Nitrostat is a stabilized sublingual compressed nitroglycerin tablet that contains 0.3 mg (1/200 grain), 0.4 mg (1/150 grain), or 0.6 mg (1/100 grain) nitroglycerin; as well as lactose monohydrate, NF; glyceryl monostearate, NF; pregelatinized starch, NF; calcium stearate, NF powder; and silicon dioxide, colloidal, NF.

Nitroglycerin, an organic nitrate, is a vasodilating agent. The chemical name for nitroglycerin is 1, 2, 3 propanetriol trinitrate and the chemical structure is:

Molecular weight: 227.09

Last updated on RxList: 8/24/2009

Nitroglycerin is indicated for the acute relief of an attack or acute prophylaxis of angina pectoris due to coronary artery disease.

One tablet should be dissolved under the tongue or in the buccal pouch at the first sign of an acute anginal attack. The dose may be repeated approximately every 5minutes, until relief is obtained. If the pain persists after a total of3 tablets in a15-minute period, prompt medical attention is recommended. Nitrostat may be used prophylactically5 to 10 minutes prior to engaging in activities which might precipitate an acute attack.

During administration the patient should rest, preferably in the sitting position. No dosage adjustmentis required in patients with renal failure.

Nitrostat is supplied as white, round, flat-faced tablets in 3 strengths (0.3 mg, 0.4 mg, and 0.6 mg) in bottles containing 100 tablets each, with color-coded labels, and in color-coded Patient Convenience Packages of 4 bottles of 25 tablets each.

0.3 mg (½00 grain): Coded "N" on one side and "3" on the other
N 0071 -0417-24—Bottle of 100 tablets

0.4 mg (1/150 grain): Coded "N" on one side and "4" on the other
N 0071-0418-13—Convenience Package
N 0071-0418-24—Bottle of100 tablets

0.6 mg (1/100 grain): Coded "N" on one side and "6" on the other.
N 0071-0419-24—Bottle of100 tablets

Store at Controlled Room Temperature 20°-25°C (68°-77°F) [see USP].

Distributed by: Parke-Davis., Division of Pfizer Inc, NY, NY 10017. December 2005

Last updated on RxList: 8/24/2009

Headache which may be severe and persistent may occur immediately after use. 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.

Patients receiving antihypertensive drugs, beta-adrenergic blockers, or phenothiazines 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. Concomitant use of nitrates and alcohol may cause hypotension.

The vasodilatory and hemodynamic effects of nitroglycerin maybe enhanced by concomitant administration of aspirin. Intravenous administration of nitroglycerin decreases the thrombolytic effect of alteplase. Therefore, caution should be observed in patients receiving sublingual nitroglycerin during alteplase therapy.

Intravenous nitroglycerin reduces the anticoagulant effect of heparin and activated partial thromboplastin times (APTT) should be monitored in patients receiving heparin and intravenous nitroglycerin. It is not known if this effect occurs following single sublingual nitroglycerin doses.

Tricyclic antidepressants (amitriptyline, desipramine, doxepin, others) and anticholinergic drugs may cause dry mouth and diminished salivary secretions. This may make dissolution of sublingual nitroglycerin difficult. Increasing salivation with chewing gum or artificial saliva products may prove useful in aiding dissolution of sublingual nitroglycerin.

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. Administration of nitroglycerin is contraindicated in patients who are using Viagra (sildenafil citrate). Viagra has been shown to potentiate the hypotensive effects of organic nitrates.

A decrease in therapeutic effect of sublingual nitroglycerin may result from use of long-acting nitrates.

Drug/Laboratory Test Interactions

Nitrates may interfere with the Zlatkis-Zak color reaction causing a false report of decreased serum cholesterol.

Last updated on RxList: 8/24/2009

The benefits of sublingual nitroglycerin in patients with acute myocardial infarction or congestive heart failure have not been established. If one elects to use nitroglycerin in these conditions, careful clinical or hemodynamic monitoring must be used because of the possibility of hypotension and tachycardia.

General

Only the smallest dose required for effective relief of the acute anginal attack should be used. Excessive use may lead to the development of tolerance. Nitrostat tablets are intended for sublingual or buccal administration and should not be swallowed. Severe hypotension, particularly with up right posture, may occur with small doses of nitroglycerin. This drug should therefore be used with caution in patients who may be volume-depleted or who, for whatever reason, are already hypotensive. Hypotension induced by nitroglycerin may be accompanied by paradoxical bradycardia and increased angina pectoris. Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.

As tolerance to other forms of nitroglycerin develops, the effects of sublingual nitroglycerin on exercise tolerance, although still observable, is blunted.

In industrial workers who have had long-term exposure to unknown (presumably high) doses of organic nitrates, tolerance rarely occurs. Chest pain, acute myocardial infraction, and even sudden death have occurred during temporary withdrawal of nitrates from these workers, demonstrating the existence of true physical dependence.

Several clinical trials of nitroglycerin patches or infusions in patients with angina pectoris have evaluated regimens which incorporated a 10 to 12 hour nitrate free interval. In some of these trials, an increase in the frequency of anginal attacks during the nitrate free interval was observed in a small number of patients. In one trial, patients had decreased exercise tolerance at the end of the nitrate interval. Hemodynamic rebound has been observed only rarely; on the other hand, few studies were so designed that rebound, if it had occurred, would have been detected.

Nitrate tolerance as a result of sublingual nitroglycerin administration is probably possible, but only in patients who maintain high continuous nitrate levels for more than 10 or12 hours daily. Such use of sublingual nitroglycerin would entail administration of scores of tablets daily and is not recommended.

The drug should be discontinued if blurring of vision or drying of the mouth occurs. Excessive dosage of nitroglycerin may produce severe headaches.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal carcinogenesis studies with sublingually administered nitroglycerin have not been performed.

Rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years developed dose-related fibrotic and neoplastic changes in liver, including carcinomas and interstitial cell tumors in testes. At high dose the incidences of hepatocellular carcinomas in males was 48% and in females was 33% compared to 0% in untreated controls. Incidences of testicular tumors were 52% vs 8% in controls. Lifetime dietary administration of up to 1058 mg/kg/day of nitroglycerin was not tumorigenic in mice.

Nitroglycerin was weakly mutagenic in Ames tests performed in 2 different laboratories. Nevertheless, there was no evidence of mutagenicity in an in vivo dominant lethal assay with male rats treated with doses up to about 363 mg/kg/day, PO, or in ex vivo cytogenetic tests in rat and dog tissues.

In a 3-generation reproduction study, rats received dietary nitroglycerin at doses up to about 434 mg/kg/day for 6 months prior to mating of the F0 generation with treatment continuing through successive F1 and F2 generations. The high dose was associated with decreased feed intake and body weight gain in both sexes at all matings. No specific effect on the fertility of the F0 generation was seen. Infertility noted in subsequent generations, however, was attributed to increased interstitial cell tissue and aspermatogenesis in the high-dose males. In this 3-generation study there was no clear evidence of teratogenicity.

Pregnancy Category C

Animal reproduction and teratogenicity studies have not been conducted with nitroglycerin sublingual tablets. Teratology studies in rats and rabbits, however, were conducted with topically applied nitroglycerin ointment at doses up to 80 mg/kg/day and 240 mg/kg/day, respectively. No toxic effects on dams or fetuses were seen at any dose tested. There are no adequate and well-controlled studies in pregnant women. Nitroglycerin should be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether nitroglycerin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nitroglycerin is administered to a nursing woman.

Pediatric Use

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

Geriatric Use

Clinical studies of Nitrostat 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 the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting 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.

Last updated on RxList: 8/24/2009

Hemodynamic Effects

The effects of nitroglycerin overdose are generally the results of nitroglycerin's capacity to induce vasodi-latation, venous pooling, reduced cardiac output, and hypotension. These hemodynamic changes may have protean manifestations, including increased intracranial pressure, with any or all of persistent throbbing headache, confusion, and moderate fever; vertigo; palpitations; tachycardia; visual disturbances; nausea and vomiting (possibly with colic and even bloody diarrhea); syncope (especially in the upright posture); dyspnea, later followed by reduced ventilatory effort, diaphoresis, with the skin either flushed or cold and clammy; heartblock and bradycardia; paralysis; coma; seizures; and death.

No specific antagonist to the vasodilator effects of nitroglycerin is known, and no intervention has been subject to controlled study as a therapy of nitroglycerin overdose. Because the hypotension associated with nitroglycerin overdose is the result of veno dilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. Passive elevation of the patient's legs maybe sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary. The use of epinephrine or other arterial vasoconstrictors in this setting is likely to do more harm than good. In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of nitroglycerin overdose in these patients may be subtle and difficult, and invasive monitoring may be required.

Methemoglobinemia

Methemoglobinemia has been rarely reported in association with organic nitrates. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate cardiac output and adequate arterial PO2. Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air. If methemoglobinemia is present, intravenous administration of methylene blue, 1 to 2 mg/kg of body weight, may be required.

Allergic reactions to organic nitrates are extremely rare, but they do occur. Nitroglycerin is contraindicated in patients who are allergic to it.

Sublingual nitroglycerin therapy is contraindicated in patients with early myocardial infarction, severe anemia, increased intracranial pressure, and those with a known hypersensitivity to nitroglycerin.

Administration of Nitrostat (nitroglycerin tablets, USP) is contraindicated in patients who are using Viagra® since Viagra has been shown to potentiate the hypotensive effects of organic nitrates.

Last updated on RxList: 8/24/2009

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 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 (afterload), and dilates large epicardial coronary arteries; however, the extent to which this latter effect contributes to the reliefofexertional angina is unclear.

Therapeutic doses of nitroglycerin may reduce systolic, diastolic, and mean arterial blood pressure. Effective coronary perfusion pressure is usuallymaintained, butcan be compromised ifblood pressure falls excessivelyor increased heartrate decreases diastolic filling time.

Elevated central venous and pulmonary capillarywedge pressures, and pulmonary and systemic vascularresistance are also reduced by nitroglycerin therapy. Heart rate is usually slightly increased, presumably due to a compensatory 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 pressures 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 indexmaybe slightlyreduced following nitroglycerin administration.

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 othertissues. These events lead to dephosphorylation of myosin lightchains, which regulate the contractile state in smooth muscle, and resultin vasodilatation.

Pharmacodynamics

Consistent with the symptomatic relief of angina, digital plethysmography indicates that onset of the vasodilatory effect occurs approximately 1 to 3 minutes after sublingual nitroglycerin administration and reaches a maximum by 5 minutes postdose. Effects persistfor atleast25 minutes following Nitrostatadministration.

Pharmacokinetics and Drug Metabolism

Absorption

Nitroglycerin is rapidly absorbed following sublingual administration of Nitrostat tablets. Mean peak nitroglycerin plasma concentrations occur at a mean time of approximately 6 to 7 minutes postdose (Table 1). Maximum plasma nitroglycerin concentrations (Cmax) and area underthe plasma concentration-time curves (AUC) increase dose-proportionallyfollowing 0.3 to 0.6 mg Nitrostat. The absolute bioavailabilityofnitroglycerin from Nitrostattabletsis approximately 40% but tends to be variable due to factors influencing drug absorption such as sublingual hydration and mucosal metabolism.

Table 1

	Mean Nitroglycerin (SD) Values
	2 x 0.3 mg	1 x 0.6 mg
Parameter	Nitrostat Tablets	Nitrostat Tablets
Cmax, ng/mL	2.3(1.7)	2.1 (1.5)
tmax, min	6.4(2.5)	7.2 (3.2)
AUC(0-∞), min	14.9 (8.2)	14.9(11.4)
t½, min	2.8(1.1)	2.6 (0.6)

Distribution

The volume of distribution (Vato) of nitroglycerin following intravenous administration is 3.3 L/kg. At plasma concentrations between 50 and 500 ng/mL, the binding of nitroglycerin to plasma proteins is approximately 60%, while that of 1.2- and 1,3-dinitroglycerin is 60% and 30%, respectively.

Metabolism

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. Mean peak 1,2-and 1,3-dinitroglycerin plasma concentrations occur at approximately 15 minutes postdose. The elimination half-life of 1,2- and 1.3- dinitroglycerin is 36 and 32 minutes, respectively. The 1,2- and 1,3-dinitroglycerin metabolites have been reported to possess approximately 2% and 10% of the pharmacological activity of nitroglycerin. Higher plasma concentrations of the dinitro metabolites, along with their nearly 10-fold longer elimination half-lives, may contribute significantly to the duration of pharmacologic effect. Glycerol mononitrate metabolites of nitroglycerin are biologically inactive.

Elimination

Nitroglycerin plasma concentrations decrease rapidly with a mean elimination half-life of2 to 3 minutes. Half-life values range from 1.5 to 7.5 minutes. Clearance (13.6 L/min) greatly exceeds hepatic blood flow. Metabolism is the primary route of drug elimination.

Last updated on RxList: 8/24/2009

If possible, patients should sit down when taking Nitrostat tablets. This eliminates the possibility of falling due to lightheadedness or dizziness.

Nitroglycerin may produce a burning or tingling sensation when administered sublingually; however, the ability to produce a burning or tingling sensation should not be considered a reliable method for determining the potency of the tablets. Headaches can sometimes accompany treatment with nitroglycerin. In patients who get these headaches, the headaches may be a marker of the activity of the drug.

Treatment with nitroglycerin may be associated with lightheadedness on standing, especially just after rising from a recumbent or seated position. This effect may be more frequent in patients who have also consumed alcohol. Nitroglycerin should be kept in the original glass container, tightly capped.

Last updated on RxList: 8/24/2009

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

NITROGLYCERIN EXTENDED-RELEASE - ORAL

(nye-troh-GLISS-er-in)

USES: Nitroglycerin extended release capsules are used to prevent chest pain (angina). When used regularly, nitroglycerin can decrease the number and severity of attacks of chest pain from angina and improve your ability to exercise. This medication is called a nitrate. It works by relaxing blood vessels and allowing more blood to flow to the heart.

This medication should not be used to treat angina when it occurs. Use other medications (e.g., sublingual nitroglycerin) to relieve an angina attack as directed by your doctor. Consult your doctor or pharmacist for details.

HOW TO USE: Take this medication by mouth, usually once daily in the morning without food or as directed by your doctor. Swallow this medication whole with at least half a glass of water (4 ounces or 120 milliliters). Do not crush, chew, or split the capsules. Doing so can destroy the long action of the drug and may increase your risk of side effects. Exactly follow your doctor's directions on how often to take this drug. The dosage is based on your age, medical condition, and response to therapy.

Use this medication regularly in order to get the most benefit from it. To help you remember, take it at the same time each day. It is important to continue using this medication even if you feel well.

If you take this drug continuously all day, your body will become used to it and it will not work as well. To prevent this effect, your doctor will usually direct you to avoid taking this drug during a daily break time (usually 14 hours). Consult your doctor for more details.

Do not suddenly stop taking this medication without consulting your doctor. Your condition may become worse when the drug is suddenly stopped. Your dose may need to be gradually decreased.

Inform your doctor if your condition worsens (e.g., the number of angina attacks increases).

SIDE EFFECTS: Headache, lightheadedness, flushing, dizziness, nervousness, nausea, and vomiting may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Headache generally means that the medication is working. Treat headaches with an over-the-counter pain reliever (e.g., acetaminophen) as directed by your doctor. If the headaches continue or become severe, notify your doctor.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: severe dizziness, fainting, fast/pounding heartbeat with headaches, paleness, sweating, blurred vision, dry mouth.

Tell your doctor immediately if any of these rare but very serious side effects occur: dark urine, bluish lips/skin/nails, unusual tiredness, severe weakness, irregular heartbeat, seizures.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using this medication, tell your doctor or pharmacist if you are allergic to it; or to any other nitrates; or if you have any other allergies.

This medication should not be used if you have a certain medical condition. Before using this medicine, consult your doctor or pharmacist if you have: severe anemia.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: low blood pressure, a severe loss of body water (dehydration), certain heart problems (e.g., recent heart attack, chronic heart failure, cardiomyopathy), increased pressure in the brain (e.g., due to head trauma, cerebral hemorrhage), exposure to nitrates while on the job.

This drug may make you dizzy or cause temporary blurred vision; use caution engaging in activities requiring alertness and clear vision such as driving or using machinery. Limit alcoholic beverages.

To minimize dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

Caution is advised when using this drug in the elderly because they may be more sensitive to the effects of the drug, especially dizziness, increased risk of falling, and worsening chest pain.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious (possibly fatal) interactions may occur: drugs used to treat sexual problems (e.g., sildenafil, tadalafil, vardenafil).

If you are currently using any of these medications, tell your doctor or pharmacist before starting nitroglycerin.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: alcohol, alteplase, migraine drugs (e.g., ergotamine), water pills/diuretics (e.g., furosemide, hydrochlorothiazide), other drugs for high blood pressure (e.g., beta blockers, calcium channel blockers, ACE inhibitors).

Check the labels on all your medicines (e.g., cough-and-cold products, diet aids, nonsteroidal anti-inflammatory drugs-NSAIDs for pain/fever reduction) because they may contain ingredients that could increase your blood pressure, cause a fast heartbeat, or increase chest pain (e.g., pseudoephedrine, phenylephrine, chlorpheniramine, diphenhydramine, clemastine, ibuprofen, naproxen). Ask your pharmacist about the safe use of those products.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include: persistent throbbing headache, fainting, confusion, fever, slow/irregular heartbeat, vision changes, severe nausea/vomiting, sweating, shortness of breath, cold/clammy skin, seizures.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., blood pressure) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

Lifestyle changes such as stress-reduction programs, exercise, stopping smoking, and dietary changes may increase the effectiveness of this medicine. Talk to your doctor or pharmacist about lifestyle changes that might benefit you.

Avoid situations that may lead to chest pain (e.g., vigorous exercise, cold air, heavy meals). Discuss with your doctor.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C) away from light and moisture. Close the container tightly right after each use. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.