4.1. Therapeutic indications

• 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 (see sections 4.3, 4.4, 4.5 and 5.1).

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

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

4.2. Posology and method of administration

Posology

Hypertension

The usual starting and maintenance dose is 50 mg once daily for most patients. The maximal antihypertensive effect is attained 3-6 weeks after initiation of therapy. Some patients may receive an additional benefit by increasing the dose to 100 mg once daily (in the morning).

Losartan may be administered with other antihypertensive agents, especially with diuretics (e.g. hydrochlorothiazide) (see sections 4.3, 4.4, 4.5 and 5.1).

Paediatric population

6 months – less than 6 years

The safety and efficacy of children aged 6 months to less than 6 years has not been established. Currently available data are described in sections 5.1 and 5.2 but no recommendation on posology can be made.

6 years to 18 years

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

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

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

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

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

Hypertensive type II diabetic patients with proteinuria ≥ 0.5 g/day

The usual starting dose is 50 mg once daily. The dose may be increased to 100 mg once daily based on blood pressure response from one month onwards after initiation of therapy. Losartan may be administered with other antihypertensive agents (e.g. diuretics, calcium channel blockers, alpha- or beta-blockers, and centrally acting agents) (see sections 4.3, 4.4, 4.5, and 5.1) as well as with insulin and other commonly used hypoglycemic agents (e.g. sulfonylureas, glitazones and glucosidase inhibitors).

Heart Failure

The usual initial dose of Losartan in patients with heart failure is 12.5 mg once daily. The dose should generally be titrated at weekly intervals (i.e. 12.5 mg daily, 25 mg daily, 50 mg daily, 100 mg daily, up to a maximum dose of 150 mg once daily) as tolerated by the patient.

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

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

Special Population

Use in patients with intravascular volume depletion

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

Use in patients with renal impairment and haemodialysis patients

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

Use in patients with hepatic impairment

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

Use in 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.

Method of administration

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

Losartan tablets may be administered with or without food.

4.3. Contraindications

• Hypersensitivity to active substance, or to any of the excipients listed in sections 4.4 and 6.1.

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

• Severe hepatic impairment.

• The concomitant use of Losartan with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

4.4. Special warnings and precautions for use

Intestinal angioedema

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists [including Losartan Potassium] (see section 4.8). These patients presented with abdominal pain, nausea, vomiting and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, Losartan Potassium should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

Hypersensitivity

Angioedema. Patients with a history of angioedema (swelling of the face, lips, throat, and/ or tongue) should be closely monitored (See section 4.8).

Hypotension and Electrolyte/Fluid Imbalance

Symptomatic hypotension, especially after the first dose and after increasing of the dose, may occur in patients who are volume- and/or 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 (see section 4.2). This also applies to children 6 to 18 years of age.

Electrolyte imbalances

Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed. In a clinical study conducted in type 2 diabetic patients with nephropathy, the incidence of hyperkalemia was higher in the group treated with Losartan as compared to the placebo group (see section 4.8). Therefore, the plasma concentrations of potassium as well as creatinine clearance values should be closely monitored, especially patients with heart failure and a Creatinine Clearance between 30-50 ml/ min should be closely monitored.

The concomitant use of potassium sparing diuretics, potassium supplements, potassium containing salt substitutes, or other drugs that may increase serum potassium (e.g., trimethoprim-containing products) with losartan is not recommended (see section 4.5).

Hepatic Impairment

Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, a lower dose should be considered for patients with a history of hepatic impairment. There is no therapeutic experience with losartan in patients with severe hepatic impairment. Therefore, losartan must not be administered in patients with severe hepatic impairment (see sections 4.2, 4.3 and 5.2).

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

Renal Impairment

As a consequence of inhibiting the renin-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 renin-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 function impairment

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

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

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

Renal transplantation

There is no experience in patients with recent kidney transplantation.

Primary hyperaldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Losartan tablets 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 (see section 5.1).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

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

Excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total 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 anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with losartan should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Other warnings and precautions

As observed for angiotensin converting enzyme inhibitors, losartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in 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 (see sections 4.5 and 5.1).

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.

4.5. Interaction with other medicinal products and other forms of interaction

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

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

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

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

When angiotensin II antagonists are administered simultaneously with NSAIDs (i.e. selective COX-2 inhibitors, acetylsalicylic acid at anti-inflammatory doses and non-selective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of angiotensin II antagonists or diuretics and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Grapefruit juice contains components that inhibit CYP450 enzymes and may lower the concentration of the active metabolite of losartan which may reduce the therapeutic effect. Consumption of grapefruit juice should be avoided while taking losartan tablets.

4.6. Fertility, pregnancy and lactation

Pregnancy

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

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

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

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

Lactation

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

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Losartan has been evaluated in clinical studies as follows:

• In a controlled clinical trial in > 3,000 adult patients 18 years of age and older for essential hypertension.

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

• In a controlled clinical trial in > 9,000 hypertensive patients 55 to 80 years of age with left ventricular hypertrophy (see LIFE Study, section 5.1).

• In controlled clinical trials in > 7,700 adult patients with chronic heart failure (see ELITE I, ELITE II, and HEAAL study, section 5.1).

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

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

The frequency of adverse events 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

Adverse reaction

Frequency of adverse reaction by indication

Other

Hypertension

Hypertensive patients with left ventricular hypertrophy

Chronic Heart Failure

Hypertension and type 2 diabetes with renal disease

Post-marketing experience

Blood and lymphatic system disorders

anaemia

common

frequency not known

thrombocytopenia

frequency not known

Immune system disorders

hypersensitivity reactions, anaphylactic reactions, angioedema*, and vasculitis**

rare

Psychiatric disorders

depression

frequency not known

Nervous system disorders

dizziness

common

common

common

common

somnolence

uncommon

headache

uncommon

uncommon

sleep disorders

uncommon

paraesthesia

rare

migraine

frequency not known

dysgeusia

frequency not known

Ear and labyrinth disorders

vertigo

common

common

tinnitus

frequency not known

Cardiac disorders

palpitations

uncommon

angina pectoris

uncommon

syncope

rare

atrial fibrillation

rare

cerebrovascular accident

rare

Vascular disorders

(orthostatic) hypotension (including dose related orthostatic effects)‖

uncommon

common

common

Respiratory, thoracic and mediastinal disorders

dyspnoea

uncommon

cough

uncommon

frequency not known

Gastrointestinal disorders

abdominal pain

uncommon

obstipation

uncommon

diarrhoea

uncommon

frequency not known

nausea

uncommon

vomiting

uncommon

Intestinal angioedema

rare

Hepatobiliary disorders

pancreatitis

frequency not known

hepatitis

rare

liver function abnormalities

frequency not known

Skin and subcutaneous tissue disorders

urticaria

uncommon

frequency not known

pruritus

uncommon

frequency not known

rash

uncommon

uncommon

frequency not known

photosensitivity

frequency not known

Musculoskeletal and connective tissue disorders

myalgia

frequency not known

arthralgia

frequency not known

rhabdomyolysis

frequency not known

Renal and urinary disorders

renal impairment

common

renal failure

common

Reproductive system and breast disorders

erectile dysfunction / impotence

frequency not known

General disorders and administration site conditions

asthenia

uncommon

common

uncommon

common

fatigue

uncommon

common

uncommon

common

oedema

uncommon

malaise

frequency not known

Investigations

hyperkalaemia

common

uncommon†

common‡

increased alanine aminotransferase (ALT) §

rare

increase in blood urea, serum creatinine, and serum potassium

common

hyponatraemia

frequency not known

hypoglycaemia

common

*Including swelling of the larynx, glottis, face, lips, pharynx, and/or tongue (causing airway obstruction); in some of these patients angioedema 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 (see section 4.4)

Paediatric population

The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients. Data in the pediatric 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, website www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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.