Ntr-087 physician pi march2011_pg

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 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 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, 230 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: 03/2011
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 or two metered sprays should be administered on or under the tongue. A spray 5 WARNINGS AND PRECAUTIONS
may be repeated approximately every 5 minutes as needed. If two sprays are used initially, the patient may 5.1 Tolerance
only administer one more spray after waiting 5 minutes. No more than 3 metered sprays are recommended Excessive use may lead to the development of tolerance. Only the smallest number of doses required for within a 15-minute period. If chest pain persists after a total of 3 sprays, prompt medical attention is effective relief of the acute anginal attack should be used [see DOSAGE AND ADMINISTRATION (2)]. recommended. NitroMist may be used prophylactically 5 to 10 minutes before engaging in activities that 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 400 mcg 5.2 Hypotension
of nitroglycerin. It will remain adequately primed for 6 weeks. If the product is not used within 6 weeks, it can Severe hypotension, particularly with upright posture, may occur even with small doses of nitroglycerin. The be adequately re-primed with 2 sprays. There are 230 metered sprays per container, but the total number of drug should therefore be used with caution in patients who may be volume-depleted or who, for whatever available doses depends on the number of sprays per use (1 or 2 sprays), and the frequency of priming.
reason, are already hypotensive. Hypotension induced by nitroglycerin may be accompanied by paradoxical bradycardia and increased angina pectoris.
2.3 Administration
During use the patient should rest, ideally in the sitting position. The container should be held vertically with The benefits of NitroMist in patients with acute myocardial infarction or congestive heart failure have not the valve head uppermost and the spray orifice as close to the mouth as possible. The dose should preferably been established. If one elects to use NitroMist in these conditions, careful clinical or hemodynamic be sprayed into the mouth on or under the tongue by pressing the button firmly and the mouth should be monitoring must be used because of the possibility of hypotension and tachycardia.
closed immediately after each dose. THE SPRAY SHOULD NOT BE INHALED. Patients should be instructed to 5.3 Hypertrophic Cardiomyopathy
familiarize themselves with the position of the spray orifice, which can be identified by the finger rest on top Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.
of the valve, in order to facilitate orientation for administration at night.
5.4 Headache
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 (holding unit away from yourself and others).
Headache, which may be severe and persistent, may occur immediately after nitroglycerin use. 4. Hold container upright with forefinger on top of the actuator button.
6.2 Flushing, drug rash and exfoliative dermatitis have been reported in patients receiving nitrate therapy.
5. Open mouth and bring the container as close as possible.
6.3 Postural hypotension, as manifest by vertigo, weakness, palpitation, and other symptoms, may develop
6. Press the actuator button firmly with forefinger to release spray(s) onto or under the tongue.
occasionally, particularly in erect, immobile patients. Marked sensitivity to the hypotensive effects of nitrates 7. Release button and close mouth. The medication should not be spit out or the mouth rinsed (manifested by nausea, vomiting, weakness, diaphoresis, pallor, and collapse) may occur at therapeutic doses. for 5 to 10 minutes following administration.
8. If a second administration is required to obtain relief, repeat steps 4, 5, and 6. No more than 3 metered 6.4 Syncope due to nitrate vasodilatation has been reported.
sprays can be given within a 15-minute period.
7 DRUG INTERACTIONS
7.1 PDE5 Inhibitors
10. If the product is not used for more than 6 weeks, then it can be adequately re-primed with 2 sprays.
Administration of NitroMist is contraindicated in patients who are using a selective inhibitor of cyclic The level of the liquid in the container should be periodically checked. While the container is in the upright guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). PDE5 inhibitors such as position, if the liquid reaches the top or middle of the hole on the side of the container, one should order sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates.
more. When the liquid reaches the bottom of the hole, the remaining doses will have less than label content.
The time course and dose dependence of this interaction have not been studied, and use within a few days 3 DOSAGE FORMS AND STRENGTHS
of one another cannot be recommended. Appropriate supportive care for the severe hypotension has not Lingual aerosol, 400 mcg per spray, 230 metered sprays per container.
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 4 CONTRAINDICATIONS
myocardial infarction requires particular attention to hemodynamic monitoring and clinical status.
4.1 PDE5 inhibitor use
Administration of NitroMist is contraindicated in patients who are using a selective inhibitor of cyclic 7.2 Antihypertensives
guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), as PDE5 inhibitors such as Patients receiving antihypertensive drugs, beta-adrenergic blockers, and nitrates should be observed for sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates possible additive hypotensive effects. Marked orthostatic hypotension has been reported when calcium [see DRUG INTERACTIONS (7.1)].
channel blockers and organic nitrates were used concomitantly.
4.2 Severe anemia
Labetolol blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effects. If NitroMist is contraindicated in patients with severe anemia.
labetolol is used with nitroglycerin in patients with angina pectoris, additional hypotensive effects may occur.
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 concentrations by as much as 67% and AUC by 73% when administered as a single dose. The vasodilatory single 1200 mcg dose (three activations of a 400 mcg dose) of NitroMist was administered to healthy and hemodynamic effects of nitroglycerin may be enhanced by concomitant administration of aspirin.
volunteers (n=12), all subjects had detectable trinitroglycerin plasma levels (mean C 0.8 ± 0.7 ng/mL and 7.4 Tissue-type Plasminogen Activator (t-PA)
t of 8 minutes, range 4 to 15 minutes) beginning at 2 minutes post-dose and higher levels of the 1,2- Intravenous administration of nitroglycerin decreases the thrombolytic effect of tissue-type plasminogen (mean C 3.7 ± 1 ng/mL and t 34 ± 21 minutes, range 15 to 90 minutes) and 1,3-dinitroglycerin activator (t-PA). Plasma levels of t-PA are reduced when coadministered with nitroglycerin. Therefore, caution metabolites (mean C 1 ± 0.3 ng/mL and mean t 41 ± 20 minutes, range 20 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 (T ) of nitroglycerin, and its 1,2- and 1,3-dinitroglycerin metabolites were estimated to be 3, 10, and 11 minutes, respectively. The half-life of 8 USE IN SPECIFIC POPULATIONS
disappearance of the nitroglycerin (T ) (5 minutes) was significantly less than the half-life of appearance (T ) of 8.1 Pregnancy
the 1,2- and 1,3-dinitroglycerin metabolites suggesting the possibility of an additional compartment into which Pregnancy category C: Animal reproduction and teratogenicity studies have not been conducted with NitroMist the nitroglycerin disappears from plasma prior to being metabolized into the dinitroglycerin metabolites. A or nitroglycerin sublingual tablets. It is also not known whether NitroMist can cause fetal harm when second indication of this other compartment is that the appearance of nitroglycerin metabolites in plasma was administered to a pregnant woman or can affect reproduction capacity. A teratogenicity study was conducted delayed in some subjects, with zero plasma levels seen for 4-6 minutes after dosing. In some subjects, in the third mating of F generation female rats administered dietary nitroglycerin for gestation days 6 to 15 at nitroglycerin metabolites appeared only after nitroglycerin C had been observed.
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 (≥65 years) and younger (<65 years) patients. In general, dose (males) to 452 mg/kg/day (females) for 5 months (females) or 6 months (males) prior to mating of the selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, F generation with treatment continuing through successive F and F generations. The highest dose was reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease associated with decreased feed intake and body weight gain in both sexes at all matings. No specific effect 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 These hemodynamic changes may have protean manifestations, including increased intracranial pressure with in 30 subjects with stable angina pectoris, statistically significant dose-related increases in exercise tolerance were any or all of persistent throbbing headache, confusion, and moderate fever; vertigo; palpitations; tachycardia; seen following doses of 200, 400, 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. Each unit contains 8.5 g (Net Content) of No specific antagonist to the vasodilator effects of nitroglycerin is known, and no intervention has been nitroglycerin lingual aerosol and will deliver 230 metered sprays containing 400 mcg of nitroglycerin per actuation.
subject to controlled study as a therapy of nitroglycerin overdose. Because the 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. Passive elevation of the patient’s legs may be sufficient, but intravenous infusion of normal saline or similar fluid may also be necessary.
Store at room temperature (25°C, 77°F); excursions permitted to 15-30°C (59 - 85°F) 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 NitroMist contains a highly flammable propellant (butane). Do not forcefully open a NitroMist bottle, do not without hazard. Treatment of nitroglycerin overdose in these patients may be subtle and difficult, and have the container burned after use, and do not spray directly toward flames.
invasive monitoring may be required.
17 PATIENT COUNSELING INFORMATION
Methemoglobinemia: Methemoglobinemia has been rarely reported with organic nitrates. The diagnosis 17.1 Interaction with PDE5 inhibitors
should be suspected in patients who exhibit signs of impaired oxygen delivery despite adequate arterial PO . NitroMist should not be used in patients who are using medications for erectile dysfunction such as Classically, methemoglobinemic blood is described as chocolate brown, without color change on exposure to air.
sildenafil, vardenafil, and tadalafil. These products have been shown to increase the hypotensive effects of If methemoglobinemia is present, intravenous administration of methylene blue, 1 to 2 mg/kg of body weight, 17.2 Administration
Patients should be instructed that prior to initial use of NitroMist Lingual aerosol, the pump must be primed 11 DESCRIPTION
by pressing the actuator button 10 times to ensure proper dose priming. If the product is not used for more Nitroglycerin, an organic nitrate, is a vasodilator which has effects on both arteries and veins. The chemical than 6 weeks, the bottle can be adequately reprimed with 2 sprays. name for nitroglycerin is 1,2,3-propanetriol trinitrate (C H N O ). The compound has a molecular weight of NitroMist is meant to be sprayed on or under the tongue at the beginning of angina or to prevent an angina CH –ONO
attack. Treatment with nitroglycerin products such as NitroMist may be associated with lightheadedness on standing, especially just after rising from a laying or seated position. This effect may be more frequent in CH–ONO2
patients who have consumed alcohol, since alcohol use contributes to hypotension. If possible, patients should be seated when taking NitroMist. This reduces the likelihood of falling due to lightheadedness or CH –ONO
dizziness [see DOSAGE AND ADMINISTRATION (2.3)].
NitroMist (nitroglycerin) lingual aerosol is a metered-dose spray containing 230 metered sprays of nitroglycerin. This product delivers 400 mcg of nitroglycerin per actuation in the form of spray droplets on or under 17.3 Headache
the tongue. Inactive ingredients: caprylic/capric diglycerol succinate, peppermint oil, L(-)-menthol, n-butane.
Headaches can sometimes accompany treatment with nitroglycerin. In patients who get these headaches, the headaches may indicate activity of the drug. Tolerance to headaches develops.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
17.4 Flushing
Nitroglycerin forms free radical nitric oxide (NO), which activates guanylate cyclase, resulting in an increase Flushing, drug rash and exfoliative dermatitis have been reported in patients receiving nitrate therapy. of guanosine 3’,5’-monophosphate (cyclic GMP) in smooth muscle and other tissues. This eventually leads to 17.5 Container information
dephosphorylation of myosin light chains, which regulates the contractile state in smooth muscle and results The NitroMist bottle should not be forcefully opened. Because NitroMist contains a highly flammable propellant (butane), do not have the container burned after use and do not spray directly towards flames.
12.2 Pharmacodynamics
While the container is in the upright position, if the liquid reaches the top to middle of the hole on the side of The principal pharmacological action of nitroglycerin is relaxation of vascular smooth muscle. Although the container, a new supply should be obtained. When the liquid reaches the bottom of the hole, the venous effects predominate, nitroglycerin produces, in a dose-related manner, dilation of both arterial and remaining doses will have less than label content.
venous beds. Dilation of the postcapillary vessels, including large veins, promotes peripheral pooling of blood, decreases venous return to the heart, and reduces left ventricular end-diastolic pressure (preload). 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 Manufactured for Akrimax Pharmaceuticals, LLC, Cranford, NJ 07016
excessively or increased heart rate decreases diastolic filling time.
By Dynamit Nobel GmbH, Leverkusen, Germany
Elevated central venous and pulmonary capillary wedge pressures, and pulmonary and systemic vascular resistance are also reduced by nitroglycerin therapy. Heart rate is usually slightly increased, presumably a reflex Marketed and Distributed by:
response to the fall in blood pressure. Cardiac index may be increased, decreased, or unchanged. Myocardial Akrimax Pharmaceuticals, LLC
oxygen consumption or demand (as measured by the pressure-rate product, tension-time index, and stroke-work Cranford, NJ 07016 USA
index) is decreased and a more favorable supply-demand ratio can be achieved. Patients with elevated left ventricular filling pressure and increased systemic vascular resistance in association with a depressed cardiac NitroMist is a registered trademark of
index are likely to experience an improvement in cardiac index. In contrast, when filling pressures and cardiac NovaDel Pharma Inc., used by permission.
index are normal, cardiac index may be slightly reduced following nitroglycerin administration.

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