Formoterol Fumarate (Page 4 of 7)

10 OVERDOSAGE

The expected signs and symptoms with overdosage of formoterol fumarate inhalation solution are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms listed under ADVERSE REACTIONS. Signs and symptoms may include angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, and metabolic acidosis. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of formoterol fumarate inhalation solution.

Treatment of overdosage consists of discontinuation of formoterol fumarate inhalation solution together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of formoterol fumarate inhalation solution. Cardiac monitoring is recommended in cases of overdosage.

For additional information about overdose treatment, call a poison control center (1-800-222-1222).

11 DESCRIPTION

Formoterol fumarate inhalation solution is supplied as 2 mL of formoterol fumarate inhalation solution packaged in a 3 mL single-dose low-density polyethylene vial and overwrapped in a foil pouch. Each vial contains 2 mL of a clear, colorless solution composed of formoterol fumarate dihydrate, USP equivalent to 20 mcg of formoterol fumarate in an isotonic, sterile aqueous solution containing sodium chloride, water, pH adjusted to 5.0 with citric acid and sodium citrate.

The active component of formoterol fumarate inhalation solution is formoterol fumarate dihydrate, USP, a racemate. Formoterol fumarate dihydrate, USP is a beta2 -adrenergic bronchodilator. Its chemical name is (±)-2´-Hydroxy-5´-[(R *)-1-hydroxy-2-[[(R *)-p -methoxy-α -methylphenethyl]amino]ethyl]formanilide fumarate (2:1) (salt), dihydrate; its structural formula is:

1
(click image for full-size original)

Formoterol fumarate dihydrate, USP has a molecular weight of 840.91 and its molecular formula is (C19 H24 N2 O4 )2 •C4 H4 O4 •2H2 O. Formoterol fumarate dihydrate, USP is a white to yellowish crystalline powder, which is freely soluble in glacial acetic acid, soluble in methanol, sparingly soluble in ethanol and isopropanol, slightly soluble in water, and practically insoluble in acetone, ethyl acetate, and diethyl ether.

Formoterol fumarate inhalation solution does not require dilution prior to administration by nebulization. Like all other nebulized treatments, the amount delivered to the lungs will depend on patient factors and the nebulization system used and its performance.

Using the PARI-LC Plus® nebulizer (with a facemask or mouthpiece) connected to a PRONEB® Ultra compressor under in vitro conditions, the mean delivered dose from the mouthpiece was approximately 7.3 mcg (37% of label claim). The mean nebulizer flow rate was 4 LPM and the nebulization time was 9 minutes. Formoterol fumarate inhalation solution should be administered from a standard jet nebulizer at adequate flow rates via a facemask or mouthpiece.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Formoterol fumarate is a long-acting, beta2 -adrenergic receptor agonist (beta2 -agonist). Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta2 -receptors than at beta1 -receptors. Although beta2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1 -receptors are the predominant receptors in the heart, there are also beta2 -receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2 -agonists may have cardiac effects.

The pharmacologic effects of beta2 -adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenylyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′, 5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans with COPD is unknown.

12.2 Pharmacodynamics

Systemic Safety and Pharmacokinetic / Pharmacodynamic Relationships

The major adverse effects of inhaled beta2 -agonists occur as a result of excessive activation of the systemic beta-adrenergic receptors. The most common adverse effects in adults include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma glucose.

Changes in serum potassium and serum glucose were evaluated in 12 COPD patients following inhalation of single doses of formoterol fumarate inhalation solution containing 10, 20 and 244 mcg of formoterol fumarate (calculated on an anhydrous basis) in a crossover study. At 1 hour after treatment with formoterol fumarate inhalation solution, mean (± standard deviation) serum glucose rose 26 ± 30, 29 ± 28, and 38 ± 44 mg/dL, respectively, and was not significantly different from baseline or trough level at 24 hours post-dose. At 1 hour after dosing with formoterol fumarate inhalation solution 244 mcg, serum potassium fell by 0.68 ± 0.4 mEq/L, and was not different from baseline or trough level at 24 hours post-dose.

Linear pharmacokinetic/pharmacodynamic (PK/PD) relationships between urinary formoterol excretion and decreases in serum potassium, increases in plasma glucose, and increases in heart rate were generally observed with another inhalation formulation of formoterol fumarate and hence would be expected with formoterol fumarate inhalation solution also. Following single dose administration of 10-fold the recommended clinical dose of the other formoterol fumarate inhalation formulation having comparable exposure to single dose of 244 mcg of formoterol fumarate inhalation solution (approximately 12-fold the recommended clinical dose) in healthy subjects, the formoterol plasma concentration was found to be highly correlated with the reduction in plasma potassium concentration. Data from this study showed that maximum reductions from baseline in plasma potassium ranged from 0.55 to 1.52 mmol/L with a median maximum reduction of 1.01 mmol/L. Generally, the maximum effect on plasma potassium was noted 1 to 3 hours after peak formoterol plasma concentrations were achieved.

Electrophysiology

In the dose-ranging study of formoterol fumarate inhalation solution, ECG-determined heart rate increased by a mean of 6 ±3 beats per minute at 6 hours after a single dose of 244 mcg, but was back to predose level at 16 to 24 hours.

The effect of formoterol fumarate inhalation solution on heart rate and cardiac rhythm was studied in a 12-week clinical trial comparing formoterol fumarate inhalation solution to placebo and an active control treatment. COPD patients, including 105 patients exposed to formoterol fumarate inhalation solution, underwent continuous electrocardiographic (Holter) monitoring during two 24-hour periods (study baseline and after 8 to 12 weeks of treatment). ECGs were performed pre-dose and at 2 to 3 hours post-dose at study baseline (prior to dosing) and after 4, 8 and 12 weeks of treatment. Bazett’s and Fridericia’s methods were used to correct the QT interval for heart rate (QTcB and QTcF, respectively). The mean increase from baseline in QTcB interval over the 12-week treatment period was ≤ 4.8 msec for formoterol fumarate inhalation solution and ≤ 4.6 msec for placebo. The percent of patients who experienced a maximum change in QTc greater than 60 msec at any time during the 12-week treatment period was 0% and 1.8% for formoterol fumarate inhalation solution and placebo, respectively, based on Bazett’s correction, and 1.6% and 0.9%, respectively, based on Fridericia’s correction. Prolonged QT was reported as an adverse event in 1 (0.8%) patient treated with formoterol fumarate inhalation solution and 2 (1.8%) placebo patients. No occurrences of atrial fibrillation or ventricular tachycardia were observed during 24-hour Holter monitoring or reported as adverse events in patients treated with formoterol fumarate inhalation solution after the start of dosing. No increase in supraventricular tachycardia over placebo-treated subjects was observed. The mean increase in maximum heart rate from baseline to 8 to 12 weeks after the start of dosing was 0.6 beats per minute (bpm) for patients treated with formoterol fumarate inhalation solution twice daily compared to 1.2 bpm for placebo patients. There were no clinically meaningful differences from placebo in acute or chronic effects on heart rate, including QTcB and QTcF, or cardiac rhythm resulting from treatment with formoterol fumarate inhalation solution.

At an exposure from formoterol fumarate dry powder formulation comparable to approximately 12-fold the recommended dose of formoterol fumarate inhalation solution, a mean maximum increase of pulse rate of 26 bpm was observed 6 hours post dose in healthy subjects. This study showed that the maximum increase of mean corrected QT interval (QTc) was 25 msec when calculated using Bazett’s correction and was 8 msec when calculated using Fridericia’s correction. The QTc returned to baseline within 12 to 24 hours post-dose. Formoterol plasma concentrations were weakly correlated with pulse rate and increase of QTc duration. The effects on pulse rate and QTc interval are known pharmacological effects of this class of study drug and were not unexpected at this supratherapeutic formoterol fumarate inhalation dose.

Tachyphylaxis / Tolerance

Tolerance to the effects of inhaled beta-agonists can occur with regularly-scheduled, chronic use. In a placebo-controlled clinical trial in 351 adult patients with COPD, the bronchodilating effect of formoterol fumarate inhalation solution was determined by the FEV1 area under the curve over 12 hours following dosing on Day 1 and after 12 weeks of treatment. The effect of formoterol fumarate inhalation solution did not decrease after 12 weeks of twice-daily treatment (Figures 1 and 2).

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2021. All Rights Reserved.