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1 INDICATIONS AND USAGE Nitroglycerin ointment 0.4% is indicated for the treatment of moderate to severe pain associated with chronic anal fissure. Nitroglycerin ointment is a nitrate vasodilator indicated for the treatment of moderate to severe pain associated with chronic anal fissure ( 1 ).

2 DOSAGE AND ADMINISTRATION Apply 1 inch of ointment (375 mg of ointment equivalent to 1.5 mg of nitroglycerin) intra-anally every 12 hours for up to 3 weeks. A finger covering, such as plastic-wrap, disposable surgical glove or a finger cot, should be placed on the finger to apply the ointment. To obtain a 1.5 mg dose of nitroglycerin, the covered finger is laid alongside the 1 inch dosing line on the carton. Refer to carton for accurate dosage guide. The tube is gently squeezed until a line of ointment the length of the measuring line is expressed onto the covered finger. The ointment is gently inserted into the anal canal using the covered finger no further than to the first finger joint and the ointment is applied around the side of the anal canal. If this cannot be achieved due to pain, application of the ointment should be made directly to the outside of the anus. Treatment may be continued for up to three weeks. Nitroglycerin ointment is not for oral, ophthalmic, or intravaginal use. Hands should be washed after application of the ointment [see Patient Instruction ] . Apply 1 inch of ointment (375 mg of ointment equivalent to 1.5 mg of nitroglycerin) intra-anally every 12 hours for up to 3 weeks ( 2 ). Nitroglycerin ointment is not for oral, ophthalmic, or intravaginal use ( 2 ) dosing-card

4 CONTRAINDICATIONS • Use of PDE5 inhibitors (e.g. sildenafil, vardenafil and tadalafil) as these are shown to potentiate the hypotensive effects of organic nitrates. ( 4.1 ). • Severe anemia ( 4.2 ) • Increased intracranial pressure ( 4.3 ) • Known hypersensitivity to nitroglycerin, other nitrates and nitrites, or any components of the ointment. ( 4.4 ) 4.1 PDE5 inhibitor use Administration of nitroglycerin ointment is contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), such as sildenafil, vardenafil, and tadalafil, as these are shown to potentiate the hypotensive effects of organic nitrates [see DRUG INTERACTIONS (7.1) ]. 4.2 Severe anemia Nitroglycerin ointment is contraindicated in patients with severe anemia. 4.3 Increased intracranial pressure Nitroglycerin ointment is contraindicated in patients with increased intracranial pressure. 4.4 Hypersensitivity Nitroglycerin ointment is contraindicated in patients who have shown hypersensitivity to it or to other nitrates or nitrites. Skin reactions consistent with hypersensitivity have been observed with organic nitrates.

5 WARNINGS AND PRECAUTIONS • Cardiovascular Disorders: Venous and arterial dilatation as a consequence of nitroglycerin treatment can result in hypotension. Exercise caution when treating patients with any of the following conditions: blood volume depletion, existing hypotension, cardiomyopathies, congestive heart failure, acute myocardial infarction, or poor cardiac function for other reasons ( 5.1 ). • Headache: Nitroglycerin produces dose-related headaches which may be severe ( 5.2 ) 5.1 Cardiovascular disorders Venous and arterial dilatation as a consequence of nitroglycerin treatment including nitroglycerin ointment, can decrease venous blood returning to the heart and reduce arterial vascular resistance and systolic pressure. Exercise caution when treating patients with any of the following conditions: blood volume depletion, existing hypotension, cardiomyopathies, congestive heart failure, acute myocardial infarction, or poor cardiac function for other reasons. If patients with any of these conditions are treated with nitroglycerin ointment, monitor cardiovascular status and clinical condition. The adverse reactions of nitroglycerin ointment are likely to be more pronounced in the elderly. 5.2 Headache Nitroglycerin ointment produces dose-related headaches, which may be severe. Tolerance to headaches occurs.

6 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.

<table width="100%"><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><thead align="center"><tr><th styleCode="Botrule Lrule Rrule Toprule"> </th><th colspan="2" styleCode="Botrule Rrule Toprule" align="center"><content styleCode="bold">Nitroglycerin</content> <content styleCode="bold">Ointment</content> <content styleCode="bold">N = 123</content></th><th colspan="2" styleCode="Botrule Rrule Toprule" align="center"><content styleCode="bold">Placebo</content> <content styleCode="bold">N = 124</content></th></tr></thead><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" valign="top"><paragraph><content styleCode="bold">System Organ Class</content> Preferred term</paragraph></td><td styleCode="Botrule Rrule Toprule" valign="top" align="center"><paragraph><content styleCode="bold">Patients</content> <content styleCode="bold">n (%)</content></paragraph></td><td styleCode="Botrule Rrule Toprule" valign="top" align="center"><paragraph><content styleCode="bold">Events</content> <content styleCode="bold">n</content></paragraph></td><td styleCode="Botrule Rrule Toprule" valign="top" align="center"><paragraph><content styleCode="bold">Patients</content> <content styleCode="bold">n (%)</content></paragraph></td><td styleCode="Botrule Rrule Toprule" valign="top" align="center"><paragraph><content styleCode="bold">Events</content> <content styleCode="bold">n</content></paragraph></td></tr><tr><td colspan="5" styleCode="Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Nervous system disorders</content></paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Headache</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>79 (64)</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>938</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>51 (41)</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>225</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Dizziness</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>6 (5)</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>26</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>0</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph>0</paragraph></td></tr></tbody></table>

7 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 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 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 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 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 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 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 should be considered. 7.7 Alcohol The vasodilating effects of nitroglycerin have been shown to be additive to the effects observed with alcohol.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no data on the use of nitroglycerin ointment intra-anally during pregnancy to determine a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, no malformations were observed in offspring of pregnant rats and rabbits administered nitroglycerin by topical or dietary route during the period of organogenesis ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Animal reproduction studies in rats and rabbits were conducted with topically applied nitroglycerin ointment at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively. No toxic effects on dams or fetuses were seen at any dose tested. An animal reproduction study was conducted in rats with nitroglycerin administered in the diet at levels up to 1% content (approximately 430 mg/kg/day) on days 6 to 15 of gestation. In offspring of the high-dose group, an increased but not statistically significant incidence of diaphragmatic hernias was noted together with decreased hyoid bone ossification. The latter finding probably reflects delayed development, thus indicating no clear evidence of a potential teratogenic effect of nitroglycerin. 8.2 Lactation Risk Summary There are no data on the presence of nitroglycerin in either human or animal milk following topical administration, or the effects of nitroglycerin on milk production. A publication describing 40 lactating patients who used nitroglycerin ointment to treat chronic anal fissures for varied durations did not report signs of adverse effects in their breastfed infants, however, the dosing regimens were not described. The developmental and health benefits of breastfeeding should be considered along with the clinical need for nitroglycerin ointment and any potential adverse effects on the breastfed infant from nitroglycerin ointment or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of nitroglycerin ointment in pediatric patients under 18 years of age have not been established. 8.5 Geriatric Use Clinical studies of nitroglycerin ointment did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Clinical data from the published literature indicate that the elderly demonstrate increased sensitivity to nitrates, which may be therapeutic but also manifest by more frequent or severe hypotension and related dizziness or fainting. Increased sensitivity may reflect the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.1 Pregnancy Risk Summary There are no data on the use of nitroglycerin ointment intra-anally during pregnancy to determine a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, no malformations were observed in offspring of pregnant rats and rabbits administered nitroglycerin by topical or dietary route during the period of organogenesis ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Animal reproduction studies in rats and rabbits were conducted with topically applied nitroglycerin ointment at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively. No toxic effects on dams or fetuses were seen at any dose tested. An animal reproduction study was conducted in rats with nitroglycerin administered in the diet at levels up to 1% content (approximately 430 mg/kg/day) on days 6 to 15 of gestation. In offspring of the high-dose group, an increased but not statistically significant incidence of diaphragmatic hernias was noted together with decreased hyoid bone ossification. The latter finding probably reflects delayed development, thus indicating no clear evidence of a potential teratogenic effect of nitroglycerin.

8.2 Lactation Risk Summary There are no data on the presence of nitroglycerin in either human or animal milk following topical administration, or the effects of nitroglycerin on milk production. A publication describing 40 lactating patients who used nitroglycerin ointment to treat chronic anal fissures for varied durations did not report signs of adverse effects in their breastfed infants, however, the dosing regimens were not described. The developmental and health benefits of breastfeeding should be considered along with the clinical need for nitroglycerin ointment and any potential adverse effects on the breastfed infant from nitroglycerin ointment or from the underlying maternal condition.

8.5 Geriatric Use Clinical studies of nitroglycerin ointment did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Clinical data from the published literature indicate that the elderly demonstrate increased sensitivity to nitrates, which may be therapeutic but also manifest by more frequent or severe hypotension and related dizziness or fainting. Increased sensitivity may reflect the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE Nitroglycerin toxicity is generally mild. The estimated adult oral lethal dose of nitroglycerin is 200 mg to 1,200 mg. Infants may be more susceptible to toxicity from nitroglycerin. Consultation with a poison center should be considered. Laboratory determinations of serum levels of nitroglycerin and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of nitroglycerin overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of nitroglycerin and its active metabolites. Similarly, it is not known which, if any, of these substances can usefully be removed from the body by hemodialysis. No specific antagonist to the vasodilator effects of nitroglycerin is known, and no intervention has been subject to controlled study as a therapy of nitroglycerin overdose. Because the hypotension associated with nitroglycerin overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. Passive elevation of the patient's legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary. The use of epinephrine or other arterial vasoconstrictors in this setting is not recommended. In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of nitroglycerin ointment overdose in these patients may be subtle and difficult, and invasive monitoring may be required. Methemoglobinemia Methemoglobinemia has been rarely reported with organic nitrates. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate arterial PO2. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air. If methemoglobinemia is present, intravenous administration of methylene blue, 1 to 2 mg/kg of body weight, may be required.

11 DESCRIPTION Nitroglycerin ointment, USP 0.4% is intended for intra-anal use. Nitroglycerin is 1,2,3,-propanetriol trinitrate, an organic nitrate vasodilator whose structural formula is as follows: and whose molecular weight is 227.09. Nitroglycerin ointment, USP 0.4% contains 0.4% nitroglycerin w/w (4 mg nitroglycerin/1 g ointment), propylene glycol, lanolin, sorbitan sesquioleate, paraffin wax, and white petrolatum. Nitroglycerin ointment, USP 0.4% is available in tubes with a one-inch dosing line on the carton allowing the measurement of approximately 375 mg of nitroglycerin ointment, USP 0.4% (1.5 mg nitroglycerin) for application. structure

12 CLINICAL PHARMACOLOGY 12.1 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. This leads to dephosphorylation of myosin light chains, which regulates the contractile state in smooth muscle and results in vasodilatation. 12.2 Pharmacodynamics The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle. Intra- anal application of nitroglycerin reduces sphincter tone and resting intra-anal pressure. 12.3 Pharmacokinetics Absorption: In six healthy subjects, the average absolute bioavailability of nitroglycerin applied to the anal canal as a 0.2% w/w ointment was approximately 50% of the 0.75 mg nitroglycerin dose. Distribution: The volume of distribution of nitroglycerin following intravenous administration is about 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: Nitroglycerin is metabolized by a liver reductase enzyme 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, the two major metabolites, 1,2- and 1,3- dinitroglycerols are found in plasma. The contribution of metabolites to the relaxation of the internal anal sphincter is unknown. The dinitrates are further metabolized to nonvasoactive mononitrates and ultimately to glycerol and carbon dioxide. Elimination: Metabolism is the primary route of drug elimination. Nitroglycerin plasma concentrations decrease rapidly with a mean elimination half-life of two to three minutes. Half-life values range from 1.5 to 7.5 minutes. Clearance (13.6 L/min) greatly exceeds hepatic blood flow.

12.1 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. This leads to dephosphorylation of myosin light chains, which regulates the contractile state in smooth muscle and results in vasodilatation.

12.2 Pharmacodynamics The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle. Intra- anal application of nitroglycerin reduces sphincter tone and resting intra-anal pressure.

12.3 Pharmacokinetics Absorption: In six healthy subjects, the average absolute bioavailability of nitroglycerin applied to the anal canal as a 0.2% w/w ointment was approximately 50% of the 0.75 mg nitroglycerin dose. Distribution: The volume of distribution of nitroglycerin following intravenous administration is about 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: Nitroglycerin is metabolized by a liver reductase enzyme 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, the two major metabolites, 1,2- and 1,3- dinitroglycerols are found in plasma. The contribution of metabolites to the relaxation of the internal anal sphincter is unknown. The dinitrates are further metabolized to nonvasoactive mononitrates and ultimately to glycerol and carbon dioxide. Elimination: Metabolism is the primary route of drug elimination. Nitroglycerin plasma concentrations decrease rapidly with a mean elimination half-life of two to three minutes. Half-life values range from 1.5 to 7.5 minutes. Clearance (13.6 L/min) greatly exceeds hepatic blood flow.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Animal carcinogenicity studies with topically applied nitroglycerin have not been performed. Rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years developed dose-related fibrotic and neoplastic changes in liver, including carcinomas, and interstitial cell tumors in testes. At the highest dose, the incidence of hepatocellular carcinomas was 52% compared to 0% in untreated controls. Incidence 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. Mutagenesis Nitroglycerin was mutagenic in the in vitro bacterial reverse mutation (Ames) assay with Salmonella typhimurium. A similar mutation in this S. typhimurium was also reported with other NO donors.There was no evidence of clastogenic potential in multiple assays including a rodent dominant lethal assay, an in vitro Chinese Hamster Ovary assay that was conducted in the absence of metabolic activation, and several in vivo chromosomal aberration assays conducted in rats and dogs. Impairment of Fertility In a three-generation reproduction study, rats received dietary nitroglycerin at doses up to approximately 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Animal carcinogenicity studies with topically applied nitroglycerin have not been performed. Rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years developed dose-related fibrotic and neoplastic changes in liver, including carcinomas, and interstitial cell tumors in testes. At the highest dose, the incidence of hepatocellular carcinomas was 52% compared to 0% in untreated controls. Incidence 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. Mutagenesis Nitroglycerin was mutagenic in the in vitro bacterial reverse mutation (Ames) assay with Salmonella typhimurium. A similar mutation in this S. typhimurium was also reported with other NO donors.There was no evidence of clastogenic potential in multiple assays including a rodent dominant lethal assay, an in vitro Chinese Hamster Ovary assay that was conducted in the absence of metabolic activation, and several in vivo chromosomal aberration assays conducted in rats and dogs. Impairment of Fertility In a three-generation reproduction study, rats received dietary nitroglycerin at doses up to approximately 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.

14 CLINICAL STUDIES Nitroglycerin ointment was evaluated in a 3-week double-blind, randomized, multi-center, placebo- controlled study. Patients with a painful chronic anal fissure for at least 6 weeks and moderate or severe pain prior to treatment (≥ 50 mm on the 100mm visual analog scale, VAS) were randomized to receive 0.4% (1.5mg) nitroglycerin or placebo ointment applied to the anal canal every 12 hours. Pain as assessed by the change in VAS from baseline to Days 14-18 was lower in patients receiving 0.4% ointment compared to placebo. The mean change from baseline was 44mm for nitroglycerin ointment and 37mm for placebo. The difference in the mean change in pain between nitroglycerin ointment and placebo was -7.0mm (95% Confidence Interval: -13.6 to -0.4mm).

16 HOW SUPPLIED/STORAGE AND HANDLING Nitroglycerin ointment, USP 0.4% is available in 30 g (NDC 21922-048-05) aluminum tubes with polyethylene screw caps. Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature]. Keep the tube tightly closed immediately after each use. Use within 8 weeks of first opening.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use) Interaction with PDE5 inhibitors Advise patient not to use nitroglycerin ointment with medications for erectile dysfunction such as Viagra (sildenafil), Levitra (vardenafil), and Cialis (tadalafil). These products have been shown to increase the hypotensive effects of nitroglycerin ointment and other nitrate drugs [see Contraindications (4) ]. Hypotension Advise patients that treatment with nitroglycerin ointment may be associated with light-headedness on standing, especially just after rising from a lying or seated position. The effect may be more frequent in patients who have also consumed alcohol, since alcohol use contributes to hypotension. Advise patients to stand up from the supine or sitting position slowly. Headaches Advise patients that headaches sometimes accompany treatment with nitroglycerin ointment. For patients who get these headaches, the headaches may indicate the activity of the drug. Tolerance to headaches develops. Advise patients that if they experience headache they should not alter the schedule of their nitroglycerin ointment treatment to avoid the occurrence of headache. An analgesic, such as acetaminophen, may be used to prevent or relieve the headaches. Dizziness Advise patients that dizziness has been reported as a side-effect of treatment with nitroglycerin ointment. Advise patients not to drive or operate machinery immediately after applying nitroglycerin ointment. Manufactured by: Encube Ethicals Pvt. Ltd. Plot No. C-1, Madkaim Industrial Estate, Madkaim, Post: Mardol, Ponda, Goa - 403 404, India. Distributed by: Encube Ethicals, Inc. 200 Meredith Drive, Suite 202 Durham, NC 27713 USA Revised: 10/2024

PATIENT INFORMATION Nitroglycerin (nye" troe glis' er in) Ointment 0.4% IMPORTANT: For intra-anal use only Read the Patient Information that comes with nitroglycerin ointment before you start using the product and each time you get a refill because there may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. If you have any questions about nitroglycerin ointment, ask your healthcare provider. What is nitroglycerin ointment? Nitroglycerin ointment is a prescription medicine used to treat moderate to severe pain caused by chronic anal fissures. An anal fissure is a tear in the skin lining the anal canal. Nitroglycerin ointment is not suitable for children and adolescents under the age of 18 years because it has not been assessed in people in this age group. Who should not use nitroglycerin ointment? Do not use nitroglycerin ointment if you: are taking a medicine for erectile dysfunction (male impotence), for example Viagra (sildenafil), Cialis (tadalafil) or Levitra (vardenafil). have been told by your doctor that you have severe anemia (low numbers of red blood cells in your blood) have increased intracranial pressure or high pressure within your skull e.g. following head trauma or bleeding in your brain are allergic to any of the ingredients in nitroglycerin ointment or if you have had allergic reactions to similar medicines in the past. See the end of this leaflet for a list of ingredients in nitroglycerin ointment. What should I tell my healthcare provider before using nitroglycerin ointment? Tell your healthcare provider about all your medical conditions, including if you: have low blood pressure have recently had a heart attack have heart or blood vessel disorders suffer from migraine or recurrent headaches are pregnant or plan to become pregnant. It is not known if nitroglycerin ointment will harm your unborn baby. are breast-feeding or plan to breast-feed. It is not known if the components of nitroglycerin ointment will harm your child if you breast-feed. Nitroglycerin ointment may lower your blood pressure. When getting up from a lying or sitting position, you should get up slowly, otherwise you might feel faint. Tell your healthcare provider about all the medicines you take, including prescription and non- prescription medicines, vitamins and herbal supplements. Other medicines may affect how nitroglycerin ointment works. Nitroglycerin ointment may also affect how other medicines work. Specifically, tell your doctor if you are taking any of the following: other nitroglycerin containing products a medicine for erectile dysfunction (male impotence), for example sildenafil, tadalafil or vardenafil (see the section above ‘Who should not use nitroglycerin ointment’) medicines used to treat high blood pressure are taking aspirin, ergotamine (used to treat migraine) or are receiving tissue-type plasminogen activator (used to help dissolve blood clots formed in blood vessels in the heart, lungs and brain) are to be given heparin. If so, close monitoring of your blood will be required as your dose of heparin may need to be altered. Please discuss with your doctor before stopping nitroglycerin ointment. How should nitroglycerin ointment be used? Use nitroglycerin ointment exactly as prescribed. See detailed Patient Instructions for Applying nitroglycerin ointment at the end of this Patient Information leaflet.

se of heparin may need to be altered. Please discuss with your doctor before stopping nitroglycerin ointment. How should nitroglycerin ointment be used? Use nitroglycerin ointment exactly as prescribed. See detailed Patient Instructions for Applying nitroglycerin ointment at the end of this Patient Information leaflet. Treatment may be continued for up to 3 weeks. If your anal pain does not get better after using nitroglycerin ointment you should talk to your doctor. What should I avoid while using nitroglycerin ointment? Do not drive or operate machinery immediately after applying nitroglycerin ointment. If you feel dizzy or light-headed after applying the ointment do not drive or operate machinery until the dizziness has stopped. Avoid consuming alcohol while you are being treated with nitroglycerin ointment as your blood pressure is more likely to be affected if you consume alcoholic beverages. What are the possible side effects of nitroglycerin ointment? Nitroglycerin ointment can cause serious side-effects: Stop using the ointment and seek medical attention immediately if you have an allergic reaction. You may have swelling of the face, lips, tongue or throat, or difficulty breathing. Common side-effects of nitroglycerin ointment are: Headaches, which can be severe. You could take painkillers for this (such as acetaminophen). If the headaches are unpleasant, you may need to ask your doctor whether you should stop using nitroglycerin ointment. Dizziness, faintness on standing, or light-headedness These are not all the possible side effects of nitroglycerin ointment. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800- FDA-1088. How should I store nitroglycerin ointment? Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature]. Keep the tube tightly closed immediately after each use. Use within 8 weeks of first opening. Keep nitroglycerin ointment out of the reach of children. Do not use nitroglycerin ointment after the expiry date which is stated on the label and carton after ‘EXP.’ The expiry date refers to the last day of that month. General information about nitroglycerin ointment Medicines are sometimes prescribed for conditions that are not mentioned in Patient Information leaflets. Do not use nitroglycerin ointment for a condition for which it is not prescribed. Do not give nitroglycerin ointment to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about nitroglycerin ointment. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about nitroglycerin ointment that is written for health professionals. For more information call 1-833-285-4151 Patient Instructions for Use When do I apply the ointment? Apply the ointment every 12 hours exactly as your doctor has told you to. How do I apply the ointment? Cover your finger with plastic-wrap, a disposable surgical glove or a finger cot. Lay the covered finger alongside the 1 inch dosing line marked on the side of the medicine box (see figure below) so that the tip of your finger is at one end of the dosing line. Starting at the tip of the finger, squeeze the ointment onto your finger for the same length marked on the box. Refer to carton for accurate dosage guide. Gently insert the finger with the ointment into the anal canal, up to the first finger joint. Carefully smear the ointment around the inner sides of the anal canal.

Starting at the tip of the finger, squeeze the ointment onto your finger for the same length marked on the box. Refer to carton for accurate dosage guide. Gently insert the finger with the ointment into the anal canal, up to the first finger joint. Carefully smear the ointment around the inner sides of the anal canal. If this cannot be achieved due to pain, application of the ointment should be made directly to the outside of the anus. What do I do after I have applied the ointment? Throw away the finger covering in the garbage, out of the reach of children and pets. Wash your hands. What are the ingredients in nitroglycerin ointment? Active ingredient: nitroglycerin Inactive ingredients: propylene glycol, lanolin, sorbitan sesquioleate, paraffin wax and white petrolatum. Manufactured by: Encube Ethicals Pvt. Ltd. Plot No. C-1, Madkaim Industrial Estate, Madkaim, Post: Mardol, Ponda, Goa - 403 404, India. Distributed by: Encube Ethicals, Inc. 200 Meredith Drive, Suite 202 Durham, NC 27713 USA Revised: 10/2024 dosing-card

<table styleCode="Noautorules" width="100%"><col width="100%" align="left" valign="middle"/><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule"><paragraph>IMPORTANT: For intra-anal use only </paragraph></td></tr></tbody></table>

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

<table width="100%"><col width="27%"/><col width="16%"/><col width="17%"/><col width="15%"/><col width="13%"/><tbody><tr><td colspan="5" valign="top"/></tr><tr><td rowspan="2" styleCode="Rrule " valign="middle"><paragraph>Table <linkHtml href="#">1</linkHtml></paragraph></td><td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Composition</paragraph></td><td rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><footnote ID="_Ref460914947">Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (&#x2265;600 mOsmol/L) may cause vein damage.</footnote>Osmolarity (mOsmol/L) (calc) </paragraph></td><td rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>pH</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Nitroglycerin (mcg/mL) </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Dextrose Hydrous, USP (g/L) </paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>25 mg Nitroglycerin in 5% Dextrose Injection </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>100</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>50</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>428</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>4.0</paragraph><paragraph>(3.0 to 5.0)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>50 mg Nitroglycerin in 5% Dextrose Injection </paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>200</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>50</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>440</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>4.0</paragraph><paragraph>(3.0 to 5.0)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>100 mg Nitroglycerin in 5% Dextrose Injection </paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>400</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>50</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>465</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>4.0</paragraph><paragraph>(3.0 to 5.0)</paragraph></td></tr></tbody></table>

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.

side. 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.

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.

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.

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.

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 and 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.

PRECAUTIONS Severe hypotension and shock may occur with even small doses of nitroglycerin. Monitor 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. Tolerance development and occurrence of cross tolerance to other nitro compounds have been reported. In industrial workers who have 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 of intravenous nitroglycerin is not known. 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. Administer nitroglycerin in 5% Dextrose Injection via an infusion pump that can maintain a constant infusion rate. Intracoronary injection of Nitroglycerin in 5% Dextrose Injection has not been studied. Monitor patients with known sub-clinical or overt diabetes mellitus when using solutions containing dextrose. Laboratory Tests: Because of the propylene glycol content of intravenous nitroglycerin, serum triglyceride assays that rely on glycerol oxidase may give falsely elevated results in patients receiving this medication. Drug Interactions: The vasodilating effects of nitroglycerin may be additive with those of antihypertensives (e.g., beta-blockers, calcium channel blockers and tricyclic antidepressants) and may cause increased hypotensive effects.. Concomitant use of Nitroglycerin in 5% Dextrose Injection with phosphodiesterase inhibitors (e.g. sildenafil, tadalafil, or vardenafil) can cause hypotension and is contraindicated (see Contraindications ). Concomitant use of Nitroglycerin in 5% Dextrose Injection with riociguat, a soluble guanylate cyclase stimulator, can cause hypotension and is contraindicated (see Contraindications ). Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination. Nitroglycerin at higher dosages may interfere with the anticoagulant effect of heparin. Intravenous nitroglycerin can induce heparin resistance. Administration of Nitroglycerin in 5% Dextrose Injection through the same infusion set as blood can result in pseudoagglutination and hemolysis. Do not mix Nitroglycerin in 5% Dextrose Injection with any other medication of any kind. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Animal carcinogenesis studies with injectable nitroglycerin have not been performed.

through the same infusion set as blood can result in pseudoagglutination and hemolysis. Do not mix Nitroglycerin in 5% Dextrose Injection with any other medication of any kind. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Animal carcinogenesis studies with injectable nitroglycerin have not been performed. Rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years 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 both sexes were 52% vs. 0% in controls and 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 weakly mutagenic in Ames tests performed in two 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, p.o., or in in vitro cytogenetic tests in rat and dog tissues. In a three-generation reproduction study, rats received dietary nitroglycerin at doses up to about 434 mg/kg/day for six 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 three-generation study there was no clear evidence of teratogenicity. Pregnancy: Animal teratology studies have not been conducted with nitroglycerin injection. Teratology studies in rats and rabbits were conducted with topically applied nitroglycerin ointment at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively, and no toxic effects on dams or fetuses were seen. 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 if nitroglycerin is present in human milk or if nitroglycerin has effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for nitroglycerin and any potential adverse effects on the breastfed child from nitroglycerin or from the underlying maternal condition. Pediatric Use: Safety and effectiveness in the pediatric population have not been established. However, the relationship between hemodynamic effects of nitroglycerin and dose in the pediatric population have been documented in the literature. Studies in the literature used doses of nitroglycerin injection in pediatric patients ranging from 0.5 to 5 mcg/kg/min. The following equation can be used to calculate the flow rate in mL/hour of nitroglycerin using the 100 mcg/mL (25 mg/250 mL) concentration of nitroglycerin. Infusion Rate (mL/h) = [Dose (mcg/kg/min) x Weight (kg) x 60 min/h] Final Concentration (mcg/mL) Example calculations for infusion rates are as follows: Example 1: for a 2 kg child at a dose of 0.5 µg/kg/min using a 100 mcg/mL concentration, the infusion rate would be as follows: Infusion Rate (mL/h) = [0.5 (mcg/kg/min) x 2 (kg) x 60 (min/h) ] = 0.6 (mL/h) 100 (mcg/mL) Example 2: for a 10 kg child at a dose of 5 mcg/kg/min using a 100 mcg/mL concentration, the infusion rate would be as follows: Infusion Rate (mL/h) = [5 (mcg/kg/min) x 10 (kg) x 60 (min/h) ] = 30 (mL/h) 100 (mcg/mL) Note: Very low infusion rates may require that a more dilute concentration of nitroglycerin infusion solution be prepared.

kg child at a dose of 5 mcg/kg/min using a 100 mcg/mL concentration, the infusion rate would be as follows: Infusion Rate (mL/h) = [5 (mcg/kg/min) x 10 (kg) x 60 (min/h) ] = 30 (mL/h) 100 (mcg/mL) Note: Very low infusion rates may require that a more dilute concentration of nitroglycerin infusion solution be prepared. 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. Do not use unless vacuum is present and solution is clear.

Laboratory Tests: Because of the propylene glycol content of intravenous nitroglycerin, serum triglyceride assays that rely on glycerol oxidase may give falsely elevated results in patients receiving this medication.

Drug Interactions: The vasodilating effects of nitroglycerin may be additive with those of antihypertensives (e.g., beta-blockers, calcium channel blockers and tricyclic antidepressants) and may cause increased hypotensive effects.. Concomitant use of Nitroglycerin in 5% Dextrose Injection with phosphodiesterase inhibitors (e.g. sildenafil, tadalafil, or vardenafil) can cause hypotension and is contraindicated (see Contraindications ). Concomitant use of Nitroglycerin in 5% Dextrose Injection with riociguat, a soluble guanylate cyclase stimulator, can cause hypotension and is contraindicated (see Contraindications ). Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination. Nitroglycerin at higher dosages may interfere with the anticoagulant effect of heparin. Intravenous nitroglycerin can induce heparin resistance. Administration of Nitroglycerin in 5% Dextrose Injection through the same infusion set as blood can result in pseudoagglutination and hemolysis. Do not mix Nitroglycerin in 5% Dextrose Injection with any other medication of any kind.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Animal carcinogenesis studies with injectable nitroglycerin have not been performed. Rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years 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 both sexes were 52% vs. 0% in controls and 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 weakly mutagenic in Ames tests performed in two 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, p.o., or in in vitro cytogenetic tests in rat and dog tissues. In a three-generation reproduction study, rats received dietary nitroglycerin at doses up to about 434 mg/kg/day for six 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 three-generation study there was no clear evidence of teratogenicity.

Nursing Mothers: It is not known if nitroglycerin is present in human milk or if nitroglycerin has effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for nitroglycerin and any potential adverse effects on the breastfed child from nitroglycerin or from the underlying maternal condition.

Pediatric Use: Safety and effectiveness in the pediatric population have not been established. However, the relationship between hemodynamic effects of nitroglycerin and dose in the pediatric population have been documented in the literature. Studies in the literature used doses of nitroglycerin injection in pediatric patients ranging from 0.5 to 5 mcg/kg/min. The following equation can be used to calculate the flow rate in mL/hour of nitroglycerin using the 100 mcg/mL (25 mg/250 mL) concentration of nitroglycerin. Infusion Rate (mL/h) = [Dose (mcg/kg/min) x Weight (kg) x 60 min/h] Final Concentration (mcg/mL) Example calculations for infusion rates are as follows: Example 1: for a 2 kg child at a dose of 0.5 µg/kg/min using a 100 mcg/mL concentration, the infusion rate would be as follows: Infusion Rate (mL/h) = [0.5 (mcg/kg/min) x 2 (kg) x 60 (min/h) ] = 0.6 (mL/h) 100 (mcg/mL) Example 2: for a 10 kg child at a dose of 5 mcg/kg/min using a 100 mcg/mL concentration, the infusion rate would be as follows: Infusion Rate (mL/h) = [5 (mcg/kg/min) x 10 (kg) x 60 (min/h) ] = 30 (mL/h) 100 (mcg/mL) Note: Very low infusion rates may require that a more dilute concentration of nitroglycerin infusion solution be prepared.

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. Do not use unless vacuum is present and solution is clear.

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.

OVERDOSAGE Signs and symptoms of overdose are generally similar to the described adverse reactions (see Adverse Reactions ). There is no specific antidote for overdose of nitroglycerin. The risk of overdose can be minimized by close monitoring during treatment. Hemodynamic Effects: The ill effects of nitroglycerin overdose are generally the results of nitroglycerin's capacity to induce 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. Laboratory determinations of serum levels of nitroglycerin and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of nitroglycerin overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of nitroglycerin and its active metabolites. Similarly, it is not known which -if any- of these substances can usefully be removed from the body by hemodialysis. No specific antagonist to the vasodilator effects of nitroglycerin is known, and no intervention has been subject to controlled study as a therapy of nitroglycerin overdose. Because the hypotension associated with nitroglycerin overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. Passive elevation of the patient's legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary. The use of epinephrine or other arterial vasoconstrictors in this setting is likely to do more harm than good. In patients with renal disease or heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of nitroglycerin overdose in these patients may be subtle and difficult, and invasive monitoring may be required. Methemoglobinemia: Nitrate ions liberated during metabolism of nitroglycerin can oxidize hemoglobin into methemoglobin. Even in patients totally without cytochrome b 5 reductase activity, however, and even assuming that the nitrate moieties of nitroglycerin are quantitatively applied to oxidation of hemoglobin, about 1 mg/kg of nitroglycerin should be required before any of these patients manifests clinically significant (≥ 10%) methemoglobinemia. In patients with normal reductase function, significant production of methemoglobin should require even larger doses of nitroglycerin. In one study in which 36 patients received 2-4 weeks of continuous nitroglycerin therapy at 3.1 to 4.4 mg/hr, the average methemoglobin level measured was 0.2%; this was comparable to that observed in parallel patients who received placebo. Cases of methemoglobinemia have been reported with moderate doses of organic nitrates. Methemoglobin levels are available from most clinical laboratories.

cerin therapy at 3.1 to 4.4 mg/hr, the average methemoglobin level measured was 0.2%; this was comparable to that observed in parallel patients who received placebo. Cases of methemoglobinemia have been reported with moderate doses of organic nitrates. 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 pO 2 . Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air. When methemoglobinemia is diagnosed, discontinue treatment of nitroglycerin. If condition is not reversed, treat with methylene blue, 1-2 mg/kg intravenously.

DOSAGE AND 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.

ired 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)

HOW SUPPLIED Nitroglycerin in 5% Dextrose Injection is supplied in glass container as follows: Size (mL) NDC Product Name 250 84549-147-02 25 mg Nitroglycerin in 5% Dextrose Injection Minimize exposure of pharmaceutical products to heat. Avoid excessive heat. Protect from freezing. Store the product at room temperature (25°C). Brief exposure up to 40°C does not adversely affect the product. Protect from light until time of use. Discard any unused portion.

<table width="100%" styleCode="Noautorules"><colgroup><col width="18%"/><col width="17%"/><col width="25%"/><col width="40%"/></colgroup><tbody><tr><td valign="top"><paragraph/></td><td align="center" valign="top"><paragraph><content styleCode="bold">Size (mL)</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">NDC</content></paragraph></td><td align="center" valign="top"><paragraph><content styleCode="bold">Product Name</content></paragraph></td></tr><tr><td valign="top"><paragraph/></td><td align="center" valign="top"><paragraph>250</paragraph></td><td align="center" valign="top"><paragraph>84549-147-02</paragraph></td><td valign="top"><paragraph>25 mg Nitroglycerin in 5% Dextrose Injection</paragraph></td></tr><tr><td valign="top"><paragraph/></td><td align="center" valign="top"/><td align="center" valign="top"/><td valign="top"/></tr></tbody></table>

1 INDICATIONS AND USAGE Nitroglycerin sublingual tablets are indicated for the acute relief of an attack or acute prophylaxis of angina pectoris due to coronary artery disease. Nitroglycerin is a nitrate vasodilator indicated for relief of an attack or prophylaxis of angina pectoris due to coronary artery disease. ( 1 )

2 DOSAGE AND ADMINISTRATION Administer one tablet under the tongue or in the buccal pouch at the first sign of an acute anginal attack. Allow tablet to dissolve without swallowing. One additional tablet may be administered every 5 minutes until relief is obtained. No more than three tablets are recommended within a 15-minute period. If the pain persists after a total of 3 tablets in a 15-minute period, or if the pain is different than is typically experienced, seek prompt medical attention. Nitroglycerin sublingual tablets may be used prophylactically 5 to 10 minutes prior to engaging in activities that might precipitate an acute attack. For patients with xerostomia, a small sip of water prior to placing the tablet under the tongue may help maintain mucosal hydration and aid dissolution of the tablet. Administer nitroglycerin sublingual tablets at rest, preferably in the sitting position. At the onset of an attack, administer one tablet under the tongue or buccal pouch. One additional tablet may be administered every 5 minutes as needed. No more than 3 total tablets are recommended within a 15 minute period. ( 2 ) If chest pain persists after three tablets, seek prompt medical attention. ( 2 ) May be used prophylactically 5 to 10 minutes prior to engaging in activities that might precipitate an acute attack. ( 2 )

3 DOSAGE FORMS AND STRENGTHS Nitroglycerin sublingual tablets, USP are supplied as white to off white, round, flat-faced tablets in three strengths: 0.3 mg ("Ʌ 6" debossed on one side and plain on the other side). 0.4 mg ("Ʌ 7" debossed on one side and plain on the other side). 0.6 mg ("Ʌ 8" debossed on one side and plain on the other side). Sublingual tablets, 0.3 mg; 0.4 mg; 0.6 mg ( 3 )

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 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 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 in patients who are taking the soluble guanylate cyclase stimulators, such as riociguat. Concomitant use can cause hypotension. 4.2 Severe Anemia Nitroglycerin is 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 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 is contraindicated in patients who are allergic to nitroglycerin, other nitrates or nitrites or any excipient. 4.5 Circulatory Failure and Shock Nitroglycerin is contraindicated in patients with acute circulatory failure or shock.

5 WARNINGS AND PRECAUTIONS Tolerance: Excessive use may lead to tolerance. ( 5.1 ) Hypotension: Severe hypotension may occur. ( 5.2 ) 5.1 Tolerance Excessive use may lead to the development of tolerance. Only the smallest dose required for effective relief of the acute angina attack should be used. A decrease in therapeutic effect of sublingual nitroglycerin may result from use of long-acting nitrates. 5.2 Hypotension Severe hypotension, particularly with upright posture, may occur with small doses of nitroglycerin particularly in patients with constrictive pericarditis, aortic or mitral stenosis, patients who may be volume-depleted, or are already hypotensive. Hypotension induced by nitroglycerin may be accompanied by paradoxical bradycardia and increased angina pectoris. Symptoms of severe hypotension (nausea, vomiting, weakness, pallor, perspiration and collapse/syncope) may occur even with therapeutic doses. 5.3 Hypertrophic Obstructive Cardiomyopathy Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy. 5.4 Headache Nitroglycerin produces dose-related headaches, especially at the start of nitroglycerin therapy, which may be severe and persist but usually subside with continued use.

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail elsewhere in the label: Hypotension [see Warnings and Precautions (5.2) ] Headache [see Warnings and Precautions (5.4) ] Hypersensitivity [see Contraindications (4.4) ] Vertigo, dizziness, weakness, palpitation, and other manifestations of postural hypotension may develop occasionally, particularly in erect, immobile patients. Marked sensitivity to the hypotensive effects of nitrates (manifested by nausea, vomiting, weakness, diaphoresis, pallor, and collapse) may occur at therapeutic doses. Syncope due to nitrate vasodilatation has been reported. Flushing, drug rash, and exfoliative dermatitis have been reported in patients receiving nitrate therapy. Most common adverse reactions occurring at a frequency greater than 2% are headache, dizziness and paresthesia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Advagen Pharma Ltd, at 866-488-0312 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

7 DRUG INTERACTIONS Ergotamine: increased bioavailability of ergotamine. Avoid concomitant use. ( 7.2 ) 7.1 PDE-5-Inhibitors and sGC-Stimulators Nitroglycerin is contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE-5). PDE-5-Inhibitors such as avanafil, sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates. Nitroglycerin is contraindicated in patients who are taking soluble guanylate cyclase (sGC) stimulators. Concomitant use can cause hypotension. The time course and dose dependence of these interactions have not been studied, and use within a few days of one another is not recommended. Appropriate supportive care for the severe hypotension 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. 7.2 Ergotamine 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk summary Limited published data on the use of nitroglycerin are insufficient to determine a drug associated risk of major birth defects or miscarriage. In animal reproduction studies, there were no adverse developmental effects when nitroglycerin was administered intravenously to rabbits or intraperitoneally to rats during organogenesis at doses greater than 64-times the human dose (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data No embryotoxic or postnatal development effects were observed with transdermal application in pregnant rabbits and rats at doses up to 80 and 240 mg/kg/day, respectively, at intraperitoneal doses in pregnant rats up to 20 mg/kg/day from gestation day 7-17, and at intravenous doses in pregnant rabbits up to 4 mg/kg/day from gestation day 6-18. 8.2 Lactation Risk summary Sublingual nitroglycerin has not been studied in lactating women. It is not known if nitroglycerin is present in human milk or if nitroglycerin has effects on milk production. 8.4 Pediatric Use The safety and effectiveness of nitroglycerin in pediatric patients have not been established. 8.5 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.

8.1 Pregnancy Risk summary Limited published data on the use of nitroglycerin are insufficient to determine a drug associated risk of major birth defects or miscarriage. In animal reproduction studies, there were no adverse developmental effects when nitroglycerin was administered intravenously to rabbits or intraperitoneally to rats during organogenesis at doses greater than 64-times the human dose (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data No embryotoxic or postnatal development effects were observed with transdermal application in pregnant rabbits and rats at doses up to 80 and 240 mg/kg/day, respectively, at intraperitoneal doses in pregnant rats up to 20 mg/kg/day from gestation day 7-17, and at intravenous doses in pregnant rabbits up to 4 mg/kg/day from gestation day 6-18.

8.5 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.

10 OVERDOSAGE 10.1 Signs and Symptoms, Methemoglobinemia Nitrate overdosage may result in: severe hypotension, persistent throbbing headache, vertigo, palpitation, visual disturbance, flushing and perspiring skin (later becoming cold and cyanotic), nausea and vomiting (possibly with colic and even bloody diarrhea), syncope (especially in the upright posture), methemoglobinemia with cyanosis and anorexia, initial hyperpnea, dyspnea and slow breathing, slow pulse (dicrotic and intermittent), heart block, increased intracranial pressure with cerebral symptoms of confusion and moderate fever, paralysis and coma followed by clonic convulsions, and possibly death due to circulatory collapse. Case reports of clinically significant methemoglobinemia are rare at conventional doses of organic nitrates. The formation of methemoglobin is dose-related and in the case of genetic abnormalities of hemoglobin that favor methemoglobin formation, even conventional doses of organic nitrates could produce harmful concentrations of methemoglobin. 10.2 Treatment of Overdosage As hypotension associated with nitroglycerin overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. No specific antagonist to the vasodilator effects of nitroglycerin is known. Keep the patient recumbent in a shock position and comfortably warm. Passive movement of the extremities may aid venous return. Intravenous infusion of normal saline or similar fluid may also be necessary. Administer oxygen and artificial ventilation, if necessary. If methemoglobinemia is present, administration of methylene blue (1% solution), 1-2 mg per kilogram of body weight intravenously, may be required unless the patient is known to have G-6-PD deficiency. If an excessive quantity of nitroglycerin has been recently swallowed gastric lavage may be of use. As epinephrine is ineffective in reversing the severe hypotensive events associated with overdosage, it is not recommended for resuscitation.

11 DESCRIPTION Nitroglycerin sublingual tablets, USP are stabilized sublingual compressed nitroglycerin tablet that contains 0.3 mg, 0.4 mg , or 0.6 mg nitroglycerin; as well as lactose monohydrate, colloidal silicon dioxide, sodium starch glycolate, calcium stearate and glyceryl behenate. Nitroglycerin, an organic nitrate, is a vasodilating agent. The chemical name for nitroglycerin is 1, 2, 3 propanetriol trinitrate and the chemical structure is: Molecular weight: 227.09 Nitroglycerin Chemical Structure

12 CLINICAL PHARMACOLOGY 12.1 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.

ration- 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. Table 1 Mean Nitroglycerin (SD) Values 2 × 0.3 mg 1 × 0.6 mg Parameter Nitroglycerin sublingual tablets Nitroglycerin sublingual tablets C max , ng/mL 2.3 (1.7) 2.1 (1.5) T max , min 6.4 (2.5) 7.2 (3.2) AUC(0–∞), min 14.9 (8.2) 14.9 (11.4) t½, min 2.8 (1.1) 2.6 (0.6) 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.

12.1 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. Table 1 Mean Nitroglycerin (SD) Values 2 × 0.3 mg 1 × 0.6 mg Parameter Nitroglycerin sublingual tablets Nitroglycerin sublingual tablets C max , ng/mL 2.3 (1.7) 2.1 (1.5) T max , min 6.4 (2.5) 7.2 (3.2) AUC(0–∞), min 14.9 (8.2) 14.9 (11.4) t½, min 2.8 (1.1) 2.6 (0.6) 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 width="90%"><caption>Table 1</caption><col width="33%" align="center" valign="top"/><col width="34%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr><th styleCode="Lrule"/><th colspan="2" styleCode="Botrule Lrule Rrule">Mean Nitroglycerin (SD) Values</th></tr><tr><th styleCode="Lrule"/><th styleCode="Lrule">2 &#xD7; 0.3 mg</th><th styleCode="Lrule Rrule">1 &#xD7; 0.6 mg</th></tr><tr><th align="center" styleCode="Lrule" valign="middle">Parameter</th><th styleCode="Lrule" valign="middle">Nitroglycerin sublingual tablets</th><th styleCode="Lrule Rrule" valign="middle">Nitroglycerin sublingual tablets</th></tr></thead><tbody><tr><td styleCode="Botrule Lrule">C _max, ng/mL </td><td styleCode="Botrule Lrule">2.3 (1.7)</td><td styleCode="Botrule Lrule Rrule">2.1 (1.5)</td></tr><tr><td styleCode="Botrule Lrule">T _max, min </td><td styleCode="Botrule Lrule">6.4 (2.5)</td><td styleCode="Botrule Lrule Rrule">7.2 (3.2)</td></tr><tr><td styleCode="Botrule Lrule">AUC(0&#x2013;&#x221E;), min</td><td styleCode="Botrule Lrule">14.9 (8.2)</td><td styleCode="Botrule Lrule Rrule">14.9 (11.4)</td></tr><tr><td styleCode="Lrule">t&#xBD;, min</td><td styleCode="Lrule">2.8 (1.1)</td><td styleCode="Lrule Rrule">2.6 (0.6)</td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 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 F0 generation, with treatment continuing through successive F1 and F2 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 F0 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.

13.1 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 F0 generation, with treatment continuing through successive F1 and F2 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 F0 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Nitroglycerin sublingual tablets, USP are supplied as white to off white , round, flat-faced tablets in three strengths (0.3 mg, 0.4 mg, and 0.6 mg) in bottles containing 100 tablets each, additionally 0.4 mg strength is available in bottles of 25 tablets also. 0.3 mg: "Ʌ6" debossed on one side and plain on the other side. NDC 72888-138-01- Bottle of 100 tablets 0.4 mg: "Ʌ7" debossed on one side and plain on the other side. NDC 72888-139-01- Bottle of 100 tablets NDC 72888-139-33- Patient Convenience Package of 4 Bottles of 25 tablets. 0.6 mg: "Ʌ8" debossed on one side and plain on the other side. NDC 72888-140-01- Bottle of 100 tablets Store at Controlled Room Temperature 20°–25°C (68°–77°F) [see USP]. Nitroglycerin sublingual tablets should be kept in the original glass container and must be tightly capped after each use to prevent loss of tablet potency.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). This product’s label may have been updated. For full prescribing information, please visit www.advagenpharma.com . All the brands are trademarks of their respective owners. Manufactured by: Rubicon Research Limited Thane, 421506 India Distributed by: Advagen Pharma Ltd East Windsor, NJ 08520, USA. Revised: 1/2026

Nitroglycerin (nye" troe glis' er in) Sublingual Tablets, USP Read this information carefully before you start nitroglycerin sublingual tablets and each time you refill your prescription. There may be new information. This information does not replace talking with your doctor. If you have any questions about nitroglycerin sublingual tablets , ask your doctor. Your doctor will know if nitroglycerin sublingual tablets are right for you. What are nitroglycerin sublingual tablets? Nitroglycerin is a type of medicine known as an organic nitrate and is a vasodilating agent. It is used to treat a type of chest pain called angina. What is Angina? Angina is a pain or discomfort that keeps coming back when part of your heart does not get enough blood. Angina feels like a pressing or squeezing pain, usually in your chest under the breastbone. Sometimes you can feel it in your shoulders, arms, neck, jaws, or back. Nitroglycerin can relieve this pain. Who should not use nitroglycerin sublingual tablets? Do not use nitroglycerin if you are allergic to organic nitrates (like the active ingredient in nitroglycerin sublingual tablets ). You should not take nitroglycerin sublingual tablets if you have the following conditions: very recent heart attack severe anemia increased pressure in the head Do not take nitroglycerin sublingual tablets with drugs for erectile dysfunction, like VIAGRA ® (sildenafil citrate), CIALIS ® (tadalafil), or LEVITRA ® (vardenafil hydrochloride), as this may lead to extreme lowering of your blood pressure . Do not take nitroglycerin sublingual tablets if you take medicines called guanylate cyclase stimulators which include riociguat, a medicine that treats pulmonary arterial hypertension and chronic-thromboembolic pulmonary hypertension. What should I tell my doctor before taking nitroglycerin sublingual tablets? Before using nitroglycerin sublingual tablets , tell your doctor if: You are taking any medicines that are used to treat angina, heart failure, or an irregular heartbeat. You are taking any medicines that reduce blood pressure. You are taking any diuretics (water pills). You are taking medicines that can cause dry mouth such as tricyclic antidepressants (e.g. amitriptyline, desipramine, doxepin), anticholinergic drugs, or any antimuscarinic drugs (e.g. atropine). You are taking ergotamine or similar drugs for migraine headaches. You are taking aspirin. You are taking any medicines for erectile dysfunction. You are pregnant or plan to become pregnant. You are breastfeeding. How should I take nitroglycerin sublingual tablets? Do not chew, crush, or swallow nitroglycerin sublingual tablets. You should sit down when taking nitroglycerin sublingual tablets and use caution when you stand up. This eliminates the possibility of falling due to lightheadedness or dizziness. One tablet should be dissolved under the tongue or in the oral cavity at the first sign of chest pain. The dose may be repeated approximately every 5 minutes, until the chest pain is relieved. If the pain persists after a total of 3 tablets in a 15-minute period, or is different than you typically experience, call your doctor or seek emergency help. Nitroglycerin sublingual tablets may be used 5 to 10 minutes prior to activities that might cause chest pain. You may feel a burning or tingling sensation in your mouth when you take nitroglycerin sublingual tablets . What should I avoid while taking nitroglycerin sublingual tablets? Do not breastfeed.

emergency help. Nitroglycerin sublingual tablets may be used 5 to 10 minutes prior to activities that might cause chest pain. You may feel a burning or tingling sensation in your mouth when you take nitroglycerin sublingual tablets . What should I avoid while taking nitroglycerin sublingual tablets? Do not breastfeed. It is not known if nitroglycerin will pass through your milk. Do not consume alcohol while taking nitroglycerin sublingual tablets , as this can lower your blood pressure. Do not start any new prescription or non-prescription medicines or supplements, unless you check with your doctor first. What are the possible side effects of nitroglycerin sublingual tablets? Nitroglycerin sublingual tablet may cause the following side effects: headache vertigo (a major symptom of balance disorder) dizziness weakness heart palpitations (unusual awareness of the heartbeat) low blood pressure upon rising from a seated position nausea and vomiting sweating paleness fainting flushing (warm or red condition of your skin) other skin reactions that may be severe Tell your doctor if you are concerned about any side effects you experience. These are not all the possible side effects of nitroglycerin sublingual tablets . For a complete list, ask your doctor or pharmacist. How do I store nitroglycerin sublingual tablets? Nitroglycerin sublingual tablets should be kept in the original glass container and tightly capped after each use to prevent loss of tablet potency. Store nitroglycerin sublingual tablets at room temperature (between 68° and 77°F). General advice about nitroglycerin sublingual tablets Sometimes doctors will prescribe a medicine for a condition that is not included in the patient information leaflets. Only use nitroglycerin sublingual tablets the way your doctor told you to. Do not give nitroglycerin sublingual tablets to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or doctor for information about nitroglycerin sublingual tablets , or you can visit Advagen Pharma website at www.advagenpharma.com or call at 866-488-0312. All the brands are trademarks of their respective owners. Manufactured by: Rubicon Research Limited Thane, 421506 India Distributed by: Advagen Pharma Ltd East Windsor, NJ 08520, USA. Revised: 1/2026

1 INDICATIONS AND USAGE Nitroglycerin sublingual tablets are indicated for the acute relief of an attack or acute prophylaxis of angina pectoris due to coronary artery disease. Nitroglycerin sublingual tablets are a nitrate vasodilator indicated for relief of an attack or prophylaxis of angina pectoris due to coronary artery disease. ( 1 )

2 DOSAGE AND ADMINISTRATION Administer one tablet under the tongue or in the buccal pouch at the first sign of an acute anginal attack. Allow tablet to dissolve without swallowing. One additional tablet may be administered every 5 minutes until relief is obtained. No more than three tablets are recommended within a 15-minute period. If the pain persists after a total of 3 tablets in a 15-minute period, or if the pain is different than is typically experienced, seek prompt medical attention. Nitroglycerin sublingual tablets may be used prophylactically 5 minutes to 10 minutes prior to engaging in activities that might precipitate an acute attack. For patients with xerostomia, a small sip of water prior to placing the tablet under the tongue may help maintain mucosal hydration and aid dissolution of the tablet. Administer nitroglycerin sublingual tablets at rest, preferably in the sitting position. At the onset of an attack, administer one tablet under the tongue or buccal pouch. One additional tablet may be administered every 5 minutes as needed. No more than 3 total tablets are recommended within a 15 minute period. ( 2 ) If chest pain persists after three tablets, seek prompt medical attention. ( 2 ) May be used prophylactically 5 to 10 minutes prior to engaging in activities that might precipitate an acute attack. ( 2 )

3 DOSAGE FORMS AND STRENGTHS Nitroglycerin sublingual tablets, USP are supplied as white, round, flat-faced tablets in three strengths: 0.4 mg (Coded with “V” on one side and “4” on the other) Sublingual tablets, 0.4 mg ( 3 )

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 [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.

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail elsewhere in the label: Hypotension [see Warnings and Precautions (5.2)] Headache [see Warnings and Precautions (5.4)] Hypersensitivity [see Contraindications (4.4)] Vertigo, dizziness, weakness, palpitation, and other manifestations of postural hypotension may develop occasionally, particularly in erect, immobile patients. Marked sensitivity to the hypotensive effects of nitrates (manifested by nausea, vomiting, weakness, diaphoresis, pallor, and collapse) may occur at therapeutic doses. Syncope due to nitrate vasodilatation has been reported. Flushing, drug rash, and exfoliative dermatitis have been reported in patients receiving nitrate therapy. Most common adverse reactions occurring at a frequency greater than 2% are headache, dizziness and paresthesia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact NATCO PHARMA USA LLC at 1-201-786-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

7 DRUG INTERACTIONS Ergotamine: increased bioavailability of ergotamine. Avoid concomitant use. ( 7.2 ) 7.1 PDE-5-Inhibitors and sGC-Stimulators Nitroglycerin sublingual tablets are contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE-5). PDE-5-Inhibitors such as avanafil, sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates. Nitroglycerin sublingual tablets are contraindicated in patients who are taking soluble guanylate cyclase (sGC) stimulators. Concomitant use can cause hypotension. The time course and dose dependence of these interactions have not been studied, and use within a few days of one another is not recommended. Appropriate supportive care for the severe hypotension 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. 7.2 Ergotamine 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk summary Limited published data on the use of nitroglycerin are insufficient to determine a drug associated risk of major birth defects or miscarriage. In animal reproduction studies, there were no adverse developmental effects when nitroglycerin was administered intravenously to rabbits or intraperitoneally to rats during organogenesis at doses greater than 64-times the human dose (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data No embryotoxic or postnatal development effects were observed with transdermal application in pregnant rabbits and rats at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively, at intraperitoneal doses in pregnant rats up to 20 mg/kg/day from gestation day 7 to 17, and at intravenous doses in pregnant rabbits up to 4 mg/kg/day from gestation day 6 to 18. 8.2 Lactation Risk summary Sublingual nitroglycerin has not been studied in lactating women. It is not known if nitroglycerin is present in human milk or if nitroglycerin has effects on milk production. 8.4 Pediatric Use The safety and effectiveness of nitroglycerin in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of nitroglycerin sublingual tablets 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.

8.1 Pregnancy Risk summary Limited published data on the use of nitroglycerin are insufficient to determine a drug associated risk of major birth defects or miscarriage. In animal reproduction studies, there were no adverse developmental effects when nitroglycerin was administered intravenously to rabbits or intraperitoneally to rats during organogenesis at doses greater than 64-times the human dose (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data No embryotoxic or postnatal development effects were observed with transdermal application in pregnant rabbits and rats at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively, at intraperitoneal doses in pregnant rats up to 20 mg/kg/day from gestation day 7 to 17, and at intravenous doses in pregnant rabbits up to 4 mg/kg/day from gestation day 6 to 18.

8.2 Lactation Risk summary Sublingual nitroglycerin has not been studied in lactating women. It is not known if nitroglycerin is present in human milk or if nitroglycerin has effects on milk production.

8.5 Geriatric Use Clinical studies of nitroglycerin sublingual tablets 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.

11 DESCRIPTION Nitroglycerin sublingual tablets USP, are a stabilized sublingual compressed nitroglycerin tablet that contains 0.4 mg nitroglycerin. The sublingual tablets also contain the inactive ingredients lactose monohydrate, glyceryl monostearate, pregelatinized corn starch, calcium stearate, and hydrophobic colloidal silica. Nitroglycerin, an organic nitrate, is a vasodilating agent. The chemical name for nitroglycerin is 1, 2, 3 propanetriol trinitrate and the chemical structure is: Molecular weight: 227.09 STRUCTURE

12 CLINICAL PHARMACOLOGY 12.1 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 sublingual 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 mg to 0.6 mg nitroglycerin sublingual tablets. 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.

UC) increase dose-proportionally following 0.3 mg to 0.6 mg nitroglycerin sublingual tablets. 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. Table 1 Mean Nitroglycerin (SD) Values Parameter 2 × 0.3 mg Nitroglycerin Sublingual Tablets 1 × 0.6 mg Nitroglycerin Sublingual Tablets C max , ng/mL 2.3 (1.7) 2.1 (1.5) T max , min 6.4 (2.5) 7.2 (3.2) AUC(0–∞), min 14.9 (8.2) 14.9 (11.4) t½, min 2.8 (1.1) 2.6 (0.6) Distribution The volume of distribution (V Area ) of nitroglycerin following intravenous administration is 3.3 L/kg. At plasma concentrations between 50 ng/mL 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 (1,000 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.

12.1 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.

12.3 Pharmacokinetics Absorption Nitroglycerin is rapidly absorbed following sublingual administration of nitroglycerin sublingual 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 mg to 0.6 mg nitroglycerin sublingual tablets. 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. Table 1 Mean Nitroglycerin (SD) Values Parameter 2 × 0.3 mg Nitroglycerin Sublingual Tablets 1 × 0.6 mg Nitroglycerin Sublingual Tablets C max , ng/mL 2.3 (1.7) 2.1 (1.5) T max , min 6.4 (2.5) 7.2 (3.2) AUC(0–∞), min 14.9 (8.2) 14.9 (11.4) t½, min 2.8 (1.1) 2.6 (0.6) Distribution The volume of distribution (V Area ) of nitroglycerin following intravenous administration is 3.3 L/kg. At plasma concentrations between 50 ng/mL 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 (1,000 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 cellspacing="0" cellpadding="0" border="0"><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold"/></td><td colspan="3" styleCode="Rrule" valign="middle"><content styleCode="bold"> Mean Nitroglycerin (SD) Values </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"><content styleCode="bold"> Parameter</content></td><td styleCode="Rrule" valign="middle"><content styleCode="bold"> 2 &#xD7; 0.3 mg Nitroglycerin Sublingual Tablets </content></td><td colspan="2" styleCode="Rrule" valign="middle"><content styleCode="bold"> 1 &#xD7; 0.6 mg Nitroglycerin Sublingual Tablets </content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> C _max, ng/mL </td><td styleCode="Rrule" valign="middle"> 2.3 (1.7)</td><td colspan="2" styleCode="Rrule" valign="middle"> 2.1 (1.5)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> T _max, min </td><td styleCode="Rrule" valign="middle"> 6.4 (2.5)</td><td colspan="2" styleCode="Rrule" valign="middle"> 7.2 (3.2)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="middle"> AUC(0&#x2013;&#x221E;), min</td><td styleCode="Rrule" valign="middle"> 14.9 (8.2)</td><td colspan="2" styleCode="Rrule" valign="middle"> 14.9 (11.4)</td></tr><tr><td styleCode="Lrule Rrule" valign="middle"> t&#xBD;, min</td><td styleCode="Rrule" valign="middle"> 2.8 (1.1)</td><td colspan="2" styleCode="Rrule" valign="middle"> 2.6 (0.6)</td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 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 1,058 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 F0 generation, with treatment continuing through successive F1 and F2 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 F0 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.

13.1 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 1,058 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 F0 generation, with treatment continuing through successive F1 and F2 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 F0 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Nitroglycerin sublingual tablets, USP 0.4 mg sublingual tablets are a white, round, flat faced tablet debossed with “4” on one side and “V” on other side. They are supplied as: NDC 85766-116-01 Bottle of 100 tablets (relabeled from NDC 69339-174-01) NDC 85766-116-00 Patient Convenience Package of 4 bottles of 25 tablets (relabeled from NDC 69339-174-41) NDC 85766-116-10 Bottle of 10 tablets (repackaged from NDC 69339-174-XX) NDC 85766-116-20 Bottle of 20 tablets (repackaged from NDC 69339-174-XX) NDC 85766-116-25 Bottle of 25 tablets (repackaged from NDC 69339-174-XX) NDC 85766-116-30 Bottle of 30 tablets (repackaged from NDC 69339-174-XX) NDC 85766-116-60 Bottle of 60 tablets (repackaged from NDC 69339-174-XX) NDC 85766-116-90 Bottle of 90 tablets (repackaged from NDC 69339-174-XX) Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Nitroglycerin should be kept in the original glass container and must be tightly capped after each use to prevent loss of tablet potency.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Distributed by: Sportpharm 2237 N Commerce Parkway, STE 1, Weston, Florida-33326 Relabeled and Repackaged by: Enovachem PHARMACEUTICALS Torrance, CA 90501 PATIENT INFORMATION Nitroglycerin (nye” troe glis’ er in) Sublingual Tablets, USP Read this information carefully before you start nitroglycerin sublingual tablets and each time you refill your prescription. There may be new information. This information does not replace talking with your doctor. If you have any questions about nitroglycerin sublingual tablets , ask your doctor. Your doctor will know if nitroglycerin sublingual tablets are right for you. What is Nitroglycerin? Nitroglycerin is a type of medicine known as an organic nitrate and is a vasodilating agent. It is used to treat a type of chest pain called angina. What is Angina? Angina is a pain or discomfort that keeps coming back when part of your heart does not get enough blood. Angina feels like a pressing or squeezing pain, usually in your chest under the breastbone. Sometimes you can feel it in your shoulders, arms, neck, jaws, or back. Nitroglycerin sublingual tablets can relieve this pain. Who should not use nitroglycerin sublingual tablets? Do not use nitroglycerin sublingual tablets if you are allergic to organic nitrates (like the active ingredient in nitroglycerin sublingual tablets). You should not take nitroglycerin sublingual tablets if you have the following conditions: very recent heart attack severe anemia increased pressure in the head Do not take nitroglycerin sublingual tablets with drugs for erectile dysfunction, like VIAGRA® (sildenafil citrate), CIALIS® (tadalafil), or LEVITRA® (vardenafil hydrochloride), as this may lead to extreme lowering of your blood pressure. Do not take nitroglycerin sublingual tablets if you take medicines called guanylate cyclase stimulators which include riociguat, a medicine that treats pulmonary arterial hypertension and chronic-thromboembolic pulmonary hypertension. What should I tell my doctor before taking nitroglycerin sublingual tablets? Before using nitroglycerin sublingual tablets , tell your doctor if: You are taking any medicines that are used to treat angina, heart failure, or an irregular heartbeat. You are taking any medicines that reduce blood pressure. You are taking any diuretics (water pills). You are taking medicines that can cause dry mouth such as tricyclic antidepressants (e.g. amitriptyline, desipramine, doxepin), anticholinergic drugs, or any antimuscarinic drugs (e.g. atropine). You are taking ergotamine or similar drugs for migraine headaches. You are taking aspirin. You are taking any medicines for erectile dysfunction. You are pregnant or plan to become pregnant. You are breastfeeding. How should I take nitroglycerin sublingual tablets? Do not chew, crush, or swallow nitroglycerin sublingual tablets . You should sit down when taking nitroglycerin sublingual tablets and use caution when you stand up. This eliminates the possibility of falling due to lightheadedness or dizziness. One tablet should be dissolved under the tongue or in the oral cavity at the first sign of chest pain. The dose may be repeated approximately every 5 minutes, until the chest pain is relieved. If the pain persists after a total of 3 tablets in a 15-minute period, or is different than you typically experience, call your doctor or seek emergency help.

under the tongue or in the oral cavity at the first sign of chest pain. The dose may be repeated approximately every 5 minutes, until the chest pain is relieved. If the pain persists after a total of 3 tablets in a 15-minute period, or is different than you typically experience, call your doctor or seek emergency help. Nitroglycerin sublingual tablets may be used 5 minutes to 10 minutes prior to activities that might cause chest pain. You may feel a burning or tingling sensation in your mouth when you take nitroglycerin sublingual tablets. What should I avoid while taking nitroglycerin sublingual tablets? Do not breastfeed. It is not known if nitroglycerin will pass through your milk. Do not consume alcohol while taking nitroglycerin sublingual tablets , as this can lower your blood pressure. Do not start any new prescription or non-prescription medicines or supplements, unless you check with your doctor first. What are the possible side effects of nitroglycerin sublingual tablets? Nitroglycerin sublingual tablets may cause the following side effects: headache vertigo (a major symptom of balance disorder) dizziness weakness heart palpitations (unusual awareness of the heartbeat) low blood pressure upon rising from a seated position nausea and vomiting sweating paleness fainting flushing (warm or red condition of your skin) other skin reactions that may be severe Tell your doctor if you are concerned about any side effects you experience. These are not all the possible side effects of nitroglycerin sublingual tablets . For a complete list, ask your doctor or pharmacist. How do I store nitroglycerin sublingual tablets? Nitroglycerin sublingual tablets should be kept in the original glass container and tightly capped after each use to prevent loss of tablet potency. Store nitroglycerin sublingual tablets at room temperature (between 68° and 77°F). General advice about nitroglycerin sublingual tablets Sometimes doctors will prescribe a medicine for a condition that is not included in the patient information leaflets. Only use nitroglycerin sublingual tablets the way your doctor told you to. Do not give nitroglycerin sublingual tablets to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or doctor for information about nitroglycerin sublingual tablets , or you can call NATCO Pharma USA LLC at 201-786-6500. Distributed by: Sportpharm LLC 379 Van Ness Ave 1401, Torrance, CA 90501 Relabeled and Repackaged by: Enovachem PHARMACEUTICALS Torrance, CA 90501

Description Rx Only FOR INTRAVENOUS USE ONLY. NOT FOR DIRECT INTRAVENOUS INJECTION. NITROGLYCERIN INJECTION MUST BE DILUTED IN DEXTROSE (5%) INJECTION OR SODIUM CHLORIDE (0.9%) INJECTION PRIOR TO ITS INFUSION (SEE DOSAGE AND ADMINISTRATION SECTION). THE ADMINISTRATION SET USED FOR INFUSION WILL AFFECT THE AMOUNT OF NITROGLYCERIN INJECTION DELIVERED TO THE PATIENT. (SEE WARNINGS, AND DOSAGE AND ADMINISTRATION SECTIONS). CAUTION SEVERAL PREPARATIONS OF NITROGLYCERIN FOR INJECTION ARE AVAILABLE. THEY DIFFER IN CONCENTRATION AND/OR VOLUME PER VIAL. WHEN SWITCHING FROM ONE PRODUCT TO ANOTHER, ATTENTION MUST BE PAID TO THE DILUTION AND DOSAGE AND ADMINISTRATION INSTRUCTIONS. DESCRIPTION: Nitroglycerin is 1,2,3-propanetriol trinitrate, an organic nitrate whose structural formula is: whose empiric formula is C3H5N3O9, and whose molecular weight is 227.09. The organic nitrates are vasodilators, active on both arteries and veins. Nitroglycerin Injection, USP is a clear, practically colorless additive solution for intravenous infusion after dilution. Each mL contains: Nitroglycerin 5 mg, Alcohol 30% (v/v), Propylene Glycol 30%, and Water for Injection q.s. pH (range 3.0 to 6.5) may have been adjusted with Sodium Hydroxide and/or Hydrochloric Acid. The solution is sterile, non-pyrogenic, and nonexplosive. Formula1.jpg

Clinical Pharmacology The principal pharmacological action of Nitroglycerin Injection 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.

side. 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.

Indications and Usage Nitroglycerin Injection is indicated for treatment of peri-operative hypertension; for control of congestive heart failure in the setting of acute myocardial infarction; for treatment of angina pectoris in patients who have not responded to sublingual nitroglycerin and b-blockers; and for induction of intraoperative hypotension.

Contraindications Allergic reactions to organic nitrates are extremely rare, but they do occur. Nitroglycerin 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.

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 volume expansion. Nitroglycerin readily migrates into many plastics, including the polyvinyl chloride (PVC) plastics commonly used for intravenous administration sets. Nitroglycerin absorption 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. Some in-line intravenous filters also absorb nitroglycerin; these filters should be avoided. Because of the problem of nitroglycerin absorption by polyvinyl chloride (PVC) tubing, Nitroglycerin Injection should be used with the least absorptive infusion tubing (i.e., non-PVC tubing) available. DOSING INSTRUCTIONS MUST BE FOLLOWED WITH CARE. WHEN THE APPROPRIATE INFUSION SETS ARE USED, THE CALCULATED DOSE WILL BE DELIVERED TO THE PATIENT, BECAUSE THE LOSS OF NITROGLYCERIN INJECTION SEEN WITH STANDARD PVC TUBING WILL BE AVOIDED. THE DOSAGES REPORTED IN PUBLISHED STUDIES UTILIZED GENERAL-USE PVC ADMINISTRATION SETS, AND RECOMMENDED DOSES BASED ON THIS EXPERIENCE WILL BE TOO HIGH WHEN THE LOW-ABSORBING INFUSION SETS ARE USED.

Precautions General : Severe hypotension and shock 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 to 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 of intravenous nitroglycerin is not known. Lower concentrations of nitroglycerin 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. Nitroglycerin infusions should be administered only via a pump that can maintain a constant infusion rate. Intracoronary injection of nitroglycerin infusions has not been studied. Laboratory Tests : Because of the propylene glycol content of intravenous nitroglycerin, serum triglyceride assays that rely on glycerol oxidase may give falsely elevated results in patients receiving this medication. Drug Interactions : The vasodilating effects of nitroglycerin may be additive with those of other vasodilators. Administration of nitroglycerin infusions through the same infusion set as blood can result in pseudoagglutination and hemolysis. More generally, nitroglycerin in 5% dextrose or sodium chloride 0.9% should not be mixed with any other medication of any kind. Intravenous nitroglycerin interferes, at least in some patients, with the anticoagulant effect of heparin. In patients receiving intravenous nitroglycerin, concomitant heparin therapy should be guided by frequent measurement of the activated partial thromboplastin time. Carcinogenesis, Mutagenesis, Impairment of Fertility : Animal carcinogenesis studies with injectable nitroglycerin have not been performed. Rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years 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 both sexes were 52% vs. 0% in controls, and 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 weakly mutagenic in Ames tests performed in two different laboratories.

ocellular carcinomas in both sexes were 52% vs. 0% in controls, and 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 weakly mutagenic in Ames tests performed in two different laboratories. 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, p.o., or in in vitro cytogenetic tests in rat and dog tissues. In a three-generation reproduction study, rats received dietary nitroglycerin at doses up to about 434 mg/kg/day for six months prior to mating of the F0 generation with treatment continuing through successive F1 and F2 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 F0 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 three-generation study there was no clear evidence of teratogenicity. Pregnancy : Pregnancy Category C: Animal teratology studies have not been conducted with nitroglycerin injection. Teratology studies in rats and rabbits, however, were conducted with topically applied nitroglycerin ointment at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively. No toxic effects on dams or fetuses were seen at any dose tested. There are no adequate and wellcontrolled studies in pregnant women. Nitroglycerin should be given to a pregnant woman only if clearly needed. Nursing Mother s: 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 : Safety and effectiveness in children have not been established.

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. 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).

Overdosage Hemodynamic Effects : The ill effects of nitroglycerin overdose are generally the results of nitroglycerin's capacity to induce vasodilatation, 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; palpitation; 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. Laboratory determinations of serum levels of nitroglycerin and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of nitroglycerin overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of nitroglycerin and its active metabolites. Similarly, it is not known which- if any-of these substances can usefully be removed from the body by hemodialysis. No specific antagonist to the vasodilator effects of nitroglycerin is known, and no intervention has been subject to controlled study as a therapy of nitroglycerin overdose. Because the hypotension associated with nitroglycerin overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. Passive elevation of the patient's legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary. The use of epinephrine or other arterial vasoconstrictors in this setting is likely to do more harm than good. In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of nitroglycerin overdose in these patients may be subtle and difficult, and invasive monitoring may be required. Methemoglobinemi a : Nitrate ions liberated during metabolism of nitroglycerin can oxidize hemoglobin into methemoglobin. Even in patients totally without cytochrome b5 reductase activity, however, and even assuming that the nitrate moieties of nitroglycerin are quantitatively applied to oxidation of hemoglobin, about 1 mg/kg of nitroglycerin should be required before any of these patients manifests clinically significant (³10%) methemoglobinemia. In patients with normal reductase function, significant production of methemoglobin should require even larger doses of nitroglycerin. In one study in which 36 patients received 2-4 weeks of continuous nitroglycerin therapy at 3.1 to 4.4 mg/hr, the average methemoglobin level measured was 0.2%; this was comparable to that observed in parallel patients who received placebo. Notwithstanding these observations, there are case reports of significant methemoglobinemia in association with moderate overdoses of organic nitrates. None of the affected patients had been thought to be unusually susceptible. 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.

oses of organic nitrates. None of the affected patients had been thought to be unusually susceptible. 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, the treatment of choice is methylene blue, 1-2 mg/kg intravenously.

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.

n 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.

How Supplied Nitroglycerin Injection, USP, 5mg/mL is available as follows: NDC 0517-4810-25 50mg/10 mL Single Dose Vial Package of 25 PROTECT FROM LIGHT. RETAIN IN CARTON UNTIL TIME OF USE. Store at 20°-25°C (68°-77°F); excursions permitted to 15° to 30°C (59° to 86°F) (See USP Controlled Room Temperature). DISCARD UNUSED PORTION. Product repackaged by: Henry Schein, Inc., Bastian, VA 24314 From Original Manufacturer/Distributor's NDC and Unit of Sale To Henry Schein Repackaged Product NDC and Unit of Sale Total Strength/Total Volume (Concentration) per unit NDC 0517-4810-25 Packages of 25 NDC 0404-9928-10 1 10 mL Single Dose Vial in a bag (Vial bears NDC 0517-4810-01) 50 mg/10 mL AMERICAN REGENT LABORATORIES, INC. SHIRLEY, NY 11967 IN4805 Rev. 11/05

<table width="100%"><caption> Product repackaged by: Henry Schein, Inc., Bastian, VA 24314</caption><tbody><tr><td>From Original Manufacturer/Distributor&apos;s NDC and Unit of Sale</td><td>To Henry Schein Repackaged Product NDC and Unit of Sale </td><td>Total Strength/Total Volume (Concentration) per unit </td></tr><tr><td>NDC 0517-4810-25 Packages of 25</td><td>NDC 0404-9928-10 1 10 mL Single Dose Vial in a bag (Vial bears NDC 0517-4810-01)</td><td>50 mg/10 mL</td></tr></tbody></table>