Drug Monograph and Literature Review: "Arcapta Neohaler"
Arcapta™ Neohaler™Drug Monograph andLiterature ReviewJoy A. Awoniyi4th Year Professional Pharmacy StudentFlorida Agricultural and Mechanical UniversityCollege of Pharmacy and Pharmaceutical SciencesCommunity Health Systems Pharmacy RotationWalgreens Store #9915Preceptor: Dr. Kayon Samuels-Dennis
Arcapta Neohaler® Indacaterol Maleate Inhalation PowderFDA APPROVAL DATE: July 1, 2011INDICATIONS AND USES: Indacaterol is approved for the use of chronic obstructive pulmonary disease (COPD) This drug is NOT indicated for the treatment of asthma or acute deteriorations of COPD Safety and effectiveness of Indacaterol has not been established in pediatric patients Holds the place in therapy as the first once daily long acting beta agonist approved in the United StatesDOSAGE FORMS AND STRENGTHS: The active medication is supplied in gelatin capsules containing a dry powder blend of 75mcg of Indacaterol maleate with 25mg of lactose monohydrate as a carrier. o Capsules are packaged in aluminum blister-cards o Unit dose blister pack is supplied in a box containing 30 capsules (5 blister cards, 6 capsules each) The capsules containing active medication may only be used with the Neohaler inhaler. Also available as Obrenz™, Hirobriz™, and Oslif™ in other countries for use at higher dosesMECHANISM OF ACTION:Indacaterol maleate is a long-acting beta-2-adrenergic agonist. When inhaled, the drug stimulates adenyl cyclaseintracellularly. Adenyl cyclase is the enzyme responsible for catalyzing the conversion of adenosine triphosphate (ATP) tocyclic adenosine monophosphate (AMP). Increasing the levels of this enzyme causes the relaxation of the bronchialsmooth muscle. Therefore, this medication acts locally as a bronchodilator in the lungs.Although beta-2-adrenergic receptors are located primarily in the bronchial smooth muscle, there are also receptors inthe human heart that comprise 10%-50% of the total adrenergic receptors. Therefore, even drugs that are highly beta-2selective may have cardiac effects.PHARMACOKINETICS: Absorption o Steady state is achieved within 10-15 days of repeated once daily administration 2 ARCAPTA™ NEOHALER™ DRUG MONOGRAPH AND LITERATURE REVIEW
o The bioavailability following oral inhalation is 43% - 45% o The time to maximum concentration (Tmax) is 15 minutes Distribution o Vd = 2361 – 2557 Liters o Protein Binding Human Serum Protein Binding: 94.1 – 95.3% Plasma Protein Binding: 95.1 – 96.2% Elimination o Elimination half-life: 40 – 56 hours o Clearance Rate: 18.8 – 23.3 liters per hour o Excretion Fecal: 90% or greater Renal: less than 2% unchanged at a rate of 0.46 – 1.2 liters per hourCONTRAINDICATIONS: Arcapta, along with all long acting beta-2-agonists are contraindicated in patients with asthma without the use of a long-term asthma control medication Arcapta is also contraindicated in patients with a known hypersensitivity to the drugWARNINGS AND PRECAUTIONS: Asthma Related Death (Black Box Warning) o May increase the risk of asthma-related death. Data is not yet available to determine whether the rate of death in patients with COPD is increased with long acting beta-2-adrenergic agonists. Deterioration of Disease and Acute Episodes o Arcapta should not be used in patients with acutely deteriorating COPD, which may be a life threatening condition, as it has not been studied under these conditions. It should not be used for the relief of acute symptoms o Patients who begin therapy with this medication and have been using short acting beta agonist medications on a regular basis (four or more times per day) should be instructed to stop the regular use of the short acting medication and use them for symptomatic relieve of acute respiratory symptoms. Paradoxical Bronchospasm o This medication is associated with the serious side effect of paradoxical bronchospasm. If this condition occurs, the medication should be discontinued and an alternative therapy instituted. Cardiovascular Effects o Patients should be advised not to exceed recommended daily doses. Excessive doses may result in potentially fatal cardiovascular effects including increases in pulse rate, systolic or diastolic blood pressure. The drug may need to be discontinued if the medication was given within normal dosage ranges. o The drug should be used with caution in patients with cardiovascular disorders as other medications in its class have been associated with ECG changes, such s flattening of the T wave, prolongation of the QTc interval and ST segment depression. Coexisting Conditions o Use with caution in patients with convulsive disorders or thyrotoxicosis. o Use with caution in patients who are unusually responsive to sympathomimetic amines o Arcapta is related to a beta-2 agonist, albuterol, that has been reported to aggravate preexisting diabetes mellitus and ketoacidosis Hypokalemia and Hyperglycemia o Beta-2 agonists may produce significant hypokalemia in some patients through intracellular shunting. This decrease in potassium is usually transient and does not require supplementation o Inhaling high doses of beta-2 adrenergic agonist may produce increases in plasma glucose. The medication has not been investigated in patients whose diabetes mellitus is not well controlled. ARCAPTA™ NEOHALER™ DRUG MONOGRAPH AND LITERATURE REVIEW 3
SPECIFIC POPULATIONS: Pregnancy. Category C. Although Indacaterol was not teratogenic following subcutaneous administrations to rats and rabbits, there are no adequate and well-controlled clinical studies using Arcapta in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery. There are no adequate and well-controlled human studies that have investigated effects of Arcapta on preterm labor or at labor term. o Beta-agonists have the potential to interfere with uterine contractility; therefore, use of this medication during labor should be restricted to patients in whom benefits clearly outweigh the risks. Pediatric Use. Safety and effectiveness have not been established in children. Geriatric Use. No dosing adjustment is warranted in geriatric patients. No overall differences in effectiveness have been observed and the adverse drug reaction profile was similar in the elderly population. Hepatic Impairment. Patients with mild and moderate hepatic impairment showed no relevant changes in Cmax or AUC. In addition there were no changes in protein bindings between this group of individuals and their healthy controls. Subjects with severe hepatic impairment were not studied. Renal Impairment. Studies in renally impaired patients were not performed due to the very low contribution of the urinary pathway to total body elimination of the drug. (See “Pharmacokinetics”)ADVERSE EFFECTS: The most commonly reported adverse reactions are related to the neurologic and respiratory systems o Headache: 5.1% o Cough: 6.5% - 24% The cough observed in clinical trials usually occurred within 15 seconds following inhalation and lasted no more than 15 seconds. In clinical trials, this side effect was not associated with bronchospasm, exacerbations, deteriorations or disease, or loss of efficacy o Nasopharyngitis: 5.3% Paradoxical bronchospasm may occur as a severe adverse effect Post-marketing experience revealed additional adverse reactions o Tachycardia/heart rate increase/palpitations o Pruritus/rash o DizzinessDRUG INTERACTIONS Adrenergic Drugs. Additional adrenergic drugs, administered by any route, should be used with caution because the sympathetic effects of Arcapta may be potentiated Strong Dual Inhibitors of CYP3A4 and P-gp. These drugs may delay the systemic clearance of Indacaterol almost 2 fold. o No dose adjustment is warranted o Examples of dual inhibitors include ketoconazole, erythromycin, verapamil, and ritonavir Xanthine Derivatives, Steroids, or Diuretics. These drugs may potentiate any hypokalemic effect of Arcapta. o Non-potassium sparing diuretics may result in ECG changes or hypokalemia and these effects can be acutely worsened by beta-agonists, especially when the recommended dose is exceeded Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, QTc Prolonging Agents. These drugs are known to prolong the QTc interval and may increase the risk of ventricular arrhythmias when administered with Arcapta. Beta-Blockers. Beta-adrenergic receptor agonists may interfere with the effect of Arcapta when administered concurrently. Beta-blockers also have the potential to produce severe bronchospasm in COPD patients. o In the event that there are no acceptable alternatives to beta-blocker use (such as post myocardial infarction prophylaxis) patients with COPD are advised to be treated with cardio-selective beta-blocking agents. 4 ARCAPTA™ NEOHALER™ DRUG MONOGRAPH AND LITERATURE REVIEW
DOSING AND ADMINISTRATION: Dosing o The recommended dosage regimen for the treatment of adult patients is once daily inhalation of the contents contained in the supplied75 mcg capsule. o No dosage adjustment is required for geriatric patients, patients with mild and moderate hepatic impairment, or renally impaired patients Administration o The use of Arcapta capsule is indicated only with the Neohaler device. o The drug is administered by oral inhalation only. The capsules must not be swallowed, as the intended effects on the lungs will not be observed. o Arcapta should be used once daily every day at the same time of the day. The medication should not be utilized more than one time every 24 hours. o Upon missing a dose, the next dose should be taken as soon as it is remembered Overdosage o The expected signs and symptoms of overdosage are those associated with excessive stimulation of beta-adrenergic receptors. This includes angina, increase or decrease in blood pressure, tachycardia with rates up to 200 BPM, arrhythmias, nervousness, headache, tremors, dry mouth, palpitations, muscle craps, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia. o Cardiac monitoring is recommended in cases of overdoses o In single doses of 40 times the indicated dose, symptoms of moderate increases in pulse rate, systolic blood pressure, and QTc interval have been observed in COPD patientsMONITORING PARAMETERS: Improvement in FEV1 and COPD symptoms Frequency of rescue medication useSTORAGE AND STABILITY Arcapta capsules must always be stored in the blister. They should only be removed immediately before administration Store medication in a dry place at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) Protect capsule from light and moisture Patients are advised to always use the new Neohaler inhaler provided with each new prescription Keep out of the reach of children.COSTNo average wholesale price currently availableREFERENCES: 1. Indacaterol inhalation powder Monograph . DRUGDEX® Evaluations. Thompson RuetersMICROMEDEX® Healthcare Series 1.0. Last modified on August 24, 2011. 2. Product Information: Arcapta™ Neohaler™ oral inhalation powder, Indacaterol oral inhalation powder. Novartis Pharmaceuticals Corp, East Hanover, New Jersey, July 2011. 3. Chapman KR, Rennard SI, Dorga A, et al. Long-term Safety and Efficacy of Indacaterol, a Long-Acting Beta2-Agonist, in Subjects With COPD. Chest 2011; 140(1):68-75. 4. Dahl R, Chung KF, Buhl R, et al. Efficacy of a new once-daily long-acting inhaled beta2-agonist Indacaterol versus twice daily formoterol in COPD. Thorax 2010; 65:473-479. ARCAPTA™ NEOHALER™ DRUG MONOGRAPH AND LITERATURE REVIEW 5
LITERATURE REVIEW Long-term Safety and Efficacy of Indacaterol, a Long-Acting Efficacy of a new once-daily long-acting inhaled beta2- Title Beta2-Agonist, in Subjects With COPD agonist Indacaterol versus twice-daily formoterol in COPD (Chapman 2011) (Dahl 2010) To evaluate the 52-week long-term safety of To compare the efficacy and safety of Indacaterol with Purpose Indacaterol, its bronchodilator efficacy, and effects on twice daily LABA formoterol and placebo over one exacerbations and health status. year. Randomized, double-blinded, placebo-controlled Randomized, Double-blind, double-dummy, parallel trial group trial Extension of a randomized 1:1:1:1 26-week core Study treatments: Indacaterol 300mcg and 600mcg study involving double-blinded treatment with once daily + placebo, formoterol 12 mcg twice daily, Indacaterol 150 or 300mcg, placebo, or open label matching placebo twice daily. Salbutamol use as- Study Design and Methods Tiotropium. needed. Study treatments: Indacaterol 150mcg, 300mcg, or Inclusion: Age 40 yrs +, moderate-severe COPD, placebo smoking history of at least 20 pack years, FEV1<80% Inclusion: Moderate-Severe COPD (FEV1<80% >30% >30% predicted, FEV1/FVC ratio <70%. (n=1732) predicted), Age 40 yrs +, Smoking history of at least Exclusion: oral corticosteroid use, history of asthma, 20 pack years. (n=415) respiratory tract infection, hospitalization for COPD Exclusion: history of asthma, respiratory tract exacerbation within 6 wks. infection, or hospitalization for COPD exacerbation Assessments:Days 1,2, 15,29,84,113,168,197,253, within 6 wks. 364,365 for trough FEV1 values. Diary to record PEF Assessments: Day 1, Weeks 2,4,8,12,36,44, and 52 symptoms and salbutamol use, adverse events, or for recording of adverse events, vital signs, change in medications, and health status, dyspnea spirometry, and monitoring of ECG Efficacy Endpoints: Trough FEV1 at 52 weeks, time to Superiority of Indacaterol to placebo in the effect of Endpoints first COPD Exacerbation. trough FEV1 after 12 weeks. Albuterol use Days of poor COPD control, exacerbation rates Rate of Exacerbations (many others) St. George Respiratory Questionnaire total score Safety and tolerability Mild-moderate adverse events in 76% and 77% of Increased 24-hour pose dose FEV1 by 170mL vs. patients receiving Indacaterol compared to 68% placebo, 100 mL vs. formoterol. (P<0.001 for all) placebo. differences maintained at 52 weeks. Serious adverse events in 10.4, 12.3% of patients Symptomatic outcomes improved compared with receiving Indacaterol compared to 10.5% placebo. placebo for both treatments. Indacaterol increased FEV1 relative to placebo Indacaterol more effective than formoterol in Results (difference of at least 170 mL) by week 52. improving TID score (transition dyspnea index) and Compared to placebo, drug offered reduction in reducing need for as-needed salbutamol. COPD exacerbations (RR: 0.62-0.64; P<0.05) and Indacaterol well tolerated and good safety profile: albuterol use (1.2-1.4 puffs/day decrease, P<0.001) minimal impact on QTc interval and systemic Beta2- Health Status improvement with drug treatment, mediated events determined by decrease from baseline in mean total SGRQ score generally > 4 units. During one year of treatment, Indacaterol was well Once daily Indacaterol is an effective 24 hours Conclusion tolerated and provided significant and well-maintained bronchodilator that improves symptoms and health bronchodilation that was accompanied by improved status and confers clinical improvements over a twice clinical outcomes daily 12 hour LABA as treatment for patients with moderate to severe COPD*Journal articles provided 6 ARCAPTA™ NEOHALER™ DRUG MONOGRAPH AND LITERATURE REVIEW