ISOSORBIDE MONONITRATE, EXTENDED-RELEASE, TABLETS, USP, Rev. 05/16, Rx Only

/ISOSORBIDE MONONITRATE, EXTENDED-RELEASE, TABLETS, USP, Rev. 05/16, Rx Only
ISOSORBIDE MONONITRATE, EXTENDED-RELEASE, TABLETS, USP, Rev. 05/16, Rx Only2018-09-06T09:12:40+00:00

Prescription Drug Name:

ISOSORBIDE MONONITRATE, EXTENDED-RELEASE, TABLETS, USP, Rev. 05/16, Rx Only

ID:

69968dad-9a65-6eda-e053-2a91aa0a17ef

Code:

34391-3

DESCRIPTION


id: 699683d6-f359-7d3a-e053-2991aa0a3340
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3

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.

CLINICAL TRIALS


id: 699683d6-f35f-7d3a-e053-2991aa0a3340
displayName: CLINICAL STUDIES SECTION
FDA Article Code: 34092-7

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


id: 699683d6-f360-7d3a-e053-2991aa0a3340
displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

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


id: 699683d6-f361-7d3a-e053-2991aa0a3340
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

Isosorbide Mononitrate Extended-Release Tablets are contraindicated in patients who have shown hypersensitivity or idiosyncratic reactions to other nitrates or nitrites.

WARNINGS


id: 699683d6-f362-7d3a-e053-2991aa0a3340
displayName: WARNINGS SECTION
FDA Article Code: 34071-1

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.

ADVERSE REACTIONS


id: 699683d6-f36e-7d3a-e053-2991aa0a3340
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

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.

DOSAGE AND ADMINISTRATION


id: 699683d6-f372-7d3a-e053-2991aa0a3340
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

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


id: 69968dad-9a7b-6eda-e053-2a91aa0a17ef
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

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. NDC 68071-4390-3 BOTTLES OF 30 NDC 68071-4390-6 BOTTLES OF 60 NDC 68071-4390-9 BOTTLES OF 90 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 07724 Revised May 2016

PRINCIPAL DISPLAY PANEL


id: 699691ae-d2a6-a8bb-e053-2991aa0acfea
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4