OLMESARTAN MEDOXOMIL- olmesartan medoxomil tablet, film coated

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

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Active ingredient:
OLMESARTAN MEDOXOMIL (UNII: 6M97XTV3HD) (OLMESARTAN - UNII:8W1IQP3U10)
Available from:
A-S Medication Solutions
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Olmesartan medoxomil tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with olmesartan medoxomil tablets. 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 one 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, Eva
Product summary:
Product: 50090-4451 NDC: 50090-4451-0 30 TABLET, FILM COATED in a BOTTLE NDC: 50090-4451-1 90 TABLET, FILM COATED in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
50090-4451-0, 50090-4451-1

OLMESARTAN MEDOXOMIL- olmesartan medoxomil tablet, film coated

A-S Medication Solutions

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use OLMESARTAN MEDOXOMIL TABLETS

safely and effectively. See full prescribing information for OLMESARTAN MEDOXOMIL TABLETS.

OLMESARTAN MEDOXOMIL tablets, for oral use

Initial U.S. Approval: 2002

WARNING: FETAL TOXICITY

See full prescribing information for complete boxed warning.

RECENT MAJOR CHANGES

INDICATIONS AND USAGE

DOSAGE AND ADMINISTRATION

Indication (2)

Starting dose (2)

Dose Range (2)

Adult Hypertension (2.1) (2)

20 mg once daily (2)

20 to 40 mg once daily (2)

Pediatric Hypertension

(6 – 16 years) (2.2) (2)

20 to < 35 kg

10 mg once daily

>35 kg

20 mg once daily (2)

20 to < 35 kg

10 to 20 mg once daily

>35 kg

20 to 40 mg once daily (2)

DOSAGE FORMS AND STRENGTHS

Tablets: 5 mg, 20 mg, and 40 mg (3). (3)

CONTRAINDICATIONS

Do not co-administer aliskiren with olmesartan medoxomil tablets in patients with diabetes (4). (4)

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

The most common adverse reaction in adults was dizziness (3%) (6.1). (6)

To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888)721-

7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. (6)

When pregnancy is detected, discontinue olmesartan medoxomil as soon as possible (5.1).

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

fetus (5.1)

Warnings and Precautions (5.6) 11/2016

Olmesartan medoxomil tablets are an angiotensin II receptor blocker (ARB) indicated for the treatment of

hypertension, alone or with other antihypertensive agents, to lower blood pressure. Lowering blood pressure

reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (1).

Olmesartan medoxomil tablets may be administered with or without food

If blood pressure is not controlled by olmesartan medoxomil alone, a diuretic may be added. Olmesartan medoxomil

may be administered with other antihypertensive agents.

Avoid fetal (in utero) exposure (5.1).

Children <1 year of age must not receive olmesartan medoxomil for hypertension (5.2).

Observe for signs and symptoms of hypotension in volume- or salt-depleted patients with treatment initiation (5.3).

Monitor for worsening renal function in patients with renal impairment (5.4).

Sprue-like enteropathy has been reported. Consider discontinuation of olmesartan medoxomil in cases where no

other etiology is found (5.5).

DRUG INTERACTIONS

USE IN SPECIFIC POPULATIONS

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 8/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: FETAL TOXICITY

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Adult Hypertension

2.2 Pediatric Hypertension (6 to 16 years of age)

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Fetal Toxicity

5.2 Morbidity in Infants

5.3 Hypotension in Volume- or Salt-Depleted Patients

5.4 Impaired Renal Function

5.5 Sprue-like Enteropathy

5.6 Electrolyte Imbalances

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Post-Marketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

8.8 Black Patients

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

NSAID use may lead to increased risk of renal impairment and loss of antihypertensive effect (7).

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

(7).

Colesevelam hydrochloride: Consider administering olmesartan at least 4 hours before colesevelam hydrochloride

dose (7).

Lithium: Increases in serum lithium concentrations and lithium toxicity (7).

Nursing mothers: Choose to discontinue nursing or drug (8.3).

In patients with an activated renin-angiotensin system, such as volume- or salt-depletion, renin-angiotensin-

aldosterone system (RAAS) blockers such as olmesartan medoxomil can cause excessive hypotension. In

susceptible patients, e.g., with renal artery stenosis, RAAS blockers can cause renal failure (5.3, 5.4).

Geriatrics: No overall difference in efficacy or safety vs. younger adult patients, but greater sensitivity of some older

individuals cannot be ruled out (8.5).

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Adult Hypertension

14.2 Pediatric Hypertension

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING: FETAL TOXICITY

1 INDICATIONS AND USAGE

Olmesartan medoxomil tablets are indicated for the treatment of hypertension, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes

and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs

from a wide variety of pharmacologic classes including the class to which this drug principally

belongs. There are no controlled trials demonstrating risk reduction with olmesartan medoxomil tablets.

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 one drug to achieve blood

pressure goals. For specific advice on goals and management, see published guidelines, such as those

of the National High Blood Pressure Education Program’s Joint National Committee on Prevention,

Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different

mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular

morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other

pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and

most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions

in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk

increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe

hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is

similar across populations with varying absolute risk, so the absolute benefit is greater in patients who

are at higher risk independent of their hypertension (for example, patients with diabetes or

hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a

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

When pregnancy is detected, discontinue olmesartan medoxomil as soon as possible

(5.1).

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

the developing fetus (5.1)

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.

It may be used alone or in combination with other antihypertensive agents.

2 DOSAGE AND ADMINISTRATION

2.1 Adult Hypertension

Dosage must be individualized. The usual recommended starting dose of olmesartan medoxomil tablets

is 20 mg once daily when used as monotherapy in patients who are not volume-contracted. For patients

requiring further reduction in blood pressure after 2 weeks of therapy, the dose of olmesartan

medoxomil tablets may be increased to 40 mg. Doses above 40 mg do not appear to have greater effect.

Twice-daily dosing offers no advantage over the same total dose given once daily.

No initial dosage adjustment is recommended for elderly patients, for patients with moderate to marked

renal impairment (creatinine clearance <40 mL/min) or with moderate to marked hepatic dysfunction [see

Warnings and Precautions (5.4), Use in Specific Populations (8.5, 8.6, 8.7) and Clinical Pharmacology

(12.3)]. For patients with possible depletion of intravascular volume (e.g., patients treated with

diuretics, particularly those with impaired renal function), initiate olmesartan medoxomil tablets under

close medical supervision and give consideration to use of a lower starting dose [see Warnings and

Precautions (5.3)].

Olmesartan medoxomil tablets may be administered with or without food.

If blood pressure is not controlled by olmesartan medoxomil tablets alone, a diuretic may be added.

Olmesartan medoxomil tablets may be administered with other antihypertensive agents.

2.2 Pediatric Hypertension (6 to 16 years of age)

Dosage must be individualized. For children who can swallow tablets, the usual recommended starting

dose of olmesartan medoxomil is 10 mg once daily for patients who weigh 20 to <35 kg (44 to 77 lb),

or 20 mg once daily for patients who weigh ≥35 kg. For patients requiring further reduction in blood

pressure after 2 weeks of therapy, the dose of olmesartan medoxomil may be increased to a maximum of

20 mg once daily for patients who weigh <35 kg or 40 mg once daily for patients who weigh ≥35 kg.

Children <1 year of age must not receive olmesartan medoxomil tablets for hypertension.

For children who cannot swallow tablets, the same dose can be given using an extemporaneous

suspension as described below [see Clinical Pharmacology (12.3)]. Follow the suspension preparation

instructions below to administer olmesartan medoxomil as a suspension.

Preparation of Suspension (for 200 mL of a 2 mg/mL suspension)

Add 50 mL of Purified Water to an amber polyethylene terephthalate (PET) bottle containing twenty

olmesartan medoxomil 20 mg tablets and allow to stand for a minimum of 5 minutes. Shake the container

for at least 1 minute and allow the suspension to stand for at least 1 minute. Repeat 1-minute shaking and

1-minute standing for four additional times. Add 100 mL of Ora-Sweet

* and 50 mL of Ora-Plus

* to

the suspension and shake well for at least 1 minute. The suspension should be refrigerated at 2-8°C (36-

46°F) and can be stored for up to 4 weeks. Shake the suspension well before each use and return

promptly to the refrigerator.

* Ora-Sweet

and Ora-Plus

are registered trademarks of Paddock Laboratories, Inc.

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

Do not co-administer aliskiren with olmesartan medoxomil tablets in patients with diabetes [See Drug

Interactions (7)].

5 WARNINGS AND PRECAUTIONS

5.1 Fetal Toxicity

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 olmesartan medoxomil as soon as possible [see Use in specific

Populations (8.1)].

5.2 Morbidity in Infants

Children <1 year of age must not receive olmesartan medoxomil for hypertension. Drugs that act

directly on the renin-angiotensin aldosterone system (RAAS) can have effects on the development of

immature kidneys [see Use in Specific Populations (8.4)].

5.3 Hypotension in Volume- or Salt-Depleted Patients

In patients with an activated renin-angiotensin aldosterone system, such as volume- and/or salt-depleted

patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may be

anticipated after initiation of treatment with olmesartan medoxomil. Initiate treatment under close medical

supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an

intravenous infusion of normal saline [see Dosage and Administration (2.1)]. A transient hypotensive

response is not a contraindication to further treatment, which usually can be continued without difficulty

once the blood pressure has stabilized.

5.4 Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may

be anticipated in susceptible individuals treated with olmesartan medoxomil. In patients whose renal

function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with

severe congestive heart failure), treatment with angiotensin converting enzyme (ACE) inhibitors and

angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and

rarely with acute renal failure and/or death. Similar results may be anticipated in patients treated with

olmesartan medoxomil [see Dosage and Administration (2.1), Drug Interactions (7), Use in Specific

Populations (8.7) and Clinical Pharmacology (12.3)].

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in

serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of

olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar results may

be expected.

5 mg light yellow to yellow, round, film-coated tablets debossed with ‘C’ on one side and plain on

the other side

20 mg white to off white, round, film-coated tablets debossed with ‘437’ on one side and plain on

the other side

40 mg white to off white, oval-shaped, film-coated tablets debossed with ‘438’ on one side and

plain on the other side

5.5 Sprue-like Enteropathy

Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan

months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If

a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider

discontinuation of olmesartan medoxomil in cases where no other etiology is identified.

5.6 Electrolyte Imbalances

Olmesartan medoxomil tablets contain olmesartan, a drug that inhibits the renin-angiotensin system

(RAS). Drugs that inhibit the RAS can cause hyperkalemia. Monitor serum electrolytes periodically.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates

observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of

another drug and may not reflect the rates observed in practice.

Adult Hypertension

Olmesartan medoxomil has been evaluated for safety in more than 3825 patients/subjects, including more

than 3275 patients treated for hypertension in controlled trials. This experience included about 900

patients treated for at least 6 months and more than 525 for at least 1 year. Treatment with olmesartan

medoxomil was well tolerated, with an incidence of adverse reactions similar to placebo. Events

generally were mild, transient and had no relationship to the dose of olmesartan medoxomil.

The overall frequency of adverse reactions was not dose-related. Analysis of gender, age and race

groups demonstrated no differences between olmesartan medoxomil and placebo-treated patients. The

rate of withdrawals due to adverse reactions in all trials of hypertensive patients was 2.4% (i.e.,

79/3278) of patients treated with olmesartan medoxomil and 2.7% (i.e., 32/1179) of control patients. In

placebo-controlled trials, the only adverse reaction that occurred in more than 1% of patients treated

with olmesartan medoxomil and at a higher incidence versus placebo was dizziness (3% vs. 1%).

The following adverse reactions occurred in placebo-controlled clinical trials at an incidence of more

than 1% of patients treated with olmesartan medoxomil, but also occurred at about the same or greater

incidence in patients receiving placebo: back pain, bronchitis, creatine phosphokinase increased,

diarrhea, headache, hematuria, hyperglycemia, hypertriglyceridemia, influenza-like symptoms,

pharyngitis, rhinitis and sinusitis.

The incidence of cough was similar in placebo (0.7%) and olmesartan medoxomil (0.9%) patients.

Other potentially important adverse reactions that have been reported with an incidence of greater than

0.5%, whether or not attributed to treatment, in the more than 3100 hypertensive patients treated with

olmesartan medoxomil monotherapy in controlled or open-label trials are listed below.

Body as a Whole: chest pain, peripheral edema

Central and Peripheral Nervous System: vertigo

Gastrointestinal: abdominal pain, dyspepsia, gastroenteritis, nausea

Heart Rate and Rhythm Disorders: tachycardia

Metabolic and Nutritional Disorders: hypercholesterolemia, hyperlipemia, hyperuricemia

Musculoskeletal: arthralgia, arthritis, myalgia

Skin and Appendages: rash

Facial edema was reported in five patients receiving olmesartan medoxomil. Angioedema has been

reported with angiotensin II antagonists.

Laboratory Test Findings: In controlled clinical trials, clinically important changes in standard laboratory

parameters were rarely associated with administration of olmesartan medoxomil.

Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases of

approximately 0.3 g/dL and 0.3 volume percent, respectively) were observed.

Liver Function Tests: Elevations of liver enzymes and/or serum bilirubin were observed infrequently.

Five patients (0.1%) assigned to olmesartan medoxomil and one patient (0.2%) assigned to placebo in

clinical trials were withdrawn because of abnormal liver chemistries (transaminases or total bilirubin).

Of the five olmesartan medoxomil patients, three had elevated transaminases, which were attributed to

alcohol use, and one had a single elevated bilirubin value, which normalized while treatment continued.

Pediatric Hypertension

No relevant differences were identified between the adverse experience profile for pediatric patients

aged 1 to 16 years and that previously reported for adult patients.

6.2 Post-Marketing Experience

The following adverse reactions have been reported in post-marketing experience. Because these

reactions are reported voluntarily from a population of uncertain size, it is not always possible to

reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: Asthenia, angioedema, anaphylactic reactions

Gastrointestinal: Vomiting, sprue-like enteropathy [see Warnings and Precautions (5.6)]

Metabolic and Nutritional Disorders: Hyperkalemia

Musculoskeletal: Rhabdomyolysis

Urogenital System: Acute renal failure, increased blood creatinine levels

Skin and Appendages: Alopecia, pruritus, urticaria

Data from one controlled trial and an epidemiologic study have suggested that high-dose olmesartan

may increase cardiovascular (CV) risk in diabetic patients, but the overall data are not conclusive. The

randomized, placebo-controlled, double-blind ROADMAP trial (Randomized Olmesartan And Diabetes

MicroAlbuminuria Prevention trial, n=4447) examined the use of olmesartan, 40 mg daily, vs. placebo

in patients with type 2 diabetes mellitus, normoalbuminuria, and at least one additional risk factor for CV

disease. The trial met its primary endpoint, delayed onset of microalbuminuria, but olmesartan had no

beneficial effect on decline in glomerular filtration rate (GFR). There was a finding of increased CV

mortality (adjudicated sudden cardiac death, fatal myocardial infarction, fatal stroke, revascularization

death) in the olmesartan group compared to the placebo group (15 olmesartan vs. 3 placebo, HR 4.9,

95% confidence interval [CI], 1.4, 17), but the risk of non-fatal myocardial infarction was lower with

olmesartan (HR 0.64, 95% CI 0.35, 1.18).

The epidemiologic study included patients 65 years and older with overall exposure of > 300,000

patient-years. In the sub-group of diabetic patients receiving high-dose olmesartan (40 mg/d) for > 6

months, there appeared to be an increased risk of death (HR 2.0, 95% CI 1.1, 3.8) compared to similar

patients taking other angiotensin receptor blockers. In contrast, high-dose olmesartan use in non-diabetic

patients appeared to be associated with a decreased risk of death (HR 0.46, 95% CI 0.24, 0.86)

compared to similar patients taking other angiotensin receptor blockers. No differences were observed

between the groups receiving lower doses of olmesartan compared to other angiotensin blockers or

those receiving therapy for < 6 months.

Overall, these data raise a concern of a possible increased CV risk associated with the use of high-

dose olmesartan in diabetic patients. There are, however, concerns with the credibility of the finding of

increased CV risk, notably the observation in the large epidemiologic study for a survival benefit in

non-diabetics of a magnitude similar to the adverse finding in diabetics.

7 DRUG INTERACTIONS

No significant drug interactions were reported in studies in which olmesartan medoxomil was co-

administered with digoxin or warfarin in healthy volunteers.

The bioavailability of olmesartan was not significantly altered by the co-administration of antacids

[Al(OH) /Mg(OH) ].

Olmesartan medoxomil is not metabolized by the cytochrome P450 system and has no effects on P450

enzymes; thus, interactions with drugs that inhibit, induce, or are metabolized by those enzymes are not

expected.

Non-Steroidal Anti-Inflammatory Agents 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, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II

receptor antagonists, including olmesartan medoxomil, may result in deterioration of renal function,

including possible acute renal failure. These effects are usually reversible. Monitor renal function

periodically in patients receiving olmesartan medoxomil and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including olmesartan medoxomil may

be attenuated by NSAIDs including selective COX-2 inhibitors.

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, hyperkalemia, and changes in renal function (including

acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS

inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use

of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on

olmesartan medoxomil and other agents that affect the RAS.

Do not co-administer aliskiren with olmesartan medoxomil in patients with diabetes [see

Contraindications (4)]. Avoid use of aliskiren with olmesartan medoxomil in patients with renal

impairment (GFR <60 ml/min).

Colesevelam hydrochloride

Concurrent administration of bile acid sequestering agent colesevelam hydrochloride reduces the

systemic exposure and peak plasma concentration of olmesartan. Administration of olmesartan at least 4

hours prior to colesevelam hydrochloride decreased the drug interaction effect. Consider

administering olmesartan at least 4 hours before the colesevelam hydrochloride dose [see Clinical

Pharmacology (12.3)].

Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant

administration of lithium with angiotensin II receptor antagonists, including olmesartan medoxomil.

Monitor serum lithium levels during concomitant use.

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 olmesartan medoxomil 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 olmesartan medoxomil, 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 olmesartan medoxomil for hypotension, oliguria, and

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

8.3 Nursing Mothers

It is not known whether olmesartan is excreted in human milk, but olmesartan is secreted at low

concentration in the milk of lactating rats. 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 olmesartan medoxomil:

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.

Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or

substituting for disordered renal function.

The antihypertensive effects of olmesartan medoxomil were evaluated in one randomized, double-blind

clinical study in pediatric patients 1 to 16 years of age [see Clinical Studies (14.2)]. The

pharmacokinetics of olmesartan medoxomil were evaluated in pediatric patients 1 to 16 years of age

[see Clinical Pharmacology (12.3)]. Olmesartan medoxomil was generally well tolerated in pediatric

patients, and the adverse experience profile was similar to that described for adults.

Olmesartan medoxomil has not been shown to be effective for hypertension in children <6 years of age.

Children <1 year of age must not receive olmesartan medoxomil for hypertension [see Warnings and

Precautions (5.2)]. The renin-angiotensin aldosterone system (RAAS) plays a critical role in kidney

development. RAAS blockade has been shown to lead to abnormal kidney development in very young

mice. Administering drugs that act directly on the renin-angiotensin aldosterone system (RAAS) can

alter normal renal development.

8.5 Geriatric Use

Of the total number of hypertensive patients receiving olmesartan medoxomil in clinical studies, more

than 20% were 65 years of age and over, while more than 5% were 75 years of age and older. No

overall differences in effectiveness or safety were observed between elderly patients and younger

patients. Other reported clinical experience has not identified differences in responses between the

elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see

Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

Increases in AUC

and C

were observed in patients with moderate hepatic impairment compared to

0-∞

those in matched controls, with an increase in AUC of about 60%. No initial dosage adjustment is

recommended for patients with moderate to marked hepatic dysfunction [see Dosage and Administration

(2.1) and Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Patients with renal insufficiency have elevated serum concentrations of olmesartan compared to subjects

with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with

severe renal impairment (creatinine clearance <20 mL/min). No initial dosage adjustment is

recommended for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min)

[see Dosage and Administration (2.1), Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

8.8 Black Patients

The antihypertensive effect of olmesartan medoxomil was smaller in black patients (usually a low-renin

population), as has been seen with ACE inhibitors, beta-blockers and other angiotensin receptor

blockers.

10 OVERDOSAGE

Limited data are available related to overdosage in humans. The most likely manifestations of

overdosage would be hypotension and tachycardia; bradycardia could be encountered if

parasympathetic (vagal) stimulation occurs. If symptomatic hypotension occurs, initiate supportive

treatment. The dialyzability of olmesartan is unknown.

11 DESCRIPTION

Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the

gastrointestinal tract. Olmesartan is a selective AT subtype angiotensin II receptor antagonist.

Olmesartan medoxomil USP is described chemically as 4-(1-Hydroxy-1-methylethyl)-2-propyl-1-2-

(1H-5-tetrazolyl) biphenyl-4-ylmethyl] imidazole-5-carboxylic acid 5-methyl-2-oxo-1,3-dioxol-4-

ylmethyl ester.

Its empirical formula is C

H N O and its structural formula is:

0-∞

Olmesartan medoxomil USP is a white to off-white powder with a molecular weight of 558.58. It is

sparingly soluble in methanol; practically insoluble in water. Olmesartan medoxomil tablets are

available for oral use as film-coated tablets containing 5 mg, 20 mg, or 40 mg of olmesartan medoxomil

USP and the following inactive ingredients: microcrystalline cellulose, low-substituted hydroxypropyl

cellulose, lactose monohydrate, hydrogenated castor oil, magnesium stearate, hydroxypropyl cellulose,

hypromellose, titanium dioxide, talc, and (5 mg only) yellow iron oxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme

(ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with

effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac

stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor effects of

angiotensin II by selectively blocking the binding of angiotensin II to the AT receptor in vascular

smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis.

An AT receptor is found also in many tissues, but this receptor is not known to be associated with

cardiovascular homeostasis. Olmesartan has more than a 12,500-fold greater affinity for the AT

receptor than for the AT receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of

angiotensin II from angiotensin I, is a mechanism of many drugs used to treat hypertension. ACE

inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because

olmesartan medoxomil does not inhibit ACE (kininase II), it does not affect the response to bradykinin.

Whether this difference has clinical relevance is not yet known.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on

renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II levels do

not overcome the effect of olmesartan on blood pressure.

12.2 Pharmacodynamics

Olmesartan medoxomil doses of 2.5 mg to 40 mg inhibit the pressor effects of angiotensin I infusion.

The duration of the inhibitory effect was related to dose, with doses of olmesartan medoxomil >40 mg

giving >90% inhibition at 24 hours.

Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increase after

single and repeated administration of olmesartan medoxomil to healthy subjects and hypertensive

patients. Repeated administration of up to 80 mg olmesartan medoxomil had minimal influence on

aldosterone levels and no effect on serum potassium.

12.3 Pharmacokinetics

Abs orption

Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during

absorption from the gastrointestinal tract.

Olmesartan medoxomil tablets and the suspension formulation prepared from olmesartan medoxomil

tablets are bioequivalent [see Dosage and Administration (2.2)].

The absolute bioavailability of olmesartan is approximately 26%. After oral administration, the peak

plasma concentration (C

) of olmesartan is reached after 1 to 2 hours. Food does not affect the

bioavailability of olmesartan.

Dis tribution

The volume of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound to plasma

proteins (99%) and does not penetrate red blood cells. The protein binding is constant at plasma

olmesartan concentrations well above the range achieved with recommended doses.

In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across the

placental barrier in rats and was distributed to the fetus. Olmesartan was distributed to milk at low levels

in rats.

Metabolism and Excretion

Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption,

there is virtually no further metabolism of olmesartan. Total plasma clearance of olmesartan is 1.3 L/h,

with a renal clearance of 0.6 L/h. Approximately 35% to 50% of the absorbed dose is recovered in

urine while the remainder is eliminated in feces via the bile.

Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of

approximately 13 hours. Olmesartan shows linear pharmacokinetics following single oral doses of up

to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within

3 to 5 days and no accumulation in plasma occurs with once-daily dosing.

Geriatric

The pharmacokinetics of olmesartan were studied in the elderly (≥65 years). Overall, maximum plasma

concentrations of olmesartan were similar in young adults and the elderly. Modest accumulation of

olmesartan was observed in the elderly with repeated dosing; AUCss, τ was 33% higher in elderly

patients, corresponding to an approximate 30% reduction in CLR [see Dosage and Administration (2.1)

and Use in Specific Populations (8.5)].

Pediatric

The pharmacokinetics of olmesartan were studied in pediatric hypertensive patients aged 1 to 16 years.

The clearance of olmesartan in pediatric patients was similar to that in adult patients when adjusted by

the body weight [see Use in Specific Populations (8.4)].

Olmesartan pharmacokinetics have not been investigated in pediatric patients less than 1 year of age [see

Warnings and Precautions (5.2) and Use in Specific Populations (8.4)].

Gender

Minor differences were observed in the pharmacokinetics of olmesartan in women compared to men.

AUC and C

were 10-15% higher in women than in men.

Hepatic Insufficiency

Increases in AUC

and C

were observed in patients with moderate hepatic impairment compared to

those in matched controls, with an increase in AUC of about 60% [see Dosage and Administration (2.1)

and Use in Specific Populations (8.6)].

Renal Insufficiency

In patients with renal insufficiency, serum concentrations of olmesartan were elevated compared to

subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in

patients with severe renal impairment (creatinine clearance <20 mL/min). The pharmacokinetics of

olmesartan in patients undergoing hemodialysis has not been studied [see Dosage and Administration

(2.1), Warnings and Precautions (5.4) and Use in Specific Populations (8.7)].

Drug Interaction

Bile acid sequestering agent colesevelam

Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in

healthy subjects resulted in 28% reduction in C

and 39% reduction in AUC of olmesartan. Lesser

effects, 4% and 15% reduction in C

and AUC respectively, were observed when olmesartan

medoxomil was administered 4 hours prior to colesevelam hydrochloride [see Drug Interactions (7)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Olmesartan medoxomil was not carcinogenic when administered by dietary administration to rats for up

to 2 years. The highest dose tested (2000 mg/kg/day) was, on a mg/m basis, about 480 times the

maximum recommended human dose (MRHD) of 40 mg/day. Two carcinogenicity studies conducted in

mice, a 6-month gavage study in the p53 knockout mouse and a 6-month dietary administration study in

the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (about 120 times the MRHD), revealed

no evidence of a carcinogenic effect of olmesartan medoxomil.

Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell

transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity)

test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese

hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay.

Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney and

for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg

(olmesartan not tested).

Fertility of rats was unaffected by administration of olmesartan medoxomil at dose levels as high as

1000 mg/kg/day (240 times the MRHD) in a study in which dosing was begun 2 (female) or 9 (male)

weeks prior to mating.

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at

oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose [MRHD] of

olmesartan medoxomil on a mg/m basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the

0-∞

MRHD on a mg/m basis; higher doses could not be evaluated for effects on fetal development as they

were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were

observed at doses ≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear

auricula, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of

eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at

doses ≥8 mg/kg/day. The no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day,

about one-tenth the MRHD of 40 mg/day.

14 CLINICAL STUDIES

14.1 Adult Hypertension

The antihypertensive effects of olmesartan medoxomil have been demonstrated in seven placebo-

controlled studies at doses ranging from 2.5 mg to 80 mg for 6 to 12 weeks, each showing statistically

significant reductions in peak and trough blood pressure. A total of 2693 patients (2145 olmesartan

medoxomil; 548 placebo) with essential hypertension were studied. Olmesartan medoxomil once daily

lowered diastolic and systolic blood pressure. The response was dose-related, as shown in the

following graph. An olmesartan medoxomil dose of 20 mg daily produces a trough sitting BP reduction

over placebo of about 10/6 mmHg and a dose of 40 mg daily produces a trough sitting BP reduction

over placebo of about 12/7 mmHg. Olmesartan medoxomil doses greater than 40 mg had little additional

effect. The onset of the antihypertensive effect occurred within 1 week and was largely manifest after 2

weeks.

Olmesartan Medoxomil Dose Response Placebo-Adjusted Reduction in Blood Pressure (mmHg )

Data above are from seven placebo-controlled studies (2145 olmesartan medoxomil patients, 548

placebo patients). The blood pressure lowering effect was maintained throughout the 24-hour period

with olmesartan medoxomil once daily, with trough-to-peak ratios for systolic and diastolic response

between 60 and 80%.

The blood pressure lowering effect of olmesartan medoxomil, with and without hydrochlorothiazide,

was maintained in patients treated for up to 1 year. There was no evidence of tachyphylaxis during long-

term treatment with olmesartan medoxomil or rebound effect following abrupt withdrawal of olmesartan

medoxomil after 1 year of treatment.

The antihypertensive effect of olmesartan medoxomil was similar in men and women and in patients

older and younger than 65 years. The effect was smaller in black patients (usually a low-renin

population), as has been seen with ACE inhibitors, beta-blockers and other angiotensin receptor

blockers. Olmesartan medoxomil had an additional blood pressure lowering effect when added to

hydrochlorothiazide.

There are no trials of olmesartan medoxomil demonstrating reductions in cardiovascular risk in patients

with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.

14.2 Pediatric Hypertension

The antihypertensive effects of olmesartan medoxomil in the pediatric population were evaluated in a

randomized, double-blind study involving 302 hypertensive patients aged 6 to 16 years. The study

population consisted of an all black cohort of 112 patients and a mixed racial cohort of 190 patients,

including 38 blacks. The etiology of the hypertension was predominantly essential hypertension (87%

of the black cohort and 67% of the mixed cohort). Patients who weighed 20 to <35 kg were randomized

to 2.5 or 20 mg of olmesartan medoxomil once daily and patients who weighed ≥35 kg were randomized

to 5 or 40 mg of olmesartan medoxomil once daily. At the end of 3 weeks, patients were re-randomized

to continuing olmesartan medoxomil or to taking placebo for up to 2 weeks. During the initial dose-

response phase, olmesartan medoxomil significantly reduced both systolic and diastolic blood pressure

in a weight-adjusted dose-dependent manner. Overall, the two dose levels of olmesartan medoxomil

(low and high) significantly reduced systolic blood pressure by 6.6 and 11.9 mmHg from the baseline,

respectively. These reductions in systolic blood pressure included both drug and placebo effect.

During the randomized withdrawal to placebo phase, mean systolic blood pressure at trough was 3.2

mmHg lower and mean diastolic blood pressure at trough was 2.8 mmHg lower in patients continuing

olmesartan medoxomil than in patients withdrawn to placebo. These differences were statistically

different. As observed in adult populations, the blood pressure reductions were smaller in black

patients.

In the same study, 59 patients aged 1 to 5 years who weighed ≥5 kg received 0.3 mg/kg of olmesartan

medoxomil once daily for three weeks in an open label phase and then were randomized to receiving

olmesartan medoxomil or placebo in a double-blind phase. At the end of the second week of

withdrawal, the mean systolic/diastolic blood pressure at trough was 3/3 mmHg lower in the group

randomized to olmesartan medoxomil; this difference in blood pressure was not statistically significant

(95% C.I. -2 to 7/-1 to 7).

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 50090-4451

NDC: 50090-4451-0 30 TABLET, FILM COATED in a BOTTLE

NDC: 50090-4451-1 90 TABLET, FILM COATED in a BOTTLE

17 PATIENT COUNSELING INFORMATION

Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to

olmesartan medoxomil during pregnancy. Discuss treatment options with women planning to become

pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.

Manufactured by:

Glenmark Pharmaceuticals Ltd.

Colvale-Bardez, Goa 403 513, India

Manufactured for:

Glenmark Pharmaceuticals Inc., USA

Mahwah, NJ 07430

Questions? 1 (888)721-7115

www.glenmarkpharma.com/usa

November 2016

Storage

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].

Olmesartan Medoxomil

OLMESARTAN MEDOXOMIL

olmesartan medoxomil tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:50 0 9 0 -4451(NDC:6 8 46 2-438 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

O LMESARTAN MEDO XO MIL (UNII: 6 M9 7XTV3HD) (OLMESARTAN -

UNII:8 W1IQP3U10 )

OLMESARTAN MEDOXOMIL 40 mg

A-S Medication Solutions

UNII:8 W1IQP3U10 )

Inactive Ingredients

Ingredient Name

Stre ng th

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

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

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

HYDRO GENATED CASTO R O IL (UNII: ZF9 4AP8 MEY)

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, UNSPECIFIED (UNII: 3NXW29 V3WO)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TALC (UNII: 7SEV7J4R1U)

Product Characteristics

Color

WHITE (white to o ff-white)

S core

no sco re

S hap e

OVAL

S iz e

15mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:50 0 9 0 -4451-0

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

0 8 /0 5/20 19

2

NDC:50 0 9 0 -4451-1

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

0 8 /0 5/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 328 1

0 5/25/20 17

Labeler -

A-S Medication Solutions (830016429)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

A-S Medicatio n So lutio ns

8 30 0 16 429

RELABEL(50 0 9 0 -4451) , REPACK(50 0 9 0 -4451)

Revised: 8/2019

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