DrugindexOnline^{2nd edition}

Pronouncation: (low-SAHR-tan poe-TASS-ee-uhm)
Class: Angiotensin II antagonist

Trade Names:
Cozaar
- Tablets 25 mg
- Tablets 50 mg
- Tablets 100 mg

Mechanism of Action

Pharmacology

Blocks vasoconstriction and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the angiotensin II receptor (AT ₁ receptor) in vascular smooth muscle and the adrenal gland.

Pharmacokinetics

Absorption

Well absorbed. Food decreases absorption but has only minor effects on losartan AUC or AUC of active metabolite. Systemic bioavailability is about 33%. T _max is 1 h (losartan) and 3 to 4 h (metabolite). While C _max of drug and active metabolite are equal, metabolite AUC is 4 times greater than that of losartan.

Distribution

Linear pharmacokinetics. Vd is 34 L (losartan) and 12 L (metabolite). Losartan and active metabolite are highly bound to plasma proteins, primarily albumin. Neither losartan or metabolite accumulates in plasma upon repeated daily dosing.

Metabolism

Undergoes substantial first-pass metabolism by CYP-450 2C9 and 3A4 enzymes. Fourteen percent of an oral dose is converted to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonist activity.

Elimination

The t _½ is 2 h (losartan) and 6 to 9 h (metabolite). Renal Cl is 75 mL/min (losartan) and 25 mL/min (metabolite). Total plasma Cl is 600 mL/min (losartan) and 50 mL/min (metabolite). Biliary excretion contributes to the elimination of losartan and metabolite. About 4% is excreted unchanged in the urine and 6% excreted as active metabolite in urine.

Special Populations

Renal Function Impairment

Plasma concentrations and AUC of losartan and its active metabolite are increased 50% to 90% and renal Cl reduced 55% to 85% in patients with mild (CrCl 50 to 74 mL/min) and moderate (CrCl 30 to 49 mL/min) renal function impairment. Make dose adjustments as needed unless the patient is volume depleted.

Hepatic Function Impairment

Plasma concentrations of losartan are increased 5 times and active metabolite increased 1.7 times in patients with mild to moderate alcoholic cirrhosis. Total plasma Cl of losartan is reduced about 50% and oral bioavailability is increased 2 times. A lower starting dose is recommended.

Gender

Plasma losartan concentrations are twice as high in hypertensive women as hypertensive men, but plasma concentrations of active metabolite are similar. No dosage adjustment is necessary.

Indications and Usage

Treatment of hypertension; nephropathy in type 2 diabetic patients; reduce risk of stroke in patients with hypertension and left ventricular hypertrophy.

Contraindications

Standard considerations.

Dosage and Administration

Hypertension
Adults Initial dose

PO 50 mg/day; 25 mg/day if volume depleted or history of hepatic impairment.

Maintenance dose

PO 25 to 100 mg/day.

Children 6 yr of age and older Initial dose

PO 0.7 mg/kg (max, 50 mg) once daily.

Maintenance dose

PO 0.7 to 1.4 mg/kg/day (max, 100 mg).

Nephropathy in Type 2 Diabetes
Adults Initial dose

PO 50 mg/day; the dose may be increased to 100 mg/day based on BP response.

Hypertension in Patients with Left Ventricular Hypertrophy
Adults

PO 50 mg/day; add hydrochlorothiazide 12.5 mg/day and/or increase the dose of losartan to 100 mg/day followed by an increase in hydrochlorothiazide to 25 mg/day based on BP response.

General Advice

• May use alone or in combination with other antihypertensive agents.
• Administer without regard to meals. Administer with food if GI upset occurs.
• Preparation of 2.5 mg/mL suspension for pediatric use: Add 10 mL purified water to an 8 oz (240 mL) amber polyethylene terephthalate (PET) bottle containing ten 50 mg losartan tablets; immediately shake for 2 min; let stand for 1 h then shake for 1 min to disperse tablet contents; add 190 mL of 50/50 mixture of Ora-Plus and Ora-Sweet SF and shake for 1 min to disperse ingredients.
• Shake suspension well before measuring and administering prescribed dose. Use dosing syringe, dosing spoon, or dosing cup to measure and administer dose. Return suspension to refrigerator immediately after measuring dose.

Storage/Stability

Store tablets at controlled room temperature (59° to 86°F). Protect from light. Store suspension in refrigerator (36° to 46°F) for up to 4 wk. Discard any unused suspension after 4 wk.

Drug Interactions

Fluconazole

Losartan plasma levels may be elevated, increasing the antihypertensive and adverse effects.

Grapefruit juice

Rate and magnitude of losartan metabolism to its active metabolite may be decreased, possibly reducing the efficacy; however, based on available data, a clinically important interaction is unlikely.

Indomethacin

The antihypertensive effect of losartan may be blunted.

Lithium

Plasma concentrations may be increased by losartan, resulting in an increase in the pharmacologic and adverse effects of lithium.

Potassium supplement

Concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.

Rifamycins (eg, rifampin)

Losartan plasma levels may be reduced, decreasing the antihypertensive effects.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypotension (7%); orthostatic hypotension (4%).

CNS

Asthenia/fatigue (14%); hypesthesia (5%); dizziness (3%).

Dermatologic

Cellulitis (7%).

EENT

Cataract (7%); nasal congestion (2%).

GI

Diarrhea (15%); gastritis (5%); dyspepsia (4%).

Genitourinary

UTI (16%).

Hematologic-Lymphatic

Anemia (14%).

Hepatic

Hepatitis (postmarketing).

Hypersensitivity

Anaphylactic reactions, angioedema (including swelling of the larynx and glottis, swelling of the face, lips, pharynx, and tongue), vasculitis (including Henoch-Schönlein purpura) (postmarketing).

Lab Tests

Minor increases in BUN or serum creatinine, small decreases in Hgb and Hct, occasional elevations in liver enzymes and serum bilirubin (postmarketing).

Metabolic-Nutritional

Hypoglycemia (14%); hyperkalemia (7%); weight gain (4%); hyponatremia (postmarketing).

Musculoskeletal

Back pain (12%); muscular weakness (7%); knee pain, leg pain (5%); muscle cramp (1%); rhabdomyolysis (postmarketing).

Respiratory

Cough (11%); bronchitis (10%); upper respiratory tract infection (8%); sinusitis (6%); dry cough (postmarketing).

Miscellaneous

Chest pain (12%); diabetic vascular disease, influenza‐like symptoms (10%); infection (5%); diabetic neuropathy, fever, trauma (4%).

Precautions

Warnings Pregnancy When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, discontinue therapy as soon as possible.

Pregnancy

Category D (second and third trimester); Category C (first trimester).

Lactation

Undetermined.

Children

Safety and efficacy not established in hypertensive patients younger than 6 yr of age or in children with GFR less than 30 mL/min/1.73 m ² .

Hypersensitivity

Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and tongue have been reported rarely.

Renal Function

Use caution in treating patients whose renal function may depend on the renin-angiotension-aldosterone system (eg, patients with severe CHF).

Hepatic Function

A lower starting dose is recommended for patients with hepatic impairment.

Black patients

May not be as effective in black hypertensive patients, especially those with left ventricular hypertrophy.

Hypotension/Volume-depleted patients

Symptomatic hypotension may occur after initiation of losartan in patients who are volume depleted (eg, those treated with diuretics). Correct these conditions prior to administration of losartan or use a lower starting dose.

Overdosage

Symptoms

Bradycardia, hypotension, tachycardia.

Patient Information

• Advise patient to take daily or bid as prescribed, without regard to meals, but to take with food if stomach upset occurs.
• Advise patient to try to take each dose at about the same time each day.
• Inform patient that drug controls, but does not cure, hypertension and to continue taking drug as prescribed even when BP is not elevated.
• Caution patient not to change the dose or stop taking unless advised by health care provider.
• Instruct patient to continue taking other BP medications as prescribed by health care provider.
• Instruct patient in BP and pulse measurement skills.
• Advise patient to monitor and record BP and pulse at home and to inform health care provider if abnormal measurements are noted. Advise patient to take record of BP and pulse to each follow‐up visit.
• Instruct patient to lie or sit down if they experience dizziness or light‐headedness when standing.
• Emphasize importance of other modalities of BP control: moderate intake of alcohol and salt, regular exercise, smoking cessation, and weight control.
• Caution patient that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to excessive fall in BP resulting in light‐headedness or fainting.
• Advise patient that medication may cause dizziness or light‐headedness and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
• Advise women to notify health care provider if pregnant, planning to become pregnant, or breastfeeding.
• Instruct patient to immediately discontinue drug and notify health care provider if any of the following occur: swelling of the face, lips, eyelids, or tongue, difficulty breathing, or difficulty swallowing.
• Instruct patient to inform health care provider if persistent cough develops while taking this medication.
• Caution patient not to take any prescription or OTC medications, potassium‐containing salt substitutes, potassium supplements, dietary supplements, or herbal preparations unless advised by health care provider.