NITROGLYCERIN: 7,431 Adverse Event Reports & Safety Profile

DESCRIPTION Nitroglycerin is 1,2,3-propanetriol trinitrate, an organic nitrate whose structural formula is whose empiric formula is C 3 H 5 N 3 O 9 , and whose molecular weight is 227.09. The organic nitrates are vasodilators, active on both arteries and veins. Dextrose (Dextrose Hydrous, USP) is D-glucose monohydrate, a hexose sugar whose structural formula is whose empiric formula is C 6 H 12 O 6

• H 2 O, and whose molecular weight is 198.17. Dextrose is derived from corn. Nitroglycerin in 5% Dextrose Injection is a sterile, nonpyrogenic solution of nitroglycerin and dextrose in water for injection. The solution is clear and practically colorless.

Each

100 mL contains 10 mg, 20 mg, or 40 mg nitroglycerin (added as Diluted Nitroglycerin, USP with propylene glycol); 5 g Dextrose Hydrous, USP; 0.84 mL Alcohol, USP (added as a dissolution aid); and 105 mg Citric Acid Hydrous, USP (added as a buffer). The pH of the solution is adjusted with sodium hydroxide and, if necessary, hydrochloric acid. Although dry nitroglycerin is explosive, nitroglycerin in 5% dextrose is not. Composition, osmolarity and pH are given in Table 1.

Table

1 Composition Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥600 mOsmol/L) may cause vein damage. Osmolarity (mOsmol/L) (calc) pH Nitroglycerin (mcg/mL)

Dextrose

Hydrous, USP (g/L) 25 mg Nitroglycerin in 5% Dextrose Injection 100 50 428 4.0 (3.0 to 5.0) 50 mg Nitroglycerin in 5% Dextrose Injection 200 50 440 4.0 (3.0 to 5.0) 100 mg Nitroglycerin in 5% Dextrose Injection 400 50 465 4.0 (3.0 to 5.0)

Nitroglycerin Structural Formula Dextrose Structural

Formula

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.

4 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 <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span>. 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.

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.

WARNINGS: Amplification of the vasodilatory effects of nitroglycerin 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 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.

PRECAUTIONS General Only the smallest dose required for effective relief of the acute anginal attack should be used. Excessive use may lead to the development of tolerance. Nitroglycerin sublingual tablets are intended for sublingual or buccal administration and should not be swallowed. Severe hypotension, particularly with upright posture, may occur with 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 to other forms of nitroglycerin develops, the effects of sublingual nitroglycerin on exercise tolerance, although still observable, is blunted. In industrial workers who have had long-term exposure to unknown (presumably high) doses of organic nitrates, tolerance rarely 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. Several clinical trials of nitroglycerin patches or infusions in patients with angina pectoris have evaluated regimens that incorporated a 10- to 12-hour nitrate free interval. In some of these trials, an increase in the frequency of anginal attacks during the nitrate free interval was observed in a small number of patients. In one trial, patients had decreased exercise tolerance at the end of the nitrate interval. Hemodynamic rebound has been observed only rarely; on the other hand, few studies were so designed that rebound, if it had occurred, would have been detected. Nitrate tolerance as a result of sublingual nitroglycerin administration is probably possible, but only in patients who maintain high continuous nitrate levels for more than 10 or 12 hours daily. Such use of sublingual nitroglycerin would entail administration of scores of tablets daily and is not recommended. The drug should be discontinued if blurring of vision or drying of the mouth occurs. Excessive dosage of nitroglycerin may produce severe headaches. Information for Patients Nitroglycerin is a sublingual tablet and should not be chewed, crushed, or swallowed. If possible, patients should sit down when taking nitroglycerin sublingual tablets and should use caution when returning to a standing position. This eliminates the possibility of falling due to lightheadedness or dizziness. One tablet should be dissolved under the tongue or in the buccal pouch at the first sign of an acute anginal attack. The dose may be repeated approximately every 5 minutes until relief is obtained. If chest pain persists after a total of 3 tablets in a 15-minute period, or if the pain is different than is typically experienced, prompt medical attention is recommended. Nitroglycerin may be used prophylactically 5 to 10 minutes prior to engaging in activities that might precipitate an acute attack. Nitroglycerin may produce a burning or tingling sensation when administered sublingually; however, the ability to produce a burning or tingling sensation should not be considered a reliable method for determining the potency of the tablets. Headaches can sometimes accompany treatment with nitroglycerin. In patients who get these headaches, the headaches may be a marker of the activity of the drug. Treatment with nitroglycerin may be associated with lightheadedness upon standing, especially just after rising from a recumbent or seated position. This effect may be more frequent in patients who have also consumed alcohol. Nitroglycerin should be kept in the original glass container and must be tightly capped after each use to prevent loss of tablet potency.

Drug Interactions

Concomitant use of nitroglycerin with soluble guanylate cyclasestimulators is contraindicated (see CONTRAINDICATIONS ). Concomitant use of nitrates and alcohol may cause hypotension. The vasodilatory and hemodynamic effects of nitroglycerin may be enhanced by concomitant administration of aspirin. Intravenous administration of nitroglycerin decreases the thrombolytic effect of alteplase. Therefore, caution should be observed in patients receiving sublingual nitroglycerin during alteplase therapy. Intravenous nitroglycerin reduces the anticoagulant effect of heparin and activated partial thromboplastin times (APTT) should be monitored in patients receiving heparin and intravenous nitroglycerin. It is not known if this effect occurs following single sublingual nitroglycerin doses. Tricyclic antidepressants (amitriptyline, desipramine, doxepin, others) and anticholinergic drugs may cause dry mouth and diminished salivary secretions. This may make dissolution of sublingual nitroglycerin difficult. Increasing salivation with chewing gum or artificial saliva products may prove useful in aiding dissolution of sublingual nitroglycerin. Oral administration of nitroglycerin markedly decreases the first-pass metabolism of dihydroergotamine and subsequently increases its oral bioavailability. Ergotamine is known to precipitate angina pectoris. Therefore, patients receiving sublingual nitroglycerin should avoid ergotamine and related drugs or be monitored for symptoms of ergotism if this is not possible. Administration of nitroglycerin is contraindicated in patients who are using PDE-5 inhibitors (e.g., sildenafil citrate, tadalafil, vardenafil hydrochloride). These compounds have been shown to potentiate the hypotensive effects of organic nitrates. A decrease in therapeutic effect of sublingual nitroglycerin may result from use of long-acting nitrates.

Drug/Laboratory

Test Interactions Nitrates may interfere with the Zlatkis-Zak color reaction, causing a false report of decreased serum cholesterol. Carcinogenesis, Mutagenesis, Impairment of Fertility Animal carcinogenesis studies with sublingually administered nitroglycerin have not been performed. Carcinogenicity potential of nitroglycerin was evaluated in rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years. Rats developed dose-related fibrotic and neoplastic changes in liver, including carcinomas, and interstitial cell tumors in testes. At high dose, the incidences of hepatocellular carcinomas in males was 48% and in females was 33%, compared to 0% in untreated controls. Incidences of testicular tumors were 52% vs. 8% in controls. Lifetime dietary administration of up to 1058 mg/kg/day of, nitroglycerin was not tumorigenic in mice. Nitroglycerin was mutagenic in Ames tests performed in 2 different laboratories. Nevertheless, there was no evidence of mutagenicity in an in vivo dominant lethal assay with male rats treated with doses up to about 363 mg/kg/day, PO, or in ex vivo cytogenetic tests in rat and dog cells. In a 3-generation reproduction study, rats received dietary nitroglycerin at doses up to about 434 mg/kg/day for 6 months prior to mating of the F 0 generation, with treatment continuing through successive F 1 and F 2 generations. The high dose was associated with decreased feed intake and body weight gain in both sexes at all matings. No specific effect on the fertility of the F 0 generation was seen. Infertility noted in subsequent generations, however, was attributed to increased interstitial cell tissue and aspermatogenesis in the high-dose males. In this 3-generation study, there was no clear evidence of teratogenicity. Pregnancy: Category B . Animal reproduction and teratogenicity studies have not been conducted with nitroglycerin sublingual tablets. However, teratology studies conducted in rats and rabbits with topically applied nitroglycerin ointment at dosages up to 80 mg/kg/day and 240 mg/kg/day, respectively revealed no toxic effects on dams or fetuses. There are no adequate and well-controlled studies in pregnant women. Nitroglycerin should be given to a pregnant woman only if clearly needed.

Nursing

Mothers It is not known whether nitroglycerin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nitroglycerin is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of nitroglycerin in pediatric patients have not been established.

Geriatric Use

Clinical studies of nitroglycerin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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.

Glonoinum 200CK (**contains 0.443 mg of the active ingredient per pellet)

INACTIVE INGREDIENTS Active: As Above; Inactive: ENA 50% v/v and Purified Water q.s.