LOSORTAN 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 molecular formula is C 22 H 22 ClKN 6 O, and its structural formula is: Losartan potassium, USP is white to off-white powder with a molecular weight of 461.01. It is freely soluble in water; soluble in isopropyl alcohol; slightly soluble in acetonitrile. Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan. Each losartan potassium tablet intended for oral administration contains 25 mg or 50 mg or 100 mg of losartan potassium. In addition, each tablet contains the following inactive ingredients: colloidal silica anhydrous, hydroxypropyl cellulose (low substituted), hypromellose, lactose monohydrate, magnesium stearate, maize starch (corn starch), microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, talc and titanium dioxide. Losartan potassium 25 mg, 50 mg and 100 mg tablets 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. Structured formula for losartan

Hypertension: Losartan potassium tablets 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 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 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 reduces 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 tablets may be administered with other antihypertensive agents, and with or without food. Dosing must be individualized. The usual starting dose of losartan potassium tablets 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 tablets 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 to 6 weeks (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Hypertension ). If blood pressure is not controlled by losartan potassium tablets 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 patient ≥ 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 tablets are not recommended in pediatric patients <6 years of age or in pediatric patients with glomerular filtration rate <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 to 8°C (36 to 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 tablets once daily. Hydrochlorothiazide 12.5 mg daily should be added and/or the dose of losartan potassium tablets 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 tablets are contraindicated in patients who are hypersensitive to any component of this product. Do not co-administer aliskiren with losartan potassium tablets in patients with diabetes.

Hypertension: Losartan potassium tablets have 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 tablets was well-tolerated. The overall incidence of adverse experiences reported with losartan potassium tablets 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 tablets 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 to 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 tablets and more commonly than placebo are shown in the table below. Losartan (n=1075) Incidence % Placebo (n=334) Incidence % Musculoskeletal Cramp, muscle Pain, back Pain, leg 1 2 1 0 1 0 Nervous System/Psychiatric Dizziness 3 2 Respiratory Congestion, nasal Infection, upper respiratory Sinusitis 2 8 1 1 7 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 tablets, 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. * Demographics = (89% caucasian, 64% female) † Demographics = (90% caucasian, 51% female) Study 1 * HCTZ Losartan Lisinopril Cough 25% 17% 69% Study 2 † 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 tablets 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. Losartan and Conventional Antihypertensive Therapy Incidence % (n=751) Placebo and Conventional Antihypertensive Therapy Incidence % (n=762) Body as a Whole Asthenia/Fatigue 14 10 Chest Pain 12 8 Fever 4 3 Infection 5 4 Influenza-like disease 10 9 Trauma 4 3 Cardiovascular Hypotension 7 3 Orthostatic hypotension 4 1 Digestive Diarrhea 15 10 Dyspepsia 4 3 Gastritis 5 4 Endocrine Diabetic neuropathy 4 3 Diabetic vascular disease 10 9 Eyes, Ears, Nose and Throat Cataract 7 5 Sinusitis 6 5 Hemic Anemia 14 11 Metabolic and Nutrition Hyperkalemia 7 3 Hypoglycemia 14 10 Weight gain 4 3 Musculoskeletal Back pain 12 10 Leg pain 5 4 Knee pain 5 4 Muscular weakness 7 4 Nervous System Hypesthesia 5 4 Respiratory Bronchitis 10 9 Cough 11 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-Schonlein 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 tablets. 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 tablets 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 tablets 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 tablets alone, one patient (<0.1%) was discontinued due to these laboratory adverse experiences.