NITROGLYCERIN LINGUAL

Nitroglycerin, an organic nitrate, is a vasodilator which has effects on both arteries and veins. The chemical name for nitroglycerin is 1,2,3-propanetriol trinitrate (C 3 H 5 N 3 O 9 ). The compound has a molecular weight of 227.09. The chemical structure is: CH 2 –ONO 2 | CH–ONO 2 | CH 2 –ONO 2 Nitroglycerin Lingual Spray (nitroglycerin lingual spray 400 mcg) is a metered dose spray containing nitroglycerin. This product delivers nitroglycerin (400 mcg per spray, 60 or 200 metered sprays) in the form of spray droplets onto or under the tongue. Inactive ingredients: medium-chain triglycerides, dehydrated alcohol, medium-chain partial glycerides, peppermint oil, sodium lactate, lactic acid.

Nitroglycerin Lingual Spray is indicated for acute relief of an attack or prophylaxis of angina pectoris due to coronary artery disease. Nitroglycerin Lingual Spray is a nitrate vasodilator indicated for acute relief of an attack or prophylaxis of angina pectoris due to coronary artery disease ( 1 ).

At the onset of an attack, administer onto or under the tongue. Repeat every 5 minutes as needed ( 2.1 ). Do up to three metered sprays within a 15-minute period. If chest pain persists, advise prompt medical attention ( 2.1 ). May be used prophylactically 5 to 10 minutes prior to engaging in activities that might precipitate an acute attack ( 2.1 ). 2.1 Recommended Dosage Instruct the patient to administer one or two metered sprays (400 mcg of nitroglycerin per spray) at the onset of an attack onto or under the tongue. A spray may be repeated approximately every five minutes as needed. No more than three metered sprays are recommended within a 15-minute period. If the chest pain persists after a total of three sprays, advise prompt medical attention. Nitroglycerin Lingual Spray may be used prophylactically 5 to 10 minutes prior to engaging in activities that might precipitate an acute attack. 2.2 Priming The pump must be primed prior to the first use. Each metered spray of Nitroglycerin Lingual Spray delivers 48 mg of solution containing 400 mcg of nitroglycerin after an initial priming of five sprays. It will remain adequately primed for 6 weeks. If the product is not used within 6 weeks it can be adequately re-primed with one spray. If the product is not used within 3 months it can be adequately re-primed with up to five sprays. There are 60 or 200 metered sprays per bottle. The total number of available doses is dependent, however, on the number of sprays per use (1 or 2 sprays), and the frequency of priming. 2.3 Administration Instruct patients that during administration, the patient should rest, ideally in the sitting position. Hold the container vertically with the valve head uppermost and the spray orifice as close to the mouth as possible. Spray the dose preferably onto or under the tongue by pressing the grooved-button firmly and the mouth closed immediately after each dose. THE SPRAY SHOULD NOT BE INHALED. The medication should not be expectorated or the mouth rinsed for 5 to 10 minutes following administration. Instruct patients to familiarize themselves with the position of the spray orifice, which can be identified by the finger rest on top of the valve, in order to facilitate orientation for administration at night [see Patient Information (17) ]. The amount of liquid remaining in the container should be checked periodically. The transparent container can be used for continuous monitoring of the consumption. With the container upright and level, check to be sure the end of the center tube extends below the level of the liquid. Once fluid falls below the level of the center tube, remaining sprays will not deliver intended dose.

Use of phosphodiesterase type 5 (PDE-5) Inhibitors, such as avanafil, sildenafil, tadalafil, or vardenafil, or soluble guanylate cyclase (sGC) stimulator (riociguat). ( 4.1 , 7.1 ) Severe anemia. ( 4.2 ) Increased intracranial pressure. ( 4.3 ) Hypersensitivity to Nitroglycerin Lingual Spray or to other nitrates or nitrites or any excipient. ( 4.4 ) 4.1 P DE-5 - I nhibitors and sGC- S timulators Do not use Nitroglycerin Lingual Spray in patients who are taking PDE-5-Inhibitors, such as avanafil, sildenafil, tadalafil, or vardenafil. Concomitant use can cause severe hypotension, syncope, or myocardial ischemia [see Drug Interactions (7.1) ]. Do not use Nitroglycerin Lingual Spray in patients who are taking soluble guanylate cyclase (sGC) stimulators, such as riociguat. Concomitant use can cause hypotension. 4.2 Severe Anemia Nitroglycerin Lingual Spray 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 I ntracranial P ressure Nitroglycerin Lingual Spray 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 Lingual Spray is contraindicated in patients who are allergic to nitroglycerin, other nitrates or nitrites or any excipient. 4. 5 Circulatory F ailure and S hock Nitroglycerin Lingual Spray is contraindicated in patients with acute circulatory failure or shock.

Most common adverse reactions occurring at a frequency greater than 2 % are headache, dizzinesss and paresthesia ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Allegis Pharmaceuticals, LLC at 1-866-633-9033 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 clinical practice. Adverse reactions occurring at a frequency greater than 2 % and greater than placebo included: headache, dizziness, and paresthesia. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Nitroglycerin Lingual Spray and other nitroglycerin drugs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure. Neurologic: weakness, drowsiness Dermatologi c: cutaneous vasodilation, flushing, drug rash, exfoliative dermatitits Gastrointestinal: nausea, vomiting Respiratory: transient hypoxemia Cardiovascular: tachycardia

Antihypertensives: Possible additive hypotensive effects. ( 7.2 ) Ergotamine: increased bioavailability of ergotamine. Avoid concomitant use ( 7.3 ) 7. 1 P DE -5- I nhibitors and sGC- S timulators Nitroglycerin Lingual Spray 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 Lingual Spray 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 Antihypertensives Patients receiving antihypertensive drugs, beta-adrenergic blockers, and nitrates should be observed for possible additive hypotensive effects. Marked orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used concomitantly. Beta-adrenergic blockers blunt the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effects. If beta-blockers are used with nitroglycerin in patients with angina pectoris, additional hypotensive effects may occur. 7. 3 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.