NITROLINGUAL (Page 2 of 4)

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.

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 240 mg/kg/day for 13 days, at intraperitoneal doses in pregnant rats up to 20 mg/kg/day for 11 days, and at intravenous doses in pregnant rabbits up to 4 mg/kg/day for 13 days.

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. 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.

8.4 Pediatric Use

Safety and effectiveness of nitroglycerin in pediatric patients have not been established.

8.5 Geriatric U se

Clinical studies 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 elderly (greater than or equal to 65 years) and younger (less than 65 years) patients. In general, dose selection for an elderly patient should start 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 Nitrolingual Pumpspray 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, 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 (C3 H5 N3 O9 ). The compound has a molecular weight of 227.09. The chemical structure is:

CH2 –ONO2

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CH–ONO2

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CH2 –ONO2

Nitrolingual Pumpspray (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.

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 eventually 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. Although venous effects predominate, nitroglycerin produces, in a dose-related manner, dilation of both arterial and venous beds. Dilation of the 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 (after load), 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 a reflex 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 pressure 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.

12.3 Pharmacokinetics

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. The mean elimination half-life of both 1,2- and 1,3-dinitroglycerin is about 40 minutes. The 1,2- and 1,3-dinitroglycerin metabolites have been reported to possess some pharmacological activity, whereas the glycerol mononitrate metabolites of nitroglycerin are essentially inactive. Higher plasma concentrations of the dinitro metabolites, with their nearly 8-fold longer elimination half-lives, may contribute significantly to the duration of pharmacologic effect.

In a pharmacokinetic study when a single 0.8 mg dose of Nitrolingual Pumpspray was administered to healthy volunteers (n = 24), the mean Cmax and tmax were 1,041 pg/ml and 7.5 minutes, respectively. Additionally, in these subjects the mean area under the curve (AUC) was 12,769 pg/ml * min.

The volume of distribution of nitroglycerin following intravenous administration is 3.3 L/kg.

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.

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