Cozaar Information
Cozaar (Losartan potassium) Use In Pregnancy
When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus.
WARNINGS, Fetal/Neonatal Morbidity and Mortality
Cozaar (Losartan potassium) Description
Cozaar (Losartan potassium) is an angiotensin II receptor (type AT) antagonist. Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-[-(-1-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt.
Its empirical formula is CHClKNO, and its structural formula is:
Losartan potassium 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.
Cozaar (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 hydrous, pregelatinized starch, magnesium stearate, hydroxypropyl cellulose, hypromellose, and titanium dioxide.
Cozaar (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. Cozaar (Losartan potassium) 25 mg, Cozaar (Losartan potassium) 50 mg, and Cozaar (Losartan potassium) 100 mg may also contain carnauba wax.
Cozaar (Losartan potassium) Clinical Pharmacology
Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)], is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). There is also an AT receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Both losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT receptor and have much greater affinity (about 1000-fold) for the AT receptor than for the AT receptor. binding studies indicate that losartan is a reversible, competitive inhibitor of the AT receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT receptor.
Neither losartan nor its active metabolite inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin); nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Cozaar (Losartan potassium) Contraindications
Cozaar (Losartan potassium) is contraindicated in patients who are hypersensitive to any component of this product.
Cozaar (Losartan potassium) Warnings
Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, Cozaar (Losartan potassium) should be discontinued as soon as possible.
The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.
These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.
Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Cozaar (Losartan potassium) as soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.
If oligohydramnios is observed, Cozaar (Losartan potassium) should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with histories of exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.
Losartan potassium has been shown to produce adverse effects in rat fetuses and neonates, including decreased body weight, delayed physical and behavioral development, mortality and renal toxicity. With the exception of neonatal weight gain (which was affected at doses as low as 10 mg/kg/day), doses associated with these effects exceeded 25 mg/kg/day (approximately three times the maximum recommended human dose of 100 mg on a mg/mbasis). These findings are attributed to drug exposure in late gestation and during lactation. Significant levels of losartan and its active metabolite were shown to be present in rat fetal plasma during late gestation and in rat milk.
Cozaar (Losartan potassium) Precautions
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been reported in susceptible individuals treated with Cozaar (Losartan potassium) ; in some patients, these changes in renal function were reversible upon discontinuation of therapy.
In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with Cozaar (Losartan potassium) .
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. Similar effects have been reported with Cozaar (Losartan potassium) ; in some patients, these effects were reversible upon discontinuation of therapy.
Pregnancy:
Potassium Supplements:
PRECAUTIONS, Drug Interactions
No significant drug-drug pharmacokinetic interactions have been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. Rifampin, an inducer of drug metabolism, decreased the concentrations of losartan and its active metabolite. (See .) In humans, two inhibitors of P450 3A4 have been studied. Ketoconazole did not affect the conversion of losartan to the active metabolite after intravenous administration of losartan, and erythromycin had no clinically significant effect after oral administration. Fluconazole, an inhibitor of P450 2C9, decreased active metabolite concentration and increased losartan concentration. The pharmacodynamic consequences of concomitant use of losartan and inhibitors of P450 2C9 have not been examined. Subjects who do not metabolize losartan to active metabolite have been shown to have a specific, rare defect in cytochrome P450 2C9. These data suggest that the conversion of losartan to its active metabolite is mediated primarily by P450 2C9 and not P450 3A4.
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.
Lithium:
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors):
The antihypertensive effect of angiotensin II receptor antagonists, including losartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors.
Dual blockade of the renin-angiotensin-aldosterone system:
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 alkaline elution and and chromosomal aberration assays. In addition, the active metabolite showed no evidence of genotoxicity in the microbial mutagenesis, alkaline elution, and 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).
Cozaar (Losartan potassium) Adverse Reactions
Cozaar (Losartan potassium) 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 (Losartan potassium) was well-tolerated. The overall incidence of adverse experiences reported with Cozaar (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 Cozaar (Losartan potassium) 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 (Losartan potassium) and more commonly than placebo are shown in the table below.
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 (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 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: facial edema, fever, orthostatic effects, syncope; angina pectoris, second degree AV block, CVA, hypotension, myocardial infarction, arrhythmias including atrial fibrillation, palpitation, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation; anorexia, constipation, dental pain, dry mouth, flatulence, gastritis, vomiting; anemia; gout; arm pain, hip pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, fibromyalgia, muscle weakness; 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; dyspnea, bronchitis, pharyngeal discomfort, epistaxis, rhinitis, respiratory congestion; alopecia, dermatitis, dry skin, ecchymosis, erythema, flushing, photosensitivity, pruritus, rash, sweating, urticaria; blurred vision, burning/stinging in the eye, conjunctivitis, taste perversion, tinnitus, decrease in visual acuity; 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.
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:
The following additional adverse reactions have been reported in post-marketing experience:
Digestive:
General Disorders and Administration Site Conditions:
Hemic:
Hypersensitivity:
Metabolic and Nutrition:
Musculoskeletal:
Nervous system disorders:
Respiratory:
Skin:
In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Cozaar (Losartan potassium) .
Creatinine, Blood Urea Nitrogen:
PRECAUTIONS, Impaired Renal Function
Hemoglobin and Hematocrit:
Liver Function Tests:
Cozaar (Losartan potassium) Overdosage
Significant lethality was observed in mice and rats after oral administration of 1000 mg/kg and 2000 mg/kg,respectively, about 44 and 170 times the maximum recommended human dose on a mg/m basis.
Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.
Neither losartan nor its active metabolite can be removed by hemodialysis.
Cozaar (Losartan potassium) Dosage And Administration
Cozaar (Losartan potassium) may be administered with other antihypertensive agents, and with or without food.
Dosing must be individualized. The usual starting dose of Cozaar (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 ) and patients with a history of hepatic impairment (see ). Cozaar (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 ).
If blood pressure is not controlled by Cozaar (Losartan potassium) alone, a low dose of a diuretic may be added. Hydrochlorothiazide has been shown to have an additive effect (see ).
No initial dosage adjustment is necessary for elderly patients or for patients with renal impairment, including patients on dialysis.
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 ). 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 and , and .)
Cozaar (Losartan potassium) is not recommended in pediatric patients <6 years of age or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m(see , , and ).
Cozaar (Losartan potassium) How Supplied
No. 8441 — Tablets Cozaar (Losartan potassium) , 25 mg, are white, oval,
film-coated tablets with code 951 on one side and plain on the other.
They are supplied as follows:
No.
8442 — Tablets Cozaar (Losartan potassium) , 50 mg, are white, oval, film-coated tablets with
code 952 on one side and scored on the other. They are supplied as
follows:
No.
3849 — Tablets Cozaar (Losartan potassium) , 100 mg, are white, teardrop-shaped, film-coated
tablets with code 960 on one side and plain on the other. They are
supplied as follows:
Cozaar (Losartan potassium)
Cozaar (Losartan potassium)
Cozaar (Losartan potassium)
Cozaar (Losartan potassium) Principal Display Panel - Mg Bottle Label
Each tablet contains 25 mg of losartan potassium. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from light.
Cozaar (Losartan potassium) Principal Display Panel - Mg Bottle Label
Each tablet contains 50 mg of losartan potassium. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from light.
Cozaar (Losartan potassium) Principal Display Panel - Mg Bottle Label
Each tablet contains 100 mg of losartan potassium. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from light.
