Nitroglycerin

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 & STRENGTHS Nitroglycerin is supplied as white, round, flat-faced tablets in three strengths: 0.3 mg sublingual tablets are white to off-white, modified rectangle shaped tablets debossed with "CL" on one side and "3" on the other side and are supplied in bottles of 100 tablets. 0.4 mg sublingual tablets are white to off-white, modified rectangle shaped tablets debossed with "CL" on one side and "4" on the other side and are supplied in bottles of 25 and 100 tablets. 0.6 mg sublingual tablets are white to off-white, modified rectangle shaped tablets debossed with "CL" on one side and "6" on the other side and are supplied in bottles of 100 tablets. 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 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 Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

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 Error! Hyperlink reference not valid. ] . 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 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.

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.

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 calcium stearate, croscarmellose sodium, silica dimethyl silylate and lactose monohydrate. 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 g/mol Z:\Regulatory Affairs\_Compliance\Drug Listings\Electronic\Gateway Submissions\Nitroglycerin SL Tablets\Version 7\structure.jpg

OVERDOSAGE Hemodynamic Effects: The 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; palpitations; tachycardia; visual disturbances; nausea and vomiting (possibly with colic and even bloody diarrhea); syncope (especially in the upright posture); 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. 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. Methemoglobinemia: Methemoglobinemia has been rarely reported in association with organic nitrates. 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. If methemoglobinemia is present, intravenous administration of methylene blue, 1 to 2 mg/kg of body weight, may be required.

HOW SUPPLIED NITROGLYCERIN SUBLINGUAL TABLETS, USP 0.4mg/TABLET is supplied in the following dosage forms. NDC 51662-1282-2 NITROGLYCERIN SUBLINGUAL TABLETS, USP 0.4mg/TABLET 25TABS NDC 51662-1282-3 NITROGLYCERIN SUBLINGUAL TABLETS, USP 0.4mg/TABLET 25TABS (BOX OF 24) HF Acquisition Co LLC, DBA HealthFirst Mukilteo, WA 98275 Also supplied in the following manufacture supplied dosage forms: Nitroglycerin sublingual tablets are supplied in 3 strengths (0.3 mg, 0.4 mg, and 0.6 mg) in bottles containing 100 tablets each, with color-coded labels, and in color-coded Patient Convenience Packages of 4 bottles of 25 tablets each. 0.3 mg sublingual tablets are white to off-white, modified rectangle shaped tablets debossed with "CL" on one side and "3" on the other side and are supplied in bottles of 100 tablets. Bottle of 100 NDC 43598-435-01 0.4 mg sublingual tablets are white to off-white, modified rectangle shaped tablets debossed with "CL" on one side and "4" on the other side and are supplied in bottles of 25 and 100 tablets. Bottle of 100 NDC 43598-436-01 Convenience Package NDC 43598-436-11 0.6 mg sublingual tablets are white to off-white, modified rectangle shaped tablets debossed with "CL" on one side and "6" on the other side and are supplied in bottles of 100 tablets. Bottle of 100 NDC 43598-437-01 Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Rx only Manufactured by: Ingenus Pharmaceuticals NJ, LLC Fairfield, NJ 07004, USA Manufactured for: Dr. Reddy’s Laboratories Inc. Princeton, New Jersey 08540, USA Revised: 0217