LOSARTAN POTASSIUM- losartan potassium tablet, film coated

United States - English - NLM (National Library of Medicine)

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Active ingredient:
LOSARTAN POTASSIUM (UNII: 3ST302B24A) (LOSARTAN - UNII:JMS50MPO89)
Available from:
NuCare Pharmaceuticals,Inc.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Losartan potassium tablets are 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 antih
Product summary:
Losartan Potassium Tablets USP, 50 mg are green colored, oval shaped, biconvex film-coated tablets debossed with E on one side and 4 and 6 separated by scoreline on other side. NDC 68071-5040-3 BOTTLES OF 30 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Protect from light.
Authorization status:
Abbreviated New Drug Application
Authorization number:
68071-5040-3

LOSARTAN POTASSIUM- losartan potassium tablet, film coated

NuCare Pharmaceuticals,Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use LOSARTAN POTASSIUM TABLETS safely

and effectively. See full prescribing information for LOSARTAN POTASSIUM TABLETS.

LOSARTAN POTASSIUM tablets, for oral use

Initial U.S. Approval: 1995

WARNING: FETAL TOXICITY

See full prescribing information for complete boxed warning.

When pregnancy is detected, discontinue losartan potassium as soon as possible. Drugs that act directly

on the renin-angiotensin system can cause injury and death to the developing fetus. ( 5.1)

RECENT MAJOR CHANGES

Warnings and Precautions

Hyperkalemia ( 5.4) 10/2018

INDICATIONS AND USAGE

Losartan potassium tablets are an angiotensin II receptor blocker (ARB) indicated 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. ( 1.1)

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. ( 1.2)

Treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria in patients with type 2 diabetes

and a history of hypertension. ( 1.3)

DOSAGE AND ADMINISTRATION

Hype rte nsion

Usual adult dose: 50 mg once daily. ( 2.1)

Usual pediatric starting dose: 0.7 mg per kg once daily (up to 50 mg). ( 2.1)

Hypertensive Patients with Left Ventricular Hypertrophy

Usual starting dose: 50 mg once daily. ( 2.2)

Add hydrochlorothiazide 12.5 mg and/or increase losartan potassium tablets to 100 mg followed by an increase to

hydrochlorothiazide 25 mg if further blood pressure response is needed. ( 2.2, 14.2)

Nephropathy in Type 2 Diabetic Patients

Usual dose: 50 mg once daily. ( 2.3)

Increase dose to 100 mg once daily if further blood pressure response is needed. ( 2.3)

DOSAGE FORMS AND STRENGTHS

Tablets: 25 mg; 50 mg; and 100 mg. ( 3)

CONTRAINDICATIONS

Hypersensitivity to any component. ( 4)

Coadministration with aliskiren in patients with diabetes. ( 4)

WARNINGS AND PRECAUTIONS

Hypotension: Correct volume or salt depletion prior to administration of losartan potassium. ( 5.2)

Monitor renal function and potassium in susceptible patients. ( 5.3, 5.4)

ADVERSE REACTIONS

Most common adverse reactions (incidence ≥2% and greater than placebo) are: dizziness, upper respiratory infection,

nasal congestion, and back pain. ( 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or

FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

DRUG INTERACTIONS

Agents increasing serum potassium: Risk of hyperkalemia. ( 7.1)

Lithium: Risk of lithium toxicity. ( 7.2)

NSAIDs: Increased risk of renal impairment and reduced diuretic, natriuretic, and antihypertensive effects. ( 7.3)

Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, syncope, and

hyperkalemia. ( 7.4)

USE IN SPECIFIC POPULATIONS

Losartan potassium is not recommended in pediatric patients less than 6 years of age or in pediatric patients with

glomerular filtration rate less than 30 mL/min/1.73 m

. ( 2.1, 8.4)

Hepatic Impairment: Recommended starting dose 25 mg once daily. ( 2.4, 8.8, 12.3)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 3/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: FETAL TOXICITY

1 INDICATIONS AND USAGE

1.1 Hypertension

1.2 Hypertensive Patients with Left Ventricular Hypertrophy

1.3 Nephropathy in Type 2 Diabetic Patients

2 DOSAGE AND ADMINISTRATION

2.1 Hypertension

2.2 Hypertensive Patients with Left Ventricular Hypertrophy

2.3 Nephropathy in Type 2 Diabetic Patients

2.4 Dosage Modifications in Patients with Hepatic Impairment

2.5 Preparation of Suspension (for 200 mL of a 2.5 mg/mL suspension)

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Fetal Toxicity

5.2 Hypotension in Volume- or Salt-Depleted Patients

5.3 Renal Function Deterioration

5.4 Hyperkalemia

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Agents Increasing Serum Potassium

7.2 Lithium

7.3 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2

Inhibitors (COX-2 Inhibitors)

7.4 Dual Blockade of the Renin-Angiotensin System (RAS)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Race

8.7 Renal Impairment

8.8 Hepatic Impairment

10 OVERDOSAGE

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Hypertension

14.2 Hypertensive Patients with Left Ventricular Hypertrophy

14.3 Nephropathy in Type 2 Diabetic Patients

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING: FETAL TOXICITY

When pregnancy is detected, discontinue losartan potassium as soon as possible. Drugs

that act directly on the renin-angiotensin system can cause injury and death to the

developing fetus [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

1.1 Hypertension

Losartan potassium tablets are 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

Sections or subsections omitted from the full prescribing information are not listed.

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.

Losartan potassium tablets may be administered with other antihypertensive agents.

1.2 Hypertensive Patients with Left Ventricular Hypertrophy

Losartan potassium tablets are 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 (8.6) and Clinical Pharmacology (12.3)].

1.3 Nephropathy in Type 2 Diabetic Patients

Losartan potassium tablets are 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, losartan potassium tablets 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 (14.3)].

2 DOSAGE AND ADMINISTRATION

2.1 Hypertension

Adult Hypertension

The usual starting dose of losartan potassium tablets 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 [see Clinical Studies

(14.1)]. A starting dose of 25 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 [see Dosage and Administration (2.5)] . 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 [see Clinical Pharmacology (12.3), Clinical Studies (14.1), and Warnings and

Precautions (5.2)].

Losartan potassium tablets are not recommended in pediatric patients less than 6 years of age or in

pediatric patients with estimated glomerular filtration rate less than 30 mL/min/1.73 m

[see Use in

Specific Populations (8.4), Clinical Pharmacology (12.3), and Clinical Studies (14)].

2.2 Hypertensive Patients with Left Ventricular Hypertrophy

The usual starting dose is 50 mg of losartan potassium tablets once daily. Hydrochlorothiazide 12.5 mg

daily should be added and/or the dose of losartan potassium tablets should be increased to 100 mg once

daily followed by an increase in hydrochlorothiazide to 25 mg once daily based on blood pressure

response [see Clinical Studies (14.2)] .

2.3 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 [see Clinical Studies (14.3)] .

2.4 Dosage Modifications in Patients with Hepatic Impairment

In patients with mild-to-moderate hepatic impairment the recommended starting dose of losartan

potassium tablets is 25 mg once daily. Losartan potassium tablets have not been studied in patients with

severe hepatic impairment [see Use in Special Populations (8.8) and Clinical Pharmacology (12.3)] .

2.5 Preparation of Suspension (for 200 mL of a 2.5 mg/mL suspension)

Add 10 mL of Purified Water USP to an 8 ounce (240 mL) amber polyethylene terephthalate (PET)

bottle containing ten 50 mg losartan potassium tablets. Immediately shake for at least 2 minutes. Let the

concentrate stand for 1 hour and then shake for 1 minute to disperse the tablet contents. Separately

prepare a 50/50 volumetric mixture of Ora-Plus

and Ora-Sweet SF

. Add 190 mL of the 50/50 Ora-

Plus

/Ora-Sweet SF

mixture to the tablet and water slurry in the PET bottle and shake for 1 minute to

disperse the ingredients. The suspension should be refrigerated at 2 to 8°C (36 to 46°F) and can be

stored for up to 4 weeks. Shake the suspension prior to each use and return promptly to the refrigerator.

3 DOSAGE FORMS AND STRENGTHS

Losartan Potassium Tablets USP, 25 mg are green colored, oval shaped, biconvex film-coated

tablets debossed with ‘E’ on one side and ‘45’ on other side.

Losartan Potassium Tablets USP, 50 mg are green colored, oval shaped, biconvex film-coated

tablets debossed with ‘E’ on one side and ‘4’ and ‘6’ separated by scoreline on other side.

Losartan Potassium Tablets USP, 100 mg are green colored, oval shaped, biconvex film-coated

tablets debossed with ‘E’ on one side and ‘47’ on other side.

4 CONTRAINDICATIONS

Losartan potassium tablets are contraindicated:

In patients who are hypersensitive to any component of this product.

For coadministration with aliskiren in patients with diabetes.

5 WARNINGS AND PRECAUTIONS

5.1 Fetal Toxicity

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 potassium as soon as possible [see Use in Specific

Populations (8.1)].

5.2 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 losartan potassium. Correct volume or salt depletion prior to administration of losartan

potassium [see Dosage and Administration (2.1)] .

5.3 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 losartan potassium. Monitor renal function periodically in these patients. Consider withholding or

discontinuing therapy in patients who develop a clinically significant decrease in renal function on

losartan potassium [see Drug Interactions (7.3) and Use in Specific Populations (8.7)] .

5.4 Hyperkalemia

Monitor serum potassium periodically and treat appropriately. Dosage reduction or discontinuation of

losartan potassium may be required . Monitor serum potassium periodically and treat appropriately.

Dosage reduction or discontinuation of losartan potassium may be required [see Adverse Reactions (6.1)]

Concomitant use of other drugs that may increase serum potassium may lead hyperkalemia .

Concomitant use of other drugs that may increase serum potassium may lead to hyperkalemia [see Drug

Interactions (7.1)] .

6 ADVERSE REACTIONS

6.1 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

Losartan potassium 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 losartan potassium 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 losartan potassium and 3.7% of patients given placebo. In 4

clinical trials involving over 1000 patients on various doses (10 to 150 mg) of losartan potassium and

over 300 patients given placebo, the adverse events that occurred in ≥2% of patients treated with

losartan potassium 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:

* Demographics = (89% Caucasian, 64% female)

† Demographics = (90% Caucasian, 51% female)

Study 1*

HCTZ

Losartan

Lisinopril

Cough

Study 2

Placebo

Losartan

Lisinopril

Cough

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 losartan potassium 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 losartan potassium or placebo, the overall

incidences of reported adverse events were similar for the two groups. Discontinuations of losartan

potassium because of side effects were similar to placebo (19% for losartan potassium, 24% for

placebo). The adverse events, regardless of drug relationship, reported with an incidence of ≥4% of

patients treated with losartan potassium 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.

6.2 Postmarketing Experience

The following additional adverse reactions have been reported in postmarketing experience with

losartan potassium. 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.

7 DRUG INTERACTIONS

7.1 Agents Increasing Serum Potassium

Coadministration of losartan with other drugs that raise serum potassium levels may result in

hyperkalemia. Monitor serum potassium in such patients.

7.2 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.

7.3 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 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.

7.4 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 Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) trial enrolled 1448 patients with

type 2 diabetes, elevated urinary-albumin-to-creatinine ratio, and decreased estimated glomerular

filtration rate (GFR 30 to 89.9 mL/min), randomized them to lisinopril or placebo on a background of

losartan therapy and followed them for a median of 2.2 years. Patients receiving the combination of

losartan and lisinopril did not obtain any additional benefit compared to monotherapy for the combined

endpoint of decline in GFR, end stage renal disease, or death, but experienced an increased incidence of

hyperkalemia and acute kidney injury compared with the monotherapy group.

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 coadminister aliskiren with losartan potassium in patients with diabetes. Avoid use of aliskiren

with losartan potassium in patients with renal impairment (GFR <60 mL/min).

8 USE IN SPECIFIC POPULATIONS

8.1 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 renin-

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, 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 for hypotension, oliguria, and

hyperkalemia [see Use in Specific Populations (8.4)] .

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.

8.3 Nursing Mothers

It is not known whether losartan is excreted in human milk, but significant levels of losartan 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.

8.4 Pediatric Use

Neonates with a history of in utero exposure to losartan potassium: 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 hypotension and/or substituting for disordered renal function.

Antihypertensive effects of losartan potassium 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 rate <30 mL/min/1.73 m

[see Dosage and

Administration (2.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)] .

8.5 Geriatric Use

Of the total number of patients receiving losartan potassium 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.

8.6 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 losartan potassium (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

losartan potassium. 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 losartan potassium

on reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy

apply to Black patients [see Clinical Studies (14.2)] .

8.7 Renal Impairment

Patients with renal insufficiency have elevated plasma concentrations of losartan and its active

metabolite compared to subjects with normal renal function. No dose adjustment is necessary in patients

with renal impairment unless a patient with renal impairment is also volume depleted [see Dosage and

Administration (2.3), Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)] .

8.8 Hepatic Impairment

The recommended starting dose of losartan potassium is 25 mg in patients with mild-to-moderate hepatic

impairment. Following oral administration in patients with mild-to-moderate hepatic impairment, plasma

concentrations of losartan and its active metabolite were, respectively, 5 times and 1.7 times those seen

in healthy volunteers. Losartan potassium has not been studied in patients with severe hepatic impairment

[see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)] .

10 OVERDOSAGE

Significant lethality was observed in mice and rats after oral administration of 1000 mg/kg and 2000

mg/kg, respectively, about 44 and 170 times the maximum recommended human dose on a mg/m

basis.

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 should occur, supportive treatment should be instituted.

Neither losartan nor its active metabolite can be removed by hemodialysis.

11 DESCRIPTION

Losartan potassium tablets are an angiotensin II receptor blocker acting on the AT

receptor subtype.

Losartan potassium, a non-peptide molecule, is chemically described as 2-butyl-4-chloro-1-[ p-( o-1

H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt.

Its molecular formula is C

ClKN

O, and its structural formula is:

Losartan potassium USP is a white to off-white powder with a molecular weight of 461.01. It is freely

soluble in water, soluble in alcohols, and slightly soluble in common organic solvents, such as

acetonitrile and methyl ethyl ketone. Oxidation of the 5-hydroxymethyl group on the imidazole ring

results in the active metabolite of losartan.

Losartan potassium is available as tablets for oral administration containing either 25 mg, 50 mg or 100

mg of losartan potassium and the following inactive ingredients: microcrystalline cellulose, lactose

monohydrate, pregelatinized starch (maize), low substituted hydroxypropyl cellulose, magnesium

stearate, hydroxypropyl cellulose, hypromellose 6 cP, titanium dioxide, FD&C blue #2/indigo carmine

aluminum lake, D&C yellow #10 aluminum lake, and purified water.

Losartan potassium tablets USP, 25 mg, 50 mg and 100 mg contain potassium in the following amounts:

2.12 mg (0.054 mEq), 4.24 mg (0.108 mEq) and 8.48 mg (0.216 mEq), respectively.

12 CLINICAL PHARMACOLOGY

12.1 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 AT

receptor found in many tissues, (e.g., vascular smooth muscle, adrenal

gland). There is also an AT

receptor found in many tissues but it is not known to be associated with

cardiovascular homeostasis. Neither losartan nor its principal active metabolite exhibits any partial

agonist activity at the AT

receptor, and both have much greater affinity (about 1000-fold) for the AT

receptor than for the AT

receptor. In vitro binding studies indicate that losartan is a reversible,

competitive inhibitor of the AT

receptor. The active metabolite is 10 to 40 times more potent by

weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT

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.

12.2 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 to 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 to 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.

12.3 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 to 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 C

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 to 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

C-labeled losartan, about 35% of radioactivity is

recovered in the urine and about 60% in the feces. Following an intravenous dose of

C-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.

Special Populations

Pediatric: Pharmacokinetic parameters after multiple doses of losartan (average dose 0.7 mg/kg, range

0.36 to 0.97 mg/kg) as a tablet to 25 hypertensive patients aged 6 to 16 years are shown in Table 4

below. Pharmacokinetics of losartan and its active metabolite were generally similar across the studied

age groups and similar to historical pharmacokinetic data in adults. The principal pharmacokinetic

parameters in adults and children are shown in the table below.

Table 2: Pharmacokinetic Parameters in Hypertensive Adults and Children Age 6 to 16 Following

Multiple Dosing

* Mean ± standard deviation

† Harmonic mean and standard deviation

‡ Median

Adults given 50 mg once daily for 7

days N=12

Age 6 to 16 given 0.7 mg/kg once

daily for 7 days (N=25)

Parent

Active Metabolite

Parent

Active Metabolite

(nghr/mL)*

442 ± 173

1685 ± 452

368 ± 169

1866 ± 1076

(ng/mL)*

224 ± 82

212 ± 73

141 ± 88

222 ± 127

2.1 ± 0.70

7.4 ± 2.4

2.3 ± 0.8

5.6 ± 1.2

(mL/min)*

56 ± 23

20 ± 3

53 ± 33

17 ± 8

The bioavailability of the suspension formulation was compared with losartan tablets in healthy adults.

The suspension and tablet are similar in their bioavailability with respect to both losartan and the active

metabolite [see Dosage and Administration (2.5)] .

Geriatric and Gender: Losartan pharmacokinetics have been investigated in the elderly (65 to 75 years)

0-24

PEAK

and in both genders. Plasma concentrations of losartan and its active metabolite are similar in elderly and

young hypertensives. Plasma concentrations of losartan were about twice as high in female

hypertensives as male hypertensives, but concentrations of the active metabolite were similar in males

and females. No dosage adjustment is necessary [see Dosage and Administration (2.1)] .

Race: Pharmacokinetic differences due to race have not been studied [see Use in Specific Populations

(8.6)].

Renal Insufficiency: Following oral administration, plasma concentrations and AUCs of losartan and its

active metabolite are increased by 50 to 90% in patients with mild (creatinine clearance of 50 to 74

mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal insufficiency. In this study, renal

clearance was reduced by 55 to 85% for both losartan and its active metabolite in patients with mild or

moderate renal insufficiency. Neither losartan nor its active metabolite can be removed by hemodialysis

[see Warnings and Precautions (5.3) and Use in Specific Populations (8.7)] .

Hepatic Insufficiency: Following oral administration in patients with mild to moderate alcoholic cirrhosis

of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5-times and

about 1.7-times those in young male volunteers. Compared to normal subjects the total plasma clearance

of losartan in patients with hepatic insufficiency was about 50% lower and the oral bioavailability was

about doubled. Use a starting dose of 25 mg for patients with mild to moderate hepatic impairment.

Losartan potassium has not been studied in patients with severe hepatic impairment [see Dosage and

Administration (2.4) and Use in Specific Populations (8.8)].

Drug Interactions

No clinically significant drug interactions have been found in studies of losartan potassium with

hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. However, rifampin has been

shown to decrease the AUC of losartan and its active metabolite by 30% and 40%, respectively.

Fluconazole, an inhibitor of cytochrome P450 2C9, decreased the AUC of the active metabolite by

approximately 40%, but increased the AUC of losartan by approximately 70% following multiple

doses. Conversion of losartan to its active metabolite after intravenous administration is not affected by

ketoconazole, an inhibitor of P450 3A4. The AUC of active metabolite following oral losartan was not

affected by erythromycin, an inhibitor of P450 3A4, but the AUC of losartan was increased by 30%.

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Losartan potassium was not carcinogenic when administered at maximally tolerated dosages to rats and

mice for 105 and 92 weeks, respectively. Female rats given the highest dose (270 mg/kg/day) had a

slightly higher incidence of pancreatic acinar adenoma. The maximally tolerated dosages (270

mg/kg/day in rats, 200 mg/kg/day in mice) provided systemic exposures for losartan and its

pharmacologically active metabolite that were approximately 160 and 90 times (rats) and 30 and 15

times (mice) the exposure of a 50 kg human given 100 mg per day.

Losartan potassium was negative in the microbial mutagenesis and V-79 mammalian cell mutagenesis

assays and in the in vitro alkaline elution and in vitro and in vivo chromosomal aberration assays. In

addition, the active metabolite showed no evidence of genotoxicity in the microbial mutagenesis, in vitro

alkaline elution, and in vitro chromosomal aberration assays.

Fertility and reproductive performance were not affected in studies with male rats given oral doses of

losartan potassium up to approximately 150 mg/kg/day. The administration of toxic dosage levels in

females (300/200 mg/kg/day) was associated with a significant (p<0.05) decrease in the number of

corpora lutea/female, implants/female, and live fetuses/female at C-section. At 100 mg/kg/day only a

decrease in the number of corpora lutea/female was observed. The relationship of these findings to

drug-treatment is uncertain since there was no effect at these dosage levels on implants/pregnant female,

percent post-implantation loss, or live animals/litter at parturition. In nonpregnant rats dosed at 135

mg/kg/day for 7 days, systemic exposure (AUCs) for losartan and its active metabolite were

approximately 66 and 26 times the exposure achieved in man at the maximum recommended human daily

dosage (100 mg).

14 CLINICAL STUDIES

14.1 Hypertension

Adult Hypertension

The antihypertensive effects of losartan potassium were demonstrated principally in 4 placebo-

controlled, 6- to 12-week trials of dosages from 10 to 150 mg per day in patients with baseline diastolic

blood pressures of 95 to 115. The studies allowed comparisons of two doses (50 to 100 mg/day) as

once-daily or twice-daily regimens, comparisons of peak and trough effects, and comparisons of

response by gender, age, and race. Three additional studies examined the antihypertensive effects of

losartan and hydrochlorothiazide in combination.

The 4 studies of losartan monotherapy included a total of 1075 patients randomized to several doses of

losartan and 334 to placebo. The 10 and 25 mg doses produced some effect at peak (6 hours after

dosing) but small and inconsistent trough (24 hour) responses. Doses of 50, 100 and 150 mg once daily

gave statistically significant systolic/diastolic mean decreases in blood pressure, compared to placebo

in the range of 5.5 to 10.5/3.5 to 7.5 mmHg, with the 150 mg dose giving no greater effect than 50 to

100 mg. Twice-daily dosing at 50 to 100 mg/day gave consistently larger trough responses than once-

daily dosing at the same total dose. Peak (6 hour) effects were uniformly, but moderately, larger than

trough effects, with the trough-to-peak ratio for systolic and diastolic responses 50 to 95% and 60 to

90%, respectively.

Addition of a low dose of hydrochlorothiazide (12.5 mg) to losartan 50 mg once daily resulted in

placebo-adjusted blood pressure reductions of 15.5/9.2 mmHg.

Analysis of age, gender, and race subgroups of patients showed that men and women, and patients over

and under 65, had generally similar responses. Losartan potassium was effective in reducing blood

pressure regardless of race, although the effect was somewhat less in Black patients (usually a low-

renin population).

Pediatric Hypertension

The antihypertensive effect of losartan was studied in one trial enrolling 177 hypertensive pediatric

patients aged 6 to 16 years old. Children who weighed <50 kg received 2.5, 25 or 50 mg of losartan

daily and patients who weighed ≥50 kg received 5, 50 or 100 mg of losartan daily. Children in the

lowest dose group were given losartan in a suspension formulation [see Dosage and Administration

(2.1)] . The majority of the children had hypertension associated with renal and urogenital disease. The

sitting diastolic blood pressure (SiDBP) on entry into the study was higher than the 95

percentile

level for the patient’s age, gender, and height. At the end of three weeks, losartan reduced systolic and

diastolic blood pressure, measured at trough, in a dose-dependent manner. Overall, the two higher

doses (25 to 50 mg in patients <50 kg; 50 to 100 mg in patients ≥50 kg) reduced diastolic blood

pressure by 5 to 6 mmHg more than the lowest dose used (2.5 mg in patients <50 kg; 5 mg in patients

≥50 kg). The lowest dose, corresponding to an average daily dose of 0.07 mg/kg, did not appear to

offer consistent antihypertensive efficacy. When patients were randomized to continue losartan at the

two higher doses or to placebo after 3 weeks of therapy, trough diastolic blood pressure rose in

patients on placebo between 5 and 7 mmHg more than patients randomized to continuing losartan. When

the low dose of losartan was randomly withdrawn, the rise in trough diastolic blood pressure was the

same in patients receiving placebo and in those continuing losartan, again suggesting that the lowest

dose did not have significant antihypertensive efficacy. Overall, no significant differences in the

overall antihypertensive effect of losartan were detected when the patients were analyzed according to

age (<, ≥12 years old) or gender. While blood pressure was reduced in all racial subgroups examined,

too few non-White patients were enrolled to compare the dose-response of losartan in the non-White

subgroup.

14.2 Hypertensive Patients with Left Ventricular Hypertrophy

The LIFE study was a multinational, double-blind study comparing losartan potassium and atenolol in

9193 hypertensive patients with ECG-documented left ventricular hypertrophy. Patients with myocardial

infarction or stroke within six months prior to randomization were excluded. Patients were randomized

to receive once daily losartan potassium 50 mg or atenolol 50 mg. If goal blood pressure (<140/90

mmHg) was not reached, hydrochlorothiazide (12.5 mg) was added first and, if needed, the dose of

losartan potassium or atenolol was then increased to 100 mg once daily. If necessary, other

antihypertensive treatments (e.g., increase in dose of hydrochlorothiazide therapy to 25 mg or addition

of other diuretic therapy, calcium-channel blockers, alpha-blockers, or centrally acting agents, but not

ACE inhibitors, angiotensin II antagonists, or beta-blockers) were added to the treatment regimen to

reach the goal blood pressure.

Of the randomized patients, 4963 (54%) were female and 533 (6%) were Black. The mean age was 67

with 5704 (62%) age ≥65. At baseline, 1195 (13%) had diabetes, 1326 (14%) had isolated systolic

hypertension, 1469 (16%) had coronary heart disease, and 728 (8%) had cerebrovascular disease.

Baseline mean blood pressure was 174/98 mmHg in both treatment groups. The mean length of follow-

up was 4.8 years. At the end of study or at the last visit before a primary endpoint, 77% of the group

treated with losartan potassium and 73% of the group treated with atenolol were still taking study

medication. Of the patients still taking study medication, the mean doses of losartan potassium and

atenolol were both about 80 mg/day, and 15% were taking atenolol or losartan as monotherapy, while

77% were also receiving hydrochlorothiazide (at a mean dose of 20 mg/day in each group). Blood

pressure reduction measured at trough was similar for both treatment groups but blood pressure was not

measured at any other time of the day. At the end of study or at the last visit before a primary endpoint,

the mean blood pressures were 144.1/81.3 mmHg for the group treated with losartan potassium and

145.4/80.9 mmHg for the group treated with atenolol; the difference in systolic blood pressure (SBP)

of 1.3 mmHg was significant (p<0.001), while the difference of 0.4 mmHg in diastolic blood pressure

(DBP) was not significant (p=0.098).

The primary endpoint was the first occurrence of cardiovascular death, nonfatal stroke, or nonfatal

myocardial infarction. Patients with nonfatal events remained in the trial, so that there was also an

examination of the first event of each type even if it was not the first event (e.g., a stroke following an

initial myocardial infarction would be counted in the analysis of stroke). Treatment with losartan

potassium resulted in a 13% reduction (p=0.021) in risk of the primary endpoint compared to the

atenolol group (see Figure 1 and Table 3); this difference was primarily the result of an effect on fatal

and nonfatal stroke. Treatment with losartan potassium reduced the risk of stroke by 25% relative to

atenolol (p=0.001) (see Figure 2 and Table 3).

Figure 1: Kaplan-Meier estimates of the primary endpoint of time to cardiovascular death, nonfatal

stroke, or nonfatal myocardial infarction in the groups treated with losartan potassium and atenolol. The

Risk Reduction is adjusted for baseline Framingham risk score and level of electrocardiographic left

ventricular hypertrophy.

Figure 2: Kaplan-Meier estimates of the time to fatal/nonfatal stroke in the groups treated with losartan

potassium and atenolol. The Risk Reduction is adjusted for baseline Framingham risk score and level of

electrocardiographic left ventricular hypertrophy.

Table 3 shows the results for the primary composite endpoint and the individual endpoints. The primary

endpoint was the first occurrence of stroke, myocardial infarction or cardiovascular death, analyzed

using an ITT approach. The table shows the number of events for each component in two different

ways. The Components of Primary Endpoint (as a first event) counts only the events that define the

primary endpoint, while the Secondary Endpoints count all first events of a particular type, whether or

not they were preceded by a different type of event.

Table 3: Incidence of Primary Endpoint Events

Losartan

Atenolol

Ris k

Reduction

95%

CI

p-Value

* Rate per 1000 patient-years of follow-up

† Adjusted for baseline Framingham risk score and level of electrocardiographic left ventricular

hypertrophy

‡ Death due to heart failure, non-coronary vascular disease, pulmonary embolism, or a cardiovascular

cause other than stroke or coronary heart disease

Potassium

Atenolol

Reduction

95%

CI

p-Value

N (%)

Rate*

N (%)

Rate*

Primary Composite

Endpoint

508 (11)

23.8

588 (13)

27.9

2% to 23%

0.021

Components of Primary Composite Endpoint (as a first

event)

Stroke (nonfatal)

209 (5)

286 (6)

Myocardial infarction

(nonfatal)

174 (4)

168 (4)

Cardiovascular mortality

125 (3)

134 (3)

Secondary Endpoints (any time in study)

Stroke (fatal/nonfatal)

232 (5)

10.8

309 (7)

14.5

11% to 37%

0.001

Myocardial infarction

(fatal/nonfatal)

198 (4)

188 (4)

-13% to 12% 0.491

Cardiovascular mortality

204 (4)

234 (5)

10.6

-7% to 27%

0.206

Due to CHD

125 (3)

124 (3)

-32% to 20%

0.839

Due to Stroke

40 (1)

62 (1)

4% to 67%

0.032

Other

39 (1)

48 (1)

-28% to 45% 0.411

Although the LIFE study favored losartan potassium over atenolol with respect to the primary endpoint

(p=0.021), this result is from a single study and, therefore, is less compelling than the difference

between losartan potassium and placebo. Although not measured directly, the difference between

losartan potassium and placebo is compelling because there is evidence that atenolol is itself effective

(vs. placebo) in reducing cardiovascular events, including stroke, in hypertensive patients.

Other clinical endpoints of the LIFE study were: total mortality, hospitalization for heart failure or

angina pectoris, coronary or peripheral revascularization procedures, and resuscitated cardiac arrest.

There were no significant differences in the rates of these endpoints between the losartan potassium and

atenolol groups.

For the primary endpoint and stroke, the effects of losartan potassium in patient subgroups defined by

age, gender, race and presence or absence of isolated systolic hypertension (ISH), diabetes, and history

of cardiovascular disease (CVD) are shown in Figure 3 below. Subgroup analyses can be difficult to

interpret and it is not known whether these represent true differences or chance effects.

Symbols are proportional to sample size.

# Other includes Asian, Hispanic, Asiatic, Multi-race, Indian, Native American, European.

† Adjusted for baseline Framingham risk score and level of electrocardiographic left ventricular

hypertrophy.

14.3 Nephropathy in Type 2 Diabetic Patients

The RENAAL study was a randomized, placebo-controlled, double-blind, multicenter study conducted

worldwide in 1513 patients with type 2 diabetes with nephropathy (defined as serum creatinine 1.3 to 3.0

mg/dL in females or males ≤60 kg and 1.5 to 3.0 mg/dL in males >60 kg and proteinuria [urinary albumin

to creatinine ratio ≥300 mg/g]).

Patients were randomized to receive losartan potassium 50 mg once daily or placebo on a background

of conventional antihypertensive therapy excluding ACE inhibitors and angiotensin II antagonists. After

one month, investigators were instructed to titrate study drug to 100 mg once daily if the trough blood

pressure goal (140/90 mmHg) was not achieved. Overall, 72% of patients received the 100 mg daily

dose more than 50% of the time they were on study drug. Because the study was designed to achieve

equal blood pressure control in both groups, other antihypertensive agents (diuretics, calcium-channel

blockers, alpha- or beta-blockers, and centrally acting agents) could be added as needed in both groups.

Patients were followed for a mean duration of 3.4 years.

The study population was diverse with regard to race (Asian 16.7%, Black 15.2%, Hispanic 18.3%,

White 48.6%). Overall, 63.2% of the patients were men, and 66.4% were under the age of 65 years.

Almost all of the patients (96.6%) had a history of hypertension, and the patients entered the trial with a

mean serum creatinine of 1.9 mg/dL and mean proteinuria (urinary albumin/creatinine) of 1808 mg/g at

baseline.

The primary endpoint of the study was the time to first occurrence of any one of the following events:

doubling of serum creatinine, end-stage renal disease (ESRD) (need for dialysis or transplantation), or

death. Treatment with losartan potassium resulted in a 16% risk reduction in this endpoint (see Figure 4

and Table 4). Treatment with losartan potassium also reduced the occurrence of sustained doubling of

serum creatinine by 25% and ESRD by 29% as separate endpoints, but had no effect on overall mortality

(see Table 4).

The mean baseline blood pressures were 152/82 mmHg for losartan potassium plus conventional

antihypertensive therapy and 153/82 mmHg for placebo plus conventional antihypertensive therapy. At

the end of the study, the mean blood pressures were 143/76 mmHg for the group treated with losartan

potassium and 146/77 mmHg for the group treated with placebo.

Figure 4: Kaplan-Meier curve for the primary composite endpoint of doubling of serum creatinine, end

stage renal disease (need for dialysis or transplantation) or death.

Table 4: Incidence of Primary Endpoint Events

Incidence

Ris k

Reduction

95% C.I.

p-Value

Losartan

Placebo

Primary Composite Endpoint

43.5%

47.1%

16.1%

2.3% to 27.9%

0.022

Doubling of Serum Creatinine, ESRD and Death Occurring as a First Event

Doubling of Serum Creatinine

21.6%

26.0%

ESRD

8.5%

8.5%

Death

13.4%

12.6%

Overall Incidence of Doubling of Serum Creatinine, ESRD and Death

Doubling of Serum Creatinine

21.6%

26.0%

25.3%

7.8% to 39.4%

0.006

ESRD

19.6%

25.5%

28.6%

11.5% to 42.4%

0.002

Death

21.0%

20.3%

-1.7%

-26.9% to 18.6%

0.884

The secondary endpoints of the study were change in proteinuria, change in the rate of progression of

renal disease, and the composite of morbidity and mortality from cardiovascular causes (hospitalization

for heart failure, myocardial infarction, revascularization, stroke, hospitalization for unstable angina, or

cardiovascular death). Compared with placebo, losartan potassium significantly reduced proteinuria by

an average of 34%, an effect that was evident within 3 months of starting therapy, and significantly

reduced the rate of decline in glomerular filtration rate during the study by 13%, as measured by the

reciprocal of the serum creatinine concentration. There was no significant difference in the incidence

of the composite endpoint of cardiovascular morbidity and mortality.

The favorable effects of losartan potassium were seen in patients also taking other anti-hypertensive

medications (angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors were not

allowed), oral hypoglycemic agents and lipid-lowering agents.

For the primary endpoint and ESRD, the effects of losartan potassium in patient subgroups defined by

age, gender and race are shown in Table 5 below. Subgroup analyses can be difficult to interpret and it

is not known whether these represent true differences or chance effects.

Table 5: Efficacy Outcomes within Demographic Subgroups

No. of

Patients

Primary Composite Endpoint

ESRD

Los artan

Potas s ium

Event Rate

%

Placebo

Event

Rate %

Hazard Ratio

(95% CI)

Los artan

Potas s ium

Event Rate

%

Placebo

Event

Rate %

Hazard Ratio

(95% CI)

Overall

Results

1513

43.5

47.1

0.84 (0.72, 0.98)

19.6

25.5

0.71 (0.58, 0.89)

<65 years

1005

44.1

49.0

0.78 (0.65, 0.94)

21.1

28.5

0.67 (0.52, 0.86)

≥65 years

42.3

43.5

0.98 (0.75, 1.28)

16.5

19.6

0.85 (0.56, 1.28)

Gender

Female

47.8

54.1

0.76 (0.60, 0.96)

22.8

32.8

0.60 (0.44, 0.83)

Male

40.9

43.3

0.89 (0.73, 1.09)

17.5

21.5

0.81 (0.60, 1.08)

Race

Asian

41.9

54.8

0.66 (0.45, 0.95)

18.8

27.4

0.63 (0.37, 1.07)

Black

40.0

39.0

0.98 (0.65, 1.50)

17.6

21.0

0.83 (0.46, 1.52)

Hispanic

55.0

54.0

1.00 (0.73, 1.38)

30.0

28.5

1.02 (0.66, 1.59)

White

40.5

43.2

0.81 (0.65, 1.01)

16.2

23.9

0.60 (0.43, 0.83)

16 HOW SUPPLIED/STORAGE AND HANDLING

Losartan Potassium Tablets USP, 50 mg are green colored, oval shaped, biconvex film-coated

tablets debossed with E on one side and 4 and 6 separated by scoreline on other side.

NDC 68071-5040-3 BOTTLES OF 30

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP

Controlled Room Temperature]. Keep container tightly closed. Protect from light.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Pregnancy

Advise female patients of childbearing age about the consequences of exposure to losartan potassium

during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to

report pregnancies to their physicians as soon as possible [see Warnings and Precautions (5.1) and Use

in Specific Populations (8.1)].

Potassium Supplements

Advise patients receiving losartan potassium not to use potassium supplements or salt substitutes

containing potassium without consulting their healthcare provider [see Drug Interactions (7.1)] .

Patient Information

Losartan Potassium Tablets USP

(loe sar' tan poe tas' ee um)

25 mg, 50 mg, 100 mg

Rx only

Read the Patient Information that comes with losartan potassium tablets before you start taking them and

each time you get a refill. There may be new information. This leaflet does not take the place of talking

with your doctor about your condition and treatment.

What is the most important information I should know about losartan potassium tablets?

Losartan potassium tablets can cause harm or death to an unborn baby.

Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant.

If you get pregnant while taking losartan potassium tablets, tell your doctor right away.

What are losartan potassium tablets?

Losartan potassium tablets is a prescription medicine called an angiotensin receptor blocker (ARB). It is

used:

alone or with other blood pressure medicines to lower high blood pressure (hypertension).

to lower the chance of stroke in patients with high blood pressure and a heart problem called left

ventricular hypertrophy. Losartan potassium tablets may not help Black patients with this problem.

to slow the worsening of diabetic kidney disease (nephropathy) in patients with type 2 diabetes who

have or had high blood pressure.

Losartan potassium tablets have not been studied in children less than 6 years old or in children with

certain kidney problems.

High Blood Pressure (hypertension). Blood pressure is the force in your blood vessels when your

heart beats and when your heart rests. You have high blood pressure when the force is too much.

Losartan potassium tablets can help your blood vessels relax so your blood pressure is lower.

Left Ventricular Hypertrophy (LVH) is an enlargement of the walls of the left chamber of the heart

(the heart’s main pumping chamber). LVH can happen from several things. High blood pressure is the

most common cause of LVH.

Type 2 Diabetes with Nephropathy. Type 2 diabetes is a type of diabetes that happens mainly in adults.

If you have diabetic nephropathy it means that your kidneys do not work properly because of damage

from the diabetes.

Who should not take losartan potassium tablets?

Do not take losartan potassium tablets if you are allergic to any of the ingredients in losartan

potassium tablets. See the end of this leaflet for a complete list of ingredients in losartan

potassium tablets.

Do not take losartan potassium tablets if you have diabetes and are taking a medicine called aliskiren

to reduce blood pressure.

What should I tell my doctor before taking losartan potassium tablets?

Tell your doctor about all of your medical conditions including if you:

are pregnant or planning to become pregnant. See “What is the most important information I

should know about losartan potassium tablets?”

are breastfeeding. It is not known if losartan potassium passes into your breast milk. You should

choose either to take losartan potassium tablets or breastfeed, but not both.

are vomiting a lot or having a lot of diarrhea

have liver problems

have kidney problems

Tell your doctor about all the medicines you take, including prescription and non-prescription

medicines, vitamins, and herbal supplements. Losartan potassium tablets and certain other medicines

may interact with each other. Especially tell your doctor if you are taking:

potassium supplements

salt substitutes containing potassium

other medicines that may increase serum potassium

water pills (diuretics)

lithium (a medicine used to treat a certain kind of depression)

medicines used to treat pain and arthritis, called non-steroidal anti-inflammatory drugs (NSAIDs),

including COX-2 inhibitors

other medicines to reduce blood pressure

How should I take losartan potassium tablets?

Take losartan potassium tablets exactly as prescribed by your doctor. Your doctor may change your

dose if needed.

Losartan potassium tablets can be taken with or without food.

If you miss a dose, take it as soon as you remember. If it is close to your next dose, do not take the

missed dose. Just take the next dose at your regular time.

If you take too much losartan potassium, call your doctor or Poison Control Center, or go to the

nearest hospital emergency room right away.

What are the possible side effects of losartan potassium tablets?

Losartan potassium tablets may cause the following side effects that may be serious:

Injury or death of unborn babies. See “What is the most important information I should know

about losartan potassium tablets?”

Allergic reaction. Symptoms of an allergic reaction are swelling of the face, lips, throat or tongue.

Get emergency medical help right away and stop taking losartan potassium tablets.

Low blood pressure (hypotension). Low blood pressure may cause you to feel faint or dizzy. Lie

down if you feel faint or dizzy. Call your doctor right away.

For people who already have kidney problems, you may see a worsening in how well your

kidneys work. Call your doctor if you get swelling in your feet, ankles, or hands, or unexplained

weight gain.

High blood levels of potassium

The most common side effects of losartan potassium tablets in people with high blood pressure are:

“colds” (upper respiratory infection)

dizziness

stuffy nose

back pain

The most common side effects of losartan potassium tablets in people with type 2 diabetes with diabetic

kidney disease are:

diarrhea

tiredness

low blood sugar

chest pain

high blood potassium

low blood pressure

Tell your doctor if you get any side effect that bothers you or that won’t go away.

This is not a complete list of side effects. For a complete list, ask your doctor or pharmacist.

How do I store losartan potassium tablets?

Store losartan potassium tablets USP at 59°F to 86°F (15°C to 30°C).

Keep losartan potassium tablets in a tightly closed container that protects the medicine from light.

Keep losartan potassium tablets and all medicines out of the reach of children.

General information about losartan potassium tablets

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets.

Do not use losartan potassium tablets for a condition for which it was not prescribed. Do not give

losartan potassium tablets to other people, even if they have the same symptoms that you have. They may

harm them.

This leaflet summarizes the most important information about losartan potassium tablets. If you would

like more information, talk with your doctor. You can ask your pharmacist or doctor for information

about losartan potassium tablets that is written for health professionals.

What are the ingredients in losartan potassium tablets?

Active ingredient: losartan potassium

Inactive ingredients: microcrystalline cellulose, lactose monohydrate, pregelatinized starch (maize),

low substituted hydroxypropyl cellulose, magnesium stearate, hydroxypropyl cellulose, hypromellose

6 cP, titanium dioxide, FD&C blue #2/indigo carmine aluminum lake, D&C yellow #10 aluminum lake,

and purified water.

Ora-Plus™ and Ora-Sweet SF™ are the trademarks of Paddock Laboratories, Inc.

Distributed by:

Aurobindo Pharma USA, Inc.

279 Princeton-Hightstown Road

East Windsor, NJ 08520

Manufactured by:

Aurobindo Pharma Limited

Hyderabad-500 038, India

Revised: 03/2019

PACKAGE LABEL PRINCIPAL DISPLAY PANEL -

LOSARTAN POTASSIUM

losartan potassium tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 8 0 71-50 40 (NDC:6 58 6 2-20 2)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

LO SARTAN PO TASSIUM (UNII: 3ST30 2B24A) (LOSARTAN - UNII:JMS50 MPO8 9 )

LOSARTAN POTASSIUM

50 mg

Inactive Ingredients

Ingredient Name

Stre ng th

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

STARCH, CO RN (UNII: O8 232NY3SJ)

LO W-SUBSTITUTED HYDRO XYPRO PYL CELLULO SE, UNSPECIFIED (UNII: 216 5RE0 K14)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

HYDRO XYPRO PYL CELLULO SE ( 16 0 0 0 0 0 WAMW) (UNII: RFW2ET6 71P)

HYPRO MELLO SE 2 9 10 ( 6 MPA.S) (UNII: 0 WZ8 WG20 P6 )

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

FD&C BLUE NO . 2 (UNII: L0 6 K8 R7DQK)

D&C YELLO W NO . 10 (UNII: 35SW5USQ3G)

WATER (UNII: 0 59 QF0 KO0 R)

Product Characteristics

Color

gre e n

S core

2 pieces

S hap e

OVAL (Bico nvex)

S iz e

10 mm

Flavor

Imprint Code

E;4;6

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 8 0 71-50 40 -3

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /28 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 9 0 0 8 3

10 /0 6 /20 10

Labeler -

NuCare Pharmaceuticals,Inc. (010632300)

NuCare Pharmaceuticals,Inc.

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

NuCare Pharmaceuticals,Inc.

0 10 6 3230 0

re la be l(6 8 0 71-50 40 )

Revised: 8/2019

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