Isosorbide Mononitrate

Isosorbide mononitrate is in a group of drugs called nitrates. Isosorbide mononitrate dilates (widens) blood vessels, making it easier for blood to flow through them and easier for the heart to pump.

Isosorbide mononitrate is used to prevent angina attacks (chest pain).

This medicine will not treat an angina attack that has already begun.

Isosorbide mononitrate may also be used for purposes not listed in this medication guide.

Do not use isosorbide mononitrate if you are taking medicine to treat erectile dysfunction or pulmonary arterial hypertension (PAH). This includes sildenafil (Viagra, Revatio), avanafil (Stendra), tadalafil (Cialis, Adcirca), vardenafil (Levitra, Staxyn), and riociguat (Adempas). Serious, life-threatening side effects may occur.

You should not use isosorbide mononitrate if you have early signs of a heart attack (chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling).

Do not use isosorbide mononitrate if you are taking medicine to treat erectile dysfunction or pulmonary arterial hypertension (PAH). This includes sildenafil (Viagra, Revatio), avanafil (Stendra), tadalafil (Cialis, Adcirca), vardenafil (Levitra, Staxyn), and riociguat (Adempas). Serious, life-threatening side effects may occur.

You should not use isosorbide mononitrate if:

• you are allergic to isosorbide mononitrate, isosorbide dinitrate, or nitroglycerin; or
• you have early signs of a heart attack (chest pain or pressure, pain spreading to your jaw or shoulder, nausea, sweating).

To make sure isosorbide mononitrate is safe for you, tell your doctor if you have:

• congestive heart failure;
• low blood pressure; or
• kidney disease (or if you are on dialysis);
• if you take a diuretic or "water pill"; or
• if you are on a low salt diet.

FDA pregnancy category C. It is not known whether isosorbide mononitrate will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether isosorbide mononitrate passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Isosorbide Mononitrate falls into category C:

In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans, though. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

OR

There are no well-controlled studies that have been done in pregnant women. Isosorbide Mononitrate should be used during pregnancy only if the possible benefit outweighs the possible risk to the unborn baby.

OR

No studies have been done in animals, and no well-controlled studies have been done in pregnant women. Isosorbide Mononitrate should be given to a pregnant woman only if clearly needed.

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 as IMDUR 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 IMDUR treatment be initiated at low doses for several days before being increased to desired levels.

FREQUENCY AND ADVERSE EVENTS (DISCONTINUED)*

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 IMDUR 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.

Read the entire FDA prescribing information for Imdur (isosorbide mononitrate)

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© Imdur Patient Information is supplied by Cerner Multum, Inc. and Imdur Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

Mechanism of Action

ISMN extended-release tablets are 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 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. 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 (45-64 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 (65-74 years) showed 30% lower apparent oral clearance (CI/F) following the higher dose, ie., 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 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:

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.

Isosorbide Mononitrate extended-release tablets are contraindicated in patients who have shown hypersensitivity or idiosyncratic reactions to other nitrates or nitrites.

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

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.

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 doing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of the 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.

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 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.

Not withstanding 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.

Isosorbide Mononitrate extended-release 30 mg tablets are oval, reddish pink, film-coated tablets, debossed "N" bisect "30" on one side and bisect on the other side, packaged as follows:

NDC 68382-650-01 bottle of 100 tablets

NDC 68382-650-05 bottle of 500 tablets

Isosorbide Mononitrate extended-release 60 mg tablets are oval, yellow, film-coated tablets, debossed "N" bisect "60" on one side and bisect on the other side, packaged as follows:

NDC 68382-651-01 bottle of 100 tablets

NDC 68382-651-05 bottle of 500 tablets

Isosorbide Mononitrate extended-release 120 mg tablets are oval, white, film-coated tablets, debossed "N120" on one side, packaged as follows:

NDC 68382-652-01 bottle of 100 tablets

Store at 20° to 25°C (68° - 77°F).  [See USP Controlled Room Temperature.]  Protect from excessive moisture.

Manufactured By:

Nesher Pharmaceuticals USA LLC

St. Louis, MO 63044

Distributed by:

Zydus Pharmaceuticals USA Inc.

Pennington, NJ 08534

Immediate release: ≥6 hours (Thadani1987); Extended release: ≥12 to 24 hours (Anderson 2007)

Half-Life Elimination

~5 to 6 hours (Thadani 1987)

Protein Binding

<5%