Nitroglycerin, Dextrose

INDICATIONS & USAGE Nitroglycerin in 5% Dextrose Injection is indicated for treatment of peri-operative hypertension; for control of heart failure in the setting of acute myocardial infarction; for treatment of angina pectoris in patients who have not responded to sublingual nitroglycerin and ß-blockers; and for induction of intraoperative hypotension.

DOSAGE & ADMINISTRATION Nitroglycerin in 5% Dextrose Injection is intended for intravenous administration using sterile equipment. Administer Nitroglycerin in 5% Dextrose Injection only via an infusion pump that can maintain a constant infusion rate. Do not use a container which has lost its vacuum, or one in which particulate matter is visible. Dosage is affected by the type of infusion set used (see WARNINGS ). Although the usual adult starting dose in published studies has been 25 mcg/min or more, these studies used PVC tubing, so the delivered doses were less than those reported. When nonadsorptive tubing is used, doses must be reduced (see WARNINGS and PRECAUTIONS ). The dosage must be determined by the patient’s individual requirement and depending on the required response and possible adverse effects (see ADVERSE REACTIONS ). Even using nonadsorptive tubing, the dose necessary to achieve a given response will vary greatly from patient to patient. Patients with normal or low left-ventricular filling pressure (e.g., patients with uncomplicated angina pectoris) may respond fully to as little as 5 mcg/min, while other patients may require a dose that is one or even two orders of magnitude higher. Continuous monitoring of blood pressure and heart rate is necessary in all patients receiving this medication; in many cases, invasive monitoring of pulmonary capillary wedge pressure will also be indicated. Lower concentrations of Nitroglycerin in 5% Dextrose Injection increase the potential precision of dosing, but these concentrations increase the total fluid volume that must be delivered to the patient. Total fluid load may be a dominant consideration in patients with compromised function of the heart, liver, and/or kidneys. The necessary flow rates to achieve various dose rates with the available concentrations are shown in the following table. Using nonadsorptive tubing, the initial adult dosage of Nitroglycerin in 5% Dextrose Injection should be 5 mcg/min. Subsequent titration must be guided by the clinical results, with dose increments becoming more cautious as partial response is seen. Initial titration should be in 5 mcg/min increments at intervals of 3 to 5 minutes. If no response is seen at 20 mcg/min, increments of 10 and even 20 mcg/min can be used. Once some hemodynamic response is observed, dosage increments should be smaller and less frequent. When the concentration is changed, the tubing must be disconnected from the patient and flushed with the new solution before therapy is continued. If this precaution is not taken, then depending upon the tubing, pump, and flow rate used, it might be several hours before nitroglycerin is delivered at the desired rate. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer unless the solution is clear and the seal is intact. Do not add supplementary medication to Nitroglycerin in 5% Dextrose Injection. Infusion Rate (mL/h) = [Dose (mcg/min) x 60 min/h] Concentration (mcg/mL) Example calculations for infusion rates are as follows: Example 1: for a dose of 30 µg/min using a 100 mcg/mL concentration, the infusion rate would be as follows: Infusion Rate (mL/h) = [30 (mcg/min) x 60 (min/h)] = 18 (mL/h) 100 (mcg/mL) Example 2: for a dose of 240 mcg/min using a 400 mcg/mL concentration, the infusion rate would be as follows: Infusion Rate (mL/h) = [5 (mcg/min) x 60 (min/h)] = 36 (mL/h) 400 (mcg/mL)

WARNINGS Use of PVC (polyvinyl chloride) tubing in infusion sets may lead to loss of active ingredient due to adsorption of nitroglycerin to PVC tubing, therefore dosage is affected (see DOSAGE & ADMINISTRATION ). Nitroglycerin adsorption by PVC tubing is increased when the tubing is long, the flow rates are low, and the nitroglycerin concentration of the solution is high. The delivered fraction of the solution's original nitroglycerin content has been 20-60% in published studies using PVC tubing; the fraction varies with time during a single infusion, and no simple correction factor can be used. PVC tubing has been used in most published studies of intravenous nitroglycerin, but the reported doses have been calculated by simply multiplying the flow rate of the solution by the solution's original concentration of nitroglycerin. The actual doses delivered have been less, sometimes much less, than those reported. Relatively non-adsorptive intravenous administration sets are available. If intravenous nitroglycerin is administered through non-adsorptive tubing, doses based upon published reports will generally be too high. Some in-line intravenous filters also adsorb nitroglycerin; these filters should be avoided. Solutions containing dextrose without electrolytes should not be administered through the same administration set as blood, as this may result in pseudoagglutination or hemolysis. The intravenous administration of solutions may cause fluid overloading resulting in dilution of serum electrolyte concentrations, overhydration and congested states of pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentration of the injections.

CONTRAINDICATIONS Nitroglycerin in 5% Dextrose Injection is contraindicated in patients who are allergic to it. In patients with pericardial tamponade, restrictive cardiomyopathy, or constrictive pericarditis, cardiac output is dependent upon venous return. Intravenous nitroglycerin is contraindicated in patients with these conditions. Nitroglycerin is also contraindicated in patients with increased intracranial pressure. Do not use Nitroglycerin in 5% Dextrose Injection 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 Nitroglycerin in 5% Dextrose Injection in patients who are taking the soluble guanylate cyclase stimulator riociguat. Concomitant use can cause hypotension.

ADVERSE REACTIONS Adverse reactions to nitroglycerin are generally dose-related and almost all of these reactions are the result of nitroglycerin's activity as a vasodilator. Headache, which may be severe, is the most commonly reported side effect. Headache may be recurrent with each daily dose, especially at higher doses. Transient episodes of lightheadedness, occasionally related to blood pressure changes, may also occur. Hypotension occurs infrequently, but in some patients it may be severe enough to warrant discontinuation of therapy. Syncope, crescendo angina, and rebound hypertension have been reported but are uncommon. Allergic reactions to nitroglycerin are also uncommon, and the great majority of those reported have been cases of contact dermatitis or fixed drug eruptions in patients receiving nitroglycerin in ointments or patches. There have been a few reports of genuine anaphylactoid reactions, and these reactions can probably occur in patients receiving nitroglycerin by any route. Extremely rarely, ordinary doses of organic nitrates have caused methemoglobinemia in normal-seeming patients. Methemoglobinemia is so infrequent at these doses that further discussion of its diagnosis and treatment is deferred (see OVERDOSAGE ). Dyspnea has also been reported. Data are not available to allow estimation of the frequency of adverse reactions during treatment with Nitroglycerin in 5% Dextrose Injection.

CLINICAL PHARMACOLOGY The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle and consequent dilatation of peripheral arteries and veins, especially the latter. Dilatation 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 (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. 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 anti-anginal 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 nitrate 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 anti-anginal efficacy been restored. Pharmacokinetics: The volume of distribution of nitroglycerin is about 3 L/kg, and nitroglycerin is cleared from this volume at extremely rapid rates, with a resulting serum half-life of about 3 minutes. The observed clearance rates (close to 1 L/kg/min) greatly exceed hepatic blood flow; known sites of extrahepatic metabolism include red blood cells and vascular walls. The first products in the metabolism of nitroglycerin are inorganic nitrate and the 1,2-and 1,3- dinitroglycerols. The dinitrates are less effective vasodilators than nitroglycerin, but they are longer-lived in the serum, and their net contribution to the overall effect of chronic nitroglycerin regimens is not known. The dinitrates are further metabolized to (non-vasoactive) mononitrates and, ultimately, to glycerol and carbon dioxide. To avoid development of tolerance to nitroglycerin, drug-free intervals of 10-12 hours are known to be sufficient; shorter intervals have not been well studied. In one well-controlled clinical trial, subjects receiving nitroglycerin appeared to exhibit a rebound or withdrawal effect, so that their exercise tolerance at the end of the daily drug-free interval was less than that exhibited by the parallel group receiving placebo. Clinical Trials: Blinded, placebo-controlled trials of intravenous nitroglycerin have not been reported, but multiple investigators have reported open-label studies, and there are scattered reports of studies in which intravenous nitroglycerin was tested in blinded fashion against sodium nitroprusside. In each of these studies, therapeutic doses of intravenous nitroglycerin were found to reduce systolic and diastolic arterial blood pressure. The heart rate was usually increased, presumably as a reflexive response to the fall in blood pressure. Coronary perfusion pressure was usually, but not always, maintained. Intravenous nitroglycerin reduced central venous pressure (CVP), right atrial pressure (RAP), pulmonary arterial pressure (PAP), pulmonary-capillary wedge pressure (PCWP), pulmonary vascular resistance (PVR), and systemic vascular resistance (SVR). When these parameters were elevated, reducing them toward normal usually caused a rise in cardiac output. Conversely, intravenous nitroglycerin usually reduced cardiac output when it was given to patients whose CVP, RAP, PAP, PCWP, PVR, and SVR were all normal. Most clinical trials of intravenous nitroglycerin have been brief; they have typically followed hemodynamic parameters during a single surgical procedure. In one careful study, one of the few that lasted more than a few hours, continuous intravenous nitroglycerin had lost almost all of its hemodynamic effect after 48 hours. In the same study, patients who received nitroglycerin infusions for only 12 hours out of each 24 demonstrated no similar attenuation of effect. These results are consistent with those seen in multiple large, double-blind, placebo-controlled trials of other formulations of nitroglycerin and other nitrates.