TORAASS A Tablet

Indication:

• Treatment of essential hypertension in adults and in children and adolescents 6-18 years of age.

• Treatment of renal disease in adult patients with hypertension and type 2 diabetes mellitus with proteinuria ≥ 0.5 g/day as part of an antihypertensive treatment.

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

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

• Chronic stable angina pectoris and Vasospastic (Prinzmetal's) angina.

Dosage and method of administration:

Losartan potassium and Amlodipine besilate tablets should be swallowed orally with a glass of water with or without food.

Hypersensitivity to Losartan potassium nd Amlodipine besilate tablets or to any of the excipients

- In 2nd and 3rd trimester of pregnancy

- Severe hepatic impairment.

- Losartan should not be administered with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73m2).

- Severe hypotension.

- Shock (including cardiogenic shock).

- Obstruction of the outflow tract of the left ventricle (e.g., high grade aortic stenosis).

- Haemodynamically unstable heart failure after acute myocardial infarction.

Losartan

- Common: anaemia, dizziness, vertigo, orthostatic, renal impairment, renal failure, hypoglycemia

- Uncommon: somnolence, headache, sleep disorders, palpitations, angina pectoris, dyspnea, cough, abdominal pain, obstipation, diarrhea, nausea, vomiting, rash, pruritis, urticaria

Amlodipine

- common: somnolence, dizziness, headache (especially at the beginning of the treatment), palpitation, flushing, abdominal pain, nausea, ankle swelling, odema, fatigue

- uncommon: insomnia, mood changes (including anxiety), depression, tremor, dysgeusia, syncope, hypoesthesia, paresthesia, visual disturbance (including diplopia), tinnitus, hypotension, dyspnoea, rhinitis, vomiting, dyspepsia, altered bowel habits (including diarrhea and constipation), dry mouth, alopecia, purpura, skin, discolouration, hyperhidrosis, pruritus, rash, exanthema, arthralgia, myalgia, muscle cramps, micturition disorder, nocturia, increased urinary frequency, impotence, gynaecomatia, chest pain, asthenia, pain, malaise, weight increase, weight decrease.

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, alternartive therapy should be started.

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

Losartan

Losartan is a synthetic oral angiotensin-II receptor (type AT1) antagonist. Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the renin/angiotensin system and an important determinant of the pathophysiology of hypertension. Angiotensin II binds to the AT1 receptor found in many tissues (e.g. vascular smooth muscle, adrenal gland, kidneys and the heart) and elicits several important biological actions, including vasoconstriction and the release of aldosterone. Angiotensin II also stimulates smooth muscle cell proliferation.

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

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

During administration of losartan, removal of the angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA). Increase in the PRA leads to an increase in angiotensin II in plasma. Despite these increases, antihypertensive activity and suppression of plasma aldosterone concentration are maintained, indicating effective angiotensin II receptor blockade. After discontinuation of losartan, PRA and angiotensin II values fell within three days to the baseline values.

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

Amlodipine

Pharmacotherapeutic group: Calcium channel blockers, selective calcium channel blockers with mainly vascular effects.

Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.

The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces total ischaemic burden by the following two actions.

1) Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.

2) The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina).