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LOSARTAN POTASSIUM AND HYDROCHLOROTHIAZIDE- losartan potassium and hydrochlorothiazide tablet
Roxane Laboratories, Inc.

USE IN PREGNANCY

DESCRIPTION

Losartan Potassium and Hydrochlorothiazide Tablets combine an angiotensin II receptor (type AT₁ ) antagonist and a diuretic, hydrochlorothiazide.

Losartan potassium, a non­peptide molecule, is chemically described as 2­butyl­4­chloro­1­[p­ (o­1H­ tetrazol-5­ylphenyl)benzyl]imidazole­5­methanol monopotassium salt. Its molecular formula is C₂₂ H₂₂ ClKN₆ O, and its structural formula is:

Losartan potassium is a white to off­white free­flowing crystalline powder with a molecular weight of 461.01. It is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as acetonitrile and methyl ethyl ketone.

Oxidation of the 5­hydroxymethyl group on the imidazole ring results in the active metabolite of losartan.

Hydrochlorothiazide is 6­chloro­3,4­dihydro­2H­ 1,2,4­benzothiadiazine­7­sulfonamide 1,1­dioxide. Its molecular formula is C₇ H₈ ClN₃ O₄ S₂ and its structural formula is:

Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.74, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.

Losartan Potassium and Hydrochlorothiazide Tablets are available for oral administration in three tablet combinations of losartan and hydrochlorothiazide. Losartan Potassium and Hydrochlorothiazide Tablets 50­12.5 contains 50 mg of losartan potassium USP and 12.5 mg of hydrochlorothiazide USP. Losartan Potassium and Hydrochlorothiazide Tablets 100­12.5 contains 100 mg of losartan potassium USP and 12.5 mg of hydrochlorothiazide USP. Losartan Potassium and Hydrochlorothiazide Tablets 100­25 contains 100 mg of losartan potassium USP and 25 mg of hydrochlorothiazide USP. Inactive ingredients are lactose, magnesium stearate, microcrystalline cellulose, pregelatinized starch and purified water. In addition to these ingredients the 50-12.5 mg and 100-25 mg tablets also contain Opadry II (Yellow), and the 100-12.5 mg tablet contains Opadry II (White). Opadry II (Yellow) contains D&C yellow #10 aluminum lake, hypromellose, lactose monohydrate, polyethylene glycol, titanium dioxide and triacetin. Opadry II (White) contains hypromellose, polyethylene glycol, polydextrose, titanium dioxide and triacetin.

Losartan Potassium and Hydrochlorothiazide Tablets 50­12.5 contains 4.24 mg (0.108 mEq) of potassium, Losartan Potassium and Hydrochlorothiazide Tablets 100­12.5 contains 8.48 mg (0.216 mEq) of potassium, and Losartan Potassium and Hydrochlorothiazide Tablets 100­25 contains 8.48 mg (0.216 mEq) of potassium.

CLINICAL PHARMACOLOGY

Mechanism of Action

Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)], is a potent vasoconstrictor, the primary vasoactive hormone of the renin­angiotensin 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 aldosterone­secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT₁ receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). There is also an AT₂ receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Both losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT₁ receptor and have much greater affinity (about 1000­fold) for the AT₁ receptor than for the AT₂ receptor. 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, non­competitive inhibitor of the AT₁ receptor.

Neither losartan nor its active metabolite inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin); nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

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 renin­aldosterone 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

General

Losartan Potassium

Losartan is an orally active agent that undergoes substantial first­pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows losartan treatment. The terminal half­life of losartan is about 2 hours and of the metabolite is about 6 to 9 hours. The pharmacokinetics of losartan and its active metabolite are linear with oral losartan doses up to 200 mg and do not change over time. Neither losartan nor its metabolite accumulate in plasma upon repeated once­daily dosing.

Following oral administration, losartan is well absorbed (based on absorption of radiolabeled losartan) and undergoes substantial first­pass metabolism; the systemic bioavailability of losartan is approximately 33%. About 14% of an orally­administered dose of losartan is converted to the active metabolite. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3 to 4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its C_max but has only minor effects on losartan AUC or on the AUC of the metabolite (about 10% decreased).

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. Plasma protein binding is constant over the concentration range achieved with recommended doses. Studies in rats indicate that losartan crosses the blood­brain barrier poorly, if at all.

Losartan metabolites have been identified in human plasma and urine. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. Following oral and intravenous administration of ¹⁴ C­labeled losartan potassium, circulating plasma radioactivity is primarily attributed to losartan and its active metabolite. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites. Minimal conversion of losartan to the active metabolite (less than 1% of the dose compared to 14% of the dose in normal subjects) was seen in about one percent of individuals studied.

The volume of distribution of losartan is about 34 liters and of the active metabolite is about 12 liters. Total plasma clearance of losartan and the active metabolite is about 600 mL/min and 50 mL/min, respectively, with renal clearance of about 75 mL/min and 25 mL/min, respectively. When losartan is 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. Following oral ¹⁴ C­labeled losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of ¹⁴ C­labeled losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces.

Special Populations

Pediatric

Losartan pharmacokinetics have not been investigated in patients 6 to 16 years (see PRECAUTIONS: Pediatric Use).

Geriatric and Gender

Losartan pharmacokinetics have been investigated in the elderly (65 to 75 years) and in both genders. Plasma concentrations of losartan and its active metabolite are similar in elderly and young hypertensives. Plasma concentrations of losartan were about twice as high in female hypertensives as male hypertensives, but concentrations of the active metabolite were similar in males and females.

Race

Pharmacokinetic differences due to race have not been studied (see also PRECAUTIONS: Race and CLINICAL PHARMACOLOGY: Pharmacodynamics and Clinical Effects: Losartan Potassium : Reduction in the Risk of Stroke: Race ).

Renal Insufficiency

Losartan

Following oral administration, plasma concentrations and AUCs of losartan and its active metabolite are increased by 50 to 90% in patients with mild (creatinine clearance of 50 to 74 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal insufficiency. In this study, renal clearance was reduced by 55 to 85% for both losartan and its active metabolite in patients with mild or moderate renal insufficiency. Neither losartan nor its active metabolite can be removed by hemodialysis.

Hydrochlorothiazide

Following oral administration, the AUC for hydrochlorothiazide is increased by 70 and 700% for patients with mild and moderate renal insufficiency, respectively. In this study, renal clearance of hydrochlorothiazide decreased by 45 and 85% in patients with mild and moderate renal impairment, respectively.

The usual regimens of therapy with losartan potassium and hydrochlorothiazide 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 losartan potassium and hydrochlorothiazide is not recommended. (See DOSAGE AND ADMINISTRATION.)

Hepatic Insufficiency

Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5 times and about 1.7 times those in young male volunteers. Compared to normal subjects the total plasma clearance of losartan in patients with hepatic insufficiency was about 50% lower and the oral bioavailability was about 2 times higher. The lower starting dose of losartan recommended for use in patients with hepatic impairment cannot be given using losartan potassium and hydrochlorothiazide. Its use in such patients as a means of losartan titration is, therefore, not recommended (see DOSAGE AND ADMINISTRATION).

Drug Interactions

Losartan Potassium

Losartan, administered for 12 days, did not affect the pharmacokinetics or pharmacodynamics of a single dose of warfarin. Losartan did not affect the pharmacokinetics of oral or intravenous digoxin. There is no pharmacokinetic interaction between losartan and hydrochlorothiazide. Coadministration of losartan and cimetidine led to an increase of about 18% in AUC of losartan but did not affect the pharmacokinetics of its active metabolite. Coadministration of losartan and phenobarbital led to a reduction of about 20% in the AUC of losartan and that of its active metabolite. A somewhat greater interaction (approximately 40% reduction in the AUC of active metabolite and approximately 30% reduction in the AUC of losartan) has been reported with rifampin. Fluconazole, an inhibitor of cytochrome P450 2C9, decreased the AUC of the active metabolite by approximately 40%, but increased the AUC of losartan by approximately 70% following multiple doses. Conversion of losartan to its active metabolite after intravenous administration is not affected by ketoconazole, an inhibitor of P450 3A4. The AUC of active metabolite following oral losartan was not affected by erythromycin, another inhibitor of P450 3A4, but the AUC of losartan was increased by 30%.

Hydrochlorothiazide

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 half­life 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 blood­brain barrier and is excreted in breast milk.

Pharmacodynamics and Clinical Effects

Losartan Potassium

Hypertension

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 to 40% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin activity and consequent rise in angiotensin II plasma concentration in hypertensive patients. Losartan does not affect the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin. Aldosterone plasma concentrations fall following losartan administration. In spite of the effect of losartan on aldosterone secretion, very little effect on serum potassium was observed.

In a single­dose study in normal volunteers, losartan had no effects on glomerular filtration rate, renal plasma flow or filtration fraction. In multiple-dose studies in hypertensive patients, there were no notable effects on systemic or renal prostaglandin concentrations, fasting triglycerides, total cholesterol or HDL­cholesterol or fasting glucose concentrations. There was a small uricosuric effect leading to a minimal decrease in serum uric acid (mean decrease <0.4 mg/dL) during chronic oral administration.

The antihypertensive effects of losartan were demonstrated principally in 4 placebo­controlled 6- to 12-week trials of dosages from 10 to 150 mg per day in patients with baseline diastolic blood pressures of 95 to 115. The studies allowed comparisons of two doses (50 to 100 mg/day) as once­daily or twice­daily regimens, comparisons of peak and trough effects, and comparisons of response by gender, age, and race. Three additional studies examined the antihypertensive effects of losartan and hydrochlorothiazide in combination.

The 4 studies of losartan monotherapy included a total of 1075 patients randomized to several doses of losartan and 334 to placebo. The 10 and 25 mg doses produced some effect at peak (6 hours after dosing) but small and inconsistent trough (24 hour) responses. Doses of 50, 100, and 150 mg once daily gave statistically significant systolic/diastolic mean decreases in blood pressure, compared to placebo in the range of 5.5 to 10.5/3.5 to 7.5 mmHg, with the 150 mg dose giving no greater effect than 50 to 100 mg. Twice­daily dosing at 50 to 100 mg/day gave consistently larger trough responses than once-daily dosing at the same total dose. Peak (6 hour) effects were uniformly, but moderately larger than trough effects, with the trough to peak ratio for systolic and diastolic responses 50 to 95% and 60 to 90%, respectively.

Analysis of age, gender, and race subgroups of patients showed that men and women, and patients over and under 65, had generally similar responses. Losartan was effective in reducing blood pressure regardless of race, although the effect was somewhat less in Black patients (usually a low­renin population).

The effect of losartan is substantially present within one week but in some studies the maximal effect occurred in 3 to 6 weeks. In long­term follow­up studies (without placebo control) the effect of losartan appeared to be maintained for up to a year. There is no apparent rebound effect after abrupt withdrawal of losartan. There was essentially no change in average heart rate in losartan­treated patients in controlled trials.