Losakind 50

Losakind 50 contains the salt Losartan 50 mg and is approved for use in the following clinical indications:

• Hypertension:

First-line therapy for stage 1 hypertension along with thiazide diuretics, calcium channel blockers, and ACEI. In patients with atherosclerotic cardiovascular disease (ASCVD) risk greater than or equal to 10%, combination therapy is used to attain blood pressure goals. Angiotensin II receptor blockers (ARBs) are useful as monotherapy in the absence of comorbidities like diabetes, ischemic heart disease, cerebrovascular disease, heart failure, and chronic kidney disease.

• Adult Hypertension:

The usual starting dose of Losakind 50 is 50 mg once daily. The dosage can be increased to a maximum dose of 100 mg once daily as needed to control blood pressure. A starting dose of 50 mg is recommended for patients with possible intravascular depletion (e.g., on diuretic therapy).

• Pediatric Hypertension:

The usual recommended starting dose is 0.7 mg per kg once daily (up to 50 mg total) administered as a tablet or a suspension. Dosage should be adjusted according to blood pressure response. Doses above 1.4 mg per kg (or in excess of 100 mg) daily have not been studied in pediatric patients.

Losakind 50 is not recommended in pediatric patients less than 6 years of age or in pediatric patients with an estimated glomerular filtration rate of less than 30 mL/min/1.73 m².

• Diabetic nephropathy:

Losakind 50 is indicated for the treatment of diabetic nephropathy with elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio ≥300 mg/g) in patients with type 2 diabetes and a history of hypertension. In this population, Losakind 50 reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation)

• Left Ventricular Hypertrophy:

Losakind 50 is indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to Black patients.

Although not approved, there have been certain off-label indications. These include:

• Treatment of heart failure:

A study involving elderly heart-failure patients, Evaluation of Losakind 50 in the Elderly Study (ELITE), concluded that compared to captopril, Losakind 50 correlated with lower mortality and was tolerated better than captopril. In the ELITE II study, the conclusion was that Losakind 50 was as competent as captopril in improving heart failure-related outcomes, NYHA class, and quality of life.

• Marfan’s syndrome with aortic aneurysm:

Marfan's syndrome is an inherited condition that affects connective tissue, like eyes, blood vessels, etc. Sometimes people with Marfan's syndrome develop a balloon-like outpouching of the aorta (the largest artery), which is potentially life-threatening. Treating with Losakind 50 can help to reduce the likelihood of aneurysm rupture.

It is also used to treat the acute coronary syndrome, stable coronary artery disease, and intolerant of ACEI.

Losakind 50 contains the salt Losartan 50 mg and is available in the form of tablets.

Hypertension

• Adult Hypertension:

The usual starting dose of Losakind 50 is 25-50 mg/day orally in 1 or 2 daily doses. The dosage can be increased to a maximum dose of 100 mg once daily as needed to control blood pressure. A starting dose of 50 mg is recommended for patients with possible intravascular depletion (e.g., on diuretic therapy).

• Pediatric Hypertension:

The usual recommended starting dose is 0.7 mg per kg once daily (up to 50 mg total) administered as a tablet or a suspension. Dosage should be adjusted according to blood pressure response. Doses above 1.4 mg per kg (or in excess of 100 mg) daily have not been studied in pediatric patients.

Losartan is not recommended in pediatric patients less than 6 years of age or in pediatric patients with an estimated glomerular filtration rate of less than 30 mL/min/1.73 m².

• Hypertensive Patients with Left Ventricular Hypertrophy:

The usual starting dose is 25-50 mg/day orally in 1 or 2 daily doses of Losakind 50 once daily. Hydrochlorothiazide 12.5 mg daily should be added and/or the dose of Losartan should be increased to 100 mg once daily followed by an increase in hydrochlorothiazide to 50 mg once daily based on blood pressure response.

• Nephropathy In Type 2 Diabetic Patients:

The usual starting dose is 50 mg once daily. The dose should be increased to 100 mg once daily based on blood pressure response.

Losartan can be administered orally before/ after meals. The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

Losakind 50 contains the salt Losartan 50 mg and is approved for the treatment of Hypertension, Diabetic nephropathy, and left ventricular hypertrophy.

• Hypertension: It has been observed that the low-salt Dietary Approach to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

• Diabetic Nephropathy: Limit carbohydrates with added sugars or those with refined grains, such as white bread and white rice. Instead, eat carbohydrates from fruit, vegetables, whole grains, beans, and low-fat or nonfat milk.

• Left Ventricular hypertrophy: No more than 25 to 35 percent of your daily calories should come from total fat (including saturated fat). Less than 7 % of your daily calories should come from saturated fat. Avoid trans fats and consume less than 200 milligrams a day of dietary cholesterol.

The dietary restriction should be individualized as per patient requirements.

• Fetal Toxicity

The 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. The resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformities. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Losakind 50 as soon as possible.

• Hypotension in Volume- or Salt-Depleted Patients

In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Losakind 50. Correct volume or salt depletion prior to administration of Losakind 50

• Renal Function Deterioration

Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on Losakind 50. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Losakind 50

• Hyperkalemia

Monitor serum potassium periodically and treat it appropriately. Dosage reduction or discontinuation of Losakind 50 may be required.

Potassium-Rich Foods: Bananas, sweet potatoes, nuts, and other foods rich in potassium

• Take it at the same time every day.

• Take with or without food. Food delays absorption but does not affect the extent of absorption.

There is no sufficient scientific evidence traceable regarding the use and safety of Losakind 50 in Food warnings.

The adverse reactions related to Losakind 50 contains the salt Losartan 50 mg and can be categorized as

Common Adverse effects:

• Fatigue
• Hypoglycemia
• Chest pain
• Cough

Less Common Adverse Effects:

• Diarrhea
• URI
• Hypotension
• Dizziness
• Nausea

Rare adverse effects:

• Heart failure, tachyarrhythmia, bronchospasm, depression, decreased exercise tolerance, Raynaud's phenomenon, etc.

The clinically relevant drug interactions of Losakind 50 contain the salt Losartan 50 mg and are briefly summarized here:

• Agents Increasing Serum Potassium:

Coadministration of Losakind 50 with the other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients.

• 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, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists (including Losakind 50) may result in the deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in the patient receiving Losakind 50 and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including Losakind 50, 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.

The use of Losakind 50 contains the salt Losartan 50 mg and should be prudent in the following group of special populations:

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 deformities. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Losakind 50 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 reninangiotensin 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 Losakind 50, 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 Losakind 50 for hypotension, oliguria, and hyperkalemia.

Losakind 50 has been shown to produce adverse effects in rat fetuses and neonates, including decreased body weight, delayed physical and behavioural 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 50 mg/kg/day (approximately three times the maximum recommended human dose of 100 mg on a mg/m² basis). These findings are attributed to drug exposure in late gestation and during lactation. Significant levels of Losakind 50 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 Losakind 50 is excreted in human milk, but significant levels of Losakind 50 and its 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 nursing or discontinue the drug, taking into account the importance of the drug to the mother.

• Pediatric Use:

Neonates With a History Of In Utero Exposure To Losakind 50

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing the hypotension and substituting for disordered renal function.

Antihypertensive effects of Losakind 50 have been established in hypertensive pediatric patients aged 6 to 16 years. Safety and effectiveness have not been established in pediatric patients under the age of 6 or in pediatric patients with glomerular filtration rates <30 mL/min/1.73 m².

• Geriatric Use:

Of the total number of patients receiving L in controlled clinical studies for hypertension, 391 patients (19%) were 65 years and over, while 37 patients (2%) were 75 years and over. In a controlled clinical study for renal protection in type 2 diabetic patients with proteinuria, 248 patients (33%) were 65 years and over. In a controlled clinical study for the reduction in the combined risk of cardiovascular death, stroke and myocardial infarction in hypertensive patients with left ventricular hypertrophy, 2857 patients (62%) were 65 years and over, while 808 patients (18%) were 75 years and over. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

• Race:

In the LIFE study, Black patients with hypertension and left ventricular hypertrophy treated with atenolol were at lower risk of experiencing the primary composite endpoint compared with Black patients treated with Losakind 50 (both cotreated with hydrochlorothiazide in the majority of patients). The primary endpoint was the first occurrence of stroke, myocardial infarction, or cardiovascular death, analyzed using an intention-to-treat (ITT) approach. In the subgroup of Black patients (n=533, 6% of the LIFE study patients), there were 29 primary endpoints among 263 patients on atenolol (11%, 26 per 1000 patient-years) and 46 primary endpoints among 270 patients (17%, 42 per 1000 patient-years) on Losakind 50. This finding could not be explained on the basis of differences in the populations other than race or on any imbalances between treatment groups. In addition, blood pressure reductions in both treatment groups were consistent between Black and non-Black patients. Given the difficulty in interpreting subset differences in large trials, it cannot be known whether the observed difference is the result of chance. However, the LIFE study provides no evidence that the benefits of Losakind 50 in reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to Black patients.

• Renal Impairment:

Patients with renal insufficiency have elevated plasma concentrations of Losakind 50 and its active metabolite compared to subjects with normal renal function. No dose adjustment is necessary for patients with renal impairment unless a patient with renal impairment is also volume depleted.

Pharmacodynamics:

Losakind 50 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 a consequent rise in angiotensin II plasma concentration in hypertensive patients. Losakind 50 does not affect the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin. Aldosterone plasma concentrations fall following Losakind 50 administration. In spite of the effect of Losakind 50 on aldosterone secretion, very little effect on serum potassium was observed.

The effect of Losakind 50 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 Losakind 50 appeared to be maintained for up to a year. There is no apparent rebound effect after the abrupt withdrawal of Losakind 50. There was essentially no change in average heart rate in Losakind 50-treated patients in controlled trials.

Pharmacokinetics:

• Absorption:

Following oral administration, Losakind 50 is well absorbed and undergoes substantial first-pass metabolism. The systemic bioavailability of Losakind 50 is approximately 33%. Mean peak concentrations of Losakind 50 and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of Losakind 50 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 Losakind 50. A meal slows the absorption of Losakind 50 and decreases its Cmax but has only minor effects on Losakind 50 AUC or on the AUC of the metabolite (~10% decrease). The pharmacokinetics of Losakind 50 and its active metabolite are linear with oral Losakind 50 doses up to 200 mg and do not change over time.

• Distribution:

The volume of distribution of Losakind 50 and the active metabolite is about 34 liters and 12 liters, respectively. Both Losakind 50 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 Losakind 50 crosses the blood-brain barrier poorly, if at all.

• Metabolism:

Losakind 50 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 Losakind 50 treatment. About 14% of an orally administered dose of Losakind 50 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 Losakind 50 to its metabolites.

• Elimination:

Total plasma clearance of Losakind 50 and the active metabolite is about 600 mL/min and 50 mL/min, respectively, with a renal clearance of about 75 mL/min and 25 mL/min, respectively. The terminal half-life of Losakind 50 is about 2 hours and the metabolite is about 6-9 hours. After single doses of Losakind 50 are administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as an active metabolite. Biliary excretion contributes to the elimination of Losakind 50 and its metabolites. Following oral ¹⁴C-labeled Losakind 50, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of ¹⁴C-labeled Losakind 50, about 45% of radioactivity is recovered in the urine and 50% in the feces. Neither Losakind 50 nor its metabolite accumulates in plasma upon repeated once-daily dosing.