Getzar Plus

Losartan potassium, hydrochlorothiazide.

Each 50 mg/12.5 mg film-coated tablet contains losartan potassium 50 mg and hydrochlorothiazide 12.5 mg while 100 mg/25 mg film-coated tablets contains losartan potassium 100 mg and hydrocholorothiazide 25 mg.
Losartan potassium is 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidozole-5-methanol potassium and hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide.
Losartan potassium has a molecular weight of 461 and an empirical formula of C₂₂H₂₂ClKN₆OK while hydrochlorothiazide has a molecular weight of 297.7 and an empirical formula of C₇H₈ClN₃O₄S₂.

Pharmacology: Pharmacodynamics: Losartan Potassium: It is an angiotensin II receptor antagonist with antihypertensive activity due mainly to selective blockade of AT, receptors and the consequent reduced pressure effect of angiotensin II.
Pharmacokinetics: Losartan Potassium: Losartan potassium is readily absorbed from the gastrointestinal tract (GIT) following oral administration, with an oral bioavailability about 33%. It undergoes first-pass metabolism to form an active carboxylic acid metabolite E-3174 (EXP-3174), which has greater pharmacological activity than losartan and some inactive metabolites. Metabolism is primarily by cytochrome P450 isoenzymes CYP2C9 and CYP3A4. Peak plasma concentrations of losartan and E-317 occur at 1 hr and 3-4 hrs, respectively, after an oral dose. Both losartan and E-3174 are >98% bound to plasma proteins. Losartan is excreted in the urine and in the feces via bile, as unchanged drug and metabolites. Following oral dosing, about 35% of the dose is excreted in the urine and about 60% in the feces. The terminal elimination half-lives (t_½) of losartan and E-3174 are about 1.5-2.5 hrs and 3-9 hrs, respectively.
Hydrochlorothiazide: It is a diuretic antihypertensive. It is fairly rapidly absorbed from the GIT. It is reported to have a bioavailability of about 65-70%. It has been estimated to have a plasma t_½ of between about 5 and 15 hrs, and appears to be preferentially bound to red blood cells. It is excreted mainly unchanged in the urine. Hydrochlorothiazide crosses the placenta barrier and is distributed into breast milk.

Losartan Potassium: Management of hypertension and may have a role in patients who develop cough with angiotensin converting enzyme (ACE) inhibitors and to reduce the risk of stroke in patients with left ventricular hypertrophy and in the treatment of diabetic nephropathy.
Hydrochlorothiazide: Treatment of edema associated with heart failure and with renal hepatic disorders. It is also used in hypertension, either alone or together with other antihypertensives eg, ACE inhibitors and β-blockers. Treatment of edema accompanying syndrome, prevention of water retention associated with corticosteroids and estrogens, treatment of renal calculus formation in patients with hypercalciuria.

Usual Dose: Losartan potassium 50 mg/hydrochlorothiazide 12.5 mg once daily. The dose may be increase, if necessary, to 100 mg/25 mg daily as a single dose or in 2 divided doses.
Elderly >75 years, Patients with Moderate to Severe Renal Impairment [Creatinine Clearance (CrCl) <20 mL/min] or Intravascular Fluid Depletion: Initial Dose: 25 mg once daily.

Losartan Potassium: Significant lethality was observed in mice and rats after oral administration of 1000 mg/kg and 2000 mg/kg, respectively, about 44 and 170 times the maximum recommended human dose on a mg/m² basis. Limited data are available in regard to overdosage in human. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Neither losartan potassium nor its active metabolite can be removed by hemodialysis.
Hydrochlorothiazide: The oral lethal dose 50 (LD₅₀) of hydrochlorothiazide is >10 g/kg in both mice and rats. The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia), dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.

Hydrochlorothiazide is not effective in patients with CrCl <30 mL/min and thus, should not be given to patients with severe renal impairment or anuria. Getzar Plus is also contraindicated in patients with Addison's disease. Thiazide can reduce urinary excretion of calcium, sometimes resulting in mild hypercalcemia and is therefore contraindicated to patients with preexisting hypercalcemia.
Use in pregnancy & lactation: It is contraindicated in pregnancy since it has been associated with fetal toxicity in animal studies and other drugs eg, ACE inhibitors that act on the renin-angiotensin system have been associated with fetal toxicity in humans.

Getzar Plus should be used with caution in patients with renal artery stenosis or renal impairment since it can further reduce renal function. Patients should be carefully observed for signs of fluid and electrolyte imbalance, especially in vomiting or during parenteral fluid therapy.

It is contraindicated in pregnancy since it has been associated with fetal toxicity in animal studies and other drugs eg, ACE inhibitors that act on the renin-angiotensin system have been associated with fetal toxicity in humans.

Losartan Potassium: Adverse effects include dizziness and dose-related orthostatic hypotension. Hypotension may occur particularly in patients with volume depletion (eg, those who have received high-dose diuretics). Losartan potassium may cause hyperkalemia in patients with renal disease. Other adverse effects that have been reported with angiotensin II receptor antagonist include respiratory tract disorder, back pain, gastrointestinal disturbances, fatigue and neutropenia.
Hydrochlorothiazide: Thiazide diuretics may cause a number of metabolic disturbances especially at high doses. They may provoke hyperglycemia and glycosuria in diabetic and other susceptible patients. They may cause hyperuricemia and precipitate attacks of gout in some patients. Administration of hydrochlorothiazide may be associated with electrolyte imbalances including hypochloremic alkalosis, hyponatremia and hypokalemia. Hypokalemia intensifies the effect of digitalis cardiac muscle and administration of digitalis or its glycosides may be temporarily suspended. Patients with cirrhosis of the liver are particularly at risk of hypokalemia.

Losartan Potassium: In clinical trials, no drug interactions of clinical significance have been identified with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital (phenobarbitone), (see text as follows), ketoconazole and erythromycin. Rifampicin and fluconazole have been reported to reduce levels of active metabolite. The clinical consequences have not been evaluated.
As with other drugs that block angiotensin II or its effects, concomitant use of other drugs which retain potassium or may increase potassium levels (eg, potassium-sparing diuretics, potassium supplements or salt substitutes containing potassium) may lead to increases in serum potassium.
Hydrochlorothiazide: When given concurrently, the following drugs may interact with thiazide diuretics: Alcohol, barbiturates or narcotic potentiation, or orthostatic hypotension may occur.
Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustment of the antidiabetic drug may be required.
Other Antihypertensive Drugs: There may be an additive effect.
Cholestyramine and Colestipol Resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins.
Corticosteroids, Adrenocorticotrophic Hormone: There may be intensified electrolyte depletion, particularly hypokalemia.
Pressor Amines (eg, Adrenaline): Possible decreased response to pressor amines, but no sufficient to preclude their use.

Store at temperatures not exceeding 30°C.

Angiotensin II Antagonists / Diuretics

C09DA01 - losartan and diuretics ; Belongs to the class of angiotensin II receptor blockers (ARBs) in combination with diuretics. Used in the treatment of cardiovascular disease.

Rx