Nitroglycerin

RECTIV ® (nitroglycerin) Ointment 0.4% is indicated for the treatment of moderate to severe pain associated with chronic anal fissure. RECTIV is a nitrate vasodilator indicated for the treatment of moderate to severe pain associated with chronic anal fissure ( 1 ).

Ointment, 0.4% w/w (4 mg /1 g) in 30 g tubes. Ointment 0.4% w/w (4 mg nitroglycerin/1 g ointment) ( 3 )

Use of PDE5 inhibitors (e.g. sildenafil, vardenafil and tadalafil) as these are shown to potentiate the hypotensive effects of organic nitrates. ( 4.1 ). Severe anemia ( 4.2 ) Increased intracranial pressure ( 4.3 ) Known hypersensitivity to nitroglycerin, other nitrates and nitrites, or any components of the ointment. ( 4.4 ) 4.1 PDE5 inhibitor use Administration of RECTIV 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 ( 7.1 ) ] .

4.2 Severe anemia RECTIV is contraindicated in patients with severe anemia.

4.3 Increased intracranial pressure RECTIV is contraindicated in patients with increased intracranial pressure.

4.4 Hypersensitivity RECTIV 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.

Cardiovascular Disorders: Venous and arterial dilatation as a consequence of nitroglycerin treatment can result in hypotension. 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 ( 5.1 ). Headache: Nitroglycerin produces dose-related headaches which may be severe ( 5.2 ) 5. 1 Cardi ovascular disorders Venous and arterial dilatation as a consequence of nitroglycerin treatment including RECTIV, 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 RECTIV, monitor cardiovascular status and clinical condition. The adverse reactions of RECTIV are likely to be more pronounced in the elderly. 5. 2 Headache RECTIV produces dose-related headaches, which may be severe. Tolerance to headaches occurs.

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 RECTIV ointment 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 RECTIV N = 123 Placebo N = 124 System Organ Class Preferred term Patients n (%) Events n Patients n (%) Events n Nervous system disorders Headache 79 (64) 938 51 (41) 225 Dizziness 6 (5) 26 0 0 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 ( 10 ) ] . Most common adverse reactions are headache and dizziness. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-678-1605 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

PDE5 inhibitors: potentiation of hypotensive effects of organic nitrates; concomitant use is contraindicated. ( 4.1 , 7.1 ) Antihypertensives: possible additive hypotensive effects. ( 7.2 ) Aspirin: increased nitroglycerin levels. ( 7.3 ) Tissue-type Plasminogen Activator (t-PA): decreased thrombolytic effect. ( 7.4 ) Heparin: anticoagulant effect of heparin may be reduced. Monitor APTT. ( 7.5 ) Ergotamine: increased bioavailability of ergotamine. ( 7.6 ) Alcohol: Additive vasodilatory effects to nitroglycerin. Consumption of alcohol should be avoided. ( 7.7 ) 7.1 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 RECTIV within a few days of PDE5 inhibitors is contraindicated.

7.2 Antihypertensives Patients receiving antihypertensive drugs, beta-adrenergic blockers, and other nitrates should be observed for possible additive hypotensive effects when using RECTIV. 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 RECTIV in patients with angina pectoris, additional hypotensive effects may occur.

7.3 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 RECTIV may be enhanced by concomitant administration of aspirin.

7.4 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 RECTIV during t-PA therapy.

7.5 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 RECTIV concurrently, the anticoagulation status of the patient must be checked.

7.6 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 RECTIV should be considered.

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

8.1 Pregnancy Risk Summary There are no data on the use of nitroglycerin ointment intra-anally during pregnancy to determine a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, no malformations were observed in offspring of pregnant rats and rabbits administered nitroglycerin by topical or dietary route during the period of organogenesis (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Animal reproduction 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. An animal reproduction 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. 8. 2 Lactation Risk Summary There are no data on the presence of nitroglycerin in either human or animal milk following topical administration, or the effects of nitroglycerin on milk production. A publication describing 40 lactating patients who used nitroglycerin ointment to treat chronic anal fissures for varied durations did not report signs of adverse effects in their breastfed infants, however, the dosing regimens were not described. The developmental and health benefits of breastfeeding should be considered along with the clinical need for RECTIV and any potential adverse effects on the breastfed infant from RECTIV or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of RECTIV in pediatric patients under 18 years of age have not been established.

8.5 Geriatric Use Clinical studies of RECTIV 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.

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.