Nitrolingual Pumpspray (Nitroglycerin)

NITROLINGUAL® PUMPSPRAY

Rhône-Poulenc Rorer

Nitroglycerin

Antianginal

Action And Clinical Pharmacology: The principal action of nitroglycerin is that of all nitrates, namely, relaxation of vascular smooth muscle. Nitrates act primarily by reducing myocardial oxygen demand rather than increasing its oxygen supply. This effect is thought to be brought about predominantly by peripheral action. Although venous effects predominate, nitroglycerin produces, in a dose-related manner, dilation of both arterial and venous beds. Dilation of the post capillary vessels, including large veins, promotes peripheral pooling of blood and decreases venous return to the heart, reducing left ventricular end-diastolic pressure (pre-load). Arteriolar relaxation reduces systemic vascular resistance and arterial pressure (after-load). Left ventricular end-diastolic pressure and volume are decreased, resulting in reduction of ventricular size and wall tension. The reduction in ventricular wall tension results in a net decrease in myocardial oxygen consumption and a favourable net balance between myocardial oxygen supply and demand.

Pharmacokinetics: In a pharmacokinetic study when a single 0.8 mg dose of nitroglycerin Pumpspray was administered to 24 healthy volunteers, the mean Cmax and tmax were 1.04 pg/mL.min and 7.5 min, respectively. Additionally, in these subjects the mean AUC was 12.8 pg/mL.min.

Nitroglycerin is rapidly metabolized in the liver by hepatic enzymes. The 2 active major metabolites are the hydrolysis products, 1,3-and 1,2-dinitro-glycerols. There are also two inactive minor metabolites, the 1- and 2-mononitroglycerols which are considered biologically inactive. Nitroglycerin and its major metabolites are approximately 60% protein bound.

Nitroglycerin is excreted by the renal route primarily as the 2 dinitro-metabolites, which have an excretion half-life of approximately 3 to 4 hours.

Indications And Clinical Uses: For the management and treatment of acute attacks of angina pectoris.

Contra-Indications: Severe anemia, closed angle glaucoma, increased intracranial pressure, myocardial infarction, hypotension or uncorrected hypovolemia, known hypersensitivity to nitroglycerin or previous idiosyncratic reaction to organic nitrates.

Manufacturers’ Warnings In Clinical States: The use of nitroglycerin in patients with congestive heart failure or with acute myocardial infarction requires careful clinical and/or hemodynamic monitoring.

Precautions: Headaches or symptoms of hypotension, such as weakness or dizziness, particularly when arising suddenly from a recumbent position, may be due to overdosage. When they occur, the dose or frequency of application of nitroglycerin should be reduced.

Nitroglycerin is a potent vasodilator and causes a slight decrease in mean blood pressure (approximately 10 to 15 mmHg) in some patients when used in therapeutic dosages. Caution should be exercised in using the drug in patients who are prone to, or who might be affected by hypotension. Alcohol may enhance sensitivity to the hypotensive effects of nitrates.

Tolerance to this drug and cross-tolerance to other nitrates or nitrites may occur. Physical dependence has also been described. With the chronic use of nitrates, there have been reports of anginal attacks being more easily provoked as well as reports of rebound in hemodynamic effects, occurring soon after nitrate withdrawal.

Pregnancy: Animal reproduction studies have not been done with nitroglycerin Pumpspray. As with all medication, nitroglycerin should only be given to a pregnant woman if clearly indicated.

Lactation: Because it is not known if nitroglycerin is excreted in human milk, caution should be exercised when the Pumpspray is administered to a nursing mother.

Children: The safety and effectiveness of nitroglycerin in children has not been established.

Adverse Reactions: Adverse reactions to nitroglycerin are generally dose-related. In a clinical trial studying patients with chronic stable angina, the following adverse events were reported during the use of the nitroglycerin Pumpspray: headache, dizziness, paresthesia and dyspnea. All adverse events were mild to moderate.

In clinical trials at various doses of nitroglycerin, the following adverse effects have been observed: headache, which may be severe and persistent, is the most commonly reported side effect of nitroglycerin. Cutaneous vasodilation with flushing, transient dizziness and weakness, as well as other signs associated with postural hypotension, such as tachycardia, may occasionally develop. Occasionally, an individual may exhibit marked sensitivity to the hypotensive effects of nitrates and severe responses (nausea, vomiting, weakness, restlessness, pallor, retrosternal discomfort, perspiration and collapse) may occur even with therapeutic doses. Nausea and vomiting appear to be uncommon. Drug rash and/or exfoliative dermatitis have been reported in patients receiving nitrate therapy. Clinically significant methemoglobinemia is rare at conventional doses, but may occur especially in patients with genetic hemoglobin abnormalities.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Symptoms of overdosage are primarily related to vasodilation, and include cutaneous flushing, headache, nausea, dizziness, and hypotension. Methemoglobinemia is also possible.

No specific antidote is available. Treatment should be symptomatic and supportive.

Dosage And Administration: The spray should not be inhaled and should be kept away from eyes. This spray formulation is intended to be applied and absorbed on or under the tongue.

Upon initiating therapy with the nitroglycerin Pumpspray, especially when changing from another form of nitroglycerin administration, patients should be followed closely by their physicians in order to determine the minimal effective dose for each patient.

Each metered dose contains 0.4 mg nitroglycerin. With the onset of an acute attack of angina pectoris, 1 or 2 metered doses (0.4 or 0.8 mg of nitroglycerin), as determined by experience, may be administered on or under the tongue, without inhaling . The optimal dose may be repeated twice at 5 to 10 minute intervals. Dosage must be individualized and should be sufficient to provide relief without producing untoward reactions.

During administration the patient should be at rest, ideally in the sitting position, and the container kept vertical with the nozzle head up. The opening in the nozzle head should be kept as close to the mouth as possible. Patients should familiarize themselves with the position of the spray orifice, identified by the finger rest on top of the valve, in order to facilitate administration at night.

Availability And Storage: Each metered dose contains: nitroglycerin 0.4 mg in an aromatized oily solution. Nonmedicinal ingredients: dehydrated alcohol, medium chained partial glycerides, medium chained triglycerides and peppermint oil. Spray bottles delivering 200 metered doses. Store at room temperature (15 to 30°C). Do not place in hot water or near radiators, stoves or other sources of heat. Do not open forcefully or incinerate container or expose to temperature over 40°C.

NITROLINGUAL® PUMPSPRAY Rhône-Poulenc Rorer Nitroglycerin Antianginal

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Angina Pectoris

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