Torlos-50

Losartan potassium.

Losartan Potassium (Torlos-50) 50 mg is a pink coloured, round, biconvex, film coated tablet with breakline on one side.
Each film-coated tablet contains: Losartan Potassium 50 mg.

Pharmacology: Mechanism of Action: Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)], is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to 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 (about 1000-fold) 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 1 0 to 40 times more potent by weight than Losartan and appears to be a reversible, non-competitive inhibitor of the AT1 receptor.
Neither Losartan nor its active metabolite Inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin); nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Pharmacodynamics: Losartan inhibits the pressor effect of angiotensin II (as well as angiotensin I) infusions. A dose of 100 mg inhibits the pressor effect by about 85% at peak with 25-40% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a doubling to tripling in plasma renin activity and consequent rise in angiotensin II plasma concentration in hypertensive patients. Losartan does not affect the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin. Aldosterone plasma concentrations fall following Losartan administration. In spite of the effect of Losartan on aldosterone secretion, very little effect on serum potassium was observed.
The effect of Losartan is substantially present within one week but in some studies the maximal effect occurred in 3-6 weeks. In long-term follow-up studies (without placebo control) the effect of Losartan appeared to be maintained for up to a year. There is no apparent rebound effect after abrupt withdrawal of Losartan. There was essentially no change in average heart rate in Losartan-treated patients in controlled trials.
Pharmacokinetics: Absorption: Following oral administration, Losartan is well absorbed and undergoes substantial first-pass metabolism. The systemic bioavailability of Losartan is approximately 33%. Mean peak concentrations of Losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of Losartan and Its active metabolite are approximately equal, the AUC (area under the curve) of the metabolite is about 4 times as great as that of Losartan. A meal slows absorption of Losartan and decreases its Cmax but has only minor effects on Losartan AUC or on the AUC of the metabolite (~10% decrease). The pharmacokinetics of Losartan and its active metabolite are linear with oral Losartan doses up to 200 mg and do not change over time.
Distribution: The volume of distribution of Losartan and the active metabolite is about 34 liters and 12 liters, respectively. Both Losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of 1.3% and 0.2%, respectively. Plasma protein binding is constant over the concentration range achieved with recommended doses. Studies in rats indicate that Losartan crosses the blood-brain barrier poorly, if at all.
Metabolism: Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows Losartan treatment. About 14% of an orally-administered dose of Losartan Is converted to the active metabolite. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of Losartan to its metabolites.
Elimination: Total plasma clearance of Losartan and the active metabolite is about 600 mL/min and 50 mL/min, respectively, with renal clearance of about 75 mL/min and 25 mL/min, respectively. The terminal half-life of Losartan Is about 2 hours and of the metabolite is about 6-9 hours. After single doses of Losartan administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of Losartan and its metabolites. Following oral 14C-labeled Losartan, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of 14C-labeled Losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces. Neither Losartan nor its metabolite accumulates in plasma upon repeated once-daily dosing.

Used in the management of hypertension.

The starting and maintenance dose of Losartan is 25 mg or 50 mg once daily for most patients, with or without food. The maximal antihypertensive effect is attained 3-6 weeks after initiation of therapy. Some patients may receive an additional benefit by increasing the dose to 100 mg once dally, in one or two divided doses, or as prescribed by the physician.
Use in elderly: Patients up to 75 years: No initial dose adjustment is necessary for this group of patients, or as prescribed by the physician.
Patients over 75 years: At present there is a limited clinical experience in this group: a lower starting dose of 25 mg once daily is recommended. Or as prescribed by the physician.
Use in renal impairment: No initial dosage adjustment is necessary in patients with mild renal impairment (i.e. creatinine clearance 20-50 mL/min). For patients with moderate to severe renal impairment (i.e. creatinine clearance <20 mL/min) or patients on dialysis, lower starting dose of 25 mg once daily is recommended. Or as prescribed by the physician.
Intravascular volume depletion: In patients who are intravascularly volume depleted (e.g those treated with high-dose diuretics), symptomatic hypotension may occur. Such a condition should be corrected prior to administration of Losartan, or a lower starting dose should be used. Or as prescribed by the physician.

Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia. Bradycardia could occur from parasympathetic (vagal) stimulation.
If symptomatic hypotension occurs, supportive treatment should be instituted. Neither Losartan nor the active metabolite E-3174 can be removed by haemodialysis.

Losartan is contraindicated in patients who are hypersensitive to any component of this product. Losartan is also contraindicated in pregnancy and if pregnancy is detected, Losartan should be discontinued immediately.
Do not co-administer aliskiren with Losartan potassium tablets in patients with diabetes.

Hypotension - Volume-Depleted Patients: In patients who are intravascularly volume-depleted (e.g., those treated with diuretics), symptomatic hypotension may occur after initiation of therapy with Losartan potassium tablets. These conditions should be corrected prior to administration of Losartan potassium tablets, or a lower starting dose should be used.
Electrolyte Imbalance: Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed. In a clinical study conducted in type 2 diabetic patients with proteinuria, the incidence of hyperkalemia was higher in the group treated with Losartan potassium tablets as compared to the placebo group; however, few patients discontinued therapy due to hyperkalemia.
Impaired Hepatic Function: Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of Losartan in cirrhotic patients, a lower dose should be considered for patients with impaired liver function.
Impaired Renal Function: As a consequence of Inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been reported in susceptible individuals treated with Losartan potassium tablets; in some patients, these changes in renal function were reversible upon discontinuation of therapy.
In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar outcomes have been reported with Losartan potassium tablets.
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. Similar effects have been reported with Losartan potassium tablets; in some patients, these effects were reversible upon discontinuation of therapy.
Use in Pregnancy: See Use in Pregnancy & Lactation section for further information.
Use in Children: Antihypertensive effects of Losartan potassium have been established in hypertensive pediatric aged 6 to 15 years. Safety and effectiveness have not been established in pediatric patients under the age of 6 or in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m².

Fetal Toxicity: Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Losartan potassium tablets as soon as possible.
Pregnancy: Pregnancy Category D: Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Losartan as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during-pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the rennin angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Losartan potassium tablets, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained Irreversible injury. Closely observe infants with histories of in utero exposure to Losartan potassium tablets for hypotension, oliguria, and hyperkalemia.
Losartan potassium has been shown to produce adverse effects in rat fetuses and neonates, including decreased body weight, delayed physical and behavioral development, mortality and renal toxicity. With the exception of neonatal weight gain (which was affected at doses as low as 10 mg/kg/day), doses associated with these effects exceeded 25 mg/kg/day (approximately three times the maximum recommended human dose of 100 mg on a mg/m basis). These findings are attributed to drug exposure in late gestation and during lactation. Significant levels of Losartan and its active metabolite were shown to be present in rat fetal plasma during late gestation and in rat milk.
Nursing Mothers: It is not known whether Losartan is excreted in human 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.

Side effects with Losartan 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.
The following adverse events were reported at a rate of 1% or greater in patients treated with Losartan, but were as, or more frequent, in the placebo group: asthenia/fatigue, edema/swelling, abdominal pain, chest pain, nausea, headache, pharyngitis, diarrhea, dyspepsia, myalgia, Insomnia, cough, sinus disorder, muscle cramps, back and leg pain, dizziness, nasal congestion, upper respiratory infection and sinusitis.
In addition to the adverse events previously, potentially important events that occurred in <1% of patients In clinical studies are listed as follows. It cannot be determined whether these events were causally related to Losartan: Body as a Whole: facial edema, fever, orthostatic effects, syncope.
Cardiovascular: angina pectoris, second degree AV block, CVA, hypotension, myocardial infarction, arrhythmias including atrial fibrillation, palpitation, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation.
Digestive: anorexia, constipation, dental pain, dry mouth, flatulence, gastritis, vomiting.
Hematologic: anemia.
Metabolic: gout.
Musculoskeletal: arm pain, hip pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, fibromyalgia, muscle weakness.
Nervous System/Psychiatric: anxiety, anxiety disorder, ataxia, confusion, depression, dream abnormality, hypesthesia, decreased libido, memory impairment, migraine, nervousness, paresthesia, peripheral neuropathy, panic disorder, sleep disorder, somnolence, tremor, vertigo.
Respiratory: dyspnea, bronchitis, pharyngeal discomfort, epistaxis, rhinitis, respiratory congestion.
Skin: alopecia, dermatitis, dry skin, ecchymosis, erythema, flushing, photosensitivity, pruritus, rash, sweating, urticaria.
Special Senses: blurred vision, burning/stinging in the eye, conjunctivitis, taste perversion, tinnitus, decrease in visual acuity.
Urogenital: impotence, nocturia, urinary frequency, urinary tract infection.
Persistent dry cough (with an incidence of a few percent) has been also associated with ACE-inhibitor use and in practice can be a cause of discontinuation of ACE-inhibitor therapy.

No significant drug-drug pharmacokinetic interactions have been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. Rifampin, an inducer of drug metabolism, decreased the concentrations of Losartan and its active metabolite. In humans, two inhibitors of P450 3A4 have been studied. Ketoconazole did not affect the conversion of Losartan to the active metabolite after intravenous administration of Losartan, and erythromycin had no clinically significant effect after oral administration. Fluconazole, an inhibitor of P450 2C9, decreased active metabolite concentration and increased Losartan concentration. The pharmacodynamic consequences of concomitant use of Losartan and inhibitors of P450 2C9 have not been examined. Subjects who do not metabolize Losartan to active metabolite have been shown to have a specific, rare defect in cytochrome P450 2C9. These data suggest that the conversion of Losartan to its active metabolite is mediated primarily by P450 2C9 and not P450 3A4.
As with other drugs that block angiotensin II or 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.
Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists (including Losartan) may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving Losartan and NSAID therapy.
The antihypertensive effect of angiotensin II receptor antagonists, including Losartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors.
Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.
In most patients no benefit has been associated with using two RAS inhibitors concomitantly. In general, avoid combined use of RAS Inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on Losartan potassium and other agents that affect the RAS.
Do not co-administer aliskiren with Losartan potassium in patients with diabetes. Avoid use of aliskiren with Losartan potassium in patients with renal impairment (GFR <60 mL/min).

Store at temperatures not exceeding 30°C.

Angiotensin II Antagonists

C09CA01 - losartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.

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