Formoterol fumarate

804.88

460.184570

1308068-626-2

DTXSID1023077

R03AK07|R - Respiratory system

2924299090

165.42000

3.03490

White powder

138-140 °C

603.2ºC at 760mmHg

318.6ºC

Slightly (as fumarate salt)|In water, 1.12X10+4 mg/L at 25 °C /Estimated/|4.16e-02 g/L

5.0X10-14 mm Hg at 25 °C /Estimated/

LD50 in male, female, rats, mice (mg/kg): 3130, 5580, 6700, 8310 orally; 98, 100, 72, 71 i.v.; 1000, 1100, 640, 670 s.c.; 170, 210, 240, 210 i.p. (Yoshida)

Henry's Law constant = 9.0X10-23 atm-cu m/mol at 25 °C /Estimated/

Mol wt: 840.91. Crystals from 95% isopropyl alcohol, mp 138-140 °C, pKa1 = 7.9, pKa2 = 9.2; log Kow (octanol/water) 0.4 (pH 7.4); readily soluble in water at physiological pH /Fumarate dihydrate/

178.6 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

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. /Fumurate/|Hydroxyl radical reaction rate constant = 2.0X10-14 cu cm/molc-sec at 25 °C /Estimated/

II

6.1(b)

3249

S36/37

LQ2988000

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl formoterol fumarate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Formoterol Fumarate/

Goldsmith DR, Keating GM; Budesonide/Formoterol: A Review of its Use in Asthma; Drugs 64 (14): 1597-618 (2004)

|Danger|H332 (23.08%): Harmful if inhaled [Warning Acute toxicity, inhalation]|P201, P202, P260, P261, P263, P264, P270, P271, P273, P281, P304+P312, P304+P340, P307+P311, P308+P313, P312, P314, P321, P405, and P501|Aggregated GHS information provided by 13 companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H332 (100%): Harmful if inhaled [Warning Acute toxicity, inhalation]|P260, P261, P264, P270, P271, P273, P304+P312, P304+P340, P307+P311, P312, P314, P321, P405, and P501|Aggregated GHS information provided by 3 companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The oral LD50 in rats is 3130 mg/kg. Symptoms of overdose are likely consistent with formoterol's adverse effect profile (i.e. consistent with excessive beta-adrenergic stimulation) and may include angina, hyper or hypotension, tachycardia, arrhythmia, nervousness, headache, tremor, seizures, dry mouth, etc. Patients may experience laboratory abnormalities including hypokalemia, hyperglycemia, and metabolic acidosis. Treatment of overdosage should consist of symptomatic and supportive therapy, with a particular focus on cardiac monitoring. Consider the use of a cardioselective beta-adrenergic blocker to oppose excessive adrenergic stimulation if clinically appropriate.

Concomitant treatment /with monoamine oxidase inhibitors, including furazolidine and procarbazine/ may prolong the QTc interval and increase the risk of ventricular arrhythmias; may increase chance of hypertensive reactions.|May increase risk of arrhythmias in patients receiving halogenated hydrocarbon anesthesia.|Concomitant treatment /with tricyclic antidepressants, disopyramide, phenothiazines, procainamide or quinidine/may prolong the QTc interval and increase the risk of ventricular arrhythmias.|/Alcohol, levodopa, levothyroxine, oxytocin/ may impair cardiac tolerance towards beta2-sympathomimetics.|For more Interactions (Complete) data for FORMOTEROL (6 total), please visit the HSDB record page.

LD50 Mouse ip 210 mg/kg|LD50 Mouse iv 71 mg/kg|LD50 Mouse oral 6700 mg/kg|LD50 Mouse subcutaneous 640 mg/kg|For more Non-Human Toxicity Values (Complete) data for FORMOTEROL (8 total), please visit the HSDB record page.

Plasma protein binding to serum albumin _in vitro_ is approximately 31%-38% over a plasma concentration range of 5-500 ng/mL - it should be noted, however, that these concentrations are higher than that seen following inhalation.

Formoterol's production and use as an antiasthmatic(1) may result in its release to the environment through various waste streams.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 430(SRC), determined from a structure estimation method(2), indicates that formoterol is expected to have moderate mobility in soil(SRC). Volatilization of formoterol from moist soil surfaces is not expected to be an important fate process(SRC) given the natural cationic state of the compound and an estimated Henry's Law constant of 9.0X10-23 atm-cu m/mole(SRC), using a fragment constant estimation method(3). The pKa1 (amine) and pKa2 (phenol) of formoterol are 7.9 and 9.2(5), respectively, indicating that this compound will exist primarily in the protonated form below pH 7 and in its zwitterion form in the pH range of 7 to 9. Cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts(6). Formoterol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.0X10-14 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data for soil were not available(SRC, 2004).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 430(SRC), determined from a structure estimation method(2), indicates that formoterol is not expected to adsorb to suspended solids and sediment(SRC). However, the pKa1 (amine) and pKa2 (phenol) of formoterol are 7.9 and 9.2(7), respectively, indicating that this compound will exist primarily in the protonated form below pH 7 and in its zwitterion form in the pH range of 7 to 9. Cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts(5). Volatilization from water surfaces is not expected(3) given the natural cationic state of the compound and based upon an estimated Henry's Law constant of 9.0X10-23 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(6), an estimated BCF of 0.5(SRC), from an estimated log Kow of 1.4(8) and a regression-derived equation(9), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data for water were not available(SRC, 2004).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), formoterol, which has an estimated vapor pressure of 5.0X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase formoterol may be removed from the air by wet and dry deposition(SRC).

According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), formoterol, which has an estimated vapor pressure of 5.0X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase and atmospheric reaction with hydroxyl radicals or ozone is not expected. Formoterol is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(3) nor to directly photolyze due to the lack of absorption in the environmental UV spectrum (>290 nm).

An estimated BCF of 0.5 was calculated for formoterol(SRC), using an estimated log Kow of 1.4(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc for formoterol can be estimated to be 430(SRC). According to a classification scheme(2), this estimated Koc value suggests that formoterol is expected to have moderate mobility in soil. The pKa1 (amine) and pKa2 (phenol) of formoterol are 7.9 and 9.2(3), respectively, indicating that this compound will exist primarily in the protonated form below pH 7 and in its zwitterion form in the pH range of 7 to 9(4). Cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts(4).

The Henry's Law constant for formoterol is estimated as 9.0X10-23 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that formoterol is expected to be essentially nonvolatile from water surfaces(2). Formoterol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.0X10-14 mm Hg(SRC), determined from a fragment constant method(3).

It is not known whether formoterol is distributed in human breast milk. However, it is distributed in rat milk after oral administration.

Occupational exposure to formoterol may occur through inhalation and dermal contact with this compound at workplaces where formoterol is produced or used. The general population may be exposed to formoterol via ingestion of pharmaceutical products containing formoterol. (SRC)

Formoterol is indicated in various formulations for the treatment of asthma and COPD. For the treatment of COPD, formoterol is available as a single-entity inhalation solution, in combination with the long-acting muscarinic antagonists (LAMAs) [aclidinium] and [glycopyrronium], and in combination with the corticosteroid [budesonide]. For the treatment of asthma, formoterol is available in combination with [mometasone furoate] for patients 5 years and older and with budesonide for patients 6 years and older. Formoterol may also be used on an as-needed basis for prophylaxis against exercise-induced bronchospasm.|FDA Label|Budesonide/Formoterol Teva Pharma B.V. is indicated in adults 18 years of age and older only.AsthmaBudesonide/Formoterol Teva Pharma B.V. is indicated in the regular treatment of asthma, where use of a combination (inhaled corticosteroid and long-acting β2 adrenoceptor agonist) is appropriate: orin patients not adequately controlled with inhaled corticosteroids and “as needed” inhaled short-acting β2 adrenoceptor agonists.in patients already adequately controlled on both inhaled corticosteroids and long-acting β2 adrenoceptor agonists. |Asthma

Antiasthmatic|Formoterol is indicated to treat asthma concomitantly with short-acting beta2-agonists, inhaled or systemic corticosteroids and theophylline therapy. /Included in US product labeling/|Formoterol is indicated for long-term maintenance treatment of asthma in adult and children 5 years of age and older with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma. /Included in US product labeling/|Formoterol is indicated as long-term, twice-daily administration in the treatment of patients with chronic obstructive pulmonary disease including chronic bronchitis and emphysema. /Included in US product labeling/|For more Therapeutic Uses (Complete) data for FORMOTEROL (6 total), please visit the HSDB record page.

FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./|Anaphylactic reactions, urticaria, angioedema, rash, and bronchospasm have been reported rarely with formoterol oral inhalation therapy.|Formoterol oral inhalation powder should not be initiated in patients with substantially worsening or acutely deteriorating asthma, which may be a life-threatening condition. Failure to respond to a previously effective dosage of formoterol may indicated substantially worsening asthma that requires reevaluation. If inadequate control of symptoms persists with supplemental beta2-agonist bronchodilator therapy (i.e., if there is a need to increase the dose or frequency of administration of the short-acting, inhaled bronchodilator), prompt reevaluation of asthma therapy is required, with special consideration given to the possible need for anti-inflammatory treatment (e.g., corticosteroids); however, extra/increased doses of formoterol should not be used in such situations.|Although uncommon at recommended dosages, clinically important changes in systolic and/or diastolic blood pressure, heart rate, and ECG (e.g. flattening of the T wave, prolongation of the QTc interval, ST-segment depression) have been associated with formoterol oral inhalation therapy and may necessitate discontinuance of the drug. Cardiovascular effects generally have resolved within a few hours. Like other sympathomimetic amines, formoterol should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, or hypertension; in patient s withe seizure disorders or thyrotoxicosis; and in those who are unusually responsive to sympathomimetic amines.|For more Drug Warnings (Complete) data for FORMOTEROL (19 total), please visit the HSDB record page.

Formoterol works locally in the lungs as a bronchodilator, relaxing smooth muscle and opening up the airways. It possesses both a rapid onset of action (approximately 2-3 minutes) and a long duration of action (up to 12 hours). The use of long-acting beta-agonists (LABAs), such as formoterol, without concomitant inhaled corticosteroids in asthmatic patients should be avoided, as LABA monotherapy has been associated with an increased risk of asthma-related death.

Agents that cause an increase in the expansion of a bronchus or bronchial tubes. (See all compounds classified as Bronchodilator Agents.)|Compounds bind to and activate ADRENERGIC BETA-2 RECEPTORS. (See all compounds classified as Adrenergic beta-2 Receptor Agonists.)

The pulmonary bioavailability of formoterol has been estimated to be about 43% of the delivered dose, while the total systemic bioavailability is approximately 60% of the delivered dose (as systemic bioavailability accounts for absorption in the gut). Formoterol is rapidly absorbed into plasma following inhalation. In healthy adults, formoterol T_max ranged from 0.167 to 0.5 hours. Following a single dose of 10 mcg, C_max and AUC were 22 pmol/L and 81 pmol.h/L, respectively. In asthmatic adult patients, T_max ranged from 0.58 to 1.97 hours. Following single-dose administration of 10mcg, C_max and AUC_0-12h were 22 pmol/L and 125 pmol.h/L, respectively; following multiple-dose administration of 10 mcg, C_max and AUC_0-12h were 41 pmol/L and 226 pmol.h/L, respectively. Absorption appears to be proportional to dose across standard dosing ranges.|Elimination differs depending on the route and formulation administered. Following oral administration in 2 healthy subjects, approximately 59-62% and 32-34% of an administered dose was eliminated in the urine and feces, respectively. Another study which attempted to mimic inhalation via combined intravenous/oral administration noted approximately 62% of the administered dose in the urine and 24% in the feces. Following inhalation in patients with asthma, approximately 10% and 15-18% of the administered dose was excreted in urine as unchanged parent drug and direct formoterol glucuronides, respectively, and corresponding values in patients with COPD were 7% and 6-9%, respectively.|Renal clearance of formoterol following inhalation is approximately 157 mL/min.|Protein binding: Moderate 61-64%. Serum albumin binding was 31% to 38% over a range of 5 to 500 ng/mL.|Bioavailability: Pulmonary: 21-37%; Total systemic: 46%.|It is not known whether formoterol is distributed in human breast milk. However, it is distributed in rat milk after oral administration.|In asthma patients following a 12 or 24 ug dose: 10% and 15 to 18% excreted unchanged in the urine, respectively. In chronic obstructive pulmonary disease (COPD) patients following a 12 or 24 ug dose: 7% and 6 to 9% excreted unchanged in the urine; respectively.|For more Absorption, Distribution and Excretion (Complete) data for FORMOTEROL (8 total), please visit the HSDB record page.

Formoterol is metabolized primarily via direct glucuronidation of the parent drug and via O-demethylation of the parent drug followed by glucuronidation. Minor pathways include sulfate conjugation of the parent drug and deformylation of the parent drug followed by sulfate conjugation, though these minor pathways have not been fully characterized. The major pathway of formoterol metabolism is a direct glucuronidation of the parent drug at its phenolic hydroxyl group, while the second most prominent pathway involves O-demethylation following by glucuronidation at the phenolic hydroxyl group. _In vitro_ studies of formoterol disposition indicate that O-demethylation of formoterol involves a number of cytochrome P450 isoenzymes (CYP2D6, CYP2C19, CYP2C9, and CYP2A6) and glucuronidation involves a number of UDP-glucuronosyltransferase isoenzymes (UGT1A1, UGT1A8, UGT1A9, UGT2B7, and UGT2B15), though specific roles for individual enzymes have not been elucidated.|Formoterol is metabolized primarily by direct glucuronidation at either the phenolic or aliphatic hydroxyl group and O-demethylation followed by glucuronide conjugation at either phenolic hydroxyl groups. Minor pathways involve sulfate conjugation of formoterol and deformylation followed by sulfate conjugation. The most prominent pathway involves direct conjugation at the phenolic hydroxyl group. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. Four cytochrome P450 isozymes (CYP2D6, CYP2C19, CYP2C9 and CYP2A6) are involved in the O-demethylation of formoterol. Formoterol did not inhibit CYP450 enzymes at therapeutically relevant concentrations. Some patients may be deficient in CYP2D6 or 2C19 or both. Whether a deficiency in one or both of these isozymes results in elevated systemic exposure to formoterol or systemic adverse effects has not been adequately explored.|Formoterol was conjugated to inactive glucuronides and a previously unidentified sulfate. The phenol glucuronide of formoterol was the main metabolite in urine. Formoterol was also O-demethylated and deformylated. Plasma exposure to these pharmacologically active metabolites was low. O-demethylated formoterol was seen mainly as inactive glucuronide conjugates and deformylated formoterol only as an inactive sulfate conjugate. Intact formoterol and O-demethylated formoterol dominated recovery in feces. Mean recovery of unidentified metabolites was 7. 0% in urine and 2.0% in feces.

The average terminal elimination half-life of formoterol following inhalation is 7-10 hours, depending on the formulation given. The plasma half-life of formoterol has been estimated to be 3.4 hours following oral administration and 1.7-2.3 hours following inhalation.|Mean terminal: 10 hours

Formoterol is a relatively selective long-acting agonist of beta₂-adrenergic receptors, although it does carry some degree of activity at beta₁ and beta₃ receptors. Beta₂ receptors are found predominantly in bronchial smooth muscle (with a relatively minor amount found in cardiac tissue) whereas beta₁ receptors are the predominant adrenergic receptors found in the heart - for this reason, selectivity for beta₂ receptors is desirable in the treatment of pulmonary diseases such as COPD and asthma. Formoterol has demonstrated an approximately 200-fold greater activity at beta₂ receptors over beta₁ receptors. On a molecular level, activation of beta receptors by agonists like formoterol stimulates intracellular adenylyl cyclase, an enzyme responsible for the conversion of ATP to cyclic AMP (cAMP). The increased levels of cAMP in bronchial smooth muscle tissue result in relaxation of these muscles and subsequent dilation of the airways, as well as inhibition of the release of hypersensitivity mediators (e.g. histamine, leukotrienes) from culprit cells, especially mast cells.|Formoterol is a long-acting selective stimulator of the beta2-adrenergic receptors in bronchial smooth muscle. This stimulation causes relaxation of smooth muscle fibers and produces bronchodilation.|Formoterol stimulates beta2-adrenergic receptors and apparently has little or no effect on beta1- or alpha-adrenergic receptors. The drug's beta-adrenergic effects appear to result from stimulation of the production of cyclic adeno-3'-5'-monophosphate (cAMP)by activation of adenyl cyclase. Cyclic AMP mediate numerous cellular responses, increased concentrations of cAMP are associated with relaxation of bronchial smooth muscle and suppression of some aspects of inflammation, such as inhibition of release proinflammatory mast cell mediators(eg histamine, leukotrienes).

There is no clinical experience on the management of overdose. Treatment should be symptomatic and supportive. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. Cardiac monitoring is recommended. There is insufficient evidence to determine if dialysis is beneficial for overdosage of formoterol.

/SIGNS AND SYMPTOMS/ As with other inhaled beta2-receptor agonists, a patient may develop acute bronchospasm, which may be life-threatening, immediately upon inhalation of formoterol. If paradoxical bronchospasm occurs, formoterol should be discontinued immediately and alternative therapy instituted.|/SIGNS AND SYMPTOMS/ The expected signs and symptoms with overdosage of foradil aerolizer are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms ... e.g., 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, hypokalemia, hyperglycemia, and insomnia. Metabolic acidosis may also occur. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of Foradil aerolizer.

3-formylamino-4-hydroxy-alpha-(N-1-methyl-2-p-methoxyphenethylaminomethyl)benzyl alcohol.hemifumarate

Oral Inhalation: Powder for inhalation (contained in capsules) 12 ug Foradil Aerolizer Inhaler (Novartis). /Formoterol fumarate/

Preparation: M. Murakami et al, DE 2305092; eidem, US 3994974 (1973, 1976 both to Yamanouchi)|Information available in 2004 indicated that Formoterol was used in the manufacture of pharmaceutical preparations in the following countries: Austria, Belgium, Denmark, Greece, Ireland|Information available in 2004 indicated that Formoterol fumerate was used in the manufacture of pharmaceutical preparations in the following countries: Antigua & Barbuda, Argentina, Aruba, Australia, Austria, Bahamas, Barbados, Belgium, Belize, Bermuda, Brazil, Bulgaria, Canada, Cayman Islands, Chile, Colombia, Costa Rica, Czech Republic, Denmark, Dominican Republic, El Salvador, Ethiopia, Finland, France, Germany, Ghana, Greece, Grenada, Guatemala, Guyana, Haiti, Honduras, Hong Kong, Hungary, India, Indonesia, Ireland, Israel, Italy, Jamaica, Japan, Kenya, Libyan Arab Jamahiriya, Malawi, Malaysia, Malta, Mauritius, Mexico, Mozambique, Netherlands Antilles, Netherlands, New Zealand, Nicaragua, Nigeria, Norway, Panama, Poland, Portugal, Romania, Russian Federation, Saint Lucia, Saint Vincent & The Grenadines, Singapore, South Africa, Spain, Sudan, Suriname, Sweden, Switzerland, Thailand, Trinidad & Tobago, Turkey, Uganda, United Kingdom, United Republic of Tanzania, USA, Zambia, Zimbabwe (1,2) [NOTE: Information available in 2004 indicated that Formoterol fumerate was used in the manufacture of pharmaceutical preparations in the following countries: Argentina-DI, Spain-DI (2)] /Formoterol fumerate/|Information available in 2004 indicated that Formoterol hemifumerate was used in the manufacture of pharmaceutical preparations in the following countries: Austria, Brazil, Portugal, Singapore, Spain /Formoterol hemifumerate/

HPLC determination in plasma.

Human drugs -> Budesonide/Formoterol Teva Pharma B.V. -> EMA Drug Category|Drugs for obstructive airway diseases -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients