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 )

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.

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.

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.

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 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.

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.