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 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 )

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 Viatris at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 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 Parameter Mean Nitroglycerin (SD) Values 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 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.