Cozaar®* 12.5 mg filmcoated tablets

Cozaar®* 25 mg filmcoated tablets

Cozaar®* 50 mg filmcoated tablets

Cozaar®* 100 mg filmcoated tablets

* Intensive monitoring is requested only when used for the recently-licensed indication in chronic heart failure

Each COZAAR 12.5 mg Tablet contains 12.5 mg of losartan potassium.

Each COZAAR 25 mg Tablet contains 25 mg of losartan potassium.

Each COZAAR 50 mg Tablet contains 50 mg of losartan potassium.

Each COZAAR 100 mg Tablet contains 100 mg of losartan potassium.

Each COZAAR 12.5 mg tablet contains 25.25 mg lactose monohydrate.

Each COZAAR 25 mg tablet contains 12.75 mg lactose monohydrate.

Each COZAAR 50 mg tablet contains 25.5 mg lactose monohydrate.

Each COZAAR 100 mg tablet contains 51.0 mg lactose monohydrate.

For a full list of excipients, see section 6.1.

Filmcoated tablets

COZAAR 12.5 mg tablet

Blue, oval filmcoated tablets marked 11 on one side and plain on the other.

COZAAR 25 mg tablet

White, oval unscored filmcoated tablets marked 951 on one side and plain on the other.

COZAAR 50 mg tablet

White, oval filmcoated tablets marked 952 on one side and scored on the other.

The tablet can be divided into equal halves.

COZAAR 100 mg tablet

White, teardropshaped filmcoated tablets marked 960 on one side and plain on the other.

• Treatment of essential hypertension in adults and in children and adolescents 6-18 years of age.

• Treatment of renal disease in adult patients with hypertension and type 2 diabetes mellitus with proteinuria 0.5 g/day as part of an antihypertensive treatment.

• Treatment of chronic heart failure (in patients 60 years), when treatment with Angiotensin converting enzyme (ACE) inhibitors is not considered suitable due to incompatibility, especially cough, or contraindication. Patients with heart failure who have been stabilised with an ACE inhibitor should not be switched to losartan. The patients should have a left ventricular ejection fraction 40% and should be clinically stable and on an established treatment regimen for chronic heart failure.

• Reduction in the risk of stroke in adult hypertensive patients with left ventricular hypertrophy documented by ECG (see section 5.1 LIFE study, Race).

Losartan tablets should be swallowed with a glass of water. COZAAR may be administered with or without food.

Hypertension

The usual starting and maintenance dose is 50 mg once daily for most patients. The maximal antihypertensive effect is attained 36 weeks after initiation of therapy. Some patients may receive an additional benefit by increasing the dose to 100 mg once daily (in the morning).

Losartan may be administered with other antihypertensive agents, especially with diuretics (e.g. hydrochlorothiazide).

Hypertensive type II diabetic patients with proteinuria 0.5 g/day

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

Heart failure

The usual initial dose of losartan in patients with heart failure is 12.5 mg once daily. The dose should generally be titrated at weekly intervals (i.e. 12.5 mg daily, 25 mg daily, 50 mg daily) to the usual maintenance dose of 50 mg once daily, as tolerated by the patient.

Reduction in the risk of stroke in hypertensive patients with left ventricular hypertrophy documented by ECG

The usual starting dose is 50 mg of losartan once daily. A low dose of hydrochlorothiazide should be added and/ or the dose of losartan should be increased to 100 mg once daily based on blood pressure response.

Special populations

Use in patients with intravascular volume depletion:

For patients with intravascular volumedepletion (e.g. those treated with highdose diuretics), a starting dose of 25 mg once daily should be considered (see section 4.4).

Use in patients with renal impairment and haemodialysis patients:

No initial dosage adjustment is necessary in patients with renal impairment and in haemodialysis patients.

Use in patients with hepatic impairment:

A lower dose should be considered for patients with a history of hepatic impairment. There is no therapeutic experience in patients with severe hepatic impairment. Therefore, losartan is contraindicated in patients with severe hepatic impairment (see sections 4.3 and 4.4).

Use in paediatric patients

There are limited data on the efficacy and safety of losartan in children and adolescents aged 618 years old for the treatment of hypertension (see section 5.1). Limited pharmacokinetic data are available in hypertensive children above one month of age (see section 5.2).

For patients who can swallow tablets, the recommended dose is 25 mg once daily in patients>20 to <50 kg. (In exceptional cases the dose can be increased to a maximum of 50 mg once daily). Dosage should be adjusted according to blood pressure response.

In patients>50 kg, the usual dose is 50 mg once daily. In exceptional cases the dose can be adjusted to a maximum of 100 mg once daily. Doses above 1.4 mg/ kg (or in excess of 100 mg) daily have not been studied in paediatric patients.

Losartan is not recommended for use in children under 6 years old, as limited data are available in these patient groups.

It is not recommended in children with glomerular filtration rate < 30 ml/ min / 1.73 m², as no data are available (see also section 4.4).

Losartan is also not recommended in children with hepatic impairment (see also section 4.4).

Use in Elderly

Although consideration should be given to initiating therapy with 25 mg in patients over 75 years of age, dosage adjustment is not usually necessary for the elderly.

Hypersensitivity to the active substance or to any of the excipients (see section 4.4 and 6.1).

2nd and 3rd trimester of pregnancy (see section 4.4 and 4.6).

Severe hepatic impairment.

Hypersensitivity

Angio-oedema. Patients with a history of angio-oedema (swelling of the face, lips, throat, and/ or tongue) should be closely monitored (see section 4.8).

Hypotension and electrolyte/fluid imbalance

Symptomatic hypotension, especially after the first dose and after increasing of the dose, may occur in patients who are volume and/or sodiumdepleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. These conditions should be corrected prior to administration of losartan, or a lower starting dose should be used (see section 4.2). This also applies to children 6 to 18 years of age.

Electrolyte imbalances

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 nephropathy, the incidence of hyperkalemia was higher in the group treated with losartan as compared to the placebo group (see section 4.8). Therefore, the plasma concentrations of potassium as well as creatinine clearance values should be closely monitored, especially patients with heart failure and a creatinine clearance between 3050 ml/ min should be closely monitored.

The concomitant use of potassium-sparing diuretics, potassium supplements and potassium-containing salt substitutes with losartan is not recommended (see section 4.5).

Hepatic 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. There is no therapeutic experience with losartan in patients with severe hepatic impairment. Therefore losartan must not be administered in patients with severe hepatic impairment (see sections 4.2, 4.3 and 5.2).

Losartan is not recommended in children with hepatic impairment (see section 4.2).

Renal impairment

As a consequence of inhibiting the reninangiotensin system, changes in renal function including renal failure have been reported (in particular, in patients whose renal function is dependent on the renin- angiotensin-aldosterone system such as those with severe cardiac insufficiency or preexisting renal dysfunction). As with other medicinal products that affect the reninangiotensinaldosterone system, increases in blood urea and serum creatinine have also been reported in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney; these changes in renal function may be reversible upon discontinuation of therapy. Losartan should be used with caution in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.

Use in paediatric patients with renal impairment

Losartan is not recommended in children with glomerular filtration rate < 30 ml/ min/ 1.73 m² as no data are available (see section 4.2).

Renal function should be regularly monitored during treatment with losartan as it may deteriorate. This applies particularly when losartan is given in the presence of other conditions (fever, dehydration) likely to impair renal function.

Concomitant use of losartan and ACEinhibitors has shown to impair renal function. Therefore, concomitant use is not recommended (see section 4.5).

Renal transplantation

There is no experience in patients with recent kidney transplantation.

Primary hyperaldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the reninangiotensin system. Therefore, the use of losartan is not recommended.

Coronary heart disease and cerebrovascular disease

As with any antihypertensive agents, excessive blood pressure decrease in patients with ischaemic cardiovascular and cerebrovascular disease could result in a myocardial infarction or stroke.

Heart failure

In patients with heart failure, with or without renal impairment, there is as with other medicinal products acting on the reninangiotensin system a risk of severe arterial hypotension, and (often acute) renal impairment.

There is no sufficient therapeutic experience with losartan in patients with heart failure and concomitant severe renal impairment, in patients with severe heart failure (NYHA class IV) as well as in patients with heart failure and symptomatic life threatening cardiac arrhythmias. Therefore, losartan should be used with caution in these patient groups. The combination of losartan with a betablocker should be used with caution (see section 5.1).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine.

Pregnancy

Losartan should not be initiated during pregnancy. Unless continued losartan therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with losartan should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Other warnings and precautions

As observed for angiotensin converting enzyme inhibitors, losartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in nonblacks, possibly because of higher prevalence of lowrenin states in the black hypertensive population.

Other antihypertensive agents may increase the hypotensive action of losartan. Concomitant use with other substances which may induce hypotension as an adverse reaction (like tricyclic antidepressants, antipsychotics, baclofen and amifostine) may increase the risk of hypotension.

Losartan is predominantly metabolised by cytochrome P450 (CYP) 2C9 to the active carboxyacid metabolite. In a clinical trial it was found that fluconazole (inhibitor of CYP2C9) decreases the exposure to the active metabolite by approximately 50%. It was found that concomitant treatment of losartan with rifampicin (inducer of metabolism enzymes) gave a 40% reduction in plasma concentration of the active metabolite. The clinical relevance of this effect is unknown. No difference in exposure was found with concomitant treatment with fluvastatin (weak inhibitor of CYP2C9).

As with other medicinal products that block angiotensin II or its effects, concomitant use of other medicinal products which retain potassium (e.g. potassiumsparing diuretics: amiloride, triamterene, spironolactone) or may increase potassium levels (e.g. heparin), potassium supplements or salt substitutes containing potassium may lead to increases in serum potassium. Comedication is not advisable.

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Very rare cases have also been reported with angiotensin II receptor antagonists. Coadministration of lithium and losartan should be undertaken with caution. If this combination proves essential, serum lithium level monitoring is recommended during concomitant use.

When angiotensin II antagonists are administered simultaneously with NSAIDs (i.e. selective COX2 inhibitors, acetylsalicylic acid at antiinflammatory doses and nonselective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of angiotensin II antagonists or diuretics and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor preexisting renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

Pregnancy

The use of losartan is not recommended during the first trimester of pregnancy (see section 4.4). The use of losartan is contraindicated during the 2nd and 3rd trimester of pregnancy (see section 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Inhibitors (AIIRAs), similar risks may exist for this class of medicinal products. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with losartan should be stopped immediately and, if appropriate, alternative therapy should be started.

Exposure to AIIA therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see also 5.3). Should exposure to losartan have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken losartan should be closely observed for hypotension (see also section 4.3 and 4.4).

Lactation

Because no information is available regarding the use of losartan during breastfeeding, losartan is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.

No studies on the effects on the ability to drive and use machines have been performed. However, when driving vehicles or operating machinery it must be borne in mind that dizziness or drowsiness may occasionally occur when taking antihypertensive therapy, in particular during initiation of treatment or when the dose is increased.

Losartan has been evaluated in clinical studies as follows:

• in controlled clinical trials in approximately 3300 adult patients 18 years of age and older for essential hypertension,

• in a controlled clinical trial in 9193 hypertensive patients 55 to 80 years of age with left ventricular hypertrophy

• in a controlled clinical trial in approximately 3900 patients 20 years of age and older with chronic heart failure

• in a controlled clinical trial in 1513 type 2 diabetic patients 31 years of age and older with proteinuria

• in a controlled clinical trial in 177 hypertensive paediatric patients 6 to 16 years of age

In these clinical trials, the most common adverse reaction was dizziness.

The frequency of adverse reactions listed below is defined using the following convention:

very common ( 1/10); common ( 1/100, to < 1/10); uncommon ( 1/1,000, to < 1/100); rare ( 1/10,000,to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

Hypertension

In controlled clinical trials of approximately 3300 adult patients 18 years of age and older, for essential hypertension with losartan, the following adverse reactions were reported

Nervous system disorders:

common: dizziness, vertigo

uncommon: somnolence, headache, sleep disorders

Cardiac disorder:

uncommon: palpitations, angina pectoris

Vascular disorders:

uncommon: symptomatic hypotension (especially in patients with intravascular volume depletion, e.g. patients with severe heart failure or under treatment with high dose diuretics), doserelated orthostatic effects, rash.

Gastro-intestinal disorders:

uncommon: abdominal pain, obstipation

General disorders and administration site conditions:

uncommon: asthenia, fatigue, oedema

Investigations:

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of losartan tablets. Elevations of ALT occurred rarely and usually resolved upon discontinuation of therapy. Hyperkalaemia (serum potassium>5.5 mmol/l) occurred in 1.5% of patients in hypertension clinical trials.

Hypertensive patients with left ventricular hypertrophy

In a controlled clinical trial in 9193 hypertensive patients 55 to 80 years of age, with left ventricular hypertrophy, the following adverse reactions were reported:

Nervous system disorders:

common: dizziness

Ear and labyrinth disorders:

common: vertigo

General disorders and administration site conditions:

common: asthenia/fatigue

Chronic heart failure

In a controlled clinical trial in approximately 3900 patients 20 years of age and older, with cardiac insufficiency, the following adverse reactions were reported:

Nervous system disorders:

uncommon: dizziness, headache

rare: paraesthesia

Cardiac disorders:

rare: syncope, atrial fibrillation, cerebrovascular accident

Vascular disorders:

uncommon: hypotension, including orthostatic hypotension

Respiratory, thoracic and mediastinal disorders:

uncommon: dyspnoea

Gastro-intestinal disorders:

uncommon: diarrhoea, nausea, vomiting

Skin and subcutaneous tissue disorders:

uncommon: urticaria, pruritus, rash

General disorders and administration site conditions:

uncommon: asthenia/fatigue

Investigations:

uncommon: increase in blood urea, serum creatinine and serum potassium has been reported.

Hypertension and type 2 diabetes with renal disease

In a controlled clinical trial in 1513 type 2 diabetic patients 31 years of age and older, with proteinuria (RENAAL study, see section 5.1), the most common drugrelated adverse events which were reported for losartan are as follows:

Nervous system disorders:

common: dizziness

Vascular disorders:

common: hypotension

General disorders and administration site conditions:

common: asthenia/fatigue

Investigations:

common: hypoglycaemia, hyperkalaemia

The following adverse reactions occurred more often in patients receiving losartan than placebo:

Blood and lymphatic system disorders:

not known: anaemia

Cardiac disorders:

not known: syncope, palpitations

Vascular disorders:

not known: orthostatic hypotension

Gastro-intestinal disorders:

not known: diarrhoea

Musculoskeletal and connective tissue disorders:

not known: back pain

Renal and urinary disorders:

not known: urinary tract infections

General disorders and administration site conditions:

not known: flulike symptoms

Investigations:

In a clinical study conducted in type 2 diabetic patients with nephropathy, 9.9% of patients treated with losartan tablets developed hyperkalaemia>5.5 mEq/l and 3.4% of patients treated with placebo.

Postmarketing experience

The following adverse reactions have been reported in postmarketing experience:

Blood and lymphatic system disorders:

not known: anaemia, thrombocytopenia

Ear and labyrinth disorders:

not known: tinnitus

Immune system disorders:

rare: hypersensitivity: anaphylactic reactions, angio-oedema including swelling of the larynx and glottis causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue; in some of these patients angio-oedema had been reported in the past in connection with the administration of other medicines, including ACE inhibitors; vasculitis, including HenochSchonlein purpura.

Nervous system disorders:

not known: migraine

Respiratory, thoracic and mediastinal disorders:

not known: cough

Gastro-intestinal disorders:

not known: diarrhoea, pancreatitis

General disorders and administration site conditions:

not known: malaise

Hepatobiliary disorders:

rare: hepatitis

not known: liver function abnormalities

Skin and subcutaneous tissue disorders:

not known: urticaria, pruritus, rash, photosensitivity

Musculoskeletal and connective tissue disorders:

not known: myalgia, arthralgia, rhabdomyolysis

Reproductive system and breast disorders:

not known: erectile dysfunction/impotence

Renal and urinary disorders:

As a consequence of inhibiting the reninangiotensinaldosterone system, changes in renal function including renal failure have been reported in patients at risk; these changes in renal function may be reversible upon discontinuation of therapy (see section 4.4)

Psychiatric disorders:

not known: depression

Investigations:

not known: hyponatraemia

Paediatric population

The adverse reaction profile for paediatric patients appears to be similar to that seen in adult patients. Data in the paediatric population are limited.

Symptoms of intoxication

No case of overdose has been reported. The most likely symptoms, depending on the extent of overdose, are hypotension, tachycardia, possibly bradycardia.

Treatment of intoxication

Measures are depending on the time of medicinal product intake and kind and severity of symptoms. Stabilisation of the cardiovascular system should be given priority. After oral intake, the administration of a sufficient dose of activated charcoal is indicated. Afterwards, close monitoring of the vital parameters should be performed. Vital parameters should be corrected if necessary.

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

Pharmacotherapeutic group: Angiotensin II antagonists, plain ATC code: C09CA01

Losartan is a synthetic oral angiotensinII receptor (type AT₁) antagonist. Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the renin/angiotensin system and an important determinant of the pathophysiology of hypertension. Angiotensin II binds to the AT₁ receptor found in many tissues (e.g. vascular smooth muscle, adrenal gland, kidneys and the heart) and elicits several important biological actions, including vasoconstriction and the release of aldosterone. Angiotensin II also stimulates smooth muscle cell proliferation.

Losartan selectively blocks the AT₁ receptor. In vitro and in vivo losartan and its pharmacologically active carboxylic acid metabolite E3174 block all physiologically relevant actions of angiotensin II, regardless of the source or route of its synthesis.

Losartan does not have an agonist effect nor does it block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore losartan does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. Consequently, there is no potentiation of undesirable bradykininmediated effects.

During administration of losartan, removal of the angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA). Increase in the PRA leads to an increase in angiotensin II in plasma. Despite these increases, antihypertensive activity and suppression of plasma aldosterone concentration are maintained, indicating effective angiotensin II receptor blockade. After discontinuation of losartan, PRA and angiotensin II values fell within three days to the baseline values.

Both losartan and its principal active metabolite have a far greater affinity for the AT₁receptor than for the AT₂receptor. The active metabolite is 10 to 40 times more active than losartan on a weight for weight basis.

Hypertension studies

In controlled clinical studies, oncedaily administration of losartan to patients with mild to moderate essential hypertension produced statistically significant reductions in systolic and diastolic blood pressure. Measurements of blood pressure 24 hours postdose relative to 5 – 6 hours postdose demonstrated blood pressure reduction over 24 hours; the natural diurnal rhythm was retained. Blood pressure reduction at the end of the dosing interval was 70 – 80 % of the effect seen 56 hours postdose.

Discontinuation of losartan in hypertensive patients did not result in an abrupt rise in blood pressure (rebound). Despite the marked decrease in blood pressure, losartan had no clinically significant effects on heart rate.

Losartan is equally effective in males and females, and in younger (below the age of 65 years) and older hypertensive patients.

LIFEstudy

The Losartan Intervention For Endpoint Reduction in Hypertension [LIFE] study was a randomised, tripleblind, activecontrolled study in 9193 hypertensive patients aged 55 to 80 years with ECGdocumented leftventricular hypertrophy. Patients were randomised to once daily losartan 50 mg or once daily atenolol 50 mg. If goal blood pressure (< 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 ACEinhibitors, angiotensin II antagonists or betablockers were added if necessary to reach the goal blood pressure.

The mean length of follow up was 4.8 years.

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. Treatment with losartan resulted in a 13.0% risk reduction (p=0.021, 95 % confidence interval 0.770.98) compared with atenolol for patients reaching the primary composite endpoint. This was mainly attributable to a reduction of the incidence of stroke. Treatment with losartan reduced the risk of stroke by 25% relative to atenolol (p=0.001 95% confidence interval 0.630.89). The rates of cardiovascular death and myocardial infarction were not significantly different between the treatment groups.

Race

In the LIFEStudy black patients treated with losartan had a higher risk of suffering the primary combined endpoint, i.e. a cardiovascular event (e.g. cardiac infarction, cardiovascular death) and especially stroke, than the black patients treated with atenolol. Therefore the results observed with losartan in comparison with atenolol in the LIFE study with regard to cardiovascular morbidity/mortality do not apply for black patients with hypertension and left ventricular hypertrophy.

RENAALstudy

The Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist losartan RENAAL study was a controlled clinical study conducted worldwide in 1513 Type 2 diabetic patients with proteinuria, with or without hypertension. 751 patients were treated with losartan. The objective of the study was to demonstrate a nephroprotective effect of losartan potassium over and above the benefit of lowering blood pressure.

Patients with proteinuria and a serum creatinine of 1.3 – 3.0 mg/dl were randomised to receive losartan 50 mg once a day, titrated if necessary, to achieve blood pressure response, or to placebo, on a background of conventional antihypertensive therapy excluding ACEinhibitors and angiotensin II antagonists.

Investigators were instructed to titrate the study medication to 100 mg daily as appropriate; 72 % of patients were taking the100 mg daily dose for the majority of the time. Other antihypertensive agents (diuretics, calcium antagonists, alpha and betareceptor blockers and also centrally acting antihypertensives) were permitted as supplementary treatment depending on the requirement in both groups. Patients were followed up for up to 4.6 years (3.4 years on average).

The primary endpoint of the study was a composite endpoint of doubling of the serum creatinine endstage renal failure (need for dialysis or transplantation) or death.

The results showed that the treatment with losartan (327 events) as compared with placebo (359 events) resulted in a16.1 % risk reduction (p = 0.022) in the number of patients reaching the primary composite endpoint. For the following individual and combined components of the primary endpoint, the results showed a significant risk reduction in the group treated with losartan: 25.3 % risk reduction for doubling of the serum creatinine (p = 0.006); 28.6 % risk reduction for endstage renal failure (p = 0.002); 19.9 % risk reduction for endstage renal failure or death (p = 0.009); 21.0 % risk reduction for doubling of serum creatinine or endstage renal failure (p = 0.01).

Allcause mortality rate was not significantly different between the two treatment groups. In this study losartan was generally well tolerated, as shown by a therapy discontinuation rate on account of adverse reactions that was comparable to the placebo group.

ELITE I and ELITE II studies

In the ELITE Study carried out over 48 weeks in722 patients with heart failure (NYHA Class IIIV), no difference was observed between the patients treated with losartan and those treated with captopril with regard to the primary endpoint of a longterm change in renal function. The observation of the ELITE I Study, that, compared with captopril, losartan reduced the mortality risk, was not confirmed in the subsequent ELITE II Study.

In the ELITE II Study losartan 50 mg once daily (starting dose 12.5 mg, increased to 25 mg, then 50 mg once daily) was compared with captopril 50 mg three times daily (starting dose 12.5 mg, increased to 25 mg and then to 50 mg three times daily). The primary endpoint of this prospective study was the allcause mortality.

In this study, 3152 patients with heart failure (NYHA Class IIIV) were followed for almost two years (median: 1.5 years) in order to determine whether losartan is superior to captopril in reducing all cause mortality. The primary endpoint did not show any statistically significant difference between losartan and captopril in reducing allcause mortality.

In both comparatorcontrolled (not placebocontrolled) clinical studies on patients with heart failure the tolerability of losartan was superior to that of captopril, measured on the basis of a significantly lower rate of discontinuations of therapy on account of adverse reactions and a significantly lower frequency of cough.

An increased mortality was observed in ELITE II in the small subgroup (22% of all HF patients) taking betablockers at baseline.

Paediatric Population

Paediatric hypertension

The antihypertensive effect of losartan was established in a clinical study involving 177 hypertensive paediatric patients 6 to 16 years of age with a body weight> 20 kg and a glomerular filtration rate> 30 ml/ min/ 1.73 m². Patients who weighed> 20kg to < 50 kg received either 2.5, 25 or 50 mg of losartan daily and patients who weighed> 50 kg received either 5, 50 or 100 mg of losartan daily. At the end of three weeks, losartan administration once daily lowered trough blood pressure in a dose-dependent manner.

Overall, there was a doseresponse. The doseresponse relationship became very obvious in the low dose group compared to the middle dose group (period I: 6.2 mmHg vs. 11.65 mmHg), but was attenuated when comparing the middle dose group with the high dose group (period I: 11.65 mmHg vs. 12.21 mmHg). The lowest doses studied, 2.5 mg and 5 mg, corresponding to an average daily dose of 0.07 mg/ kg, did not appear to offer consistent antihypertensive efficacy.

These results were confirmed during period II of the study where patients were randomised to continue losartan or placebo, after three weeks of treatment. The difference in blood pressure increase as compared to placebo was largest in the middle dose group (6.70 mmHg middle dose vs. 5.38 mmHg high dose). The rise in trough diastolic blood pressure was the same in patients receiving placebo and in those continuing losartan at the lowest dose in each group, again suggesting that the lowest dose in each group did not have significant antihypertensive effect.

Longterm effects of losartan on growth, puberty and general development have not been studied. The longterm efficacy of antihypertensive therapy with losartan in childhood to reduce cardiovascular morbidity and mortality has also not been established.

In hypertensive (N=60) and normotensive (N=246) children with proteinuria, the effect of losartan on proteinuria was evaluated in a 12-week placebo- and active-controlled (amlodipine) clinical study. Proteinuria was defined as urinary protein/creatinine ratio of 0.3. The hypertensive patients (ages 6 through 18 years) were randomised to receive either losartan (n=30) or amlodipine (n=30). The normotensive patients (ages 1 through 18 years) were randomised to receive either losartan (n=122) or placebo (n=124). Losartan was given at doses of 0.7 mg/kg to 1.4 mg/kg (up to maximum dose of 100 mg per day). Amlodipine was given at doses of 0.05 mg/kg to 0.2 mg/kg (up to a maximum dose of 5 mg per day).

Overall, after 12 weeks of treatment, patients receiving losartan experienced a statistically significant reduction from baseline in proteinuria of 36% versus 1% increase in placebo/amlodipine group (p0.001). Hypertensive patients receiving losartan experienced a reduction from baseline proteinuria of -41.5% (95% CI -29.9;-51.1) versus +2.4% (95% CI -22.2;14.1) in the amlodipine group. The decline in both systolic blood pressure and diastolic blood pressure was greater in the losartan group (5.5/-3.8 mmHg) versus the amlodipine group (-0.1/+0.8 mm Hg). In normotensive children a small decrease in blood pressure was observed in the losartan group (-3.7/-3.4 mm Hg) compared to placebo. No significant correlation between the decline in proteinuria and blood pressure was noted, however it is possible that the decline in blood pressure was responsible, in part, for the decline in proteinuria in the losartan treated group. Long-term effects of reduction of proteinuria in children have not been studied.

Absorption

Following oral administration, losartan is well absorbed and undergoes firstpass 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 34 hours, respectively.

Distribution

Both losartan and its active metabolite are 99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 litres.

Biotransformation

About 14% of an intravenously or orallyadministered dose of losartan is converted to its active metabolite. Following oral and intravenous administration of ¹⁴Clabelled losartan potassium, circulating plasma radioactivity primarily is attributed to losartan and its active metabolite. Minimal conversion of losartan to its active metabolite was seen in about 1% of individuals studied.

In addition to the active metabolite, inactive metabolites are formed.

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 active metabolite. The pharmacokinetics of losartan and its active metabolite are linear with oral losartan potassium doses up to 200 mg.

Following oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially, with a terminal halflife of about 2 hours and 69 hours, respectively. During oncedaily dosing with 100 mg, neither losartan nor its active metabolite accumulates significantly in plasma.

Both biliary and urinary excretions contribute to the elimination of losartan and its metabolites. Following an oral dose/intravenous administration of ¹⁴Clabelled losartan in man, about 35% / 43% of radioactivity is recovered in the urine and 58%/ 50% in the faeces.

Characteristics in patients

In elderly hypertensive patients the plasma concentrations of losartan and its active metabolite do not differ essentially from those found in young hypertensive patients.

In female hypertensive patients the plasma levels of losartan were up to twice as high as in male hypertensive patients, while the plasma levels of the active metabolite did not differ between men and women.

In patients with mild to moderate alcoholinduced hepatic cirrhosis, the plasma levels of losartan and its active metabolite after oral administration were respectively 5 and 1.7 times higher than in young male volunteers (see section 4.2 and 4.4).

Plasma concentrations of losartan are not altered in patients with a creatinine clearance above 10 ml/minute. Compared to patients with normal renal function, the AUC for losartan is about 2times higher in haemodialysis dialysis patients.

The plasma concentrations of the active metabolite are not altered in patients with renal impairment or in haemodialysis patients.

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

Pharmacokinetics in paediatric patients

The pharmacokinetics of losartan have been investigated in 50 hypertensive paediatric patients> 1 month to < 16 years of age following once daily oral administration of approximately 0.54 to 0.77 mg/ kg of losartan (mean doses).

The results showed that the active metabolite is formed from losartan in all age groups. The results showed roughly similar pharmacokinetic parameters of losartan following oral administration in infants and toddlers, preschool children, school age children and adolescents. The pharmacokinetic parameters for the metabolite differed to a greater extent between the age groups. When comparing preschool children with adolescents these differences became statistically significant. Exposure in infants/ toddlers was comparatively high.

Preclinical data reveal no special hazard for humans based on conventional studies of general pharmacology, genotoxicity and carcinogenic potential. In repeated dose toxicity studies, the administration of losartan induced a decrease in the red blood cell parameters (erythrocytes, haemoglobin, haematocrit), a rise in ureaN in the serum and occasional rises in serum creatinine, a decrease in heart weight (without a histological correlate) and gastro-intestinal changes (mucous membrane lesions, ulcers, erosions, haemorrhages). Like other substances that directly affect the reninangiotensin system, losartan has been shown to induce adverse effects on the late foetal development, resulting in foetal death and malformations.

microcrystalline cellulose (E460)

lactose monohydrate

pregelatinized maize starch

magnesium stearate (E572)

hydroxypropyl cellulose (E463)

hypromellose (E464)

COZAAR 12.5 mg, 25 mg, 50 mg and 100 mg contain potassium in the following amounts: 1.06 mg (0.027 mEq), 2.12 mg (0.054 mEq), 4.24 mg (0.108 mEq) and 8.48 mg (0.216 mEq) respectively.

COZAAR 12.5 mg tablets also contain carnauba wax (E903), titanium dioxide (E171), indigo carmine (E132) aluminum lake.

COZAAR 25 mg tablets also contain carnauba wax (E903), titanium dioxide (E171).

COZAAR 50 mg tablets also contain carnauba wax (E903), titanium dioxide (E171).

COZAAR 100 mg tablets also contain carnauba wax (E903), titanium dioxide (E171).

Not applicable.

3 years

Blisters: Store in the original package in order to protect from light and moisture. HDPE Bottle: do not store above 25^oC. Store in original container. Keep the bottle tightly closed in order to protect from light and moisture.

COZAAR 12.5 mg PVC/PE/PVDC blister packages with aluminum foil lidding in cartons containing 7, 14, 21, 28, 50, 98, 210 or 500 tablets. HDPE bottles of 100 tablets.

COZAAR 25 mg PVC/PE/PVDC blister packages with aluminum foil lidding in cartons containing 7 or 28 tablets.

COZAAR 50 mg PVC/PE/PVDC blister packages with aluminum foil lidding in cartons containing 7, 10, 14, 20, 28, 30, 50, 56, 84, 90, 98, 280 or 500 tablets. HDPE bottles of 100 or 300 tablets.

COZAAR 100 mg - PVC/PE/PVDC blister packages with aluminum foil lidding in cartons containing 7, 10, 14, 15, 20, 28, 30, 50, 56, 84, 90, 98 or 280 tablets. HDPE bottles of 100 tablets.

Not all pack sizes may be marketed.

No special requirements.

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

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EN11 9BU

12.5 mg: PL 0025/0515

25 mg: PL 0025/0336

50 mg: PL 0025/0324

100 mg: PL 0025/0416

12.5 mg: 6 January 2009

25 mg/50 mg: 15 December 1994

100 mg: 28 November 2001

August 2009

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SPC.CZR.08.UK.3005-II-003