Rasoltan

- 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 adult patients, 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 Rasoltan. 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.

- 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 adult patients, 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.

Hypertension

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

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

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

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

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

Rasoltan may be administered with other antihypertensive agents.

Hypertensive Patients With Left Ventricular Hypertrophy

Rasoltan is indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to Black patients.

Nephropathy In Type 2 Diabetic Patients

Rasoltan is indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio ≥300 mg/g) in patients with type 2 diabetes and a history of hypertension. In this population, Rasoltan reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end stage renal disease (need for dialysis or renal transplantation).

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.

Rasoltan potassium tablets are available in 25 mg, 50 mg and 100 mg.

Method of administration

Rasoltan tablets should be swallowed with a glass of water.

Rasoltan potassium may be administered with or without food.

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.

Rasoltan tablets are available in 25 mg, 50 mg and 100 mg.

Method of administration

Losartan tablets should be swallowed with a glass of water.

Rasoltan may be administered with or without food.

Hypertension

Adult Hypertension

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

Pediatric Hypertension

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

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

Hypertensive Patients With Left Ventricular Hypertrophy

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

Nephropathy In Type 2 Diabetic Patients

The usual starting dose is 50 mg once daily. The dose should be increased to 100 mg once daily based on blood pressure response.

Dosage Modifications In Patients With Hepatic Impairment

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

Preparation Of Suspension (for 200 mL of a 2.5 mg/mL suspension)

Add 10 mL of Purified Water USP to an 8 ounce (240 mL) amber polyethylene terephthalate (PET) bottle containing ten 50 mg Rasoltan tablets. Immediately shake for at least 2 minutes. Let the concentrate stand for 1 hour and then shake for 1 minute to disperse the tablet contents. Separately prepare a 50/50 volumetric mixture of Ora-Plus™ and Ora-Sweet SF™. Add 190 mL of the 50/50 Ora-Plus™/Ora- Sweet SF™ mixture to the tablet and water slurry in the PET bottle and shake for 1 minute to disperse the ingredients. The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 4 weeks. Shake the suspension prior to each use and return promptly to the refrigerator.

2^nd and 3^rd trimester of pregnancy.

Severe hepatic impairment.

The concomitant use of Rasoltan potassium with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²).

2^nd and 3^rd trimester of pregnancy.

Severe hepatic impairment.

The concomitant use of Rasoltan with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²).

Rasoltan is contraindicated:

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

Hypersensitivity

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

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 sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. These conditions should be corrected prior to administration of Rasoltan, or a lower starting dose should be used. 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 Rasoltan as compared to the placebo group. 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 30-50 ml/ min should be closely monitored.

The concomitant use of potassium-sparing diuretics, potassium supplements and potassium-containing salt substitutes with Rasoltan is not recommended.

Hepatic impairment

Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of Rasoltan in cirrhotic patients, a lower dose should be considered for patients with a history of hepatic impairment. There is no therapeutic experience with Rasoltan in patients with severe hepatic impairment. Therefore Rasoltan must not be administered in patients with severe hepatic impairment.

Rasoltan is not recommended in children with hepatic impairment.

Renal impairment

As a consequence of inhibiting the rennin-angiotensin 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 pre-existing renal dysfunction). As with other medicinal products that affect the rennin-angiotensin-aldosterone 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. Rasoltan 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

Rasoltan is not recommended in children with glomerular filtration rate <30 ml/ min/ 1.73 m² as no data are available.

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

Concomitant use of Rasoltan and ACE inhibitors has shown to impair renal function. Therefore, concomitant use is not recommended.

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 rennin-angiotensin system. Therefore, the use of Rasoltan 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 renin angiotensin system a risk of severe arterial hypotension, and (often acute) renal impairment.

There is no sufficient therapeutic experience with Rasoltan 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, Rasoltan should be used with caution in these patient groups. The combination of Rasoltan with a beta-blocker should be used with caution.

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 glucose-galactose malabsorption should not take this medicine.

Pregnancy

Rasoltan should not be initiated during pregnancy. Unless continued Rasoltan 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 Rasoltan should be stopped immediately, and, if appropriate, alternative therapy should be started.

Other warnings and precautions

As observed for angiotensin converting enzyme inhibitors, Rasoltan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non- blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Hypersensitivity

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

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 sodium depleted 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. 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. 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 30-50 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.

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.

Losartan is not recommended in children with hepatic impairment.

Renal impairment

As a consequence of inhibiting the rennin-angiotensin 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 pre-existing renal dysfunction). As with other medicinal products that affect the rennin-angiotensin-aldosterone 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.

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 ACE inhibitors has shown to impair renal function. Therefore, concomitant use is not recommended.

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 rennin-angiotensin 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 renin angiotensin 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 beta-blocker should be used with caution.

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 glucose-galactose 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.

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 non- blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Fetal Toxicity

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

Hypotension In Volume- Or Salt-Depleted Patients

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

Renal Function Deterioration

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

Hyperkalemia

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

Patient Counseling Information

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

Pregnancy

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

Potassium Supplements

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

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Losartan potassium was not carcinogenic when administered at maximally tolerated dosages to rats and mice for 105 and 92 weeks, respectively. Female rats given the highest dose (270 mg/kg/day) had a slightly higher incidence of pancreatic acinar adenoma. The maximally tolerated dosages (270 mg/kg/day in rats, 200 mg/kg/day in mice) provided systemic exposures for losartan and its pharmacologically active metabolite that were approximately 160 and 90 times (rats) and 30 and 15 times (mice) the exposure of a 50 kg human given 100 mg per day.

Losartan potassium was negative in the microbial mutagenesis and V-79 mammalian cell mutagenesis assays and in the in vitro alkaline elution and in vitro and in vivo chromosomal aberration assays. In addition, the active metabolite showed no evidence of genotoxicity in the microbial mutagenesis, in vitro alkaline elution, and in vitro chromosomal aberration assays.

Fertility and reproductive performance were not affected in studies with male rats given oral doses of losartan potassium up to approximately 150 mg/kg/day. The administration of toxic dosage levels in females (300/200 mg/kg/day) was associated with a significant (p<0.05) decrease in the number of corpora lutea/female, implants/female, and live fetuses/female at C-section. At 100 mg/kg/day only a decrease in the number of corpora lutea/female was observed. The relationship of these findings to drugtreatment is uncertain since there was no effect at these dosage levels on implants/pregnant female, percent post-implantation loss, or live animals/litter at parturition. In nonpregnant rats dosed at 135 mg/kg/day for 7 days, systemic exposure (AUCs) for losartan and its active metabolite were approximately 66 and 26 times the exposure achieved in man at the maximum recommended human daily dosage (100 mg).

Use In Specific Populations

Pregnancy

Pregnancy Category D

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

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

Losartan potassium has been shown to produce adverse effects in rat fetuses and neonates, including decreased body weight, delayed physical and behavioral development, mortality and renal toxicity. With the exception of neonatal weight gain (which was affected at doses as low as 10 mg/kg/day), doses associated with these effects exceeded 25 mg/kg/day (approximately three times the maximum recommended human dose of 100 mg on a mg/m² basis). These findings are attributed to drug exposure in late gestation and during lactation. Significant levels of losartan and its active metabolite were shown to be present in rat fetal plasma during late gestation and in rat milk.

Nursing Mothers

It is not known whether losartan is excreted in human milk, but significant levels of losartan and its active metabolite were shown to be present in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Neonates with a history of in utero exposure to Rasoltan: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

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

Geriatric Use

Of the total number of patients receiving Rasoltan in controlled clinical studies for hypertension, 391 patients (19%) were 65 years and over, while 37 patients (2%) were 75 years and over. In a controlled clinical study for renal protection in type 2 diabetic patients with proteinuria, 248 patients (33%) were 65 years and over. In a controlled clinical study for the reduction in the combined risk of cardiovascular death, stroke and myocardial infarction in hypertensive patients with left ventricular hypertrophy, 2857 patients (62%) were 65 years and over, while 808 patients (18%) were 75 years and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Race

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

Renal Impairment

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

Hepatic Impairment

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

- in a controlled clinical trial in > 1,500 type 2 diabetic patients 31 years of age and older with proteinuria (see RENAAL study 5.1)

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).

Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies and post marketing experience

*Including swelling of the larynx, glottis, face, lips, pharynx, and/or tongue (causing airway obstruction); in some of these patients angiooedema had been reported in the past in connection with the administration of other medicines, including ACE inhibitors

** Including Henoch-Schönlein purpura

II Especially in patients with intravascular depletion, e.g. patients with severe heart failure or under treatment with high dose diuretics

†Common in patients who received 150 mg Rasoltan instead of 50 mg

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

§Usually resolved upon discontinuation

The following additional adverse reactions occurred more frequently in patients who received Rasoltan than placebo (frequencies not known): back pain, urinary tract infection, and flu-like symptoms.

Renal and urinary disorders:

As a consequence of inhibiting the renin angiotensin aldosterone 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

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

- in a controlled clinical trial in > 1,500 type 2 diabetic patients 31 years of age and older with proteinuria (see RENAAL study 5.1)

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).

Table 1. The frequency of adverse reactions identified from placebo-controlled clinical studies and post marketing experience

*Including swelling of the larynx, glottis, face, lips, pharynx, and/or tongue (causing airway obstruction); in some of these patients angiooedema had been reported in the past in connection with the administration of other medicines, including ACE inhibitors

** Including Henoch-Schönlein purpura

II Especially in patients with intravascular depletion, e.g. patients with severe heart failure or under treatment with high dose diuretics

†Common in patients who received 150 mg losartan instead of 50 mg

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

§Usually resolved upon discontinuation

The following additional adverse reactions occurred more frequently in patients who received losartan than placebo (frequencies not known): back pain, urinary tract infection, and flu-like symptoms.

Renal and urinary disorders:

As a consequence of inhibiting the renin angiotensin aldosterone 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

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Clinical Trials Experience

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

Hypertension

Rasoltan has been evaluated for safety in more than 3300 adult patients treated for essential hypertension and 4058 patients/subjects overall. Over 1200 patients were treated for over 6 months and more than 800 for over one year.

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

The following less common adverse reactions have been reported:

Blood and lymphatic system disorders: Anemia.

Psychiatric disorders: Depression.

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

Ear and labyrinth disorders: Vertigo, tinnitus.

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

Respiratory, thoracic and mediastinal disorders: Dyspnea.

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

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

Musculoskeletal and connective tissue disorders: Myalgia, arthralgia.

Reproductive system and breast disorders: Impotence.

General disorders and administration site conditions: Edema.

Cough

Persistent dry cough (with an incidence of a few percent) has been associated with ACE-inhibitor use and in practice can be a cause of discontinuation of ACE-inhibitor therapy. Two prospective, parallel-group, double-blind, randomized, controlled trials were conducted to assess the effects of losartan on the incidence of cough in hypertensive patients who had experienced cough while receiving ACE-inhibitor therapy. Patients who had typical ACE-inhibitor cough when challenged with lisinopril, whose cough disappeared on placebo, were randomized to losartan 50 mg, lisinopril 20 mg, or either placebo (one study, n=97) or 25 mg hydrochlorothiazide (n=135). The double-blind treatment period lasted up to 8 weeks. The incidence of cough is shown in Table 1 below.

Table 1

These studies demonstrate that the incidence of cough associated with losartan therapy, in a population that all had cough associated with ACE-inhibitor therapy, is similar to that associated with hydrochlorothiazide or placebo therapy.

Cases of cough, including positive re-challenges, have been reported with the use of losartan in postmarketing experience.

Hypertensive Patients With Left Ventricular Hypertrophy

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

Nephropathy In Type 2 Diabetic Patients

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

Postmarketing Experience

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

Digestive: Hepatitis.

General Disorders and Administration Site Conditions: Malaise.

Hematologic: Thrombocytopenia.

Hypersensitivity: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue has been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Vasculitis, including Henoch-Schonlein purpura, has been reported. Anaphylactic reactions have been reported.

Metabolic and Nutrition: Hyponatremia.

Musculoskeletal: Rhabdomyolysis.

Nervous system disorders: Dysgeusia.

Skin: Erythroderma.

Symptoms of intoxication

Limited data are available with regard to overdose in humans. The most likely manifestation of overdose would be hypotension and tachycardia. Bradycardia could occur from parasympathetic (vagal) stimulation.

Treatment of intoxication

If symptomatic hypotension should occur, supportive treatment should be instituted.

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 Rasoltan nor the active metabolite can be removed by haemodialysis.

Symptoms of intoxication

Limited data are available with regard to overdose in humans. The most likely manifestation of overdose would be hypotension and tachycardia. Bradycardia could occur from parasympathetic (vagal) stimulation.

Treatment of intoxication

If symptomatic hypotension should occur, supportive treatment should be instituted.

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.

Significant lethality was observed in mice and rats after oral administration of 1000 mg/kg and 2000 mg/kg, respectively, about 44 and 170 times the maximum recommended human dose on a mg/m² basis.

Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.

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

Rasoltan is a synthetic oral angiotensin-II 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.

Rasoltan selectively blocks the AT₁ receptor. In vitro and in vivo Rasoltan and its pharmacologically active carboxylic acid metabolite E-3174 block all physiologically relevant actions of angiotensin II, regardless of the source or route of its synthesis.

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

During administration of Rasoltan, 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 Rasoltan, PRA and angiotensin II values fell within three days to the baseline values.

Both Rasoltan and its principal active metabolite have a far greater affinity for the AT₁ receptor than for the AT₂ receptor. The active metabolite is 10 to 40 times more active than Rasoltan on a weight for weight basis.

Hypertension studies

In controlled clinical studies, once daily administration of Rasoltan to patients with mild to moderate essential hypertension produced statistically significant reductions in systolic and diastolic blood pressure. Measurements of blood pressure 24 hours post dose relative to 5 - 6 hours post dose 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 5-6 hours post dose.

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

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

LIFE-study

The Rasoltan Intervention for Endpoint Reduction in Hypertension [LIFE] study was a randomised, triple-blind, active-controlled study in 9193 hypertensive patients aged 55 to 80 years with ECG documented left ventricular hypertrophy. Patients were randomised to once daily Rasoltan 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 Rasoltan 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 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 Rasoltan resulted in a 13.0% risk reduction (p=0.021, 95 % confidence interval 0.77-0.98) compared with atenolol for patients reaching the primary composite endpoint.

This was mainly attributable to a reduction of the incidence of stroke. Treatment with Rasoltan reduced the risk of stroke by 25% relative to atenolol (p=0.001 95% confidence interval 0.63-0.89). The rates of cardiovascular death and myocardial infarction were not significantly different between the treatment groups.

Race

In the LIFE Study black patients treated with Rasoltan 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 Rasoltan 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.

RENAAL-study

The Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Rasoltan 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 Rasoltan. The objective of the study was to demonstrate a nephroprotective effect of Rasoltan 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 Rasoltan 50 mg once a day, titrated if necessary, to achieve blood pressure response, or to placebo, on a background of conventional antihypertensive therapy excluding ACE-inhibitors and angiotensin II antagonists.

Investigators were instructed to titrate the study medication to 100 mg daily as appropriate; 72 % of patients were taking the 100 mg daily dose for the majority of the time. Other antihypertensive agents (diuretics, calcium antagonists, alpha and beta receptor 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 end stage renal failure (need for dialysis or transplantation) or death.

The results showed that the treatment with Rasoltan (327 events) as compared with placebo (359 events) resulted in a 16.1 % 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 Rasoltan: 25.3 % risk reduction for doubling of the serum creatinine (p = 0.006); 28.6 % risk reduction for end stage renal failure (p = 0.002); 19.9 % risk reduction for end stage renal failure or death (p = 0.009); 21.0 % risk reduction for doubling of serum creatinine or end stage renal failure (p = 0.01). All cause mortality rate was not significantly different between the two treatment groups.

In this study Rasoltan was generally well tolerated, as shown by a therapy discontinuation rate on account of adverse reactions that was comparable to the placebo group.

HEAAL Study

The Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Rasoltan (HEAAL) study was a controlled clinical study conducted worldwide in 3834 patients aged 18 to 98 years with heart failure (NYHA Class II-IV) who were intolerant of ACE inhibitor treatment. Patients were randomised to receive Rasoltan 50 mg once a day or Rasoltan 150 mg, on a background of conventional therapy excluding ACE-inhibitors.

Patients were followed for over 4 years (median 4.7 years). The primary endpoint of the study was a composite endpoint of all cause death or hospitalisation for heart failure.

The results showed that treatment with 150 mg Rasoltan (828 events) as compared with 50 mg Rasoltan (889 events) resulted in a 10.1% risk reduction (p=0.027 95% confidence interval 0.82-0.99) in the number of patients reaching the primary composite endpoint. This was mainly attributable to a reduction of the incidence of hospitalisation for heart failure. Treatment with 150 mg Rasoltan reduced the risk of hospitalisation for heart failure by 13.5% relative to 50 mg Rasoltan (p=0.025 95% confidence interval 0.76-0.98). The rate of all cause death was not significantly different between the treatment groups. Renal impairment, hypotension, and hyperkalaemia were more common in the 150 mg group than in the 50 mg group, but these adverse events did not lead to significantly more treatment discontinuations in the 150 mg group.

ELITE I and ELITE II studies

In the ELITE Study carried out over 48 weeks in 722 patients with heart failure (NYHA Class II-IV), no difference was observed between the patients treated with Rasoltan and those treated with captopril with regard to the primary endpoint of a long term change in renal function. The observation of the ELITE I Study that, compared with captopril, Rasoltan reduced the mortality risk, was not confirmed in the subsequent ELITE II Study, which is described in the following.

In the ELITE II Study Rasoltan 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 all cause mortality.

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

In both comparator controlled (not placebo controlled) clinical studies on patients with heart failure the tolerability of Rasoltan 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 beta blockers at baseline.

Paediatric Population

Paediatric hypertension

The antihypertensive effect of Rasoltan 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 Rasoltan daily and patients who weighed> 50 kg received either 5, 50 or 100 mg of Rasoltan daily. At the end of three weeks, Rasoltan administration once daily lowered trough blood pressure in a dose-dependent manner.

Overall, there was a dose response. The dose response 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 Rasoltan 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 Rasoltan at the lowest dose in each group, again suggesting that the lowest dose in each group did not have significant antihypertensive effect.

Long term effects of Rasoltan on growth, puberty and general development have not been studied.

The long-term efficacy of antihypertensive therapy with Rasoltan 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 Rasoltan 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 Rasoltan (n=30) or amlodipine (n=30). The normotensive patients (ages 1 through 18 years) were randomised to receive either Rasoltan (n=122) or placebo (n=124). Rasoltan 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 Rasoltan experienced a statistically significant reduction from baseline in proteinuria of 36% versus 1% increase in placebo/amlodipine group (p≤0.001). Hypertensive patients receiving Rasoltan 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 Rasoltan 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 Rasoltan 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 Rasoltan treated group.

Long-term effects of Rasoltan in children with proteinuria were studied for up to 3 years in the open-label safety extension phase of the same study, in which all patients completing the 12-week base study were invited to participate. A total of 268 patients entered the open-label extension phase and were re-randomized to Rasoltan (N=134) or enalapril (N=134) and 109 patients had >3 years of follow-up (pre-specified termination point of >100 patients completing 3 years of followup in the extension period). The dose ranges of Rasoltan and enalapril, given according to investigator discretion, were 0.30 to 4.42 mg/kg/day and 0.02 to 1.13 mg/kg/day, respectively. The maximum daily doses of 50 mg for <50 kg body weight and 100 mg>50 kg were not exceeded for most patients during the extension phase of the study.

In summary, the results of the safety extension show that Rasoltan was well-tolerated and led to sustained decreases in proteinuria with no appreciable change in glomerular filtration rate (GFR) over 3 years. For normotensive patients (n=205), enalapril had a numerically greater effect compared to Rasoltan on proteinuria (-33.0% (95%CI -47.2;-15.0) vs -16.6% (95%CI -34.9; 6.8)) and on GFR (9.4(95%CI 0.4; 18.4) vs -4.0(95%CI -13.1; 5.0) ml/min/1.73m2)). For hypertensive patients (n=49), Rasoltan had a numerically greater effect on proteinuria (-44.5% (95%CI -64.8; -12.4) vs -39.5% (95%CI -62.5; -2.2)) and GFR (18.9(95%CI 5.2; 32.5) vs -13.4(95%CI -27.3; 0.6)) ml/min/1.73m².

An open label, dose-ranging clinical trial was conducted to study the safety and efficacy of Rasoltan in paediatric patients aged 6 months to 6 years with hypertension. A total of 101 patients were randomized to one of three different starting doses of open-label Rasoltan: a low dose of 0.1 mg/kg/day (N=33), a medium dose of 0.3 mg/kg/day (N=34), or a high dose of 0.7 mg/kg/day (N=34). Of these, 27 were infants which were defined as children aged 6 months to 23 months.

Study medication was titrated to the next dose level at Weeks 3, 6, and 9 for patients that were not at blood pressure goal and not yet on the maximal dose (1.4 mg/kg/day, not to exceed 100 mg/day) of Rasoltan.

Of the 99 patients treated with study medication, 90 (90.9 %) patients continued to the extension study with follow up visits every 3 months. The mean duration of therapy was 264 days.

In summary, the mean blood pressure decrease from baseline was similar across all treatment groups (change from baseline to Week 3 in SBP was -7.3, -7.6, and -6.7 mmHg for the low-, medium-, and high dose groups, respectively; the reduction from baseline to Week 3 in DBP was -8.2, -5.1, and 6.7 mmHg for the low-, medium-, and high-dose groups.); however, there was no statistically significant dose -dependent response effect for SBP and DBP.

Rasoltan, at doses as high as 1.4 mg/kg, was generally well tolerated in hypertensive children aged 6 months to 6 years after 12 weeks of treatment. The overall safety profile appeared comparable between treatment groups.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes) have examined the use of combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE- inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. CV death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Losartan is a synthetic oral angiotensin-II 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 E-3174 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 bradykinin mediated 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 AT₁ receptor than for the AT₂ receptor. The active metabolite is 10 to 40 times more active than losartan on a weight for weight basis.

Hypertension studies

In controlled clinical studies, once daily 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 post dose relative to 5 - 6 hours post dose 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 5-6 hours post dose.

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.

LIFE-study

The Losartan Intervention for Endpoint Reduction in Hypertension [LIFE] study was a randomised, triple-blind, active-controlled study in 9193 hypertensive patients aged 55 to 80 years with ECG documented left ventricular 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 ACE inhibitors, angiotensin II antagonists or beta blockers 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 0.77-0.98) 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 0.63-0.89). The rates of cardiovascular death and myocardial infarction were not significantly different between the treatment groups.

Race

In the LIFE Study 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.

RENAAL-study

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 Rasoltan 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 ACE-inhibitors and angiotensin II antagonists.

Investigators were instructed to titrate the study medication to 100 mg daily as appropriate; 72 % of patients were taking the 100 mg daily dose for the majority of the time. Other antihypertensive agents (diuretics, calcium antagonists, alpha and beta receptor 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 end stage 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 a 16.1 % 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 end stage renal failure (p = 0.002); 19.9 % risk reduction for end stage renal failure or death (p = 0.009); 21.0 % risk reduction for doubling of serum creatinine or end stage renal failure (p = 0.01). All cause 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.

HEAAL Study

The Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan (HEAAL) study was a controlled clinical study conducted worldwide in 3834 patients aged 18 to 98 years with heart failure (NYHA Class II-IV) who were intolerant of ACE inhibitor treatment. Patients were randomised to receive losartan 50 mg once a day or losartan 150 mg, on a background of conventional therapy excluding ACE-inhibitors.

Patients were followed for over 4 years (median 4.7 years). The primary endpoint of the study was a composite endpoint of all cause death or hospitalisation for heart failure.

The results showed that treatment with 150 mg losartan (828 events) as compared with 50 mg losartan (889 events) resulted in a 10.1% risk reduction (p=0.027 95% confidence interval 0.82-0.99) in the number of patients reaching the primary composite endpoint. This was mainly attributable to a reduction of the incidence of hospitalisation for heart failure. Treatment with 150 mg losartan reduced the risk of hospitalisation for heart failure by 13.5% relative to 50 mg losartan (p=0.025 95% confidence interval 0.76-0.98). The rate of all cause death was not significantly different between the treatment groups. Renal impairment, hypotension, and hyperkalaemia were more common in the 150 mg group than in the 50 mg group, but these adverse events did not lead to significantly more treatment discontinuations in the 150 mg group.

ELITE I and ELITE II studies

In the ELITE Study carried out over 48 weeks in 722 patients with heart failure (NYHA Class II-IV), no difference was observed between the patients treated with losartan and those treated with captopril with regard to the primary endpoint of a long term 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, which is described in the following.

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 all cause mortality.

In this study, 3152 patients with heart failure (NYHA Class II-IV) 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 all cause mortality.

In both comparator controlled (not placebo controlled) 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 beta blockers 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 dose response. The dose response 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.

Long term effects of losartan on growth, puberty and general development have not been studied.

The long-term 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 (p≤0.001). 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 losartan in children with proteinuria were studied for up to 3 years in the open-label safety extension phase of the same study, in which all patients completing the 12-week base study were invited to participate. A total of 268 patients entered the open-label extension phase and were re-randomized to losartan (N=134) or enalapril (N=134) and 109 patients had >3 years of follow-up (pre-specified termination point of >100 patients completing 3 years of followup in the extension period). The dose ranges of losartan and enalapril, given according to investigator discretion, were 0.30 to 4.42 mg/kg/day and 0.02 to 1.13 mg/kg/day, respectively. The maximum daily doses of 50 mg for <50 kg body weight and 100 mg>50 kg were not exceeded for most patients during the extension phase of the study.

In summary, the results of the safety extension show that losartan was well-tolerated and led to sustained decreases in proteinuria with no appreciable change in glomerular filtration rate (GFR) over 3 years. For normotensive patients (n=205), enalapril had a numerically greater effect compared to losartan on proteinuria (-33.0% (95%CI -47.2;-15.0) vs -16.6% (95%CI -34.9; 6.8)) and on GFR (9.4(95%CI 0.4; 18.4) vs -4.0(95%CI -13.1; 5.0) ml/min/1.73m2)). For hypertensive patients (n=49), losartan had a numerically greater effect on proteinuria (-44.5% (95%CI -64.8; -12.4) vs -39.5% (95%CI -62.5; -2.2)) and GFR (18.9(95%CI 5.2; 32.5) vs -13.4(95%CI -27.3; 0.6)) ml/min/1.73m².

An open label, dose-ranging clinical trial was conducted to study the safety and efficacy of losartan in paediatric patients aged 6 months to 6 years with hypertension. A total of 101 patients were randomized to one of three different starting doses of open-label losartan: a low dose of 0.1 mg/kg/day (N=33), a medium dose of 0.3 mg/kg/day (N=34), or a high dose of 0.7 mg/kg/day (N=34). Of these, 27 were infants which were defined as children aged 6 months to 23 months.

Study medication was titrated to the next dose level at Weeks 3, 6, and 9 for patients that were not at blood pressure goal and not yet on the maximal dose (1.4 mg/kg/day, not to exceed 100 mg/day) of losartan.

Of the 99 patients treated with study medication, 90 (90.9 %) patients continued to the extension study with follow up visits every 3 months. The mean duration of therapy was 264 days.

In summary, the mean blood pressure decrease from baseline was similar across all treatment groups (change from baseline to Week 3 in SBP was -7.3, -7.6, and -6.7 mmHg for the low-, medium-, and high dose groups, respectively; the reduction from baseline to Week 3 in DBP was -8.2, -5.1, and 6.7 mmHg for the low-, medium-, and high-dose groups.); however, there was no statistically significant dose -dependent response effect for SBP and DBP.

Losartan, at doses as high as 1.4 mg/kg, was generally well tolerated in hypertensive children aged 6 months to 6 years after 12 weeks of treatment. The overall safety profile appeared comparable between treatment groups.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial), VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes) have examined the use of combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE- inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. CV death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

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

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

Absorption

Following oral administration, Rasoltan is well absorbed and undergoes first pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites. The systemic bioavailability of Rasoltan tablets is approximately 33%. Mean peak concentrations of Rasoltan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively.

Distribution

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

Biotransformation

About 14% of an intravenously or orally administered dose of Rasoltan is converted to its active metabolite. Following oral and intravenous administration of ¹⁴C labelled Rasoltan potassium, circulating plasma radioactivity primarily is attributed to Rasoltan and its active metabolite. Minimal conversion of Rasoltan 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 Rasoltan and its active metabolite is about 600 ml/min and 50 ml/min, respectively. Renal clearance of Rasoltan and its active metabolite is about 74 ml/min and 26 ml/min, respectively.

When Rasoltan 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 Rasoltan and its active metabolite are linear with oral Rasoltan potassium doses up to 200 mg.

Following oral administration, plasma concentrations of Rasoltan and its active metabolite decline polyexponentially, with a terminal half life of about 2 hours and 6-9 hours, respectively. During once daily dosing with 100 mg, neither Rasoltan nor its active metabolite accumulates significantly in plasma.

Both biliary and urinary excretions contribute to the elimination of Rasoltan and its metabolites. Following an oral dose/intravenous administration of ¹⁴C labelled Rasoltan 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 Rasoltan and its active metabolite do not differ essentially from those found in young hypertensive patients.

In female hypertensive patients the plasma levels of Rasoltan 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 alcohol-induced hepatic cirrhosis, the plasma levels of Rasoltan and its active metabolite after oral administration were respectively 5 and 1.7 times higher than in young male volunteers.

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

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

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

Pharmacokinetics in paediatric patients

The pharmacokinetics of Rasoltan 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 Rasoltan (mean doses).

The results showed that the active metabolite is formed from Rasoltan in all age groups. The results showed roughly similar pharmacokinetic parameters of Rasoltan 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.

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.

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 orally administered dose of losartan is converted to its active metabolite. Following oral and intravenous administration of ¹⁴C labelled Rasoltan, 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 Rasoltan doses up to 200 mg.

Following oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially, with a terminal half life of about 2 hours and 6-9 hours, respectively. During once daily 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 ¹⁴C labelled 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 alcohol-induced 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.

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 2 times higher in haemodialysis 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.

Absorption

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

Distribution

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

Metabolism

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

Elimination

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

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 Rasoltan induced a decrease in the red blood cell parameters (erythrocytes, haemoglobin, haematocrit), a rise in urea N 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 renin-angiotensin system, Rasoltan has been shown to induce adverse effects on the late foetal development, resulting in foetal death and malformations.

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 urea N 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 renin-angiotensin system, losartan has been shown to induce adverse effects on the late foetal development, resulting in foetal death and malformations.