Perforomist Information
Perforomist (Formoterol)
Perforomist (Formoterol) Indications And Usage
Perforomist (Formoterol) Inhalation Solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease
Perforomist (Formoterol) Inhalation Solution is not indicated to treat asthma. The safety and effectiveness of Perforomist (Formoterol) Inhalation Solution in asthma have not been established.
Perforomist (Formoterol) Dosage And Administration
The recommended dose of Perforomist (Formoterol) (formoterol fumarate) Inhalation Solution is one 20 mcg unit-dose vial administered twice daily (morning and evening) by nebulization. A total daily dose greater than 40 mcg is not recommended.
Perforomist (Formoterol) Inhalation Solution should be administered by the orally inhaled route via a standard jet nebulizer connected to an air compressor. The safety and efficacy of Perforomist (Formoterol) Inhalation Solution have been established in clinical trials when administered using the PARI-LC Plus nebulizer (with a facemask or mouthpiece) and the PRONEB Ultra compressor. The safety and efficacy of Perforomist (Formoterol) Inhalation Solution delivered from non-compressor based nebulizer systems have not been established.
Perforomist (Formoterol) Inhalation Solution should always be stored in the foil pouch, and only removed IMMEDIATELY BEFORE USE. Contents of any partially used container should be discarded.
If the recommended maintenance treatment regimen fails to provide the usual response, medical advice should be sought immediately, as this is often a sign of destabilization of COPD. Under these circumstances, the therapeutic regimen should be re-evaluated and additional therapeutic options should be considered.
The drug compatibility (physical and chemical), efficacy, and safety of Perforomist (Formoterol) Inhalation Solution when mixed with other drugs in a nebulizer have not been established.
Perforomist (Formoterol) Dosage Forms And Strengths
Perforomist (Formoterol) (formoterol fumarate) Inhalation Solution is supplied as a sterile solution for nebulization in low-density polyethylene unit-dose vials. Each vial contains formoterol fumarate dihydrate, USP equivalent to 20 mcg/2 mL of formoterol fumarate.
Perforomist (Formoterol) Contraindications
All LABA, including Perforomist (Formoterol) , are contraindicated in patients with asthma without use of a long-term asthma control medication. .
Perforomist (Formoterol) Warnings And Precautions
[See BOXED WARNING]
Data from a large placebo-controlled study in asthma patients showed that long-acting beta-adrenergic agonists may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by long-acting beta-adrenergic agonists.
A 28-week, placebo-controlled US study comparing the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of the long-acting beta-adrenergic agonists, including Perforomist (Formoterol) Inhalation Solution. No study adequate to determine whether the rate of asthma related death is increased in patients treated with Perforomist (Formoterol) Inhalation Solution has been conducted. The safety and efficacy of Perforomist (Formoterol) in patients with asthma have not been established. All LABA, including Perforomist (Formoterol) , are contraindicated in patients with asthma without the use of a long-term asthma control medication. .
Clinical studies with formoterol fumarate administered as a dry powder inhaler suggested a higher incidence of serious asthma exacerbations in patients who received formoterol than in those who received placebo. The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups.
Perforomist (Formoterol) Inhalation Solution should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. Perforomist (Formoterol) Inhalation Solution has not been studied in patients with acutely deteriorating COPD. The use of Perforomist (Formoterol) Inhalation Solution in this setting is inappropriate.
Perforomist (Formoterol) Inhalation Solution should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Perforomist (Formoterol) Inhalation Solution has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta-agonist.
When beginning Perforomist (Formoterol) Inhalation Solution, patients who have been taking inhaled, short-acting beta-agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing Perforomist (Formoterol) Inhalation Solution, the healthcare provider should also prescribe an inhaled, short-acting beta-agonist and instruct the patient how it should be used. Increasing inhaled beta-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated. COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If Perforomist (Formoterol) Inhalation Solution no longer controls the symptoms of bronchoconstriction, or the patient’s inhaled, short-acting beta-agonist becomes less effective or the patient needs more inhalation of short-acting beta-agonist than usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of Perforomist (Formoterol) Inhalation Solution beyond the recommended 20 mcg twice daily dose is not appropriate in this situation.
Beta-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist medications may produce transient hyperglycemia in some patients.
Clinically significant changes in serum potassium and blood glucose were infrequent during clinical studies with long-term administration of Perforomist (Formoterol) Inhalation Solution at the recommended dose.
Perforomist (Formoterol) Adverse Reactions
Long acting beta-adrenergic agonists such as formoterol increase the risk of asthma-related death .
Perforomist (Formoterol) Use In Specific Populations
There are no adequate and well-controlled human studies that have investigated the effects of Perforomist (Formoterol) Inhalation Solution during labor and delivery.
Because beta-agonists may potentially interfere with uterine contractility, Perforomist (Formoterol) Inhalation Solution should be used during labor only if the potential benefit justifies the potential risk.
In reproductive studies in rats, formoterol was excreted in the milk. It is not known whether formoterol is excreted in human milk, but because many drugs are excreted in human milk, caution should be exercised if Perforomist (Formoterol) Inhalation Solution is administered to nursing women. There are no well-controlled human studies of the use of Perforomist (Formoterol) Inhalation Solution in nursing mothers.
Women should be advised to contact their physician if they are nursing while taking Perforomist (Formoterol) Inhalation Solution.
Of the 586 subjects who received Perforomist (Formoterol) Inhalation Solution in clinical studies, 284 were 65 years and over, while 89 were 75 years and over. Of the 123 subjects who received Perforomist (Formoterol) Inhalation Solution in the 12-week safety and efficacy trial, 48 (39%) were 65 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.
The pharmacokinetics of Perforomist (Formoterol) Inhalation Solution has not been studied in elderly subjects.
Perforomist (Formoterol) Overdosage
The expected signs and symptoms with overdosage of Perforomist (Formoterol) 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 Perforomist (Formoterol) Inhalation Solution.
Treatment of overdosage consists of discontinuation of Perforomist (Formoterol) 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 Perforomist (Formoterol) Inhalation Solution. Cardiac monitoring is recommended in cases of overdosage.
The minimum lethal inhalation dose of formoterol fumarate in rats is 156 mg/kg (approximately 32,000 times the maximum recommended daily inhalation dose in humans on a mg/m basis). The median lethal oral doses in Chinese hamsters, rats, and mice provide even higher multiples of the maximum recommended daily inhalation dose in humans.
For additional information about overdose treatment, call a poison control center (1-800-222-1222).
Perforomist (Formoterol) Description
Perforomist (Formoterol) (formoterol fumarate) Inhalation Solution is supplied as 2 mL of formoterol fumarate inhalation solution packaged in a 2.5 mL single-use 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, pH adjusted to 5.0 with citric acid and sodium citrate.
The active component of Perforomist (Formoterol) Inhalation Solution is formoterol fumarate dihydrate, USP, a racemate. Formoterol fumarate dihydrate is a beta-adrenergic bronchodilator. Its chemical name is (±)-2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl]formanilide fumarate dihydrate; its structural formula is:
Formoterol fumarate dihydrate, USP has a molecular weight of 840.92 and its empirical formula is (CHNO)•CHO•2HO. 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.
Perforomist (Formoterol) 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. Perforomist (Formoterol) Inhalation Solution should be administered from a standard jet nebulizer at adequate flow rates via a facemask or mouthpiece.
Perforomist (Formoterol) Clinical Pharmacology
Formoterol fumarate is a long-acting, beta-adrenergic receptor agonist (beta-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 beta-receptors than at beta-receptors. Although beta-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta-receptors are the predominant receptors in the heart, there are also beta-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 beta-agonists may have cardiac effects.
The pharmacologic effects of beta-adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenyl 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.
Information on the pharmacokinetics of formoterol (dry powder and/or inhalation solution) in plasma and/or urine is available in healthy subjects as well as patients with chronic obstructive pulmonary disease after oral inhalation of doses at and above the therapeutic dose.
Urinary excretion of unchanged formoterol was used as an indirect measure of systemic exposure. Plasma drug disposition data parallel urinary excretion, and the elimination half-lives calculated for urine and plasma are similar.
Perforomist (Formoterol) Nonclinical Toxicology
The carcinogenic potential of formoterol fumarate has been evaluated in 2-year drinking water and dietary studies in both rats and mice. In rats, the incidence of ovarian leiomyomas was increased at doses of 15 mg/kg and above in the drinking water study and at 20 mg/kg in the dietary study (AUC exposure approximately 2300 times human exposure at the maximum recommended daily inhalation dose), but not at dietary doses up to 5 mg/kg (AUC exposure approximately 570 times human exposure at the maximum recommended daily inhalation dose). In the dietary study, the incidence of benign ovarian theca-cell tumors was increased at doses of 0.5 mg/kg (AUC exposure was approximately 57 times human exposure at the maximum recommended daily inhalation dose) and above. This finding was not observed in the drinking water study, nor was it seen in mice (see below).
In mice, the incidence of adrenal subcapsular adenomas and carcinomas was increased in males at doses of 69 mg/kg (AUC exposure approximately 1000 times human exposure at the maximum recommended daily inhalation dose) and above in the drinking water study, but not at doses up to 50 mg/kg (AUC exposure approximately 750 times human exposure at the maximum recommended daily inhalation dose) in the dietary study. The incidence of hepatocarcinomas was increased in the dietary study at doses of 20 and 50 mg/kg in females (AUC exposures approximately 300 and 750 times human exposure at the maximum recommended daily inhalation dose, respectively) and 50 mg/kg in males, but not at doses up to 5 mg/kg (AUC exposure approximately 75 times human exposure at the maximum recommended daily inhalation dose). Also in the dietary study, the incidence of uterine leiomyomas and leiomyosarcomas was increased at doses of 2 mg/kg (AUC exposure was approximately 30 times human exposure at the maximum recommended daily inhalation dose) and above. Increases in leiomyomas of the rodent female genital tract have been similarly demonstrated with other beta-agonist drugs.
Formoterol fumarate was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacterial and mammalian cells, chromosomal analyses in mammalian cells, unscheduled DNA synthesis repair tests in rat hepatocytes and human fibroblasts, transformation assay in mammalian fibroblasts and micronucleus tests in mice and rats.
Reproduction studies in rats revealed no impairment of fertility at oral doses up to 3 mg/kg (approximately 600 times the maximum recommended daily inhalation powder dose in humans on a mg/m basis).
Perforomist (Formoterol) Clinical Studies
Perforomist (Formoterol) (formoterol fumarate) Inhalation Solution was evaluated in a 12-week, double-blind, placebo- and active-controlled, randomized, parallel-group, multicenter trial conducted in the United States. Of a total enrollment of 351 adults (age range: 40 to 86 years; mean age: 63 years) with COPD who had a mean pre-bronchodilator FEVof 1.34 liters (44% of predicted), 237 patients were randomized to Perforomist (Formoterol) Inhalation Solution 20 mcg or placebo, administered twice daily via a PARI-LC Plus nebulizer with a PRONEB Ultra compressor. The diagnosis of COPD was based upon a prior clinical diagnosis of COPD, a smoking history (at least 10 pack-years), age (at least 40 years), and spirometry results (pre-bronchodilator baseline FEV at least 30% and less than 70% of the predicted value, and the FEV/FVC less than 70%). About 58% of patients had bronchodilator reversibility, defined as a 10% or greater increase in FEV after inhalation of 2 actuations (180 mcg) of albuterol from a metered dose inhaler. About 86% (106) of patients treated with Perforomist (Formoterol) Inhalation Solution and 74% (84) of placebo patients completed the trial.
Perforomist (Formoterol) Inhalation Solution 20 mcg twice daily resulted in significantly greater post-dose bronchodilation (as measured by serial FEV for 12 hours post-dose; the primary efficacy analysis) compared to placebo when evaluated at endpoint (week 12 for completers and last observation for dropouts). Similar results were seen on Day 1 and at subsequent timepoints during the trial.
Mean FEV measurements at Day 1 (Figure 1) and at endpoint (Figure 2) are shown below.
Patients treated with Perforomist (Formoterol) Inhalation Solution used less rescue albuterol during the trial compared to patients treated with placebo.
Examination of age (≥ 65 or younger) and gender subgroups did not identify differences in response to Perforomist (Formoterol) Inhalation Solution. There were too few non-Caucasian subjects to assess differences in populations defined by race adequately.
In the 12 week study, 78% of subjects achieved a 15% increase from baseline FEV following the first dose of Perforomist (Formoterol) Inhalation Solution 20 mcg. In these subjects, the median time to onset of bronchodilation, defined as 15% increase in FEV, was 11.7 minutes. When defined as an increase in FEV of 12% and 200 mL, the time to onset of bronchodilation was 13.1 minutes after dosing. The median time to peak bronchodilator effect was 2 hours after dosing.
Perforomist (Formoterol) How Supplied/storage And Handling
Perforomist (Formoterol) (formoterol fumarate) Inhalation Solution is supplied as a 2 mL sterile solution for nebulization in 2.5 mL low-density polyethylene unit dose vials. Each vial is overwrapped in a foil pouch and supplied in cartons as listed below.
Carton of 60 individually wrapped unit dose vials,
Perforomist (Formoterol) Patient Counseling Information
Perforomist (Formoterol) Inhalation Solution is not indicated for relief of acute symptoms, and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta-agonist (the healthcare provider should provide the patient with such medication and instruct the patient in how it should be used). Patients should be instructed to seek medical attention if their symptoms worsen despite recommended doses of Perforomist (Formoterol) Inhalation Solution, if Perforomist (Formoterol) Inhalation Solution treatment becomes less effective, or if they need more inhalations of a short-acting beta-agonist than usual.
Patients should not stop using Perforomist (Formoterol) Inhalation Solution unless told to do so by a healthcare provider because symptoms may get worse. Patients should not inhale more than the prescribed number of vials at any one time. The daily dosage of Perforomist (Formoterol) Inhalation Solution should not exceed one vial twice daily (40 mcg total daily dose). Excessive use of sympathomimetics may cause significant cardiovascular effects, and may be fatal.
Patients who have been taking inhaled, short-acting beta-agonists (e.g., albuterol) on a regular basis should be instructed to discontinue the regular use of these products and use them only for symptomatic relief of acute symptoms. Perforomist (Formoterol) Inhalation Solution should not be used in conjunction with other inhaled medications containing long-acting beta-agonists. Patients should be warned not to stop or change the dose of other concomitant COPD therapy without medical advice, even if symptoms improve after initiating treatment with Perforomist (Formoterol) Inhalation Solution.
Patients should be informed that treatment with beta-agonists may lead to adverse reactions that include palpitations, chest pain, rapid heart rate, increased or decreased blood pressure, headache, tremor, nervousness, dry mouth, muscle cramps, nausea, dizziness, fatigue, malaise, low blood potassium, high blood sugar, high blood acid, or trouble sleeping
It is important that patients understand how to use Perforomist (Formoterol) Inhalation Solution with a nebulizer appropriately . Patients should be instructed not to mix other medications with Perforomist (Formoterol) Inhalation Solution or ingest Perforomist (Formoterol) Inhalation Solution. Patients should throw the plastic dispensing container away immediately after use. Due to their small size, the container and top pose a danger of choking to young children.
See the accompanying .
Perforomist (Formoterol) Medication Guide
Read the Medication Guide that comes with Perforomist (Formoterol) Inhalation Solution before you start using it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment.
Perforomist (Formoterol) Inhalation Solution is not for use to treat sudden symptoms of COPD.
Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time you get a new medicine.
Tell your healthcare provider if you get any side effect that bothers you or that does not go away.
These are not all the side effects with Perforomist (Formoterol) Inhalation Solution. Ask your healthcare provider or pharmacist for more information.
Medicines are sometimes prescribed for purposes that are not mentioned in a Medication Guide. Do not use Perforomist (Formoterol) Inhalation Solution for a condition for which it was not prescribed. Do not give Perforomist (Formoterol) Inhalation Solution to other people, even if they have the same condition. It may harm them.
This Medication Guide summarizes the most important information about Perforomist (Formoterol) Inhalation Solution. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Perforomist (Formoterol) Inhalation Solution that was written for healthcare professionals.
Perforomist (Formoterol) Inhalation Solution comes sealed in a foil pouch. Do not open a sealed pouch until you are ready to use a dose of Perforomist (Formoterol) Inhalation Solution.
Dey Pharma, L.P. Napa, CA 94558 U.S.A.
Revised May 2010
This Medication Guide has been approved by the U.S. Food and Drug Administration
03-848-03
Perforomist (Formoterol)
