COZAAR (losartan potassium) is indicated for the treatment of essential hypertension.

COZAAR may be used alone or concomitantly with thiazide diuretics.

A great majority of patients with severe hypertension in controlled clinical trials required combination therapy. COZAAR has been used concomitantly with beta-blockers and calcium channel blockers, but the data on such use are limited.

The safety and efficacy of concurrent use with angiotensin converting enzyme inhibitors have not been established.

COZAAR is also indicated to delay the progression of renal disease as measured by the occurrence of doubling of serum creatinine, and end stage renal disease, and to reduce proteinuria.

In clinical studies, there was no age-related difference in the efficacy or safety profile of losartan (see Warnings and Precautions).

The product is not approved for pediatric use.

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see Dosage Forms, Composition and Packaging.

  
  

There is no evidence of carcinogenesis and mutagenesis associated with losartan.

Occasionally, symptomatic hypotension has occurred after administration of losartan, in some cases after the first dose. It is more likely to occur in patients who are volume-depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In these patients, because of the potential fall in blood pressure, therapy should be started under close medical supervision. Similar considerations apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident.

There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan and its active metabolite in cirrhotic patients after administration of COZAAR, a lower dose should be considered for patients with hepatic impairment, or a history of hepatic impairment (see Dosage and Administration).

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been reported in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.

Use of losartan should include appropriate assessment of renal function.

In a clinical study conducted in patients with type 2 diabetes with proteinuria and hypertension, the incidence of hyperkalemia was higher in the group treated with COZAAR (9.9%) as compared to the placebo group (3.4%), however, few patients discontinued therapy due to hyperkalemia. Careful monitoring of serum potassium is recommended (see Adverse Reactions, Abnormal Hematologic and Clinical Chemistry Findings).

Anaphylactic reactions, angioedema (involving swelling of the larynx and glottis causing airway obstruction and/or swelling of the face, lips, and/or tongue and pharynx, requiring intubation/tracheotomy in some cases) have been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with ACE inhibitors. Vasculitis, including Henoch-Schoenlein purpura, has been reported rarely.

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, COZAAR 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 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, 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 in utero 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 may be required as means of reversing hypotension and/or substituting for impaired renal function. Neither losartan nor the active metabolite can be removed by hemodialysis.

Losartan potassium has been shown to produce adverse effects in rat fetuses and neonates, which include decreased body weight, mortality and/or renal toxicity. Significant levels of losartan and its active metabolite were shown to be present in rat milk. Based on pharmacokinetic assessments, these findings are attributed to drug exposure in late gestation and during lactation.

It is not known whether losartan or its active metabolite are excreted in human milk, however significant levels of both of these compounds have been shown to be present in the milk of lactating rats. Because many drugs are excreted in human milk, and because of their potential for affecting the nursing infant adversely, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

No overall differences in safety were observed between elderly and younger patients, but appropriate caution should nevertheless be used when prescribing to elderly, as increased vulnerability to drug effect is possible in this patient population. This conclusion is based on 391 of 2085 (19%) patients, 65 years and over who received losartan monotherapy in controlled trials for hypertension. This was also the finding in a controlled clinical study in type 2 diabetic patients with proteinuria and hypertension with 248 (33%) of patients over 65 years of age.

The product is not approved for pediatric use.

Not applicable.

COZAAR has been evaluated for safety in more than 3300 patients treated for essential hypertension. Of these, 2085 were treated with losartan monotherapy in controlled clinical trials.

In open studies, over 1200 patients were treated with losartan for more than 6 months, and over 800 for more than one year.

In controlled clinical trials, discontinuation of therapy due to clinical adverse experiences occurred in 2.3% and 3.7% of patients treated with COZAAR and placebo, respectively.

The following potentially serious adverse reactions have been reported rarely with losartan in controlled clinical trials: syncope, hypotension.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

In these double-blind controlled clinical trials, the following adverse reactions reported with COZAAR occurred in ≥1% of patients, regardless of drug relationship: see Table 1.

In these controlled clinical trials for essential hypertension, dizziness was the only adverse experience, occurring in more than 1% of cases, that was reported as drug-related, and that occurred at a greater incidence in losartan-treated (2.4%) than placebo-treated (1.3%) patients.

COZAAR was generally well tolerated in a controlled clinical trial in type 2 diabetic patients with proteinuria and hypertension. The most common drug-related side effects were asthenia/fatigue, dizziness, hypotension and hyperkalemia.

In double-blind, controlled clinical trials for essential hypertension, the following adverse reactions were reported with COZAAR at an occurrence rate of less than 1%, regardless of drug relationship: orthostatic effects, somnolence, vertigo, epistaxis, tinnitus, constipation, malaise, rash.

In controlled clinical trials for essential hypertension, clinically important changes in standard laboratory parameters were rarely associated with administration of COZAAR.

In double-blind hypertensive trials, elevations of AST and ALT occurred in 1.1% and 1.9% of patients treated with losartan monotherapy and in 0.8% and 1.3% of patients treated with placebo, respectively. When AST or ALT elevations ≥2×upper limit of normal were compared, the frequency was similar to that seen in placebo.

In controlled clinical trials for essential hypertension, hyperkalemia (serum potassium >5.5 mEq/L) occurred in 1.5% of patients treated with COZAAR.

In a clinical study conducted in type 2 diabetic patients with proteinuria and hypertension, 9.9% of patients treated with COZAAR and 3.4% of patients treated with placebo developed hyperkalemia (see Warnings and Precautions, Renal, Hyperkalemia).

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 COZAAR alone. No patient discontinued taking COZAAR alone due to increased BUN or serum creatinine.

Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.11 g percent and 0.09 volume percent, respectively) occurred frequently in patients treated with COZAAR alone, but were rarely of clinical importance. In controlled clinical trials no patients were discontinued due to anemia. Discontinuation of losartan treatment due to anemia was reported with post-marketing use of losartan.

In clinical trials, the following were noted to occur with an incidence of <1%, regardless of drug relationship: thrombocytopenia, eosinophilia.

Other adverse reactions reported rarely in open-label studies or post-marketing use in patients with essential hypertension, regardless of drug relationship, include anemia, thrombocytopenia (reported rarely), hepatitis, liver function tests abnormalities, drug induced cough, asthenia, diarrhea, migraine, arthralgia, pruritus, taste disorder and urticaria. Cases of muscle pain, muscle weakness, myositis and rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Anaphylactic reactions, angioedema (involving swelling of the larynx and glottis causing airway obstruction and/or swelling of the face, lips, and/or tongue and pharynx, requiring intubation/tracheotomy in some cases) have been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with ACE inhibitors. Vasculitis, including Henoch-Schoenlein purpura, has been reported rarely.

Patients on diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with COZAAR. The possibility of symptomatic hypotension with the use of COZAAR can be minimized by discontinuing the diuretic prior to initiation of treatment and/or lowering the initial dose of losartan (see Warnings and Precautions, Cardiovascular, Hypotension and Dosage and Administration). No drug interaction of clinical significance has been identified with thiazide diuretics.

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.

Since COZAAR decreases the production of aldosterone, potassium-sparing diuretics or potassium supplements should be given only for documented hypokalemia and with frequent monitoring of serum potassium. Potassium-containing salt substitutes should also be used with caution.

As with other drugs which eliminate sodium, lithium clearance may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be administered.

In 9 healthy volunteers, when a single oral dose of 0.5 mg digoxin was administered to patients receiving losartan for 11 days, digoxin AUC and digoxin C_max ratios, relative to placebo, were found to be 1.06 (90% C.I. 0.98-1.14) and 1.12 (90% C.I. 0.97-1.28), respectively. The effect of losartan on steady-state pharmacokinetics of cardiac glycosides is not known.

Losartan administered for 7 days did not affect the pharmacokinetics or pharmacodynamic activity of a single dose of warfarin. The effect of losartan on steady-state pharmacokinetics of warfarin is not known.

Rifampin, an inducer of drug metabolism, decreases the concentrations of the active metabolite of losartan. 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 losartan administration. Fluconazole, an inhibitor of P450 2C9, decreased active metabolite concentration. The pharmacodynamic consequences of concomitant use of losartan and inhibitors of P450 2C9 have not been examined.

When losartan was administered to 10 healthy male volunteers as a single dose in steady-state conditions of phenobarbital, a cytochrome P450 inducer, losartan AUC, relative to baseline, was 0.80 (90% C.I. 0.72-0.88), while AUC of the active metabolite, E-3174, was 0.80 (90% C.I. 0.78-0.82).

When losartan was administered to 8 healthy male volunteers as a single dose in steady-state conditions of cimetidine, a cytochrome P450 inhibitor, losartan AUC, relative to baseline, was 1.18 (90% C.I. 1.10-1.27), while AUC of the active metabolite, E-3174, was 1.00 (90% C.I. 0.92-1.08).

Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists may be attenuated by NSAIDs including selective COX-2 inhibitors.

In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists may result in a further deterioration of renal function. These effects are usually reversible.

COZAAR may be administered with or without food.

Interactions with herbal products have not been established.

Interactions with laboratory tests have not been established.

COZAAR may be administered with or without food, however it should be taken consistently with respect to food intake at about the same time every day.

The dosage of COZAAR must be individualized.

Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction, and other pertinent clinical factors. The dosage of other antihypertensive agents used with COZAAR may need to be adjusted.

The usual starting dose of COZAAR is 50 mg once daily.

Dosage should be adjusted according to blood pressure response. The maximal antihypertensive effect is attained 3-6 weeks after initiation of therapy.

The usual dose range for COZAAR is 50 to 100 mg once daily. A dose of 100 mg daily should not be exceeded, as no additional antihypertensive effect is obtained with higher doses.

In most patients taking COZAAR 50 mg once daily, the antihypertensive effect is maintained. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. This can be evaluated by measuring the blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, either twice daily administration with the same total daily dosage, or an increase in the dose should be considered. If blood pressure is not adequately controlled with COZAAR alone, a non-potassium-sparing diuretic may be administered concomitantly.

For patients with volume-depletion, a starting dose of 25 mg once daily should be considered (see Warnings and Precautions, Cardiovascular, Hypotension and Drug Interactions).

In patients receiving diuretics, COZAAR therapy should be initiated with caution, since these patients may be volume-depleted and thus more likely to experience hypotension following initiation of additional antihypertensive therapy. Whenever possible, all diuretics should be discontinued two to three days prior to the administration of COZAAR, to reduce the likelihood of hypotension (see Warnings and Precautions, Cardiovascular, Hypotension and Drug Interactions). If this is not possible because of the patient's condition, COZAAR should be administered with caution and the blood pressure monitored closely. Thereafter, the dosage should be adjusted according to the individual response of the patient.

The usual starting dose is 50 mg once daily. The dose may be increased to 100 mg once daily based on blood pressure response. COZAAR may be administered with other antihypertensive agents (e.g., diuretics, calcium channel blockers, alpha- or beta-blockers, and centrally acting agents) as well as with insulin and other commonly used hypoglycemic agents (e.g., sulfonylureas, glitazones and glucosidase inhibitors).

No initial dosage adjustment is necessary for most elderly patients. However, appropriate monitoring of these patients is recommended.

No initial dosage adjustment is usually necessary for patients with renal impairment, including those requiring hemodialysis. However, appropriate monitoring of these patients is recommended.

An initial dosage of 25 mg should be considered for patients with hepatic impairment, or a history of hepatic impairment (see Warnings and Precautions, Hepatic/Biliary/Pancreatic, Hepatic Impairment).

If a dose is missed, an extra dose should not be taken. The usual schedule must be resumed.

Limited data are available in regard to overdosage with COZAAR in humans. The most likely manifestation of overdosage would be hypotension and/or tachycardia. If symptomatic hypotension should occur, supportive treatment should be instituted.

Neither losartan nor the active metabolite can be removed by hemodialysis.

COZAAR antagonizes angiotensin II by blocking the angiotensin type one (AT₁) receptor.

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin system. Its effects include vasoconstriction and the stimulation of aldosterone secretion by the adrenal cortex.

Losartan, and its active metabolite, E-3174, block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to AT₁ receptors found in many tissues, including vascular smooth muscle. A second type of angiotensin II receptor has been identified as the AT₂ receptor, but it plays no known role in cardiovascular homeostasis to date. Both losartan and its active metabolite do not exhibit any agonist activity at the AT₁ receptor, and have much greater affinity, in the order of 1000-fold, for the AT₁ receptor than for the AT₂ receptor. In vitro binding studies indicate that losartan itself is a reversible, competitive antagonist at the AT₁ receptor, while the active metabolite is 10 to 40 times more potent than losartan, and is a reversible, non-competitive antagonist of the AT₁ receptor.

Neither losartan nor its active metabolite inhibits angiotensin converting enzyme (ACE), also known as 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.

Losartan inhibits the pressor effect of angiotensin II. A dose of 100 mg inhibits this effect by about 85% at peak, with 25-40% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a 2-3 fold rise in plasma renin activity, and a consequent rise in angiotensin II plasma concentration, in hypertensive patients.

Maximum blood pressure lowering, following oral administration of a single dose of losartan, as seen in hypertensive patients, occurs at about 6 hours.

In losartan-treated patients during controlled trials, there was no meaningful change in heart rate.

There is no apparent rebound effect after abrupt withdrawal of losartan therapy.

Black hypertensive patients show a smaller average blood pressure response to losartan monotherapy than other hypertensive patients.

Following oral administration, losartan is well absorbed, with systemic bioavailability of losartan approximately 33%. About 14% of an orally-administered dose of losartan is converted to the active metabolite, although about 1% of subjects did not convert losartan efficiently to the active metabolite.

Mean peak concentrations of losartan occur at about one hour, and that of its active metabolite at about 3-4 hours. Although maximum plasma concentrations of losartan and its active metabolite are approximately equal, the AUC of the metabolite is about 4 times greater than that of losartan.

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.

The volume of distribution of losartan is about 34 L, and that of the active metabolite is about 12 L.

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, E-3174, that is responsible for most of the angiotensin II receptor antagonism that follows oral losartan administration.

Various losartan metabolites have been identified in human plasma and urine. In addition to the active carboxylic acid metabolite, E-3174, several inactive metabolites are formed. In vitro studies indicate that the cytochrome P450 isoenzymes 2C9 and 3A4 are involved in the biotransformation of losartan to its metabolites.

The terminal half-life of losartan itself is about 2 hours, and that of the active metabolite, about 6-9 hours. The pharmacokinetics of losartan and this metabolite are linear with oral losartan doses up to 200 mg and do not change over time. Neither losartan nor its metabolite accumulate in plasma upon repeated once-daily administration.

Total plasma clearance of losartan is about 600 mL/min, with about 75 mL/min accounted for by renal clearance. Total plasma clearance of the active metabolite is about 50 mL/min, with about 25 mL/min accounted for by renal clearance. Both biliary and urinary excretion contribute substantially 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.