Losartan Potassium

Name: Losartan Potassium

Indications

Hypertension

COZAAR® is indicated for the treatment of hypertension in adults and pediatric patients 6 years of age and older, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and nonfatal cardiovascular (CV) events, primarily strokes and myocardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including losartan.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

COZAAR may be administered with other antihypertensive agents.

Hypertensive Patients With Left Ventricular Hypertrophy

COZAAR 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 [see Use In Specific Populations and CLINICAL PHARMACOLOGY].

Nephropathy In Type 2 Diabetic Patients

COZAAR is indicated for the treatment of diabetic nephropathy with an 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, COZAAR 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) [see Clinical Studies].

How supplied

Dosage Forms And Strengths

  • COZAAR, 25 mg, are white, oval, film-coated tablets with code 951 on one side.
  • COZAAR, 50 mg, are white, oval, film-coated tablets with code 952 on one side and scored on the other.
  • COZAAR, 100 mg, are white, teardrop-shaped, film-coated tablets with code 960 on one side.

Storage And Handling

COZAAR is a white film-coated tablet supplied as follows:

Losartan Shape Engraving (reverse) NDC 0006-xxxx-xx
Bottle/30 Bottle/90
25 mg oval 951 n/a 0951-54
50 mg oval 952 (scored) 0952-31 0952-54
100 mg teardrop 960 0960-31 0960-54

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from light.

Manufactured for: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA. Revised: Dec 2015

Side effects

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Hypertension

COZAAR has been evaluated for safety in more than 3300 adult patients treated for essential hypertension and 4058 patients/subjects overall. Over 1200 patients were treated for over 6 months and more than 800 for over one year.

Treatment with COZAAR was well-tolerated with an overall incidence of adverse events similar to that of placebo. In controlled clinical trials, discontinuation of therapy for adverse events occurred in 2.3% of patients treated with COZAAR and 3.7% of patients given placebo. In 4 clinical trials involving over 1000 patients on various doses (10-150 mg) of losartan potassium and over 300 patients given placebo, the adverse events that occurred in ≥2% of patients treated with COZAAR and more commonly than placebo were: dizziness (3% vs. 2%), upper respiratory infection (8% vs. 7%), nasal congestion (2% vs. 1%), and back pain (2% vs. 1%).

The following less common adverse reactions have been reported:

Blood and lymphatic system disorders: Anemia.

Psychiatric disorders: Depression.

Nervous system disorders: Somnolence, headache, sleep disorders, paresthesia, migraine.

Ear and labyrinth disorders: Vertigo, tinnitus.

Cardiac disorders: Palpitations, syncope, atrial fibrillation, CVA.

Respiratory, thoracic and mediastinal disorders: Dyspnea.

Gastrointestinal disorders: Abdominal pain, constipation, nausea, vomiting.

Skin and subcutaneous tissue disorders: Urticaria, pruritus, rash, photosensitivity.

Musculoskeletal and connective tissue disorders: Myalgia, arthralgia.

Reproductive system and breast disorders: Impotence.

General disorders and administration site conditions: Edema.

Cough

Persistent dry cough (with an incidence of a few percent) has been associated with ACE-inhibitor use and in practice can be a cause of discontinuation of ACE-inhibitor therapy. Two prospective, parallel-group, double-blind, randomized, controlled trials were conducted to assess the effects of losartan on the incidence of cough in hypertensive patients who had experienced cough while receiving ACE-inhibitor therapy. Patients who had typical ACE-inhibitor cough when challenged with lisinopril, whose cough disappeared on placebo, were randomized to losartan 50 mg, lisinopril 20 mg, or either placebo (one study, n=97) or 25 mg hydrochlorothiazide (n=135). The double-blind treatment period lasted up to 8 weeks. The incidence of cough is shown in Table 1 below.

Table 1

Study 1* HCTZ Losartan Lisinopril
Cough 25% 17% 69%
Study 2† Placebo Losartan Lisinopril
Cough 35% 29% 62%
* Demographics = (89% Caucasian, 64% female)
† Demographics = (90% Caucasian, 51% female)

These studies demonstrate that the incidence of cough associated with losartan therapy, in a population that all had cough associated with ACE-inhibitor therapy, is similar to that associated with hydrochlorothiazide or placebo therapy.

Cases of cough, including positive re-challenges, have been reported with the use of losartan in postmarketing experience.

Hypertensive Patients With Left Ventricular Hypertrophy

In the Losartan Intervention for Endpoint (LIFE) study, adverse reactions with COZAAR were similar to those reported previously for patients with hypertension.

Nephropathy In Type 2 Diabetic Patients

In the Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study involving 1513 patients treated with COZAAR or placebo, the overall incidences of reported adverse events were similar for the two groups. Discontinuations of COZAAR because of side effects were similar to placebo (19% for COZAAR, 24% for placebo). The adverse events, regardless of drug relationship, reported with an incidence of ≥4% of patients treated with COZAAR and occurring with ≥2% difference in the losartan group vs. placebo on a background of conventional antihypertensive therapy, were asthenia/fatigue, chest pain, hypotension, orthostatic hypotension, diarrhea, anemia, hyperkalemia, hypoglycemia, back pain, muscular weakness, and urinary tract infection.

Postmarketing Experience

The following additional adverse reactions have been reported in postmarketing experience with COZAAR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or to establish a causal relationship to drug exposure:

Digestive: Hepatitis.

General Disorders and Administration Site Conditions: Malaise.

Hematologic: Thrombocytopenia.

Hypersensitivity: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue has been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Vasculitis, including Henoch-Schönlein purpura, has been reported. Anaphylactic reactions have been reported.

Metabolic and Nutrition: Hyponatremia.

Musculoskeletal: Rhabdomyolysis.

Nervous system disorders: Dysgeusia.

Skin: Erythroderma.

Warnings

Included as part of the PRECAUTIONS section.

What is the most important information i should know about losartan (cozaar)?

Do not use if you are pregnant. Stop using and tell your doctor right away if you become pregnant. losartan can cause injury or death to the unborn baby if you take the medicine during your second or third trimester. Use effective birth control.

You should not use this medication if you are allergic to losartan.

Before you use losartan, tell your doctor about all your other medical conditions and allergies. Also make sure your doctor knows if you are pregnant or breast-feeding. In some cases, you may not be able to use losartan, or you may need a dose adjustment or special precautions.

Certain other drugs may interact with losartan or should not be used at the same time. Tell each of your healthcare providers about all medicines you use now, and any medicine you start or stop using.

Call your doctor if you have ongoing vomiting or diarrhea, or if you are sweating more than usual. You can easily become dehydrated while taking this medicine, which can lead to severely low blood pressure or a serious electrolyte imbalance.

In rare cases, losartan can cause a condition that results in the breakdown of skeletal muscle tissue, leading to kidney failure. Call your doctor right away if you have unexplained muscle pain, tenderness, or weakness especially if you also have fever, unusual tiredness, and dark colored urine.

  • Angiotensin Receptor Blockers (ARBs)
  • Raynaud's Phenomenon

Losartan Potassium Dosage and Administration

General

BP Monitoring and Treatment Goals

  • Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.500 501

  • When available, use evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) to determine target dosages; target dosages usually can be achieved within 2–4 weeks but may take up to several months.501

  • If adequate BP response not achieved with a single antihypertensive agent, add a second drug with demonstrated benefit; if goal BP still not achieved with optimal dosages of 2 antihypertensive agents, add a third drug.501 May maximize dosage of the first drug before adding a second drug, or add a second drug before maximizing dosage of the initial drug.501

  • Consider initiating antihypertensive therapy with a combination of drugs if patient's BP exceeds goal BP by >20/10 mm Hg.500 501 503 504

  • Goal is to achieve and maintain optimal control of BP; individualize specific target BP based on consideration of multiple factors, including patient age and comorbidities, and currently available evidence from clinical studies.500 501 (See Hypertension under Uses.)

Administration

Oral Administration

Administer losartan orally once or twice daily without regard to meals.1 2 Administer losartan as extemporaneously prepared oral suspension in patients unable to swallow tablets.1 Administer losartan in fixed combination with hydrochlorothiazide once daily without regard to meals.2

Reconstitution

Preparation of extemporaneous suspension containing losartan potassium 2.5 mg/mL: Add 10 mL of purified water to a 240-mL polyethylene terephthalate (PET) bottle containing ten 50-mg tablets of losartan potassium; shake contents for ≥2 minutes.1 Allow concentrated suspension to stand for 60 minutes following reconstitution, then shake for an additional minute.1 Prepare a mixture containing equal parts (by volume) of syrup (Ora-Sweet) and suspending vehicle (Ora-Plus) separately.1 Dilute the concentrated suspension of losartan potassium with 190 mL of the Ora-Sweet and Ora-Plus mixture; shake the container an additional minute to disperse ingredients.1 Shake suspension before dispensing each dose.1

Dosage

Available as losartan potassium; dosage expressed in terms of the salt.1 2

Pediatric Patients

Hypertension Oral

Children ≥6 years of age: Initially, 0.7 mg/kg (up to 50 mg) once daily.1 52 Adjust dosage until the desired BP goal is achieved52 (up to maximum dosage of 1.4 mg/kg or 100 mg daily).1 52

Adults

Hypertension Losartan Therapy Oral

JNC 8 expert panel recommends initial dosage of 50 mg daily and target dosage of 100 mg daily (given in 1 dose or 2 divided doses) based on dosages used in randomized controlled studies.501

Manufacturer recommends initial dosage of 50 mg once daily in adults without intravascular volume depletion.1 In adults with depletion of intravascular volume, the usual initial dosage is 25 mg once daily.1

Manufacturer states usual dosage is 25–100 mg daily, given in 1 dose or 2 divided doses; no additional therapeutic benefit with higher dosages.1

If effectiveness diminishes toward end of dosing interval in patients treated once daily, consider increasing dosage or administering drug in 2 divided doses.1

If intolerable adverse effects occur, consider dosage reduction; if adverse effects worsen or fail to resolve, may need to discontinue and switch to another antihypertensive drug class.501

Losartan/Hydrochlorothiazide Fixed-combination Therapy Oral

Manufacturer states fixed-combination preparation should not be used for initial treatment of hypertension, except in severe hypertension when benefits of achieving prompt BP reduction are considered to outweigh risks of initiating combination therapy.2

If BP is not adequately controlled by monotherapy with losartan potassium or hydrochlorothiazide (25 mg daily), if BP is controlled but hypokalemia is problematic at this hydrochlorothiazide dosage, or in those with severe hypertension in whom the potential benefit of achieving prompt BP control outweighs the potential risk of initiating therapy with the commercially available fixed combination, can use the fixed-combination tablets once daily (losartan potassium 50 mg and hydrochlorothiazide 12.5 mg; then losartan potassium 100 mg and hydrochlorothiazide 25 mg, if BP remains uncontrolled after about 3 weeks of therapy [or after 2–4 weeks of therapy in those with severe hypertension]).2

If BP is not adequately controlled by monotherapy with losartan potassium 100 mg daily, can switch to fixed-combination tablets once daily (losartan potassium 100 mg and hydrochlorothiazide 12.5 mg; then losartan potassium 100 mg and hydrochlorothiazide 25 mg [administered as 2 tablets of the fixed combination containing 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide, or alternatively, as 1 tablet of the fixed combination containing 100 mg of losartan potassium and 25 mg of hydrochlorothiazide] if BP remains uncontrolled after about 3 weeks of therapy).2

Prevention of Cardiovascular Morbidity and Mortality Oral

Initially, 50 mg once daily.1 Adjust dosage based on BP response.1 2 If indicated, add hydrochlorothiazide 12.5 mg daily and/or increase dosage of losartan to 100 mg once daily.1 2 Subsequently, may increase hydrochlorothiazide dosage to 25 mg once daily.1 2 Alternatively, administer fixed combination of losartan potassium and hydrochlorothiazide at appropriate dosages.2

Diabetic Nephropathy Oral

Initially, 50 mg once daily.1 If BP is not adequately controlled, increase dosage to 100 mg once daily.1

Heart Failure† Oral

Initially, 25–50 mg once daily recommended by ACCF and AHA in patients with prior or current symptoms of heart failure and reduced LVEF† (ACCF/AHA stage C heart failure).524

ACCF and AHA recommend maximum dosage of 50–150 mg once daily in patients with ACCF/AHA stage C heart failure.524

Reevaluate BP, renal function, and serum potassium concentrations within 1–2 weeks after initiation of therapy and monitor such parameters closely after dosage changes.524

Prescribing Limits

Pediatric Patients

Hypertension Oral

Maximum 1.4 mg/kg or 100 mg daily.1 52

Adults

Hypertension Losartan/Hydrochlorothiazide Fixed-combination Therapy Oral

Maximum 100 mg of losartan potassium and 25 mg of hydrochlorothiazide daily as the fixed combination.2

Special Populations

Hepatic Impairment

Manufacturer recommends initial dosage of 25 mg once daily in adults with a history of hepatic impairment.1

Use of losartan in fixed combination with hydrochlorothiazide is not recommended in patients with hepatic impairment.2

Renal Impairment

No initial dosage adjustments recommended by manufacturer for adults with renal impairment, including those undergoing hemodialysis.1 Use not recommended in pediatric patients with Clcr <30 mL/minute per 1.73 m2.1 52

Use of losartan in fixed combination with hydrochlorothiazide is not recommended in patients with severe renal impairment.2

Geriatric Patients

No initial dosage adjustments necessary.1

Volume- and/or Salt-depleted Patients

Correct volume and/or salt depletion prior to initiation of therapy or initiate therapy under close medical supervision using lower initial dosage (25 mg once daily).1 2

Use of losartan in fixed combination with hydrochlorothiazide is not recommended in patients with intravascular volume depletion (e.g., patients receiving diuretics).2

Losartan Potassium Pharmacokinetics

Absorption

Bioavailability

Well absorbed after oral administration but undergoes substantial first-pass metabolism.1 2

Systemic bioavailability of losartan is about 33%.1 2 Bioavailability of the suspension formulation (see Oral Administration under Dosage and Administration) is similar to that of losartan tablets with respect to both the drug and its active metabolite.1

Peak plasma concentrations of losartan and its active metabolite attained 1 and 3–4 hours, respectively, following oral administration.1

Onset

Antihypertensive effect evident within 1 week, with maximum BP reduction after 3–6 weeks.1

Food

Food slows absorption of losartan and decreases its peak plasma concentration but has minimal effect on AUC of losartan or its active metabolite.1 2

Special Populations

In pediatric patients, pharmacokinetics of losartan and its active metabolite generally are similar to historical data in adults.1

In patients with hepatic impairment, oral bioavailability is about 2 times higher than in those with normal hepatic function.1

In patients with mild to moderate alcoholic cirrhosis, plasma concentration of losartan and its active metabolite were about 5 and 2 times those of healthy individuals, respectively.1 2

In patients with mild (Clcr 50–74 mL/minute) or moderate (Clcr 30–49 mL/minute) renal impairment, plasma concentrations and AUC of losartan and its active metabolite are increased by 50–90%.2

Distribution

Extent

Crosses the placenta and is distributed in the fetus in animals.1 2

Crosses the blood-brain barrier poorly, if at all, in animals.1 2

Distributed into milk in rats; not known whether distributed into human milk.1 2

Plasma Protein Binding

Losartan and its active metabolite: >98%.1 2

Elimination

Metabolism

Undergoes biotransformation through CYP2C9 to an active carboxylic acid metabolite that is responsible for most of the drug’s angiotensin II receptor antagonism.2 CYP3A4 apparently contributes to formation of inactive metabolites.2

Elimination Route

Eliminated mainly in urine and feces (via bile).1 2

Half-life

Terminal half-life of losartan and its active metabolite is approximately 2 and 6–9 hours, respectively.1 2

Special Populations

In patients with mild to moderate alcoholic cirrhosis, total plasma clearance of losartan is about 50% lower than in those with normal hepatic function.1

In patients with mild or moderate renal impairment, renal clearance of losartan and its active metabolite is decreased by 55–85%.2 Neither losartan nor its active metabolite is removed by hemodialysis.1 2

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