ALSARTAN H Tablet

For the treatment of hypertension.

Dosage and Administration

The usual starting dose of losartan is 50mg once daily, with 25mg recommended for patients with intravascular volume depletion (e.g. patients treated with diuretics), and patients with a history of hepatic impairment. Losartan can be administered once or twice daily at total daily doses of 25-100mg. If the antihypertensive effect measured at trough using once-a-day dosing is inadequate, a twice-a-day regimen at the same total daily dose or an increase in dose may give a more satisfactory response.

Hydrochlorothiazide is effective in doses of 12.5-100mg once daily and can be given at doses of 12.5-25mg as Alsartan-H.

To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.

The side effects of losartan are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of losartan and hydrochlorothiazide will be associated with both sets of dose-independent side effects.

Replacement: The combination may be substituted for the titrated components.

Dose Titration by Clinical Effect: A patient whose blood pressure is not adequately controlled with losartan monotherapy may be switched to losartan 50mg/hydrochlorothiazide 12.5mg once daily. If blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to 2 tablets once daily.

A patient whose blood pressure in inadequately controlled by 25mg once daily of hydrochlorothiazide, or is controlled but who experiences hypokalemia with the regimen, may be switched to losartan-H once daily, reducing the dose of hydrochlorothiazide without reducing the overall expected antihypertensive response. The clinical response to Alsartan-H should be subsequently evaluated and if blood pressure remains uncontrolled after about 3 weeks of therapy, the dose may be increased to 2 tablets once daily.

The usual dose is 1 tablet once daily. More than 2 tablets once daily is not recommended. The maximal antihypertensive effect is attained about 3 weeks after initiation of therapy.

See the package insert about the details below:

- Use in patients with renal impairment

- Patients with hepatic impairment.

In patients with who are hypersensitive to any component of this product. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Losartan Potassium:

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 in 1% 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 post marketing experience:

(See the package insert about the details below.)

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 (reported rarely), diarrhoea, liver function abnormalities.

Haematologic: Anaemia.

Musculoskeletal: Myalgia.

Nervous system/Psychiatric: Migraine.

Skin: Urticaria, pruritus, rash.

Hydrochlorothiazide:

Other adverse experiences that have been reported with hydrochlorothiazide, without regard to causality, are listed below:

Body as a whole: weakness.

Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, gastric irritation.

Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia.

Hypersensitivity: Purpura, photosensitivity, urticaria, necrotizing anglitis (vasculitis and cutareous vasculitis), fever, respiratory distress including pneumonitis and pulmonary edema, anaphylactic reactions.

Metabolic: Hyperglycemia, glycosuria, hyperuricemia.

Musculoskeletal: Muscle spasm.

Nervous System/ Psychiatric: Restlessness.

Renal: Renal failure, renal dysfunction, interstitial nephritis.

Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis.

Special Senses: Transient blurred vision, xanthopsia.

Post-Marketing Experience

Hypersensitivity: Angioedema (involving 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.

Digestive: Hepatitis has been reported rarely in patients treated with losartan. Hyperkalemia has been reported with losartan.

Pregnancy

Losartan Potassium:

Pregnancy Category C and 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.

Hydrochlorothiazide:

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. When patients become pregnant, physicians should have the patient discontinue the use of Alsartan-H as soon as possible.

Lactation

Losartan potassium:

It is not known whether losartan is excreted in human milk. However, significant levels of losartan and the active metabolite were shown to be present in rat milk. 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.

Hydrochlorothiazide:

Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

General

Losartan Potassium-Hydrochlorothiazide:

In patients treated with various doses of losartan and hydrochlorothiazide, there was also a dose-related decrease in the hypokalemic response to hydrochlorothiazide as the dose of losartan was increased, as well as a dose-related decrease in serum uric acid with increasing doses of losartan.

Hydrochlorothiazide:

Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains, or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy.

WARNING:

Fetal/Neonatal Morbidity and Mortality

See the package insert about the details.

Losartan Potassium

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 homeostasis. 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. Neither losartan nor 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.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increase in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensinⅡ, so coadministration of an angiotensinⅡreceptor antagonist tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is unknown.