Isosorbide for Aneurysms

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.

DOSAGE AND ADMINISTRATION: The recommended regimen of Isosorbide Mononitrate Tablets is 20 mg twice daily, with the doses seven hours apart. A starting dose of 5 mg (½ tablet of the 10 mg dosing strength) might be appropriate for persons of particularly small stature but should be increased to at least 10 mg by the second or third day of therapy. Dosage adjustments are not necessary for elderly patients or patients with altered hepatic or renal function. As noted above ( Clinical Pharmacology ), multiple studies of organic nitrates have shown that maintenance of continuous 24-hour plasma levels results in refractory tolerance. The asymmetric (2 doses, 7 hours apart) dosing regimen for Isosorbide Mononitrate Tablets provides a daily nitrate-free interval to minimize the development of tolerance. As also noted under Clinical Pharmacology , well-controlled studies have shown that tolerance to Isosorbide Mononitrate Tablets occurs to some extent when using the twice-daily regimen in which the two doses are given seven hours apart. This regimen has been shown to have antianginal efficacy beginning one hour after the first dose and lasting at least seven hours after the second dose. The duration (if any) of antianginal activity beyond fourteen hours has not been studied. In clinical trials, isosorbide mononitrate has been administered in a variety of regimens and doses. Doses above 20 mg twice a day (with the doses seven hours apart) have not been adequately studied. Doses of 5 mg twice a day are clearly effective (effectiveness based on exercise tolerance) for only the first day of a twice-a-day (with doses 7 hours apart) regimen.

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 isosorbide mononitrate 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.

Drug Interactions Concomitant use of isosorbide mononitrate with phosphodiesterase inhibitors in any form is contraindicated (see CONTRAINDICATIONS ). Concomitant use of isosorbide mononitrate with riociguat, a soluble guanylate cyclase stimulator, is contraindicated (see CONTRAINDICATIONS ). 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.

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 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) a 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%) a Some individuals discontinued for multiple reasons. * Patients were started on 60 mg and titrated to their final dose. 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 Edenbridge Pharmaceuticals, LLC at 877-381-3336 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.