WARNING: FETAL TOXICITY When pregnancy is detected, discontinue Losartan potassium as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See WARNINGS, Fetal Toxicity .
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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 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 7 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.