Imdur

After oral administration of isosorbide-5-mononitrate as a solution or immediate-release tablets, maximum plasma concentrations of isosorbide-5-mononitrate are achieved in 30 to 60 minutes with an absolute bioavailability of approximately 100%. After i.v. administration, isosorbide-5-mononitrate 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-5-mononitrate is approximately 5% bound to human plasma proteins and is distributed into blood cells and saliva. Isosorbide-5-mononitrate is primarily metabolized by the liver, but unlike oral isosorbide dinitrate, it is not subject to first-pass metabolism. Isosorbide-5-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 6 different compounds have been detected in urine, with about 2% of the dose excreted as the unchanged drug and at least 5 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 isosorbide-5-mononitrate is approximately 5 hours.

The disposition of isosorbide-5-mononitrate 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 isosorbide-5-mononitrate was not prolonged, and there was no drug accumulation in patients with chronic renal failure after multiple oral dosing.

Impaired liver or kidney function has no major influence on the pharmacokinetic properties.

Food intake may decrease the rate (increase in T_max) but not the extent (AUC) of absorption of isosorbide-5-mononitrate.

With the extended release formulation of Imdur, isosorbide-5-mononitrate is gradually released, independent of pH, over a 10 hour period, according to a first order process.

This prolongation of the absorption phase results in reduced and delayed peak plasma levels compared to conventional tablets of isosorbide-5-mononitrate. After administration of 60 mg of isosorbide-5-mononitrate extended release tablets, peak plasma levels of around 3000 nmol/L are usually obtained within approximately 4 hours. The plasma concentrations then gradually fall to around 500 nmol/L at the end of the dosage interval (24 hours after dose intake).

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.

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.

Concomitant use of isosorbide-5-mononitrate and phosphodiesterase type 5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) can potentiate the hypotensive effect of isosorbide-5-mononitrate. This could result in life-threatening hypotension with syncope or myocardial infarction and death. Therefore, phosphodiesterase type 5 inhibitors (e.g. sildenafil, tadalafil, vardenafil) should not be given to patients receiving isosorbide-5-mononitrate therapy.

Alcohol may enhance sensitivity to the hypotensive effects of nitrates.

As patients may experience faintness and/or dizziness, reaction time when driving or operating machinery may be impaired, especially at the start of treatment.

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 administered to a nursing mother.

The safety and efficacy of isosorbide-5-mononitrate in children have not been established. Therefore, its use is not recommended.

Teratogenic Effects: In studies designed to detect effects of isosorbide-5-mononitrate on embryo-fetal development, doses of up to 240 to 248 mg/kg/day, administered to pregnant rats and rabbits, were unassociated with evidence of such effects. No adverse effects on reproduction or fetal development were reported. These animal doses are about 100 times the maximum recommended human dose 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 no studies in pregnant women. Because animal reproduction studies are not always predictive of human response, isosorbide-5-mononitrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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-5-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.

atrophic vaginitis, prostatic disorder, renal calculus, urinary bladder diverticulum, urinary tract infection, polyuria.

duodenal ulcer, eructation, hemorrhagic gastric ulcer, gastritis, hemorrhoids, intestinal obstruction, melena, dry mouth, pharynx disorder, tooth disorder, vomiting, loose stools, glossitis.

arthralgia, arthritis, arthropathy, arthrosis, frozen shoulder, muscle weakness, myalgia, myositis, torticollis, tendon disorder.

allergic reaction, asthenia, female breast pain, edema, feeling of warmth, fever, flu-like symptoms, malaise, rigors, earache, biliary pain, cholecystitis, hepatomegaly, diabetes mellitus, gout, weight decrease, weight increase, peripheral edema, tinnitus, epistaxis, purpura, infection, bacterial infection, cerebrovascular disorder, intermittent claudication, leg ulcer, peripheral ischemia, varicose vein, amaurosis fugax, conjunctivitis, diplopia, photophobia, moniliasis, skin nodule, tympanic membrane perforation, allergy, pain.

bronchitis, bronchospasm, pharyngitis, pneumonia, rales, respiratory disorder, pulmonary infiltration, increased sputum, sinusitis, nasal congestion.

rash, pruritus, eczema, acne, rash erythematous, rash psoriaform, abnormal hair texture, skin disorder.

albuminuria, hematuria, gamma GT increased, AST increased, ALT increased, hypercholesterolemia, hyperlipemia, hyperuricemia, hypocalcemia, hypokalemia, increased non-protein nitrogen, thrombocytopenia, anemia, leukopenia, leukocytosis, glycosuria.

hypoesthesia, migraine, neuritis, tremor, agitation, amnesia, impaired concentration, depression, decreased libido, nervousness, paroniria, confusion, anxiety, paresis, ptosis, impotence.

bundle branch block, cardiac failure, circulatory failure, hypotension, hypertension, syncope, arrhythmia, AV block, bradycardia, atrial fibrillation, heart murmur, abnormal heart sound, Q-wave abnormality, T-wave changes, ECG abnormal.

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 vasoconstrictors is ineffective in reversing the severe hypotensive effects of overdose and is 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 (≥10%) 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.

See Symptoms.