Drug Use Criteria: Ivacaftor (Kalydeco ) and Lumacaftor/Ivacaftor (Orkambi )

Transcription

1 Texas Vendor Program Use Criteria: (Kalydeco ) and Lumacaftor/ (Orkambi ) Publication History Developed: October 2012 Revised: December 2017; February 2016; June Notes: Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document. Medications listed in the tables and non-fda approved indications included in these retrospective criteria are not indicative of Vendor Program formulary coverage. Prepared by: Information Service, UT Health San Antonio. The College of Pharmacy, the University of Texas at Austin. i

2 1 Dosage [1-7] is categorized as a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator. Cystic fibrosis (CF) occurs as a result of genetic mutations of the CFTR causing mucosal obstruction of the distal lung airway and submucosal glands. Malfunction of the CFTR alters electrolyte homeostasis which changes cell potentials and can lead to organ damage in CF patients. Patient genotyping shows that approximately 4% of the 30,000 CF patients in America are believed to have a G551D-CFTR mutation. targets multi-organ chloride channels at the surface of epithelial cells to enhance the opening of the G551D-CFTR protein. was initially FDA-approved for treating CF patients age six years and older who have a G551D mutation of the CFTR gene in Most recently, has gained additional FDA approval to include CF patients 2 years and older with G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H CFTR gene mutations. Patients who are homozygous for the F508del mutation in the CFTR gene are unaffected by potentiation. is available as 50 mg or 75 mg granule packets or 150 mg tablets. A new combination product containing lumacaftor and (Orkambi ) was approved July 2nd, 2015 for use in patients with two copies of the F508del mutation. The F508del mutation is the most common cause of CF, with approximately half of the CF population in the U.S. being homozygous for the mutation. The combined effect of lumacaftor and increases the quantity (lumacaftor) and function () of the F508del-CFTR ion channel, resulting in improved channel function and clinical benefit. Lumacaftor/ is available as 200 mg/125 mg and 100 mg/125 mg tablets. 1.1 Adults The recommended dose of in adults is one 150 mg tablet taken orally every 12 hours (300 mg total daily dose) with fat-containing food. Doses should be reduced to 150 mg twice weekly in patients receiving strong CYP3A inhibitors ketoconazole) concurrently, and 150 mg once daily in patients receiving adjunctive moderate CYP3A4 inhibitors fluconazole). Lumacaftor/ combination dosage recommendations include two lumacaftor 200 mg/ 125 mg tablets every 12 hours (total daily dose of lumacaftor 800 1

3 mg/ 500 mg). Doses should be reduced to lumacaftor 200 mg/ 125 mg once daily in patients receiving strong CYP3A inhibitors for the first week, followed by lumacaftor 400 mg/ 250 mg every 12 hours thereafter. No dosage adjustments are needed if initiating CYP3A inhibitors in patients already taking Dosing in Renal Impairment Because and have not been studied in patients with renal insufficiency, these medications should be used cautiously in patients with CrCl less than or equal to 30 ml/min Dosing in Hepatic Impairment It is recommended that ALT and AST values be assessed prior to initiating, every 3 months during the first year, and annually thereafter. Dosing should be interrupted in patients with ALT or AST values of greater than 5 times the upper limit of normal (ULN). Following the resolution of transaminase elevations, consider the benefits and risks of resuming. Table 1 summarizes dosing recommendations in patients with hepatic impairment. Table 1. Dosing in Hepatic Impairment Child-Pugh Class Recommendation A B C No dosage adjustment 150 mg once daily 150 mg once daily or less frequently (not studied) Table 2 summarizes /lumacaftor dosing recommendations in patients with hepatic impairment. Table 2. /Lumacaftor Dosing in Hepatic Impairment Child-Pugh Class Recommendation A B C No dosage adjustment Lumacaftor 400 mg/ 250 mg in morning, and lumacaftor 200 mg/ 125 mg in evening Maximum dose of lumacaftor 200 mg/ 125 mg every 12 hours; use with caution 2

4 1.2 Pediatrics Table 3 summarizes dosing recommendations for pediatric patients. safety and efficacy in children less than 2 years of age have not been established. Safety and efficacy of combination therapy in children less than 6 years of age have not been established. Adult dosing regimens should be used for patients greater than or equal to 12 years of age. All doses should be administered with fat-containing food. Table 3. and Lumacaftor/ Dosing in Pediatric Patients Therapy Patient Age Usual Recommended Dose Total Daily Dose Monotherapy < 2 years old Not recommended Not recommended Monotherapy 2 5 years old and < 14 kg One 50 mg packet every 12 hours 100 mg/day Monotherapy 2-5 years old and > 14 kg One 75 mg packet every 12 hours 150 mg/day Monotherapy 6 years old One 150 mg tablet every 12 hours 300 mg/day Lumacaftor/ Combination Therapy < 6 years old Not recommended Not recommended Lumacaftor/ Combination Therapy 6-11 years old Two lumacaftor 100 mg/ 125 mg tablets every 12 hours lumacaftor 400 mg/ 500 mg per day Lumacaftor/ Combination Therapy 12 years old Two lumacaftor 200 mg/ 125 mg tablets every 12 hours lumacaftor 800 mg/ 500 mg per day 2 Duration of Therapy [1-10] There is no basis for limiting the duration of in CF patients who have a GG551D mutation of the CFTR gene. Randomized, double-blind, placebo-controlled trials have shown a significant increase in pulmonary function following 3

5 therapy in patients with GG551D mutations, with maintenance of effect and safety data through 48 weeks. While treatment duration in the available clinical trial lasted only 16 weeks, CF patients with G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, and S549R mutations may benefit from long-term therapy provided that improved treatment response is observed. R117H mutations were studied until week 24, but may benefit from longer therapy. Lumacaftor/ combination product efficacy has been demonstrated in randomized, double-blind, placebocontrolled, 24-week trials. Although not directly studied beyond 24 weeks, CF patients with F508del mutations may benefit from long-term therapy. 3 - Interactions Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. -drug interactions considered clinically relevant for are summarized in Table 4. Only those drug-drug interactions classified as clinical significance level 1 or those considered lifethreatening which have not yet been classified will be reviewed: [1-6, 11] Table 4. and Lumacaftor/ - Interactions Target Interacting Interaction Recommendation Clinical Significanc e Level strong CYP3A inhibitors ketoconazole, voriconazole, posaconazole, telithromycin, clarithromycin) Concurrent use significantly increased exposure (8.5- fold in AUC with ketoconazole) Reduce dose to 150 mg twice weekly in patients 6 years; reduce dose to one 50 mg packet twice weekly in patients 2-5 years old and < 14 kg; reduce dose to one 75 mg packet twice weekly in patients 2-5 years old and 14 kg major (Reax) 4

6 Target Interacting Interaction Recommendation Clinical Significanc e Level moderate CYP3A inhibitors fluconazole) concurrent use increased exposure (3- fold AUC with fluconazole) reduce dose to 150 mg once daily in patients 6 years; reduce dose to one 50 mg packet once daily in patients 2 5 years old and < 14 kg; reduce dose to one 75 mg packet once daily in patients 2 5 years old and 14 kg; food containing grapefruit or Seville oranges should be avoided while taking moderate (Reax), strong CYP3A inducers rifampin, phenobarbital, carbamazepin e, phenytoin, St. John s wort) concurrent use decreased exposure [9- fold AUC with rifampin (57% )] strong CYP3A inducers should be avoided while taking, major (Rea x) CYP3A and/or P- glycoprotein (P-gp) substrates midazolam, alprazolam, cyclosporine, tacrolimus) is weak CYP3A and P-gp transport inhibitor; concurrent use with midazolam midazolam AUC 1.5-fold use with caution and monitor drugrelated side effects and/or monitor therapeutic levels tacrolimus : 2- major; others - 3- moderate moderate (Rea x) 5

7 Target Interacting Interaction Recommendation Clinical Significanc e Level CYP3A substrates (antibiotics, antifungals) lumacaftor is strong CYP3A inducer; concurrent use may result in reduced efficacy of CYP3A substrates consider alternative antibiotics such as azithromycin, ciprofloxacin, or levofloxacin whenever possible; if an antifungal is required, monitor for breakthrough fungal infection; consider alternative treatment with fluconazole whenever possible major (Rea x) hormonal contraceptive concurrent administration may reduce hormonal contraceptive exposure and efficacy and may increase menstruationassociated adverse events menorrhagia) avoid concurrent use; use alternate methods of birth control major (Rea x) 6

8 Target Interacting Interaction Recommendation Clinical Significanc e Level lumacaftor / warfarin warfarin exposure may be modified with adjunctive administratio n, as is CYP3A4 inducer, the enzyme that metabolizes R-warfarin, and has potential to induce CYP2C9, the primary enzyme that metabolizes S-warfarin monitor international normalized ratio and adjust warfarin dosages as needed moderat e (Re ax) * CP = Clinical Pharmacology AUC = area under the curve 4 References 1. DRUGDEX System (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at micromedexsolutions.com.libproxy.uthscsa.edu/. Accessed December 4, Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; Available at clinicalpharmacologyip.com.ezproxy.lib.utexas.edu/. Accessed December 4, Lexi-s Online. Lexi-Comp Online [database online]. Hudson, OH: Lexi-Comp, Inc.; Available at online.lexi.com.ezproxy.lib.utexas.edu. Accessed December 4,

9 4. Facts and Comparisons eanswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Information, Inc.; Available at eanswers.factsandcomparisons.com.ezproxy.lib.utexas.edu/. Accessed December 4, (Kalydeco ) package insert. Vertex Pharmaceuticals, Inc., July Lumacaftor/ (Orkambi ) package insert. Vertex Pharmaceuticals, Inc., September U.S. Food and Administration. FDA approves new treatment for cystic fibrosis. Available at fda.gov/newsevents/newsroom/pressannouncements/ucm htm. Accessed February 22, Wright CC, Vera YY. Chapter 29. Cystic fibrosis. In: Talbert RL, DiPiro JT, Matzke GR, et al, eds. Pharmacotherapy: a pathophysiologic approach. 10th ed. New York: McGraw-Hill; Available at accesspharmacy.mhmedical.com.ezproxy.lib.utexas.edu/content.aspx?bookid =1861&sectionid= Accessed December 4, Ramsey BW, Davies J, McElvaney NG, et al. A CFTR potentiator in patients with cystic fibrosis and the GG51D mutation. N Engl J Med. 2011; 365(18): Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of in patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J Respir Crit Care Med. 2013; 187(11): DRUG-REAX System (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at micromedexsolutions.com.libproxy.uthscsa.edu/. Accessed December 4,