LOSARITE Losartan Potassium / Hydrochlorothiazide 50mg / 12.5mg Film-Coated Tablet 30's

 

Use in Pregnancy: When used in pregnancy during the second and third trimesters, drugs that act on the renin-angiotensin system (e.g., losartan) can cause injury and even death to the developing fetus. When pregnancy is detected, discontinue losartan as soon as possible.

 

Use in Pregnancy: When used in pregnancy during the second and third trimesters, drugs that act on the renin-angiotensin system (e.g., losartan) can cause injury and even death to the developing fetus. When pregnancy is detected, discontinue losartan as soon as possible.
Use in Lactation: It is not known whether losartan is excreted in human milk. HCTZ appears in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

 

Store at temperatures not exceeding 30°C.

 

Pharmacology: Losartan potassium: Angiotensin II is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. 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. There is also an AT₂ receptor found in many tissues but is not known to be associated with cardiovascular homeostasis. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT₁ receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT₁ receptor.
Neither losartan nor its active metabolite inhibits ACE, nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Hydrochlorothiazide (HCTZ): Hydrochlorothiazide is a thiazide diuretic. Thiazides increase the excretion of water by inhibiting the reabsorption of sodium and chloride ions at the distal renal tubule. The natriuretic effects are accompanied by a secondary loss of potassium and bicarbonate which can cause a mild hypokalemic, hypochloremic, metabolic alkalosis. Thiazides also decrease the elimination of calcium and uric acid. Thiazide diuretics usually do not affect normal blood pressure. When chronically administered, thiazide diuretics decrease peripheral vascular resistance. The exact mechanism responsible for lowered peripheral resistance is not known, however, excretion of urinary sodium by the kidneys is required to achieve blood pressure reduction. Initially, diuretics lower blood pressure by decreasing cardiac output, plasma volume and extracellular fluid volume. Cardiac output eventually returns to normal, plasma and extracellular fluid values return slightly less than normal, but peripheral vascular resistance is reduced, resulting in lower blood pressure.
Pharmacokinetics: The combination of losartan and hydrochlorothiazide (HCTZ) is administered orally The blood pressure lowering effect of losartan is additive with that of HCTZ.
Losartan Potassium: Following oral administration, losartan is well absorbed but undergoes presystemic metabolism, forming an active metabolite (E-3174) and other inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations of losartan and its active metabolites are reached in 1 hour and in 3-4 hours, respectively. There is no clinically significant effect on the plasma concentration profile of losartan when the drug is administered with a meal.
Both losartan and its metabolite are ≥ 99% bound to plasma proteins, primarily albumin.
The volume of distribution of losartan is relatively low at 34 liters.
Plasma concentrations of the active metabolite are higher than those of losartan at all doses, Cmax and AUC for E-3174 are approximately 2 and 5-8 times greater than the corresponding values for losartan itself.
Following oral administration, the plasma concentration of losartan, and its active metabolite, decline polyexponentially, with terminal half-lives of about 2 hours (1.5-2.5 hours) and 6-9 hours, respectively. As anticipated from their short half-lives, neither losartan nor its active metabolite accumulates significantly in plasma during once daily dosing with 100 mg.
The plasma clearance of losartan and its active metabolite is about 600 mL/min and 50 mL/min, respectively. Losartan is extensively metabolized in the liver. Approximately 35% of an oral dose is excreted in the urine as unchanged compound and metabolites. Only 4% of the dose is eliminated unchanged via the kidneys. The renal clearance of losartan is 74 mL/min. Approximately 6% of the dose is excreted in urine as the active metabolite with a renal clearance of 26 mL/min. Losartan and its metabolites are also eliminated by biliary excretion, with 58% of an oral dose recovered in the feces.
Hydrochlorothiazide (HCTZ): Hydrochlorothiazide is variably absorbed from the gastrointestinal tract depending on the formulation and dose. The systemic bioavailability is approximately 50-60%. After oral administration of HCTZ, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6-12 hours. The duration of action ranges from 6-12 hours. The drug crosses the placenta, but not the blood-brain barrier and is distributed in breast milk. HCTZ is not metabolised but is eliminated unchanged within 24 hours. The elimination half-life of HCTZ was originally reported to range from 5.6-14.8 hours when plasma levels were followed for at least 24 hours. A more recent study reports a mean elimination half-life of 2.5 hours in patients with normal renal function. The elimination half-life is estimated to increase 12-20 hours in patients with severe renal disease (e.g. creatinine clearance < 10 mL/min).