Losapil

Uses

Losapil is an angiotensin II receptor blocker (ARB) used for:

• Treatment of hypertension, to lower blood pressure in adults and children greater than 6 years old. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.
• Reduction of the risk of stroke in patients with hypertension and left ventricular hypertrophy. There is evidence that this benefit does not apply to Black patients.
• Treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria in patients with type 2 diabetes and a history of hypertension.

Losapil is also used to associated treatment for these conditions: Diabetic Nephropathy, Heart Failure, High Blood Pressure (Hypertension), Marfan Syndrome, Stroke

How Losapil works

Losapil reversibly and competitively prevents angiotensin II binding to the AT₁ receptor in tissues like vascular smooth muscle and the adrenal gland. Losapil and its active metabolite bind the AT₁ receptor with 1000 times more affinity than they bind to the AT₂ receptor. The active metabolite of losartan is 10-40 times more potent by weight than unmetabolized losartan as an inhibitor of AT₁ and is a non-competitive inhibitor. Losapil's prevention of angiotensin II binding causes vascular smooth muscle relaxation, lowering blood pressure.

Angiotensin II would otherwise bind to the AT₁ receptor and induce vasoconstriction, raising blood pressure.

Dosage

Losapil dosage

Hypertension:

• Usual adult dose: 50 mg once daily.
• Usual pediatric starting dose: 0.7 mg per kg once daily (up to 50 mg).

Hypertensive Patients with Left Ventricular Hypertrophy:

• Usual starting dose: 50 mg once daily.
• Add hydrochlorothiazide 12.5 mg and/or increase Losapil to 100 mg followed by an increase to hydrochlorothiazide 25 mg if further blood pressure response is needed.

Nephropathy in Type 2 Diabetic Patients:

• Usual dose: 50 mg once daily.
• Increase dose to 100 mg once daily if further blood pressure response is needed.

Use in elderly:

• Patients up to 75 years: No initial dosage adjustment is necessary for this group of patients.
• Patients over 75 years: A lower starting dose of 25 mg once daily is recommended.

Side Effects

In controlled clinical trials in patients with essential hypertension, dizziness was the only side effect reported that occurred with an incidence greater than placebo in 1% or more of patients treated with Losapil. Rarely, rash was reported although the incidence in controlled clinical trials was less than placebo. Angioedema, involving swelling of the face, lips and/or tongue has been reported rarely in patients treated with Losapil. Serious hypotension (particularly on initiating treatment in salt-depleted patients) or renal failure (mainly in patients with renal artery stenosis) may be encountered during Losapil treatment.

Toxicity

The oral TDLO in mice is 1000mg/kg and in rats is 2000mg/kg. In humans the TDLO for men is 10mg/kg/2W and for women is 1mg/kg/1D.

Symptoms of overdose are likely to include hypotension, tachycardia, or bradycardia due to vagal stimulation. Supportive treatment should be instituted for symptomatic hypotension. Hemodialysis will not remove losartan or its active metabolite due to their high rates of protein binding.

Precaution

A lower dose should be considered for patients with a history of hepatic and renal impairment. Losapil should not be used with potassium-sparing diuretic

Interaction

No drug interaction of clinical significance has been identified. Compounds which have been studied in clinical pharmacokinetic trials include hydrochlorothiazide, digoxin, warfarin, cimetidine, ketoconazole and phenobarbital.

Food Interaction

• Take at the same time every day.
• Take with or without food. Food delays absorption, but does not affect the extent of absorption.

[Moderate] GENERALLY AVOID: Moderate-to-high dietary intake of potassium, especially salt substitutes, may increase the risk of hyperkalemia in some patients who are using angiotensin II receptor blockers (ARBs).

ARBs can promote hyperkalemia through inhibition of angiotensin II-induced aldosterone secretion.

Patients with diabetes, heart failure, dehydration, or renal insufficiency have a greater risk of developing hyperkalemia.

MANAGEMENT: Patients should receive dietary counseling and be advised to not use potassium-containing salt substitutes or over-the-counter potassium supplements without consulting their physician.

If salt substitutes are used concurrently, regular monitoring of serum potassium levels is recommended.

Patients should also be advised to seek medical attention if they experience symptoms of hyperkalemia such as weakness, irregular heartbeat, confusion, tingling of the extremities, or feelings of heaviness in the legs.

MONITOR: Grapefruit juice may modestly decrease and delay the conversion of losartan to its active metabolite, E3174.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

The clinical significance is unknown.

Moreover, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability.

MANAGEMENT: Patients who regularly consume grapefruits and grapefruit juice should be monitored for altered efficacy of losartan.

Grapefruits and grapefruit juice should be avoided if an interaction is suspected.

Orange juice is not expected to interact.

Losapil Drug Interaction

Moderate: aspirin, aspirin, pregabalin, alprazolamUnknown: ubiquinone, rosuvastatin, duloxetine, apixaban, omega-3 polyunsaturated fatty acids, furosemide, atorvastatin, metoprolol, metoprolol, clopidogrel, levothyroxine, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol, cetirizine

Losapil Disease Interaction

Major: diabetes, angioedema, hypotensionModerate: CHF, hyperkalemia, renal artery stenosis, renal impairment, renal/liver disease

Volume of Distribution

The volume of distribution of losartan is 34.4±17.9L and 10.3±1.1L for the active metabolite (E-3174).

Elimination Route

Losapil is approximately 33% orally bioavailable. Losapil has a T_max of 1 hour and the active metabolite has a T_max of 3-4 hours. Taking losartan with food decreases the C_max but does only results in a 10% decrease in the AUC of losartan and its active metabolite. A 50-80mg oral dose of losartan leads to a C_max of 200-250ng/mL.

Half Life

The terminal elimination half life of losartan is 1.5-2.5 hours while the active metabolite has a half life of 6-9 hours.

Clearance

Losapil has a total plasma clearance of 600mL/min and a renal clearance of 75mL/min. E-3174, the active metabolite, has a total plasma clearance of 50mL/min and a renal clearance of 25mL/min.

Elimination Route

A single oral dose of losartan leads to 4% recovery in the urine as unchanged losartan, 6% in the urine as the active metabolite. Oral radiolabelled losartan is 35% recovered in urine and 60% in feces. Intravenous radiolabelled losartan is 45% recovered in urine and 50% in feces.

Pregnancy & Breastfeeding use

Although there is no experience with the use of Losapil in pregnant women, animal studies with Losapil potassium have demonstrated fetal and neonatal injury and death, the mechanism of which is believed to be pharmacologically mediated through effects on the renin angiotensinaldosterone system. Losapil should not be used in pregnancy and if pregnancy is detected Losapil should be discontinued as soon as possible.

It is not known whether Losapil is excreted in human breast milk. However, significant level of Losapil found in rat milk which suggests that the drug should not be used in lactating mother.

Contraindication

It is also contraindicated to patients who are hypersensitive to any component of this product. In patients who are intravenously volume depleted (e.g. those treated with high dose diuretics), symptomatic hypotension may occur. These conditions Losapil potassium should be corrected prior to administer Losapil or a lower starting dose (usually 25 mg) should be used.

Special Warning

No initial dosage adjustment is necessary in patients with mild renal impairment (CrCl 20-50 ml/min). For patients with moderate to severe renal impairment (CrCl <20 ml/min) or patients on dialysis, a lower starting dose of 25 mg is recommended.

Acute Overdose

Limited data are available regarding overdose in humans. The most likely manifestation of overdose would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Supportive treatment should include repletion of the intravascular volume. Neither Losapil nor the active metabolite can be removed by hemodialysis.

Storage Condition

Store between 15-30°C

Innovators Monograph

You find simplified version here Losapil