WARNINGS
Amplification of the vasodilatory effects of Nitrolingual® Pumpspray by certain drugs (phosphodiesterase inhibitors) used to treat erectile dysfunction can result in severe hypotension. The time course and dose dependence of this interaction have not been studied. Appropriate supportive care has not been studied, but it seems reasonable to treat this as a nitrate overdose, with elevation of the extremities and with central volume expansion. The use of any form of nitroglycerin during the early days of acute myocardial infarction requires particular attention to hemodynamic monitoring and clinical status.
PRECAUTIONS: (General)
Severe hypotension, particularly with upright posture, may occur even with small doses of nitroglycerin. The drug, therefore, should be used with caution in subjects who may have volume depletion from diuretic therapy or in patients who have low systolic blood pressure (e.g., below 90 mm Hg). Paradoxical bradycardia and increased angina pectoris may accompany nitroglycerin-induced hypotension. Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.
Tolerance to this drug and cross-tolerance to other nitrates and nitrites may occur. Tolerance to the vascular and anti-anginal effects of nitrates has been demonstrated in clinical trials, experience through occupational exposure, and in isolated tissue experiments in the laboratory.
In industrial workers continuously exposed to nitroglycerin, tolerance clearly occurs. Moreover, physical dependence also occurs since chest pain, acute myocardial infarction, and even sudden death have occurred during temporary withdrawal of nitroglycerin from the workers. In various clinical trials in angina patients, there are reports of anginal attacks being more easily provoked and of rebound in the hemodynamic effects soon after nitrate withdrawal. The relative importance of these observations to the routine, clinical use of nitroglycerin is not known.
PRECAUTIONS: (INFORMATION FOR PATIENTS)
Physicians should discuss with patients that Nitrolingual® Pumpspray should not be used with certain drugs taken for erectile dysfunction (phosphodiesterase inhibitors) because of the risk of lowering their blood pressure dangerously.
DRUG INTERACTIONS
Alcohol may enhance sensitivity to the hypotensive effects of nitrates. Nitroglycerin acts directly on vascular muscle. Therefore, any other agents that depend on vascular smooth muscle as the final common path can be expected to have decreased or increased effect depending upon the agent.
Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and oral controlled-release nitroglycerin were used in combination. Dose adjustments of either class of agents may be necessary.
Concomitant use of nitric oxide donors (like Nitrolingual® Pumpspray) and certain drugs for the treatment of erectile dysfunction (phosphodiesterase inhibitors) can amplify their vasodilatory effects, resulting in severe hypotension.
The concomitant use of these drugs is contraindicated (see
CONTRAINDICATIONS) and alternative therapies should be used to treat acute angina episodes.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Animal carcinogenesis studies with sublingual 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 both sexes were 52% vs. 0% in controls, and 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 two 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, p.o., or in in vitro cytogenic tests in rat and dog tissues.
In a three-generation reproduction study, rats received dietary nitroglycerin at doses up to about 434 mg/kg/day for six 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 three-generation study there was no clear evidence of teratogenicity.
PREGNANCY
Pregnancy Category C
Animal teratology studies have not been conducted with nitroglycerin-pumpspray. 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 pregnant women 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 Nitrolingual® Pumpspray is administered to a nursing woman.
PEDIATRIC USE
Safety and effectiveness of nitroglycerin in pediatric patients have not been established.
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