losartan potassium and hydrochlorothiazide

1 INDICATIONS AND USAGE Losartan potassium and hydrochlorothiazide tablets USP are a combination of losartan, an angiotensin II receptor blocker (ARB) and hydrochlorothiazide, a diuretic indicated for: · Treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. (1.1) · Reduction of the risk of stroke in patients with hypertension and left ventricular hypertrophy. There is evidence that this benefit does not apply to Black patients. (1.2) 1.1 Hypertension Losartan potassium and hydrochlorothiazide tablets USP are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular (CV) events, primarily strokes and myocardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including losartan and hydrochlorothiazide. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. This fixed dose combination is not indicated for initial therapy of hypertension, except when the hypertension is severe enough that the value of achieving prompt blood pressure control exceeds the risk of initiating combination therapy in these patients [see Clinical Studies (14) and Dosage and Administration (2.1)]. Losartan potassium and hydrochlorothiazide tablets USP may be administered with other antihypertensive agents. 1.2 Hypertensive Patients with Left Ventricular Hypertrophy Losartan potassium and hydrochlorothiazide tablets USP are indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to Black patients. [See Use in Specific Populations (8.6), Clinical Pharmacology (12.3), and Dosage and Administration (2.5).]

DOSAGE AND ADMINISTRATION Hypertension Dosing must be individualized. The usual starting dose of losartan is 50 mg once daily, with 25 mg recommended for patients with intravascular volume depletion (e.g., patients treated with diuretics) (see WARNINGS , Hypotension — Volume-Depleted Patients ) and patients with a history of hepatic impairment (see WARNINGS , Impaired Hepatic Function ). Losartan can be administered once or twice daily at total daily doses of 25 to 100 mg. If the antihypertensive effect measured at trough using once-a-day dosing is inadequate, a twice-a-day regimen at the same total daily dose or an increase in dose may give a more satisfactory response. Hydrochlorothiazide is effective in doses of 12.5 to 50 mg once daily and can be given at doses of 12.5 to 25 mg as losartan potassium and hydrochlorothiazide tablets USP. To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. The side effects (see WARNINGS ) of losartan are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of losartan and hydrochlorothiazide will be associated with both sets of dose-independent side effects. Replacement Therapy The combination may be substituted for the titrated components. Dose Titration by Clinical Effect A patient whose blood pressure is not adequately controlled with losartan monotherapy (see above) or hydrochlorothiazide alone may be switched to losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg (losartan 50 mg/hydrochlorothiazide 12.5 mg) once daily. If blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to two tablets of losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg once daily or one tablet of losartan potassium and hydrochlorothiazide tablets USP, 100 mg/25 mg (losartan 100 mg/hydrochlorothiazide 25 mg) once daily. A patient whose blood pressure is not adequately controlled with losartan 100 mg monotherapy (see above) may be switched to losartan potassium and hydrochlorothiazide tablets USP, 100 mg/12.5 mg once daily. If blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to two tablets of losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg once daily or one tablet of losartan potassium and hydrochlorothiazide tablets USP, 100 mg/25 mg (losartan 100 mg/hydrochlorothiazide 25 mg) once daily. A patient whose blood pressure is inadequately controlled by 25 mg once daily of hydrochlorothiazide, or is controlled but who experiences hypokalemia with this regimen, may be switched to losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg, (losartan 50 mg/hydrochlorothiazide 12.5 mg) once daily, reducing the dose of hydrochlorothiazide without reducing the overall expected antihypertensive response. The clinical response to losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg should be subsequently evaluated, and if blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to two tablets of losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg once daily or one tablet of losartan potassium and hydrochlorothiazide tablets USP, 100 mg/25 mg (losartan 100 mg/hydrochlorothiazide 25 mg) once daily. The usual dose of losartan potassium and hydrochlorothiazide tablets USP is one tablet of losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg once daily. More than two tablets of losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg once daily or more than one tablet of losartan potassium and hydrochlorothiazide tablets USP, 100 mg/25 mg once daily i …

3 DOSAGE FORMS AND STRENGTHS Losartan Potassium and Hydrochlorothiazide Tablets USP , 50 mg/12.5 mg are yellow colored, oval shaped, beveled edge, biconvex film-coated tablets debossed with ‘E’ on one side and ‘48’ on the other side. Losartan Potassium and Hydrochlorothiazide Tablets USP, 100 mg/12.5 mg are white, oval shaped, beveled edge, biconvex film-coated tablets debossed with ‘F’ on one side and ‘74’ on the other side. Losartan Potassium and Hydrochlorothiazide Tablets USP, 100 mg/25 mg are yellow colored, oval shaped, beveled edge, biconvex film-coated tablets debossed with ‘E’ on one side and ‘49’ on the other side. Tablets (losartan potassium/hydrochlorothiazide content): 50 mg/12.5 mg; 100 mg/12.5 mg; and 100 mg/25 mg. ( 3 )

4 CONTRAINDICATIONS Losartan potassium and hydrochlorothiazide tablets are contraindicated: • In patients who are hypersensitive to any component of this product. • In patients with anuria • For coadministration with aliskiren in patients with diabetes • Hypersensitivity to any component of losartan potassium and hydrochlorothiazide tablets. ( 4 ) • Anuria. ( 4 ) • Coadministration with aliskiren in patients with diabetes. ( 4 )

ADVERSE REACTIONS Losartan potassium and hydrochlorothiazide has been evaluated for safety in 858 patients treated for essential hypertension and 3889 patients treated for hypertension and left ventricular hypertrophy. In clinical trials with losartan potassium and hydrochlorothiazide, no adverse experiences peculiar to this combination have been observed. Adverse experiences have been limited to those that were reported previously with losartan potassium and/or hydrochlorothiazide. The overall incidence of adverse experiences reported with the combination was comparable to placebo. In general, treatment with losartan potassium and hydrochlorothiazide was well tolerated. For the most part, adverse experiences have been mild and transient in nature and have not required discontinuation of therapy. In controlled clinical trials, discontinuation of therapy due to clinical adverse experiences was required in only 2.8% and 2.3% of patients treated with the combination and placebo, respectively. In these double-blind controlled clinical trials, the following adverse experiences reported with losartan and hydrochlorothiazide occurred in ≥1 percent of patients, and more often on drug than placebo, regardless of drug relationship: Table 1: Losartan Potassium and Hydrochlorothiazide (n=858) Placebo (n=173) Body as a Whole Abdominal pain 1.2 0.6 Edema/swelling 1.3 1.2 Cardiovascular Palpitation 1.4 0 Musculoskeletal Back pain 2.1 0.6 Nervous/Psychiatric Dizziness 5.7 2.9 Respiratory Cough 2.6 2.3 Sinusitis 1.2 0.6 Upper respiratory infection 6.1 4.6 Skin Rash 1.4 0 The following adverse events were also reported at a rate of 1% or greater, but were as, or more, common in the placebo group in studies of essential hypertension: asthenia/fatigue, diarrhea, nausea, headache, bronchitis, pharyngitis. Adverse events occurred at about the same rates in men and women. Adverse events were somewhat more frequent in the elderly compared to non-elderly patients and somewhat more frequent in Blacks compared to non-Blacks for both the losartan and hydrochlorothiazide and the control groups. A patient with known hypersensitivity to aspirin and penicillin, when treated with losartan potassium, was withdrawn from study due to swelling of the lips and eyelids and facial rash, reported as angioedema, which returned to normal 5 days after therapy was discontinued. Superficial peeling of palms and hemolysis were reported in one subject treated with losartan potassium. Losartan Potassium Other adverse experiences that have been reported with losartan, without regard to causality, are listed below: Body as a Whole: chest pain, facial edema, fever, orthostatic effects, syncope Cardiovascular: angina pectoris, arrhythmias including atrial fibrillation, sinus bradycardia, tachycardia, ventricular tachycardia and ventricular fibrillation, CVA, hypotension, myocardial infarction, second degree AV block Digestive: anorexia, constipation, dental pain, dry mouth, dyspepsia, flatulence, gastritis, vomiting General disorders and administration site conditions: malaise Hematologic: anemia Metabolic: gout Musculoskeletal: arm pain, arthralgia, arthritis, fibromyalgia, hip pain, joint swelling, knee pain, leg pain, muscle cramps, muscle weakness, musculoskeletal pain, myalgia, shoulder pain, stiffness Nervous System/Psychiatric: anxiety, anxiety disorder, ataxia, confusion, depression, dream abnormality, hypesthesia, insomnia, libido decreased, memory impairment, migraine, nervousness, panic disorder, paresthesia, peripheral neuropathy, sleep disorder, somnolence, tremor, vertigo Respiratory: dyspnea, epistaxis, nasal congestion, pharyngeal discomfort, respiratory congestion, rhinitis, sinus disorder Skin: alopecia, dermatitis, dry skin, ecchymosis, erythema, flushing, photosensitivity, pruritus, sweating, urticaria Special Senses: blurred vision, burning/stinging in the eye, conjunctivitis, decrease in visual acuity, taste perversion, tinnitus Urogenital: impotence, noctu …

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 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.

Drug Interactions Losartan Potassium No significant drug-drug pharmacokinetic interactions have been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. Rifampin, an inducer of drug metabolism, decreased the concentrations of losartan and its active metabolite (see CLINICAL PHARMACOLOGY , Drug Interactions ). In humans, two inhibitors of P450 3A4 have been studied. Ketoconazole did not affect the conversion of losartan to the active metabolite after intravenous administration of losartan, and erythromycin had no clinically significant effect after oral administration. Fluconazole, an inhibitor of P450 2C9, decreased active metabolite concentration and increased losartan concentration. The pharmacodynamic consequences of concomitant use of losartan and inhibitors of P450 2C9 have not been examined. Subjects who do not metabolize losartan to active metabolite have been shown to have a specific, rare defect in cytochrome P450 2C9. These data suggest that the conversion of losartan to its active metabolite is mediated primarily by P450 2C9 and not P450 3A4. As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium (see PRECAUTIONS , Information for Patients, Potassium Supplements ). Lithium Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (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 angiotensin II receptor antagonists (including losartan) may result in deterioration of renal function, including possible acute renal failure. These effects …

8 USE IN SPECIFIC POPULATIONS · Hepatic Impairment: Losartan potassium and hydrochlorothiazide tablet is not recommended for initial therapy, because the recommended starting dose is not available. ( 8.7 ) 8.1 Pregnancy Risk Summary Losartan potassium and hydrochlorothiazide tablets 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. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. When pregnancy is detected, discontinue losartan potassium and hydrochlorothiazide tablets as soon as possible ( see Clinical Considerations ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions Losartan: Use of drugs that act on the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: oligohydramnios, reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue losartan potassium and hydrochlorothiazide tablets, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe neonates with histories of in utero exposure to losartan potassium and hydrochlorothiazide tablets for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to losartan potassium and hydrochlorothiazide tablets, if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function. Hydrochlorothiazide: Thiazides can cross the placenta, and concentrations reached in the umbilical vein approach those in the maternal plasma. Hydrochlorothiazide, like other diuretics, can cause placental hypoperfusion. It accumulates in the amniotic fluid, with reported concentrations up to 19 times higher than in umbilical vein plasma. Use of thiazides during pregnancy is associated with a risk of fetal or neonatal jaundice or thrombocytopenia. Since they do not alter the course of pre-eclampsia, these drugs should not be used to treat hypertension in pregnant women. The use of hydrochlorothiazide for other indications in pregnancy should be avoided. Data Animal Data There was no evidence of teratogenicity in rats or rabbits treated with a maximum losartan potassium dose of 10 mg/kg/day in …

12.1 Mechanism of Action Losartan Potassium 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 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 AT 1 receptor found in many tissues (e.g., vascular smooth muscle, adrenal gland). There is also an AT 2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Neither losartan nor its principal active metabolite exhibits any partial agonist activity at the AT 1 receptor, and both have much greater affinity (about 1,000-fold) for the AT 1 receptor than for the AT 2 receptor. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT 1 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 AT 1 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 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 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. The mechanism of the antihypertensive effect of thiazides is unknown.

11 DESCRIPTION Losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg, losartan potassium and hydrochlorothiazide tablets USP, 100 mg/12.5 mg and losartan potassium and hydrochlorothiazide tablets USP, 100 mg/25 mg combine an angiotensin II receptor blocker acting on the AT 1 receptor subtype and a diuretic, hydrochlorothiazide. Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-[ p- ( o -1 H -tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt. Its empirical formula is C 22 H 22 ClKN 6 O, and its structural formula is: Losartan potassium, USP is a white to off-white free-flowing 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 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan. Hydrochlorothiazide is 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C 7 H 8 ClN 3 O 4 S 2 and its structural formula is: Hydrochlorothiazide, USP 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, USP are available for oral administration in three tablet combinations of losartan and hydrochlorothiazide. Losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg contain 50 mg of losartan potassium, USP and 12.5 mg of hydrochlorothiazide, USP. Losartan potassium and hydrochlorothiazide tablets USP, 100 mg/12.5 mg contain 100 mg of losartan potassium, USP and 12.5 mg of hydrochlorothiazide, USP. Losartan potassium and hydrochlorothiazide tablets USP, 100 mg/25 mg contain 100 mg of losartan potassium, USP and 25 mg of hydrochlorothiazide, USP. Inactive ingredients are colloidal silicon dioxide, lactose monohydrate, macrogol/polyethylene glycol, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol-part hydrolyzed, pregelatinized starch, talc and titanium dioxide. Losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg and 100 mg/25 mg also contain D&C yellow No. 10 aluminum lake and FD&C blue No. 1/brilliant blue FCF aluminum lake. Losartan potassium and hydrochlorothiazide tablets USP, 100 mg/12.5 mg also contain lecithin. Losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg contain 4.24 mg (0.108 mEq) of potassium, losartan potassium and hydrochlorothiazide tablets USP, 100 mg/12.5 mg contain 8.48 mg (0.216 mEq) of potassium, and losartan potassium and hydrochlorothiazide tablets USP, 100 mg/25 mg contain 8.48 mg (0.216 mEq) of potassium. figure-01 figure-02

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 LD50 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 and hydrochlorothiazide tablets, USP 50/12.5, losartan potassium and hydrochlorothiazide tablets, USP 100/12.5 and losartan potassium and hydrochlorothiazide tablets, USP 100/25 combine an angiotensin II receptor blocker acting on the AT1 receptor subtype and a diuretic, hydrochlorothiazide USP. Losartan potassium USP, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt. Its molecular formula is C22H22ClKN6O, and its structural formula is: Losartan potassium Losartan potassium USP is a white to off-white free-flowing 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 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan. Hydrochlorothiazide USP is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its molecular formula is C7H8ClN3O4S2 and its structural formula is: Hydrochlorothiazide Hydrochlorothiazide USP 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, USP 50/12.5 contains 50 mg of losartan potassium USP and 12.5 mg of hydrochlorothiazide USP. Losartan potassium and hydrochlorothiazide tablets, USP 100/12.5 contains 100 mg of losartan potassium USP and 12.5 mg of hydrochlorothiazide USP. Losartan potassium and hydrochlorothiazide tablets, USP 100/25 contains 100 mg of losartan potassium USP and 25 mg of hydrochlorothiazide USP. Inactive ingredients are microcrystalline cellulose, lactose monohydrate, pregelatinized starch, colloidal silicon dioxide, magnesium stearate, hydroxypropyl cellulose, hypromellose, and titanium dioxide. Losartan potassium and hydrochlorothiazide tablets, USP 50/12.5 and losartan potassium and hydrochlorothiazide tablets, USP 100/25 also contain yellow ferric oxide. Losartan potassium and hydrochlorothiazide tablets, USP 50/12.5 contains 4.24 mg (0.108 mEq) of potassium, losartan potassium and hydrochlorothiazide tablets, USP 100/12.5 contains 8.48 mg (0.216 mEq) of potassium, and losartan potassium and hydrochlorothiazide tablets, USP 100/25 contains 8.48 mg (0.216 mEq) of potassium.

16 HOW SUPPLIED/STORAGE AND HANDLING Losartan potassium and Hydrochlorothiazide Tablets USP, 50/12.5 mg Yellow, oval, film coated tablet debossed with "C" on one side and "337" on other side. Bottles of 30 tablets with Child Resistant Closure, NDC 59746-337-30. Bottles of 90 tablets with Child Resistant Closure, NDC 59746-337-90. Bottles of 100 tablets with Child Resistant Closure, NDC 59746-337-01. Bottles of 1000 tablets with Plain Closure, NDC 59746-337-10. Losartan potassium and Hydrochlorothiazide Tablets USP, 100/12.5 mg White, oval, film coated tablet debossed with "C" on one side and "338" on other side. Bottles of 30 tablets with Child Resistant Closure, NDC 59746-338-30. Bottles of 90 tablets with Child Resistant Closure, NDC 59746-338-90. Bottles of 100 tablets with Child Resistant Closure, NDC 59746-338-01. Bottles of 1000 tablets with Plain Closure, NDC 59746-338-10. Losartan potassium and Hydrochlorothiazide Tablets USP, 100/25 mg Yellow, oval, film coated tablet debossed with "C" on one side and "339" on other side. Bottles of 30 tablets with Child Resistant Closure, NDC 59746-339-30. Bottles of 90 tablets with Child Resistant Closure, NDC 59746-339-90. Bottles of 100 tablets with Child Resistant Closure, NDC 59746-339-01. Bottles of 1000 tablets with Plain Closure, NDC 59746-339-10. Storage Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from light. Keep this and all medicines out of the reach of children.