Wilopres Plus 50 mg/12.5 mg/Wilopres Plus 100 mg/25 mg

Losartan potassium, hydrochlorothiazide.

Pharmacologic Category: Angiotensin II Receptor Blocker/Diuretic.
Pharmacology: Pharmacodynamics and Pharmacokinetics: Losartan Potassium: Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT₁ receptor found in many tissues. Losartan inhibits the pressor effect of angiotensin II (as well as angiotensin I) infusions. A dose of 100 mg inhibits the pressor effect by about 85% at peak with 25-40% inhibition persisting for 24 hours.
Following oral administration, losartan is well absorbed and undergoes substantial first-pass metabolism by cytochrome P450 enzymes. The systemic bioavailability of losartan is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and 3-4 hours, respectively. The volume of distribution of losartan and the active metabolite is about 34 liters and 12 liters, respectively. Both Losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of 1.3% and 0.2%, respectively. The terminal half-life of losartan is about 2 hours and of the metabolites is about 6-9 hours. After single doses of losartan administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of losartan and its metabolites.
Hydrochlorothiazide: 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. The mechanism of the antihypertensive effect of thiazides is unknown. After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours.
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Losartan Potassium + Hydrochlorothiazide is indicated for the treatment of hypertension. It is also indicated to reduce risk of stroke in patients with hypertension and left ventricular hypertrophy.

Hypertension: Usual dose: 50 mg + 12.5 mg once daily.
The dosage can be increased after 3 weeks of therapy to a maximum of 100 mg + 25 mg once daily as needed to control blood pressure.
Hypertensive Patients with Left Ventricular Hypertrophy: Initial dose: 50 mg + 12.5 mg once daily.
If additional blood pressure reduction is needed, increase the dose to 100 mg + 25 mg once daily.

Losartan Potassium: Significant lethality was observed in mice and rats after oral administration of 1000 mg/kg and 2000 mg/kg, respectively, about 44 and 170 times the maximum recommended human dose on a mg/m² basis.
Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.
Neither losartan nor its active metabolite can be removed by hemodialysis.
Hydrochlorothiazide: The oral Lethal Dose50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats. The most common signs and symptoms observed 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. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.

Losartan Potassium + Hydrochlorothiazide is contraindicated in patients who are hypersensitive to any component of this product. It is also contraindicated in patients with anuria, and in diabetic patients who are taking aliskiren.

Fetal Toxicity: When pregnancy is detected, discontinue drug as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
Hypotension in Volume or Salt depleted Patients: Volume or salt-depleted patients may experience symptomatic hypotension after initiation of treatment with Losartan Potassium + Hydrochlorothiazide. Do not use this drug as initial therapy in patients with intravascular volume depletion.
Electrolyte and Metabolic Effects: Hydrochlorothiazide can cause hypokalemia, hyponatremia and hypomagnesemia. Hypomagnesemia can result in hypokalemia which may be difficult to treat despite potassium repletion. Hydrochlorothiazide decreases urinary calcium excretion and may cause elevation of serum calcium. This drug also contains losartan which can cause hyperkalemia. Monitor serum electrolytes periodically.
Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.
Hyperuricemia may occur or frank gout may be precipitated in patients receiving thiazide therapy. Because losartan decreases uric acid, losartan in combination with hydrochlorothiazide attenuates the diuretic-induced hyperuricemia.
Impaired Renal Function: Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part of the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function.
Acute Myopia and Secondary Angle-Closure Glaucoma: Hydrochlorothiazide can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to two weeks of drug initiation. The primary treatment is to discontinue hydrochlorothiazide as soon as possible. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Systemic Lupus Erythematosus: Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Non-Melanoma Skin Cancer (NMSC): An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SSC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of hydrochlorothiazide could act as a possible mechanism for NMSC.
Patients taking hydrochlorothiazide should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays, and in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examination of biopsies. The use of hydrochlorothiazide may also need to be reconsidered in patients who have experienced previous NMSC.

Pregnancy: Losartan Potassium + Hydrochlorothiazide can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. When pregnancy is detected, discontinue drug as soon as possible.
Lactation: It is not known whether losartan is excreted in human milk, but significant levels of losartan and its active metabolite were shown to be present in rat milk. Hydrochlorothiazide appears in human milk. Because of the potential for serious adverse effects on the nursing infant, a decision should be made whether to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

Agents Increasing Serum Potassium: Coadministration of losartan with other drugs that raise serum potassium levels may result in hyperkalemia.
Lithium: Increases in serum lithium concentrations have been reported with concomitant use of angiotensin II receptor antagonists (including losartan) or thiazide diuretics (including hydrochlorothiazide).
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) including selective COX-2 Inhibitors: In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs including selective COX-2 inhibitors, with losartan and hydrochlorothiazide may result in deterioration of renal function, including possible acute renal failure. These effects are reversible. Co-administration of NSAIDs including COX-2 inhibitors can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. NSAIDs including COX-2 inhibitors may also attenuate antihypertensive effect of losartan.
ACE Inhibitors and Aliskiren: Dual blockade of renin-angiotensin system (RAS) with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.
Do not co-administer aliskiren with Losartan Potassium + Hydrochlorothiazide in patients with diabetes and in patients with renal impairment (GFR <60 mL/min).
Antidiabetic drugs: Dosage adjustment of the antidiabetic drug may be required.
Cholestyramine and Colestipol resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Hydrochlorothiazide should be administered at least 4 hours before or 4 to 6 hours after the administration of the resin.
Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur when co-administered with hydrochlorothiazide.
Other antihypertensive drugs: Additive effect or potentiation.
Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to muscle relaxant if administered with hydrochlorothiazide.
Corticosteroids, ACTH, or glycyrrhizin (found in liquorice): Concomitant use with hydrochlorothiazide may intensify electrolyte depletion, particularly hypokalemia.
Pressor amines (e.g., norepinephrine): Co-administration of hydrochlorothiazide can cause possible decreased response to pressor amines but not sufficient to preclude their use.

Angiotensin II Antagonists / Diuretics

C09DA01 - losartan 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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