Nitromist.com

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use NitroMist safely and effectively.
• Increased intracranial pressure (4.3) See full prescribing information for NitroMist.
• History of hypersensitivity to NitroMist or to other nitrates or nitrites (4.4) NitroMist® (nitroglycerin) lingual aerosol
WARNINGS AND PRECAUTIONS
Initial U.S. Approval: 2006
• Tolerance: Excessive use may lead to tolerance (5.1).
INDICATIONS AND USAGE
ADVERSE REACTIONS
NitroMist® is a nitrate vasodilator indicated for acute relief of an attack or acute prophylaxis of angina Most common adverse reactions are headache, flushing, hypotension, and syncope (6).
pectoris due to coronary artery disease (1).
To report SUSPECTED ADVERSE REACTIONS, contact Akrimax Pharmaceuticals at 1-888 383 1733 or
DOSAGE AND ADMINISTRATION
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch/report.htm.
• At the onset of an attack, one metered spray or two metered sprays should be administered on or under the tongue. DRUG INTERACTIONS
A spray may be repeated approximately every 5 minutes as needed (2). • PDE5 inhibitors: Concomitant use contraindicated (4.1, 7.1) • Maximum of 3 metered sprays are recommended within a 15-minute period. If chest pain persists after • Antihypertensives: Possible additive hypotensive effects (7.2) a total of 3 sprays, prompt medical attention is recommended (2).
• Aspirin: increased nitroglycerin levels (7.3) • May be used prophylactically 5 minutes to 10 minutes before engaging in activities that might precipitate an • Tissue-type plasminogen activator (t-PA): decreased thrombolytic effect (7.4) • Heparin: anticoagulant effect of heparin may be reduced. Monitor APTT. (7.5) DOSAGE FORMS AND STRENGTHS
• Ergotamine: increased bioavailability of ergotamine. Avoid concomitant use. (7.6) Lingual aerosol, 400 mcg per spray is available in either 230 metered sprays or 90 metered sprays per container. (3) See 17 for PATIENT COUNSELING INFORMATION
CONTRAINDICATIONS
• Use of a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase Revised: 02/2012
type 5 (PDE5 inhibitors), such as sildenafil, vardenafil, and tadalafil (4.1) FULL PRESCRIBING INFORMATION: CONTENTS*
7.4 Tissue-type plasminogen activator (t-PA) 1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
8 USE IN SPECIFIC POPULATIONS
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
5 WARNINGS AND PRECAUTIONS
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES
6 ADVERSE REACTIONS
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
7 DRUG INTERACTIONS
*Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
4.3 Increased Intracranial Pressure
1 INDICATIONS AND USAGE
NitroMist is contraindicated in patients with increased intracranial pressure.
NitroMist is indicated for acute relief of an attack or acute prophylaxis of angina pectoris due to coronary artery disease.
4.4 Hypersensitivity
2 DOSAGE AND ADMINISTRATION
NitroMist is contraindicated in patients who have shown hypersensitivity to it or to other nitrates or nitrites.
2.1 Recommended Dosage
Skin reactions consistent with hypersensitivity have been observed with organic nitrates.
At the onset of an attack, one metered spray or two metered sprays should be administered on or under the 5 WARNINGS AND PRECAUTIONS
tongue. A spray may be repeated approximately every 5 minutes as needed. If two sprays are used initially, 5.1 Tolerance
the patient may only administer one more spray after waiting 5 minutes. No more than 3 metered sprays are Excessive use may lead to the development of tolerance. Only the smallest number of doses required for recommended within a 15-minute period. If chest pain persists after a total of 3 sprays, prompt medical effective relief of the acute anginal attack should be used [see DOSAGE AND ADMINISTRATION (2)]. attention is recommended. NitroMist may be used prophylactically 5 minutes to 10 minutes before engaging in activities that might precipitate an acute attack.
As tolerance to other forms of nitroglycerin develops, the effect of sublingual nitroglycerin on exercise tolerance, although still observable, is reduced.
2.2 Priming the Container
After an initial priming of 10 sprays, each metered spray of NitroMist delivers 33 mg of solution containing 5.2 Hypotension
400 mcg of nitroglycerin. It will remain adequately primed for 6 weeks. If the product is not used within Severe hypotension, particularly with upright posture, may occur even with small doses of nitroglycerin. The 6 weeks, it can be adequately re-primed with 2 sprays. NitroMist is available in either 230 metered sprays or drug should therefore be used with caution in patients who may be volume-depleted or who, for whatever 90 metered sprays per container, but the total number of available doses depends on the number of sprays reason, are already hypotensive. Hypotension induced by nitroglycerin may be accompanied by paradoxical per use (1 spray or 2 sprays), and the frequency of priming.
bradycardia and increased angina pectoris.
2.3 Administration
The benefits of NitroMist in patients with acute myocardial infarction or congestive heart failure have not During use the patient should rest, ideally in the sitting position. The container should be held vertically with been established. If one elects to use NitroMist in these conditions, careful clinical or hemodynamic the valve head uppermost and the spray orifice as close to the mouth as possible. The dose should preferably monitoring must be used because of the possibility of hypotension and tachycardia.
be sprayed into the mouth on or under the tongue by pressing the button firmly and the mouth should be 5.3 Hypertrophic Cardiomyopathy
closed immediately after each dose. THE SPRAY SHOULD NOT BE INHALED. Patients should be instructed to Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.
familiarize themselves with the position of the spray orifice, which can be identified by the finger rest on top 5.4 Headache
of the valve, in order to facilitate orientation for administration at night.
Nitroglycerin produces dose-related headaches, which may be severe. Tolerance to headaches occurs.
6 ADVERSE REACTIONS
3. If this is the first time using the bottle, press actuator button 10 times to ensure proper dose priming Headache, which may be severe and persistent, may occur immediately after nitroglycerin use. (holding unit away from yourself and others).
6.2 Flushing, drug rash and exfoliative dermatitis have been reported in patients receiving nitrate therapy.
4. Hold container upright with forefinger on top of the actuator button.
6.3 Postural hypotension, as manifest by vertigo, weakness, palpitation, and other symptoms, may develop
5. Open mouth and bring the container as close as possible.
occasionally, particularly in erect, immobile patients. Marked sensitivity to the hypotensive effects of nitrates 6. Press the actuator button firmly with forefinger to release spray(s) onto or under the tongue.
(manifested by nausea, vomiting, weakness, diaphoresis, pallor, and collapse) may occur at therapeutic doses. 7. Release button and close mouth. The medication should not be spit out or the mouth rinsed for 5 minutes to 10 minutes following administration.
6.4 Syncope due to nitrate vasodilatation has been reported.
8. If a second administration is required to obtain relief, repeat steps 4, 5, and 6. No more than 3 metered 7 DRUG INTERACTIONS
sprays can be given within a 15-minute period.
7.1 PDE5 Inhibitors
Administration of NitroMist is contraindicated in patients who are using a selective inhibitor of cyclic 10. If the product is not used for more than 6 weeks, then it can be adequately re-primed with 2 sprays.
guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). PDE5 inhibitors such as The level of the liquid in the container should be periodically checked. While the container is in the upright sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates.
position, if the liquid reaches the top or middle of the hole on the side of the container, one should order The time course and dose dependence of this interaction have not been studied, and use within a few days more. When the liquid reaches the bottom of the hole, the remaining doses will have less than label content.
of one another cannot be recommended. Appropriate supportive care for the severe hypotension has not 3 DOSAGE FORMS AND STRENGTHS
been studied, but it seems reasonable to treat this as a nitrate overdose, with elevation of the extremities Lingual aerosol, 400 mcg per spray is available in either 230 metered sprays or 90 metered sprays per container. and with central volume expansion. The use of any form of nitroglycerin during the early days of acute 4 CONTRAINDICATIONS
myocardial infarction requires particular attention to hemodynamic monitoring and clinical status.
4.1 PDE5 Inhibitor Use
7.2 Antihypertensives
Administration of NitroMist is contraindicated in patients who are using a selective inhibitor of cyclic Patients receiving antihypertensive drugs, beta-adrenergic blockers, and nitrates should be observed for guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), as PDE5 inhibitors such as possible additive hypotensive effects. Marked orthostatic hypotension has been reported when calcium sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates channel blockers and organic nitrates were used concomitantly.
[see DRUG INTERACTIONS (7.1)].
Labetolol blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effects. If 4.2 Severe Anemia
labetolol is used with nitroglycerin in patients with angina pectoris, additional hypotensive effects may occur.
NitroMist is contraindicated in patients with severe anemia.
7.3 Aspirin
12.3 Pharmacokinetics
Coadministration of aspirin and nitroglycerin has been reported to result in increased nitroglycerin maximum Nitroglycerin is rapidly absorbed following lingual spray administration. In a pharmacokinetic study when a single concentrations by as much as 67% and AUC by 73% when administered as a single dose. The vasodilatory 1200 mcg dose (three activations of a 400 mcg dose) of NitroMist was administered to healthy volunteers (n=12), all and hemodynamic effects of nitroglycerin may be enhanced by concomitant administration of aspirin.
subjects had detectable trinitroglycerin plasma levels (mean C 0.8 ng/mL ± 0.7 ng/mL and t of 8 minutes, range 7.4 Tissue-type Plasminogen Activator (t-PA)
4 minutes to 15 minutes) beginning at 2 minutes post-dose and higher levels of the 1,2- (mean C 3.7 ng/mL ± 1 Intravenous administration of nitroglycerin decreases the thrombolytic effect of tissue-type plasminogen ng/mL and t 34 minutes ± 21 minutes, range 15 minutes to 90 minutes) and 1,3-dinitroglycerin metabolites activator (t-PA). Plasma levels of t-PA are reduced when coadministered with nitroglycerin. Therefore, caution (mean C 1 ng/mL ± 0.3 ng/mL and mean t 41 minutes ± 20 minutes, range 20 minutes to 90 minutes). should be observed in patients receiving nitroglycerin during t-PA therapy.
The volume of distribution of nitroglycerin following intravenous administration is 3.3 L/kg. 7.5 Heparin
A liver reductase enzyme is of primary importance in the metabolism of nitroglycerin to glycerol di- and Intravenous nitroglycerin reduces the anticoagulant effect of heparin. Activated partial thromboplastin times mononitrate metabolites and ultimately to glycerol and organic nitrate. Known sites of extrahepatic metabolism (APTT) should be monitored in patients receiving heparin and intravenous nitroglycerin. It is not known if this include red blood cells and vascular walls. In addition to nitroglycerin, 2 major metabolites, 1,2- and effect occurs following single nitroglycerin doses.
1,3-dinitroglycerin are found in plasma. The mean elimination half-life of both 1,2- and 1,3-dinitroglycerin is about 40 minutes. The 1,2- and 1,3-dinitroglycerin metabolites have been reported to possess some 7.6 Ergotamine
pharmacological activity, whereas the glycerol mononitrate metabolites of nitroglycerin are essentially inactive. Oral administration of nitroglycerin markedly decreases the first-pass metabolism of dihydroergotamine and Higher plasma concentrations of the dinitro metabolites, with their nearly 8-fold longer elimination half-lives, subsequently increases its oral bioavailability. Ergotamine is known to precipitate angina pectoris. Therefore, may contribute significantly to the duration of pharmacologic effect.
patients receiving sublingual nitroglycerin should avoid ergotamine and related drugs or be monitored for symptoms of ergotism if this is not possible.
In the above referenced pharmacokinetic study the average initial half-lives (T½α) of nitroglycerin, and its 1,2- and 1,3-dinitroglycerin metabolites were estimated to be 3 minutes, 10 minutes, and 11 minutes, respectively. The 8 USE IN SPECIFIC POPULATIONS
half-life of disappearance of the nitroglycerin (T 8.1 Pregnancy
½β) (5 minutes) was significantly less than the half-life of Pregnancy category C: Animal reproduction and teratogenicity studies have not been conducted with NitroMist ½α) of the 1,2- and 1,3-dinitroglycerin metabolites suggesting the possibility of an additional compartment into which the nitroglycerin disappears from plasma prior to being metabolized into the or nitroglycerin sublingual tablets. It is also not known whether NitroMist can cause fetal harm when dinitroglycerin metabolites. A second indication of this other compartment is that the appearance of nitroglycerin administered to a pregnant woman or can affect reproduction capacity. A teratogenicity study was conducted metabolites in plasma was delayed in some subjects, with zero plasma levels seen for 4 minutes to 6 minutes in the third mating of F generation female rats administered dietary nitroglycerin for gestation day 6 to day 15 after dosing. In some subjects, nitroglycerin metabolites appeared only after nitroglycerin C had been observed.
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 13 NONCLINICAL TOXICOLOGY
finding probably reflects delayed development rather than a potential teratogenic effect, thus indicating no 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
clear evidence of teratogenicity of nitroglycerin.
Animal carcinogenicity studies with sublingually administered or lingual spray nitroglycerin have not been performed.
There are no adequate and well controlled studies in pregnant women. NitroMist should be given to a pregnant 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 incidences of hepatocellular carcinomas was 52% compared to 0% in untreated controls. Incidences of 8.3 Nursing Mothers
testicular tumors were 52% vs 8% in controls. Lifetime dietary administration of up to 1058 mg/kg/day of It is not known whether nitroglycerin is excreted in human milk. Because many drugs are excreted in human nitroglycerin was not tumorigenic in mice.
milk, caution should be exercised when NitroMist is administered to a nursing woman.
Nitroglycerin was found to have reverse mutation activity in the Salmonella typhimurium strain TA1535 (Ames 8.4 Pediatric Use
assay). A similar mutation in S. typhimurium strain was also reported for other NO donors. Nevertheless, there The safety and effectiveness of nitroglycerin in pediatric patients have not been established.
was no evidence of mutagenicity in an in vivo dominant lethal assay with male rats treated with oral doses of 8.5 Geriatric Use
up to about 363 mg/kg/day or in ex vitro cytogenic tests in rat and dog tissues. In vitro cytogenetic assay Clinical studies of NitroMist did not include sufficient numbers of subjects aged 65 and over to determine using Chinese hamster ovary cells showed no chromosomal aberrations.
whether they respond differently from younger subjects. Other reported clinical experience has not identified In a 3-generation reproduction study, rats received dietary nitroglycerin at doses up to about 408 mg/kg/day differences in responses between elderly (greater than or equal to 65 years) and younger (less than 65 years) (males) to 452 mg/kg/day (females) for 5 months (females) or 6 months (males) prior to mating of the patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end F generation with treatment continuing through successive F and F generations. The highest dose was of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of associated with decreased feed intake and body weight gain in both sexes at all matings. No specific effect concomitant disease or other drug therapy.
on the fertility of the F generation was seen. Infertility noted in subsequent generations, however, was 10 OVERDOSAGE
attributed to increased interstitial cell tissue and aspermatogenesis in the high-dose males.
Signs and symptoms of hemodynamic effects: The effects of nitroglycerin overdose are generally the results of 14 CLINICAL STUDIES
nitroglycerin’s capacity to induce vasodilatation, venous pooling, reduced cardiac output, and hypotension. In a randomized, double-blind, single-center, single-administration, placebo-controlled, 4-period cross-over study in These hemodynamic changes may have protean manifestations, including increased intracranial pressure with 30 subjects with stable angina pectoris, statistically significant dose-related increases in exercise tolerance were seen any or all of persistent throbbing headache, confusion, and moderate fever; vertigo; palpitations; tachycardia; following doses of 200 mcg, 400 mcg, and 800 mcg of nitroglycerin delivered by NitroMist compared to placebo.
visual disturbances; nausea and vomiting (possibly with colic and even bloody diarrhea); syncope (especially in the upright posture); dyspnea, later followed by reduced ventilatory effort, diaphoresis, with the skin either 16 HOW SUPPLIED/STORAGE AND HANDLING
flushed or cold and clammy; heart block and bradycardia; paralysis; coma; seizures; and death.
Each box of NitroMist contains one glass bottle coated with red/orange transparent plastic which assists in containing the glass and medication should the bottle be shattered. NitroMist is available as an 8.5 g (Net Content) No specific antagonist to the vasodilator effects of nitroglycerin is known, and no intervention has been of nitroglycerin lingual aerosol that will deliver 230 metered sprays containing 400 mcg of nitroglycerin per subject to controlled study as a therapy of nitroglycerin overdose. Because the hypotension associated with actuation or as a 4.1 g (Net Content) of nitroglycerin lingual aerosol that will deliver 90 metered sprays containing nitroglycerin overdose is the result of venodilatation and arterial hypovolemia, prudent therapy in this 400 mcg of nitroglycerin per actuation.
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 Store at room temperature (25°C, 77°F); excursions permitted to 15° to 30°C (59° to 85°F) without hazard. Treatment of nitroglycerin overdose in these patients may be subtle and difficult, and invasive monitoring may be required.
NitroMist contains a highly flammable propellant (butane). Do not forcefully open a NitroMist bottle, do not Methemoglobinemia: Methemoglobinemia has been rarely reported with organic nitrates. The diagnosis have the container burned after use, and do not spray directly toward flames.
should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate arterial PO . Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air.
17 PATIENT COUNSELING INFORMATION
17.1 Interaction with PDE5 Inhibitors
If methemoglobinemia is present, intravenous administration of methylene blue, 1 mg/kg to 2 mg/kg of body NitroMist should not be used in patients who are using medications for erectile dysfunction such as sildenafil, vardenafil, and tadalafil. These products have been shown to increase the hypotensive effects of 11 DESCRIPTION
Nitroglycerin, an organic nitrate, is a vasodilator which has effects on both arteries and veins. The chemical 17.2 Administration
name for nitroglycerin is 1,2,3-propanetriol trinitrate (C H N O ). The compound has a molecular weight of Patients should be instructed that prior to initial use of NitroMist Lingual aerosol, the pump must be primed by pressing the actuator button 10 times to ensure proper dose priming. If the product is not used for more CH –ONO
than 6 weeks, the bottle can be adequately re-primed with 2 sprays. CH–ONO2
NitroMist is meant to be sprayed on or under the tongue at the beginning of angina or to prevent an angina attack. Treatment with nitroglycerin products such as NitroMist may be associated with lightheadedness on CH –ONO
standing, especially just after rising from a laying or seated position. This effect may be more frequent in NitroMist (nitroglycerin) lingual aerosol is a metered-dose spray containing 230 metered sprays or 90 patients who have consumed alcohol, since alcohol use contributes to hypotension. If possible, patients metered sprays of nitroglycerin per container. This product delivers 400 mcg of nitroglycerin per actuation in the should be seated when taking NitroMist. This reduces the likelihood of falling due to lightheadedness or form of spray droplets on or under the tongue. Inactive ingredients: caprylic/capric diglycerol succinate, dizziness [see DOSAGE AND ADMINISTRATION (2.3)].
peppermint oil, L(-)-menthol, n-butane.
17.3 Headache
12 CLINICAL PHARMACOLOGY
Headaches can sometimes accompany treatment with nitroglycerin. In patients who get these headaches, 12.1 Mechanism of Action
the headaches may indicate activity of the drug. Tolerance to headaches develops.
Nitroglycerin forms free radical nitric oxide (NO), which activates guanylate cyclase, resulting in an increase 17.4 Flushing
of guanosine 3’,5’-monophosphate (cyclic GMP) in smooth muscle and other tissues. This eventually leads to Flushing, drug rash and exfoliative dermatitis have been reported in patients receiving nitrate therapy. dephosphorylation of myosin light chains, which regulates the contractile state in smooth muscle and results 17.5 Container information
The NitroMist bottle should not be forcefully opened. Because NitroMist contains a highly flammable 12.2 Pharmacodynamics
propellant (butane), do not have the container burned after use and do not spray directly towards flames.
The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle. Although venous effects predominate, nitroglycerin produces, in a dose-related manner, dilation of both arterial and While the container is in the upright position, if the liquid reaches the top to middle of the hole on the side of venous beds. Dilation of the postcapillary vessels, including large veins, promotes peripheral pooling of the container, a new supply should be obtained. When the liquid reaches the bottom of the hole, the blood, decreases venous return to the heart, and reduces left ventricular end-diastolic pressure (preload). remaining doses will have less than label content.
Nitroglycerin also produces arteriolar relaxation, thereby reducing peripheral vascular resistance and arterial pressure (after load), and dilates large epicardial coronary arteries; however, the extent to which this latter effect contributes to the relief of exertional angina is unclear.
Therapeutic doses of nitroglycerin may reduce systolic, diastolic and mean arterial blood pressure. Effective coronary perfusion pressure is usually maintained, but can be compromised if blood pressure falls excessively or increased heart rate decreases diastolic filling time.
Manufactured for Akrimax Pharmaceuticals, LLC, Cranford, NJ 07016
Elevated central venous and pulmonary capillary wedge pressures, and pulmonary and systemic vascular By Dynamit Nobel GmbH, Leverkusen, Germany
resistance are also reduced by nitroglycerin therapy. Heart rate is usually slightly increased, presumably a reflex response to the fall in blood pressure. Cardiac index may be increased, decreased, or unchanged. Myocardial Marketed and Distributed by:
oxygen consumption or demand (as measured by the pressure-rate product, tension-time index, and stroke-work Akrimax Pharmaceuticals, LLC
index) is decreased and a more favorable supply-demand ratio can be achieved. Patients with elevated left Cranford, NJ 07016 USA
ventricular filling pressure and increased systemic vascular resistance in association with a depressed cardiac index are likely to experience an improvement in cardiac index. In contrast, when filling pressures and cardiac NitroMist is a registered trademark of
index are normal, cardiac index may be slightly reduced following nitroglycerin administration.
NovaDel Pharma Inc., used by permission.

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