Losartan Potassium (Page 3 of 5)

Carcinogenesis, Mutagenesis, Impairment of Fertility


Losartan potassium was not carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. Female rats given the highest dose (270 mg/kg/day) had a slightly higher incidence of pancreatic acinar adenoma. The maximally tolerated dosages (270 mg/kg/day in rats, 200 mg/kg/day in mice) provided systemic exposures for losartan and its pharmacologically active metabolite that were approximately 160- and 90-times (rats) and 30- and 15-times (mice) the exposure of a 50 kg human given 100 mg per day.
Losartan potassium was negative in the microbial mutagenesis and V-79 mammalian cell mutagenesis assays and in the in vitro alkaline elution and in vitro and in vivo chromosomal aberration assays. In addition, the active metabolite showed no evidence of genotoxicity in the microbial mutagenesis, in vitro alkaline elution, and in vitro chromosomal aberration assays.Fertility and reproductive performance were not affected in studies with male rats given oral doses of losartan potassium up to approximately 150 mg/kg/day. The administration of toxic dosage levels in females (300/200 mg/kg/day) was associated with a significant (p<0.05) decrease in the number of corpora lutea/female, implants/female, and live fetuses/female at C-section. At 100 mg/kg/day only a decrease in the number of corpora lutea/female was observed. The relationship of these findings to drug-treatment is uncertain since there was no effect at these dosage levels on implants/pregnant female, percent post-implantation loss, or live animals/litter at parturition. In nonpregnant rats dosed at 135 mg/kg/day for 7 days, systemic exposure (AUCs) for losartan and its active metabolite were approximately 66 and 26 times the exposure achieved in man at the maximum recommended human daily dosage (100 mg).

Pregnancy

Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

Nursing Mothers

It is not known whether losartan is excreted in human milk, but significant levels of losartan and its active metabolite were shown to be present in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Antihypertensive effects of losartan potassium tablets have been established in hypertensive pediatric patients aged 6 to 16 years. There are no data on the effect of losartan potassium tablets on blood pressure in pediatric patients under the age of 6 or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m2 (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations and Pharmacodynamics and Clinical Effects and DOSAGE AND ADMINISTRATION).

Geriatric Use


Of the total number of patients receiving losartan potassium tablets in controlled clinical studies for hypertension, 391 patients (19%) were 65 years and over, while 37 patients (2%) were 75 years and over.In a controlled clinical study for renal protection in type 2 diabetic patients with proteinuria, 248 patients (33%) were 65 years and over. In a controlled clinical study for the reduction in the combined risk of cardiovascular death, stroke and myocardial infarction in hypertensive patients with left ventricular hypertrophy, 2857 patients (62%) were 65 years and over, while 808 patients (18%) were 75 years and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Race
In the LIFE study, Black patients with hypertension and left ventricular hypertrophy had a lower risk of stroke on atenolol than on losartan potassium tablets. Given the difficulty in interpreting subset differences in large trials, it cannot be known whether the observed difference is the result of chance. However, the LIFE study does not provide evidence that the benefits of losartan potassium tablets on reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to Black patients. (see CLINICAL PHARMACOLOGY, Pharmacodynamics and Clinical Effects, Reduction in the Risk of Stroke).

ADVERSE REACTIONS


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 (10-150 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 121 010
Nervous System/Psychiatric Dizziness 3 2
Respiratory Congestion, nasal Infection, upper respiratory Sinusitis 281 170


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.

Study 1 † HCTZ Losartan Lisinopril
Cough 25% 17% 69%
Study 2 Placebo Losartan Lisinopril
Cough 35% 29% 62%

† Demographics = (89% caucasian, 64% female)
†† Demographics = (90% caucasian, 51% female)
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 post-marketing 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 tablets or placebo, the overall incidences of reported adverse experiences were similar for the two groups. Losartan potassium tablets were generally well tolerated as evidenced by a similar incidence of discontinuations due to side effects compared to placebo (19% for losartan potassium tablets, 24% for placebo). The adverse experiences, regardless of drug relationship, reported with an incidence of >4% of patients treated with losartan potassium tablets and occurring more commonly than placebo, on a background of conventional antihypertensive therapy, are shown in the table below.
Post-Marketing Experience
The following additional adverse reactions have been reported in post-marketing experience:

Losartan and Conventional AntihypertensiveTherapy Incidence%(n=751) Placebo and Conventional AntihypertensiveTherapy 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

Post-Marketing Experience
The following additional adverse reactions have been reported in post-marketing 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 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.

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