Composition

Each film-coated tablet contains Losartan potassium 50 mg.

Description

KSART (Losartan potassium) is in a class of drugs called angiotensin II receptor antagonists. It is available as mono-potassium salt of 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl) benzyl] imidazole-5-methanol. 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.

Mechanism of Action

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

Losartan does not have an agonist effect nor does it block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore losartan does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. Consequently, there is no potentiation of undesirable 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 AT2receptor. The active metabolite is 10 to 40 times more active than losartan on a weight for weight basis.

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.

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

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

Dosage and Administration

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

Adverse Reactions

Losartan has been evaluated in clinical studies as follows:

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

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

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

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

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

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

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

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

Hypertension

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

Nervous system disorders

Common:

Dizziness, vertigo

Uncommon:

Somnolence, headache, sleep disorders

Cardiac disorder:

Uncommon:

Palpitations, angina pectoris

Vascular disorders:

Uncommon:

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

Gastro-intestinal disorders:

Uncommon: abdominal pain, obstipation

General disorders and administration site conditions:

Uncommon:

Asthenia, fatigue, oedema

Investigations:

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

Hypertensive patients with left ventricular hypertrophy

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

Nervous system disorders:

Common:

dizziness

Ear and labyrinth disorders:

Common:

vertigo

General disorders and administration site conditions:

Common:

asthenia/fatigue

Chronic heart failure

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

Nervous system disorders:

Uncommon:

dizziness, headache

Rare: paraesthesia

Cardiac disorders:

Rare:

Syncope, atrial fibrillation, cerebrovascular accident

Vascular disorders:

Uncommon: Hypotension, including orthostatic hypotension

Respiratory, thoracic and mediastinal disorders:

Uncommon:

Dyspnoea

Gastro-intestinal disorders:

Uncommon:

Diarrhoea, nausea, vomiting

Skin and subcutaneous tissue disorders:

Uncommon:

Urticaria, pruritus, rash

General disorders and administration site conditions:

Uncommon:

Asthenia/fatigue

Investigations:

Uncommon:

Increase in blood urea, serum creatinine and serum potassium has been reported.

Hypertension and type 2 diabetes with renal disease

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

Nervous system disorders:

Common:

Dizziness

Vascular disorders:

Common:

Hypotension

General disorders and administration site conditions:

Common:

Asthenia/fatigue

Investigations:

Common:

Hypoglycaemia, hyperkalaemia

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

Blood and lymphatic system disorders:

Not known:

Anaemia

Cardiac disorders:

Not known:

Syncope, palpitations

Vascular disorders:

Not known:

Orthostatic hypotension

Gastro-intestinal disorders:

Not known:

Diarrhoea

Musculoskeletal and connective tissue disorders:

Not known:

Back pain

Renal and urinary disorders:

Not known:

Urinary tract infections

General disorders and administration site conditions:

Not known:

Flu like symptoms

Investigations:

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

Postmarketing experience

The following adverse reactions have been reported in postmarketing experience

Blood and lymphatic system disorders:

Not known:

anaemia, thrombocytopenia

Ear and labyrinth disorders:

Not known:

Tinnitus

Immune system disorders:

rare:

hypersensitivity:

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

Nervous system disorders:

Not known:

Migraine

Respiratory, thoracic and mediastinal disorders:

Not known:

Cough

Gastro-intestinal disorders:

Not known:

Diarrhoea, pancreatitis

General disorders and administration site conditions:

Not known:

Malaise

Hepatobiliary disorders:

Rare:

Hepatitis

Not known:

liver function abnormalities

Skin and subcutaneous tissue disorders:

Not known:

Urticaria, pruritus, rash, photosensitivity

Musculoskeletal and connective tissue disorders:

Not known:

Myalgia, arthralgia, rhabdomyolysis

Reproductive system and breast disorders:

Not known:

Erectile dysfunction/impotence

Renal and urinary disorders:

As a consequence of inhibiting the 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)

Psychiatric disorders:

Not known:

Depression

Investigations:

Not known:

Hyponatraemia

Paediatric population

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

Drug 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 and amifostine) may increase the risk of hypotension.

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

As with other medicinal products that block angiotensin II or its effects, concomitant use of other medicinal products which retain potassium (e.g. potassium sparing diuretics

amiloride, triamterene, spironolactone) or may increase potassium levels (e.g. heparin), potassium supplements or salt substitutes containing potassium may lead to increases in serum potassium. 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 COX2 inhibitors, acetylsalicylic acid at anti-inflammatory doses and nonselective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of angiotensin II antagonists or diuretics and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor 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.

Overdose

Symptoms of intoxication

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

Treatment of intoxication

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

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

Contraindications

 Hypersensitivity to the active substance or to any of the excipients .

2nd and 3rd trimester of pregnancy .

Severe hepatic impairment.

Pharmacokinetics:

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 34 hours, respectively.

Distribution

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

Biotransformation

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

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

Elimination

Plasma clearance of losartan and its active metabolite is about 600 ml/min and 50 ml/min, respectively. Renal clearance of losartan and its active metabolite is about 74 ml/min and 26 ml/min, respectively. When losartan is administered orally, about 4% of the dose is excreted unchanged in the urine, and about 6% of the dose is excreted in the urine as active metabolite. The pharmacokinetics of losartan and its active metabolite are linear with oral losartan potassium doses up to 200 mg.

Following oral administration, plasma concentrations of losartan and its active metabolite decline poly-exponentially, with a terminal half-life of about 2 hours and 69 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 14Clabelled losartan in man, about 35% / 43% of radioactivity is recovered in the urine and 58%/ 50% in the faeces.

Characteristics in patients

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

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

In patients with mild to moderate 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 (see section 4.2 and 4.4).

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

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

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

Pharmacokinetics in paediatric patients

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

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

Expiry Date

2 years from the date of manufacture.

Storage

Store below 30°C.

Keep out of reach of children.

How supplied

Supplied in PVC/PVDC blister of 14’s tablets. Two such strips are packed in a carton along with package insert.

Manufactured by:

Kusum Healthcare Private Limited

SP 289 (A), RIICO Industrial Area

Chopanki, Bhiwadi

Distt. Alwar – 301707

India