ISOSORBIDE MONONITRATE tablet extended release

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

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Active ingredient:
ISOSORBIDE MONONITRATE (UNII: LX1OH63030) (ISOSORBIDE MONONITRATE - UNII:LX1OH63030)
Available from:
Unit Dose Services
INN (International Name):
ISOSORBIDE MONONITRATE
Composition:
ISOSORBIDE MONONITRATE 60 mg
Prescription type:
PRESCRIPTION DRUG
Authorization status:
Abbreviated New Drug Application

ISOSORBIDE MONONITRATE- isosorbide mononitrate tablet, extended release

Unit Dose Services

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Isosorbide Mononitrate Extended-release Tablets, USP Rx only

DESCRIPTION

Isosorbide Mononitrate (ISMN), an organic nitrate and the major biologically active metabolite of

isosorbide dinitrate (ISDN), is a vasodilator with effects on both arteries and veins.

Each Isosorbide mononitrate extended-release tablet, USP, for oral administration contains either 30 mg

or 60 mg of ISMN.

ISMN 30 mg tablets, USP containes the following inactive ingredients: colloidal silicon dioxide,

compressible sugar, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate.

ISMN 60 mg tablets, USP contains the following inactive ingredients: colloidal silicon dioxide,

compressible sugar, hydroxypropyl methylcellulose, yellow iron oxide, lactose monohydrate,

magnesium stearate.

The molecular formula of ISMN is C H NO and the molecular weight is 191.14. The chemical name

for ISMN is 1,4:3,6-dianhydro-D-glucitol 5-nitrate; the compound has the following structural formula:

ISMN is a white, crystalline, odorless compound which is stable in air and in solution, has a melting

point of about 90°C, and an optical rotation of +144° (2% in water, 20°C). ISMN is freely soluble in

water, ethanol, methanol, chloroform, ethyl acetate and dichloromethane.

CLINICAL PHARMACOLOGY

Mechanism of Action

This product is an oral extended-release formulation of ISMN, the major active metabolite of

isosorbide dinitrate; most of the clinical activity of the dinitrate is attributable to the mononitrate.

The principal pharmacological action of ISMN and all organic nitrates in general is relaxation of

vascular smooth muscle, producing dilatation of peripheral arteries and veins, especially the latter.

Dilatation of the veins promotes peripheral pooling of blood, decreases venous return to the heart,

thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure

(preload). Arteriolar relaxation reduces systemic vascular resistance, and systolic arterial pressure and

mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs. The relative

importance of preload reduction, afterload reduction and coronary dilatation remains undefined.

Pharmacodynamics

Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that

are continuously greater than a minimally effective concentration. This strategy is inappropriate for

organic nitrates. Several well-controlled clinical trials have used exercise testing to assess the

antianginal efficacy of continuously delivered nitrates. In the large majority of these trials, active agents

were indistinguishable from placebo after 24 hours (or less) of continuous therapy. Attempts to

overcome tolerance by dose escalation, even to doses far in excess of those used acutely, have

consistently failed. Only after nitrates have been absent from the body for several hours has their

antianginal efficacy been restored.

Isosorbide mononitrate extended-release tablets during long-term use over 42 days dosed at 120 mg

once daily continued to improve exercise performance at 4 hours and at 12 hours after dosing but their

effects (although better than placebo) are less than or at best equal to the effects of the first dose of 60

Pharmacokinetics and Metabolism:

After oral administration of ISMN as a solution or immediate-release tablets, maximum plasma

concentrations of ISMN are achieved in 30 to 60 minutes, with an absolute bioavailability of

approximately 100%. After intravenous administration, ISMN is distributed into total body water in

about 9 minutes with a volume of distribution of approximately 0.6 to 0.7 L/kg. ISMN is approximately

5% bound to human plasma proteins and is distributed into blood cells and saliva. ISMN is primarily

metabolized by the liver, but unlike oral isosorbide dinitrate, it is not subject to first-pass metabolism.

ISMN is cleared by denitration to isosorbide and glucuronidation as the mononitrate, with 96% of the

administered dose excreted in the urine within 5 days and only about 1% eliminated in the feces. At least

six different compounds have been detected in urine, with about 2% of the dose excreted as the

unchanged drug and at least five metabolites. The metabolites are not pharmacologically active. Renal

clearance accounts for only about 4% of total body clearance. The mean plasma elimination half-life of

ISMN is approximately 5 hours.

The disposition of ISMN in patients with various degrees of renal insufficiency, liver cirrhosis, or

cardiac dysfunction was evaluated and found to be similar to that observed in healthy subjects. The

elimination half-life of ISMN was not prolonged, and there was no drug accumulation in patients with

chronic renal failure after multiple oral dosing.

The pharmacokinetics and/or bioavailability of Isosorbide mononitrate extended-release tablets have

been studied in both normal volunteers and patients following single-and multiple-dose administration.

Data from these studies suggest that the pharmacokinetics of ISMN administered as Isosorbide

mononitrate extended-release tablets are similar between normal healthy volunteers and patients with

angina pectoris. In single and multiple-dose studies, the pharmacokinetics of ISMN were dose

proportional between 30 mg and 240 mg.

In a multiple - dose study, the effect of age on the pharmacokinetic profile of Isosorbide mononitrate

extended-release 60 mg and 120 mg (2 x 60 mg) tablets was evaluated in subjects ≥ 45 years. The

results of that study indicate that there are no significant differences in any of the pharmacokinetic

variables of ISMN between elderly (≥65 years) and younger individuals (45 to 64 years) for the ISMN

extended-release 60 mg dose. The administration of Isosorbide mononitrate extended-release tablets

120 mg (2 x 60 mg) tablets every 24 hours for 7 days) produced a dose-proportional increase in Cmax

and AUC, without changes in Tmax or the terminal half-life. The older group (65 to 74 years) showed

30% lower apparent oral clearance (CI/F) following the higher dose, i.e., 120 mg, compared to the

younger group (45 to 64 years); CI/F was not different between the two groups following the 60 mg

regimen. While CI/F was independent of dose in the younger group, the older group showed slightly

lower CI/F following the 120 mg regimen compared to the 60 mg regimen. Differences between the

two age groups, however, were not statistically significant. In the same study, females showed a slight

(15%) reduction in clearance when the dose was increased. Females showed higher AUCs and Cmax

compared to males, but these differences were accounted for by differences in body weight between

the two groups. When the data were analyzed using age as a variable, the results indicated that there

were no significant differences in any of the pharmacokinetic variables of ISMN between older (≥65

years) and younger individuals (45 to 64 years). The results of this study, however, should be viewed

with caution due to the small numbers of subjects in each age subgroup and consequently the lack of

sufficient statistical power.

The following table summarizes key pharmacokinetic parameters of Isosorbide Mononitrate (ISMN)

after single- and multiple-dose administration of ISMN as an oral solution or Isosorbide mononitrate

extended-release tablets:

SINGLE-DOSE STUDIES

MULTIPLE-DOSE STUDIES

PARAMETER

ISMN

60 mg

ISMN extended-

release tablets 60 mg

ISMN extended-

release tablets 60 mg

ISMN extended-

release tablets 120 mg

Cmax (ng/mL)

1242 to

1534

424 to 541

557 to 572

1151 to 1180

Tmax (hr)

0.6 to

3.1 to 4.5

2.9 to 4.2

3.1 to 3.2

(ng▪hr/mL)

8189

to 8313

5990 to 7452

6625 to 7555

14241 to 16800

(hr)

4.8 to

6.3 to 6.6

6.2 to 6.3

6.2 to 6.4

CI/F (mL/min)

120 to

151 to 187

132 to 151

119 to 140

Food Effects: The influence of food on the bioavailability of ISMN after single-dose administration of

Isosorbide mononitrate extended-release tablets 60 mg was evaluated in three different studies

involving either a "light" breakfast or a high-calorie, high-fat breakfast. Results of these studies

indicate that concomitant food intake may decrease the rate (increase in Tmax) but not the extent (AUC)

of absorption of ISMN.

CLINICAL TRIALS

Controlled trials with Isosorbide mononitrate extended-release tablets have demonstrated antianginal

activity following acute and chronic dosing. Administration of Isosorbide mononitrate extended-release

tablets once daily, taken early in the morning on arising, provided at least 12 hours of antianginal

activity.

In a placebo-control parallel study, 30 mg, 60 mg, 120 mg, and 240 mg of Isosorbide mononitrate

extended-release tablets were administered once daily for up to 6 weeks. Prior to randomization, all

patients completed a 1-to 3-week single-blind placebo phase to demonstrate nitrate responsiveness and

total exercise treadmill time reproducibility. Exercise tolerance tests using the Bruce Protocol were

conducted prior to and at 4 and 12 hours after the morning dose on days 1, 7, 14, 28 and 42 of the

double-blind period. Isosorbide mononitrate extended-release tablets 30 mg and 60 mg (only doses

evaluated acutely) demonstrated a significant increase from baseline in total treadmill time relative to

placebo at 4 and 12 hours after the administration of the first dose. At day 42, the 120 mg and 240 mg

dose of Isosorbide mononitrate extended-release tablets demonstrated a significant increase in total

treadmill time at 4 and 12 hours post dosing, but by day 42 the 30 mg and 60 mg doses no longer were

differentiable from placebo. Throughout chronic dosing rebound was not observed in any Isosorbide

mononitrate extended-release tablets treatment group.

Pooled data from two other trials, comparing Isosorbide mononitrate extended-release tablets 60 mg

once daily, isosorbide dinitrate 30 mg QID, and placebo QID in patients with chronic stable angina

using a randomized, double-blind, three-way crossover design found statistically significant increases

in exercise tolerance times for Isosorbide mononitrate extended-release tablets compared to placebo at

hours 4, 8 and 12 and to isosorbide dinitrate at hour 4. The increases in exercise tolerance on day 14,

although statistically significant compared to placebo, were about half of that seen on day 1 of the trial.

INDICATIONS AND USAGE

Isosorbide mononitrate extended-release tablets, USP are indicated for the prevention of angina

pectoris due to coronary artery disease. The onset of action of oral ISMN is not sufficiently rapid for

this product to be useful in aborting an acute anginal episode.

CONTRAINDICATIONS

Isosorbide mononitrate extended-release tablets are contraindicated in patients who have shown

hypersensitivity or idiosyncratic reactions to other nitrates or nitrites.

WARNINGS

Amplification of the vasodilatory effects of Isosorbide mononitrate extended-release tablets by

sildenafil can result in severe hypotension. The time course and dose dependence of this

interaction have not been studied. Appropriate supportive care has not been studied, but it seems

reasonable to treat this as a nitrate overdose, with elevation of the extremities and with central

volume expansion.

The benefits of ISMN in patients with acute myocardial infarction or congestive heart failure have not

been established; because the effects of ISMN are difficult to terminate rapidly, this drug is not

recommended in these settings. If ISMN is used in these conditions, careful clinical or hemodynamic

monitoring must be used to avoid the hazards of hypotension and tachycardia.

PRECAUTIONS

General

Severe hypotension, particularly with upright posture, may occur with even small doses of ISMN. This

drug should therefore be used with caution in patients who may be volume depleted or who, for

whatever reason, are already hypotensive. Hypotension induced by ISMN may be accompanied by

paradoxical bradycardia and increased angina pectoris.

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy

In industrial workers who have had long term exposure to unknown (presumably high) doses of organic

nitrates, tolerance clearly occurs. Chest pain, acute myocardial infarction, and even sudden death have

occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of

true physical dependence. The importance of these observations to the routine, clinical use of oral

ISMN is not known.

Information for Patients

Patients should be told that the antianginal efficacy of Isosorbide mononitrate extended-release tablets

can be maintained by carefully following the prescribed schedule of dosing. For most patients, this can

be accomplished by taking the dose on arising.

As with other nitrates, daily headaches sometimes accompany treatment with ISMN. In patients who get

these headaches, the headaches are a marker of the activity of the drug. Patients should resist the

temptation to avoid headaches by altering the schedule of their treatment with ISMN, since loss of

headache may be associated with simultaneous loss of antianginal efficacy. Aspirin or acetaminophen

often successfully relieves ISMN induced headaches with no deleterious effect on ISMN’s antianginal

efficacy. Treatment with ISMN may be associated with light-headedness on standing, especially just

after rising from a recumbent or seated position. This effect may be more frequent in patients who have

also consumed alcohol.

Drug Interactions

The vasodilating effects of ISMN may be additive with those of other vasodilators. Alcohol, in

particular, has been found to exhibit additive effects of this variety. Marked symptomatic orthostatic

hypotension has been reported when calcium channel blockers and organic nitrates were used in

combination.

Dose adjustments of either class of agents may be necessary.

DRUG / LABORATORY TEST INTERACTIONS

Nitrates and nitrites may interfere with the Zlatkis-Zak color reaction, causing falsely low readings in

serum cholesterol determinations.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenicity was observed in rats exposed to Isosorbide Mononitrate (ISMN) in

their diets at doses of up to 900 mg/kg/day for the first 6 months and 500 mg/kg/day for the remaining

duration of a study in which males were dosed for up to 121 weeks and females were dosed for up to

137 weeks. No evidence of carcinogenicity was observed in mice exposed to isosorbide mononitrate in

their diets for up to 104 weeks at doses of up to 900 mg/kg/day.

ISMN did not produce gene mutations (Ames test, mouse lymphoma test) or chromosome aberrations

(human lymphocyte and mouse micronucleus tests) at biologically relevant concentrations. No effects

on fertility were observed in a study in which male and female rats were administered doses of up to

750 mg/kg/day beginning, in males, 9 weeks prior to mating, and in females, 2 weeks prior to mating.

Pregnancy

Teratogenic Effects

Pregnancy Category B

In studies designed to detect effects of ISMN on embryo-fetal development, doses of up to 240 or 248

mg/kg/day, administered to pregnant rats and rabbits, were unassociated with evidence of such effects.

These animal doses are about 100 times the maximum recommended human dose (120 mg in a 50 kg

woman) when comparison is based on body weight; when comparison is based on body surface area, the

rat dose is about 17 times the human dose and the rabbit dose is about 38 times the human dose. There

are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction

studies are not always predictive of human response, Isosorbide mononitrate extended-release tablets

should be used during pregnancy only if clearly needed.

Nonteratogenic Effects

Neonatal survival and development and incidence of stillbirths were adversely affected when pregnant

rats were administered oral doses of 750 (but not 300) mg ISMN/kg/day during late gestation and

lactation. This dose (about 312 times the human dose when comparison is based on body weight and 54

times the human dose when comparison is based on body surface area) was associated with decreases

in maternal weight gain and motor activity and evidence of impaired lactation.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human

milk, caution should be exercised when ISMN is administered to a nursing mother.

Pediatric Use

The safety and effectiveness of ISMN in pediatric patients have not been established.

Geriatric Use

Clinical studies of Isosorbide Mononitrate Extended-release Tablets did not include sufficient

information on patients age 65 and over to determine whether they respond differently from younger

patients. Other reported clinical experience for Isosorbide Mononitrate Extended-release Tablets has

not identified differences in response between elderly and younger patients. Clinical experience for

organic nitrates reported in the literature identified a potential for severe hypotension and increased

sensitivity to nitrates in the elderly. In general, dose selection for an elderly patient should be cautious,

usually starting at the low end of the dosing range, reflecting the greater frequency of decreased

hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Elderly patients may have reduced baroreceptor function and may develop severe orthostatic

hypotension when vasodilators are used. Isosorbide Mononitrate Extended-release Tablets should

therefore be used with caution in elderly patients who may be volume depleted, on multiple medications

or who, for whatever reason, are already hypotensive. Hypotension induced by isosorbide mononitrate

may be accompanied by paradoxical bradycardia and increased angina pectoris.

Elderly patients may be more susceptible to hypotension and may be at greater risk of falling at

therapeutic doses of nitroglycerin.

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy, particularly in the

elderly.

ADVERSE REACTIONS

The table below shows the frequencies of the adverse events that occurred in >5% of the subjects in

three placebo-controlled North American studies, in which patients in the active treatment arm received

30 mg, 60 mg, 120 mg or 240 mg of ISMN as Isosorbide mononitrate extended-release tablets once

daily. In parentheses, the same table shows the frequencies with which these adverse events were

associated with the discontinuation of treatment. Overall, 8% of the patients who received 30 mg, 60

mg, 120 mg or 240 mg of ISMN in the three placebo-controlled North American studies discontinued

treatment because of adverse events. Most of these discontinued because of headache. Dizziness was

rarely associated with withdrawal from these studies. Since headache appears to be a dose-related

adverse effect and tends to disappear with continued treatment, it is recommended that Isosorbide

mononitrate extended-release tablets treatment be initiated at low doses for several days before being

increased to desired levels.

FREQUENCY AND ADVERSE EVENTS (DISCONTINUED)*

Three controlled North America Studies

Dos e

Placebo

30 mg

60 mg

120 mg**

240 mg**

*Some individuals discontinued for multiple reasons

** Patients were started on 60 mg and titrated to their final dose

Patients

Headache

15%(0%)

38%(5%)

51%(8%)

42%(5%)

57%(8%)

Dizziness

4%(0%)

8%(0%)

11%(1%)

9%(2%)

9%(2%)

In addition, the three North American trials were pooled with 11 controlled trials conducted in Europe.

Among the 14 controlled trials, a total of 711 patients were randomized to Isosorbide mononitrate

extended-release tablets. When the pooled data were reviewed, headache and dizziness were the only

adverse events that were reported by >5% of patients. Other adverse events, each reported by ≤5% of

exposed patients, and in many cases of uncertain relation to drug treatment, were:

Autonomic Nervous System Disorders: Dry mouth, hot flushes

Body as a Whole: Asthenia, back pain, chest pain, edema, fatigue, fever, flu-like symptoms, malaise,

rigors.

Cardiovascular Disorders, General: Cardiac failure, hypertension, hypotension.

Central and Peripheral Nervous System Disorders: Dizziness, headache, hypoesthesia, migraine, neuritis,

paresis, paresthesia, ptosis, tremor, vertigo.

Gastrointestinal System Disorders: Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gastric

ulcer, gastritis, glossitis, hemorrhagic gastric ulcer, hemorrhoids, loose stools, melena, nausea,

vomiting.

Hearing and Vestibular Disorders: Earache, tinnitus, tympanic membrane perforation.

Heart Rate and Rhythm Disorders: Arrhythmia, arrhythmia atrial, atrial fibrillation, bradycardia, bundle

branch block, extrasystole, palpitation, tachycardia, ventricular tachycardia.

Liver and Biliary System Disorders: SGOT increase, SGPT increase.

Metabolic and Nutritional Disorders: Hyperuricemia, hypokalemia.

Musculoskeletal System Disorders: Arthralgia, frozen shoulder, muscle weakness, musculoskeletal pain,

myalgia, myositis,tendon disorder, torticollis.

Myo-, Endo-, Pericardial and Valve Disorders: Angina pectoris aggravated, heart murmur, heart sound

abnormal, myocardial infarction, Q-Wave abnormality.

Platelet, Bleeding and Clotting Disorders: Purpura, thrombocytopenia.

Psychiatric Disorders: Anxiety, concentration impaired, confusion, decreased libido, depression,

impotence, insomnia, nervousness, paroniria, somnolenc

Red Blood Cell Disorder: Hypochromic anemiae.

Reproductive Disorders, Female: Atrophic vaginitis, breast pain.

Resistance Mechanism Disorders: Bacterial infection, moniliasis, viral infection.

Respiratory System Disorders: Bronchitis, bronchospasm, coughing, dyspnea, increased sputum, nasal

congestion, pharyngitis, pneumonia, pulmonary infiltration, rales, rhinitis, sinusitis.

Skin and Appendages Disorders: Acne, hair texture abnormal, increased sweating, pruritus, rash, skin

nodule.

Urinary System Disorders: Polyuria, renal calculus, urinary tract infection.

Vascular (Extracardiac) Disorders: Flushing, intermittent claudication, leg ulcer, varicose vein.

Vision Disorders: Conjunctivitis, photophobia, vision abnormal.

In addition, the following spontaneous adverse event has been reported during the marketing of

Isosorbide Mononitrate (ISMN): syncope.

OVERDOSAGE

Hemodynamic Effects

The ill effects of ISMN overdose are generally the results of ISMN’s capacity to induce

vasodilatation, venous pooling, reduced cardiac output, and hypotension. These hemodynamic changes

may have protean manifestations, including increased intracranial pressure, with any or all of persistent

throbbing headache, confusion and moderate fever; vertigo; palpitations; visual disturbances; nausea and

vomiting (possibly with colic and even bloody diarrhea); syncope (especially in the upright posture); air

hunger and dyspnea, later followed by reduced ventilatory effort; diaphoresis, with the skin either

flushed or cold and clammy; heart block and bradycardia; paralysis; coma; seizures and death.

Laboratory determinations of serum levels of ISMN and its metabolites are not widely available, and

such determinations have, in any event, no established role in the management of ISMN overdose.

There are no data suggesting what dose of ISMN is likely to be life threatening in humans. In rats and

mice, there is significant lethality at doses of 2000 mg/kg and 3000 mg/kg, respectively. No data are

mice, there is significant lethality at doses of 2000 mg/kg and 3000 mg/kg, respectively. No data are

available to suggest physiological maneuvers (e.g. maneuvers to change the pH of the urine) that might

accelerate elimination of ISMN. In particular, dialysis is known to be ineffective in removing ISMN

from the body. No specific antagonist to the vasodilator effects of ISMN is known, and no intervention

has been subject to controlled study as a therapy of ISMN overdose. Because the hypotension

associated with ISMN overdose is the result of venodilatation and arterial hypovolemia, prudent therapy

in this situation should be directed toward an increase in central fluid volume. Passive elevation of the

patient’s legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be

necessary.

The use of epinephrine or other arterial vasoconstrictors in this setting is likely to do more harm than

good. In patients with renal disease or congestive heart failure, therapy resulting in central volume

expansion is not without hazard. Treatment of ISMN overdose in these patients may be subtle and

difficult, and invasive monitoring may be required.

Methemoglobinemia

Methemoglobinemia has been reported in patients receiving other organic nitrates, and it probably could

also occur as a side effect of ISMN. Certainly nitrate ions liberated during metabolism of ISMN can

oxidize hemoglobin into methemoglobin. Even in patients totally without cytochrome b5 reductase

activity, however, and even assuming that the nitrate moiety of ISMN is quantitatively applied to

oxidation of hemoglobin, about 2 mg/kg of ISMN should be required before any of these patients

manifest clinically significant (≥10%) methemoglobinemia. In patients with normal reductase function,

significant production of methemoglobin should require even larger doses of ISMN. In one study in

which 36 patients received 2 to 4 weeks of continuous nitroglycerin therapy at 3.1 to 4.4 mg/hr

(equivalent, in total administered dose of nitrate ions, to 7.8 - 11.1 mg of ISMN per hour), the average

methemoglobin level measured was 0.2%; this was comparable to that observed in parallel patients who

received placebo.

Notwithstanding these observations, there are case reports of significant methemoglobinemia in

association with moderate overdoses of organic nitrates. None of the affected patients had been thought

to be unusually susceptible.

Methemoglobin levels are available from most clinical laboratories. The diagnosis should be suspected

in patients who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate

arterial pO2. Classically, methemoglobinemic blood is described as chocolate brown, without color

change on exposure to air.

When methemoglobinemia is diagnosed, the treatment of choice is methylene blue, 1 to 2 mg/kg

intravenously.

DOSAGE AND ADMINISTRATION

The recommended starting dose of Isosorbide mononitrate extended-release tablets is 30 mg (given as

1/2 of a 60 mg tablet) or 60 mg (given as a single tablet) once daily. After several days the dosage may

be increased to 120 mg (given as two 60 mg tablets) once daily. Rarely, 240 mg may be required. The

daily dose of Isosorbide mononitrate extended-release tablets should be taken in the morning on arising.

Isosorbide mononitrate extended-release tablets should not be chewed or crushed and should be

swallowed together with a half-glassful of fluid. Do not break 30 mg tablet.

HOW SUPPLIED

Product: 50436-3945

NDC: 50436-3945-1 30 TABLET, EXTENDED RELEASE in a BOTTLE

NDC: 50436-3945-3 90 TABLET, EXTENDED RELEASE in a BOTTLE

ISOSORBIDE MONONITRATE TABLET, EXTENDED RELEASE

ISOSORBIDE MONONITRATE

isosorbide mononitrate tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:50 436 -39 45(NDC:23155-178 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

ISO SO RBIDE MO NO NITRATE (UNII: LX1OH6 30 30 ) (ISOSORBIDE MONONITRATE -

UNII:LX1OH6 30 30 )

ISOSORBIDE

MONONITRATE

6 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

SUCRO SE (UNII: C151H8 M554)

HYDRO XYPRO PYL CELLULO SE ( 12 0 0 0 0 0 MW) (UNII: RFW2ET6 71P)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

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

Product Characteristics

Color

YELLOW

S core

2 pieces

S hap e

OVAL (bico nvex)

S iz e

13mm

Flavor

Imprint Code

DX;31

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:50 436 -39 45-1

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

0 6 /0 7/20 10

Unit Dose Services

2

NDC:50 436 -39 45-3

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

0 6 /0 7/20 10

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 75522

0 6 /0 7/20 10

Labeler -

Unit Dose Services (831995316)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Unit Do se Services

8 319 9 5316

REPACK(50 436 -39 45) , RELABEL(50 436 -39 45)

Revised: 3/2017

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