Nitroglycerin

INDICATIONS AND 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 and Administration NOT FOR DIRECT INTRAVENOUS INJECTION NITROGLYCERIN INJECTION IS A CONCENTRATED, POTENT DRUG WHICH MUST BE DILUTED IN DEXTROSE (5%) INJECTION OR SODIUM CHLORIDE (0.9%) INJECTION PRIOR TO ITS INFUSION. NITROGLYCERIN INJECTION SHOULD NOT BE MIXED WITH OTHER DRUGS. 1. Initial Dilution : Aseptically transfer the contents of one nitroglycerin vial (containing 25 mg or 50 mg of nitroglycerin) into a 500 mL glass bottle of either Dextrose (5%) Injection or Sodium Chloride Injection (0.9%). This yields a final concentration of 50 mcg/mL or 100 mcg/mL. Diluting 5 mg nitroglycerin into 100 mL will also yield a final concentration of 50 mcg/mL. 2. Maintenance Dilution: It is important to consider the fluid requirements of the patient as well as the expected duration of infusion in selecting the appropriate dilution of Nitroglycerin Injection. After the initial dosage titration, the concentration of the solution may be increased, if necessary, to limit fluids given to the patient. The nitroglycerin concentration should not exceed 400 mcg/mL. See chart. Note: If the concentration is adjusted, it is imperative to flush or replace the infusion set before a new concentration is utilized. If the set were not flushed or replaced, it could take minutes to hours, depending upon the flow rate and the dead space of the set, for the new concentration to reach the patient. Invert the glass parenteral bottle several times to assure uniform dilution of the nitroglycerin. Dosage is affected by the type of container and administration set used. See WARNINGS. Although the usual starting adult dose range reported in clinical studies was 25 mcg/min or more, these studies used PVC administration sets. THE USE OF NON-ABSORBING TUBING WILL RESULT IN THE NEED FOR REDUCED DOSES. If a peristaltic action infusion pump is used, an appropriate administration set should be selected with a drip chamber that delivers approximately 60 microdrops/mL. Table 1 and the Nitroglycerin Injection Dilution Table below may be used to calculate the nitroglycerin dilution and flow rate in microdrops/minute to achieve the desired Nitroglycerin Injection administration rate. If a volumetric infusion pump is used, an appropriate volumetric infusion pump connector set should be selected. Table 1 below may still be used; however, flow rate will be determined directly by the infusion pump, independent of the drop size of the appropriate set drip chambers. Thus, the reference to ``microdrops/min## is not applicable, and the corresponding flow rate in mL/hr should be used to determine pump settings. When using a non-absorbing infusion set, the initial dosage should be 5 mcg/min delivered through an infusion pump capable of exact and constant delivery of the drug. Subsequent titration must be adjusted to the clinical situation, with dose increments becoming more cautious as partial response is seen. Initial titration should be in 5 mcg/min increments, with increases every 3-5 minutes until some response is noted. If no response is seen at 20 mcg/min, increments of 10 and later 20 mcg/min can be used. Once a partial blood pressure response is observed, the dose increase should be reduced and the interval between increases should be lengthened. Some patients with normal or low left ventricular filling pressures or pulmonary capillary wedge pressure (e.g., angina patients without other complications) may be hypersensitive to the effects of nitroglycerin and may respond fully to doses as small as 5 mcg/ min. These patients require especially careful titration and monitoring. There is no fixed optimum dose of nitroglycerin. Due to variations in the responsiveness of individual patients to the drug, each patient must be titrated to the desired level of hemodynamic function. Therefore, continuous monitoring of physiologic parameters (i.e., blood pressure and heart rate in all patients, other measurements such as pulmonary capillary wedge pressure, as appropriate) MUST be performed to achieve the correct dose. Adequate systemic blood pressure and coronary perfusion pressure must be maintained. Dilution: Nitroglycerin Injection is supplied in 5 mg/mL solution. A dilution and administration scheme for Nitroglycerin Injection is shown in Table 1 below. 60 MICRODROPS=1mL Solution Concentration (mcg/mL) 100 200 400 Dose (mcg/min) FLOW RATE (microdrops/min=mL/hr 5 3 - - 10 6 3 - 15 9 - - 20 12 6 3 30 18 9 - 40 24 12 6 60 36 18 9 80 48 24 12 120 72 36 18 160 96 48 24 240 - 72 36 320 - 96 48 480 - - 72 640 - - 96 60MICRODROPS=1 mL NITROGLYCERIN INJECTION DILUTION TABLE Each mL of Nitroglycerin Injection contains 5 mg of nitroglycerin. Total Contents: Each 10 mL vial contains 50 mg of nitroglycerin. FINAL CONCENTRATION mL of Nitroglycerin Injection Volume mg 100 mcg/mL q.s. to 200 mcg/mL q.s. to 400 mcg/mL q.s. to 5 mL 25 mg 250 mL 125 mL --- 10 mL 50 mg 500 mL 250 mL 125 mL 20 mL 100 mg 1000 mL 500 mL 250 mL 40 mL 200 mg --- 1000 mL 500 mL (Diluent: Dectrose 5% Injection of Sodium Chloride Injection (0.9%) NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

WARNINGS: Amplification of the vasodilatory effects of nitroglycerin by phosphodiesterase inhibitors 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 oral nitroglycerin in patients with acute myocardial infarction or congestive heart failure have not been established. If one elects to use nitroglycerin in these conditions, careful clinical or hemodynamic monitoring must be used to avoid the hazards of hypotension and tachycardia. Because the effects at capsules are so difficult to terminate rapidly, that are not recommended in these settings. PRECAUTIONS: General: Severe hypotension, particularly with upright posture, may occur with even small doses of nitroglycerin. This drug should therefore be used with caution in patients who may be volume depleted or who, for whatever reason, are already hypotensive. Hypotension induced by nitroglycerin may be accompanied by paradoxical bradycardia and increased angina pectoris. Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy. As tolerance in other forms of nitroglycerin develops, the effect of sublingual nitroglycerin on exercise tolerance, although still observable, is somewhat blunted. In industrial workers who have had long-term exposure to unknown (presumably high) doses of organic nitrates, tolerance clearly occurs. Chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of true physical dependence. Some clinical trials in angina patients have provided nitroglycerin for about 12 continuous hours of every 24-hour day. During the nitrate-free intervals in some of these trials, anginal attacks have been more easily provoked than before treatment, and patients have demonstrated hemodynamic rebound and decreased exercise tolerance. The importance of these observations to the routine, clinical use at oral nitroglycerin is not known.

CONTRAINDICATIONS • Use of phosphodiesterase type 5 (PDE-5) inhibitors, such as avanafil, sildenafil, tadalafil, or vardenafil, or soluble guanylate cyclase (sGC) stimulators. ( 4.1 , 7.1 ) • Severe anemia ( 4.2 ) • Increased intracranial pressure ( 4.3 ) • Hypersensitivity to nitroglycerin sublingual tablets or to other nitrates or nitrites or any excipient ( 4.4 ) • Circulatory failure and shock ( 4.5 ) 4.1 PDE-5-Inhibitors and sGC-Stimulators Do not use nitroglycerin sublingual tablets in patients who are taking PDE-5 Inhibitors, such as avanafil, sildenafil, tadalafil, vardenafil hydrochloride. Concomitant use can cause severe hypotension, syncope, or myocardial ischemia [see Drug Interactions (7.1) ]. Do not use nitroglycerin sublingual tablets in patients who are taking the soluble guanylate cyclase stimulators, such as riociguat. Concomitant use can cause hypotension. 4.2 Severe Anemia Nitroglycerin sublingual tablets are contraindicated in patients with severe anemia (large doses of nitroglycerin may cause oxidation of hemoglobin to methemoglobin and could exacerbate anemia). 4.3 Increased Intracranial Pressure Nitroglycerin sublingual tablets may precipitate or aggravate increased intracranial pressure and thus should not be used in patients with possible increased intracranial pressure (e.g., cerebral hemorrhage or traumatic brain injury). 4.4 Hypersensitivity Nitroglycerin sublingual tablets are contraindicated in patients who are allergic to nitroglycerin, other nitrates or nitrites or any excipient. 4.5 Circulatory Failure and Shock Nitroglycerin sublingual tablets are contraindicated in patients with acute circulatory failure or shock.

DRUG INTERACTIONS PDE5 inhibitors: potentiation of hypotensive effects of organic nitrates; concomitant use is contraindicated. ( 4.1 , 7.1 ) Antihypertensives: possible additive hypotensive effects. ( 7.2 ) Aspirin: increased nitroglycerin levels. ( 7.3 ) Tissue-type Plasminogen Activator (t-PA): decreased thrombolytic effect. ( 7.4 ) Heparin: anticoagulant effect of heparin may be reduced. Monitor APTT. ( 7.5 ) Ergotamine: increased bioavailability of ergotamine. ( 7.6 ) Alcohol: Additive vasodilatory effects to nitroglycerin. Consumption of alcohol should be avoided. ( 7.7 ) 7.1 PDE5 Inhibitors Phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates. The time course of the interaction appears to be related to the half-life of the PDE5 inhibitor, however, the dose dependence of this interaction has not been studied. Use of nitroglycerin ointment, 0.4% within a few days of PDE5 inhibitors is contraindicated. 7.2 Antihypertensives Patients receiving antihypertensive drugs, beta-adrenergic blockers, and other nitrates should be observed for possible additive hypotensive effects when using nitroglycerin ointment, 0.4%. Marked orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used concomitantly. Beta-blockers blunt the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effects. If beta-blockers are used with nitroglycerin ointment, 0.4% in patients with angina pectoris, additional hypotensive effects may occur. 7.3 Aspirin Coadministration of aspirin (at doses between 500 mg and 1000 mg) and nitroglycerin has been reported to result in increased nitroglycerin maximum concentrations by as much as 67% and AUC by 73% when administered as a single dose. The pharmacological effects of nitroglycerin ointment, 0.4% may be enhanced by concomitant administration of aspirin. 7.4 Tissue-type Plasminogen Activator (t-PA) Intravenous administration of nitroglycerin decreases the thrombolytic effect of tissue-type plasminogen activator (t-PA). Plasma levels of t-PA are reduced when coadministered with nitroglycerin. Therefore, caution should be observed in patients receiving nitroglycerin ointment, 0.4% during t-PA therapy. 7.5 Heparin Although an interaction has been reported between intravenous heparin and intravenous nitroglycerin (resulting in a decrease in the anticoagulant effect of heparin), the data are not consistent. If patients are to receive intravenous heparin and nitroglycerin ointment, 0.4% concurrently, the anticoagulation status of the patient must be checked. 7.6 Ergotamine Oral administration of nitroglycerin markedly decreases the first-pass metabolism of dihydroergotamine and consequently increases its oral bioavailability. Ergotamine is known to precipitate angina pectoris. Therefore the possibility of ergotism in patients receiving nitroglycerin ointment, 0.4% should be considered. 7.7 Alcohol The vasodilating effects of nitroglycerin have been shown to be additive to the effects observed with alcohol.

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reaction of nitroglycerin ointment applied to the anal canal is headache. Headache may be recurrent following each dose. Headaches are typically of short duration and can be treated with an analgesic, e.g. acetaminophen, and are reversible upon discontinuation of treatment. In Study REC-C-001, a double-blind, placebo-controlled trial in patients with a painful chronic anal fissure, the most frequent ( > 2%) adverse reactions reported were as follows (Table 1) Table 1: Incidence of Adverse Reactions ( > 2%) in Study REC-C-001 Nitroglycerin Ointment N = 123 Placebo N = 124 System Organ Class Preferred term Patients n (%) Events n Patients n (%) Events n Nervous system disorders Headache 79 (64) 938 51 (41) 225 Dizziness 6 (5) 26 0 0 Hypotension Transient episodes of light-headedness, occasionally related to blood pressure changes, also may occur. Hypotension (including orthostatic hypotension) occurs infrequently, but in some patients may be severe enough to warrant discontinuation of therapy. Allergic Reactions Flushing, allergic reactions, and application site reactions (including drug rash and exfoliative dermatitis) have been reported rarely. Methemoglobinemia In rare cases, therapeutic doses of organic nitrates have caused methemoglobinemia [see OVERDOSAGE (10) ]. Most common adverse reactions are headache and dizziness. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Private Limited, at 1-833-285-4151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Mechanism of Action Nitroglycerin forms free radical nitric oxide (NO) which activates guanylate cyclase, resulting in an increase of guanosine 3'5' monophosphate (cyclic GMP) in smooth muscle and other tissues. These events lead to dephosphorylation of myosin light chains, which regulate the contractile state in smooth muscle, and result in vasodilatation. 12.2 Pharmacodynamics The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle. Although venous effects predominate, nitroglycerin produces, in a dose-related manner, dilation of both arterial and venous beds. Dilation of postcapillary vessels, including large veins, promotes peripheral pooling of blood, decreases venous return to the heart, and reduces left ventricular end-diastolic pressure (preload). Nitroglycerin also produces arteriolar relaxation, thereby reducing peripheral vascular resistance and arterial pressure (afterload), and dilates large epicardial coronary arteries; however, the extent to which this latter effect contributes to the relief of exertional angina is unclear. Therapeutic doses of nitroglycerin may reduce systolic, diastolic, and mean arterial blood pressure. Effective coronary perfusion pressure is usually maintained, but can be compromised if blood pressure falls excessively, or increased heart rate decreases diastolic filling time. Elevated central venous and pulmonary capillary wedge pressures, and pulmonary and systemic vascular resistance are also reduced by nitroglycerin therapy. Heart rate is usually slightly increased, presumably due to a compensatory response to the fall in blood pressure. Cardiac index may be increased, decreased, or unchanged. Myocardial oxygen consumption or demand (as measured by the pressure-rate product, tension-time index, and stroke-work index) is decreased and a more favorable supply-demand ratio can be achieved. Patients with elevated left ventricular filling pressures and increased systemic vascular resistance in association with a depressed cardiac index are likely to experience an improvement in cardiac index. In contrast, when filling pressures and cardiac index are normal, cardiac index may be slightly reduced following nitroglycerin administration. Consistent with the symptomatic relief of angina, digital plethysmography indicates that onset of the vasodilatory effect occurs approximately 1 to 3 minutes after sublingual nitroglycerin administration and reaches a maximum by 5 minutes postdose. Effects persist for at least 25 minutes following nitroglycerin sublingual tablets administration. 12.3 Pharmacokinetics Absorption Nitroglycerin is rapidly absorbed following sublingual administration of nitroglycerin tablets. Mean peak nitroglycerin plasma concentrations occur at a mean time of approximately 6 to 7 minutes postdose (Table 1). Maximum plasma nitroglycerin concentrations (C max) and area under the plasma concentration- time curves (AUC) increase dose-proportionally following 0.3 to 0.6 mg nitroglycerin. The absolute bioavailability of nitroglycerin from nitroglycerin sublingual tablets is approximately 40% but tends to be variable due to factors influencing drug absorption, such as sublingual hydration and mucosal metabolism. Distribution The volume of distribution (V Area) of nitroglycerin following intravenous administration is 3.3 L/kg. At plasma concentrations between 50 and 500 ng/mL, the binding of nitroglycerin to plasma proteins is approximately 60%, while that of 1,2- and 1,3-dinitroglycerin is 60% and 30%, respectively. Metabolism A liver reductase enzyme is of primary importance in the metabolism of nitroglycerin to glycerol di- and mononitrate metabolites and ultimately to glycerol and organic nitrate. Known sites of extrahepatic metabolism include red blood cells and vascular walls. In addition to nitroglycerin, 2 major metabolites 1,2­ and 1,3-dinitroglycerin, are found in plasma. Mean peak 1,2- and 1,3-dinitroglycerin plasma concentrations occur at approximately 15 minutes postdose. The elimination half-life of 1,2- and 1,3-dinitroglycerin is 36 and 32 minutes, respectively. The 1,2- and 1,3-dinitroglycerin metabolites have been reported to possess approximately 2% and 10%, respectively, of the pharmacological activity of nitroglycerin. Higher plasma concentrations of the dinitro metabolites, along with their nearly 10-fold longer elimination half-lives, may contribute significantly to the duration of pharmacologic effect. Glycerol mononitrate metabolites of nitroglycerin are biologically inactive. Elimination Nitroglycerin plasma concentrations decrease rapidly, with a mean elimination half-life of 2 to 3 minutes. Half-life values range from 1.5 to 7.5 minutes. Clearance (13.6 L/min) greatly exceeds hepatic blood flow. Metabolism is the primary route of drug elimination. Drug interactions Aspirin:Coadministration of nitroglycerin with high dose aspirin (1000 mg) results in increased exposure to nitroglycerin. The vasodilatory and hemodynamic effects of nitroglycerin may be enhanced by concomitant administration of nitroglycerin with high dose aspirin. Tissue-type plasminogen activator (t-PA): Concomitant administration of t-PA and intravenous nitroglycerin has been shown to reduce plasma levels of t-PA and its thrombolytic effect. Table