NDC 0143-2230 Isosorbide

Isosorbide Mononitrate

NDC Product Code 0143-2230

NDC CODE: 0143-2230

Proprietary Name: Isosorbide What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Isosorbide Mononitrate What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Isosorbide mononitrate is used to prevent chest pain (angina) in patients with a certain heart condition (coronary artery disease). This medication belongs to a class of drugs known as nitrates. It works by relaxing and widening blood vessels so blood can flow more easily to the heart. This medication will not relieve chest pain once it occurs. Also, it is not intended to be taken just before physical activities (such as exercise or sexual intercourse) to prevent chest pain. Other medications may be prescribed by your doctor for these conditions. Consult your doctor for more details.

Product Characteristics

Color(s):
PINK (C48328 - LIGHT ROSE)
Shape: OVAL (C48345)
Size(s):
6 MM
Imprint(s):
WW;30
Score: 2

NDC Code Structure

NDC 0143-2230-01

Package Description: 100 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE, PLASTIC

NDC 0143-2230-05

Package Description: 500 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE, PLASTIC

NDC 0143-2230-10

Package Description: 1000 TABLET, FILM COATED, EXTENDED RELEASE in 1 BOTTLE, PLASTIC

NDC Product Information

Isosorbide with NDC 0143-2230 is a a human prescription drug product labeled by Hikma Pharmaceuticals Usa Inc.. The generic name of Isosorbide is isosorbide mononitrate. The product's dosage form is tablet, film coated, extended release and is administered via oral form.

Labeler Name: Hikma Pharmaceuticals Usa Inc.

Dosage Form: Tablet, Film Coated, Extended Release - A solid dosage form that contains medicinal substances with or without suitable diluents and is coated with a thin layer of a water-insoluble or water-soluble polymer; the tablet is formulated in such manner as to make the contained medicament available over an extended period of time following ingestion.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Isosorbide Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • ISOSORBIDE MONONITRATE 30 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • AMMONIUM PHOSPHATE, DIBASIC (UNII: 10LGE70FSU)
  • CARNAUBA WAX (UNII: R12CBM0EIZ)
  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)
  • POLYETHYLENE GLYCOLS (UNII: 3WJQ0SDW1A)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.
  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Nitrate Vasodilator - [EPC] (Established Pharmacologic Class)
  • Nitrates - [CS]
  • Vasodilation - [PE] (Physiologic Effect)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Hikma Pharmaceuticals Usa Inc.
Labeler Code: 0143
FDA Application Number: ANDA076813 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 03-30-2006 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

End Marketing Date: 12-31-2020 What is the End Marketing Date?
This is the date the product will no longer be available on the market. If a product is no longer being manufactured, in most cases, the FDA recommends firms use the expiration date of the last lot produced as the EndMarketingDate, to reflect the potential for drug product to remain available after manufacturing has ceased. Products that are the subject of ongoing manufacturing will not ordinarily have any EndMarketingDate. Products with a value in the EndMarketingDate will be removed from the NDC Directory when the EndMarketingDate is reached.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Information for Patients

Isosorbide

Isosorbide is pronounced as (eye soe sor' bide)

Why is isosorbide medication prescribed?
Isosorbide immediate-release tablets are used for the management of angina (chest pain) in people who have coronary artery disease (narrowing of the blood vessels that su...
[Read More]

* Please review the disclaimer below.

Isosorbide Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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.Isosorbide Mononitrate Extended-Release Tablets, USP, for oral administration, contain 30 mg or 60 mg of isosorbide mononitrate in an extended-release formulation. In addition, each tablet contains the following inactive ingredients: ammonium phosphate dibasic, anhydrous lactose, carnauba wax, colloidal silicon dioxide, magnesium stearate, and synthetic paraffin wax. Film coating and polishing solution contains: hypromellose, polyethylene glycol, red iron oxide (30 mg tablet only), titanium dioxide, and yellow iron oxide (60 mg tablet only).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).Isosorbide mononitrate is freely soluble in water, ethanol, methanol, chloroform, ethyl acetate, and dichloromethane. This drug product meets USP Dissolution Test No. 3.

Mechanism Of Action

The Isosorbide Mononitrate Extended-Release Tablets, USP 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 and 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, 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 its effects (although better than placebo) are less than or, at best, equal to the effects of the first dose of 60 mg.

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. Isosorbide mononitrate is approximately 5% bound to human plasma proteins and is distributed into blood cells and saliva. Isosorbide mononitrate is primarily metabolized by the liver, but unlike oral isosorbide dinitrate, it is not subject to first-pass metabolism. Isosorbide mononitrate 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 Tablets 60 mg and 120 mg (2 x 60 mg) 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 (45-64 years) for the isosorbide mononitrate 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 (65-74 years) showed 30% lower apparent oral clearance (Cl/F) following the higher dose, i.e., 120 mg, compared to the younger group (45-64 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 (45-64 years). The results of this study, however, should be viewed with caution due to the small number of subjects in each age subgroup and consequently the lack of sufficient statistical power.The following table summarizes key pharmacokinetic parameters of 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      ISMN Extended-  ISMN Extended-  ISMN Extended-  PARAMETER  ISMN  Release Tablets  Release Tablets  Release Tablets    60 mg  60 mg  60mg  120 mg  Cmax (ng/mL)  1242-1534  424-541  557-572  1151-1180  Tmax (hr)  0.6-0.7  3.1-4.5  2.9-4.2  3.1-3.2  AUC (ng•hr/mL)  8189-8313  5990-7452  6625-7555  14241-16800  t1/2 (hr)  4.8-5.1  6.3-6.6  6.2-6.3  6.2-6.4  Cl/F (mL/min)  120-122  151-187  132-151  119-140

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-controlled parallel study, 30, 60, 120, 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 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 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 and 60 mg doses no longer were differentiable from placebo. Throughout chronic dosing, rebound was not observed in any isosorbide mononitrate extended-release treatment group.Pooled data from two other trials, comparing Isosorbide Mononitrate Extended-Release Tablets 60 mg once daily, ISDN 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 ISDN 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 isosorbide mononitrate 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 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 isosorbide mononitrate are difficult to terminate rapidly, this drug is not recommended in these settings.If isosorbide mononitrate is used in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia.

General

Severe hypotension, particularly with upright posture, may occur with even small doses of isosorbide mononitrate. 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 isosorbide mononitrate 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 isosorbide mononitrate 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 isosorbide mononitrate. 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 isosorbide mononitrate, since loss of headache may be associated with simultaneous loss of antianginal efficacy. Aspirin or acetaminophen often successfully relieves isosorbide mononitrate-induced headaches with no deleterious effect on isosorbide mononitrate's antianginal efficacy.Treatment with isosorbide mononitrate 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 isosorbide mononitrate 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 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.Isosorbide mononitrate 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 isosorbide mononitrate 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 isosorbide mononitrate/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 if 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 a 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 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 isosorbide mononitrate 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 ISMN treatment be initiated at low doses for several days before being increased to desired levels.FREQUENCY AND ADVERSE EVENTS (DISCONTINUED)*  
*Some individuals discontinued for multiple reasons. 
**Patients were started on 60 mg and titrated to their final dose.  Three Controlled North American Studies  Dose  Placebo  30 mg  60 mg  120 mg**  240 mg**  Patients  96  60  102  65  65  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, somnolence.Red Blood Cell Disorder: Hypochromic anemia.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: syncope.To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-877-233-2001, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Hemodynamic Effects

The ill effects of isosorbide mononitrate overdose are generally the results of isosorbide mononitrate'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 isosorbide mononitrate and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of isosorbide mononitrate overdose.There are no data suggesting what dose of isosorbide mononitrate 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 available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of isosorbide mononitrate. In particular, dialysis is known to be ineffective in removing isosorbide mononitrate from the body.No specific antagonist to the vasodilator effects of isosorbide mononitrate is known, and no intervention has been subject to controlled study as a therapy of isosorbide mononitrate overdose. Because the hypotension associated with isosorbide mononitrate 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 isosorbide mononitrate 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 isosorbide mononitrate. Certainly, nitrate ions liberated during metabolism of isosorbide mononitrate can oxidize hemoglobin into methemoglobin. Even in patients totally without cytochrome b5 reductase activity, however, and even assuming that the nitrate moiety of isosorbide mononitrate is quantitatively applied to oxidation of hemoglobin, about 2 mg/kg of isosorbide mononitrate 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 isosorbide mononitrate. 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 isosorbide mononitrate 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 p02. 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, USP is 30 mg (given as a single 30 mg tablet or 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 a single 120 mg tablet or as two 60 mg tablets) once daily. Rarely, 240 mg may be required. The daily dose of Isosorbide Mononitrate Tablets should be taken in the morning on arising. Isosorbide Mononitrate Extended-Release Tablets, USP should not be chewed or crushed and should be swallowed together with a half-glassful of fluid.

How Supplied

Isosorbide Mononitrate Extended-Release Tablets, 30 mg: Film-Coated Light Rose, Oval Tablets; Debossed "WW" on one Scored side and "30" on the other Scored side. Bottles of 100 tablets.
Bottles of 500 tablets.
Bottles of 1000 tablets. Isosorbide Mononitrate Extended-Release Tablets, 60 mg: Film-Coated Light Yellow, Oval Tablets; Debossed "WW" on one Scored side and "60" on the other Scored side. Bottles of 100 tablets.
Bottles of 500 tablets.
Bottles of 1000 tablets. Store at 20 to 25°C (68 to 77°F) [See USP Controlled Room Temperature]. Protect from light and moisture.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.Manufactured by:West-Ward Pharmaceuticals Corp.Eatontown, NJ 07724Revised May 2016

* Please review the disclaimer below.