rsi ad
 
drx ad
 
ad space

Nitroglycerin Ointment, 0.4%

For intra-anal use

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING


1. DESCRIPTION

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

Nitroglycerin ointment 0.4% contains 0.4% nitroglycerin w/w (4 mg nitroglycerin/1 g ointment), propylene glycol, lanolin, sorbitan sesquioleate, paraffin wax, and white petrolatum.

Nitroglycerin ointment 0.4% is available in tubes with a one-inch dosing line on the carton allowing the measurement of approximately 375 mg of nitroglycerin ointment 0.4% (1.5 mg nitroglycerin) for application.

2. INDICATIONS AND USAGE

Nitroglycerin ointment 0.4% is indicated for the treatment of moderate to severe pain associated with chronic anal fissure.

3. DOSAGE AND ADMINISTRATION

Apply 1 inch of ointment (375 mg of ointment equivalent to 1.5 mg of nitroglycerin) intra-anally every 12 hours for up to 3 weeks. A finger covering, such as plastic-wrap, disposable surgical glove or a finger cot, should be placed on the finger to apply the ointment. To obtain a 1.5 mg dose of nitroglycerin, the covered finger is laid alongside the 1 inch dosing line on the carton.

Refer to carton for accurate dosage guide.

The tube is gently squeezed until a line of ointment the length of the measuring line is expressed onto the covered finger. The ointment is gently inserted into the anal canal using the covered finger no further than to the first finger joint and the ointment is applied around the side of the anal canal. If this cannot be achieved due to pain, application of the ointment should be made directly to the outside of the anus. Treatment may be continued for up to three weeks.

Nitroglycerin ointment is not for oral, ophthalmic, or intravaginal use. Hands should be washed after application of the ointment.

4. CONTRAINDICATIONS

4.1 PDE5 Inhibitor Use

Administration of nitroglycerin ointment is contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), such as sildenafil, vardenafil, and tadalafil, as these are shown to potentiate the hypotensive effects of organic nitrates [see DRUG INTERACTIONS].

4.2 Severe Anemia

Nitroglycerin ointment is contraindicated in patients with severe anemia.

4.3 Increased Intracranial Pressure

Nitroglycerin ointment is contraindicated in patients with increased intracranial pressure.

4.4 Hypersensitivity

Nitroglycerin ointment is contraindicated in patients who have shown hypersensitivity to it or to other nitrates or nitrites. Skin reactions consistent with hypersensitivity have been observed with organic nitrates.

5. 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 leads to dephosphorylation of myosin light chains, which regulates the contractile state in smooth muscle and results in vasodilatation.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

Animal reproduction and teratogenicity studies have not been conducted with nitroglycerin ointment. Nitroglycerin was not teratogenic when administered by topical or dietary route. There are no adequate and well-controlled studies in pregnant women. Nitroglycerin ointment should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Teratology studies in rats and rabbits 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.

A teratogenicity study was conducted in rats with nitroglycerin administered in the diet at levels up to 1% content (approximately 430 mg/kg/day) on days 6 to 15 of gestation. In offspring of the high-dose group, an increased but not statistically significant incidence of diaphragmatic hernias was noted together with decreased hyoid bone ossification. The latter finding probably reflects delayed development, thus indicating no clear evidence of a potential teratogenic effect of nitroglycerin.

6.2 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.

6.3 Pediatric Use

Safety and effectiveness in pediatric patients under 18 years of age have not been established.

6.4 Geriatric Use

Clinical studies of nitroglycerin ointment did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Clinical data from the published literature indicate that the elderly demonstrate increased sensitivity to nitrates, which may be therapeutic but also manifest by more frequent or severe hypotension and related dizziness or fainting. Increased sensitivity may reflect the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

7. WARNINGS AND PRECAUTIONS

7.1 Cardiovascular Disorders

Venous and arterial dilatation as a consequence of nitroglycerin treatment including nitroglycerin ointment, can decrease venous blood returning to the heart and reduce arterial vascular resistance and systolic pressure. Exercise caution when treating patients with any of the following conditions: blood volume depletion, existing hypotension, cardiomyopathies, congestive heart failure, acute myocardial infarction, or poor cardiac function for other reasons. If patients with any of these conditions are treated with nitroglycerin ointment, monitor cardiovascular status and clinical condition. The adverse reactions of nitroglycerin ointment are likely to be more pronounced in the elderly.

7.2 Headache

Nitroglycerin ointment produces dose-related headaches, which may be severe. Tolerance to headaches occurs.

8. ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reaction of nitroglycerin ointment 0.4% applied to the anal canal is headache.

Headache may be recurrent following each dose. Headaches are typically of short duration and can be treated with an analgesic, e.g. acetaminophen, and are reversible upon discontinuation of treatment.

In Study REC-C-001, a double-blind, placebo-controlled trial in patients with a painful chronic anal fissure, the most frequent (≥ 2%) adverse reactions reported were as follows (Table 1):

Table 1: Incidence of Adverse Reactions (≥ 2%) in Study REC-C-001

Hypotension

Transient episodes of light-headedness, occasionally related to blood pressure changes, also may occur. Hypotension (including orthostatic hypotension) occurs infrequently, but in some patients may be severe enough to warrant discontinuation of therapy.

Allergic Reactions

Flushing, allergic reactions, and application site reactions (including drug rash and exfoliative dermatitis) have been reported rarely.

Methemoglobinemia

In rare cases, therapeutic doses of organic nitrates have caused methemoglobinemia (see OVERDOSAGE).

9. OVERDOSAGE

Nitroglycerin toxicity is generally mild. The estimated adult oral lethal dose of nitroglycerin is 200 mg to 1,200 mg. Infants may be more susceptible to toxicity from nitroglycerin. Consultation with a poison center should be considered.

Laboratory determinations of serum levels of nitroglycerin and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of nitroglycerin overdose.

No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of nitroglycerin and its active metabolites. Similarly, it is not known which if any of these substances can usefully be removed from the body by hemodialysis. 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 venodilatation and arterial hypovolemia, prudent therapy in this situation should be directed toward increase in central fluid volume. Passive elevation of the patient’s legs may be 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 not recommended.

In patients with renal disease or congestive heart failure, therapy resulting in central volume expansion is not without hazard. Treatment of nitroglycerin ointment overdose in these patients may be subtle and difficult, and invasive monitoring may be required.

Methemoglobinemia

Methemoglobinemia has been rarely reported with organic nitrates. The diagnosis should be suspected in patients who exhibit signs of impaired oxygen delivery despite 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.

10. DRUG INTERACTIONS

10.1 PDE5 Inhibitors

Phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates.

The time course of the interaction appears to be related to the half-life of the PDE5 inhibitor, however, the dose dependence of this interaction has not been studied. Use of nitroglycerin ointment within a few days of PDE5 inhibitors is contraindicated.

10.2 Antihypertensives

Patients receiving antihypertensive drugs, beta-adrenergic blockers, and other nitrates should be observed for possible additive hypotensive effects when using nitroglycerin ointment. Marked orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used concomitantly.

Beta-blockers blunt the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effects. If beta-blockers are used with nitroglycerin ointment in patients with angina pectoris, additional hypotensive effects may occur.

10.3 Aspirin

Coadministration of aspirin (at doses between 500 mg and 1000 mg) and nitroglycerin has been reported to result in increased nitroglycerin maximum concentrations by as much as 67% and AUC by 73% when administered as a single dose. The pharmacological effects of nitroglycerin ointment may be enhanced by concomitant administration of aspirin.

10.4 Tissue-type Plasminogen Activator (t-PA)

Intravenous administration of nitroglycerin decreases the thrombolytic effect of tissue-type plasminogen activator (t-PA). Plasma levels of t-PA are reduced when coadministered with nitroglycerin. Therefore, caution should be observed in patients receiving nitroglycerin ointment during t-PA therapy.

10.5 Heparin

Although an interaction has been reported between intravenous heparin and intravenous nitroglycerin (resulting in a decrease in the anticoagulant effect of heparin), the data are not consistent. If patients are to receive intravenous heparin and nitroglycerin ointment concurrently, the anticoagulation status of the patient must be checked.

10.6 Ergotamine

Oral administration of nitroglycerin markedly decreases the first-pass metabolism of dihydroergotamine and consequently increases its oral bioavailability. Ergotamine is known to precipitate angina pectoris. Therefore the possibility of ergotism in patients receiving nitroglycerin ointment should be considered.

10.7 Alcohol

The vasodilating effects of nitroglycerin have been shown to be additive to the effects observed with alcohol.

11. PHARMACOKINETICS

Absorption

In six healthy subjects, the average absolute bioavailability of nitroglycerin applied to the anal canal as a 0.2% w/w ointment was approximately 50% of the 0.75 mg nitroglycerin dose.

Distribution

The volume of distribution of nitroglycerin following intravenous administration is about 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

Nitroglycerin is metabolized by a liver reductase enzyme 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, the two major metabolites, 1,2- and 1,3- dinitroglycerols are found in plasma. The contribution of metabolites to the relaxation of the internal anal sphincter is unknown. The dinitrates are further metabolized to nonvasoactive mononitrates and ultimately to glycerol and carbon dioxide.

Elimination

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

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: RECTIV, by ProStrakan, Inc.

b) Generic drugs: None.

2) How Supplied:

RECTIV (nitroglycerin) Ointment 0.4% is available in 30 g (NDC 42747-235-30) aluminum tubes with polyethylene screw caps.

3) Storage:

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15°-30°C (59°-86°F). [See USP for Controlled Room Temperature.]

Keep the tube tightly closed. Use within 8 weeks of first opening.

Rx only

Rev 06/11