LOSARTAN POTASSIUM

Losartan potassium is an angiotensin II receptor (type AT 1 ) antagonist. Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-[ p -( o-1H -tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt. Its empirical formula is C 22 H 22 ClKN 6 O, and its structural formula is: Losartan potassium USP is a white to off-white free-flowing crystalline powder with a molecular weight of 461.01. It is freely soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as acetonitrile and methyl ethyl ketone. Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan. Losartan potassium is available as tablets for oral administration containing either 25 mg, 50 mg or 100 mg of losartan potassium and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, pregelatinized starch, magnesium stearate, hydroxypropyl cellulose, hypromellose and titanium dioxide. Losartan potassium tablets, USP, 25 mg, 50 mg and 100 mg, contain potassium in the following amounts: 2.12 mg (0.054 mEq), 4.24 mg (0.108 mEq) and 8.48 mg (0.216 mEq), respectively. Losartan potassium tablets USP, 25 mg and 50 mg meet USP Dissolution Test 1 and Losartan potassium tablets USP, 100 mg meet USP dissolution Test 3. Structural Formula

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. (See PRECAUTIONS, Race and CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Reduction in the Risk of Stroke, Race.) 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).

Adult Hypertensive Patients Losartan potassium may be administered with other antihypertensive agents, and with or without food. Dosing must be individualized. The usual starting dose of Losartan potassium is 50 mg once daily, with 25 mg used in patients with possible depletion of intravascular volume (e.g., patients treated with diuretics) (see WARNINGS, Hypotension — Volume-Depleted Patients ) and patients with a history of hepatic impairment (see PRECAUTIONS, General ). Losartan potassium can be administered once or twice daily with total daily doses ranging from 25 mg to 100 mg. If the antihypertensive effect measured at trough using once-a-day dosing is inadequate, a twice-a-day regimen at the same total daily dose or an increase in dose may give a more satisfactory response. The effect of losartan is substantially present within one week but in some studies the maximal effect occurred in 3-6 weeks (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Hypertension ). If blood pressure is not controlled by Losartan potassium alone, a low dose of a diuretic may be added. Hydrochlorothiazide has been shown to have an additive effect (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Hypertension ). No initial dosage adjustment is necessary for elderly patients or for patients with renal impairment, including patients on dialysis. Pediatric Hypertensive Patients greater than or equal to 6 years of age The usual recommended starting dose is 0.7 mg/kg once daily (up to 50 mg total) administered as a tablet or a suspension (see Preparation of Suspension ). Dosage should be adjusted according to blood pressure response. Doses above 1.4 mg/kg (or in excess of 100 mg) daily have not been studied in pediatric patients. (See CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations and Pharmacodynamics and Clinical Effects, and WARNINGS, Hypotension — Volume-Depleted Patients .) Losartan potassium is not recommended in pediatric patients less than 6 years of age or in pediatric patients with glomerular filtration rate less than 30 mL/min/1.73 m 2 (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations , Pharmacodynamics and Clinical Effects , and PRECAUTIONS ). Preparation of Suspension (for 200 mL of a 2.5 mg/mL suspension) Add 10 mL of Purified Water USP to an 8 ounce (240 mL) amber polyethylene terephthalate (PET) bottle containing ten 50 mg Losartan potassium tablets. Immediately shake for at least 2 minutes. Let the concentrate stand for 1 hour and then shake for 1 minute to disperse the tablet contents. Separately prepare a 50/50 volumetric mixture of Ora-Plus™ and Ora-Sweet SF™. Add 190 mL of the 50/50 Ora-Plus™/Ora-Sweet SF™ mixture to the tablet and water slurry in the PET bottle and shake for 1 minute to disperse the ingredients. The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 4 weeks. Shake the suspension prior to each use and return promptly to the refrigerator. Hypertensive Patients with Left Ventricular Hypertrophy The usual starting dose is 50 mg of Losartan potassium once daily. Hydrochlorothiazide 12.5 mg daily should be added and/or the dose of Losartan potassium should be increased to 100 mg once daily followed by an increase in hydrochlorothiazide to 25 mg once daily based on blood pressure response (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Reduction in the Risk of Stroke ). Nephropathy in Type 2 Diabetic Patients The usual starting dose is 50 mg once daily. The dose should be increased to 100 mg once daily based on blood pressure response (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Nephropathy in Type 2 Diabetic Patients ). Losartan potassium may be administered with insulin and other commonly used hypoglycemic agents (e.g., sulfonylureas, glitazones and glucosidase inhibitors).

Losartan potassium is contraindicated in patients who are hypersensitive to any component of this product. Do not co-administer aliskiren with Losartan potassium in patients with diabetes.

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.

Losartan, administered for 12 days, did not affect the pharmacokinetics or pharmacodynamics of a single dose of warfarin. Losartan did not affect the pharmacokinetics of oral or intravenous digoxin. There is no pharmacokinetic interaction between losartan and hydrochlorothiazide. Coadministration of losartan and cimetidine led to an increase of about 18% in AUC of losartan but did not affect the pharmacokinetics of its active metabolite. Coadministration of losartan and phenobarbital led to a reduction of about 20% in the AUC of losartan and that of its active metabolite. A somewhat greater interaction (approximately 40% reduction in the AUC of active metabolite and approximately 30% reduction in the AUC of losartan) has been reported with rifampin. Fluconazole, an inhibitor of cytochrome P450 2C9, decreased the AUC of the active metabolite by approximately 40%, but increased the AUC of losartan by approximately 70% following multiple doses. Conversion of losartan to its active metabolite after intravenous administration is not affected by ketoconazole, an inhibitor of P450 3A4. The AUC of active metabolite following oral losartan was not affected by erythromycin, another inhibitor of P450 3A4, but the AUC of losartan was increased by 30%.

Storage Store at 20° to 25°C (68° to 77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from light. You may report side effects to Solco Healthcare US, LLC at 1-866-257-2597 or FDA at 1-800-FDA-1088. Manufactured by: Zhejiang Huahai Pharmaceutical Co., Ltd. Xunqiao, Linhai, Zhejiang 317024, China Distributed by: Solco Healthcare US, LLC Cranbury, NJ 08512, USA Revised: 03/2015 07777-01