INDICATIONS AND USAGE Hypertension Losartan potassium tablets USP are indicated for the treatment of hypertension.

It may be used alone or in combination with other antihypertensive agents, including diuretics.

Hypertensive Patients with Left Ventricular Hypertrophy Losartan potassium 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.

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Nephropathy in Type 2 Diabetic Patients Losartan potassium tablets USP are indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio ≥300 mg/g) in patients with type 2 diabetes and a history of hypertension.

In this population, Losartan potassium tablets USP are reduce the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end stage renal disease (need for dialysis or renal transplantation) (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects).

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 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 renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.

Perform serial ultrasound examinations to assess the intra-amniotic environment.

If oligohydramnios is observed, discontinue Losartan potassium, 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 for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use ).

Losartan potassium has been shown to produce adverse effects in rat fetuses and neonates, including decreased body weight, delayed physical and behavioral development, mortality and renal toxicity.

With the exception of neonatal weight gain (which was affected at doses as low as 10 mg/kg/day), doses associated with these effects exceeded 25 mg/kg/day (approximately three times the maximum recommended human dose of 100 mg on a mg/m 2 basis).

These findings are attributed to drug exposure in late gestation and during lactation.

Significant levels of losartan and its active metabolite were shown to be present in rat fetal plasma during late gestation and in rat milk.

Hypotension — Volume-Depleted Patients In patients who are intravascularly volume-depleted (e.g., those treated with diuretics), symptomatic hypotension may occur after initiation of therapy with Losartan potassium.

These conditions should be corrected prior to administration of Losartan potassium, or a lower starting dose should be used (see DOSAGE AND ADMINISTRATION ).

ADVERSE REACTIONS Hypertension Losartan potassium has been evaluated for safety in more than 3300 adult patients treated for essential hypertension and 4058 patients/subjects overall.

Over 1200 patients were treated for over 6 months and more than 800 for over one year.

In general, treatment with Losartan potassium was well-tolerated.

The overall incidence of adverse experiences reported with Losartan potassium was similar to placebo.

In controlled clinical trials, discontinuation of therapy due to clinical adverse experiences was required in 2.3 percent of patients treated with Losartan potassium and 3.7 percent of patients given placebo.

The following table of adverse events is based on four 6- to 12-week, placebo-controlled trials involving over 1000 patients on various doses (10-150 mg) of losartan and over 300 patients given placebo.

All doses of losartan are grouped because none of the adverse events appeared to have a dose-related frequency.

The adverse experiences reported in ≥1% of patients treated with Losartan potassium and more commonly than placebo are shown in the table below.

Table Losartan Placebo (n=1075) (n=334) Incidence Incidence % % Musculoskeletal Cramp, muscle 1 0 Pain, back 2 1 Pain, leg 1 0 Nervous System/Psychiatric Dizziness 3 2 Respiratory Congestion, nasal 2 1 Infection, upper respiratory 8 7 Sinusitis 1 0 The following adverse events were also reported at a rate of 1% or greater in patients treated with losartan, but were as, or more frequent, in the placebo group: asthenia/fatigue, edema/swelling, abdominal pain, chest pain, nausea, headache, pharyngitis, diarrhea, dyspepsia, myalgia, insomnia, cough, sinus disorder.

Adverse events occurred at about the same rates in men and women, older and younger patients, and Black and non-Black patients.

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.

In addition to the adverse events above, potentially important events that occurred in at least two patients/subjects exposed to losartan or other adverse events that occurred in <1% of patients in clinical studies are listed below.

It cannot be determined whether these events were causally related to losartan: Body as a Whole : facial edema, fever, orthostatic effects, syncope; Cardiovascular : angina pectoris, second degree AV block, CVA, hypotension, myocardial infarction, arrhythmias including atrial fibrillation, palpitation, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation; Digestive : anorexia, constipation, dental pain, dry mouth, flatulence, gastritis, vomiting; Hematologic : anemia; Metabolic: gout; Musculoskeletal : arm pain, hip pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, fibromyalgia, muscle weakness; Nervous System/Psychiatric : anxiety, anxiety disorder, ataxia, confusion, depression, dream abnormality, hypesthesia, decreased libido, memory impairment, migraine, nervousness, paresthesia, peripheral neuropathy, panic disorder, sleep disorder, somnolence, tremor, vertigo; Respiratory: dyspnea, bronchitis, pharyngeal discomfort, epistaxis, rhinitis, respiratory congestion; Skin: alopecia, dermatitis, dry skin, ecchymosis, erythema, flushing, photosensitivity, pruritus, rash, sweating, urticaria; Special Senses : blurred vision, burning/stinging in the eye, conjunctivitis, taste perversion, tinnitus, decrease in visual acuity; Urogenital : impotence, nocturia, urinary frequency, urinary tract infection.

Persistent dry cough (with an incidence of a few percent) has been associated with ACE-inhibitor use and in practice can be a cause of discontinuation of ACE-inhibitor therapy.

Two prospective, parallel-group, double-blind, randomized, controlled trials were conducted to assess the effects of losartan on the incidence of cough in hypertensive patients who had experienced cough while receiving ACE-inhibitor therapy.

Patients who had typical ACE-inhibitor cough when challenged with lisinopril, whose cough disappeared on placebo, were randomized to losartan 50 mg, lisinopril 20 mg, or either placebo (one study, n=97) or 25 mg hydrochlorothiazide (n=135).

The double-blind treatment period lasted up to 8 weeks.

The incidence of cough is shown below.

Table Study 1 Demographics = (89% caucasian, 64% female) HCTZ Losartan Lisinopril Cough 25% 17% 69% Study 2 Demographics = (90% caucasian, 51% female) Placebo Losartan Lisinopril Cough 35% 29% 62% These studies demonstrate that the incidence of cough associated with losartan therapy, in a population that all had cough associated with ACE-inhibitor therapy, is similar to that associated with hydrochlorothiazide or placebo therapy.

Cases of cough, including positive re-challenges, have been reported with the use of losartan in postmarketing experience.

Pediatric Patients: No relevant differences between the adverse experience profile for pediatric patients and that previously reported for adult patients were identified.

Hypertensive Patients with Left Ventricular Hypertrophy In the LIFE study, adverse events with Losartan potassium were similar to those reported previously for patients with hypertension.

Nephropathy in Type 2 Diabetic Patients In the RENAAL study involving 1513 patients treated with Losartan potassium or placebo, the overall incidences of reported adverse experiences were similar for the two groups.

Losartan potassium was generally well tolerated as evidenced by a similar incidence of discontinuations due to side effects compared to placebo (19% for Losartan potassium, 24% for placebo).

The adverse experiences, regardless of drug relationship, reported with an incidence of ≥4% of patients treated with Losartan potassium and occurring more commonly than placebo, on a background of conventional antihypertensive therapy, are shown in the table below.

Table Losartan and Conventional Antihypertensive Therapy Incidence % (n=751) Placebo and Conventional Antihypertensive Therapy Incidence % (n=762) Body as a Whole Asthenia/Fatigue Chest Pain Fever Infection Influenza-like disease Trauma 14 12 4 5 10 4 10 8 3 4 9 3 Cardiovascular Hypotension Orthostatic hypotension 7 4 3 1 Digestive Diarrhea Dyspepsia Gastritis 15 4 5 10 3 4 Endocrine Diabetic neuropathy Diabetic vascular disease 4 10 3 9 Eyes, Ears, Nose and Throat Cataract Sinusitis 7 6 5 5 Hemic Anemia 14 11 Metabolic and Nutrition Hyperkalemia Hypoglycemia Weight gain 7 14 4 3 10 3 Musculoskeletal Back pain Leg pain Knee pain Muscular weakness 12 5 5 7 10 4 4 4 Nervous System Hypesthesia 5 4 Respiratory Bronchitis Cough 10 11 9 10 Skin Cellulitis 7 6 Urogenital Urinary tract infection 16 13 Postmarketing Experience The following additional adverse reactions have been reported in postmarketing experience: Digestive : Hepatitis (reported rarely).

General Disorders and Administration Site Conditions: Malaise.

Hemic : Thrombocytopenia (reported rarely).

Hypersensitivity : 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 in patients treated with losartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors.

Vasculitis, including Henoch-Schönlein purpura, has been reported.

Anaphylactic reactions have been reported.

Metabolic and Nutrition : Hyperkalemia, hyponatremia have been reported with losartan.

Musculoskeletal : Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Nervous system disorders : Dysgeusia.

Respiratory : Dry cough (see above).

Skin : Erythroderma.

Laboratory Test Findings In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Losartan potassium.

Creatinine, Blood Urea Nitrogen : Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.1 percent of patients with essential hypertension treated with Losartan potassium alone (see PRECAUTIONS, Impaired Renal Function ).

Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.11 grams percent and 0.09 volume percent, respectively) occurred frequently in patients treated with Losartan potassium alone, but were rarely of clinical importance.

No patients were discontinued due to anemia.

Liver Function Tests : Occasional elevations of liver enzymes and/or serum bilirubin have occurred.

In patients with essential hypertension treated with Losartan potassium alone, one patient (<0.1%) was discontinued due to these laboratory adverse experiences.