ALSARTAN AM Tablet

For the treatment of hypertension.

Dosage

Therapy should be initiated at a dosage of 50m/5mg administered once daily.

Scored tablet allows flexibility for dose titration.

In patients who are hypersensitive to any component of this product.

Losartan Potassium

Side effects have usually been mild and transient in nature and have not required discontinuation of therapy. The overall incidence of side effects reported with losartan was comparable to placebo.

In controlled clinical trials for essential hypertension, dizziness was the only side effect reported as drug related that occurred with an incidence greater than placebo in1% or more of patients treated with losartan. In addition, dose-related orthostatic effects were seen in less than 1% of patients.

The following adverse reactions have been reported in patients marketing experience:

Hypersensitivity: Angioedema including swelling of the larynx and glottis causing airway obstruction (and/or swelling of the face, lips, pharynx, and/or tongue) has been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors.

Gastro-intestinal: Hepatitis, diarrhoea, liver function abnormalities.

Respiratory: Dry cough.

Hyperkalemia and hyponatremia have been reported.

Haematologic: Anaemia.

Musculoskeletal: Myalgia.

Nervous System/ Psychiatric: Migraine.

Skin: Urticaria, pruritus, rash.

Amlodipine besilate:

(See the package insert about the details.) The most common side effects are headache and edema.

Losartan Potassium

Losartan, administered for 12 days, did not affect the pharmacokinetics or pharmacodynamics of a single dose of warfarin.

Losartan did not affect the pharmacokinetics of oral or intravenous digoxin.

Coadministration of losartan and cimetidine led to an increase of about 18% in AUC of losartan but did not affect the pharmacokinetics of its active metabolite. Coadministration of losartan and phenobarbital led to a reduction of about 20% in the AUC of losartan and that of its active metabolite. There is no pharmacokinetic interaction between losartan and hydrochlorothiazide.

Potent inhibits of CYP3A4 and 2C9 have not been studied clinically but in vitro studies show significant inhibition of the formation of the active metabolite by inhibitor of CYP3A4 (ketoconazole, troleandomycin. gestodene), or CYP2C9 (sulphaphenazole) and nearly complete inhibition by the combination of sulphaphenazole and ketoconazole. In humans, ketoconazole, an inhibitor of CYP3A4, did not affect the conversion of losartan to the active metabolite after intravenous administration of losartan, inhibitors of CYP2C9 have not been studied clinically. The pharmacodynamic consequences of concomitant use of losartan and inhibitors of CYP2C9 have not been examined.

As with other drugs that block angiotensinⅡor its effects, concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.

Amlodipine besilate

In vitro data in human plasma indicate that amlodipine besilate has no effect on the protein binding of drugs tested (digoxin, phenytoin, warfarin,, and indomethacin). Special studies have indicated that the co-administration of amlodipine besilate with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers; that co-administration with cimetidine did not after the pharmacokinetics of amlodipine; and that co-administration with warfarin did not change the warfarin prothrombin response time.

In clinical trials, amlodipine besilate has been safely administered with thiazide diuretics, beta-blockers, angiotensin converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, NSAIDs, antibiotics, and oral hypoglycemic drugs.

Pregnancy

Losartan Potassium

Pregnancy Category C & D: When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can case injury and even death to the developing fetus. When pregnancy is detected, losartan potassium should be discontinued as soon as possible.

Amlodipine Besilate

Carcinogenesis, Mutagenesis, and Impairment of Fertility: See the package insert.

Pregnancy Category C: There are no adequate and well controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Using during lactation

Losartan potassium

Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue breast-feeding or discontinue the drug, taking into account the importance of the drug to the mother.

Amlodipine Besilate

It is not known whether amlodipine is excreted in human milk. In the absence of this information, it is recommended that nursing be discontinued while amlodipine besilate is administered.

Losartan potassium

Hypersensitivity: Angioedema.

(See the package insert about the details below.)

Hypotension and electrolyte/fluid imbalance

Liver function impairment

Renal function impairment

Amlodipine Besilate

General: Since the vasodilation induced by amlodipine besilate is gradual in onset, acute hypotension has rarely been reported after oral administration of amlodipine besilate. Nonetheless, caution should be exercised when administering amlodipine besilate as with any other peripheral vasodilator particularly in patients with severe aortic stenosis.

(See the package insert about the details below.)

Use in patients with Congestive Heart Failure

Beta-Blocker Withdrawal

Patients with Hepatic Failure.

Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensinⅡby selectively blocking the binding of angiotensinⅡto the AT1 receptor found in many tissues, (e.g. vascular smooth muscle, adrenal gland). There is also an AT2 receptor found in many tissues but it is not known to be associated with cardiovascular hemostasis. Both losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT1 receptor and have much greater affinity for the AT1 receptor than for the AT2 receptor. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT1 receptor. The active metabolite is 10-40 times more potent by weight than losartan and appears to be reversible, non-competitive inhibitor of the AT1 receptor. Neither losartan not its active metabolite inhibits ACE (kininaseⅡ, the enzyme that converts angiotensinⅠto angiotensinⅡ and degrades bradykinin); nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Amlodipine Besilate

Amlodipine besilate is a dihydropyridine calcium antagonist (calcium ion antagonist or channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine besilate binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine besilate inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine besilate. Within the physiologic pH range, amlodipine besilate is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

Amlodipine besilate is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

Exertional Angina

In patients with exertional angina, amlodipine besilate reduces the total peripheral resistance (after-load) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.

Vasospastic Angina

Amlodipine besilate has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane. A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of amlodipine besilate in vasospastic (Prinzmetal's or variant) angina.