Cozaar

Dosage Forms And Strengths

• COZAAR, 25 mg, are white, oval, film-coated tablets with code 951 on one side.
• COZAAR, 50 mg, are white, oval, film-coated tablets with code 952 on one side and scored on the other.
• COZAAR, 100 mg, are white, teardrop-shaped, film-coated tablets with code 960 on one side.

Storage And Handling

COZAAR is a white film-coated tablet supplied as follows:

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Keep container tightly closed. Protect from light.

Manufactured for: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA. Revised: Dec 2015

Hypertension

COZAAR^® is indicated for the treatment of hypertension in adults and pediatric patients 6 years of age and older, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and nonfatal cardiovascular (CV) events, primarily strokes and myocardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including losartan.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

COZAAR may be administered with other antihypertensive agents.

Hypertensive Patients With Left Ventricular Hypertrophy

COZAAR is 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.

Nephropathy In Type 2 Diabetic Patients

COZAAR is 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, COZAAR 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) .

Hypertension

Adult Hypertension

The usual starting dose of COZAAR is 50 mg once daily. The dosage can be increased to a maximum dose of 100 mg once daily as needed to control blood pressure. A starting dose of 25 mg is recommended for patients with possible intravascular depletion (e.g., on diuretic therapy).

Pediatric Hypertension

The usual recommended starting dose is 0.7 mg per kg once daily (up to 50 mg total) administered as a tablet or a suspension. Dosage should be adjusted according to blood pressure response. Doses above 1.4 mg per kg (or in excess of 100 mg) daily have not been studied in pediatric patients.

COZAAR is not recommended in pediatric patients less than 6 years of age or in pediatric patients with estimated glomerular filtration rate less than 30 mL/min/1.73 m².

Hypertensive Patients With Left Ventricular Hypertrophy

The usual starting dose is 50 mg of COZAAR once daily. Hydrochlorothiazide 12.5 mg daily should be added and/or the dose of COZAAR should be increased to 100 mg once daily followed by an increase in hydrochlorothiazide to 25 mg once daily based on blood pressure response.

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.

Dosage Modifications In Patients With Hepatic Impairment

In patients with mild-to-moderate hepatic impairment the recommended starting dose of COZAAR is 25 mg once daily. COZAAR has not been studied in patients with severe hepatic impairment.

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 COZAAR 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 2-8°C (36-46°F) and can be stored for up to 4 weeks. Shake the suspension prior to each use and return promptly to the refrigerator.

COZAAR is contraindicated:

• In patients who are hypersensitive to any component of this product.
• For coadministration with aliskiren in patients with diabetes.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Fetal Toxicity

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue COZAAR as soon as possible.

Hypotension In Volume- Or Salt-Depleted Patients

In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with COZAAR. Correct volume or salt depletion prior to administration of COZAAR .

Renal Function Deterioration

Changes in renal function including acute renal failure can be caused by drugs that inhibit the reninangiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on COZAAR. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on COZAAR.

Hyperkalemia

Monitor serum potassium periodically and treat appropriately. Dosage reduction or discontinuation of COZAAR may be required.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Pregnancy

Advise female patients of childbearing age about the consequences of exposure to COZAAR during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible.

Potassium Supplements

Advise patients receiving COZAAR not to use potassium supplements or salt substitutes containing potassium without consulting their healthcare provider.

Nonclinical Toxicology

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 drugtreatment 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).

Use In Specific Populations

Pregnancy

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue losartan as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the reninangiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue COZAAR, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to COZAAR for hypotension, oliguria, and hyperkalemia.

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/m² basis). 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.

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

Neonates with a history of in utero exposure to COZAAR: If oliguria or hypotension occurs, direct attention 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.

Antihypertensive effects of COZAAR have been established in hypertensive pediatric patients aged 6 to 16 years. Safety and effectiveness have not been established in pediatric patients under the age of 6 or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m².

Geriatric Use

Of the total number of patients receiving COZAAR 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 treated with atenolol were at lower risk of experiencing the primary composite endpoint compared with Black patients treated with COZAAR (both cotreated with hydrochlorothiazide in the majority of patients). The primary endpoint was the first occurrence of stroke, myocardial infarction or cardiovascular death, analyzed using an intention-to-treat (ITT) approach. In the subgroup of Black patients (n=533, 6% of the LIFE study patients), there were 29 primary endpoints among 263 patients on atenolol (11%, 26 per 1000 patientyears) and 46 primary endpoints among 270 patients (17%, 42 per 1000 patient-years) on COZAAR. This finding could not be explained on the basis of differences in the populations other than race or on any imbalances between treatment groups. In addition, blood pressure reductions in both treatment groups were consistent between Black and non-Black patients. 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 provides no evidence that the benefits of COZAAR on reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to Black patients.

Renal Impairment

Patients with renal insufficiency have elevated plasma concentrations of losartan and its active metabolite compared to subjects with normal renal function. No dose adjustment is necessary in patients with renal impairment unless a patient with renal impairment is also volume depleted.

Hepatic Impairment

The recommended starting dose of COZAAR is 25 mg in patients with mild-to-moderate hepatic impairment. Following oral administration in patients with mild-to-moderate hepatic impairment, plasma concentrations of losartan and its active metabolite were, respectively, 5 times and 1.7 times those seen in healthy volunteers. COZAAR has not been studied in patients with severe hepatic impairment.

No clinically significant drug interactions have been found in studies of losartan potassium with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. However, rifampin has been shown to decrease the AUC of losartan and its active metabolite by 30% and 40%, respectively. Fluconazole, an inhibitor of cytochrome P450 2C9, decreased the AUC of the active metabolite by approximately 40%, but increased the AUC of losartan by approximately 70% following multiple doses. Conversion of losartan to its active metabolite after intravenous administration is not affected by ketoconazole, an inhibitor of P450 3A4. The AUC of active metabolite following oral losartan was not affected by erythromycin, an inhibitor of P450 3A4, but the AUC of losartan was increased by 30%.

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.

Advise female patients of childbearing age about the consequences of exposure to COZAAR during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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.

Treatment with COZAAR was well-tolerated with an overall incidence of adverse events similar to that of placebo. In controlled clinical trials, discontinuation of therapy for adverse events occurred in 2.3% of patients treated with COZAAR and 3.7% of patients given placebo. In 4 clinical trials involving over 1000 patients on various doses (10-150 mg) of losartan potassium and over 300 patients given placebo, the adverse events that occurred in ≥2% of patients treated with COZAAR and more commonly than placebo were: dizziness (3% vs. 2%), upper respiratory infection (8% vs. 7%), nasal congestion (2% vs. 1%), and back pain (2% vs. 1%).

The following less common adverse reactions have been reported:

Blood and lymphatic system disorders: Anemia.

Psychiatric disorders: Depression.

Nervous system disorders: Somnolence, headache, sleep disorders, paresthesia, migraine.

Ear and labyrinth disorders: Vertigo, tinnitus.

Cardiac disorders: Palpitations, syncope, atrial fibrillation, CVA.

Respiratory, thoracic and mediastinal disorders: Dyspnea.

Gastrointestinal disorders: Abdominal pain, constipation, nausea, vomiting.

Skin and subcutaneous tissue disorders: Urticaria, pruritus, rash, photosensitivity.

Musculoskeletal and connective tissue disorders: Myalgia, arthralgia.

Reproductive system and breast disorders: Impotence.

General disorders and administration site conditions: Edema.

Cough

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 in Table 1 below.

Table 1

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.

Hypertensive Patients With Left Ventricular Hypertrophy

In the Losartan Intervention for Endpoint (LIFE) study, adverse reactions with COZAAR were similar to those reported previously for patients with hypertension.

Nephropathy In Type 2 Diabetic Patients

In the Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study involving 1513 patients treated with COZAAR or placebo, the overall incidences of reported adverse events were similar for the two groups. Discontinuations of COZAAR because of side effects were similar to placebo (19% for COZAAR, 24% for placebo). The adverse events, regardless of drug relationship, reported with an incidence of ≥4% of patients treated with COZAAR and occurring with ≥2% difference in the losartan group vs. placebo on a background of conventional antihypertensive therapy, were asthenia/fatigue, chest pain, hypotension, orthostatic hypotension, diarrhea, anemia, hyperkalemia, hypoglycemia, back pain, muscular weakness, and urinary tract infection.

Postmarketing Experience

The following additional adverse reactions have been reported in postmarketing experience with COZAAR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure:

Digestive: Hepatitis.

General Disorders and Administration Site Conditions: Malaise.

Hematologic: Thrombocytopenia.

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: Hyponatremia.

Musculoskeletal: Rhabdomyolysis.

Nervous system disorders: Dysgeusia.

Skin: Erythroderma.

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/m² 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.

Losartan inhibits the pressor effect of angiotensin II (as well as angiotensin I) infusions. A dose of 100 mg inhibits the pressor effect by about 85% at peak with 25-40% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a doubling to tripling in plasma renin activity and consequent rise in angiotensin II plasma concentration in hypertensive patients. Losartan does not affect the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin. Aldosterone plasma concentrations fall following losartan administration. In spite of the effect of losartan on aldosterone secretion, very little effect on serum potassium was observed.

The effect of losartan is substantially present within one week but in some studies the maximal effect occurred in 3-6 weeks. In long-term follow-up studies (without placebo control) the effect of losartan appeared to be maintained for up to a year. There is no apparent rebound effect after abrupt withdrawal of losartan. There was essentially no change in average heart rate in losartan-treated patients in controlled trials.

Absorption

Following oral administration, losartan is well absorbed and undergoes substantial first-pass metabolism. The systemic bioavailability of losartan is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC (area under the curve) of the metabolite is about 4 times as great as that of losartan. A meal slows absorption of losartan and decreases its C_max but has only minor effects on losartan AUC or on the AUC of the metabolite (~10% decrease). The pharmacokinetics of losartan and its active metabolite are linear with oral losartan doses up to 200 mg and do not change over time.

Distribution

The volume of distribution of losartan and the active metabolite is about 34 liters and 12 liters, respectively. Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of 1.3% and 0.2%, respectively. Plasma protein binding is constant over the concentration range achieved with recommended doses. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.

Metabolism

Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows losartan treatment. About 14% of an orally-administered dose of losartan is converted to the active metabolite. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites.

Elimination

Total plasma clearance of losartan and the active metabolite is about 600 mL/min and 50 mL/min, respectively, with renal clearance of about 75 mL/min and 25 mL/min, respectively. The terminal half-life of losartan is about 2 hours and of the metabolite is about 6-9 hours. After single doses of losartan administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of losartan and its metabolites. Following oral ¹⁴C-labeled losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of ¹⁴C-labeled losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces. Neither losartan nor its metabolite accumulates in plasma upon repeated once-daily dosing.