ISMO®
Wyeth-Ayerst
Isosorbide-5-Mononitrate
Antianginal
Action And Clinical Pharmacology: As with other organic nitrates, the principal pharmacological action of isosorbide-5-mononitrate, the major active metabolite of isosorbide dinitrate, is relaxation of vascular smooth muscle and consequent dilation of peripheral arteries and veins, especially the latter. Dilation 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 (pre-load). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure (after-load). Dilation of the coronary arteries also occurs. The hemodynamic responses to isosorbide-5-mononitrate are similar to those produced by other nitrates.
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. Prolonged administration of nitrate drugs according to traditionally recommended dosage regimens has been shown to produce tolerance. Tolerance results in a loss of efficacy. 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, nitrate effectiveness was 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. Drug-free intervals of 10 to 12 hours are known to be sufficient to restore response. The drug-free interval sufficient to avoid tolerance to isosorbide-5-mononitrate has not been completely defined. In the only regimen of twice-daily isosorbide-5-mononitrate the 2 doses are given 7 hours apart. This asymmetric twice-daily regimen provides antianginal efficacy for up to 12 hours (i.e. 7 hours between doses and 5 hours after second dose). Considering the pharmacokinetic profile of isosorbide-5-mononitrate and its long half-life (see Pharmacokinetics), clinical efficacy is consistent with that observed for other organic nitrates.
Pharmacokinetics: In humans, isosorbide-5-mononitrate is not subject to significant first pass metabolic changes in liver. The absolute bioavailability of isosorbide-5-mononitrate from tablets is nearly 100%. The absorption is rapid, and maximum serum concentrations are achieved 30 to 60 minutes after dosing. The volume of distribution of isosorbide-5-mononitrate is approximately 0.6 L/kg, and less than 4% is bound to plasma proteins. It is cleared from the serum by denitration to isosorbide; glucuronidation to the mononitrate glucuronide; and denitration/hydration to sorbitol. None of these metabolites is vasoactive. Less than 1% of administered isosorbide-5-mononitrate is eliminated in the urine.
The overall elimination half-life of isosorbide-5-mononitrate is about 5 hours; the rate of clearance is the same in healthy young adults, in patients with various degrees of renal, hepatic, or cardiac dysfunction, and in the elderly.
Indications And Clinical Uses: For the prevention of anginal attacks in patients with chronic stable angina pectoris associated with coronary artery disease.
Not intended for the immediate relief of acute attacks of angina pectoris.
Contra-Indications: Known hypersensitivity to isosorbide mononitrate or to other nitrates or nitrites. Acute circulatory failure associated with marked hypotension (shock and states of collapse). Postural hypotension. Myocardial insufficiency due to obstruction (e.g. in presence of aortic or mitral stenosis or of constrictive pericarditis). Increased intracranial pressure. Increased intraocular pressure. Severe anemia.
Manufacturers’ Warnings In Clinical States: The benefits and safety of isosorbide-5-mononitrate in anginal 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.
Precautions: Headaches or symptoms of severe hypotension, such as weakness or dizziness, particularly when arising suddenly from a recumbent position, may occur.
Caution should be exercised when using nitrates in patients prone to, or who might be affected by hypotension. Isosorbide-5-mononitrate should therefore be used with caution in patients who may have volume depletion from diuretic therapy or in patients who have low systolic blood pressure (e.g., below 90 mmHg). Paradoxical bradycardia and increased angina pectoris may accompany nitrate-induced hypotension.
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. There is moreover, physical dependence since chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers. In clinical trials of angina patients, there are reports of anginal attacks being more easily provoked and of rebound in the hemodynamic effects soon after nitrate withdrawal. The importance of these observations to the routine, clinical use of oral isosorbide mononitrate has not been fully elucidated.
Caution should be exercised in patients with arterial hypoxemia due to anemia (see Contraindications). Similarly, caution is called for in patients with hypoxemia and a ventilation/perfusion imbalance due to lung disease or ischemic heart failure. Patients with angina pectoris, myocardial infarction, or cerebral ischemia frequently suffer from abnormalities of the small airways (especially alveolar hypoxia). Under these circumstances vasoconstriction occurs within the lung to shift perfusion from areas of alveolar hypoxia to better ventilated regions of the lung. As a potent vasodilator, isosorbide-5-mononitrate could reverse this protective vasoconstriction and thus result in increased perfusion to poorly ventilated areas, worsening of the ventilation/perfusion imbalance, and a further decrease in the arterial partial pressure of oxygen.
Tolerance to isosorbide-5-mononitrate with cross tolerance to other nitrates or nitrites may occur (see Pharmacology). As tolerance to isosorbide-5-mononitrate develops, the effect of sublingual nitroglycerin on exercise tolerance, although still observable, is somewhat blunted.
Occupational Hazards: As patients may experience faintness and/or dizziness, reaction time when driving or operating machinery may be impaired, especially at the start of treatment.
Pregnancy: In rats receiving isosorbide-5-mononitrate 500 mg/kg/day (125 times the human exposure comparing body surface area) there were small but statistically significant increases in the rates of prolonged gestation, prolonged parturition, stillbirth, and neonatal death; and there were small but statistically significant decreases in birth weight, live litter size, and pup survival. At 250 mg/kg/day, no adverse effects on reproduction and development were reported.
In rats and rabbits receiving isosorbide-5-mononitrate at up to 250 mg/kg/day, no developmental abnormalities, fetal abnormalities, or other effects on reproductive performance were detected; these doses are larger than the maximum recommended human dose by factors between 70 (body-surface-area basis in rabbits) and 310 (body-weight basis, in either species).
There are no studies in pregnant women. Isosorbide-5-mononitrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: It is not known whether isosorbide-5-mononitrate is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when isosorbide-5-mononitrate is used to treat a nursing woman.
Children: The safety and effectiveness of isosorbide-5- mononitrate in children have not been established. Therefore, its use is not recommended.
Drug Interactions: Concomitant treatment with other vasodilators, calcium antagonists, ACE inhibitors, beta-blockers, diuretics, antihypertensives, tricyclic antidepressants and major tranquilizers may potentiate the blood pressure lowering effect of isosorbide-5-mononitrate.
Alcohol may enhance sensitivity to the hypotensive effects of nitrates.
Information for the Patient: Patients should be told that in order to maintain the antianginal efficacy of isosorbide-5-mononitrate tablets they must carefully follow the prescribed schedule of dosing (2 doses taken 7 hours apart) in a 24-hour period. For most patients, this can be accomplished by taking the first dose on awakening and the second dose 7 hours later.
As with other nitrates, headache may occur during therapy with isosorbide-5-mononitrate. Patients who get these headaches, should not alter the schedule of their treatment with isosorbide-5-mononitrate, since loss of headache may be associated with simultaneous loss of antianginal efficacy. Headaches may be relieved by the use of standard analgesics, such as ASA or acetaminophen.
Treatment with isosorbide-5-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.
Adverse Reactions: In controlled clinical trials 20 mg twice daily of isosorbide-5-mononitrate was administered to 219 patients alone or in combination with beta-adrenergic blocking agents. Adverse reactions were reported in 47% of patients. Discontinuation of therapy due to adverse reactions was required in 11% of patients. Most of these discontinued because of headache. Dizziness, nausea and chest pain were also frequently associated with withdrawal from these studies. The most common adverse reactions (incidence of at least 1%) were: headache, nausea, dizziness, flu-like symptoms, chest pain and rash.
In addition, the following adverse reactions were reported with an incidence lower than 1% in controlled as well as other studies in which 3 344 patients received 5 to 240 mg/day in a variety of regimens:
- Cardiovascular: angina pectoris, arrhythmias, atrial fibrillation, hypotension, palpitations, postural hypotension, premature ventricular contractions, supraventricular tachycardia, syncope.
- Dermatological: pruritus, rash.
- Gastrointestinal: abdominal pain, diarrhea, dyspepsia, tenesmus, vomiting.
- Genitourinary: dysuria, impotence, urinary frequency.
- Miscellaneous: asthenia, blurred vision, cold sweat, diplopia, edema, malaise, neck stiffness, rigors.
- Musculoskeletal: arthralgia.
- Neurological: agitation, anxiety, confusion, dyscoordination, hypoesthesia, hypokinesia, increased appetite, insomnia, nervousness, nightmares.
- Respiratory: bronchitis, pneumonia, upper respiratory tract infection.
Extremely rarely, ordinary doses of organic nitrates have caused methemoglobinemia; for further discussion of its diagnosis and treatment see Overdose: Symptoms and Treatment.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Hemodynamic Effects: Symptoms of isosorbide-5-mononitrate overdose are generally the results of vasodilation, 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.
No specific antagonist to the vasodilator effects of isosorbide-5-mononitrate is known, and no intervention has been subject to controlled study as a therapy of isosorbide-5- mononitrate overdose. Because the hypotension associated with isosorbide-5-mononitrate overdose is the result of venodilation 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 i.v. infusion of normal saline or similar fluid may also be necessary.
In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of isosorbide-5-mononitrate overdose in these patients may be subtle and difficult, and invasive monitoring may be required.
The use of epinephrine or other arterial vasoconstrictors are ineffective in reversing the severe hypotensive effects of overdose and are therefore contraindicated in this situation.
Dialysis is known to be ineffective in removing isosorbide-5-mononitrate from the body.
Methemoglobinemia: Methemoglobinemia has been reported in patients receiving other organic nitrates, and it may occur as a side effect of isosorbide-5-mononitrate. Nitrate ions liberated during metabolism of isosorbide-5-mononitrate can oxidize hemoglobin into methemoglobin. In patients totally without cytochrome b5 reductase activity, about 2 mg/kg of isosorbide-5-mononitrate would be required before any of these patients manifests clinically significant (³10%) methemoglobinemia. In patients with normal reductase function, significant production of methemoglobin would require even larger doses of isosorbide-5-mononitrate.
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, administration of methylene blue, 1 to 2 mg/kg i.v., may be required.
Dosage And Administration: The daily dosage schedule is designed to avoid or attenuate the development of tolerance of isosorbide-5-mononitrate. Patients should be watched carefully for an increase in angina pectoris during the drug-free period. Adjustment of background medication may be required.
The recommended dose of isosorbide-5-mononitrate is 20 mg twice daily given 7 hours apart. For those patients who are active during the day, this can be accomplished by taking the first dose upon awakening and the second dose 7 hours later. Dosage adjustments are not necessary for elderly patients or patients with altered renal or hepatic function.
The 20 mg twice daily dose should not be exceeded and doses lower than that are not recommended. Limited clinical experience has shown that the 10 mg twice daily dose was not unequivocally better than placebo, while the effect of the 40 mg twice daily dose was similar to that of the 20 mg dose. The 60 mg twice daily dose appeared to be less effective and was associated with an increased incidence of adverse reactions and a rebound phenomenon.
Availability And Storage: Each orange, biconvex, round, film-coated tablet, engraved with “ISMO 20” on one side and “W” on the other side, contains: isosorbide-5-mononitrate 20 mg. Nonmedicinal ingredients: alcohol, FD&C Yellow No. 6 aluminum lake, D&C Yellow No. 10 aluminum lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate, povidone USP, silicon dioxide colloidal, sodium starch glycolate and titanium dioxide. Bottles of 100. Store at controlled room temperature, between 15 and 30°C. Dispense in tight containers.
ISMO® Wyeth-Ayerst Isosorbide-5-Mononitrate Antianginal
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