and the consequent reduced pressure effect of angiotensin II. It is used in the management of hypertension.
Hydrochlorothiazide is a thiazide diuretic. Thiazides affect 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 increased plasma renin activity, increased aldosterone secretion, increased urinary potassium loss, and decreased 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.
Pharmacokinetics: Valsartan is rapidly absorbed after oral doses, with a bioavailability of about 23%. Peak plasma concentrations of valsartan occur 2 to 4 hours after an oral dose. It is between 94 and 97% bound to plasma proteins. Valsartan is not significantly metabolized and is excreted mainly via the bile as unchanged drug. The terminal elimination half- life is about 5 to 9 hours following an oral dose about 83% is excreted in the faeces and 13% in urine. Hydrochlorothiazide is well absorbed (65% to 75%) following oral administration. Peak plasma concentrations are observed within 1 to 5 hours of dosing, and range from 70 to 490 mg/mL following oral doses of 12.4 to 100 mg. The plasma elimination half-life has been reported to be 6 to 15 hours, 55% to 77% of the administered dose appears in urine and greater than 95% of the absorbed dose is excreted in urine as unchanged drug.
Use in the management of hypertension.
The recommended dose is one tablet per day. May be taken with or without food.
Overdose with valsartan may result in marked hypotension, which could lead to depressed level of consciousness, circulatory collapse and/or shock. If the digestion is recent, vomiting should be induced. Otherwise, the usual treatment would be i.v infusion of normal saline solution. Valsartan cannot be eliminated by means of hemodialysis because of its strong plasma binding behavior, whereas clearance of hydrochlorothiazide will be achieved by dialysis.
Valsartan cannot be eliminated by means of hemodialysis because of its strong plasma binding behavior, whereas clearance of hydrochlorothiazide will be achieved by dialysis.
This drug can cause serious (possible fatal) harm to unborn baby if used during pregnancy.
Women of child bearing potential: As for any drug that also acts directly on the RAAS, valsartan + hydrochloride should not be used in women planning to become pregnant. Healthcare professionals prescribing any agents on the RAAs should counsel women of childbearing about the potential risk of these agents during pregnancy.
Pregnancy: As for any that also acts directly on the RAAS, valsartan + hydrochlorothiazide must not be used during pregnancy. Due to mechanism of action of Angiotensin II antagonists, a risk for the fetus cannot be excluded. In utero exposure to angiotensin converting enzyme (ACE) inhibitors (a specifc class of drugs acting on the renin-angiotensin-aldosterone system-RAAS) given to pregnant women during the second and third trimester has been reported to cause injury and death to the developing fetus. In addition, in retrospective data, first trimester use of ACE inhibitors has been associated with a potential risk of birth defects. There have been reports of spontaneous abortion, oligohydramnios and new born renal dysfunction, when pregnant women have inadvertently take valsartan.
Intrauterine exposure to thiazide diuretics, including hydrochlorothiazides, is associated with fetal or neonatal jaundice or thrombocytopenia, and may be associated with other adverse reactions that have occurred in adults.
Breastfeeding: It is not known whether valsartan is excreted in human milk. Valsartan was excreted in the milk of lactating rats. Hydrochlorothiazide crosses the placenta and is excreted in human milk. Thus, use is not advisable in breast-feeding mothers.
Fertility: There is no information on the effects of valsartan or hydrochlorothiazide on human fertility. Studies rats did not show any effects of valsartan or hydrochlorothiazide on fertility.
Dizziness, headache, and dose-related orthostatic hypotension are some of the adverse effects. Hypotension may occur particularly in patients with volume depletion. Impaired renal function and rarely, rash, urticaria, pruritus, angioedema, and raised liver enzyme values may occur. Hyperkalemia, myalgia, and arthralgia have been reported. Other adverse effects that have been reported with angiotensin II receptor antagonists include respiratory tract disorders, back pain, gastrointestinal disturbances, fatigue and neutropenia.
Valsartan-hydrochlorothiazide: The following drug interactions may occur due to both components (valsartan and/or hydrochlorothiazides): Lithium: Reversible increase in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors, angiotensin II receptor antagonists or thiazides. Since renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity may presumably be increased further with Valsartan + Hydrochlorothiazide. Therefore, careful monitoring of serum lithium concentrations is recommended during concomitant use.
Valsartan: The following potential drug interaction may occur due to the valsartan component: Dual blockade of the Renin-Angiotensin-System (RAS) with ARB's, ACEI's, or aliskiren: The concomitant use of ARBs, including valsartan, with other agents acting on the RAS is associated with an increased incidence of hypotension, hyperkalemia, and changes in renal function compared to monotherapy. It is recommended to monitor blood pressure, renal function and electrolytes in patients on valsartan + hydrochlorothiazide and other agents that affect the RAS.
The concomitant use of ARBS - including valsartan - or of ACEIs with aliskiren, should be avoided in patients with severe renal impairment (GFR< 30 mL/min).
The concomitant use of ARBS - including valsartan - or of ACEIs with aliskiren is contraindicated in patients with Type 2 diabetes.
Potassium: Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other drugs that may alter potassium levels (heparin, etc.) should be used with caution and with frequent monitoring of potassium.
Non-Steroidal Anti-Inflammatory Agents (NSAIDs) including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur.
Furthermore, in patients who are elderly, volume-depleted (including those on diuretic therapy), or have compromised renal function, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function. Therefore, monitoring of renal function is recommended when initiating or modifying the treatment in patients on valsartan who are taking NSAIDs concomitantly.
Hydrochlorothiazide: The following potential drug interactions may occur due to the thiazide component: Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concurrent use of ACE inhibitors and thiazides. There is no experience with concomitant use of valsartan and lithium. Therefore, monitoring of serum lithium concentrations is recommended during concurrent use.
Other anti-hypertensive drugs: The thiazides potentiate the antihypertensive action of other antihypertensive drugs (e.g guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, ACE inhibitors, Angiotensin Receptor Blockers (ARBs) and Direct Renin Inhibitors (DRIs).
Skeletal muscle relaxants: Thiazides, including hydrochlorothiazide, potentiate the action of skeletal muscle relaxants such as curare derivatives.
Medicinal products affecting serum potassium levels: The hypokalemic effect of diuretics may be increased by concomitant administration of kaliuretic diuretics, corticosteroids, ACTH.
Antidiabetic agents: Thiazides may alter glucose tolerance. It may be necessary to adjust the dosage of insulin and oral antidiabetic agents.
Digitalis glycosides: Thiazide-induced hypokalemia or hypomagnesemia may occur as unwanted effects, favoring the onset of digitalis-induced cardiac arrythmias.
NSAIDs and Cox-2 selective inhibitors: Concomitant administration of NSAIDs (e.g salicylic acid derivative, indomethacin) may weaken the diuretic and antihypertensive activity of the thiazide component. Concurrent hypovolemia may include acute renal failure.
Allopurinol: Co-administration of thiazide diuretics (including hydrochlorothiazide) may increase the incidence of hypersensitivity reactions to allopurinol.
Amantadine: Co-administration of thiazide diuretics (including hydrochlorothiazide) may increase the risk of adverse effects caused by amantadine.
Antineoplastic agents (e.g cyclophosphamide, methotrexate): Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.
Anticholinergic agents: The bioavailability of thiazide-type diuretics may be increased by anticholinergic (e.g atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely prokinetic drugs such as cisapride may decrease the bioavailability of thiazide-type diuretics.
Ion exchange resin: Absorption thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine or colestipol. However, staggering the dosage of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 h before or 4 - 6 h after the administration of resins would potentially minimize the interaction.
Vitamin D: Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may potentiate the rise in serum calcium.
Ciclosporin: Concomitant treatment with ciclosporin may increase the risk of hyperuricemia and gout-type complications.
Calcium salts: Concomitant use of thiazide type diuretics may lead to hypercalcemia by increasing tubular calcium reabsoprtion.
Diazoxide: Thiazide diuretics may enhance the hyperglycemic effect of diazoxide.
Methyldopa: There have been reports in the literature of hemolytic anemia occurring with concomitant us of hydrochlorothiazide band methyldopa.
Alcohol, barbiturates or narcotics: Concomitant administration of thiazide diuretics with alcohol, barbiturates, or narcotics may potentiate orthostatic hypotension.
Pressor amines: Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline. The clinical significance of this effect is uncertain and not sufficient to preclude their use.
Store at temperatures not exceeding 30°C.
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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