Cozaar

Cozaar

losartan

Manufacturer:

MSD

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Losartan potassium.
Action
Therapeutic Class: COZAAR*(losartan potassium), the first of a new class of agents for the treatment of hypertension, is an angiotensin II receptor (type AT1) antagonist. COZAAR also provides a reduction in the combined risk of cardiovascular death, stroke, and myocardial infarction in hypertensive patients with left ventricular hypertrophy and renal protection for type 2 diabetic patients with proteinuria.
Indications/Uses
Hypertension: COZAAR is indicated for the treatment of hypertension.
Reduction in the Risk of Cardiovascular Morbidity and Mortality in Hypertensive Patients with Left Ventricular Hypertrophy: COZAAR is indicated to reduce the risk of cardiovascular morbidity and mortality as measured by the combined incidence of cardiovascular death, stroke, and myocardial infarction in hypertensive patients with left ventricular hypertrophy (see Race under Precautions).
Renal Protection in Type 2 Diabetic Patients with Proteinuria: COZAAR is indicated to delay the progression of renal disease as measured by a reduction in the combined incidence of doubling of serum creatinine, end stage renal disease (need for dialysis or renal transplantation) or death; and to reduce proteinuria.
Dosage/Direction for Use
COZAAR may be administered with or without food.
COZAAR may be administered with other antihypertensive agents.
Hypertension: The usual starting and maintenance dose is 50 mg once daily for most patients. The maximal antihypertensive effect is attained 3 6 weeks after initiation of therapy. Some patients may receive an additional benefit by increasing the dose to 100 mg once daily.
For patients with intravascular volume-depletion (e.g., those treated with high-dose diuretics), a starting dose of 25 mg once daily should be considered (see Precautions).
No initial dosage adjustment is necessary for elderly patients or for patients with renal impairment, including patients on dialysis. A lower dose should be considered for patients with a history of hepatic impairment (see Precautions).
There is insufficient safety information with the use of COZAAR in patients with renal impairment who have serum creatinine >3.0-4.0 mg/dL. Therefore, the use of COZAAR in these patients is not recommended. If COZAAR is needed to be used, renal function and serum potassium must be closely monitored.
Reduction in the Risk of Cardiovascular Morbidity and Mortality in Hypertensive Patients with Left Ventricular Hypertrophy: The usual starting dose is 50 mg of COZAAR once daily. A low dose of hydrochlorothiazide should be added and/or the dose of COZAAR should be increased to 100 mg once daily based on blood pressure response.
Renal Protection in Type 2 Diabetic Patients with Proteinuria: 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).
Overdosage
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 the active metabolite can be removed by hemodialysis.
Contraindications
COZAAR is contraindicated in patients who are hypersensitive to any component of this product.
COZAAR should not be administered with aliskiren in patients with diabetes (see Interactions).
Warnings
Cozaar is prohibited in pregnant women.
Consult the physician if lethargy, nausea or vomiting occurs.
If angioedema including swelling of the larynx and glottis causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue occurs, discontinue Cozaar and consult the physician immediately.
Impairment of renal function may occur, thus, use with caution.
Development of hyperkalemia may occur. Concomitant use of potassium supplement or potassium-sparing diuretics is not recommended.
Special 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 (See Pregnancy under Use in Pregnancy & Lactation).
Hypersensitivity: Angioedema. (See Side Effects.)
Hypotension and Electrolyte/Fluid Imbalance: In patients who are intravascularly volume-depleted (e.g., those treated with high-dose diuretics), symptomatic hypotension may occur. These conditions should be corrected prior to administration of COZAAR or a lower starting dose should be used (see Dosage & Administration).
Electrolyte imbalances are common in patients with renal impairment, with or without diabetes and should be addressed. In a clinical study conducted in type 2 diabetic patients with proteinuria, the incidence of hyperkalemia was higher in the group treated with COZAAR as compared to the placebo group; however, few patients discontinued therapy due to hyperkalemia (see Laboratory Test Findings under Side Effects).
Concomitant use of other drugs that may increase serum potassium may lead to hyperkalemia (see Interactions).
Liver Function Impairment: Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, a lower dose should be considered for patients with a history of hepatic impairment (see Dosage & Administration).
Renal Function Impairment: As a consequence of inhibiting the renin-angiotensin system, changes in renal function including renal failure have been reported in susceptible individuals; these changes in renal function may be reversible upon discontinuation of therapy.
Other drugs that affect the renin-angiotensin system may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. Similar effects have been reported with COZAAR; these changes in renal function may be reversible upon discontinuation of therapy.
Race: Based on the Losartan Intervention For Endpoint (LIFE) reduction in hypertension study, the benefits of COZAAR on cardiovascular morbidity and mortality compared to atenolol do not apply to Black patients with hypertension and left ventricular hypertrophy, although both treatment regimens effectively lowered the blood pressure in Black patients. In the overall LIFE study population (n=9193), treatment with COZAAR resulted in a 13% risk reduction (p=0.021) as compared to atenolol for patients reaching the primary composite endpoint of the combined incidence of cardiovascular death, stroke and myocardial infarction. In this study, COZAAR decreased the risk of cardiovascular morbidity and mortality compared to atenolol in non-Black, hypertensive patients with left ventricular hypertrophy (n=8660) as measured by the primary endpoint of the combined incidence of cardiovascular death, stroke and myocardial infarction (p=0.003). In this study, however, Black patients treated with atenolol were at lower risk of experiencing the primary composite endpoint compared with Black patients treated with COZAAR (p=0.03). 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%, 25.9/1000 patient-years) and 46 primary endpoints among 270 patients (17%, 41.8/1000 patient-years) on COZAAR.
Use in Children: Neonates with a history of in utero exposure to COZAAR: If oliguria or hypotension occur, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
Use in the Elderly:
In clinical studies, there was no age-related difference in the efficacy or safety profile of losartan.
Use In Pregnancy & Lactation
Pregnancy: Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. When pregnancy is detected, discontinue COZAAR as soon as possible.
Although there is no experience with the use of COZAAR in pregnant women, animal studies with losartan potassium have demonstrated fetal and neonatal injury and death, the mechanism of which is believed to be pharmacologically mediated through effects on the renin-angiotensin system. In humans, fetal renal perfusion, which is dependent upon the development of the renin-angiotensin system, begins in the second trimester; thus, risk to the fetus increases if COZAAR is administered during the second or third trimesters of pregnancy.
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.
These adverse outcomes are usually associated with the use of these drugs in the second and third trimesters 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 renin-angiotensin 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 life-saving 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.
Lactation: It is not known whether losartan is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue COZAAR, taking into account the importance of losartan potassium to the mother.
Side Effects
COZAAR has been found to be generally well tolerated in controlled clinical trials for hypertension; side effects have usually been mild and transient in nature and have not required discontinuation of therapy. The overall incidence of side effects reported with COZAAR was comparable to placebo.
In controlled clinical trials for essential hypertension, dizziness was the only side effect reported as drug-related that occurred with an incidence greater than placebo in ≥1% of patients treated with COZAAR. In addition, dose-related orthostatic effects were seen in <1% of patients. Rarely, rash was reported, although the incidence in controlled clinical trials was less than placebo.
In these double-blind controlled clinical trials for essential hypertension, the following adverse experiences reported with COZAAR occurred in ≥1 percent of patients, regardless of the drug relationship: See table.

Click on icon to see table/diagram/image

COZAAR was generally well tolerated in a controlled clinical trial in hypertensive patients with left ventricular hypertrophy. The most common drug-related side effects were dizziness, asthenia/fatigue and vertigo.
In the LIFE study, among patients without diabetes at baseline, there was a lower incidence of new onset diabetes mellitus with COZAAR as compared to atenolol (242 patients vs 320 patients, respectively, p<0.001). Because there was no placebo group included in the study, it is not known if this represents a beneficial effect of COZAAR or an adverse effect of atenolol.
COZAAR was generally well tolerated in a controlled clinical trial in type 2 diabetic patients with proteinuria. The most common drug-related side effects were asthenia/fatigue, dizziness, hypotension and hyperkalemia (see Hypotension and Electrolyte/Fluid Imbalance under Precautions).
The following additional adverse reactions have been reported in post-marketing experience: Hypersensitivity: Anaphylactic reactions, 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-Schoenlein purpura, has been reported rarely.
Gastrointestinal: Hepatitis (reported rarely), liver function abnormalities, vomiting.
General Disorders and Administration Site Conditions: Malaise.
Hematologic: Anemia, thrombocytopenia (reported rarely).
Musculoskeletal: Myalgia, arthralgia.
Nervous System/Psychiatric: Migraine, dysgeusia.
Reproductive System and Breast Disorders: Erectile dysfunction/impotence.
Respiratory: Cough.
Skin: Urticaria, pruritus, erythroderma, photosensitivity.
Laboratory Test Findings: In controlled clinical trials for essential hypertension, clinically important changes in standard laboratory parameters were rarely associated with the administration of COZAAR. Hyperkalemia (serum potassium >5.5 mEq/L) occurred in 1.5% of patients in the hypertension clinical trials. In a clinical study conducted in type 2 diabetic patients with proteinuria, 9.9% of patients treated with COZAAR and 3.4% of patients treated with placebo developed hyperkalemia (see Hypotension and Electrolyte/Fluid Imbalance under Precautions). Elevations of ALT occurred rarely and usually resolved upon discontinuation of therapy.
Drug Interactions
In clinical pharmacokinetic trials, no drug interactions of clinical significance have been identified with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole and erythromycin.
Rifampin and fluconazole have been reported to reduce levels of active metabolite. The clinical consequences of these interactions have not been evaluated.
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.
As with other drugs which affect the excretion of sodium, lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be co-administered with angiotensin II receptor antagonists.
Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 (COX-2) inhibitors may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor antagonists or ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.
In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Therefore, the combination should be administered with caution in patients with compromised renal function.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin receptor blockers, ACE inhibitors or aliskiren is associated with increased risk of hypotension, syncope, hyperkalemia and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on COZAAR and other agents that affect the RAAS. Do not co-administer aliskiren with COZAAR in patients with diabetes. Avoid the use of aliskiren with COZAAR in patients with renal impairment (GFR <60 mL/min).
ATC Classification
C09CA01 - losartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.
Presentation/Packing
Tab 50 mg x 30's. 100 mg x 30's.
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