LOSARTAN POTASSIUM AND HYDROCHLOROTHIAZIDE - losartan potassium and hydrochlorothiazide tablet, film coated

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

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Active ingredient:
LOSARTAN POTASSIUM (UNII: 3ST302B24A) (LOSARTAN - UNII:JMS50MPO89), HYDROCHLOROTHIAZIDE (UNII: 0J48LPH2TH) (HYDROCHLOROTHIAZIDE - UNII:0J48LPH2TH)
Available from:
Bryant Ranch Prepack
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Losartan potassium and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal 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 and hydrochlorothiazide. 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 antihypertensiv
Product summary:
Product: 63629-8089 NDC: 63629-8089-1 90 TABLET, FILM COATED in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
63629-8089-1

LOSARTAN POTASSIUM AND HYDROCHLOROTHIAZIDE - losartan potassium and

hydrochlorothiazide tablet, film coated

Bryant Ranch Prepack

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HIGHLIGHTS OF PRESCRIBING INFORMATION

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

HYDROCHLOROTHIAZIDE TABLETS safely and effectively. See full prescribing information for LOSARTAN

POTASSIUM AND HYDROCHLOROTHIAZIDE TABLETS.

LOSARTAN POTASSIUM AND HYDROCHLOROTHIAZIDE 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 and hydrochlorothiazide tablets 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

Electrolyte and Metabolic Effects (5.5) 10/2018

INDICATIONS AND USAGE

Losartan potassium and hydrochlorothiazide is a combination of losartan, an angiotensin II receptor blocker (ARB) and

hydrochlorothiazide, a diuretic indicated for:

Treatment of hypertension, to lower blood pressure. 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)

DOSAGE AND ADMINISTRATION

Hype rte nsion

Usual starting dose: 50 mg/12.5 mg once daily. (2.1)

Titrate as needed to a maximum dose of 100 mg/25 mg. (2.1)

Hypertensive Patients with Left Ventricular Hypertrophy

Not controlled on monotherapy: Initiate with 50 mg/12.5 mg. Titrate as needed to a maximum of 100 mg/25 mg. (2.2)

DOSAGE FORMS AND STRENGTHS

Tablets (losartan potassium/hydrochlorothiazide content): 50 mg/12.5 mg; 100 mg/12.5 mg; and 100 mg/25 mg. (3)

CONTRAINDICATIONS

Hypersensitivity to any component of losartan potassium and hydrochlorothiazide tablets. (4)

Anuria. (4)

Coadministration with aliskiren in patients with diabetes. (4)

WARNINGS AND PRECAUTIONS

Hypotension: Correct volume or salt depletion prior to administration of losartan potassium and hydrochlorothiazide.

(5.2)

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

Observe for clinical signs of fluid or electrolyte imbalance. (5.5)

Acute angle-closure glaucoma. (5.6)

Exacerbation of systemic lupus erythematosus. (5.7)

ADVERSE REACTIONS

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

cough, 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

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

Lithium: Risk of lithium toxicity. (7.2)

Non-Steroidal Anti-Inflammatory Drugs (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)

Antidiabetic drugs: dosage adjustment of antidiabetic may be required. (7.5)

Cholestyramine and colestipol: Reduced absorption of thiazides. (7.5)

USE IN SPECIFIC POPULATIONS

Hepatic Impairment: losartan potassium and hydrochlorothiazide is not recommended for initial therapy, because the

recommended starting dose is not available. (8.7)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 8/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: FETAL TOXICITY

1 INDICATIONS AND USAGE

1.1 Hypertension

1.2 Hypertensive Patients with Left Ventricular Hypertrophy

2 DOSAGE AND ADMINISTRATION

2.1 Hypertension

2.2 Hypertensive Patients with Left Ventricular Hypertrophy

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 Impaired Renal Function

5.4 Hypersensitivity

5.5 Electrolyte and Metabolic Effects

5.6 Acute Myopia and Secondary Angle-Closure Glaucoma

5.7 Systemic Lupus Erythematosus

5.8 Postsympathectomy Patients

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 Agents Including Selective Cyclooxygenase-2 Inhibitors

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

7.5 The Use of Hydrochlorothiazide with Other Drugs

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 Hepatic Impairment

8.8 Renal Impairment

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 Losartan Monotherapy

14.2 Losartan Potassium-Hydrochlorothiazide

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING: FETAL TOXICITY

When pregnancy is detected, discontinue losartan potassium and hydrochlorothiazide

tablets 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 and hydrochlorothiazide tablets are indicated for the treatment of hypertension, to

lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal 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 and

hydrochlorothiazide.

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

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

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.

This fixed dose combination is not indicated for initial therapy of hypertension, except when the

hypertension is severe enough that the value of achieving prompt blood pressure control exceeds the

risk of initiating combination therapy in these patients [see Clinical Studies (14) and Dosage and

Administration (2.1)].

Losartan potassium and hydrochlorothiazide tablets may be administered with other antihypertensive

agents.

1.2 Hypertensive Patients with Left Ventricular Hypertrophy

Losartan potassium and hydrochlorothiazide 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), Clinical Pharmacology (12.3), and Dosage and

Administration (2.2)].

2 DOSAGE AND ADMINISTRATION

2.1 Hypertension

The usual starting dose of losartan potassium and hydrochlorothiazide tablets is 50 mg/12.5 mg (losartan

50 mg/hydrochlorothiazide 12.5 mg) once daily. The dosage can be increased after 3 weeks of

therapy to a maximum of 100 mg/25 mg (losartan 100 mg/hydrochlorothiazide 25 mg) once daily as

needed to control blood pressure [see Clinical Studies (14.2)].

Initiate a patient whose blood pressure is not adequately controlled with losartan 50 mg monotherapy

with losartan potassium and hydrochlorothiazide tablets 50 mg/12.5 mg once daily. If blood pressure

remains uncontrolled after about 3 weeks of therapy, the dosage may be increased to two tablets of

losartan potassium and hydrochlorothiazide 50 mg/12.5 mg once daily or one tablet of losartan

potassium and hydrochlorothiazide 100 mg/25 mg once daily.

Initiate a patient whose blood pressure is not adequately controlled with losartan 100 mg monotherapy

with losartan potassium and hydrochlorothiazide tablets 100 mg/12.5 mg once daily. If blood pressure

remains uncontrolled after about 3 weeks of therapy, increase the dose to two tablets of losartan

potassium and hydrochlorothiazide 50 mg/12.5 mg once daily or one tablet of losartan potassium and

hydrochlorothiazide 100 mg/25 mg once daily.

Initiate a patient whose blood pressure is inadequately controlled with hydrochlorothiazide 25 mg once

daily, or is controlled but who experiences hypokalemia with this regimen, on losartan potassium and

hydrochlorothiazide tablets 50 mg/12.5 mg once daily, reducing the dose of hydrochlorothiazide

without reducing the overall expected antihypertensive response. Evaluate the clinical response to

losartan potassium and hydrochlorothiazide tablets 50 mg/12.5 mg and, if blood pressure remains

uncontrolled after about 3 weeks of therapy, increase the dose to two tablets of losartan potassium and

hydrochlorothiazide 50 mg/12.5 mg once daily or one tablet of losartan potassium and

hydrochlorothiazide 100 mg/25 mg once daily.

2.2 Hypertensive Patients with Left Ventricular Hypertrophy

In patients whose blood pressure is not adequately controlled on 50 mg losartan potassium, initiate

treatment with losartan potassium and hydrochlorothiazide tablets 50 mg/12.5 mg. If additional blood

pressure reduction is needed, increase the dose to losartan potassium and hydrochlorothiazide tablets

100 mg/12.5 mg, followed by losartan potassium and hydrochlorothiazide tablets 100 mg/25 mg. For

further blood pressure reduction add other antihypertensives [see Clinical Studies (14)].

3 DOSAGE FORMS AND STRENGTHS

Losartan Potassium and Hydrochlorothiazide Tablets USP, 50 mg/12.5 mg are yellow colored,

oval shaped, beveled edge, biconvex film-coated tablets debossed with ‘E’ on one side and ‘48’ on the

other side.

Losartan Potassium and Hydrochlorothiazide Tablets USP, 100 mg/12.5 mg are white, oval

shaped, beveled edge, biconvex film-coated tablets debossed with ‘F’ on one side and ‘74’ on the other

side.

Losartan Potassium and Hydrochlorothiazide Tablets USP, 100 mg/25 mg are yellow colored,

oval shaped, beveled edge, biconvex film-coated tablets debossed with ‘E’ on one side and ‘49’ on the

other side.

4 CONTRAINDICATIONS

Losartan potassium and hydrochlorothiazide tablets are contraindicated:

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

In patients with anuria

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 and hydrochlorothiazide as soon as possible.

Thiazides cross the placental barrier and appear in cord blood. Adverse reactions include fetal or

neonatal jaundice, thrombocytopenia [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 and hydrochlorothiazide. Correct volume or salt depletion prior to

administration of losartan potassium and hydrochlorothiazide. Do not use losartan potassium and

hydrochlorothiazide as initial therapy in patients with intravascular volume depletion.

5.3 Impaired Renal Function

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 and hydrochlorothiazide. 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 and hydrochlorothiazide [see Drug Interactions (7.3) and Use in

Specific Populations (8.8)].

5.4 Hypersensitivity

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of

allergy or bronchial asthma, but are more likely in patients with such a history.

5.5 Electrolyte and Metabolic Effects

In double-blind clinical trials of various doses of losartan potassium and hydrochlorothiazide, the

incidence of hypertensive patients who developed hypokalemia (serum potassium <3.5 mEq/L) was

6.7% versus 3.5% for placebo; the incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4%

versus 0% for placebo.

Losartan potassium and hydrochlorothiazide contains hydrochlorothiazide which can cause

hypokalemia, hyponatremia and hypomagnesemia. Hypomagnesemia can result in hypokalemia which

may be difficult to treat despite potassium repletion. Losartan potassium and hydrochlorothiazide also

contains losartan which can cause hyperkalemia. Monitor serum electrolytes periodically [see Drug

Interactions (7.1)].

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

Interactions (7.1)].

Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and

triglycerides.

Hyperuricemia may occur or frank gout may be precipitated in patients receiving thiazide therapy.

Because losartan decreases uric acid, losartan in combination with hydrochlorothiazide attenuates the

diuretic-induced hyperuricemia.

Hydrochlorothiazide decreases urinary calcium excretion and may cause elevations of serum calcium.

Monitor calcium levels.

5.6 Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient

myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or

ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure

glaucoma can lead to permanent vision loss. The primary treatment is to discontinue

hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be

considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-

closure glaucoma may include a history of sulfonamide or penicillin allergy.

5.7 Systemic Lupus Erythematosus

Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus

erythematosus.

5.8 Postsympathectomy Patients

The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.

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.

Losartan potassium and hydrochlorothiazide has been evaluated for safety in 858 patients treated for

essential hypertension and 3889 patients treated for hypertension and left ventricular hypertrophy. Most

adverse reactions have been mild and transient in nature and have not required discontinuation of therapy.

In controlled clinical trials, discontinuation of therapy due to clinical adverse events was required in

only 2.8% and 2.3% of patients treated with the combination and placebo, respectively.

In these double-blind controlled clinical trials, adverse reactions occurring in greater than 2% of

subjects treated with losartan and hydrochlorothiazide and at a greater rate than placebo were: back pain

(2.1% vs 0.6%), dizziness (5.7% vs 2.9%), and upper respiratory infection (6.1% vs 4.6%).

The following additional adverse reactions have been reported in clinical trials with losartan potassium

and hydrochlorothiazide and/or the individual components:

Blood and the lymphatic system disorders: Anemia, aplastic anemia, hemolytic anemia, leukopenia,

agranulocytosis.

Metabolism and nutrition disorders: Anorexia, hyperglycemia, hyperuricemia, electrolyte imbalance

including hyponatremia and hypokalemia.

Psychiatric disorders: Insomnia, restlessness.

Nervous system disorders: Dysgeusia, headache, migraine, paraesthesias.

Eye disorders: Xanthopsia, transient blurred vision.

Cardiac disorders: Palpitation, tachycardia.

Vascular disorders: Dose-related orthostatic effects, necrotizing angiitis (vasculitis, cutaneous

vasculitis).

Respiratory, thoracic and mediastinal disorders: Nasal congestion, pharyngitis, sinus disorder,

respiratory distress (including pneumonitis and pulmonary edema).

Gastrointestinal disorders: Dyspepsia, abdominal pain, gastric irritation, cramping, diarrhea, constipation,

nausea, vomiting, pancreatitis, sialoadenitis.

Hepato-biliary disorders: Jaundice (intrahepatic cholestatic jaundice).

Skin and subcutaneous tissue disorders: Rash, pruritus, purpura, toxic epidermal necrolysis, urticaria,

photosensitivity, cutaneous lupus erythematosus.

Musculoskeletal and connective tissue disorders: Muscle cramps, muscle spasm, myalgia, arthralgia.

Renal and urinary disorders: Glycosuria, renal dysfunction, interstitial nephritis, renal failure.

Reproductive system and breast disorders: Erectile dysfunction/impotence.

General disorders and administration site conditions: Chest pain, edema/swelling, malaise, fever,

weakness.

Investigations: Liver function abnormalities.

Cough

Persistent dry cough 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

Study2

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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of losartan potassium

and hydrochlorothiazide. 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 has been reported rarely in patients treated with losartan.

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 with losartan.

Anaphylactic reactions have been reported.

Musculoskeletal: rhabdomyolysis

Skin: Erythroderma

7 DRUG INTERACTIONS

7.1 Agents Increasing Serum Potassium

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

Monitor serum potassium in such patients.

7.2 Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use

of angiotensin II receptor antagonists or thiazide diuretics. Monitor lithium levels in patients receiving

losartan potassium and hydrochlorothiazide and lithium.

7.3 Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors

Losartan Potassium

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.

Hydrochlorothiazide

The administration of a non-steroidal anti-inflammatory agent including a selective COX-2 inhibitor can

reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide

diuretics. Therefore, when losartan potassium and hydrochlorothiazide and non-steroidal anti-

inflammatory agents including selective COX-2 inhibitors are used concomitantly, observe closely to

determine if the desired effect of the diuretic is obtained.

In patients receiving diuretic therapy, coadministration of NSAIDs with angiotensin receptor blockers,

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

hydrochlorothiazide, losartan, and NSAID therapy.

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.

Closely monitor blood pressure, renal function, and electrolytes in patients on losartan potassium and

hydrochlorothiazide and other agents that affect the RAS.

Do not coadminister aliskiren with losartan potassium and hydrochlorothiazide in patients with diabetes.

Avoid use of aliskiren with losartan potassium and hydrochlorothiazide in patients with renal impairment

(GFR <60 mL/min).

7.5 The Use of Hydrochlorothiazide with Other Drugs

When administered concurrently, the following drugs may interact with thiazide diuretics [see Clinical

Pharmacology (12.3)]:

Antidiabetic drugs (oral agents and insulin) — dosage adjustment of the antidiabetic drug may be

required.

Cholestyramine and colestipol resins — Absorption of hydrochlorothiazide is impaired in the presence

of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the

hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent,

respectively. Stagger the dosage of hydrochlorothiazide and the resin such that hydrochlorothiazide is

administered at least 4 hours before or 4 to 6 hours after the administration of the resin.

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 and hydrochlorothiazide, 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 and

hydrochlorothiazide for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4)].

There was no evidence of teratogenicity in rats or rabbits treated with a maximum losartan potassium

dose of 10 mg/kg/day in combination with 2.5 mg/kg/day of hydrochlorothiazide. At these dosages,

respective exposures (AUCs) of losartan, its active metabolite, and hydrochlorothiazide in rabbits were

approximately 5, 1.5, and 1 times those achieved in humans with 100 mg losartan in combination with 25

mg hydrochlorothiazide. AUC values for losartan, its active metabolite and hydrochlorothiazide,

extrapolated from data obtained with losartan administered to rats at a dose of 50 mg/kg/day in

combination with 12.5 mg/kg/day of hydrochlorothiazide, were approximately 6, 2, and 2 times greater

than those achieved in humans with 100 mg of losartan in combination with 25 mg of

hydrochlorothiazide. Fetal toxicity in rats, as evidenced by a slight increase in supernumerary ribs, was

observed when females were treated prior to and throughout gestation with 10 mg/kg/day losartan in

combination with 2.5 mg/kg/day hydrochlorothiazide. As also observed in studies with losartan alone,

adverse fetal and neonatal effects, including decreased body weight, renal toxicity, and mortality,

occurred when pregnant rats were treated during late gestation and/or lactation with 50 mg/kg/day

losartan in combination with 12.5 mg/kg/day hydrochlorothiazide. Respective AUCs for losartan, its

active metabolite and hydrochlorothiazide at these dosages in rats were approximately 35, 10 and 10

times greater than those achieved in humans with the administration of 100 mg of losartan in combination

with 25 mg hydrochlorothiazide. When hydrochlorothiazide was administered without losartan to

pregnant mice and rats during their respective periods of major organogenesis, at doses up to 3000 and

1000 mg/kg/day, respectively, there was no evidence of harm to the fetus.

Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal

jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

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. Thiazides appear in human 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

Safety and effectiveness of losartan potassium and hydrochlorothiazide in pediatric patients have not

been established.

Neonates with a history of in utero exposure to losartan potassium and hydrochlorothiazide: 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.

8.5 Geriatric Use

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. In an effort to control blood

pressure in this study, patients were coadministered losartan and hydrochlorothiazide 74% of the total

time they were on study drug. No overall differences in effectiveness were observed between these

patients and younger patients. Adverse events were somewhat more frequent in the elderly compared to

non-elderly patients for both the losartan-hydrochlorothiazide and the control groups [see Clinical

Pharmacology (12.3)].

8.6 Race

In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, Black patients with

hypertension and left ventricular hypertrophy treated with atenolol had a lower risk of stroke, the

primary composite endpoint, as compared with Black patients treated with losartan (both cotreated with

hydrochlorothiazide in the majority of patients). 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. 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 on

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

apply to Black patients [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Initiation of losartan potassium and hydrochlorothiazide is not recommended for patients with hepatic

impairment because the appropriate starting dose of losartan, 25 mg, is not available.

8.8 Renal Impairment

Changes in renal function have been reported in susceptible individuals [see Dosage and Administration

(2.1), Warnings and Precautions (5.4), and Clinical Pharmacology (12.3)]. Safety and effectiveness of

losartan potassium and hydrochlorothiazide in patients with severe renal impairment (creatinine

clearance <30 mL/min) have not been established.

10 OVERDOSAGE

Losartan Potassium

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.

Hydrochlorothiazide

The oral LD of hydrochlorothiazide is greater than 10 g/kg in both mice and rats. The most common

signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia,

hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been

administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which

hydrochlorothiazide is removed by hemodialysis has not been established.

11 DESCRIPTION

Losartan potassium and hydrochlorothiazide 50 mg/12.5 mg, losartan potassium and hydrochlorothiazide

100 mg/12.5 mg and losartan potassium and hydrochlorothiazide 100 mg/25 mg tablets combine an

angiotensin II receptor blocker acting on the AT receptor subtype and a diuretic, hydrochlorothiazide.

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

tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt. Its molecular formula is

H 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.

Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.

Its molecular formula is C H ClN O S and its structural formula is:

Hydrochlorothiazide USP is a white or practically white, practically odorless, crystalline powder with

a molecular weight of 297.74, which is slightly soluble in water, but freely soluble in sodium

hydroxide solution.

Losartan potassium and hydrochlorothiazide is available for oral administration in three tablet

combinations of losartan and hydrochlorothiazide. Losartan potassium and hydrochlorothiazide tablets

USP, 50 mg/12.5 mg contain 50 mg of losartan potassium USP and 12.5 mg of hydrochlorothiazide USP.

Losartan potassium and hydrochlorothiazide tablets USP, 100 mg/12.5 mg contain 100 mg of losartan

potassium USP and 12.5 mg of hydrochlorothiazide USP. Losartan potassium and hydrochlorothiazide

tablets USP, 100 mg/25 mg contain 100 mg of losartan potassium USP and 25 mg of

hydrochlorothiazide USP. Inactive ingredients are colloidal silicon dioxide, hydroxypropyl cellulose,

hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinised

starch(maize), and titanium dioxide. Losartan potassium and hydrochlorothiazide 50 mg/12.5 mg and

losartan potassium and hydrochlorothiazide 100 mg/25 mg also contain D&C yellow No. 10 aluminum

lake.

Losartan potassium and hydrochlorothiazide tablets USP, 50 mg/12.5 mg contains 4.24 mg (0.108 mEq)

of potassium, losartan potassium and hydrochlorothiazide tablets USP, 100 mg/12.5 mg contains 8.48

mg (0.217 mEq) of potassium, and losartan potassium and hydrochlorothiazide tablets USP, 100 mg/25

mg contains 8.48 mg (0.217 mEq) of potassium.

Meets USP Dissolution Test 2.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Losartan Potassium

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.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte

reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts.

Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent

increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium

loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so

coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated

with these diuretics. The mechanism of the antihypertensive effect of thiazides is unknown.

12.2 Pharmacodynamics

Losartan Potassium

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.

Hydrochlorothiazide

After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours,

and lasts about 6 to 12 hours.

Drug Interactions

Hydrochlorothiazide

Alcohol, barbiturates, or narcotics — potentiation of orthostatic hypotension may occur.

Other antihypertensive drugs — additive effect or potentiation.

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) — possible increased responsiveness to

the muscle relaxant.

Corticosteroids, ACTH, or glycyrrhizin (found in liquorice) — intensified electrolyte depletion,

particularly hypokalemia.

Pressor amines (e.g., norepinephrine) — possible decreased response to pressor amines but not

sufficient to preclude their use.

12.3 Pharmacokinetics

Losartan Potassium

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

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 accumulate in plasma upon repeated once-daily dosing.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels

have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6

and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours.

Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Special Populations

Geriatric and Gender

Losartan pharmacokinetics have been investigated in the elderly (65 to 75 years) 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.

Race

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

(8.6)].

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. The

lower starting dose of losartan recommended for use in patients with hepatic impairment cannot be given

using losartan potassium and hydrochlorothiazide. Its use in such patients as a means of losartan titration

is, therefore, not recommended [see Warnings and Precautions (5.3) and Use in Specific Populations

(8.7)].

Renal Insufficiency

Losartan

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.

Hydrochlorothiazide

Following oral administration, the AUC for hydrochlorothiazide is increased by 70 and 700% for

patients with mild and moderate renal insufficiency, respectively. In this study, renal clearance of

hydrochlorothiazide decreased by 45 and 85% in patients with mild and moderate renal impairment,

respectively.

Use the usual regimens of therapy with losartan potassium and hydrochlorothiazide as long as the

patient's creatinine clearance is greater than 30 mL/min. Safety and effectiveness of losartan potassium

and hydrochlorothiazide in patients with severe renal impairment (creatinine clearance less than 30

mL/min) have not been established [see Use in Specific Populations (8.8)].

Drug Interactions

Losartan Potassium

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-Hydrochlorothiazide

No carcinogenicity studies have been conducted with the losartan potassium-hydrochlorothiazide

combination.

Losartan potassium and hydrochlorothiazide when tested at a weight ratio of 4:1, was negative in the

Ames microbial mutagenesis assay and the V-79 Chinese hamster lung cell mutagenesis assay. In

addition, there was no evidence of direct genotoxicity in the in vitro alkaline elution assay in rat

hepatocytes and in vitro chromosomal aberration assay in Chinese hamster ovary cells at noncytotoxic

concentrations.

Losartan potassium, coadministered with hydrochlorothiazide, had no effect on the fertility or mating

behavior of male rats at dosages up to 135 mg/kg/day of losartan and 33.75 mg/kg/day of

hydrochlorothiazide. These dosages have been shown to provide respective systemic exposures

(AUCs) for losartan, its active metabolite and hydrochlorothiazide that are approximately 60, 60 and 30

times greater than those achieved in humans with 100 mg of losartan potassium in combination with 25

mg of hydrochlorothiazide. In female rats, however, the coadministration of doses as low as 10

mg/kg/day of losartan and 2.5 mg/kg/day of hydrochlorothiazide was associated with slight but

statistically significant decreases in fecundity and fertility indices. AUC values for losartan, its active

metabolite and hydrochlorothiazide, extrapolated from data obtained with losartan administered to rats at

a dose of 50 mg/kg/day in combination with 12.5 mg/kg/day of hydrochlorothiazide, were approximately

6, 2, and 2 times greater than those achieved in humans with 100 mg of losartan in combination with 25

mg of hydrochlorothiazide.

Losartan Potassium

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).

Hydrochlorothiazide

Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology

Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female

mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to

approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for

hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella

typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster

Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell

chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive

lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange

(clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of

hydrochlorothiazide from 43 to 1300 mcg/mL, and in the Aspergillus nidulans non-disjunction assay at an

unspecified concentration.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies

wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively,

prior to mating and throughout gestation.

14 CLINICAL STUDIES

14.1 Losartan Monotherapy

Reduction in the Risk of Stroke: The LIFE study was a multinational, double-blind study comparing

losartan 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 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 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.

In efforts to control blood pressure, the patients in both arms of the LIFE study were coadministered

hydrochlorothiazide the majority of time they were on study drug (73.9% and 72.4% of days in the

losartan and atenolol arms, respectively).

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 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 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 and 145.4/80.9 mmHg for the group treated

with atenolol [the difference in SBP of 1.3 mmHg was significant (p<0.001), while the difference of

0.4 mmHg in 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

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

this difference was primarily the result of an effect on fatal and nonfatal stroke. Treatment with losartan

reduced the risk of stroke by 25% relative to atenolol (p=0.001).

14.2 Losartan Potassium-Hydrochlorothiazide

The 3 controlled studies of losartan and hydrochlorothiazide included over 1300 patients assessing the

antihypertensive efficacy of various doses of losartan (25 mg, 50 mg and 100 mg) and concomitant

hydrochlorothiazide (6.25 mg, 12.5 mg and 25 mg). A factorial study compared the combination of

losartan/hydrochlorothiazide 50 mg/12.5 mg with its components and placebo. The combination of

losartan/hydrochlorothiazide 50 mg/12.5 mg resulted in an approximately additive placebo-adjusted

systolic/diastolic response (15.5/9 mmHg for the combination compared to 8.5/5 mmHg for losartan

alone and 7/3 mmHg for hydrochlorothiazide alone). Another study investigated the dose-response

relationship of various doses of hydrochlorothiazide (6.25 mg, 12.5 mg and 25 mg) or placebo on a

background of losartan (50 mg) in patients not adequately controlled (Sitting Diastolic Blood Pressure

[SiDBP] 93 to 120 mmHg) on losartan (50 mg) alone. The third study investigated the dose-response

relationship of various doses of losartan (25 mg, 50 mg and 100 mg) or placebo on a background of

hydrochlorothiazide (25 mg) in patients not adequately controlled (SiDBP 93 to 120 mmHg) on

hydrochlorothiazide (25 mg) alone. These studies showed an added antihypertensive response at trough

(24 hours post-dosing) of hydrochlorothiazide 12.5 mg or 25 mg added to losartan 50 mg of 5.5/3.5 and

10/6 mmHg, respectively. Similarly, there was an added antihypertensive response at trough when

losartan 50 mg or 100 mg was added to hydrochlorothiazide 25 mg of 9/5.5 and 12.5/6.5 mmHg,

respectively. There was no significant effect on heart rate.

There was no difference in response for men and women or in patients over or under 65 years of age.

Black patients had a larger response to hydrochlorothiazide than non-Black patients and a smaller

response to losartan. The overall response to the combination was similar for Black and non-Black

patients.

Severe Hypertension (SiDBP ≥110 mmHg)

The safety and efficacy of losartan potassium and hydrochlorothiazide as initial therapy for severe

hypertension (defined as a mean SiDBP≥110 mmHg confirmed on 2 separate occasions off all

antihypertensive therapy) was studied in a 6-week double-blind, randomized, multicenter study. Patients

were randomized to either losartan and hydrochlorothiazide (50 mg/12.5 mg, once daily) or to losartan

(50 mg, once daily) and followed for blood pressure response. Patients were titrated at 2-week

intervals if their SiDBP did not reach goal (<90 mmHg). Patients on combination therapy were

titrated from losartan 50 mg/hydrochlorothiazide 12.5 mg to losartan 50 mg/hydrochlorothiazide 12.5

mg (sham titration to maintain the blind) to losartan 100 mg/hydrochlorothiazide 25 mg. Patients on

monotherapy were titrated from losartan 50 mg to losartan 100 mg to losartan 150 mg, as needed. The

primary endpoint was a comparison at 4 weeks of patients who achieved goal diastolic blood pressure

(trough SiDBP <90 mmHg).

The study enrolled 585 patients, including 264 (45%) females, 124 (21%) blacks, and 21 (4%) ≥65 years

of age. The mean blood pressure at baseline for the total population was 171/113 mmHg. The mean age

was 53 years. After 4 weeks of therapy, the mean SiDBP was 3.1 mmHg lower and the mean SiSBP was

5.6 mmHg lower in the group treated with losartan potassium and hydrochlorothiazide. As a result, a

greater proportion of the patients on losartan potassium and hydrochlorothiazide reached the target

diastolic blood pressure (17.6% for losartan potassium and hydrochlorothiazide, 9.4% for losartan;

p=0.006). Similar trends were seen when the patients were grouped according to gender, race or age

(<, ≥ 65).

After 6 weeks of therapy, more patients who received the combination regimen reached target diastolic

blood pressure than those who received the monotherapy regimen (29.8% versus 12.5%).

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 63629-8089

NDC: 63629-8089-1 90 TABLET, FILM COATED in a BOTTLE

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 and hydrochlorothiazide 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)].

Symptomatic Hypotension: Advise patients that lightheadedness can occur, especially during the first

days of therapy, and to report this symptom to a healthcare provider. Inform patients that dehydration

from inadequate fluid intake, excessive perspiration, vomiting, or diarrhea may lead to an excessive fall

in blood pressure. If syncope occurs, advise patients to contact their healthcare provider [see Warnings

and Precautions (5.2)].

Potassium Supplements: Advise patients not to use potassium supplements or salt substitutes containing

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

Acute myopia and secondary angle-closure glaucoma: Advise patients to discontinue losartan potassium

and hydrochlorothiazide tablets and seek immediate medical attention if they experience symptoms of

Acute Myopia or Secondary Angle-Closure Glaucoma [see Warnings and Precautions (5.6)].

Patient Information

Losartan Potassium and Hydrochlorothiazide Tablets, USP

(loe sar' tan poe tas' ee um and hye'' droe klor'' oh thye' a zide)

Rx only

Read the Patient Information that comes with losartan potassium and hydrochlorothiazide 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 and

hydrochlorothiazide tablets?

Losartan potassium and hydrochlorothiazide 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 and hydrochlorothiazide tablets, tell your doctor

right away.

What are losartan potassium and hydrochlorothiazide tablets?

Losartan potassium and hydrochlorothiazide tablets contain 2 prescription medicines, an angiotensin

receptor blocker (ARB) and a diuretic (water pill). It is used to:

lower high blood pressure (hypertension). Losartan potassium and hydrochlorothiazide tablets are

not usually the first medicine used to treat high blood pressure.

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

ventricular hypertrophy (LVH). Losartan potassium and hydrochlorothiazide tablets may not help

Black patients with this problem.

Losartan potassium and hydrochlorothiazide tablets have not been studied in children less than

18 years old.

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. The

losartan ingredient in losartan potassium and hydrochlorothiazide tablets can help your blood vessels

relax so your blood pressure is lower. The hydrochlorothiazide ingredient in losartan potassium and

hydrochlorothiazide tablets work by making your kidneys pass more water and salt.

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.

Who should not take losartan potassium and hydrochlorothiazide tablets?

Do not take losartan potassium and hydrochlorothiazide tablets if you:

are allergic to any ingredients in losartan potassium and hydrochlorothiazide tablets. See a complete

list of ingredients in losartan potassium and hydrochlorothiazide tablets at the end of this leaflet.

are not passing urine.

have diabetes and are taking a medicine called aliskiren to reduce blood pressure.

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

Tell your doctor about all 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 and hydrochlorothiazide tablets?”

are breastfeeding or plan to breastfeed. Losartan potassium and hydrochlorothiazide can pass into

your milk and may harm your baby. You and your doctor should decide if you will take losartan

potassium and hydrochlorothiazide tablets or breastfeed. You should not do both.

have been vomiting (throwing up), having diarrhea, sweating a lot, or not drinking enough fluids.

These could cause you to have low blood pressure.

have liver problems

have kidney problems

have systemic lupus erythematosus (Lupus; SLE)

have diabetes

have gout

have any allergies

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

medicines, vitamins, and herbal supplements.

Losartan potassium and hydrochlorothiazide 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.

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist

when you get a new medicine.

How should I take losartan potassium and hydrochlorothiazide tablets?

Take losartan potassium and hydrochlorothiazide tablets exactly as prescribed by your doctor. Your

doctor may change your dose if needed.

Losartan potassium and hydrochlorothiazide 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 and hydrochlorothiazide tablets, call your doctor or Poison

Control Center, or go to the nearest hospital emergency room right away.

Your doctor may do blood tests from time to time while you are taking losartan potassium and

hydrochlorothiazide tablets.

What are the possible side effects of losartan potassium and hydrochlorothiazide tablets?

Losartan potassium and hydrochlorothiazide 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 and hydrochlorothiazide 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 and hydrochlorothiazide

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.

If you 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.

A new or worsening condition called systemic lupus erythematosus (Lupus; SLE)

Eye problems. One of the medicines in losartan potassium and hydrochlorothiazide tablets can

cause eye problems that, if left untreated, may lead to vision loss. Symptoms of eye problems can

happen within hours to weeks of starting losartan potassium and hydrochlorothiazide tablets. Tell

your doctor right away if you have:

decrease in vision

eye pain

The most common side effects of losartan potassium and hydrochlorothiazide tablets in people with

high blood pressure are:

“colds” (upper respiratory infection)

dizziness

stuffy nose

back pain

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 should I store losartan potassium and hydrochlorothiazide tablets?

Store losartan potassium and hydrochlorothiazide tablets at room temperature at 20° to 25°C (68° to

77°F).

Keep losartan potassium and hydrochlorothiazide tablets in a tightly closed container, and keep

losartan potassium and hydrochlorothiazide tablets out of the light.

Keep losartan potassium and hydrochlorothiazide tablets and all medicines out of the reach of

children.

General information about losartan potassium and hydrochlorothiazide tablets

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

Do not use losartan potassium and hydrochlorothiazide tablets for a condition for which it was not

prescribed. Do not give losartan potassium and hydrochlorothiazide 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 and

hydrochlorothiazide tablets. If you would like more information, talk with your doctor. You can ask

your pharmacist or doctor for information that is written for health professionals.

What are the ingredients in losartan potassium and hydrochlorothiazide tablets?

Active ingredients: losartan potassium, hydrochlorothiazide

Inactive ingredients: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, lactose

monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinised starch (maize), and titanium

dioxide. Losartan potassium and hydrochlorothiazide 50 mg/12.5 mg and losartan potassium and

hydrochlorothiazide 100 mg/25 mg also contain D&C yellow No. 10 aluminum lake.

Distributed by:

Aurobindo Pharma USA, Inc.

279 Princeton-Hightstown Road

East Windsor, NJ 08520

Manufactured by:

Aurobindo Pharma Limited

Hyderabad - 500 038, India

Revised: 11/2018

LOSARTAN POTASS HCTZ 100-25MG TABLET

LOSARTAN POTASSIUM AND HYDROCHLOROTHIAZIDE

losartan potassium and hydrochlorothiazide tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION

DRUG

Ite m Code

(S ource )

NDC:6 36 29 -8 0 8 9 (NDC:6 58 6 2-470 )

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 10 0 mg

HYDRO CHLO RO THIAZIDE (UNII: 0 J48 LPH2TH) (HYDROCHLOROTHIAZIDE -

UNII:0 J48 LPH2TH)

HYDROCHLOROTHIAZIDE 25 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

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 )

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

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

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

STARCH, CO RN (UNII: O8 232NY3SJ)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

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

Product Characteristics

Color

YELLOW

S core

no sco re

S hap e

OVAL (Beveled Edge, Bico nvex)

S iz e

17mm

Flavor

Imprint Code

E;49

Contains

Bryant Ranch Prepack

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 36 29 -8 0 8 9 -1

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 7/25/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 9 16 29

10 /0 6 /20 10

Labeler -

Bryant Ranch Prepack (171714327)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Bryant Ranch Prepack

171714327

REPACK(6 36 29 -8 0 8 9 ) , RELABEL(6 36 29 -8 0 8 9 )

Revised: 8/2019

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