COZAAR Merck Sharp & Dhome

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1 COZAAR Merck Sharp & Dhome 1. NAME OF THE MEDICINAL PRODUCT Cozaar 50 and Cozaar QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet of Cozaar contains 50 mg or 100 mg of losartan potassium. For excipients, see PHARMACEUTICAL FORM Cozaar 50, film-coated scored tablets 50 mg, are oval shaped and white, with the stamped code 952. Cozaar 100, film-coated unscored tablets 100 mg, are drop shaped, white with the stamped code CLINICAL PARTICULARS 4.1 Therapeutic indications Essential hypertension. Type 2 Diabetic Patients with Proteinuria to delay the progression of renal disease. Hypertensive Patients with Left Ventricular Hypertrophy to reduce the Risk of Cardiovascular Morbidity and Mortality. (see Pharmacodynamic properties, LIFE Study, Race) 4.2 Posology and method of administration Cozaar can be taken before, during or after meals. Cozaar may be administered with other antihypertensive agents. Hypertension The usual initial and maintenance dose is 50 mg once daily. The maximal antihypertensive effect is attained 3-6 weeks after initiation of therapy. If necessary, dosage may then be increased 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 Special warnings and special precautions for use ). No initial dosage adjustment is necessary for elderly patients or for patients with renal impairment. A lower dose should be considered for patients with hepatic impairment and patients on dialysis (see Special warnings and special precautions for use ). Type 2 Diabetic Patients with Proteinuria to delay the progression of renal disease. 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). Hypertensive Patients with Left Ventricular Hypertrophy to reduce the Risk of Cardiovascular Morbidity and Mortality 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 4.3 Contraindications Cozaar is contraindicated in patients who are hypersensitive to any component of this product. 4.4 Special warnings and special precautions for use Hypersensitivity: Angioedema. See Undesirable effects. Symptomatic hypotension and Electrolyte/Fluid Imbalance In patients who are intravascularly volume-depleted symptomatic hypotension may occur. Such situations are most likely in patients who are being treated with diuretics, are on a low-sodium diet or are experiencing vomiting or diarrhea. In patients

2 COZAAR - p.2/7 with concurrent heart insufficiency there may be an increased risk of symptomatic hypotension. This is true in particular for severe forms of heart insufficiency as may be manifest from the concomitant use of high-dose diuretics, hyponatremia or renal impairment. In such patients, treatment should preferably be initiated in the hospital. In general, intravascular volume depletion should be corrected prior to administration of losartan. Furthermore, it could be considered to start with a lower initial dosage (see Posology and method of administration ). If hypotension occurs, the patient should be laid down and intravascular volume should be replenished, for example with intravenous saline. Caution is called for in patients with aortic stenosis in view of the potential risk of reduced coronary and cerebral perfusion as a result of decreased blood pressure. 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(see Undesirable effects and Laboratory Test Findings). Liver Function impairment Based on pharmacokinetic data demonstrating significantly increased plasma concentrations of losartan in cirrhotic patients, a lower dose should be considered for patients with hepatic impairment (see Posology and method of administration and Pharmacokinetic properties ). 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 the therapy. In view of the hemodynamic effects of angiotensin II in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, use of angiotensin II receptor antagonists could cause elevation of plasma urea and creatinine in these patients. Similar effects have been reported with Cozaar ; these changes in renal function may be reversible upon discontinuation of therapy. In patients with renal impairment, acute deterioration of renal function should be taken into account. In such patients, continued renal monitoring after initiation of treatment is advised. Operation/narcosis In patients undergoing major surgery, or during narcosis with agents causing hypotension, losartan blocks the action of angiotensin II after compensatory renin secretion. If hypotension occurs, which may be attributed to this mechanism, it may be corrected by volume replenishment. Patients with hemodialysis A lower dose should be considered for patients with hemodialysis. Pharmacokinetic data indicate that the plasma concentration of losartan is highly variable in this patient group, and on average is significantly higher than in other patients. Pediatric use Cozaar has not been studied in children. 4.5 Interactions with other medicinal products and other forms of interaction Antihypertensives The use of Cozaar with other antihypertensives may potentiate the antihypertensive effect. When given together with thiazide-type diuretics, the blood pressure lowering effects of Cozaar are approximately additive. Serum potassium Although no specific research has been performed, it is to be expected that serum potassium could increase with concomitant use of potassium-sparing diuretics, potassium supplements and salt substitutes containing potassium, particularly in patients with renal impairment. Lithium Although no specific research has been performed,

3 COZAAR - p.3/7 tion, it produced renal abnormalities, reduced body weight and increased mortality in the offspring. On the basis of the pharmacologic action of losartan, harmfulness due to use in pregnancy is possible. The mechanism of this is believed to be pharmacologically mediated through the effects on the renin-angiotensin system. Fetal and neonatal morbidity and mortality can be caused by ACE inhibitors when administered to pregnant women during the second and third trimesters. Use of drugs that directly act on the reninangiotensin system during this period have been associated with fetal and neonatal disorders, including hypotension, renal insufficiency, hyperkalemia and/or skull hypoplasia. As a result of reduced renal function, oligohydramnios may occur in the fetus. This may lead to limb contractures, cranio-facial deformations and hypoplastic lung development. While no data are available, this could also occur with angiotensin II receptor antagonists. If children are desired and in case of pregnancy, Cozaar should be discontinued as soon as possible. Furthermore patient should immediately contact the treating physician in order to decide on an alternative treatment. It would be wise to point this out to the patient at the start of treatment. Use during lactation It is not known whether losartan is excreted in human milk. However, significant levels of losartan and the 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. 4.7 Effects on ability to drive and use machines There are no known data on the effect on the ability to drive. In view of possible occurrence of the side effect dizziness, one should take a negative effect on the ability to drive and operate machines into account. 4.8 Undesirable effects In controlled clinical trials in patients with essenlosartan may reduce lithium excretion. That is why serum lithium levels should be carefully monitored when administering lithium salts. Other drugs Losartan is converted into the active carboxyl acid metabolite primarily by cytochrome P450 (CYP) 2C9. Repeated administration of fluconazole, a CYP2C9 inhibitor caused approximately 50% reduction in active metabolite AUC in an interaction study with healthy volunteers. The clinical consequence of this is as yet unknown. Concomitant administration of fluvastatine, a mild CYP2C9 inhibitor, caused no clinically relevant interaction. Other interaction studies show that the cytochrome P450-3A4 inhibitors ketoconazole, itraconazole and erythromycine do not affect the metabolism of losartan. Phenobarbital, a metabolism enzyme inducer, has no clinically relevant influence on losartan metabolism. However, concomitant administration of inducer rifampin achieved a 40% reduction in the plasma concentration of the active metabolite. The clinical relevance of this is as yet unknown. No clinically relevant drug interactions have been found with hydrochlorothiazide, digoxine, warfarine and cimetidine in clinical pharmacokinetic trials. 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. The antihypertensive effect of losartan may be attenuated by non-steroidal anti-inflammatory drugs (NSAID s). 4.6 Pregnancy and lactation Use during pregnancy There are insufficient data on the use of this substance during pregnancy in man to evaluate potential harmfulness. In animal experiments this drug proved to be harmful. When losartan was administered to rats during late gestation or during lacta-

4 COZAAR - p.4/7 tial hypertension, dizziness was the only side effect reported as drug-related that occurred with an incidence greater than placebo in one percent or more of patients treated with Cozaar. In addition, doserelated orthostatic effects were seen in less than one percent of patients. Rarely, rash was reported, although the incidence in controlled clinical trials was less than placebo. 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 purpera, has been reported rarely. Cardiovascular: palpitations, hypotension Gastrointestinal: nausea, diarrhea, abdominal pain, hepatitis (reported rarely), liver function abnormalities. Hematologic: Anemia Musculoskeletal: myalgia. Nervous System/Psychiatric: migraine, dizziness. Respiratory: Cough Skin: Urticaria, pruritis. General: asthenia/fatigue Laboratory Test Findings In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of Cozaar. Hyperkalemia (serum potassium >5.5 mmol/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 Special warnings and special precautions for use, Hypotension and Electrolyte/Fluid Imbalance). Elevations of ALAT occurred rarely and usually resolved upon discontinuation of therapy 4.9 Overdose 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. If ingestion is recent, induce emesis and/or perform gastric lavage. Neither losartan nor the active metabolite can be removed by hemodialysis. 5. PHARMACOLOGICAL PROPERTIES Mechanism of action Losartan, is an effective, synthetic, orally active angiotensin II receptor antagonist. Angiotensin II, a potent vasoconstrictor, is the active hormone of the renin-angiotensin system and a major determinant in the pathophysiology of hypertension. Angiotensin II also stimulates smooth muscle cell proliferation. Angiotensin II binds to the AT1 receptor found in many tissues (e.g. vascular smooth muscles, adrenal gland, kidneys, and the heart) and elicits several important biological actions, including vasoconstriction and the release of aldosterone. AT2 receptors are not blocked by losartan. Both losartan and the pharmacologically active metabolite bind selectively to the AT1 receptor. Losartan and its active metabolite have no agonist effects. Losartan does not bind to or block other hormone receptors or ion channels important in cardiovascular regulation. Losartan differs from ACE inhibitors in that it does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. 5.1 Pharmacodynamic properties Hypertension Studies In clinical studies, once-daily administration of Cozaar to patients with mild to moderate essential hypertension produced statistically significant reductions in systolic and diastolic blood pressure; the antihypertensive effect was maintained in a clinical study for up to one year. Measurement of blood pressure at trough (24 hours postdose) relative to peak (5-6 hours postdose)

5 COZAAR - p.5/7 demonstrated relatively smooth blood pressure reduction over 24 hours. The antihypertensive effect paralleled the natural diurnal rhythms. Blood pressure reduction at the end of the dosing interval was approximately 70-80% of the effect seen 5-6 hours postdose. Despite the significant decrease in blood pressure, administration of Cozaar had no clinically significant effect on heart rate. Cozaar is effective in males and females, and in younger (<65 years) and older ( 65 years) hypertensives. Black hypertensive patients have a smaller average response to losartan monotherapy than nonblack patients. In a study specifically designed to assess the incidence of cough in patients treated with Cozaar as compared to patients treated with ACE inhibitors, the incidence of cough reported by patients receiving Cozaar or hydro-chlorothiazide was similar and was significantly less than in patients treated with the ACE inhibitor lisinopril. In subsequent research, there was no evidence of the occurrence of cough in patients given losartan. In a study among nondiabetic hypertensive patients with proteinuria, significant reduction of proteinuria occurred during treatment with losartan. This was associated with a reduction of blood pressure and of the filtration fraction, while glomerular filtration rate was maintained at the same level. Generally losartan causes a slight decrease in serum uric acid which was persistent in chronic therapy. Losartan has no effect on autonomic reflexes and no sustained effect on plasma norepinephrine. In patients with left-ventricular failure, 25-mg and 50-mg doses of losartan produced effects characterized by an increase in cardiac index and a decrease in pulmonary capillary wedge pressure, systemic vascular resistance, mean systemic arterial pressure and heart rate, and a reduction in circulating levels of aldosterone and norepinephrine, respectively. The occurrence of hypotension was doserelated in these heart failure patients. RENAAL Study The Reduction of Endpoints in NIDDM with Angiotensin II Receptor Antagonist Losartan (RENAAL) study in 1513 type 2 diabetics with proteinuria with a mean follow-up duration of 3.4 years demonstrated that treatment with Cozaar significantly reduced the risk of achieving the composite end point (doubling of serum creatinin, end-stage renal disease or death): 327 events for Cozaar versus 359 events for placebo; relative risk reduction 16.1% (95% Cl 2.3% - 2.7%). Proteinuria was defined as urinary albumin: creatinine ratio >25 mg/ mmol or 24-hour urinary protein excretion > 500 mg and serum creatinine of μmol/l (a lower limit of 133 μmol/l was used for patients heavier than 60 kg). The study was designed in such a way that both treatment groups ( Cozaar versus placebo, in addition to conventional antihypertensives except ACE inhibitors and angiotensin II antagonists) would achieve the same blood pressure control. A significant risk reduction for the individual components for the Cozaar -treated group was found for doubling of serum creatinine (25.3% [7.8%-39.4%]) and endstage renal disease (28.6% [11.5%-42.4%]). There was no difference in mortality. For the secondary endpoint, change in proteinuria, the results in the Cozaar -treated group over a mean period of 3.4 years demonstrated a mean 34.3% reduction (95% CI: 28.6%, 39.5%) in the degree of proteinuria. LIFE Study The Losartan Intervention for Endpoint Reduction (LIFE) study was a randomized, double-blind study in 9193 hypertensive patients aged 55 to 80 years with ECG-documented left ventricular hypertrophy. Patients were randomized to once daily losartan 50 mg or atenolol 50 mg. If goal blood pressure was (<140/90 mmhg) was not reached, hydrochlorothiazide (12.5 mg) was added first and, if needed, the dose of losartan or atenolol was then increased to 100 mg once daily. Other antihypertensives with the exception of ACE inhibitors, angiotensin II antagonists or beta-blockers were added if necessary to reach goal blood pressure.

6 COZAAR - p.6/7 The primary endpoint was the composite of cardiovascular morbidity and mortality as measured by a reduction in the combined incidence of cardiovascular death, stroke, and myocardial infarction. Blood pressure was significantly lowered to similar levels in the two groups. Systolic blood pressure showed a significant 1.7 mmhg difference in favor of losartan and diastolic blod pressure showed a nonsignificant 0.2 mmhg difference in favor of atenelol. Treatment with losartan resulted in a risk reduction from 13% to 11% (relative risk reduction 13%, p=0.021, 95% confidence interval ) compared with atenolol for patients reaching the primary composite endpoint. Treatment with losartan reduced the risk of stroke from 7% to 5% (relative risk reduction 25%, p=0.001). The rates of cardiovascular death and myocardial infarction were not significantly different between treatment groups. Patients treated with losartan had significantly greater reduction in ECG indices of left ventricular hypertrophy as compared to patients treated with atenolol. Losartan was well tolerated. The most common drug related adverse events were dizziness, asthenia/fatigue and vertigo. Adverse effects, particularly bradycardia, cool extremities, and sexual dysfunction, were noted significantly less often in losartan treated patients than in patients treated with atenolol. Dizziness was the most frequently reported adverse event (losartan 16% and atenolol 15%). Discontinuation due to drug-related adverse events was significantly less common in the losartan group than in the atenolol group. In the LIFE study, among patients without diabetes at baseline, there was a lower incidence of new onset diabetes mellitus with losartan as compared to atenolol (242 patients versus 320 patients, respectively, p<0.001). Race: In the LIFE study, Black patients treated with atenolol were at lower risk of experiencing the primary composite endpoint compared with Black patients treated with losartan. The small number of included patients (6%), however, alllows only limited conclusions. 5.2 Pharmacokinetic properties Absorption Following oral administration, losartan is well absorbed and undergoes first-pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. Bioavailability after administration with a standardized meal did not differ to a clinically significant extent from administration on an empty stomach. Distribution Both losartan and its active metabolite are 99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 liters. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all. Biotransformation About 14% of intravenously or orally-administered losartan is converted to its active metabolite. Following oral and intravenous administration of 14 C-labeled losartan potassium, circulating plasma radioactivity primarily is attributed to losartan and its active metabolite. The conversion of losartan into the active metabolite is primarily catalyzed by the enzyme cytochrome P450 2C9. Minimal conversion of losartan to its active metabolite was seen in about one percent of individuals studied. In addition to the active metabolite, inactive metabolites are formed, including two major metabolites formed by hydroxylation of the butyl side chain and a minor metabolite, an N-2 tetrazole glucuronide. Elimination Plasma clearance of losartan and its active metabolite is about 600 ml/min and 50 ml/min, respectively. Renal clearance of losartan and its active metabolite is about 74 ml/min and 26 ml/min, respectively. When losartan is administered orally, about 4% of the dose is excreted unchanged in the urine, and about 6% of the dose is excreted in the urine as

7 COZAAR - p.7/7 active metabolite. The pharmacokinetics of losartan and its active metabolite are linear up to doses of 200 mg. The terminal half-life of losartan and the active metabolite is about 2 hours and 6-9 hours respectively. During once-daily dosing, neither losartan nor its active metabolite accumulates significantly in plasma. Both biliary and urinary excretion contribute to the elimination of losartan and its metabolites. Following an oral dose of 14 C-labeled losartan in man, about 35% of radioactivity is recovered in the urine and 58% in the feces. Characteristics in Patients Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5-fold and 1.7-fold greater than those seen in young male volunteers. 5.3 Preclinical safety data In animal experiments, losartan had a negative effect on late-fetal development (see Use during pregnancy and lactation ). Otherwise animal experiments showed no evidence for safety risks in man. This is based on data from pharmacologic safety studies, and data on repeat-dose toxicity, genotoxicity and carcinogenicity. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Each tablet contains the following inactive ingredients: microcrystalline cellulose (E 460a), lactose hydrous, pregelatinized starch, magnesium stearate (E 572), hydroxypropyl cellulose (E 463), hydroxypropyl methylcellulose (E 464), titanium dioxide (E 171) and carnauba wax (E 903). Cozaar 50 mg, also contains 4.24 mg (0.108 meq) of potassium. Cozaar 100 mg, also contains 8.48 mg (0.216 meq) of potassium. 6.2 Incompabilities Not applicable. 6.3 Shelf-life Three years. 6.4 Special precautions for storage Do not store above 30 C in the closed original package. 6.5 Nature and contents of container Cozaar 50: Boxes with three 10-tablet PVC/PE/ PVDC/Al coated blister strips, boxes with one 15-tablet PVC/PE/PVDC/Al coated blister strip and box with five 10-tablet PVC/PE/PVDC/Al coated blister strip. Cozaar 100: Boxes with three 10-tablet PVC/PE/ PVDC/Al coated blister strips, boxes with one 15-tablet PVC/PE/PVDC/Al coated blister strip and box with five 10-tablet PVC/PE/PVDC/Al coated blister strip. 6.6 Instructions for use and handling Not applicable. 7. MARKETING AUTHORIZATION HOLDER MERCK SHARP & DOHME B.V. P.O. BOX PC HAARLEM 8. MARKETING AUTHORIZATION NUMBER Entered in the register under RVG ( Cozaar 50 ) and RVG ( Cozaar 100 ). 9. DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION 5 March DATE OF REVISION OF THE TEXT 18 February 2004 LPC-CZR-ME-Feb