Rectiv

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.

5.1 Cardiovascular 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. 

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.

12.1 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.

12.2 Pharmacodynamics

The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle. Intra-anal application of nitroglycerin reduces sphincter tone and resting intra-anal pressure.

12.3 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Animal carcinogenicity studies with topically applied 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 the highest dose, the incidence of hepatocellular carcinomas was 52% compared to 0% in untreated controls. Incidence 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.

Mutagenesis

Nitroglycerin was mutagenic in the in vitro bacterial reverse mutation (Ames) assay with Salmonella typhimurium. A similar mutation in this S. typhimurium was also reported with other NO donors. There was no evidence of clastogenic potential in multiple assays including a rodent dominant lethal assay, an in vitro Chinese Hamster Ovary assay that was conducted in the absence of metabolic activation, and several in vivo chromosomal aberration assays conducted in rats and dogs.

Impairment of Fertility

In a three-generation reproduction study, rats received dietary nitroglycerin at doses up to approximately 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.