nitroglycerin 400 MCG/ACTUAT Oral Spray
DRUG INTERACTIONS
7 Antihypertensives: Possible additive hypotensive effects.
( 7.2 ) Ergotamine: increased bioavailability of ergotamine.
Avoid concomitant use ( 7.3 ) 7.1 PDE-5-Inhibitors and sGC-Stimulators Nitrolingual Pumpspray is contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).
PDE5 inhibitors such as avanafil, sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates.
Do not use Nitrolingual Pumpspray in patients who are taking the soluble guanylate cyclase (sGC) stimulator riociguat.
Concomitant use can cause hypotension.
The time course and dose dependence of these interactions have not been studied, and use within a few days of one another cannot be recommended.
Appropriate supportive care for the severe hypotension 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.
7.2 Antihypertensives Patients receiving antihypertensive drugs, beta-adrenergic blockers, and nitrates should be observed for possible additive hypotensive effects.
Marked orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used concomitantly.
Beta-adrenergic blockers blunt the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effects.
If beta-blockers are used with nitroglycerin in patients with angina pectoris, additional hypotensive effects may occur.
7.3 Ergotamine Oral administration of nitroglycerin markedly decreases the first-pass metabolism of dihydroergotamine and subsequently increases its oral bioavailability.
Ergotamine is known to precipitate angina pectoris.
Therefore, patients receiving sublingual nitroglycerin should avoid ergotamine and related drugs or be monitored for symptoms of ergotism if this is not possible.
OVERDOSAGE
10 10.1 Signs and symptoms, methemoglobinemia Nitrate overdosage may result in: severe hypotension, persistent throbbing headache, vertigo, palpitation, visual disturbance, flushing and perspiring skin (later becoming cold and cyanotic), nausea and vomiting (possibly with colic and even bloody diarrhea), syncope (especially in the upright posture), methemoglobinemia with cyanosis and anorexia, initial hyperpnea, dyspnea and slow breathing, slow pulse (dicrotic and intermittent), heart block, increased intracranial pressure with cerebral symptoms of confusion and moderate fever, paralysis and coma followed by clonic convulsions, and possibly death due to circulatory collapse.
Case reports of clinically significant methemoglobinemia are rare at conventional doses of organic nitrates.
The formation of methemoglobin is dose-related and in the case of genetic abnormalities of hemoglobin that favor methemoglobin formation, even conventional doses of organic nitrates could produce harmful concentrations of methemoglobin.
10.2 Treatment of overdosage As 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.
No specific antagonist to the vasodilator effects of nitroglycerin is known.
Keep the patient recumbent in a shock position and comfortably warm.
Passive movement of the extremities may aid venous return.
Intravenous infusion of normal saline or similar fluid may also be necessary.
Administer oxygen and artificial ventilation, if necessary.
If methemoglobinemia is present, administration of methylene blue (1% solution), 1-2 mg per kilogram of body weight intravenously, may be required unless the patient is known to have G-6-PD deficiency.
If an excessive quantity of Nitrolingual Pumpspray has been recently swallowed gastric lavage may be of use.
As epinephrine is ineffective in reversing the severe hypotensive events associated with overdosage, it is not recommended for resuscitation.
DESCRIPTION
11 Nitroglycerin, an organic nitrate, is a vasodilator which has effects on both arteries and veins.
The chemical name for nitroglycerin is 1,2,3-propanetriol trinitrate (C 3 H 5 N 3 O 9 ).
The compound has a molecular weight of 227.09.
The chemical structure is: CH 2 –ONO 2 | CH–ONO 2 | CH 2 –ONO 2 Nitrolingual Pumpspray (nitroglycerin lingual spray 400 mcg) is a metered dose spray containing nitroglycerin.
This product delivers nitroglycerin (400 mcg per spray, 60 or 200 metered sprays) in the form of spray droplets onto or under the tongue.
Inactive ingredients: medium-chain triglycerides, dehydrated alcohol, medium-chain partial glycerides, peppermint oil, sodium lactate, lactic acid.
CLINICAL STUDIES
14 In a randomized, double-blind single-dose, 5-period cross-over study in 51 patients with exertional angina pectoris significant dose-related increases in exercise tolerance, time to onset of angina and ST-segment depression were seen following doses of 0.2, 0.4, 0.8 and 1.6 mg of nitroglycerin delivered by metered pumpspray as compared to placebo.
The drug showed a profile of mild to moderate adverse events.
HOW SUPPLIED
16 /STORAGE AND HANDLING Each box of Nitrolingual Pumpspray contains one glass bottle coated with red transparent plastic which assists in containing the glass and medication should the bottle be shattered.
Each bottle contains 4.9 g or 14.6 g (Net Content) of nitroglycerin lingual spray which will deliver 60 or 200 metered sprays containing 400 mcg of nitroglycerin per spray after priming.
Nitrolingual Pumpspray is available as: 60-dose (4.9 g) single bottle NDC 24338-300-65 200-dose (14.6 g) single bottle NDC 24338-300-20 Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Note: Nitrolingual Pumpspray contains 20% alcohol.
Do not forcefully open or burn container after use.
Do not spray toward flames.
Rx Only.
GERIATRIC USE
8.5 Geriatric Use Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Other reported clinical experience has not identified differences in responses between elderly (greater than or equal to 65 years) and younger (less than 65 years) patients.
In general, dose selection for an elderly patient should start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
DOSAGE FORMS AND STRENGTHS
3 Lingual spray, 400 mcg per spray available in either 60 or 200 metered sprays per container.
Lingual spray, 400 mcg per spray, available in 60 or 200 metered sprays per container ( 3 ).
MECHANISM OF ACTION
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 eventually leads to dephosphorylation of myosin light chains, which regulates the contractile state in smooth muscle and results in vasodilatation.
INDICATIONS AND USAGE
1 Nitrolingual Pumpspray is indicated for acute relief of an attack or prophylaxis of angina pectoris due to coronary artery disease.
Nitrolingual Pumpspray is a nitrate vasodilator indicated for acute relief of an attack or prophylaxis of angina pectoris due to coronary artery disease ( 1 ).
PEDIATRIC USE
8.4 Pediatric use Safety and effectiveness of nitroglycerin in pediatric patients have not been established.
PREGNANCY
8.1 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.
A teratogenicity study was conducted in the third mating of F0 generation female rats administered dietary nitroglycerin for gestation day 6 to day 15 at dose levels used in the 3-generation reproduction study.
In offspring of the high-dose nitroglycerin group, increased incidence of diaphragmatic hernias and decreased hyoid bone ossification were seen.
The latter finding probably reflects delayed development rather than a potential teratogenic effect, thus indicating no clear evidence of teratogenicity of nitroglycerin.
There are no adequate and well-controlled studies in pregnant women.
Nitroglycerin should be given to pregnant women only if clearly needed.
NUSRING MOTHERS
8.3 Nursing mothers It is not known whether nitroglycerin is excreted in human milk.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Tolerance: Excessive use may lead to tolerance.
( 5.1 ) Hypotension: Severe hypotension may occur.
( 5.2 ) 5.1 Tolerance Excessive use may lead to the development of tolerance.
Only the smallest number of doses required for effective relief of the acute angina attack should be used [see Dosage and Administration (2.1) ].
5.2 Hypotension Severe hypotension, particularly with upright posture, may occur even with small doses of nitroglycerin particularly in patients with constrictive pericarditis, aortic or mitral stenosis, patientswho may be volume-depleted, or are already hypotensive.
Hypotension induced by nitroglycerin may be accompanied by paradoxical bradycardia and increased angina pectoris.
Symptoms of severe hypotension (nausea, vomiting, weakness, pallor, perspiration and collapse/syncope) may occur even with therapeutic doses.
5.3 Hypertrophic Obstructive Cardiomyopathy Nitrate therapy may aggravate the angina caused by hypertrophic obstructive cardiomyopathy.
5.4 Headache Nitroglycerin produces dose-related headaches, especially at the start of nitroglycerin therapy, which may be severe and persistent but usually subside with continued use.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Instructions for Use)
DOSAGE AND ADMINISTRATION
2 At the onset of an attack, administer onto or under the tongue.
Repeat every 5 minutes as needed ( 2.1 ).
Do up to three metered sprays within a 15-minute period.
If chest pain persists, advise prompt medical attention ( 2.1 ).
May be used prophylactically 5 to 10 minutes prior to engaging in activities that might precipitate an acute attack ( 2.1 ).
2.1 Recommended dosage Instruct the patient to administer one or two metered sprays (400 mcg of nitroglycerin per spray) at the onset of an attack onto or under the tongue.
A spray may be repeated approximately every five minutes as needed.
No more than three metered sprays are recommended within a 15-minute period.
If the chest pain persists after a total of three sprays, advise prompt medical attention.
Nitrolingual Pumpspray may be used prophylactically 5 to 10 minutes prior to engaging in activities that might precipitate an acute attack.
2.2 Priming The pump must be primed prior to the first use.
Each metered spray of Nitrolingual Pumpspray delivers 48 mg of solution containing 400 mcg of nitroglycerin after an initial priming of five sprays.
It will remain adequately primed for 6 weeks.
If the product is not used within 6 weeks it can be adequately re-primed with one spray.
If the product is not used within 3 months it can be adequately re-primed with up to five sprays.
There are 60 or 200 metered sprays per bottle.
The total number of available doses is dependent, however, on the number of sprays per use (1 or 2 sprays), and the frequency of priming.
2.3 Administration Instruct patients that during administration, the patient should rest, ideally in the sitting position.
Hold the container vertically with the valve head uppermost and the spray orifice as close to the mouth as possible.
Spray the dose preferably onto or under the tongue by pressing the grooved-button firmly and the mouth closed immediately after each dose.
THE SPRAY SHOULD NOT BE INHALED.
The medication should not be expectorated or the mouth rinsed for 5 to 10 minutes following administration.
Instruct patients 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 [see Patient Information (17) ].
The amount of liquid remaining in the container should be checked periodically.
The transparent container can be used for continuous monitoring of the consumption.
With the container upright and level, check to be sure the end of the center tube extends below the level of the liquid.
Once fluid falls below the level of the center tube, remaining sprays will not deliver intended dose.