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Nitroglycerin
Note: The information in this monograph pertains to the IV form of nitroglycerin (except where noted otherwise). IV: FOR INTRAVENOUS USE ONLY: NOT FOR DIRECT INTRAVENOUS INJECTION (MUST BE DILUTED), NITROGLYCERIN MUST BE DILUTED IN DEXTROSE 5% INJECTION, USP OR SODIUM CHLORIDE (0.9%) INJECTION, USP BEFORE INTRAVENOUS ADMINISTRATION. THE ADMINISTRATION SET USED FOR INFUSION MAY AFFECT THE AMOUNT OF NITROGLYCERIN DELIVERED TO THE PATIENT. (SEE WARNINGS and DOSAGE AND ADMINISTRATION SECTIONS.) CAUTION: SEVERAL PREPARATIONS OF NITROGLYCERIN INJECTION, USP ARE AVAILABLE. THEY DIFFER IN CONCENTRATION AND/OR VOLUME PER VIAL. WHEN SWITCHING FROM ONE PRODUCT TO ANOTHER, ATTENTION MUST BE PAID TO THE DILUTION AND DOSAGE AND ADMINISTRATION INSTRUCTIONS. Nitroglycerin injection is a clear, practically colorless additive solution for intravenous infusion after dilution. Each milliliter contains 5 mg nitroglycerin and 45 mg propylene glycol. The solution is sterile, nonpyrogenic, and nonexplosive. Nitroglycerin, an organic nitrate, is a vasodilator. The chemical name for nitroglycerin is 1,2,3 propanetriol trinitrate. Extended Release Oral Tablets: Each 2.6 mg tablet for oral administration contains 2.6 mg nitroglycerin in extended-release form with light green granules containing corn-starch, D&C yellow #10 lake and iron oxide. Each 6.5 mg tablet for oral administration contains 6.5 mg nitroglycerin in extended-release form with light orange granules containing cornstarch, D&C yellow #10 lake, FD&C yellow #6 lake, iron oxide and povidone. Sublingual Tablets: This form is manufactured by a process which prevents the migration of nitroglycerin by adding the nonvolatile fixing agent polyethylene glycol 3350. This stabilized formulation has been shown to be more stable and more uniform than conventional molded tablets. Nitroglycerin sublingual tablets contain 0.15 mg (1/400 grain), 0.3 mg (1/200 grain), 0.4 mg (1/150 grain) and 0.6 (1/100 grain) nitroglycerin. Also contains lactose, NF; polyethylene glycol 3350, NF; sucrose, NF. Ointment: Contains 2% nitroglycerin ointment and lactose in a lanolin and white petrolatum base. Each inch, as squeezed from the tube, contains approximately 15 mg nitroglycerin. Lingual Aerosol Spray: Nitroglycerin spray is a metered dose aerosol containing nitroglycerin in propellants (dichlorodifluoromethane and dichlorotetrafluoroethane). Each metered dose delivers 0.4 mg of nitroglycerin per spray emission. This product delivers nitroglycerin in the form of spray droplets onto or under the tongue. Inactive ingredients are: caprylic/capric/diglycereryl succinate, ether, flavors. Transdermal Delivery System: This unit is designed to provide continuous controlled release of nitroglycerin through intact skin. the rate of release is linearly dependent upon the area of the applied system; each cm2 of applied system delivers approximately 0.02 mg of nitroglycerin per hour. Thus, 3.3, 6.7, 13.3 and 20 cm2 system delivers approximately 0.1, 0.2. 0.4. and 0.6 mg of nitroglycerin per hour, respectively. The remainder of nitroglycerin in each system serves as a reservoir and is not delivered in normal use. After 12 hours, for example, each system has delivered about 6% of its original content of nitroglycerin. This transdermal delivery system contains nitroglycerin in a hypoallergenic, medical grade, acrylic-based polymer adhesive. Each patch is packaged in foil/polymer film laminate. Prior to use, a protective
peel strip is removed from the
adhesive surface. Following
use, the patch should be discarded
in a manner that prevents accidental application or ingestion
by children or others.
Relaxation of vascular smooth muscle is the principal pharmacologic action of nitroglycerin. 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 and decreases venous return to the heart, reducing left ventricular end-diastolic pressure (preload). Arteriolar relaxation reduces systemic vascular resistance and arterial pressure (afterload). Myocardial oxygen consumption or demand (as measured by the pressure-rate product, tension-time index, and stroke-work index) is decreased by both the arterial and venous effects of nitroglycerin, and a more favorable supply-demand ratio can be achieved. Therapeutic doses of intravenous nitroglycerin reduce systolic, diastolic, and mean arterial blood pressures. 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, pulmonary vascular resistance, 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. Patients with elevated left ventricular filling pressure and systemic vascular resistance values in conjunction with a depressed cardiac index are likely to experience an improvement in cardiac index. On the other hand, when filling pressures and cardiac index are normal, cardiac index may be slightly reduced by intravenous nitroglycerin. Nitroglycerin is widely distributed in the body with an apparent volume of distribution of approximately 200 liters in adult male subjects, and is rapidly metabolized to dinitrates and mononitrates, with a short half-life, estimated at one to four minutes. This results in a low plasma concentration after intravenous infusion. At plasma concentrations of between 50 and 500 ng/ml, the binding of nitroglycerin to plasma proteins is approximately 60%, while that of 1,2 dinitroglycerin and 1,3 dinitroglycerin is 60% and 30%, respectively. The activity and half-life of the nitroglycerin metabolites are not well characterized. The mononitrate is not active. Pharmacokinetics The volume of distribution of nitroglycerin is about 3L/kg, and nitroglycerin is cleared from this volume at extremely rapid rates, with a resulting serum half-life of about 3 minutes. The observed clearance rates (close to 1 L/kg/min) greatly exceed hepatic blood flow; known sites of extrahepatic metabolism include red blood cells and vascular walls. The first products in the metabolism of nitroglycerin are inorganic nitrate and the 1,2- and 1,3-dinitroglycerols. The dinitrates are less effective vasodilators than nitroglycerin, but they are longer lived in the serum, and their net contribution to the overall effect of chronic nitroglycerin regimes is not known. The dinitrates are further metabolized to (nonvasoactive) mononitrates and, ultimately, to glycerol and carbon dioxide. To avoid development of tolerance to nitroglycerin, drug-free intervals of 10-12 hours are known to be sufficient; shorter intervals have not been well studied. In one well controlled clinical trial, subjects receiving nitroglycerin appeared to exhibit a rebound or withdrawal effect, so that their exercise tolerance at the end of the daily drug-free interval was less than that exhibited by the parallel group receiving placebo. In healthy volunteers, steady-state plasma concentrations of nitroglycerin are reached by about 2 hours after application of a patch and are maintained for the duration of wearing the system (observations have been limited to 24 hours). Upon removal of the patch, the plasma concentration declines with a half-life of about an hour. CLINICAL STUDIES Transdermal Patch Regimens in which nitroglycerin patches were worn for twelve hours daily have been studied in well-controlled trials for up to 4 weeks in duration. Starting about 2 hours after application and continuing until 10-12 hours after application, patches that deliver at least 0.4 mg of nitroglycerin per hour have consistently demonstrated greater antianginal activity than placebo. Lower dose patches have not been well-studied, but in one large, well-controlled trial in which higher-dose patched were also studied, patched delivering 0.2 mg/hr had significantlyless antianginal activity than placebo. It is reasonable to believe that the rate of nitroglycerin absorption from patches may vary with the site of application, but this relationship has not been adequately studied.
IV: Nitroglycerin injection is indicated for: 1. Control of blood pressure in perioperative hypertension, i.e., hypertension associated with surgical procedures, especially cardiovascular procedures, such as the hypertension seen during intratracheal intubation, anesthesia, skin incision, sternotomy, cardiac bypass, and in the immediate postsurgical period. 2. Congestive heart failure associated with acute myocardial infarction. 3. Treatment of angina pectoris in patients who have not responded to recommended doses of organic nitrates and/or a beta-blocker. 4. Production of controlled hypotension during surgical procedures. Extended Release Oral Tablets: Indicated for the prevention of angina pectoris due to coronary artery disease. The onset of action is not sufficiently rapid for this form to be useful in aborting an acute anginal episode. Sublingual Tablets: Indicated for the prophylaxis, treatment and management of patients with angina pectoris. Ointment: Indicated for the prevention of angina pectoris due to coronary artery disease. Controlled clinical trials have demonstrated that this form of nitroglycerin is effective in improving exercise tolerance in patients with exertional angina pectoris. Double-blind, placebo-controlled trials have shown significant improvement in exercise time until chest pain for up to six hours after single application of various doses of nitroglycerin ointment (mean doses ranged from 5 to 36 mg) to a 36 square inch area of trunk. Transdermal Delivery System: This product has been approved by the FDA for the prevention of angina pectoris due to coronary artery disease. The onset of action of transdermal nitroglycerin is not sufficiently rapid for this product to be useful in aborting an acute attack. Tolerance to the anti-anginal effects of nitrates (measured by exercise stress testing) has been shown to be a major factor limiting efficacy when transdermal nitrates are used continuously for longer than 12 hours each day. The development of tolerance can be altered (prevented or attenuated) by use of a noncontinuous (intermittent) dosing schedule with a nitrate-free interval of 10-12 hours. Controlled clinical trial data suggest that the intermittent use of nitrates is associated with decreased exercise tolerance, on comparison to placebo, during the last party of the nitrate-free interval; the clinical relevance of this observation is unknown, but the possibility of increased frequency of severity of angina during the nitrate-free interval should be considered. Further investigations of the tolerance phenomenon and best regimen are ongoing. A final evaluation of the effectiveness of the product will be announced by the FDA.
IV (NOT FOR DIRECT INTRAVENOUS INJECTION) NITROGLYCERIN INJECTION, USP IS A CONCENTRATED, POTENT DRUG WHICH MUST BE DILUTED IN DEXTROSE 5% INJECTION, USP OR SODIUM CHLORIDE (0.9%) INJECTION, USP PRIOR TO ITS INFUSION. NITROGLYCERIN SHOULD NOT BE ADMIXED WITH OTHER DRUGS. Initial Dilution Aseptically transfer the desired volume of nitroglycerin (see TABLE 1) into a glass bottle containing the stated volume of either 5% dextrose injection or 0.9% sodium chloride injection. This yields a final concentration of 100 to 400 mcg/ml (see TABLE 1.) Invert the glass parenteral bottle several times following admixture to assure uniform dilution of nitroglycerin injection. Maintenance Dilution It is important to consider the fluid requirements of the patient as well as the expected duration of infusion in selecting the appropriate dilution of nitroglycerin. After the initial dosage titration, the concentration of the admixture may be increased, if necessary, to limit fluids given to the patient. The concentration of the infusion solution should not exceed 400 mcg/ml of nitroglycerin. If the concentration is adjusted, it is imperative to flush or replace the infusion set before a new concentration is utilized. If the set were not flushed, or replaced, it could take minutes to hours, depending upon the wflow rate and the dead space of the set, for the new concentration to reach the patient.
Dosage is affected by the type of infusion set used (see WARNINGS.) Although the usual starting adult dose range reported in clinical studies was 25 mcg/min or more, those studies used PVC TUBING. The use of nonabsorbing tubing will result in the need to use reduced doses. When using a nonabsorbing infusion set, initial dosage should be 5 mcg/min delivered through an infusion pump capable of exact and constant delivery of the drug. Subsequent titration must be adjusted to the clinical situation, with dose increments becoming more cautious as partial response is seen. Initial titration should be in 5 mcg/min increments, with increases every three to five minutes until some response is noted. If no response is seen at 20 mcg/min, increments of 10 and later 20 mcg/min can be used. Once a partial blood pressure response is observed, the dose increase should be reduced and the interval between increments should be lengthened. Patients with normal or low left ventricular filling pressure or pulmonary capillary wedge pressure (e.g., angina patients without other complications) may be hypersensitive to the effects of nitroglycerin and may respond fully to doses as small as 5 mcg/min. These patients require especially careful titration and monitoring. There is no fixed optimum dose of nitroglycerin. Due to variations in the responsiveness of individual patients to the drug, each patient must be titrated to the desired level of hemodynamic function. Therefore, continuous monitoring of physiologic parameters (e.g., blood pressure, heart rate, and pulmonary capillary wedge pressure) MUST BE PERFORMED to achieve the correct dose. Adequate systemic blood pressure and coronary perfusion pressure must be maintained. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. STORE AT CONTROLLED ROOM TEMPERATURE 15-30°C (59-86°F). PROTECT FROM FREEZING. Extended Release Tablets Careful studies with other formulations of nitroglycerin have shown that maintenance of continuous 24-hour plasma levels of nitroglycerin results in tolerance (i.e., loss of clinical response). Every dosing regimen should provide a daily nitrate- free interval to avoid the development of this tolerance. The minimum necessary length of such an interval has not yet been defined, but studies with other nitroglycerin formulations have shown that 10-12 hours is sufficient. Large controlled studies with other formulations of nitroglycerin wshow that no dosing regimen with these tablets should be expected to provide more than about 12 hours of continuous antianginal efficacy per day. The pharmacokinetics of extended release nitroglycerin tablets, and the clinical effects of multiple-dose regimens, have not been well studied, In clinical trials, the initial regimen of nitroglycerin tablets has been 2.6 to 6.5 mg three times a day, with subsequent upward dose adjustment guided by symptoms and side effects. In one trial, 5 of the 18 subjects were titrated up to a dose of 26 mg four times a day. STORE AT CONTROLLED ROOM TEMPERATURE BETWEEN 15-30°C (59-86°F). Sublingual Tablets 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 five minutes until relief is obtained. If the pain persists after a total of three tablets in a fifteen minute period, the physician should be notified. These tablets may be used prophylactically five to ten minutes prior to engaging in activities which might precipitate an acute attack. STORE AT CONTROLLED ROOM TEMPERATURE BETWEEN 15-30°C (59-86°F). Ointment When applying the ointment, place the dose-determining applicator supplied with the package printed-side down and squeeze the necessary amount of ointment from the tube onto the applicator. Then place the applicator with the ointment-side down onto the desired area of skin, usually the chest or back. Several studies suggest that absorption of nitroglycerin through the skin varies with the site of the application of the drug. Application of the drug to the skin of the chest is reported to give higher blood levels of nitroglycerin and greater hemodynamic effects than the application of extremities. The amount of nitroglycerin entering the circulation varies directly with the size of the skin area exposed to the drug and the amount of ointment applied. Although in major clinical trials the dose was often applied to a 6x6-inch (150x150-mm) area of skin, in clinical practice the dose is usually applied to a smaller area. The ointment should be applied in a thin, uniform layer and the dose-to-area ratio kept reasonably constant. For example: 1 inch on a 2x3-inch area; 2 inches on a 3x4-inch area; 3 inches on a 4x5-inch area. When doubling the dose, the surface area over which the ointment is placed should be doubled. As with all nitrates, clinical studies suggest that clinical response is variable. A suggested starting dose is 1/2 inch (7.5 mg) applied to a 1x3 area every eight hours. Response to treatment should be assessed over the next several days. If angina occurs after ointment has been in place for several hours, the frequency of dosing should be increased (e.g., every six hours). Administer the smallest effective dose three to four times daily, unless clinical response suggests a different regimen. An initiation of therapy or change in dosage, blood pressure (patient standing) should be monitored. Controlled trials have been carried out for up to seven hours after dosing; therefore, it is not known whether the drug is effective in prevention of exertional angina beyond several hours after dosing. The effectiveness of repetitive applications of nitroglycerin ointment for the chronic management of angina pectoris has not been established. Nitroglycerin ointment is not intended for the immediate relief of anginal attacks. Lingual Aerosol Spray At the onset of an attack, one or two metered doses should be sprayed onto or under the tongue. No more than three metered doses are recommended within a 15-minute period. If the chest pain persists, prompt medical attention is recommended. Nitroglycerin Spray may be used prophylactically five to ten minutes prior to engaging in activities which might precipitate an acute attack. During application the patient should rest, ideally in the sitting position. The canister should be held vertically with the valve head uppermost and the spray orifice as close to the mouth as possible. The dose should be preferably sprayed onto the tongue by pressing the button firmly and the mouth should be closed immediately after each dose. THE SPRAY SHOULD NOT BE INHALED. Patients should be instructed 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. Transdermal Delivery System The suggested starting dose is between 0.2 mg/hr* and 0.4 mg/hr*. Doses between 0.4 mg/hr* and 0.8 mg/hr* have shown continued effectiveness for 10-12 hours daily for at least one month (the longest period studied) of intermittent administration. Although the minimum nitrate-free interval has not yet been defined, data wshow that a nitrate-free interval of 10-12 hours is sufficient. Thus, an appropriate dosing schedule for nitroglycerin patches would include a daily patch-on period of 12-14 hours and a patch- off period of 10-12 hours. Although some well-controlled clinical trials using exercise tolerance testing have shown maintenance of effectiveness when patches are worn continuously, the large majority of such controlled trials have shown the development of tolerance (i.e., complete loss of effect) within the first 24 hours after therapy was initiated. Dose adjustment, even to levels much higher than generally used, did not restore efficacy. *Release rates for formerly described in terms of drug delivered per 24 hrs. In these terms, the supplied systems would be rated at 2.5 mg/24 hrs. (0.1 mg/hr), 5 mg/24 hrs. (0.2 mg/hr), 10 mg/24 hrs. (0.4 mg/hr), and 15 mg/24 hrs. (0.6 mg/hr.). STORE AT CONTROLLED ROOM TEMPERATURE BETWEEN 15-30°C (59-86°F). Extremes of temperature and/or humidity should be avoided.
The most frequent adverse reaction in patients treated with nitroglycerin is headache, which occurs in approximately 2% of patients. Other adverse reactions occurring in less than 1% of patients are the following: tachycardia, nausea, vomiting, apprehension, restlessness, muscle twitching, retrosternal discomfort, palpitations, dizziness, and abdominal pain. The following additional adverse reactions have been reported with the oral and/or topical use of nitroglycerin: cutaneous flushing, weakness, and occasionally drug rash or exfoliative dermatitis.
No information provided.
Nitroglycerin readily migrates into many plastics. To avoid absorption of nitroglycerin into plastic parenteral solution containers, the dilution of nitroglycerin injection should be made only in glass parenteral solution bottles. Some filters absorb nitroglycerin; they should be avoided. Forty percent (40%) to eighty percent (80%) of the total amount of nitroglycerin in the final diluted solution for infusion is absorbed by the polyvinyl chloride (PVC) tubing of the intravenous administration sets currently in general use. The higher rates of absorption occur when wflow rates are low, nitroglycerin concentrations are high, and tubing is long. Although the rate of loss is highest during the early phase of administration (when wflow rates are lowest), the loss is neither constant nor self-limiting; consequently, no simple calculation or correction can be performed to convert the theoretical infusion rate (based on the concentration of the infusion solution) to the actual delivery rate. Because of this problem, Marion Laboratories recommends the use of the least absorptive infusion tubing available (i.e., non-PVC tubing) for infusions of Nitroglycerin IV. DOSING INSTRUCTIONS MUST BE FOLLOWED WITH CARE. IT SHOULD BE NOTED THAT WHEN THE APPROPRIATE INFUSION SETS ARE USED, THE CALCULATED DOSE WILL BE DELIVERED TO THE PATIENT BECAUSE THE LOSS OF NITROGLYCERIN DUE TO ABSORPTION IN STANDARD PVC TUBING WILL BE KEPT TO A MINIMUM. NOTE THAT THE DOSAGES COMMONLY USED IN PUBLISHED STUDIES UTILIZED GENERAL-USE PVC INFUSION SETS, AND RECOMMENDED DOSES BASED ON THIS EXPERIENCE ARE TOO HIGH IF THE LOW ABSORBING INFUSION SETS ARE USED. A potential safety problem exists with the combined use of some infusion pumps and some non-PVC infusion sets. Because the special tubing required to prevent the absorption of nitroglycerin tends to be less pliable than the conventional PVC tubing normally used with such infusion pumps, the pumps may fail to occlude the infusion sets completely. The results may be excessive flow at low infusion rate settings, causing alarms, or unregulated gravity flow when the infusion pump is stopped; this could lead to over-infusion of nitroglycerin. All infusion pumps should be tested with the infusion sets to ensure their ability to deliver nitroglycerin accurately at low wflow rates, and to occlude the infusion sets properly when the infusion is stopped.
General: Nitroglycerin injection should be used with caution in patients who have severe hepatic or renal disease. Excessive hypotension, especially for prolonged periods of time, must be avoided because of possible deleterious effects on the brain, heart, liver, and kidney from poor perfusion and the attendant risk of ischemia, thrombosis, and altered function of these organs. Paradoxical bradycardia and increased angina pectoris may accompany nitroglycerin-induced hypotension. Patients with normal or low pulmonary capillary wedge pressure are especially sensitive to the hypotensive effects of Nitroglycerin IV. If pulmonary capillary wedge pressure is being monitored, it will be noted that a fall in wedge pressure precedes the onset of arterial hypotension, and the pulmonary capillary wedge pressure is thus a useful guide to safe titration of the drug. Nitroglycerin contains alcohol and propylene glycol; safety for intracoronary injection has not been shown. Carcinogenesis, Mutagenesis, and Impairment of Fertility: No long-term studies in animals were performed to evaluate carcinogenic potential of nitroglycerin injection. Pregnancy Category C: Animal reproduction studies have not been conducted with Nitroglycerin. It is also not known whether nitroglycerin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 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 children have not been established.
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