Losartan Potassium And Hydrochlorothiazide

FDA Drug Information • Also known as: Hyzaar, Losartan Potassium And Hydrochlorothiazide

Brand Names: Hyzaar, Losartan Potassium And Hydrochlorothiazide
Drug Class: Thiazide Diuretic [EPC]
Route: ORAL
Dosage Form: TABLET, FILM COATED
Product Type: HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: FETAL TOXICITY

When pregnancy is detected, discontinue losartan potassium and hydrochlorothiazide as soon as possible.

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See WARNINGS, Fetal Toxicity .

Description

DESCRIPTION Losartan potassium and hydrochlorothiazide 50 mg/12.5 mg, losartan potassium and hydrochlorothiazide 100 mg/12.5 mg and losartan potassium and hydrochlorothiazide 100 mg/25 mg, combine an angiotensin II receptor (type AT 1 ) antagonist 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 molecular formula is C 22 H 22 ClKN 6 O, and its structural formula is: Losartan potassium USP is a white to off-white 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 molecular 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, practically odorless, 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 is 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, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate,...

What Is Losartan Potassium And Hydrochlorothiazide Used For?

INDICATIONS AND USAGE Hypertension Losartan potassium and hydrochlorothiazide tablets, USP are indicated for the treatment of hypertension. 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 PHARMACOLOGY, Pharmacodynamics and Clinical Effects , and DOSAGE AND ADMINISTRATION ). 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 PRECAUTIONS, Race , CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Losartan Potassium, Reduction in the Risk of Stroke, Race , and DOSAGE AND ADMINISTRATION ).

Dosage and Administration

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. 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 50 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 50 mg/12.5 mg once daily or one tablet of losartan potassium and hydrochlorothiazide 100 mg/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 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 50 mg/12.5 mg once daily or one tablet of losartan potassium and hydrochlorothiazide 100 mg/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 50 mg/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 50 mg/12.5 mg should be...

Side Effects (Adverse Reactions)

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,...

Warnings and Precautions

WARNINGS Fetal Toxicity Pregnancy Category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue losartan potassium and hydrochlorothiazide as soon as possible. These adverse outcomes are usually associated with the use of these drugs in the second and third trimester of pregnancy. 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. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the rennin-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, unless it is considered life-saving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to losartan potassium and hydrochlorothiazide for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use ). There was no evidence of teratogenicity in rats or rabbits treated with a maximum losartan potassium dose of 10 mg/kg/day in combination with 2.5 mg/kg/day of hydrochlorothiazide. At these dosages, respective exposures (AUCs) of losartan, its active metabolite, and hydrochlorothiazide in rabbits were approximately 5, 1.5, and 1 times those achieved in humans with 100 mg losartan in combination with 25 mg hydrochlorothiazide. AUC values for losartan, its active metabolite and hydrochlorothiazide, extrapolated from data obtained with losartan administered to rats at a dose of 50 mg/kg/day in combination with 12.5 mg/kg/day of hydrochlorothiazide, were approximately 6, 2, and 2 times greater than those achieved in humans with 100 mg of losartan in combination with 25 mg of hydrochlorothiazide. Fetal toxicity in rats, as evidenced by a slight increase in supernumerary ribs, was observed when females were treated prior to and throughout gestation with 10 mg/kg/day losartan in combination with 2.5 mg/kg/day hydrochlorothiazide. As also observed in studies with losartan alone, adverse fetal and neonatal effects, including decreased body weight, renal toxicity,...

Drug Interactions

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...

Contraindications

CONTRAINDICATIONS Losartan potassium and hydrochlorothiazide tablets are contraindicated in patients who are hypersensitive to any component of this product. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Do not co-administer aliskiren with losartan potassium and hydrochlorothiazide tablets in patients with diabetes.

Overdosage

OVERDOSAGE 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/m 2 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 LD 50 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.

How Supplied

HOW SUPPLIED 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. Bottles of 30 NDC 63187-599-30 Bottles of 60 NDC 63187-599-60 Bottles of 90 NDC 63187-599-90 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. Bottles of 30 NDC 63187-602-30 Bottles of 60 NDC 63187-602-60 Bottles of 90 NDC 63187-602-90 Storage Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Keep container tightly closed. Protect from light. Manufactured for: Aurobindo Pharma USA, Inc. 2400 Route 130 North Dayton, NJ 08810 Manufactured by: Aurobindo Pharma Limited Unit-VII (SEZ) Mahaboob Nagar (Dt) AP-509302, INDIA Repackaged by: Proficient Rx LP Thousand Oaks, CA 91320 Revised: 10/2014

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.