1. Name Of The Medicinal Product
Losartan potassium 25 mg film-coated tablets
Losartan potassium 50 mg film-coated tablets
Losartan potassium 100 mg film-coated tablets
2. Qualitative And Quantitative Composition
Losartan potassium 25 mg film-coated tablets:
Each film-coated tablet contains 25 mg losartan potassium.
Excipient: 20 mg lactose monohydrate / film-coated tablet.
Losartan potassium 50 mg film-coated tablets:
Each film-coated tablet contains 50 mg losartan potassium.
Excipient: 40 mg lactose monohydrate / film-coated tablet.
Losartan potassium 100 mg film-coated tablets:
Each film-coated tablet contains 100 mg losartan potassium.
Excipient: 80 mg lactose monohydrate / film-coated tablet.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet.
Losartan potassium 25 mg film-coated tablets:
White to off-white, oval shaped, biconvex, film-coated tablets debossed with 'E' on one side and '45' on other side.
Losartan potassium 50 mg film-coated tablets:
White to off-white, oval shaped, biconvex, film-coated tablets debossed with 'E' on one side and '4' and '6' separated by a score-line on other side.
The tablets can be divided into equal halves.
Losartan potassium 100 mg film-coated tablets:
White to off-white, oval shaped, biconvex, film-coated tablets debossed with 'E' on one side and '47' on other side.
4. Clinical Particulars
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
• Treatment of chronic heart failure (in patients
• Reduction in the risk of stroke in hypertensive patients with left ventricular hypertrophy documented by ECG (see section 5.1 LIFE study, Race).
4.2 Posology And Method Of Administration
Losartan potassium film-coated tablets should be swallowed with a glass of water.
Losartan potassium may be administered with or without food.
Losartan potassium Tablets from Pfizer are not available in the 12.5 mg dose strength for this product and can therefore not be administered to patients who must be treated with losartan doses less than 25 mg. There are other options for this strength available on the market.
Hypertension:
The usual starting and maintenance dose is 50 mg once daily for most patients. The maximal anti-hypertensive 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 potassium may be administered with other antihypertensive agents, especially with diuretics (e.g. hydrochlorothiazide).
Pediatric hypertension
There are limited data on the efficacy and safety of losartan in children and adolescents aged 6-18 years old for the treatment of hypertension (see 5.1: Pharmacodynamic properties). Limited pharmacokinetic data are available in hypertensive children above one month of age (see 5.2: Pharmacokinetic properties).
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 pediatric 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
The usual starting dose is 50 mg once a daily. The dose may be increased up to 100 mg once daily based on blood pressure response from one month after initiation of therapy onwards. Losartan potassium may be administered with other anti-hypertensive agents (e.g. diuretics, calcium channel blockers, alpha- or beta-blockers, and centrally acting agents) as well as with insulin and other commonly used hypoglycaemic agents (e.g. sulphonylureas, glitazones and glucosidase inhibitors).
Heart failure:
The usual initial dose of Losartan potassium 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 potassium once daily. A low dose of hydrochlorothiazide should be added and/or the dose of Losartan potassium should be increased to 100 mg once daily based on blood pressure response.
Special populations
Use in patients with intravascular volume depletion:
For patients with intravascular 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.
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients (see section 4.4 and 6.1).
• 2nd and 3rd trimester of pregnancy (see sections 4.4 and 4.6).
• Severe hepatic impairment
4.4 Special Warnings And Precautions For Use
Hypersensitivity
Angiooedema.Patients with a history of angiooedema (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 potassium, 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 hyperkalaemia was higher in the group treated with losartan as compared to the placebo group (see section 4.8, 'Hypertension and type 2 diabetes with renal disease - Investigations' and 'Post-marketing experience - Investigations'). 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 (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 pediatric patients with renal 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 mirtal 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 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.
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, baclofene, and amifostine) 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 these effects is unknown. No difference in exposure was found with concomitantly 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, triamterin, spironolactone) or may increase potassium levels (e.g. heparin), 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.
Dual blockade (e.g, by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should be limited to individually defined cases with close monitoring of renal function. Some studies have shown that in patients with established atherosclerotic disease, heart failure, or with diabetes with end organ damage, dual blockade of the renin-angiotensin-aldosterone system, is associated with a higher frequency of hypotension, syncope, hyperkalaemia, and changes in renal function (including acute renal failure) as compared to use of a single renin-angiotensin-aldosterone system agent.
4.6 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 contra-indicated 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.
Losartan therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See also 5.3 'Preclinical safety data').
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 sections 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 trials in > 3000 adult patients 18 years of age and older for essential hypertension,
- in a controlled clinical trial in 177 hypertensive pediatric patients 6 to 16 years of age
- in a controlled clinical trial in > 9000 hypertensive patients 55 to 80 years of age with left ventricular hypertrophy
- in a controlled clinical trial in > 7700 adult patients with chronic heart failure
- in a controlled clinical trial in > 1500 type 2 diabetic patients 31 years of age and older with proteinuria
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 (
Hypertension
In a controlled clinical trials in 3300 adult patients 18 years of age and older with essential hypertension, the following adverse reactions were reported:
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* usually resolved upon discontinuation
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Hypertensive patients with left ventricular hypertrophy
In a controlled clinical trial in 9193 hypertensive patients 55 to 80 years of age, with left ventricular hypertrophy, the following adverse reactions were reported:
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Chronic heart failure
In a controlled clinical trial in patients with chronic heart failure (see ELITE I, ELITE II, and HEAAL study, section 5.1) the following adverse reactions were reported:
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* common in patients who received 150 mg losartan instead of 50 mg losartan
Hypertension and type 2 diabetes with renal disease
In a controlled clinical trial in 1513 type 2 diabetic patients 31 years of age and older, with proteinuria (RENAAL study, see section 5.1), the most common drug-related adverse reactions which were reported for losartan are as follows:
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*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
The following adverse reactions occurred more often in patients receiving losartan than placebo:
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Post-marketing experience
The following adverse reactions have been reported in post-marketing experience:
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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 reaction profile for paediatric patients appears to be similar to that seen in adult patients. Data in the paediatric population are limited.
4.9 Overdose
Symptoms of intoxication
Limited data are available with regard to overdose in humans. The most likely symptoms, depending on the extent of overdose, are hypotension and tachycardia., Bradycardia could occur from parasympathetic (vagal) stimulation.
Treatment of intoxications
If symptomatic hypotension should occur, supportive treatment should be instituted.
Measures are dependent on the time of medicinal product intake and kind and severity of symptoms. Stabilisation of the circulatory 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.
5. Pharmacological Properties
Pharmacotherapeutic group: Angiotensin II receptor antagonists
ATC code: C09 CA 01
5.1 Pharmacodynamic Properties
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 inhibit 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. Measurement 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 effect 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, hydrochlorthiazide (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) as 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 the 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 losartan potassium over and above the benefit of a blood lowering pressure.
Patients with
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