Pharma international inc.

901005R06_07Feb11_r6_noCyan.qxd 2/9/11 12:11 PM Page 2 BROVANA® (arformoterol tartrate)
Know the medicines you take. Keep a list of them to A population PK analysis indicated that there was no effect of gender upon the pharmacokinetics of 15 mcg*/2 mL
show your healthcare provider and pharmacist each time *potency expressed as arformoterol you get a new medicine.
The influence of race on arformoterol pharmacokinetics was assessed using a population PK analysis (arformoterol tartrate) Inhalation Solution
and data from healthy subjects. There was no clinically significant impact of race upon the pharmaco- For oral inhalation only
kinetic profile of arformoterol.
WARNING: ASTHMA RELATED DEATH
How should I use BROVANA?
Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. Data
The pharmacokinetic profile of arformoterol in 24 elderly subjects (aged 65 years or older) was from a large placebo-controlled US study that compared the safety of another long-acting beta
compared to a younger cohort of 24 subjects (18-45 years) that were matched for body weight and BROVANA is only for use with a nebulizer.
adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase
gender. No significant differences in systemic exposure (AUC and C Read the step-by-step instructions for using BROVANA
max) were observed when the two in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is con-
groups were compared.
at the end of this Medication Guide.
sidered a class effect of LABA, including arformoterol, the active ingredient in BROVANA (see
Read the Medication Guide that comes with BROVANA WARNINGS). The safety and efficacy of BROVANA in patients with asthma have not been estab-
lished. All LABA, including BROVANA, are contraindicated in patients with asthma without use
• Use BROVANA exactly as prescribed. One ready-to- The pharmacokinetics of arformoterol have not been studied in pediatric subjects.
before you start using it and each time you get a refill.
of a long-term asthma control medication (see CONTRAINDICATIONS).
There may be new information. This Medication Guide use vial of BROVANA is one dose. The usual dose of The pharmacokinetic profile of arformoterol was assessed in 24 subjects with mild, moderate, and severe does not take the place of talking to your healthcare BROVANA is 1 ready-to-use vial, twice a day (morning hepatic impairment. The systemic exposure (Cmax and AUC) to arformoterol increased 1.3 to 2.4-fold BROVANA (arformoterol tartrate) Inhalation Solution is a sterile, clear, colorless, aqueous solution of in subjects with hepatic impairment compared to 16 demographically matched healthy control subjects.
provider about your medical condition or treatment.
and evening) breathed in through your nebulizer the tartrate salt of arformoterol, the (R,R)-enantiomer of formoterol.
No clear relationship between drug exposure and the severity of hepatic impairment was observed.
BROVANA should be used cautiously in patients with hepatic impairment.
Arformoterol is a selective beta machine. The 2 doses should be about 12 hours apart.
2-adrenergic bronchodilator. The chemical name for arformoterol tar- Do not use more than 2 ready-to-use vials of
amino]ethyl] phenyl]-, (2R,3R)-2,3-dihydroxybutanedioate (1:1 salt), and its established structural for- The impact of renal disease upon the pharmacokinetics of arformoterol was studied in 24 subjects mula is as follows: What is the most important information I should know
with mild, moderate, or severe renal impairment. Systemic exposure (AUC and C BROVANA a day.
max) to arformoterol was similar in renally impaired patients compared with demographically matched healthy control • Do not swallow or inject BROVANA.
BROVANA can cause serious side effects, including:
• BROVANA is for use with a standard jet nebulizer Arformoterol is eliminated through the action of multiple drug metabolizing enzymes. Direct glucu-ronidation of arformoterol is mediated by several UGT enzymes and is the primary elimination route.
• People with asthma, who take long-acting beta2
machine connected to an air compressor. Read the O-Desmethylation is a secondary route catalyzed by the CYP enzymes CYP2D6 and CYP2C19. In other-wise healthy subjects with reduced CYP2D6 and/or UGT1A1 enzyme activity, there was no impact on adrenergic agonist (LABA) medicines, such as
complete instructions for use at the end of this systemic exposure to arformoterol compared to subjects with normal CYP2D6 and/or UGT1A1 enzyme The molecular weight of arformoterol tartrate is 494.5 g/mol, and its empirical formula is C BROVANA, have an increased risk of death from
Medication Guide before starting BROVANA.
• C4H6O6 (1:1 salt). It is a white to off-white solid that is slightly soluble in water.
• Do not mix other medicines with BROVANA in your Arformoterol tartrate is the United States Adopted Name (USAN) for (R,R)-formoterol L-tartrate.
Systemic Safety and Pharmacokinetic/ Pharmacodynamic Relationships
BROVANA is supplied as 2 mL of arformoterol tartrate solution packaged in 2.1 mL unit-dose, low-den- • It is not known if LABA medicines, such as BROVANA, nebulizer machine.
The predominant adverse effects of inhaled beta2-agonists occur as a result of excessive activation of sity polyethylene (LDPE) ready-to-use vials. Each ready-to-use vial contains 15 mcg of arformoterol systemic beta-adrenergic receptors. The most common adverse effects may include skeletal muscle 15 mcg*/2 mL
increase the risk of death in people with chronic (equivalent to 22 mcg of arformoterol tartrate) in a sterile, isotonic saline solution, pH-adjusted to 5.0 • If you miss a dose of BROVANA. Just skip that dose.
tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma with citric acid and sodium citrate.
*potency expressed obstructive pulmonary disease (COPD).
Take your next dose at your usual time. Do not take BROVANA requires no dilution before administration by nebulization. Like all other nebulized treat- Effects on Serum Potassium and Serum Glucose Levels ments, the amount delivered to the lungs will depend upon patient factors, the nebulizer used, and • Get emergency medical care if:
2 doses at one time.
compressor performance. Using the PARI LC PLUS® nebulizer (with mouthpiece) connected to a PARI Changes in serum potassium and serum glucose were evaluated in a dose ranging study of twice daily DURA-NEB® 3000 compressor under in vitro conditions, the mean delivered dose from the mouth- (5 mcg, 15 mcg, or 25 mcg; 215 patients with COPD) and once daily (15 mcg, 25 mcg, or 50 mcg; 191 • breathing problems worsen quickly
• While you are using BROVANA 2 times each day: piece (% nominal) was approximately 4.1 mcg (27.6%) at a mean flow rate of 3.3 L/min. The mean neb- patients with COPD) BROVANA in COPD patients. At 2 and 6 hours post dose at week 0 (after the first ulization time was 6 minutes or less. BROVANA should be administered from a standard jet nebulizer dose), mean changes in serum potassium ranging from 0 to –0.3 mEq/L were observed in the • you use your rescue inhaler medicine, but it does
• do not use other medicines that contain a long-
at adequate flow rates via face mask or mouthpiece (see Dosage and Administration).
BROVANA groups with similar changes observed after 2 weeks of treatment. Changes in mean serumglucose levels, ranging from a decrease of 1.2 mg/dL to an increase of 32.8 mg/dL were observed for Patients should be carefully instructed on the correct use of this drug product (please refer to the not relieve your breathing problems
BROVANA dose groups at both 2 and 6 hours post dose, both after the first dose and 14 days of daily 2-agonist (LABA) for any reason.
accompanying Medication Guide).
• do not use your short-acting beta2-agonist
The effect of BROVANA on QT interval was evaluated in a dose ranging study following multiple doses medicine on a regular basis (four times a day).
of BROVANA 5 mcg, 15 mcg, or 25 mcg twice daily or 15 mcg, 25 mcg, or 50 mcg once daily for What is BROVANA?
Mechanism of Action
2 weeks in patients with COPD. ECG assessments were performed at baseline, time of peak plasma • BROVANA does not relieve sudden symptoms of
Arformoterol, the (R,R)-enantiomer of formoterol, is a selective long-acting beta2-adrenergic receptor concentration and throughout the dosing interval. Different methods of correcting for heart rate were BROVANA is used long term, 2 times each day
2-agonist) that has two-fold greater potency than racemic formoterol (which contains both employed, including a subject-specific method and the Fridericia method.
COPD. Always have a rescue inhaler medicine with
the (S,S) and (R,R)-enantiomers). The (S,S)-enantiomer is about 1,000-fold less potent as a beta2- 15 mcg*/2 mL
Relative to placebo, the mean change in subject-specific QT (morning and evening), in controlling symptoms of
agonist than the (R,R)-enantiomer. While it is recognized that beta c averaged over the dosing interval ranged 2-receptors are the predominant adren- you to treat sudden symptoms. If you do not have a from -1.8 to 2.7 msec, indicating little effect of BROVANA on cardiac repolarization after 2 weeks of ergic receptors in bronchial smooth muscle and beta *potency expressed 1-receptors are the predominant receptors in the treatment. The maximum mean change in subject-specific QT chronic obstructive pulmonary disease (COPD) in
heart, data indicate that there are also beta c for the BROVANA 15 mcg twice daily rescue inhaler medicine, call your healthcare provider 2-receptors in the human heart comprising 10% to 50% of dose was 17.3 msec, compared with 15.4 msec in the placebo group. No apparent correlation of QT the total beta-adrenergic receptors. The precise function of these receptors has not been established, arformoterol plasma concentration was observed.
adults with COPD.
but they raise the possibility that even highly selective beta to have one prescribed for you.
2-agonists may have cardiac effects.
The pharmacologic effects of beta Electrocardiographic Monitoring in Patients with COPD
BROVANA is only for use with a nebulizer.
2-adrenoceptor agonist drugs, including arformoterol, are at least in • Do not stop using BROVANA or other medicines to part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion The effect of different doses of BROVANA on cardiac rhythm was assessed using 24-hour Holter mon- of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cyclic AMP). Increased itoring in two 12-week double-blind, placebo-controlled studies of 1,456 patients with COPD (873 re- LABA medicines such as BROVANA help the muscles control or treat your COPD unless told to do so by intracellular cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release ceived BROVANA at 15 or 25 mcg twice daily or 50 mcg once daily doses; 293 received placebo; 290 of mediators of immediate hypersensitivity from cells, especially from mast cells.
received salmeterol). The 24-hour Holter monitoring occurred once at baseline, and up to 3 times dur- around the airways in your lungs stay relaxed to prevent your healthcare provider because your symptoms In vitro tests show that arformoterol is an inhibitor of the release of mast cell mediators, such as his- ing the 12-week treatment period. The rates of new-onset cardiac arrhythmias not present at baseline symptoms, such as wheezing, cough, chest tightness, might get worse. Your healthcare provider will tamine and leukotrienes, from the human lung. Arformoterol also inhibits histamine-induced plasma over the double-blind 12-week treatment period were similar (approximately 33-34%) for patients who albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in received BROVANA 15 mcg twice daily to those who received placebo. There was a dose-related and shortness of breath.
change your medicines as needed.
dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans increase in new, treatment emergent arrhythmias seen in patients who received BROVANA 25 mcg twice daily and 50 mcg once daily, 37.6% and 40.1 %, respectively. The frequencies of new treatment emer-gent events of non-sustained (3-10 beat run) and sustained (>10 beat run) ventricular tachycardia were BROVANA should not be used in children. It is not
• Do not use BROVANA:
7.4% and 1.1% in BROVANA 15 mcg twice daily and 6.9% and 1.0% in placebo. In patients who re- known if BROVANA is safe and effective in children.
ceived BROVANA 25 mcg twice daily and 50 mcg once daily the frequencies of non-sustained (6.2% In animal studies investigating its cardiovascular effects, arformoterol induced dose-dependent ° more often than prescribed
and 8.2%, respectively) and sustained ventricular tachycardia (1.0% and 1.0%, respectively) were sim- increases in heart rate and decreases in blood pressure consistent with its pharmacology as a beta- ilar. Five cases of ventricular tachycardia were reported as adverse events (1 in BROVANA 15 mcg twice It is not known if BROVANA is safe and effective in
adrenergic agonist. In dogs, at systemic exposures higher than anticipated clinically, arformoterol also ° more medicine than prescribed to you
daily and 4 in placebo), with two of these events leading to discontinuation of treatment (2 in placebo).
induced exaggerated pharmacologic effects of a beta-adrenergic agonist on cardiac function as meas- people with asthma.
ured by electrocardiogram (sinus tachycardia, atrial premature beats, ventricular escape beats, PVCs).
There were no baseline occurrences of atrial fibrillation/ flutter observed on 24-hour Holter monitor- ° with other LABA medicines
ing in patients treated with BROVANA 15 mcg twice daily or placebo. New, treatment emergent atrial Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of fibrillation/ flutter occurred in 0.4% of patients who received BROVANA 15 mcg twice daily and 0.3% Call your healthcare provider or get emergency
arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and of patients who received placebo. There was a dose-related increase in the frequency of atrial fibrilla- methylxanthines are administered concurrently. The clinical significance of these findings is unknown.
tion/ flutter reported in the BROVANA 25 mcg twice daily and 50 mcg once daily dose groups of 0.7% Who should not use BROVANA?
medical care right away if:
and 1.4%, respectively. Two cases of atrial fibrillation/ flutter were reported as adverse events (1 in BROVANA 15 mcg twice daily and 1 in placebo).
• your breathing problems worsen with BROVANA The pharmacokinetics (PK) of arformoterol have been investigated in healthy subjects, elderly sub- Do not use BROVANA if you:
Dose-related increases in mean maximum change in heart rate in the 12 hours after dosing were also jects, renally and hepatically impaired subjects, and chronic obstructive pulmonary disease (COPD) observed following 12 weeks of dosing with BROVANA 15 mcg twice daily (8.8 bpm), 25 mcg twice • you need to use your rescue inhaler medicine more patients following the nebulization of the recommended therapeutic dose and doses up to 96 mcg.
• have had a serious allergic reaction to arformoterol, daily (9.9 bpm) and 50 mcg once daily (12 bpm) versus placebo (8.5 bpm).
formoterol, or any of the ingredients in BROVANA.
In COPD patients administered 15 mcg arformoterol every 12 hours for 14 days, the mean steady- In two placebo-controlled clinical trials in patients with COPD involving approximately 725 patients in • your rescue inhaler medicine does not work as well state peak (R,R)-formoterol plasma concentration (C Ask your healthcare provider if you are not sure.
max) and systemic exposure (AUC0-12h) were each, the overall efficacy of BROVANA was maintained throughout the 12-week trial duration. However, 4.3 pg/mL and 34.5 pg*hr/mL, respectively. The median steady-state peak (R,R)-formoterol plasma tolerance to the bronchodilator effect of BROVANA was observed after 6 weeks of dosing, evidenced by for you at relieving symptoms concentration time (t See the end of this Medication Guide for a complete max) was observed approximately one half hour after drug administration.
a decrease in bronchodilator effect as measured by FEV1. FEV1 improvement at the end of the 12-hour Systemic exposure to (R,R)-formoterol increased linearly with dose in COPD patients following arfor- dosing interval decreased by approximately one third (22.1% mean improvement after the first dose list of ingredients in BROVANA.
moterol doses of 5 mcg, 15 mcg, or 25 mcg twice daily for 2 weeks or 15 mcg, 25 mcg, or 50 mcg compared to 14.6% at week 12). Tolerance to the FEV1 bronchodilator effect of BROVANA was not ac- once daily for 2 weeks.
companied by other clinical manifestations of tolerance in these trials.
• have asthma without using a long-term asthma What are the possible side effects with BROVANA?
In a crossover study in patients with COPD, when arformoterol 15 mcg inhalation solution and 12 and control medicine.
24 mcg formoterol fumarate inhalation powder (Foradil® Aerolizer™) was administered twice daily for 2 weeks, the accumulation index was approximately 2.5 based on the plasma (R,R)-formoterol con- Adult COPD Trials
BROVANA can cause serious side effects, including:
centrations in all three treatments. At steady state, geometric means of systemic exposure (AUC0-12h) BROVANA (arformoterol tartrate) Inhalation Solution was studied in two identical, 12 week, double- to (R,R)-formoterol following 15 mcg of arformoterol inhalation solution and 12 mcg of formoterol blind, placebo- and active-controlled, randomized, multi-center, parallel group trials conducted in the See "What is the most important information I
fumarate inhalation powder were 39.33 pg*hr/mL and 33.93 pg*hr/mL, respectively (ratio 1.16; 90% United States (Clinical Trial A and Clinical Trial B). A total of 1,456 adult patients (age range: 34 to 89 CI 1.00, 1.35), while the geometric means of the C What should I tell my healthcare provider before using
max were 4.30 pg/mL and 4.75 pg/mL, respectively should know about BROVANA?"
years; mean age: 63 years) with COPD who had a mean FEV (ratio 0.91; 90% CI 0.76, 1.09).
1 of 1.3 L (42% of predicted) were enrolled in the two clinical trials. The diagnosis of COPD was based on a prior clinical diagnosis of COPD, a • Sudden shortness of breath immediately after use of In a study in patients with asthma, treatment with arformoterol 50 mcg with pre- and post-treatment smoking history (greater than 15 pack-years), age (at least 35 years), spirometry results (baseline with activated charcoal resulted in a geometric mean decrease in (R,R)-formoterol AUC0-6h by 27% FEV1 ≤65% of predicted value and >0.70 L, and a FEV1/forced vital capacity (FVC) ratio ≤70%). About Tell your healthcare provider about all of your health
and Cmax by 23% as compared to treatment with arformoterol 50 mcg alone. This suggests that a sub- 80% of patients in these studies had bronchodilator reversibility, defined as a 10% or greater increase stantial portion of systemic drug exposure is due to pulmonary absorption.
in FEV1 after inhalation of 2 actuations (180 mcg racemic albuterol from a metered dose inhaler). Both conditions, including if you:
• If your COPD symptoms worsen over time do not trials compared BROVANA 15 mcg twice daily (288 patients), 25 mcg twice daily (292 patients), 50 mcg once daily (293 patients) with placebo (293 subjects). Both trials included salmeterol inhalation aerosol, • have heart problems increase your dose of BROVANA, instead call your The binding of arformoterol to human plasma proteins in vitro was 52-65% at concentrations of 0.25, 42 mcg twice daily as an active comparator (290 patients).
0.5 and 1.0 ng/mL of radiolabeled arformoterol. The concentrations of arformoterol used to assess In both 12-week trials, BROVANA 15 mcg twice daily resulted in significantly greater post-dose bron- • have high blood pressure the plasma protein binding were higher than those achieved in plasma following inhalation of multiple chodilation (as measured by percent change from study baseline FEV1 at the end of the dosing inter- doses of 50 mcg arformoterol.
val over the 12 weeks of treatment, the primary efficacy endpoint) compared to placebo. Compared to • have seizures • Increased blood pressure BROVANA 15 mcg twice daily, BROVANA 25 mcg twice daily and 50 mcg once daily did not provide suf- ficient additional benefit on a variety of endpoints, including FEV1, to support the use of higher doses.
• Fast or irregular heartbeat In vitro profiling studies in hepatocytes and liver microsomes have shown that arformoterol is pri- Plots of the mean change in FEV • have thyroid problems 1 values obtained over the 12 hours after dosing for the BROVANA 15 marily metabolized by direct conjugation (glucuronidation) and secondarily by O-demethylation. At mcg twice daily dose group and for the placebo group are provided in Figures 1 and 2 for Clinical Trial • serious allergic reactions including rash, hives,
least five human uridine diphosphoglucuronosyltransferase (UGT) isozymes catalyze arformoterol A, below. The plots include mean FEV • have diabetes 1 change observed after the first dose and after 12 weeks of treat- glucuronidation in vitro. Two cytochrome P450 isozymes (CYP2D6 and secondarily CYP2C19) catalyze ment. The results from Clinical Trial B were similar.
swelling of the face, mouth, and tongue, and
the O-demethylation of arformoterol.
• have liver problems breathing problems. Call your healthcare provider
Arformoterol did not inhibit CYP1A2, CYP2A6, CYP2C9/10, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5,or CYP4A9/11 enzymes at >1,000-fold higher concentrations than the expected peak plasma concen- • are pregnant or planning to become pregnant. It is or get emergency medical care if you get any trations following a therapeutic dose.
not known if BROVANA can harm your unborn baby.
Arformoterol was almost entirely metabolized following oral administration of 35 mcg of radiolabeled symptoms of a serious allergic reaction.
arformoterol in eight healthy subjects. Direct conjugation of arformoterol with glucuronic acid was the • are breastfeeding. It is not known if BROVANA passes major metabolic pathway. Most of the drug-related material in plasma and urine was in the form of glu- Common side effects of BROVANA include:
curonide or sulfate conjugates of arformoterol. O-Desmethylation and conjugates of the O-desmethyl into your milk and if it can harm your baby.
metabolite were relatively minor metabolites accounting for less than 17% of the dose recovered in • chest or back pain
urine and feces.
Tell your healthcare provider about all the medicines
• diarrhea
you take including prescription and non-prescription
After administration of a single oral dose of radiolabeled arformoterol to eight healthy male subjects, • sinus congestion
63% of the total radioactive dose was recovered in urine and 11% in feces within 48 hours. A total of medicines, vitamins and herbal supplements. BROVANA 89% of the total radioactive dose was recovered within 14 days, with 67% in urine and 22% in feces.
• headache
Approximately 1% of the dose was recovered as unchanged arformoterol in urine over 14 days. Renal and certain other medicines may interact with each other.
clearance was 8.9 L/hr for unchanged arformoterol in these subjects.
This may cause serious side effects.
• tremor
In COPD patients given 15 mcg inhaled arformoterol twice a day for 14 days, the mean terminal half-life of arformoterol was 26 hours.
901005R06_07Feb11_r6_noCyan.qxd 2/9/11 12:11 PM Page 3 BROVANA is not indicated to relieve acute respiratory symptoms and extra doses should not be Table 1: Number of Patients Experiencing Adverse Events from Two 12-Week, Double-Blind, Placebo
used for that purpose. Acute symptoms should be treated with an inhaled, short-acting, beta Controlled Clinical Trials
2. Carefully twist open the top of the ready-to-use vial agonist (the health-care provider should prescribe the patient with such medication and instruct • leg cramps
and use it right away (Figure 1).
the patient in how it should be used). Patients should be instructed to seek medical attention if their symptoms worsen, if BROVANA treatment becomes less effective, or if they need more inhalations • high blood potassium
of a short-acting beta2-agonist than usual. Patients should not inhale more than one dose at any one time. The daily dosage of BROVANA should not exceed one ready-to-use vial (15 mcg) by • shortness of breath
inhalation twice daily (30 mcg total daily dose).
Patients should be informed that treatment with beta2-agonists may lead to adverse events which include palpitations, chest pain, rapid heart rate, tremor, or nervousness.
• fever
Patients should be instructed to use BROVANA by nebulizer only and not to inject or swallow this • increased white blood cells
Patients should protect BROVANA ready-to-use vials from light and excessive heat. The protec- tive foil pouches should be stored under refrigeration between 2°C and 8°C (36°–46°F). They • vomiting
should not be used after the expiration date stamped on the container. After opening the pouch,unused ready-to-use vials should be returned to, and stored in, the pouch. An opened ready-to- use vial should be used right away. Discard any ready-to-use vial if the solution is not colorless.
The drug compatibility (physical and chemical), efficacy and safety of BROVANA when mixed with • leg swelling
other drugs in a nebulizer have not been established.
• chest congestion or bronchitis
3. Squeeze all of the medicine from the ready-to-use BROVANA 15 mcg twice daily significantly improved bronchodilation compared to placebo over the 12 Women should be advised to contact their physician if they become pregnant or if they are nursing.
hours after dosing (FEV1 AUC0-12h). This improvement was maintained over the 12 week study period.
It is important that patients understand how to use BROVANA appropriately and how it should be Tell your healthcare provider if you get any side effect vial into the nebulizer medicine cup (reservoir) Following the first dose of BROVANA 15 mcg, the median time to onset of bronchodilation, defined by an used in relation to other medications to treat COPD they are taking (see the accompanying Med-
*Reported terms coded to "Lung Disorder" were predominantly pulmonary or chest congestion.
FEV1 increase of 15%, occurred at 6.7 min. When defined as an increase in FEV1 of 12% and 200 mL, the ication Guide and the Instructions for Using BROVANA).
that bothers you or that does not go away.
(Figure 2).
Adverse events occurring in patients treated with BROVANA 15 mcg twice daily with a frequency of time to onset of bronchodilation was 20 min after dosing. Peak bronchodilator effect was generally seenwithin 1-3 hours of dosing.
<2%, but greater than placebo were as follows: These are not all the side effects with BROVANA.
If additional adrenergic drugs are to be administered by any route, they should be used with caution Body as a Whole: abscess, allergic reaction, digitalis intoxication, fever, hernia, injection site pain,
In both clinical trials, compared to placebo, patients treated with BROVANA demonstrated improve- because the pharmacologically predictable sympathetic effects of BROVANA may be potentiated.
neck rigidity, neoplasm, pelvic pain, retroperitoneal hemorrhage Ask your healthcare provider or pharmacist for more ments in peak expiratory flow rates, supplemental ipratropium and rescue albuterol use.
When paroxetine, a potent inhibitor of CYP2D6, was co-administered with BROVANA at steady-state, Cardiovascular: arteriosclerosis, atrial flutter, AV block, congestive heart failure, heart block, myocar-
information. Call your doctor for medical advice about INDICATIONS AND USAGE
exposure to either drug was not altered. Dosage adjustments of BROVANA are not necessary when the dial infarct, QT interval prolonged, supraventricular tachycardia, inverted T-wave drug is given concomitantly with potent CYP2D6 inhibitors.
Digestive: constipation, gastritis, melena, oral moniliasis, periodontal abscess, rectal hemorrhage
side effects. You may report side effects to FDA at BROVANA (arformoterol tartrate) Inhalation Solution is indicated for the long term, twice daily (morn-ing and evening) maintenance treatment of bronchoconstriction in patients with chronic obstructive pul- Concomitant treatment with methylxanthines (aminophylline, theophylline), steroids, or diuretics may Metabolic and Nutritional Disorders: dehydration, edema, glucose tolerance decreased, gout, hyper-
monary disease (COPD), including chronic bronchitis and emphysema. BROVANA is for use by potentiate any hypokalemic effect of adrenergic agonists.
glycemia, hyperlipemia, hypoglycemia, hypokalemia nebulization only.
The ECG changes and/or hypokalemia that may result from the administration of non-potassium spar- Musculoskeletal: arthralgia, arthritis, bone disorder, rheumatoid arthritis, tendinous contracture
ing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially Nervous: agitation, cerebral infarct, circumoral paresthesia, hypokinesia, paralysis, somnolence, tremor
when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of How should I store BROVANA?
these effects is not known, caution is advised in the co-administration of beta-agonists with non-potas- Respiratory: carcinoma of the lung, respiratory disorder, voice alteration
BROVANA (arformoterol tartrate) Inhalation Solution is contraindicated in patients with a history of sium sparing diuretics.
hypersensitivity to arformoterol, racemic formoterol or to any other components of this product.
Skin and Appendages: dry skin, herpes simplex, herpes zoster, skin discoloration, skin hypertrophy
• Store BROVANA in a refrigerator between 36° to 46°F 4. Connect the nebulizer reservoir to the mouthpiece BROVANA, as with other beta2-agonists, should be administered with extreme caution to patients being Special Senses: abnormal vision, glaucoma
All LABA, including BROVANA, are contraindicated in patients with asthma without use of a long-term treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc (2° to 8°C) in the protective foil pouch. Protect from asthma control medication (see WARNINGS).
Urogenital: breast neoplasm, calcium crystalluria, cystitis, glycosuria, hematuria, kidney calculus, noc-
(Figure 3) or face mask (Figure 4).
interval because the action of adrenergic agonists on the cardiovascular system may be potentiated bythese agents. Drugs that are known to prolong the QT turia, PSA increase, pyuria, urinary tract disorder, urine abnormality.
c interval have an increased risk of ventricular light and excessive heat. Do not open a sealed pouch
arrhythmias. The concurrent use of intravenously or orally administered methylxanthines (e.g., amino- Overall, the frequency of all cardiovascular adverse events for BROVANA in the two placebo controlled • ASTHMA RELATED DEATH
phylline, theophylline) by patients receiving BROVANA has not been completely evaluated. In two trials was low and comparable to placebo (6.9% in BROVANA 15 mcg twice daily and 13.3% in the until you are ready to use a dose of BROVANA.
combined 12-week placebo controlled trials that included BROVANA doses of 15 mcg twice daily, 25 mcg placebo group). There were no frequently occurring specific cardiovascular adverse events for Long-acting beta2-adrenergic agonists increase the risk of asthma-related death. The safety
After opening the pouch, unused ready-to-use vials
twice daily, and 50 mcg once daily, 54 of 873 BROVANA-treated subjects received concomitant theo- BROVANA (frequency ≥1% and greater than placebo). The rate of COPD exacerbations was also com- and efficacy of BROVANA in patients with asthma have not been established. All LABA, in-
phylline at study entry. In a 12-month controlled trial that included a 50 mcg once daily BROVANA dose, parable between the BROVANA 15 mcg twice daily and placebo groups, 12.2% and 15.1%, respectively.
cluding BROVANA, are contraindicated in patients with asthma without use of a long-term
should be returned to, and stored in, the pouch.
30 of the 528 BROVANA-treated subjects received concomitant theophylline at study entry. In these trials, asthma control medication (see CONTRAINDICATIONS).
Other adverse reactions which may occur with selective beta2-adrenoceptor agonists such as BROVANA heart rate and systolic blood pressure were approximately 2-3 bpm and 6-8 mm Hg higher, respectively, include: angina, hypertension or hypotension, tachycardia, arrhythmias, nervousness, headache, An opened ready-to-use vial should be used right
in subjects on concomitant theophylline compared with the overall population.
° A 28-week, placebo-controlled US study comparing the safety of salmeterol with placebo, each tremor, dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, added to usual asthma therapy, showed an increase in asthma-related deaths in patients re- Beta-adrenergic receptor antagonists (beta-blockers) and BROVANA may interfere with the effect of hyperglycemia, metabolic acidosis and insomnia.
away. BROVANA may be used directly from the
ceiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated each other when administered concurrently. Beta-blockers not only block the therapeutic effects of with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is con- Drug Abuse and Dependence
beta-agonists, but may produce severe bronchospasm in COPD patients. Therefore, patients with COPD sidered a class effect of the long-acting beta2-adrenergic agonists, including BROVANA. No should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as pro- There were no reported cases of abuse or evidence of drug dependence with the use of BROVANA in study adequate to determine whether the rate of asthma related death is increased in patients phylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-block- • BROVANA may also be stored at room temperature the clinical trials.
treated with BROVANA has been conducted.
ers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although between 68°F to 77°F (20°C to 25°C) for up to 6 weeks they should be administered with caution.
° Clinical studies with racemic formoterol (Foradil® Aerolizer™) suggested a higher incidence of serious asthma exacerbations in patients who received racemic formoterol than in those who Carcinogenesis, Mutagenesis, Impairment of Fertility
The expected signs and symptoms associated with overdosage of BROVANA (arformoterol tartrate) (42 days). If stored at room temperature, discard received placebo. The sizes of these studies were not adequate to precisely quantify the differ- 5. Connect the nebulizer to the compressor (Figure 5).
ences in serious asthma exacerbation rates between treatment groups.
Long-term studies were conducted in mice using oral administration and rats using inhalation admin- Inhalation Solution are those of excessive beta-adrenergic stimulation and/or occurrence or exagger- BROVANA if it is not used after 6 weeks or if past istration to evaluate the carcinogenic potential of arformoterol.
ation of any of the signs and symptoms listed under ADVERSE REACTIONS, e.g., angina, hypertension
• The studies described above enrolled patients with asthma. Data are not available to deter-
or hypotension, tachycardia, with rates up to 200 bpm, arrhythmias, nervousness, headache, tremor, mine whether the rate of death in patients with COPD is increased by long-acting beta
the expiration date, whichever is sooner. Space is In a 24-month carcinogenicity study in CD-1 mice, arformoterol caused a dose-related increase in the dry mouth, palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia, hyper- incidence of uterine and cervical endometrial stromal polyps and stromal cell sarcoma in female mice glycemia, metabolic acidosis and insomnia. As with all inhaled sympathomimetic medications, cardiac provided on the packaging to record room at oral doses of 1 mg/kg and above (AUC exposure approximately 70 times adult exposure at the max- arrest and even death may be associated with an overdose of BROVANA.
• BROVANA is indicated for the long term, twice daily (morning and evening) maintenance treat-
imum recommended daily inhalation dose).
ment for bronchoconstriction in chronic obstructive pulmonary disease (COPD), and is not in-
Treatment of overdosage consists of discontinuation of BROVANA together with institution of appropri- temperature storage times.
dicated for the treatment of acute episodes of bronchospasm, i.e., rescue therapy.
In a 24-month carcinogenicity study in Sprague-Dawley rats, arformoterol caused a statistically sig- ate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker nificant increase in the incidence of thyroid gland c-cell adenoma and carcinoma in female rats at an may be considered, bearing in mind that such medication can produce bronchospasm. There is insuf- • Do not use BROVANA after the expiration date • BROVANA should not be initiated in patients with acutely deteriorating COPD, which may be a
inhalation dose of 200 mcg/kg (AUC exposure approximately 130 times adult exposure at the maximum ficient evidence to determine if dialysis is beneficial for overdosage of BROVANA. Cardiac monitoring is life-threatening condition. The use of BROVANA in this setting is inappropriate.
recommended daily inhalation dose). There were no tumor findings with an inhalation dose of 40 recommended in cases of overdosage.
provided on the foil pouch and ready-to-use vial.
• BROVANA should not be used in children as the safety and efficacy of BROVANA have not been
mcg/kg (AUC exposure approximately 55 times adult exposure at the maximum recommended daily established in pediatric patients.
inhalation dose).
Clinical signs in dogs included flushing of the body surface and facial area, reddening of the ears and • BROVANA should be colorless. Discard BROVANA if gums, tremor, and increased heart rate. A death was reported in dogs after a single oral dose of 5 mg/kg • BROVANA should not be used in conjunction with other inhaled, long-acting beta2-agonists.
Arformoterol was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacteria, (approximately 4500 times the maximum recommended daily inhalation dose in adults on a mg/m2 it is not colorless.
BROVANA should not be used with other medications containing long-acting beta2-agonists.
chromosome aberration analyses in mammalian cells, and micronucleus test in mice.
basis). Death occurred for a rat that received arformoterol at a single inhalation dose of 1600 mcg/kg • When beginning treatment with BROVANA, patients who have been taking inhaled, short-
Arformoterol had no effects on fertility and reproductive performance in rats at oral doses up to (approximately 430 times the maximum recommended daily inhalation dose in adults on a mg/m2 • Keep BROVANA and all medicines out of the reach
acting beta
10 mg/kg (approximately 2700 times the maximum recommended daily inhalation dose in adults on 2-agonists on a regular basis (e.g., four times a day) should be instructed to dis-
continue the regular use of these drugs and use them only for symptomatic relief of acute
a mg/m2 basis).
of children.
6. Sit in a comfortable, upright position. Place the DOSAGE AND ADMINISTRATION
Pregnancy: Teratogenic Effects
• See PRECAUTIONS, Information for Patients and the accompanying Medication Guide.
The recommended dose of BROVANA (arformoterol tartrate) Inhalation Solution for COPD patients is mouthpiece in your mouth (Figure 6) (or put on the
Pregnancy Category C
15 mcg administered twice a day (morning and evening) by nebulization. A total daily dose greater General Information about BROVANA
Arformoterol has been shown to be teratogenic in rats based upon findings of omphalocele (umbilical than 30 mcg (15 mcg twice daily) is not recommended. BROVANA should be administered by the in- face mask) and turn on the compressor.
hernia), a malformation, at oral doses of 1 mg/kg and above (AUC exposure approximately 370 times haled route via a standard jet nebulizer connected to an air compressor (see the accompanying Med-
As with other inhaled beta2-agonists, BROVANA can produce paradoxical bronchospasm that may be adult exposure at the maximum recommended daily inhalation dose). Increased pup loss at birth and ication Guide). BROVANA should not be swallowed. BROVANA should be stored refrigerated in foil
life-threatening. If paradoxical bronchospasm occurs, BROVANA should be discontinued immediately Medicines are sometimes prescribed for purposes not during lactation and decreased pup weights were observed in rats at oral doses of 5 mg/kg and above pouches. After opening the pouch, unused ready-to-use vials should be returned to, and stored in, the and alternative therapy instituted.
(AUC exposure approximately 1100 times adult exposure at the maximum recommended daily inhala- pouch. An opened ready-to-use vial should be used right away.
mentioned in a Medication Guide. Do not use BROVANA Deterioration of Disease
tion dose). Delays in development were evident with an oral dose of 10 mg/kg (AUC exposure ap- If the recommended maintenance treatment regimen fails to provide the usual response, medical proximately 2400 times adult exposure at the maximum recommended daily inhalation dose).
for a condition for which it was not prescribed. Do not advice should be sought immediately, as this is often a sign of destabilization of COPD. Under these COPD may deteriorate acutely over a period of hours or chronically over several days or longer. IfBROVANA no longer controls the symptoms of bronchoconstriction, or the patient's inhaled, short- Arformoterol has been shown to be teratogenic in rabbits based upon findings of malpositioned right circumstances, the therapeutic regimen should be re-evaluated and additional therapeutic options give BROVANA to other people, even if they have the kidney, a malformation, at oral doses of 20 mg/kg and above (AUC exposure approximately 8400 times should be considered.
2-agonist becomes less effective or the patient needs more inhalation of short-acting beta2- agonist than usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of adult exposure at the maximum recommended daily inhalation dose). Malformations including brachy- No dose adjustment is required for patients with renal or hepatic impairment. However, since the clear- same condition. It may harm them.
the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage dactyly, bulbous aorta, and liver cysts were observed at doses of 40 mg/kg and above (approximately ance of BROVANA is prolonged in patients with hepatic impairment, they should be monitored closely.
of BROVANA beyond the recommended 15 mcg twice daily dose is not appropriate in this situation.
22,000 times the maximum recommended daily inhalation dose in adults on a mg/m2 basis). Malfor- This Medication Guide summarizes the most important mation including adactyly, lobular dysgenesis of the lung, and interventricular septal defect were ob- The drug compatibility (physical and chemical), efficacy, and safety of BROVANA when mixed with served at 80 mg/kg (approximately 43,000 times the maximum recommended daily inhalation dose in other drugs in a nebulizer have not been established.
information about BROVANA. If you would like more adults on a mg/m2 basis). Embryolethality was observed at 80 mg/kg/day (approximately 43,000 times The safety and efficacy of BROVANA have been established in clinical trials when administered using BROVANA, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some the maximum recommended daily inhalation dose in adults on a mg/m2 basis). Decreased pup body the PARI LC PLUS® nebulizers and PARI DURA-NEB® 3000 compressors. The safety and efficacy of information, talk with your healthcare provider. You patients as measured by increases in pulse rate, blood pressure, and/or symptoms. Although such weights were observed at doses of 40 mg/kg/day and above (approximately 22,000 times the maximum BROVANA when administered using other nebulizer systems has not been established.
effects are uncommon after administration of BROVANA at the recommended dose, if they occur, the recommended daily inhalation dose in adults on a mg/m2 basis). There were no teratogenic findings can ask your healthcare provider or pharmacist for drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG in rabbits with oral dose of 10 mg/kg and lower (AUC exposure approximately 4900 times adult expo- changes, such as flattening of the T wave, prolongation of the QT HOW SUPPLIED
c interval, and ST segment depression.
information about BROVANA that was written for sure at the maximum recommended daily inhalation dose).
The clinical significance of these findings is unknown. BROVANA, as with other sympathomimetic 7. Breathe as calmly, deeply, and evenly as possible BROVANA (arformoterol tartrate) Inhalation Solution is supplied in a single strength (15 mcg of arfor- amines, should be used with caution in patients with cardiovascular disorders, especially coronary There are no adequate and well-controlled studies in pregnant women. BROVANA should be used dur- moterol, equivalent to 22 mcg of arformoterol tartrate) as 2 mL of a sterile solution in low-density until no more mist is formed in the nebulizer insufficiency, cardiac arrhythmias, and hypertension (see PRECAUTIONS, General).
ing pregnancy only if the potential benefit justifies the potential risk to the fetus.
polyethylene (LDPE) ready-to-use vials overwrapped in foil. BROVANA is available in a shelf-cartoncontaining 30 or 60 ready-to-use vials.
• For customer service, call 1-888-394-7377.
reservoir. It takes about 5 to 10 minutes for each Immediate Hypersensitivity Reactions
Use in Labor and Delivery
NDC 63402-911-30: carton of 30 individually pouched ready-to-use vials.
Immediate hypersensitivity reactions may occur after administration of BROVANA as demonstrated by There are no human studies that have investigated the effects of BROVANA on preterm labor or labor • To report side effects, call 1-877-737-7226.
cases of anaphylactic reaction, urticaria, angioedema, rash and bronchospasm.
NDC 63402-911-64: carton of 60 ready-to-use vials (15x4 ready-to-use vial pouches).
Because beta-agonists may potentially interfere with uterine contractility, BROVANA should be used dur- CAUTION: Federal law (U.S.) prohibits dispensing without prescription.
• For medical information, call 1-800-739-0565.
Do Not Exceed Recommended Dose
8. Clean the nebulizer (see manufacturer's instructions).
ing labor and delivery only if the potential benefit justifies the potential risk.
Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Aswith other inhaled beta 2-adrenergic drugs, BROVANA should not be used more often, at higher doses Store BROVANA in the protective foil pouch under refrigeration at 36°-46°F (2°-8°C). Protect from than recommended, or with other long-acting beta-agonists.
Instructions for Using BROVANA (arformoterol tartrate)
In reproductive studies in rats, arformoterol was excreted in the milk. It is not known whether arfor- light and excessive heat. After opening the pouch, unused ready-to-use vials should be returned to, and moterol is excreted in human milk. Because many drugs are excreted in human milk, caution should stored in, the pouch. An opened ready-to-use vial should be used right away. Discard any ready-to-use This Medication Guide has been approved by the Food be exercised when BROVANA is administered to a nursing woman.
vial if the solution is not colorless. Unopened foil pouches of BROVANA can also be stored at room tem-perature 68°-77°F, (20°-25°C) for up to 6 weeks. If stored at room temperature, discard if not used after 6 weeks or if past the expiration date, whichever is sooner.
BROVANA is used only in a standard jet nebulizer
and Drug Administration.
BROVANA (arformoterol tartrate) Inhalation Solution should not be used to treat acute symptoms of BROVANA is approved for use in the long term maintenance treatment of bronchoconstriction associ- COPD. BROVANA has not been studied in the relief of acute symptoms and extra doses should not be machine connected to an air compressor. Make sure
ated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. This used for that purpose. When prescribing BROVANA, the physician should also provide the patient with disease does not occur in children. The safety and effectiveness of BROVANA in pediatric patients have an inhaled, short-acting beta2-agonist for treatment of COPD symptoms that occur acutely, despite you know how to use your nebulizer machine before
not been established.
regular twice-daily (morning and evening) use of BROVANA. Patients should also be cautioned thatincreasing inhaled beta you use it to breathe-in BROVANA or other medicines.
2-agonist use is a signal of deteriorating disease for which prompt medical Manufactured for: attention is indicated (see Information for Patients and the accompanying Medication Guide).
Of the 873 patients who received BROVANA in two placebo-controlled clinical studies in adults with COPD, Sunovion Pharmaceuticals Inc.
Manufactured for: BROVANA, like other sympathomimetic amines, should be used with caution in patients with cardio- 391 (45%) were 65 years of age or older while 96 (11%) were 75 years of age or older. No overall dif- Marlborough, MA 01752 USA Do not mix BROVANA with other medicines in your
vascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in pa- ferences in safety or effectiveness were observed between these subjects and younger subjects. Among BROVANA is a registered trademark of Sunovion Pharmaceuticals Inc.
Sunovion Pharmaceuticals Inc.
tients with convulsive disorders or thyrotoxicosis; and in patients who are unusually responsive to subjects age 65 years and older, 129 (33%) received BROVANA at the recommended dose of 15 mcg twice For customer service, call 1-888-394-7377.
sympathomimetic amines. Clinically significant changes in systolic and/or diastolic blood pressure, Marlborough, MA 01752 USA daily, while the remainder received higher doses. ECG alerts for ventricular ectopy in patients 65 to ≤75 pulse rate and electrocardiograms have been seen infrequently in individual patients in controlled clin- years of age were comparable among patients receiving 15 mcg twice daily, 25 mcg twice daily, and To report adverse events, call 1-877-737-7226.
BROVANA comes sealed in a foil pouch. Do not open ical studies with arformoterol tartrate. Doses of the related beta2-agonist albuterol, when administered placebo (3.9%, 5.2%, and 7.1%, respectively). A higher frequency (12.4%) was observed when BROVANA For medical information, call 1-800-739-0565.
intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
was dosed at 50 mcg once daily. The clinical significance of this finding is not known. Other reported a sealed pouch until you are ready to use a dose of BROVANA is a registered trademark of clinical experience has not identified differences in responses between the elderly and younger patients, Beta-agonist medications may produce significant hypokalemia in some patients, possibly though but greater sensitivity of some older individuals cannot be ruled out.
intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease BROVANA. After opening the pouch, unused ready-to-use Sunovion Pharmaceuticals Inc.
in serum potassium is usually transient, not requiring supplementation.
vials should be returned to, and stored in, the pouch.
Clinically significant changes in blood glucose and/or serum potassium were infrequent during clini-cal studies with long-term administration of BROVANA at the recommended dose.
Experience in Adult Patients with COPD
An opened ready-to-use vial should be used right away.
Of the 1,456 COPD patients in the two 12-week, placebo-controlled trials, 288 were treated with Information for Patients
BROVANA (arformoterol tartrate) Inhalation Solution 15 mcg twice daily and 293 were treated with Patients should be instructed to read the accompanying Medication Guide with each new pre-
placebo. Doses of 25 mcg twice daily and 50 mcg once daily were also evaluated. The numbers and 1. Open the foil pouch by tearing on the rough edge scription and refill. The complete text of the Medication Guide is reprinted at the end of this docu-
percent of patients who reported adverse events were comparable in the 15 mcg twice daily and placebo ment. Patients should be given the following information:
along the seam of the pouch. Remove a ready-to-use Patients should be informed that long-acting beta2-adrenergic agonists, such as BROVANA, The following table shows adverse events where the frequency was greater than or equal to 2% in the vial of BROVANA.
increase the risk of asthma-related death. All LABA, including BROVANA, should not be used in BROVANA 15 mcg twice daily group and where the rates of adverse events in the BROVANA 15 mcg patients with asthma without use of a long-term asthma control medication (see CONTRA-
twice daily group exceeded placebo. Ten adverse events demonstrated a dose relationship: asthenia, fever, bronchitis, COPD, headache, vomiting, hyperkalemia, leukocytosis, nervousness, and tremor.

Source: http://ronstoppable.github.io/BrovanaApprovedLabelingText.pdf