NitroMist (Page 3 of 4)

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 Cmax 0.8 ng/mL ± 0.7 ng/mL and tmax of 8 minutes, range 4 minutes to 15 minutes) beginning at 2 minutes post-dose and higher levels of the 1,2- (mean Cmax 3.7 ng/mL ± 1 ng/mL and tmax 34 minutes ± 21 minutes, range 15 minutes to 90 minutes) and 1,3-dinitroglycerin metabolites (mean Cmax 1 ng/mL ± 0.3 ng/mL and mean tmax 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 (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 half-life of disappearance of the nitroglycerin (T½β ) (5 minutes) was significantly less than the half-life of appearance (T½α ) 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 Cmax had been observed.

13 NONCLINICAL TOXICOLOGY

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 F0 generation with treatment continuing through successive F1 and F2 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 F0 generation was seen. Infertility noted in subsequent generations, however, was attributed to increased interstitial cell tissue and aspermatogenesis in the high-dose males.

14 CLINICAL STUDIES

In a randomized, double-blind, single-center, single-administration, placebo-controlled, 4-period cross-over study in 30 subjects with stable angina pectoris, statistically significant dose-related increases in exercise tolerance were seen following doses of 200 mcg, 400 mcg, and 800 mcg of nitroglycerin delivered by NitroMist compared to placebo.

16 H OW SUPPLIED/STORAGE AND HANDLING

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) of nitroglycerin lingual aerosol that will deliver 230 metered sprays containing 400 mcg of nitroglycerin per actuation or as a 4.1 g (Net Content) of nitroglycerin lingual aerosol that will deliver 90 metered sprays containing 400 mcg of nitroglycerin per actuation.

230 metered sprays: NDC 76299-430-08
90 metered sprays: NDC 76299-430-04

  • Storage
    Store at room temperature (25° C, 77° F); excursions permitted to 15° to 30° C (59° to 85° F)
  • Handling
    NitroMist contains a highly flammable propellant (butane). Do not forcefully open a NitroMist bottle, do not have the container burned after use, and do not spray directly toward flames.

17 PATIENT COUNSELING INFORMATION

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 Mist Pharmaceuticals, LLC
Cranford, NJ 07016
by Dynamit Nobel GmbH, Leverkusen, Germany

Marketed and Distributed by: Mist Pharmaceuticals, LLC
Cranford, NJ 07016 USA

NitroMist is a registered trademark of Mist Pharmaceuticals

143F002Revised 02/2018

Patient Instructions for Use
(click image for full-size original)

Patient Instructions for Use
(click image for full-size original)

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