Losartan Tetrafarma

- 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 Tetrafarma. 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.

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.

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

Method of administration

Losartan Tetrafarma tablets should be swallowed with a glass of water.

Losartan Tetrafarma potassium may be administered with or without food.

2^nd and 3^rd trimester of pregnancy.

Severe hepatic impairment.

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

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 Tetrafarma, 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 Tetrafarma 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 Tetrafarma is not recommended.

Hepatic impairment

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

Losartan Tetrafarma 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 Tetrafarma 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 Tetrafarma 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 Tetrafarma as it may deteriorate. This applies particularly when Losartan Tetrafarma is given in the presence of other conditions (fever, dehydration) likely to impair renal function.

Concomitant use of Losartan Tetrafarma 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 Tetrafarma 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 Tetrafarma 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 Tetrafarma should be used with caution in these patient groups. The combination of Losartan Tetrafarma 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 Tetrafarma should not be initiated during pregnancy. Unless continued Losartan Tetrafarma 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 Tetrafarma should be stopped immediately, and, if appropriate, alternative therapy should be started.

Other warnings and precautions

As observed for angiotensin converting enzyme inhibitors, Losartan Tetrafarma 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.

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

- 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 Tetrafarma instead of 50 mg

‡In a clinical study conducted in type 2 diabetic patients with nephropathy, 9.9% of patients treated with Losartan Tetrafarma 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 Tetrafarma 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.

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 Tetrafarma nor the active metabolite can be removed by haemodialysis.

Losartan Tetrafarma 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 Tetrafarma selectively blocks the AT₁ receptor. In vitro and in vivo Losartan Tetrafarma 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 Tetrafarma does not have an agonist effect nor does it block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore Losartan Tetrafarma 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 Tetrafarma, 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 Tetrafarma, PRA and angiotensin II values fell within three days to the baseline values.

Both Losartan Tetrafarma 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 Tetrafarma on a weight for weight basis.

Hypertension studies

In controlled clinical studies, once daily administration of Losartan Tetrafarma 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 Tetrafarma in hypertensive patients did not result in an abrupt rise in blood pressure (rebound). Despite the marked decrease in blood pressure, Losartan Tetrafarma had no clinically significant effects on heart rate.

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

LIFE-study

The Losartan Tetrafarma 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 Tetrafarma 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 Tetrafarma 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 Tetrafarma 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 Tetrafarma 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 Tetrafarma 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 Tetrafarma 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 Tetrafarma 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 Tetrafarma. The objective of the study was to demonstrate a nephroprotective effect of Losartan Tetrafarma potassium over and above the benefit of lowering blood pressure.

Patients with proteinuria and a serum creatinine of 1.3 - 3.0 mg/dl were randomised to receive Losartan Tetrafarma 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 Tetrafarma (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 Tetrafarma: 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 Tetrafarma 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 Tetrafarma (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 Tetrafarma 50 mg once a day or Losartan Tetrafarma 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 Tetrafarma (828 events) as compared with 50 mg Losartan Tetrafarma (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 Tetrafarma reduced the risk of hospitalisation for heart failure by 13.5% relative to 50 mg Losartan Tetrafarma (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 Tetrafarma 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 Tetrafarma 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 Tetrafarma 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 Tetrafarma is superior to captopril in reducing all cause mortality. The primary endpoint did not show any statistically significant difference between Losartan Tetrafarma 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 Tetrafarma 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 Tetrafarma 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 Tetrafarma daily and patients who weighed> 50 kg received either 5, 50 or 100 mg of Losartan Tetrafarma daily. At the end of three weeks, Losartan Tetrafarma 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 Tetrafarma 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 Tetrafarma 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 Tetrafarma on growth, puberty and general development have not been studied.

The long-term efficacy of antihypertensive therapy with Losartan Tetrafarma 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 Tetrafarma 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 Tetrafarma (n=30) or amlodipine (n=30). The normotensive patients (ages 1 through 18 years) were randomised to receive either Losartan Tetrafarma (n=122) or placebo (n=124). Losartan Tetrafarma 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 Tetrafarma 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 Tetrafarma 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 Tetrafarma 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 Tetrafarma 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 Tetrafarma treated group.

Long-term effects of Losartan Tetrafarma 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 Tetrafarma (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 Tetrafarma 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 Tetrafarma 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 Tetrafarma 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 Tetrafarma 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 Tetrafarma 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 Tetrafarma: 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 Tetrafarma.

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 Tetrafarma, 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.

Absorption

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

Distribution

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

Biotransformation

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

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

Following oral administration, plasma concentrations of Losartan Tetrafarma 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 Tetrafarma nor its active metabolite accumulates significantly in plasma.

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

In female hypertensive patients the plasma levels of Losartan Tetrafarma 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 Tetrafarma and its active metabolite after oral administration were respectively 5 and 1.7 times higher than in young male volunteers.

Plasma concentrations of Losartan Tetrafarma are not altered in patients with a creatinine clearance above 10 ml/minute. Compared to patients with normal renal function, the AUC for Losartan Tetrafarma 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 Tetrafarma nor the active metabolite can be removed by haemodialysis.

Pharmacokinetics in paediatric patients

The pharmacokinetics of Losartan Tetrafarma 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 Tetrafarma (mean doses).

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

Preclinical data reveal no special hazard for humans based on conventional studies of general pharmacology, genotoxicity and carcinogenic potential. In repeated dose toxicity studies, the administration of Losartan Tetrafarma 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 Tetrafarma has been shown to induce adverse effects on the late foetal development, resulting in foetal death and malformations.

Not applicable.

No special requirements.