ADVERSE REACTIONS
Hypertension
COZAAR 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 COZAAR was well-tolerated. The overall incidence of adverse experiences reported with COZAAR 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 COZAAR 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 COZAAR 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A patient with known hypersensitivity to aspirin and penicillin, when treated with COZAAR, was withdrawn from study due to swelling of the lips and eyelids and facial rash, reported as angioedema, which returned to normal 5 days after therapy was discontinued.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% |
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 COZAAR 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 COZAAR or placebo, the overall incidences of reported adverse experiences were similar for the two groups. COZAAR was generally well tolerated as evidenced by a similar incidence of discontinuations due to side effects compared to placebo (19% for COZAAR, 24% for placebo). The adverse experiences, regardless of drug relationship, reported with an incidence of ≥4% of patients treated with COZAAR 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
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 |
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 COZAAR.
Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum creatininewere observed in less than 0.1 percent of patients with essential hypertension treated with COZAAR 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 COZAAR 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 COZAAR alone, one patient (<0.1%) was discontinued due to these laboratory adverse experiences.
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