SIDE EFFECTS
Losartan potassium has been evaluated for safety in more
than 3300 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
was well-tolerated. The overall incidence of adverse experiences
reported with losartan potassium 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 and
3.7 percent of patients given placebo.
The following table of adverse events is based on four 6-12
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 table includes all adverse events, whether
or not attributed to the treatment, occurring in at least
1% of patients treated with losartan and that were more
frequent in losartan than placebo. (TABLE 1)
| TABLE 1 |
| |
Losartan |
Placebo |
| |
Incidence (n=1075) |
Incidence (n=334) |
| Digestive |
|
|
2.4 |
2.1 |
|
|
1.3 |
1.2 |
| Musculoskeletal |
|
|
1.1 |
0.3 |
|
|
1.0 |
0.9 |
|
|
1.8 |
1.2 |
|
|
1.0 |
0.0 |
| Nervous
System/Psychiatric |
|
|
3.5 |
2.1 |
|
|
1.4 |
0.6 |
| Respiratory |
|
|
2.0 |
1.2 |
|
|
3.4 |
3.3 |
Infection, upper respiratory
|
7.9 |
6.9 |
|
|
1.5 |
1.2 |
|
|
1.0 |
0.3 |
The following adverse events were also reported at a rate
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.
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, 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withdrawn from study due to swelling of the lips and eyelids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 was 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 occurred in
<1% of patients in clinical studies are listed below.
It cannot be determined whether these events were casually
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.
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 other serum bilirubin
have occurred. In patients with essential hypertension
treated with losartan potassium alone, one patient (<0.1%)
was discontinued to these laboratory adverse experiences.
DRUG INTERACTIONS
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 and intravenous digoxin. 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 reduction of about 20% in the AUC
of losartan and that of its active metabolite. There is
no pharmacokinetic interaction between losartan and hydrochlorothiazide.
No significant drug-drug pharmacokinetic interactions
have been found in interaction studies with hydrochlorothiazide,
digoxin, warfarin, cimetidine and phenobarbital. Potent
inhibitors of cytochrome P450 3A4 and 2C9 have not been
studied clinically but in vitro studies wshow significant
inhibition of the formation of the active metabolite by
inhibitors of P450 3A4 (ketoconazole, troleandomycin,
gestodene) or P450 2C9 (sulfaphenazole) and nearly complete
inhibition by the combination of sulfaphenazole and ketoconazole.
The pharmacodynamic consequences of concomitant use of
losartan and these inhibitors have not been examined.
As with other drugs that block angiotensin II or its
effects, concomitant use of potassium-sparing diuretics
(e.g., spironolactone, triamterene, amiloride), potassium
supplements, or salt substitutes containing potassium
may lead to increases in serum potassium.
|
|
