2.1 Recommended Dosage

At the onset of an attack, one metered spray or two metered sprays should be administered on or under the tongue. A spray may be repeated approximately every 5 minutes as needed. If two sprays are used initially, the patient may only administer one more spray after waiting 5 minutes. No more than 3 metered sprays are recommended within a 15-minute period. If chest pain persists after a total of 3 sprays, prompt medical attention is recommended. NitroMist may be used prophylactically 5 minutes to 10 minutes before engaging in activities that might precipitate an acute attack.

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 of nitroglycerin. It will remain adequately primed for 6 weeks. If the product is not used within 6 weeks, it can be adequately re-primed with 2 sprays. NitroMist is available in either 230 metered sprays or 90 metered sprays per container, but the total number of available doses depends on the number of sprays per use (1 spray or 2 sprays), and the frequency of priming.

2.3 Administration

During use the patient should rest, ideally in the sitting position. The container should be held vertically with the valve head uppermost and the spray orifice as close to the mouth as possible. The dose should preferably be sprayed into the mouth on or under the tongue by pressing the button firmly and the mouth should be closed immediately after each dose. THE SPRAY SHOULD NOT BE INHALED. Patients should be instructed 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.

1. Do not shake container.
   
2. Remove plastic cap.
   
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).
   
4. Hold container upright with forefinger on top of the actuator button.
   
5. Open mouth and bring the container as close as possible.
   
6. Press the actuator button firmly with forefinger to release spray(s) onto or under the tongue.
   
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.
   
8. If a second administration is required to obtain relief, repeat steps 4, 5, and 6. No more than 3 metered sprays can be given within a 15-minute period.
   
9. Replace plastic cover.
   
10. If the product is not used for more than 6 weeks, then it can be adequately re-primed with 2 sprays.

The level of the liquid in the container should be periodically checked. While the container is in the upright position, if the liquid reaches the top or middle of the hole on the side of the container, one should order more. When the liquid reaches the bottom of the hole, the remaining doses will have less than label content.

4.1 PDE5 Inhibitor Use

Administration of NitroMist is contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), as PDE5 inhibitors such as sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates. Do not use NitroMist in patients who are taking the soluble guanylate cyclase (sGC) stimulator riociguat. Concomitant use can cause hypotension. [see DRUG INTERACTIONS (7.1)].

4.2 Severe Anemia

NitroMist is contraindicated in patients with severe anemia.

4.3 Increased Intracranial Pressure

NitroMist is contraindicated in patients with increased intracranial pressure.

4.4 Hypersensitivity

NitroMist is contraindicated in patients who have shown hypersensitivity to it or to other nitrates or nitrites. Skin reactions consistent with hypersensitivity have been observed with organic nitrates.

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 anginal attack should be used [see DOSAGE AND ADMINISTRATION (2)].

As tolerance to other forms of nitroglycerin develops, the effect of sublingual nitroglycerin on exercise tolerance, although still observable, is reduced.

5.2 Hypotension

Severe hypotension, particularly with upright posture, may occur even with small doses of nitroglycerin. The drug should therefore be used with caution in patients who may be volume-depleted or who, for whatever reason, are already hypotensive. Hypotension induced by nitroglycerin may be accompanied by paradoxical bradycardia and increased angina pectoris.

The benefits of NitroMist in patients with acute myocardial infarction or congestive heart failure have not been established. If one elects to use NitroMist in these conditions, careful clinical or hemodynamic monitoring must be used because of the possibility of hypotension and tachycardia.

5.3 Hypertrophic Cardiomyopathy

Nitrate therapy may aggravate the angina caused by hypertrophic cardiomyopathy.

5.4 Headache

Nitroglycerin produces dose-related headaches, which may be severe. Tolerance to headaches occurs.

6.1 Headache

Headache, which may be severe and persistent, may occur immediately after nitroglycerin use.

6.2 Flushing

Flushing, drug rash and exfoliative dermatitis have been reported in patients receiving nitrate therapy.

6.3 Hypotension

Postural hypotension, as manifest by vertigo, weakness, palpitation, and other symptoms, may develop occasionally, particularly in erect, immobile patients. Marked sensitivity to the hypotensive effects of nitrates (manifested by nausea, vomiting, weakness, diaphoresis, pallor, and collapse) may occur at therapeutic doses.

6.4 Syncope

Syncope due to nitrate vasodilatation has been reported.

7.1 PDE5 Inhibitors

Administration of NitroMist is contraindicated in patients who are using a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). PDE5 inhibitors such as sildenafil, vardenafil, and tadalafil have been shown to potentiate the hypotensive effects of organic nitrates. Do not use NitroMist in patients who are taking the soluble guanylate cyclase (sGC) stimulator riociguat. Concomitant use may result in severe hypotension, syncope, or myocardial ischemia.

The time course and dose dependence of this interaction 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. The use of any form of nitroglycerin during the early days of acute myocardial infarction requires particular attention to hemodynamic monitoring and clinical status.

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.

Labetolol blunts the reflex tachycardia produced by nitroglycerin without preventing its hypotensive effects. If labetolol is used with nitroglycerin in patients with angina pectoris, additional hypotensive effects may occur.

7.3 Aspirin

Coadministration of aspirin 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 vasodilatory and hemodynamic effects of nitroglycerin 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 nitroglycerin during t-PA therapy.

7.5 Heparin

Intravenous nitroglycerin reduces the anticoagulant effect of heparin. Activated partial thromboplastin times (APTT) should be monitored in patients receiving heparin and intravenous nitroglycerin. It is not known if this effect occurs following single nitroglycerin doses.

7.6 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.

8.1 Pregnancy

Risk Summary

Limited published data on the use of nitroglycerin are insufficient to determine a drug associated risk of major birth defects or miscarriage. In animal reproduction studies, there were no adverse developmental effects when nitroglycerin was administered intravenously to rabbits or intraperitoneally to rats during organogenesis at doses greater than 64-times the human dose [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 – 4% and 15 – 20%, respectively.

Data

Animal Data

No embryotoxic or postnatal development effects were observed with transdermal application in pregnant rabbits and rats at doses up to 240 mg/kg/day for 13 days, at intraperitoneal doses in pregnant rats up to 20 mg/kg/day for 11 days, and at intravenous doses in pregnant rabbits up to 4 mg/kg/day for 13 days.

8.2 Lactation

Risk Summary

Sublingual nitroglycerin has not been studied in lactating women. It is not known if nitroglycerin is present in human milk, or if nitroglycerin has effects on milk production or the breastfed child. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s need for nitroglycerin and any potential adverse effects on the breastfed child from nitroglycerin or from the underlying maternal condition.

8.3 Pediatric Use

The safety and effectiveness of nitroglycerin in pediatric patients have not been established.

8.4 Geriatric Use

Clinical studies of NitroMist 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 be cautious, usually starting 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.

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.

12.2 Pharmacodynamics

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 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 excessively or increased heart rate decreases diastolic filling time.

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 response to the fall in blood pressure. Cardiac index may be increased, decreased, or unchanged. Myocardial oxygen consumption or demand (as measured by the pressure-rate product, tension-time index, and stroke-work 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 index are likely to experience an improvement in cardiac index. In contrast, when filling pressures and cardiac index are normal, cardiac index may be slightly reduced following nitroglycerin administration.

12.3 Pharmacokinetics

Nitroglycerin is rapidly absorbed following lingual spray administration. In a pharmacokinetic study when a single 1200 mcg dose (three activations of a 400 mcg dose) of NitroMist was administered to healthy volunteers (n=12), all subjects had detectable trinitroglycerin plasma levels (mean C max 0.8 ng/mL ± 0.7 ng/mL and t max of 8 minutes, range 4 minutes to 15 minutes) beginning at 2 minutes post-dose and higher levels of the 1,2- (mean C max 3.7 ng/mL ± 1 ng/mL and t max 34 minutes ± 21 minutes, range 15 minutes to 90 minutes) and 1,3-dinitroglycerin metabolites (mean C max 1 ng/mL ± 0.3 ng/mL and mean t max 41 minutes ± 20 minutes, range 20 minutes to 90 minutes).

The volume of distribution of nitroglycerin following intravenous administration is 3.3 L/kg.

A liver reductase enzyme is of primary importance in the metabolism of nitroglycerin 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, 2 major metabolites, 1,2- and 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 pharmacological activity, whereas the glycerol mononitrate metabolites of nitroglycerin are essentially inactive. Higher plasma concentrations of the dinitro metabolites, with their nearly 8-fold longer elimination half-lives, may contribute significantly to the duration of pharmacologic effect.

In the above referenced pharmacokinetic study the average initial half-lives (T ½α) of nitroglycerin, and its 1,2- and 1,3-dinitroglycerin metabolites were estimated to be 3 minutes, 10 minutes, and 11 minutes, respectively. The half-life of disappearance of the nitroglycerin (T ½β) (5 minutes) was significantly less than the half-life of appearance (T 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 dinitroglycerin metabolites. A second indication of this other compartment is that the appearance of nitroglycerin metabolites in plasma was delayed in some subjects, with zero plasma levels seen for 4 minutes to 6 minutes after dosing. In some subjects, nitroglycerin metabolites appeared only after nitroglycerin C max had been observed.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal carcinogenicity studies with sublingually administered or lingual spray 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 incidences of hepatocellular carcinomas was 52% compared to 0% in untreated controls. 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 found to have reverse mutation activity in the Salmonella typhimurium strain TA1535 (Ames assay). A similar mutation in S. typhimurium strain was also reported for other NO donors. Nevertheless, there was no evidence of mutagenicity in an in vivo dominant lethal assay with male rats treated with oral doses of up to about 363 mg/kg/day or in ex vitro cytogenic tests in rat and dog tissues. In vitro cytogenetic assay using Chinese hamster ovary cells showed no chromosomal aberrations.

In a 3-generation reproduction study, rats received dietary nitroglycerin at doses up to about 408 mg/kg/day (males) to 452 mg/kg/day (females) for 5 months (females) or 6 months (males) prior to mating of the F 0 generation with treatment continuing through successive F 1 and F 2 generations. The highest 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 F 0 generation was seen. Infertility noted in subsequent generations, however, was attributed to increased interstitial cell tissue and aspermatogenesis in the high-dose males.

17.1 Interaction with PDE5 Inhibitors

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 nitrate drugs such as NitroMist.

17.2 Administration

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 than 6 weeks, the bottle can be adequately re-primed with 2 sprays.

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 standing, especially just after rising from a laying or seated position. This effect may be more frequent in 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 dizziness [ see DOSAGE AND ADMINISTRATION (2.3)].

17.3 Headache

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.

17.4 Flushing

Flushing, drug rash and exfoliative dermatitis have been reported in patients receiving nitrate therapy.

17.5 Container information

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.

While the container is in the upright position, if the liquid reaches the top to middle of the hole on the side of the container, a new supply should be obtained. When the liquid reaches the bottom of the hole, the remaining doses will have less than label content .

Manufactured for Evus Pharmaceuticals, LLC

Scottsdale, AZ 85258 USA

by Dynamit Nobel GmbH, Leverkusen, Germany

Marketed and Distributed by: Evus Pharmaceuticals, LLC

Scottsdale, AZ 85258 USA

NitroMist is a registered trademark of Evus Pharmaceuticals

141110

143F003

Revised 09/2019