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MACLEODS PHARMA
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33342004444

losartan potassium 25 mg tab (generic cozaar)

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Uses

Hypertension

Losartan is used alone or in combination with other classes of antihypertensive agents, including diuretics, in the management of hypertension. Angiotensin II receptor antagonists, such as losartan, are considered one of several preferred antihypertensive drugs for the initial management of hypertension; other options include angiotensin-converting enzyme (ACE) inhibitors, calcium-channel blockers, and thiazide diuretics. While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes. Angiotensin II receptor antagonists or ACE inhibitors may be particularly useful in the management of hypertension in patients with certain coexisting conditions such as diabetes mellitus or chronic kidney disease; angiotensin II receptor antagonists also may be preferred, generally as an alternative to ACE inhibitors, in hypertensive patients with heart failure or ischemic heart disease and/or postmyocardial infarction.

Efficacy of losartan in the treatment of hypertension was established in placebo-controlled studies of 6-12 weeks' duration in patients with hypertension (baseline diastolic blood pressure: 95-115 mm Hg). In these patients, losartan potassium dosages of 50-150 mg once daily were associated with mean decreases in systolic blood pressure of 5.5-10.5 mm Hg and diastolic blood pressure of 3.5-7.5 mm Hg. Daily dosages of 150 mg did not result in greater decreases in blood pressure compared with daily dosages of 50-100 mg. Larger decreases in trough blood pressures were observed with twice-daily dosing compared with once daily dosing in patients receiving daily dosages of 50-100 mg. Rebound hypertension following abrupt withdrawal of the drug has not been reported.

Like ACE inhibitors, angiotensin II receptor antagonists such as losartan may produce a smaller blood pressure response in hypertensive black patients compared with nonblack patients.

For additional information on the management of hypertension, For information on overall principles and expert recommendations for treatment of hypertension,

Prevention of Cardiovascular Morbidity and Mortality

Losartan is used alone or in combination with other antihypertensive agents (e.g., hydrochlorothiazide) to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy; however, there is evidence that the benefit associated with such losartan-based antihypertensive therapy does not apply to black patients. In a randomized, double-blind, comparative study (Losartan Intervention for Endpoint [LIFE] reduction in hypertension) of approximately 4 years' duration in more than 9000 patients, losartan-based antihypertensive therapy (e.g., losartan 50-100 mg with hydrochlorothiazide 12.5-25 mg daily) reduced the risk of the primary outcome of combined cardiovascular death, stroke, and myocardial infarction (relative risk reduction of about 13%, adjusted for Framingham risk score and baseline left ventricular hypertrophy) compared with atenolol-containing therapy (e.g., atenolol 50-100 mg with hydrochlorothiazide 12.5-25 mg daily) despite similar control of blood pressure with each regimen. In addition, the rate of drug-related adverse events and the incidence of new-onset diabetes mellitus was less in patients receiving losartan-based therapy. The study population consisted primarily of white patients 55-80 years of age with ECG evidence of left ventricular hypertrophy but who did not have low left-ventricular ejection fraction (40% or less) or heart failure. The results of the study provided no evidence that the benefits of losartan in reducing the risk of cardiovascular events in patients with hypertension and left ventricular hypertrophy apply to black patients. Among black patients in the study, the risk of experiencing the primary outcome of combined cardiovascular death, stroke, and myocardial infarction was lower in patients receiving atenolol (11%) than in patients receiving losartan (17%).

Subgroup analysis of the LIFE study (mean follow-up 4.7 years) suggests that aspirin therapy at baseline in patients receiving losartan reduced the risk of the primary outcome of combined cardiovascular death, stroke, and myocardial infarction (relative risk reduction of about 32%, adjusted for Framingham risk score and baseline left ventricular hypertrophy) compared with aspirin therapy at baseline in patients receiving atenolol, despite similar control of blood pressure with each regimen. Further studies are needed to determine whether these differences are associated with a pharmacologic interaction or a selection by aspirin use of patients more likely to respond to losartan therapy.

Diabetic Nephropathy

Losartan is used in the management of diabetic nephropathy manifested by elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio of 300 mg/g or greater) in patients with type 2 diabetes mellitus and hypertension.

Both angiotensin II receptor antagonists and ACE inhibitors have been shown to slow the rate of progression of renal disease in patients with diabetes mellitus and persistent albuminuria, and use of a drug from either class is recommended in such patients with modestly elevated (30-300 mg/24 hours) or higher (exceeding 300 mg/24 hours) levels of urinary albumin excretion. Some evidence suggests that these drugs may slow the progression of nephropathy by a mechanism independent of their antihypertensive effects.

Comparative trials evaluating the efficacy of angiotensin II receptor antagonists and ACE inhibitors for improving renal outcomes in diabetic patients are lacking. Evidence supporting use of ACE inhibitors generally is based on studies in patients with type 1 diabetes mellitus, while evidence supporting use of angiotensin II receptor antagonists generally is based on studies in patients with type 2 diabetes mellitus. Findings from these studies indicate that both drug classes delay progression of increased urinary albumin excretion in patients with diabetes mellitus and also may slow the decline in renal function. Because the available data are consistent, some experts suggest that the effects of both drug classes in improving renal outcomes in patients with diabetes mellitus and proteinuria are likely to be similar.

Drugs that inhibit the renin-angiotensin system (i.e., ACE inhibitors, angiotensin II receptor antagonists) also have been shown to delay the onset of albuminuria in patients with type 2 diabetes mellitus and hypertension who have normal levels of urinary albumin excretion.

Although combined therapy with ACE inhibitors and angiotensin II receptor antagonists appears to have additive effects in reducing albuminuria, such combinations provide no additional cardiovascular benefit and increase the risk of adverse effects (e.g., impaired renal function, hyperkalemia). The usual precautions of angiotensin II receptor antagonist therapy in patients with substantial renal impairment should be observed.

The current labeled indication for losartan in hypertensive patients with type 2 diabetes mellitus and nephropathy (indicated by an elevated serum creatinine and urinary albumin to creatinine ratio of 300 mg/g or greater) is based principally on the results of a long-term (mean duration of follow-up: 3.4 years), multicenter, placebo-controlled trial, the Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study. In the RENAAL trial, therapy with losartan potassium (50 mg daily initially and titrated to 100 mg daily) reduced the risk of the primary composite clinical end point, which was defined as a doubling of the baseline serum creatinine concentration, end-stage renal disease (i.e., need for dialysis or renal transplantation), or death, by 16% compared with placebo. Additional antihypertensive agents (diuretics, calcium-channel blocking agents, α- or β-adrenergic blocking agents (β-blockers), and/or centrally acting agents) were used as needed in all treatment groups to achieve a trough blood pressure of less than 140/90 mm Hg in the sitting position; ACE inhibitors and other angiotensin II receptor antagonists could not be used. Most of the delay in time to occurrence of composite clinical events seen with losartan-containing therapy was the result of a reduction in the risk of doubling serum creatinine concentration and end-stage renal disease (25 and 28% reductions, respectively); losartan-containing therapy had no appreciable effect on overall mortality. Similar mean blood pressures were achieved with losartan or placebo plus conventional antihypertensive therapy.

Heart Failure

Angiotensin II receptor antagonists have been used in the management of heart failure.

Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure. Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart failure-related hospitalizations. Experts recommend that all asymptomatic patients with reduced left ventricular ejection fraction (LVEF) (American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage B heart failure) receive therapy with an ACE inhibitor and β-blocker to prevent symptomatic heart failure and reduce morbidity and mortality. In patients with prior or current symptoms of chronic heart failure with reduced LVEF (ACCF/AHA stage C heart failure), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality. While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction, some evidence indicates that therapy with sacubitril/valsartan, an ARNI, may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization. ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure and reduced LVEF (New York Heart Association [NYHA] functional class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality. However, in patients in whom an ARNI is not appropriate, continued use of an ACE inhibitor for all classes of heart failure with reduced ejection fraction remains strongly advised. In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used. For additional information on the use of angiotensin II receptor antagonists in the management of heart failure, and .

Several clinical trials have evaluated the use of angiotensin II receptor antagonists as add-on therapy to conventional regimens including an ACE inhibitor, as add-on therapy to conventional regimens compared with an ACE inhibitor, as combination therapy with an ACE inhibitor compared with therapy with either type of agent alone, or as an alternative therapy in patients intolerant of ACE inhibitors. Data from these and other long-term placebo-controlled clinical trials indicate that angiotensin II receptor antagonists produce hemodynamic and neurohormonal effects associated with their suppression of the renin-angiotensin system; reduced hospitalizations and mortality also have been demonstrated. However, in some studies, these drugs did not show consistent effects on cardiac symptoms or exercise tolerance.

In one comparative study (Evaluation of Losartan in the Elderly [ELITE]) in geriatric patients 65 years of age and older who received losartan (up to 50 mg daily) or captopril (up to 150 mg daily) in addition to conventional therapy for 48 weeks, patients receiving losartan had a 46% lower risk of death and also experienced a lower incidence of adverse effects than those receiving captopril. However, after interim analysis of data, the difference in survival was no longer significant and no difference in morbidity and mortality or frequency in hospitalizations for heart failure was found between the 2 therapies. Results of a follow-up study (ELITE II), failed to confirm a survival benefit for losartan therapy compared with captopril. In this study, losartan did not provide a statistically significant difference in reduction of overall death, sudden cardiac death, and/or resuscitated cardiac arrest compared with captopril, although ELITE II was not designed to demonstrate equivalence between the 2 therapies. For additional details on the use of angiotensin II receptor antagonists in the management of heart failure,

While angiotensin II receptor antagonists are considered reasonable alternatives in patients who are unable to tolerate ACE inhibitors (e.g., because of cough or angioedema), angioedema, including swelling of the larynx and glottis (causing airway obstruction) and/or swelling of the face, lips, pharynx, and/or tongue, has been reported rarely during postmarketing experience in patients receiving losartan. The manufacturer states that some of these patients had a history of angioedema associated with other drugs (e.g., ACE inhibitors).(See Sensitivity Reactions under Cautions: Warnings/Precautions.)

Dosage and Administration

Administration

Losartan is administered orally. Although food may decrease the rate of absorption of losartan and peak concentrations achieved, the magnitude of effect is not clinically important; the manufacturer states that the drug can be given without regard to meals.

For pediatric patients or patients unable to swallow tablets, losartan may be administered orally as an extemporaneously prepared suspension. An extemporaneous suspension containing losartan potassium 2.5 mg/mL can be prepared in the following manner. First, 10 mL of purified water is added to a 240-mL amber polyethylene terephthalate (PET) bottle containing ten 50-mg tablets of losartan potassium, and the contents are shaken for at least 2 minutes. The concentrated suspension should be allowed to stand for 60 minutes following reconstitution, and then should be shaken for an additional minute. A mixture containing equal parts (by volume) of syrup (Ora-Sweet SF) and suspending vehicle (Ora-Plus) should be prepared separately. The concentrated suspension of losartan should be diluted with 190 mL of the Ora-Sweet SF and Ora-Plus mixture, and the container then shaken an additional minute to disperse the ingredients. The suspension should be shaken before dispensing of each dose. The extemporaneous suspension is stable for up to 4 weeks when stored at 2-8°C.

Dosage

Available as losartan potassium; dosage expressed in terms of the salt.

Hypertension

Dosage of losartan potassium must be individualized and adjusted according to blood pressure response. Substantial therapeutic response to losartan generally occurs within 1 week of treatment initiation, but in some studies the maximum therapeutic response occurred in 3-6 weeks.

Losartan Therapy

The panel members appointed to the Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8 expert panel) state that evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) should be used when available to determine target dosages of antihypertensive agents. Based on such information, an initial adult losartan potassium dosage of 50 mg daily and a target dosage of 100 mg daily are recommended (given in 1 or 2 divided doses). The manufacturer states that the usual initial dosage of losartan potassium in adults is 50 mg daily; lower initial dosages (e.g., 25 mg daily) may be used in patients with possible depletion of intravascular volume, including those receiving a diuretic, or with hepatic impairment.(See Dosage and Administration: Special Populations.) The manufacturer states that the usual maintenance dosage is 25-100 mg daily given in 1 dose or 2 divided doses. Target dosages of antihypertensive agents generally can be achieved within 2-4 weeks, but it may take up to several months.

The usual initial dosage of losartan potassium in children 6 years of age and older is 0.7 mg/kg (up to 50 mg) once daily. Dosage may be adjusted until the desired blood pressure goal is achieved. The safety and efficacy of dosages exceeding 1.4 mg/kg or in excess of 100 mg daily have not been established. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, .

Antihypertensive therapy should be titrated until goal blood pressure is achieved. If an adequate blood pressure response is not achieved with losartan monotherapy, another antihypertensive agent with demonstrated benefit may be added; if goal blood pressure is still not achieved with the use of 2 antihypertensive agents at optimal dosages, a third drug may be added. In patients who experience intolerable adverse effects with losartan, dosage reduction should be considered; if adverse effects worsen or fail to resolve, it may be necessary to discontinue the angiotensin II receptor antagonist and initiate another class of antihypertensive agent.

Losartan/Hydrochlorothiazide Fixed-combination Therapy

In patients who do not respond adequately to monotherapy with losartan or, alternatively, with hydrochlorothiazide, combined therapy with the drugs can be used. When combination therapy is necessary, the commercially available preparation containing losartan in fixed combination with hydrochlorothiazide generally should not be used initially. Dosage preferably should first be adjusted by titrating the dosage of each drug separately; if it is determined that the optimum maintenance dosage corresponds to the ratio in the commercial combination preparation, this product may be used. Alternatively, the manufacturer states that combined therapy can be initiated with the commercially available preparation in patients whose blood pressure is not adequately controlled with losartan monotherapy or with 25 mg daily of hydrochlorothiazide alone, in those in whom control is maintained but hypokalemia is problematic at this hydrochlorothiazide dosage, or in those with severe hypertension in whom the potential benefit of achieving prompt blood pressure control outweighs the potential risk of initiating therapy with the commercially available fixed combination. In such patients, the manufacturer states that combination therapy can be initiated with 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide daily as the fixed combination. In patients whose blood pressure is not adequately controlled with losartan 100 mg monotherapy, combination therapy can be initiated with 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide once daily as the fixed combination. If blood pressure is not controlled after about 3 weeks (or after 2-4 weeks of therapy in those with severe hypertension), dosage may be increased to 100 mg of losartan potassium and 25 mg of hydrochlorothiazide daily (administered as 2 tablets of the fixed combination containing 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide, or, alternatively, as 1 tablet of the fixed combination containing 100 mg of losartan potassium and 25 mg of hydrochlorothiazide). Additional increases using the fixed combination are not recommended. The fixed combination is not recommended for use in patients with creatinine clearances of 30 mL/minute or less, those with hepatic impairment, or those with intravascular volume depletion (e.g., patients receiving diuretics).(See Dosage and Administration: Special Populations.)

Blood Pressure Monitoring and Treatment Goals

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of losartan potassium is recommended.

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure; specific target levels of blood pressure should be individualized based on consideration of multiple factors, including patient age and comorbidities, and the currently available evidence from clinical studies.

For additional information on initiating and adjusting losartan dosage in the management of hypertension, .

Diabetic Nephropathy

For the management of diabetic nephropathy in patients with type 2 diabetes mellitus, the usual initial adult dosage of losartan potassium is 50 mg once daily. Dosage of losartan potassium may be increased to 100 mg once daily based on blood pressure response. In a large clinical trial, approximately 72% of patients had dosage titrated from 50 mg daily initially up to 100 mg daily and maintained that dosage for more than 50% of the study period.

Prevention of Cardiovascular Morbidity and Mortality

When losartan potassium is used to reduce the risk of stroke in high-risk patients with hypertension and left ventricular hypertrophy, the usual starting dose is 50 mg once daily. Treatment should be adjusted based on blood pressure response. Adjustment of therapy, when indicated, should include the addition of hydrochlorothiazide 12.5 mg daily and/or an increase in losartan potassium dosage to 100 mg daily; subsequently, the hydrochlorothiazide dosage may be increased to 25 mg once daily. Alternatively, the fixed combination containing losartan potassium and hydrochlorothiazide may be used at the appropriate dosage.

Heart Failure

In patients with prior or current symptoms of heart failure and reduced left ventricular ejection fraction (LVEF) (American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage C heart failure), ACCF and AHA recommend an initial losartan potassium dosage of 25-50 mg once daily. Blood pressure (including postural blood pressure changes), renal function, and serum potassium concentrations should be reevaluated within 1-2 weeks after initiation of therapy, and these parameters should be monitored closely after changes in dosage. ACCF and AHA recommend a maximum losartan potassium dosage of 50-150 mg once daily for patients with ACCF/AHA stage C heart failure.

Special Populations

The manufacturer recommends that patients with depletion of intravascular volume (e.g., patients receiving treatment with a diuretic) should have this condition corrected prior to initiation of losartan potassium therapy, or alternatively, therapy should be initiated using a lower initial dosage (25 mg once daily). The manufacturer states that modification of losartan potassium dosage is not necessary for geriatric patients nor for other adults with renal impairment, including those undergoing hemodialysis. In patients with hepatic impairment, the manufacturer recommends that therapy be initiated with a lower dosage of losartan potassium (25 mg once daily).

The commercially available preparation containing losartan in fixed combination with hydrochlorothiazide is not recommended for patients with renal impairment whose creatinine clearance is less than 30 mL/minute, and such preparations should be used with caution in patients with hepatic impairment. The commercially available preparation containing losartan potassium in fixed combination with hydrochlorothiazide is not recommended for initial titration in patients with hepatic impairment, because the appropriate starting dose of losartan potassium (25 mg once daily) is not available as a fixed-ratio preparation.

Cautions

Contraindications

Known hypersensitivity to losartan or any ingredient in the formulation.

Concomitant use of losartan and aliskiren in patients with diabetes mellitus.(See Drug Interactions: Drugs that Block the Renin-Angiotensin System.)

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Drugs that act directly on the renin-angiotensin system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, aliskiren) cause fetal and neonatal morbidity and mortality when administered during pregnancy during the second and third trimesters. Losartan should be discontinued as soon as possible when pregnancy is detected, unless continued use is considered life-saving. Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy. All women of childbearing potential should be advised to report pregnancy to their clinician as soon as possible. For additional information on the risk of such drugs (i.e., angiotensin II antagonists and ACE inhibitors) during pregnancy, and in

Sensitivity Reactions

Sensitivity reactions, including anaphylactoid reactions and/or angioedema, have been reported with use of angiotensin II receptor antagonists, including losartan. Losartan is not recommended in patients with a history of angioedema associated with or unrelated to ACE inhibitor or angiotensin II receptor antagonist therapy.

Other Warnings and Precautions

Hypotension

Symptomatic hypotension has been reported in patients receiving losartan, especially in volume- and/or salt-depleted patients (e.g., those receiving diuretics).(See Dosage and Administration: Special Populations.)

Malignancies

In July 2010, the US Food and Drug Administration (FDA) initiated a safety review of angiotensin II receptor antagonists after a published meta-analysis suggested a possible association between the use of these agents and an increased risk of cancer. The meta-analysis, which combined cancer-related findings from 5 randomized, controlled trials in over 60,000 patients, found a modest but significant increase in the risk of new cancer occurrence in patients receiving an angiotensin II receptor antagonist (mostly telmisartan) compared with those in control groups (7.2 versus 6%, respectively; risk ratio 1.08). However, because of several limitations of the study (e.g., trials included in the meta-analysis were not specifically designed to evaluate cancer outcomes, lack of individual patient data), the validity of these findings has been questioned.

Subsequent studies, including a larger, more comprehensive meta-analysis conducted by FDA, have not shown an increased risk of cancer in patients receiving angiotensin II receptor antagonists. FDA's meta-analysis, which included trial-level data from 31 randomized studies (total of approximately 156,000 patients), found no evidence of an increased risk of cancer in patients who received an angiotensin II receptor antagonist compared with those who received other treatments (placebo or active control). The overall rate of new cancer occurrence was essentially the same in both groups of patients (1.82 and 1.84 cases per 100 patient-years, respectively). In addition, there was no difference in the risk of cancer-related death, breast cancer, lung cancer, or prostate cancer between the groups. Based on these results and a review of all currently available data related to this potential safety concern, FDA has concluded that use of angiotensin II receptor antagonists is not associated with an increased risk of cancer.

Renal Effects

Because the renin-angiotensin-aldosterone (RAA) system appears to contribute substantially to maintenance of glomerular filtration in patients with heart failure in whom renal perfusion is severely compromised, renal function may deteriorate markedly (e.g., oliguria, progressive azotemia, renal failure, death) in these patients during therapy with an ACE inhibitor or an angiotensin II receptor antagonist (e.g., losartan). Increases in BUN and serum creatinine may occur in patients with unilateral or bilateral renal artery stenosis.

Hyperkalemia

Hyperkalemia may occur, especially in patients with renal impairment with or without diabetes mellitus or in those receiving concomitant therapy with a potassium-sparing diuretic (e.g., amiloride, spironolactone, triamterene) and/or potassium supplements or salt substitutes containing potassium.

Fixed-combination Preparations

When losartan is used as a fixed combination that includes hydrochlorothiazide, the cautions, precautions, and contraindications associated with thiazide diuretics must be considered in addition to those associated with losartan.

Specific Populations

Pregnancy

Category D.

Losartan can cause fetal and neonatal morbidity and mortality when administered to a pregnant woman. Losartan should be discontinued as soon as possible when pregnancy is detected.(See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)

Lactation

Losartan is distributed into milk in rats; it is not known whether the drug is distributed into human breast milk. A decision should be made whether to discontinue nursing or the drug because of the potential risk in nursing infants.

Pediatric Use

Safety and efficacy of losartan in pediatric patients younger than 6 years of age and in pediatric patients with glomerular filtration rate less than 30 mL/minute per 1.73 m have not been established. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients,

Geriatric Use

No overall differences in safety and efficacy of losartan for the treatment of hypertension have been observed in geriatric patients relative to younger adults, but increased sensitivity cannot be ruled out.

No overall differences in efficacy with the fixed combination preparation containing losartan and hydrochlorothiazide have been observed in patients 65 years of age or older compared with younger adults. Geriatric patients had a somewhat higher incidence of adverse effects than younger patients; dosage should be selected with caution.

Hepatic Impairment

Systemic exposure to losartan and its active metabolite may be increased in patients with hepatic impairment. Initial dosage adjustment is recommended.(See Losartan Therapy under Dosage: Hypertension, in Dosage and Administration.)

Use of losartan in fixed combination with hydrochlorothiazide is not recommended in patients with hepatic impairment because the dosage of losartan potassium in the fixed-combination tablets exceeds the recommended initial dosage.

Renal Impairment

Deterioration of renal function may occur in patients with renal impairment receiving losartan.(See Renal Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Use of losartan in fixed combination with hydrochlorothiazide is not recommended in patients with creatinine clearances of 30 mL/minute or less.

Black Patients

Blood pressure reduction may be smaller in black patients compared with nonblack patients; losartan should be used in combination with a diuretic or calcium-channel blocker.

There is no evidence that the benefits of therapy in reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to black patients.

Common Adverse Effects

Adverse effects occurring in at least 1% of patients with hypertension receiving losartan and at a higher incidence than with placebo include upper respiratory infection, dizziness, nasal congestion, back pain, leg pain, muscle cramp, and sinusitis. The incidence of adverse effects was not affected by age, gender, or race. In patients receiving losartan for the treatment of diabetic nephropathy, urinary tract infection, diarrhea, anemia, asthenia/fatigue, hypoglycemia, back pain, chest pain, cough, bronchitis, diabetic vascular disease, influenza-like disease, cataracts, cellulitis, hyperkalemia, hypotension, muscular weakness, sinusitis, gastritis, hypoesthesia, infection, knee pain, and leg pain occurred with an incidence of at least 5% and were reported more frequently than in those receiving placebo.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Formation of active metabolite appears to be mediated by cytochrome P-450 (CYP) 2C9 isoenzyme. CYP3A4 apparently contributes to formation of inactive metabolites.

Potential pharmacokinetic interaction (inhibition of the formation of losartan's active metabolite) with CYP2C9 inhibitors. Clinically important interactions unlikely with CYP3A4 inhibitors (possible increased concentration of losartan, but no effects on formation of active metabolite observed).

Drugs that Block the Renin-Angiotensin System

Increased risk of renal impairment, hyperkalemia, and hypotension with concomitant use of other drugs that block the renin-angiotensin system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, aliskiren); when losartan is used concomitantly with such drugs, blood pressure, renal function, and serum concentrations of electrolytes should be monitored closely.(See Drug Interactions: Aliskiren.)

Aliskiren

Concomitant use of losartan and aliskiren is contraindicated in patients with diabetes mellitus; in addition, such concomitant use should be avoided in patients with renal impairment (glomerular filtration rate [GFR] less than 60 mL/minute).

Cimetidine

Pharmacokinetic interactions unlikely when losartan is used concomitantly with cimetidine.

Digoxin

Pharmacokinetic interactions unlikely when losartan is used concomitantly with digoxin.

Erythromycin

Clinically important pharmacokinetic interactions unlikely when losartan is used concomitantly with erythromycin.

Fluconazole

Decreased plasma concentrations of losartan's active metabolite and increased plasma losartan concentrations have been reported when losartan is used concomitantly with fluconazole.

Hydrochlorothiazide

Pharmacokinetic interactions unlikely when losartan is used concomitantly with hydrochlorothiazide.

Additive hypotensive effects observed when losartan is used concomitantly with hydrochlorothiazide, which is used for therapeutic advantage (see Uses and see Dosage and Administration: Dosage).

Ketoconazole

Conversion of losartan to its active metabolite unaffected when losartan is used concomitantly with ketoconazole.

Lithium

Lithium excretion may be reduced. Serum lithium concentrations should be carefully monitored.

Nonsteroidal Anti-inflammatory Agents

Potential pharmacologic interaction (attenuated hypotensive effects) when angiotensin II receptor antagonists are used concomitantly with nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors.

Possible deterioration of renal function in geriatric, volume-depleted (including those receiving concomitant diuretic therapy), or renally impaired patients; renal function should be monitored periodically in patients receiving concomitant therapy with losartan and an NSAIA, including selective COX-2 inhibitors.

Phenobarbital

Pharmacokinetic interactions unlikely when losartan is used concomitantly with phenobarbital.

Potassium-sparing Diuretics

Possible increased serum potassium concentrations resulting in additive hyperkalemic effects, when losartan is used concomitantly with potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene).

Potassium Supplements and Potassium-containing Salt Substitutes

Possible increased serum potassium concentrations resulting in additive hyperkalemic effects, when losartan is used concomitantly with potassium supplements or potassium-containing salt substitutes. Concomitant use not recommended.

Rifampin

Decreased plasma concentrations of losartan and its active metabolite observed when losartan is used concomitantly with rifampin.

Warfarin

Pharmacokinetic interactions unlikely when losartan is used concomitantly with warfarin.

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