Nitrolingual

Dosage Forms And Strengths

Lingual spray, 400 mcg per spray available in either 60 or 200 metered sprays per container.

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).

Note: Nitrolingual Pumpspray contains 20% alcohol. Do not forcefully open or burn container after use. Do not spray toward flames.

Manufactured for Arbor Pharmaceuticals, LLC. Atlanta, GA 30328. by G. Pohl-Boskamp GmbH & Co. KG, 25551 Hohenlockstedt, Germany. Revised: Jan 2015

Nitrolingual Pumpspray is indicated for acute relief of an attack or prophylaxis of angina pectoris due to coronary artery disease.

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.

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 usedwithin 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.

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.

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.

PDE-5-Inhibitors And sGC-Stimulators

Do not use Nitrolingual Pumpspray in patients who are taking PDE-5 inhibitors, such as avanafil, sildenafil, tadalafil, or vardenafil. Concomitant use can cause severe hypotension, syncope, or myocardial ischemia. Do not use Nitrolingual Pumpspray in patients who are taking the soluble guanylate cyclase (sGC) stimulator riociguat. Concomitant use can cause hypotension.

Severe Anemia

Nitrolingual Pumpspray is contraindicated in patients with severe anemia (large doses of nitroglycerin may cause oxidation of hemoglobin to methemoglobin and could exacerbate anemia).

Increased Intracranial Pressure

Nitrolingual Pumpspray may precipitate or aggravate increased intracranial pressure and thus should not be used in patients with possible increased intracranial pressure (e. g. cerebral hemorrhage or traumatic brain injury).

Hypersensitivity

Nitrolingual Pumpspray is contraindicated in patients who are allergic to nitroglycerin, other nitrates or nitrites or any excipient.

Circulatory Failure And Shock

Nitrolingual Pumpspray is contraindicated in patients with acute circulatory failure or shock.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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.

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.

Hypertrophic Obstructive Cardiomyopathy

Nitrate therapy may aggravate the angina caused by hypertrophic obstructive cardiomyopathy.

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.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Instructions for Use)

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Animal carcinogenesis studies with sublingual nitroglycerin have not been performed.

Rats receiving up to 434 mg/kg/day of dietary nitroglycerin for 2 years developed doserelated fibrotic and neoplastic changes in liver, including carcinomas, and interstitial cell tumors in testes. At high dose, the incidences of hepatocellular carcinomas in both sexes were 52% vs. 0% in controls, and 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 weakly mutagenic in Ames tests performed in two different laboratories. There was no evidence of mutagenicity in an in vivo dominant lethal assay with male rats treated with doses up to about 363 mg/kg/day, p.o., or in in vitro cytogenic tests in rat and dog tissues and for chromosomal aberration in Chinese hamster ovary cells.

In a three-generation reproduction study, rats received dietary nitroglycerin at doses up to about 434 mg/kg/day for six months prior to mating of the F0 generation with treatment continuing through successive F1 and F2 generations. The high 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 highdose males. In this three-generation study there was no clear evidence of teratogenicity.

Use In Specific Populations

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.

Nursing Mothers

It is not known whether nitroglycerin is excreted in human milk.

Pediatric Use

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

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.

Aspirin: Coadministration of nitroglycerin with high dose aspirin (1000 mg) results in increased exposure to nitroglycerin. The vasodilatory and hemodynamic effects of nitroglycerin may be enhanced by concomitant administration of nitroglycerin with high dose aspirin.

Tissue-type plasminogen activator (t-PA): Concomitant administration of t-PA and intravenous nitroglycerin has been shown to reduce plasma levels of t-PA and its thrombolytic effect.

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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse reactions occurring at a frequency greater than 2% and greater than placebo included: headache, dizziness, and paresthesia.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Nitrolingual Pumpspray and other nitroglycerin drugs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure.

Neurologic: weakness, drowsiness

Dermatologic: cutaneous vasodilation, flushing, drug rash, exfoliative dermatitits

Gastrointestinal: nausea, vomiting

Respiratory: transient hypoxemia

Cardiovascular: tachycardia,

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.

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.

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.

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 areessentially 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 a pharmacokinetic study when a single 0.8 mg dose of Nitrolingual Pumpspray was administered to healthy volunteers (n = 24), the mean Cmax and tmax were 1.041pg/mL and 7.5 minutes, respectively. Additionally, in these subjects the mean area under the curve (AUC) was 12.769 pg/mL · min.

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