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PFIZER US PHARM
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00071041813

brand nitrostat 0.4 mg tablet sl

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Uses

Angina

Nitroglycerin shares the actions of other nitrates and nitrites and is used for the acute relief of angina pectoris secondary to coronary artery disease, for prophylactic management in situations likely to provoke angina attacks, and for long-term prophylactic management of angina pectoris. Sublingual nitroglycerin is considered the drug of choice for the acute relief of angina pectoris, because it has a rapid onset of action, is inexpensive, and its efficacy is well established.

Hypertension

IV nitroglycerin is used to control blood pressure in perioperative hypertension, especially hypertension associated with cardiovascular procedures; to control blood pressure in patients with severe hypertension or in hypertensive crises for the immediate reduction of blood pressure in patients in whom such reduction is considered an emergency (hypertensive emergencies), especially those associated with coronary complications (e.g., coronary ischemia, acute coronary insufficiency, acute left ventricular failure, postoperative hypertension [especially following coronary bypass surgery]); and to produce controlled hypotension during surgical procedures.

Hypertensive emergencies are those rare situations requiring immediate blood pressure reduction, although not necessarily to normal ranges, in order to prevent or limit target organ damage. Examples of such emergency situations include hypertensive encephalopathy, intracerebral hemorrhage, unstable angina pectoris, acute myocardial infarction, acute left ventricular failure with pulmonary edema, dissecting aortic aneurysm, and eclampsia. Elevated blood pressure alone, in the absence of symptoms or new or progressive target organ damage, rarely is a hypertensive crisis requiring emergency therapy. If IV nitroglycerin is used in the management of a hypertensive emergency, the initial goal of such therapy is to reduce mean arterial blood pressure by no more than 25% within minutes to 1 hour, followed by further reduction if stable toward 160/100 to 110 mm Hg within the next 2-6 hours, avoiding excessive declines in pressure that could precipitate renal, cerebral, or coronary ischemia. If this blood pressure is well tolerated and the patient is clinically stable, further gradual reductions toward normal can be implemented in the next 24-48 hours. Patients with aortic dissection should have their systolic pressure reduced to less than 100 mm Hg if tolerated.

Acute Myocardial Infarction

The use of nitroglycerin is one of the principal initial therapies in the management of patients with acute myocardial infarction. The drug has been used to reduce myocardial ischemia, alleviate ischemia-induced pain, manage hypertension and persistent pulmonary congestion, and decrease the extent of infarction during and improve survival after acute myocardial infarction. Although sublingual or transdermal nitroglycerin can be used in the management of early acute myocardial infarction, IV therapy with the drug allows for more precise minute-to-minute control. For precautions associated with the use of nitroglycerin in patients with acute myocardial infarction, and also .

Heart Failure and Low-output Syndromes

IV nitroglycerin has been used effectively for the treatment of acutely decompensated (e.g., congestive) heart failure or other low cardiac output states, including those associated with acute myocardial infarction. The precipitating cause of acute heart failure decompensation should be carefully assessed to inform appropriate treatment, optimize outcomes, and prevent future acute events in patients with heart failure. Current guidelines for the management of heart failure in adults generally recommend inhibition of the renin-angiotensin-aldosterone system with a combination of drug therapies, including neurohormonal antagonists (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-adrenergic blocking agents [β-blockers], aldosterone receptor antagonists), to inhibit the detrimental compensatory mechanisms in heart failure and reduce morbidity and mortality. ( and in .) IV vasodilators have not been shown to improve outcomes in patients hospitalized for heart failure; however, in the absence of symptomatic hypotension, IV nitroglycerin may be considered as an adjunct to diuretic therapy for relief of dyspnea in patients hospitalized for acutely decompensated heart failure. IV nitroglycerin causes venodilation, which lowers preload and may help to rapidly reduce pulmonary congestion. Patients with heart failure and hypertension, coronary ischemia, or substantial mitral regurgitation are often considered ideal candidates for the use of IV nitroglycerin. However, tachyphylaxis to nitroglycerin may develop within 24 hours, and up to 20% of those with heart failure may have inadequate response to even high doses.

Chronic Anal Fissure

For topical (intra-anal) use of nitroglycerin 0.4% ointment in the treatment of chronic anal fissures,

Dosage and Administration

Administration

Nitroglycerin is administered lingually, sublingually, intrabuccally, orally, topically, or by IV infusion. Intracoronary injection of nitroglycerin infusions has not been studied. Nitroglycerin tablets for sublingual or intrabuccal administration should not be swallowed, and the extended-release tablets for buccal (transmucosal) administration should not be chewed or swallowed. The possibility that lingual, sublingual, or intrabuccal nitroglycerin may be inadequately absorbed, with resultant decreased efficacy, in patients with dry oral mucous membranes (e.g., xerostomia) should be considered. In addition, the patient should be sitting immediately after lingual, sublingual, or intrabuccal administration of nitroglycerin.

For IV infusion, the drug should be administered via a controlled-infusion device that maintains a constant infusion rate. When nitroglycerin is administered IV, the commercially available injection must be diluted in 5% dextrose or 0.9% sodium chloride injection before administration. Because nitroglycerin readily migrates into many plastics, the manufacturers' specific instructions for dilution, dosage, and administration must be carefully followed.(See Chemistry and Stability: Stability.)

A nitroglycerin transdermal system is preferably applied at the same time each day to areas of clean, dry, hairless skin of the upper arm or body; the system should not be applied to the extremities below the knee or elbow. Skin areas with irritation, extensive scarring, or calluses should be avoided, and application sites should be rotated to avoid causing skin irritation. Nitroglycerin transdermal systems should be removed from the site(s) of application prior to attempting defibrillation or cardioversion since altered electrical conductivity and enhanced potential for electrical arcing may occur.

When applied topically as an ointment, the appropriate amount of nitroglycerin ointment should be squeezed onto the manufacturer-supplied applicator and placed ointment side down on the desired non-hairy area of skin (usually on the chest or back). The ointment is then spread on the skin area in a thin, uniform layer without massaging or rubbing and using the applicator to prevent absorption of the ointment through the fingers. Using the size of the applicator to measure the coverage area allows the ointment to be absorbed through a smaller area of skin than that used in clinical trials; the clinical importance of this difference is not known. The applicator should be taped into place after application. To protect clothing, plastic wrap held in place by an elastic bandage, hosiery, or tape may be used to cover the ointment applicator. Application of the ointment over the chest may provide an additional psychological effect. As with transdermal nitroglycerin systems, nitroglycerin ointment has been reported to alter electrical conductivity, and some clinicians suggest that areas of the chest where defibrillation paddles typically are placed not be used for application of the ointment if possible.

Dosage

Dosage of nitroglycerin must be carefully adjusted according to the patient's requirements and response and the smallest effective dosage should be used. When nitroglycerin is administered IV, the type of IV administration set used, polyvinyl chloride (PVC) or non- PVC, must be considered in dosage estimations. It should be noted that dosages commonly used in early published studies were based on the use of PVC administration sets and are too high when non- PVC administration sets are used.

Continuous monitoring of blood pressure and heart rate, as well as other appropriate parameters (e.g., pulmonary capillary wedge pressure), must be performed in all patients. Adequate systemic blood pressure and coronary perfusion pressure must be maintained. Some patients with normal or low left ventricular filling pressures or pulmonary capillary wedge pressure may be extremely sensitive to the effects of IV nitroglycerin and may respond fully to dosages as low as 5 mcg/minute; these patients require particularly careful monitoring and dosage titration.

For dosage of topical (intra-anal) nitroglycerin 0.4% ointment in the treatment of chronic anal fissure,

Angina

Lingual Dosage

For the acute relief of angina pectoris or for prophylactic management in situations likely to provoke angina attacks, nitroglycerin may be sprayed onto the oral mucosa using a metered-dose spray pump. This spray pump must be primed, but not shaken, prior to first use or after a period of nonuse (i.e., 6 weeks or more) by actuating 1 spray.

When properly primed, the lingual spray delivers 0.4 mg of nitroglycerin per metered spray. The commercially available lingual spray pump delivers about 60 or 200 metered sprays per 4.9- or 12-g bottle, respectively. Once the maximum number of sprays is delivered, nitroglycerin lingual spray pumps should be discarded.

To administer the drug, the nitroglycerin lingual spray pump should be held upright with the valve head uppermost and the spray orifice as close to the opened mouth as possible. To release a spray, the valve head is pressed with the forefinger. The dose is preferably sprayed onto or under the tongue and then the mouth immediately closed; the spray should not be inhaled, and swallowing immediately after the spray is administered should be avoided. In addition, the drug should not be expectorated nor the mouth rinsed for 5-10 minutes following administration of the drug.

For the acute relief of angina pectoris, 1 or 2 sprays (0.4 or 0.8 mg, respectively) may be administered. If relief is not attained after the initial spray(s), additional single sprays may be given at intervals of approximately 3-5 minutes as necessary; no more than 3 sprays (1.2 mg) should be given in a 15-minute period. If pain persists after a total of 3 doses within a 15-minute period, prompt medical attention is recommended. The nitroglycerin lingual spray pump also may be used prophylactically 5-10 minutes before situations likely to provoke angina attacks.

Sublingual and Buccal Dosage

For the acute relief of angina pectoris or for prophylactic management in situations likely to provoke angina attacks, 0.3-0.6 mg of nitroglycerin as sublingual tablets is placed under the tongue or in the buccal pouch and allowed to dissolve. If relief is not attained after a single dose during an acute attack, additional doses may be given at 5-minute intervals. If pain persists after a total of 3 doses within a 15-minute period, prompt medical attention is recommended. For prophylactic management in situations likely to provoke angina attacks, nitroglycerin sublingual tablets should be placed under the tongue or in the buccal pouch 5-10 minutes prior to engaging in such activities.

For long-term prophylactic management of angina pectoris, nitroglycerin extended-release buccal (transmucosal) tablets are placed on the oral mucosa between the lip and gum above the upper incisors or between the cheek and gum. The tablets should not be placed under the tongue and should be allowed to dissolve undisturbed over a 3- to 5-hour period; if a tablet is inadvertently swallowed, another tablet may be administered as a replacement. The dissolution time of the tablets usually increases as patients become more familiar with use of the dosage form. The rate of dissolution of a tablet may be increased by touching the tablet with the tongue or drinking hot liquids. Because of the risk of aspiration, administration of the extended-release buccal tablet at bedtime is not recommended. The usual initial adult dosage is 1 mg 3 times daily given every 5 hours during waking hours, with the patient's response assessed over a period of 4-5 days. Dosage should be titrated upward incrementally until angina is effectively controlled or adverse effects preclude further increases. If angina occurs while a tablet is in place, the dose should be increased to the next tablet strength; if angina occurs after a tablet has dissolved, the dosing frequency should be increased. The usual dosing interval is 3-5 hours, and the usual maintenance dosage is 2 mg 3 times daily. Further studies are needed to evaluate the long-term efficacy of the extended-release buccal tablets; a controlled clinical study demonstrating the efficacy of maintenance therapy with the tablets for 2 weeks has been reported. The extended-release buccal tablets may also be used for acute relief of angina pectoris or for prophylactic management in situations likely to provoke angina attacks. If an angina attack occurs while a tablet is currently in place, another tablet may be administered on the opposite side from the one already in place. If an extended-release buccal tablet does not provide prompt relief of an acute attack, use of sublingual nitroglycerin is recommended.

Oral Dosage

For long-term prophylactic management of angina pectoris, 2.5-9 mg of nitroglycerin as an extended-release formulation has been administered orally every 8 or 12 hours. Because the onset of action of extended-release nitroglycerin formulations is not sufficiently rapid to abort acute attacks of angina, such formulations should not be used to treat acute attacks of angina.

Topical Dosage

When a nitroglycerin transdermal system is used for the long-term prophylactic management of angina pectoris, the usual initial adult dosage is one transdermal dosage system, delivering the smallest available dose of nitroglycerin in its dosage series, applied every 24 hours. To minimize the occurrence of tolerance to the effects of nitroglycerin, a nitrate-free interval of 10-14 hours has been recommended; however, the minimum nitrate-free interval necessary for restoration of full first-dose effects of nitrate therapy has not been determined. Dosage may be adjusted by changing to the next larger dosage system in the series or by a combination of dosage systems in the series. The transdermal systems should not be used to treat acute attacks of angina.

When nitroglycerin is applied topically as an ointment, a suggested initial dosage is 0.5 inch (as squeezed from the tube) of the 2% ointment (i.e., approximately 7.5 mg) applied twice daily (once upon arising in the morning and repeated 6 hours later). When the dose to be applied is in multiples of whole inches, unit-dose preparations that provide the equivalent of 1 inch of the 2% ointment also may be used. The initial dose may be doubled (i.e., increased to 1 inch or approximately 15 mg) and subsequently doubled again (i.e., increased to 2 inches or approximately 30 mg) if tolerated in patients failing to respond adequately. Doses used in clinical trials have ranged from 0.5-2 inches (approximately 7.5-30 mg). Dosage should be titrated upward until angina is effectively controlled or adverse effects preclude further dosage increases.

The amount of nitroglycerin reaching the circulation varies directly with the size of the area of application and the amount of ointment applied. Coverage of an area approximately the size of the applicator (3.5 by 2.25 inches) should be sufficient to obtain the desired clinical effects, however, a larger area may be used. In clinical trials, the ointment generally has been spread over an area of 6 by 6 inches.

As with other nitroglycerin formulations, all regimens of nitroglycerin ointment should include a daily nitrate-free interval to avoid development of tolerance. It is not known whether nitroglycerin ointment is effective in preventing exertional angina for longer than 7 hours after application of a dose. The efficacy of repeated applications of the ointment for the long-term management of angina pectoris has not been established.

The onset of action of topical nitroglycerin ointment is not sufficiently rapid to treat acute attacks of angina; therefore, the ointment should not be used for this purpose.

IV Dosage

For the treatment of angina in patients who have not responded to sublingual nitroglycerin and β-adrenergic blocking agents (β-blockers), the recommended initial adult IV dosage when non- PVC administration sets are used is 5 mcg/minute, with increases of 5 mcg/minute every 3-5 minutes until a blood pressure response is obtained or until the infusion rate is 20 mcg/minute. If no effect is obtained with 20 mcg/minute, dosage may be increased by increments of 10 mcg/minute and if later necessary, by increments of 20 mcg/minute. When PVC administration sets are used, higher dosages generally are required; the usual initial adult dosage when these sets are used is 25 mcg/minute. Dosage is then titrated according to the response and tolerance of the patient.

Hypertension

IV Dosage

When nitroglycerin is used IV to control severe hypertension or in hypertensive emergencies, an IV infusion dosage of up to 100 mcg/minute may be required, with effective dosages ranging from 5-100 mcg/minute. Once a partial blood pressure response is obtained, increases in dosage increments should be reduced and the interval between dosage increases should be lengthened. The hypotensive effect of IV nitroglycerin usually is apparent within 2-5 minutes and may persist for only several minutes (e.g., 3-5 minutes) once the infusion is discontinued if antihypertensive therapy (e.g., an oral agent) with a more prolonged duration has not been initiated.

The risks of overly aggressive therapy in any hypertensive crisis must always be considered. The initial goal of IV nitroglycerin therapy for a hypertensive emergency is to reduce mean arterial blood pressure by no more than 25% within minutes to 1 hour, followed by further reduction if stable toward 160/100 to 110 mm Hg within the next 2-6 hours, avoiding excessive declines in pressure that could precipitate renal, cerebral, or coronary ischemia. If this blood pressure is well tolerated and the patient is clinically stable, further gradual reductions toward normal can be implemented in the next 24-48 hours. Patients with aortic dissection should have their systolic pressure reduced to less than 100 mm Hg if tolerated.

Acute Myocardial Infarction

IV Dosage

When IV nitroglycerin is used after an acute myocardial infarction, some experts recommend a continuous IV infusion at a rate of 10-20 mcg/minute, increasing the dosage further in 5- to 10-mcg/minute increments at 5- to 10-minute intervals as necessary according to hemodynamic and clinical response. Dosage generally is titrated to control clinical symptoms or decrease mean arterial pressure by 10% in normotensive patients or by 30% in hypertensive patients (but never to below a systolic pressure of 90 mm Hg), increase heart rate by more than 10 bpm (but not exceeding 110 bpm), or decrease pulmonary artery end-diastolic pressure by 10-30%. The infusion should be slowed or temporarily discontinued if mean arterial blood pressure declines below 80 mm Hg or systolic pressure declines below 90 mm Hg.

Although there is not an absolute upper limit to dosage titration in patients with acute myocardial infarction, as nitrate tolerance develops and dosages approach 200 mcg/minute, the risk of hypotension increases; therefore, alternative therapy (e.g., sodium nitroprusside, ACE inhibitor) should be instituted if adequate response is not achieved at such dosages. Efficacy of nitroglycerin generally returns within 12 hours after discontinuance. An IV β-blocker may be used concomitantly with nitroglycerin, and can limit nitroglycerin-induced tachycardia, but the risk of exaggerated hypotensive response should be considered. Occasionally, IV nitroglycerin is continued beyond 48 hours such as in patients with recurrent angina or persistent pulmonary congestion. Such therapy also may be continued beyond 48 hours in patients with large or complicated infarction, although oral or topical nitrate therapy can be substituted in such patients.

Pharmacokinetics

Absorption

The approximate onset and duration of action of various dosage forms of nitroglycerin are as follows:

Table 1. Antianginal Effects
Dosage Form Onset Duration
buccal (transmucosal) extended-release within 2-3 min 3-5 h
sublingual within 2 min up to 30 min
ointment 30 min 3 h
oral extended-release 1 h up to 12 h
Table 2. Hemodynamic Effects
Dosage Form Onset Duration
buccal (transmucosal) extended-release within 2 min up to at least 3 h
sublingual 2 min up to 30 min
ointment within 1 h 3-6 h

The onset of action of transdermal systems of nitroglycerin is delayed and the duration prolonged compared with other currently available dosage forms of the drug. Transdermal systems of the drug are designed to provide continuous, controlled release of nitroglycerin to the skin from which the drug undergoes percutaneous absorption. The rates of delivery and absorption of the drug vary depending on the specific preparation, and the individual manufacturers' information should be consulted for specific descriptions of these rates and other characteristics of the preparation. The rate of delivery is linearly dependent on the active surface area of the applied system. In general, each transdermal system contains a reservoir of excess nitroglycerin, which establishes a concentration gradient to promote delivery of the drug out of the system and into the skin, and not all of the drug is delivered from the system during normal use. The preparations currently are labeled in terms of the approximate rate of drug delivery per hour; previously, they were labeled in terms of the approximate rate of drug delivery per 24 hours.

Several studies suggest that percutaneous absorption of nitroglycerin ointment varies with the site of application, with application to the chest resulting in higher blood concentrations of the drug and greater hemodynamic effects than application to the extremities; however, there are conflicting data, and further studies are needed to more fully evaluate the effect of the application site on absorption and hemodynamic effects.

Distribution

Nitroglycerin is widely distributed in the body. In adult males, nitroglycerin has an apparent volume of distribution of about 200 L. In one study in rats,C-labeled nitroglycerin was distributed mainly to the liver and carcass, and to a lesser extent to the heart, lungs, kidneys, and spleen. It is not known if nitroglycerin is distributed into milk.

At plasma concentrations of 50-500 ng/mL, nitroglycerin is about 60% bound to plasma proteins while its metabolites, 1,3-glyceryl dinitrate and 1,2-glyceryl dinitrate, are approximately 60 and 30% bound, respectively.

Elimination

The plasma half-life of nitroglycerin is about 1-4 minutes. Clearance of nitroglycerin occurs at a rate of about 1 L/kg per minute.

Nitroglycerin is metabolized to 1,3-glyceryl dinitrate, 1,2-glyceryl dinitrate, and glyceryl mononitrate. In animals, the vasodilator effects of nitroglycerin are 10-14 times greater than those of the dinitrate metabolites. Glyceryl mononitrate, which is inactive, is the principal metabolite. The dinitrate metabolites are metabolized further to inactive mononitrates and are metabolized ultimately to glycerol and carbon dioxide. Clearance of nitroglycerin exceeds hepatic blood flow. Extrahepatic sites of metabolism include red blood cells and vascular walls.

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