AHFS Class:

• Angiotensin II Receptor Antagonists 24:32.08

Generic Name(s):

• Losartan Potassium

Chemical Name:

• 2-Butyl-4-chloro-1-[[2'-(1 H -tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-methyl]-1 H -imidazole-5-methanol monopotassium salt

Molecular Formula:

• C₂₂H₂₃ClN₆O

Losartan potassium, a nonpeptide tetrazole derivative, is an angiotensin II type 1 (AT₁) receptor antagonist (also referred to as an angiotensin II receptor blocker [ARB]).1,2

Hypertension

Losartan is used alone or in combination with other classes of antihypertensive agents, including diuretics, in the management of hypertension.1,2,1200

Angiotensin II receptor antagonists, such as losartan, are considered one of several preferred antihypertensive drugs for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include angiotensin-converting enzyme (ACE) inhibitors, calcium-channel blockers, and thiazide diuretics.501,502,503,504,1200 While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501,502,504,1200,1213 (See Uses: Hypertension, in Valsartan 24:32.08.)

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 (CKD); 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 following myocardial infarction (MI).501,502,504,523,524,527,534,535,536,543,1200,1214,1215 (See Uses: Hypertension, in Valsartan 24:32.08.)

In patients with hypertension and compelling indications (e.g., CKD with albuminuria [urine albumin 300 mg/day or greater, or urine albumin:creatinine ratio of 300 mg/g or equivalent in the first morning void]), angiotensin II receptor antagonists are usually considered an alternative for ACE inhibitor-intolerant patients.1200,1218 However, data indicate no difference in efficacy between ACE inhibitors and angiotensin II receptor antagonists with regard to blood pressure lowering and clinical outcomes (i.e., all-cause mortality, cardiovascular mortality, MI, heart failure, stroke, and end-stage renal disease).1200,1218 Adverse events (e.g., cough, angioedema) leading to drug discontinuance occur more frequently with ACE inhibitor therapy than with angiotensin II receptor antagonist therapy.1218 Because of similar efficacy and a lower frequency of adverse effects, some experts believe that angiotensin II receptor antagonists should be used instead of an ACE inhibitor for the treatment of hypertension or hypertension with certain compelling indications.1218

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).1 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.1 Daily dosages of 150 mg did not result in greater decreases in blood pressure compared with daily dosages of 50-100 mg.1 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.1 Rebound hypertension following abrupt withdrawal of the drug has not been reported.1

Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 Like ACE inhibitors,47,48 angiotensin II receptor antagonists such as losartan may produce a smaller blood pressure response in hypertensive black patients compared with nonblack patients.1,2 However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar blood pressure lowering in black patients as in other racial groups.1200 (See Race under Hypertension: Other Special Considerations for Antihypertensive Drug Therapy, in Uses in Valsartan 24:32.08.)

For additional information on the management of hypertension, see Uses: Hypertension, in Valsartan 24:32.08. For information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults and also see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

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;1,2,53 however, there is evidence that the benefit associated with such losartan-based antihypertensive therapy does not apply to black patients.1,20,53 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.1,20,53 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.53 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.1,2,53 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.1 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%).1,2

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.54 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.54

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.1,33

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.38,39,41,42,43,535,536,1232 Some evidence suggests that these drugs may slow the progression of nephropathy by a mechanism independent of their antihypertensive effects.33,36,37,38,39,44,45,46

Comparative trials evaluating the efficacy of angiotensin II receptor antagonists and ACE inhibitors for improving renal outcomes in diabetic patients are lacking.536 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.536 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.536 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.536

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†;1233,1234 however, some experts state that in the absence of albuminuria, the risk of progressive kidney disease is low.1214,1215 The American Diabetes Association (ADA) states that the use of an ACE inhibitor or angiotensin II receptor antagonist is not recommended for the primary prevention of diabetic nephropathy in patients with diabetes mellitus who are normotensive, have normal levels of urinary protein excretion, and have a normal glomerular filtration rate (GFR).1232

Combined therapy with ACE inhibitors and angiotensin II receptor antagonists provides no additional cardiovascular benefit and increases the risk of adverse effects (e.g., impaired renal function, hyperkalemia).1232 The usual precautions of angiotensin II receptor antagonist therapy in patients with substantial renal impairment should be observed.1,41

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.1,33 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. 1,33 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.1,33 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.1,33 Similar mean blood pressures were achieved with losartan or placebo plus conventional antihypertensive therapy.33

Heart Failure

Angiotensin II receptor antagonists have been used in the management of heart failure†.524,528,800

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.524,701,703,800 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.524,800 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.524 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.800 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,524 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.702,800 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.800 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.800 In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used.800 For additional information on the use of angiotensin II receptor antagonists in the management of heart failure, see Uses: Heart Failure, in Valsartan 24:32.08 and in Candesartan 24:32.08. For further information on the use of ARNIs in patients with heart failure, see Uses: Heart Failure, in Sacubitril and Valsartan 24:32.92.

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.17,31,132,133 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.524,528 However, in some studies, these drugs did not show consistent effects on cardiac symptoms or exercise tolerance.17,27

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.17 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.17 Results of a follow-up study (ELITE II), failed to confirm a survival benefit for losartan therapy compared with captopril.133 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.133 For additional details on the use of angiotensin II receptor antagonists in the management of heart failure, see Uses: Heart Failure, in Valsartan 24:32.08 and in Candesartan 24:32.08.

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),524,528,800 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.1 The manufacturer states that some of these patients had a history of angioedema associated with other drugs (e.g., ACE inhibitors).1 (See Sensitivity Reactions under Cautions: Warnings/Precautions.)

Administration

Losartan is administered orally.1 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.1

For pediatric patients or patients unable to swallow tablets, losartan may be administered orally as an extemporaneously prepared suspension.1 An extemporaneous suspension containing losartan potassium 2.5 mg/mL can be prepared in the following manner.1 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.1 The concentrated suspension should be allowed to stand for 60 minutes following reconstitution, and then should be shaken for an additional minute.1 A mixture containing equal parts (by volume) of syrup (Ora-Sweet SF^®) and suspending vehicle (Ora-Plus^®) should be prepared separately.1 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.1 The suspension should be shaken before dispensing of each dose.1 The extemporaneous suspension is stable for up to 4 weeks when stored at 2-8°C.1

Dosage

Available as losartan potassium; dosage expressed in terms of the salt.1,2

Hypertension

Dosage of losartan potassium must be individualized and adjusted according to blood pressure response.1,2 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.1

Losartan Therapy

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.1,2 (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.1 Some experts state that the usual dosage range is 50-100 mg daily, given in 1 dose or 2 divided doses.1200

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.1,1150 Some experts state that the dosage may be increased every 2-4 weeks until blood pressure is controlled, the maximum dosage is reached, or adverse effects occur.1150 The safety and efficacy of dosages exceeding 1.4 mg/kg or in excess of 100 mg daily have not been established.1,1150 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

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.2 When combination therapy is necessary, the commercially available preparation containing losartan in fixed combination with hydrochlorothiazide generally should not be used initially.4 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.2,4 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,1 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.2 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.2 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.2 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).2 Additional increases using the fixed combination are not recommended.2 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).2 (See Dosage and Administration: Special Populations.)

Blood Pressure Monitoring and Treatment Goals

Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved with angiotensin II receptor antagonist monotherapy, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., calcium-channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved, a third drug may be added.1200,1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with losartan, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1200,1216

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,523,530,1201,1207,1209,1222 While previous hypertension guidelines have based target blood pressure goals on age and comorbidities,501,504,536 the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) in all adults.1200 Many patients will require at least 2 drugs from different pharmacologic classes to achieve their blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220

For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.

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.1 Dosage of losartan potassium may be increased to 100 mg once daily based on blood pressure response.1 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.1

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.1 Treatment should be adjusted based on blood pressure response.1 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.1 Alternatively, the fixed combination containing losartan potassium and hydrochlorothiazide may be used at the appropriate dosage.2

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.524 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.524 ACCF and AHA recommend a maximum losartan potassium dosage of 50-150 mg once daily for patients with ACCF/AHA stage C heart failure.524

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).1 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.1 In patients with hepatic impairment, the manufacturer recommends that therapy be initiated with a lower dosage of losartan potassium (25 mg once daily).1

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.2 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.2

Contraindications

Known hypersensitivity to losartan or any ingredient in the formulation.1,2

Concomitant therapy with aliskiren in patients with diabetes mellitus.1,2,550 (See Drug Interactions: Drugs that Block the Renin-Angiotensin System.)

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Drugs that act on the renin-angiotensin system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, aliskiren) reduce fetal renal function and increase fetal and neonatal morbidity and mortality when administered during pregnancy during the second and third trimesters.1,2,6,7,8,9,10,11,12,13,14,15,16,57 Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.1,2 Potential neonatal effects include skull hypoplasia, anuria, hypotension, renal failure, and death.1,2 Losartan should be discontinued as soon as possible when pregnancy is detected, unless continued use is considered life-saving.1,56,57 Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.1,11,13 For additional information on the risk of such drugs (i.e., angiotensin II antagonists and ACE inhibitors) during pregnancy, see Cautions: Pregnancy, Fertility, and Lactation, in Captopril 24:32.04 and in Enalaprilat/Enalapril 24:32.04.

Sensitivity Reactions

Sensitivity reactions, including anaphylactoid reactions and/or angioedema, have been reported with use of angiotensin II receptor antagonists, including losartan.1,2 Losartan is not recommended in patients with a history of angioedema associated with or unrelated to ACE inhibitor or angiotensin II receptor antagonist therapy.58,544,545

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).1,2 (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.120,121,123,126 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).120,121,123 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.129,130,131

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.126,127,128,129 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).126 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).126 In addition, there was no difference in the risk of cancer-related death, breast cancer, lung cancer, or prostate cancer between the groups.126 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.126

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).1,2 Increases in BUN and serum creatinine may occur in patients with unilateral or bilateral renal artery stenosis, chronic kidney disease (CKD), or volume depletion.1,2 The clinician should consider withholding or discontinuing losartan in patients who develop a clinically important reduction in renal function while receiving losartan.1,2 (See Cautions: Renal Effects, in Enalapril 24:32.04.)

Effects on Potassium

Hyperkalemia can develop, especially in patients receiving agents that can increase serum potassium concentration (e.g., potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes).1,2 (See Drug Interactions: Agents that Increase Serum Potassium.)

Fixed-combination Preparations

When losartan is used in fixed combination with hydrochlorothiazide, the cautions, precautions, and contraindications associated with thiazide diuretics must be considered in addition to those associated with losartan.2

Specific Populations

Pregnancy

Category D.1,2 (See Users Guide.)

Losartan can cause fetal and neonatal morbidity and mortality when administered to a pregnant woman.1,2 Losartan should be discontinued as soon as possible when pregnancy is detected.1,2 (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.1,2 A decision should be made whether to discontinue nursing or the drug because of the potential risk in nursing infants.1,2

Pediatric Use

If oliguria or hypotension occurs in neonates with a history of in utero exposure to losartan, blood pressure and renal function should be supported; exchange transfusions or dialysis may be required.1,2 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)

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 m² have not been established.1 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

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.1

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.2 Geriatric patients had a somewhat higher incidence of adverse effects than younger patients; dosage should be selected with caution.2

Hepatic Impairment

Systemic exposure to losartan and its active metabolite may be increased in patients with hepatic impairment.1 Initial dosage adjustment is recommended.1 (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.2

Renal Impairment

Deterioration of renal function may occur in patients with renal impairment receiving losartan.1,37 (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.2

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 in such patients.1,2,504,1200

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.1

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,1,2 dizziness,1,2 nasal congestion, back pain, leg pain, muscle cramp, and sinusitis.1 The incidence of adverse effects was not affected by age, gender, or race.1 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.1

Agents that Increase Serum Potassium

Hyperkalemia may occur with concomitant administration of losartan and potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that increase serum potassium concentrations.1,2 Serum potassium concentrations should be monitored in patients receiving such concomitant therapy.1,2

Drugs Affecting Hepatic Microsomal Enzymes

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

Potential pharmacokinetic interaction (inhibition of the formation of losartan's active metabolite) with CYP2C9 inhibitors.1,2 Clinically important interactions unlikely with CYP3A4 inhibitors (possible increased concentration of losartan, but no effects on formation of active metabolite observed).2

Drugs that Block the Renin-Angiotensin System

Increased risk of hypotension, hyperkalemia, and changes in renal function (e.g., renal impairment) 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.1,2 The manufacturer states that most patients do not derive additional benefit from combination therapy with 2 renin-angiotensin system inhibitors compared with monotherapy.1,2 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).1,2,550 (See Use in Combination with Angiotensin-converting Enzyme Inhibitors or Angiotensin II Receptor Antagonists under Warnings/Precautions: Other Warnings and Precautions, in Cautions in Aliskiren Hemifumarate 24:32.40.)

Cimetidine

Pharmacokinetic interactions unlikely when losartan is used concomitantly with cimetidine.1,2

Digoxin

Pharmacokinetic interactions unlikely when losartan is used concomitantly with digoxin.1,2

Erythromycin

Clinically important pharmacokinetic interactions unlikely when losartan is used concomitantly with erythromycin.2

Fluconazole

Decreased plasma concentrations of losartan's active metabolite and increased plasma losartan concentrations have been reported when losartan is used concomitantly with fluconazole.1,2

Hydrochlorothiazide

Pharmacokinetic interactions unlikely when losartan is used concomitantly with hydrochlorothiazide.1,2

Additive hypotensive effects observed when losartan is used concomitantly with hydrochlorothiazide, which is used for therapeutic advantage.1,2 (See Uses and see Dosage and Administration: Dosage).

Ketoconazole

Conversion of losartan to its active metabolite unaffected when losartan is used concomitantly with ketoconazole.1,2

Lithium

Lithium excretion may be reduced.1,2 Serum lithium concentrations should be carefully monitored. 1,2

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.1,2

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.1

Phenobarbital

Pharmacokinetic interactions unlikely when losartan is used concomitantly with phenobarbital.1,2

Rifampin

Decreased plasma concentrations of losartan and its active metabolite observed when losartan is used concomitantly with rifampin.1,2

Warfarin

Pharmacokinetic interactions unlikely when losartan is used concomitantly with warfarin.1,2

Description

Losartan, a nonpeptide tetrazole derivative, is an angiotensin II receptor (type AT₁) antagonist.1,2 Losartan is a prodrug and requires activation in the liver to exert its pharmacologic activity.1 Losartan's active carboxylic acid metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, noncompetitive inhibitor of the AT₁ receptor.1,2

Losartan blocks the physiologic actions of angiotensin II, including vasoconstrictor and aldosterone-secreting effects.1,2 Losartan does not interfere with response to bradykinins and does not share the angiotensin-converting enzyme (ACE) inhibitor common adverse effect of dry cough.1,2 For additional information on the pharmacology of angiotensin II receptor antagonists, see Description in Irbesartan 24:32.08.

Advice to Patients

Importance of advising patients not to use potassium supplements or salt substitutes containing potassium without consulting their clinician.1

Importance of informing women of risks of use during pregnancy.1,2,56,57 Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed.1,2 All women of childbearing potential should be advised to report pregnancy to their clinician as soon as possible.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings, in Cautions.)

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (including salt substitutes containing potassium).1,2

Importance of informing patients of other important precautionary information.1,2 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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