isosorbide 450 MG/ML Oral Solution

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.

CONTRAINDICATIONS: Isosorbide mononitrate is contraindicated in patients who are allergic to it. Do not use isosorbide mononitrate in patients who are taking certain drugs for erectile dysfunction (phosphodiesterase inhibitors), such as sildenafil, tadalafil, or vardenafil. Concomitant use can cause severe hypotension, syncope, or myocardial ischemia. Do not use isosorbide mononitrate in patients who are taking the soluble guanylate cyclase stimulator riociguat. Concomitant use can cause hypotension.

CLINICAL PHARMACOLOGY Mechanism of Action The isosorbide mononitrate extended-release tablet is 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, 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 its 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 0.6-0.7 L/kg. Isosorbide mononitrate is approximately 5% bound to human plasma proteins and is distributed into blood cells and saliva. Isosorbide mononitrate is primarily metabolized by the liver, but unlike oral isosorbide dinitrate, it is not subject to first-pass metabolism. Isosorbide 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 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 tablets 60 mg and 120 mg (2 x 60 mg) 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 isosorbide mononitrate extended-release 60 mg dose. The administration of isosorbide mononitrate extended-release 120 mg (2 x 60 mg tablets every 24 hours for 7 days) produced a dose-proportional increase in C max and AUC, without changes in T max or the terminal half-life. The older group (65-74 years) showed 30% lower apparent oral clearance (Cl/F) following the higher dose, i.e., 120 mg, compared to the younger group (45-64 years); Cl/F was not different between the two groups following the 60 mg regimen. While Cl/F was independent of dose in the younger group, the older group showed slightly lower Cl/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 C max 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 number of subjects in each age subgroup and consequently the lack of sufficient statistical power. The following table summarizes key pharmacokinetic parameters of ISMN after single- and multiple-dose administration of ISMN as an oral solution or isosorbide mononitrate extended-release tablets: SINGLE-DOSE STUDIES MULTIPLE-DOSE STUDIES PARAMETER ISMN 60 mg ISMN Extended-Release Tablets 60 mg ISMN Extended-Release Tablets 60 mg ISMN Extended-Release Tablets 120 mg C m a x (ng/mL) 1242-1534 424-541 557-572 1151-1180 T m a x (hr) 0.6-0.7 3.1-4.5 2.9-4.2 3.1-3.2 AUC (ng•hr/mL) 8189-8313 5990-7452 6625-7555 14241-16800 T ½ (hr) 4.8-5.1 6.3-6.6 6.2-6.3 6.2-6.4 Cl/F (mL/min) 120-122 151-187 132-151 119-140 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 T max ) but not the extent (AUC) of absorption of ISMN. Clinical Trials 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 tim