Cystic Fibrosis Module #2: Chronic Medications: Changing the Course of Cystic Fibrosis. Chronic Medications: Changing the Course of Cystic Fibrosis

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1 Module #2: Chronic Medications: Changing the Course of Chronic Medications: Changing the Course of Dr. Jeffery T. Zobell, Pharm.D., BCPPS Dr. David C. Young, Pharm.D. Objectives Discuss current guideline recommendations regarding chronic medication use in patients with CF Review the current evidence and future directions regarding chronic medications in patients with CF 1

2 Module #2: Chronic Medications: Changing the Course of Areas Where Drug Therapy Exists Gastrointestinal Endocrine Pulmonary Pulmonary Pathogenesis Primary cause of morbidity & mortality ~90% of fatalities Hypotheses have been proposed to explain the pulmonary pathogenesis Steps have been recognized as targets for therapeutic interventions Flume et al., Am J Respir Crit Care Med 2009; 180:

3 Module #2: Chronic Medications: Changing the Course of Targets of Existing Therapy Nonpharmacologic Chest physiotherapy, Vest Thick viscous secretions Infection Bronchial Obstruction Inflammation Activation of airway inflammatory cells (PMNs) Bronchiectasis Non-pharmacologic Nutrition Physical activity Psychosocial Airway clearance Chest physiotherapy (CPT) Positive expiratory pressure (PEP) devices High-frequency chest wall oscillation systems (Vest) Yankaskas et al. Chest Jan;125(1 Suppl):1S-39S. 3

4 Module #2: Chronic Medications: Changing the Course of Chronic CF Therapies Recommended Order Bronchodilator Hypertonic saline Dornase alfa Airway clearance Aerosolized antibiotics Mogayzel PJ, et al. Am J Respir Crit Care Med. 2013;187(7): Targets of Existing Therapy Bronchodilators Albuterol, Levalbuterol, Salmeterol, Formoterol, Arformoterol, Indacaterol, Olodaterol, Ipratropium, Tiotropium Infection Bronchial Obstruction Inflammation Thick viscous secretions Activation of airway inflammatory cells (PMNs) Bronchiectasis 4

5 Module #2: Chronic Medications: Changing the Course of Chronic Inhaled Beta 2 agonists (albuterol, levalbuterol, formoterol,olodaterol) 50 to 60% of CF patients have significant intermittent reactive airways May provide benefit for CF patients with airway hyper-responsiveness Insufficient evidence to recommend for or against chronic, daily use in CF pts > 6 yrs Mogayzel P et al. Am J Respir Crit Care Med (7): Chronic Inhaled Anticholinergics (ipratropium, tiotropium) Insufficient evidence to recommend for or against chronic, daily use in CF pts > 6 yrs Ratjen et al FEV 1 AUC0 4 h of 2.62% in pooled phase 2/3 trial tiotropium vs placebo CF pt >5yrs Brandt et al Adult CF pt w/fev 1 >70% improvement annual FEV 1 decline (3.5%) Brandt C et al. PLoS One Jun 28;11(6):e Mogayzel P et al. Am J Respir Crit Care Med (7): Ratjen F et al. J Cyst Fibros Sep;14(5):

6 Module #2: Chronic Medications: Changing the Course of Inhaled Bronchodilators Evidence Summary? Insufficient evidence to recommend for or against chronic, daily use in CF pts > 6 yrs Future Chronic, daily use in CF pts > 6 yrs 11 Targets of Existing Therapy Infection Mucolytics Dornase alfa, Hypertonic saline Bronchial Obstruction Inflammation Thick viscous secretions Activation of airway inflammatory cells (PMNs) Bronchiectasis 6

7 Module #2: Chronic Medications: Changing the Course of Hypertonic Saline (Sodium chloride, HyperSal, Nebusal, Pulmosal ) Dose: 4 ml nebulized twice daily Available in 3, 3.5, 6, 7, & 10% / 4ml CFF recommends chronic use >6yrs FEV 1 (3-12%), QOL(?) pulmonary exacerba ons (56%) Adverse effects Bronchospasm Administer albuterol/levalbuterol prior to hypertonic saline to prevent bronchospasm Flume P et al. Am J Respir Crit Care Med : Mogayzel P et al. Am J Respir Crit Care Med (7): Hypertonic saline Rosenfeld, et al No change in APE in pts 4-60months Rosenfeld, et al Currently enrolling phase 2 study hypertonic saline in pts 3-5yrs Rosenfeld M, et al. JAMA 2012;307(21): ClinicalTrials.gov Identifier: NCT

8 Module #2: Chronic Medications: Changing the Course of Dornase alfa (Pulmozyme ) CF pts > 6 yrs w/fvc >40% FDA approved >5yrs 2.5mg nebulized every day Moderate-severe disease FEV1 (6%), Increase QOL APE (28%) Mild disease FEV1 (3%), Increase QOL APE (34%) Flume P et al. Am J Respir Crit Care Med : Mogayzel P et al. Am J Respir Crit Care Med (7): Dornase alfa (Pulmozyme ) Yang, et al FEV1 (4-10% in trials of 1 mo-2yrs), QOL APE (22% up to 2yrs) Cost savings offset 18-38% of med cost Dentice, et al Timing of dornase alfa inhalation (before or after airway clearance or the time of day) can be based on practical reasons or individual preference Yang C, Chilvers M, et al. Cochrane Database of Systematic Reviews 2016 Dentice R, Elkins M. Cochrane Database of Systematic Reviews

9 Module #2: Chronic Medications: Changing the Course of Chronic CF Therapies Recommended Order Bronchodilator Hypertonic saline Dornase alfa Airway clearance Aerosolized antibiotics Dentice R, Elkins M. Cochrane Database of Systematic Reviews 2016 Dornase alfa (Pulmozyme ) Adverse effects voice alteration, pharyngitis, rash, laryngitis, chest pain, conjunctivitis, rhinitis, decrease in FVC of 10%, fever, and dyspnea Storage/Stability In refrigerator (2-8 C/36-46 F) Ampules should be protected from strong light Do not use beyond the expiration date stamped on the ampule Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; June

10 Module #2: Chronic Medications: Changing the Course of Inhaled Dry Powdered Mannitol Aitken, et al Double-blind, randomized, controlled >6yrs; FEV %; N= mg BID vs placebo x 26 weeks + 26 weeks open label Increase relative FEV1 (3.75%) No difference in APE, hospitalizations, QOL Aitken, et al 2014 Currently enrolling phase 3 study inhaled dry powdered mannitol in pts >18yrs w/ FEV % Aitken M et al. Am J Respir Crit Care Med Mar 15;185(6): ClinicalTrials.gov identifier: NCT Mucolytics Evidence Summary Yes Hypertonic saline in pts > 6yrs Dornase alfa in pts > 6yrs with moderate to severe dx Dornase alfa in pts > 6yrs with mild dx Future Hypertonic saline in pts 3-5yrs with FEV 1 <99% (Phase 2) Inhaled dry powdered mannitol in pts >18yrs w/ FEV % (Phase 3) 20 10

11 Module #2: Chronic Medications: Changing the Course of Targets of Existing Therapy Antimicrobials Inhaled tobramycin; Inhaled aztreonam; IV antibiotics Infection Bronchial Obstruction Inflammation Thick viscous secretions Activation of airway inflammatory cells (PMNs) Bronchiectasis Aerosolized ABX in CF Aminoglycosides β-lactams Quinolone Others Amikacin Aztreonam Levofloxacin Colistimethate sodium Tobramycin Ciprofloxacin Vancomycin 11

12 Module #2: Chronic Medications: Changing the Course of Tobramycin inhaled solution (TIS) Guideline Dose Dose Interval (hrs) Comments CFF (Mogayzel et al.) 300mg BID 28days on/28 days off UK CF Trust 300mg BID 28days on/28 days off Initial treatment should be nebulized colistin European Consensus (Heijerman et al.) 300mg BID 28days on/28 days off CFF, 1994; Mogayzel et al. 2013; UK CF Trust 2009; Doring et al. 2000; Heijerman et al Tobramycin (TOBI, TOBI Podhaler, Bethkis,Kitabis ) Medication Indication Dosage Adverse effects Tobi Bethkis Kitabis Tobi Podhaler >6yrs with P. aeruginosa (FEV1 25%-75%) >6yrs with P. aeruginosa (FEV1 40%-80%) >6yrs with P. aeruginosa (FEV1 25%-75%) >6yrs with P. aeruginosa (FEV1 25%-80%) 300mg/5ml nebulized BID 28days on/off via DeVilbiss Pulmo- Aide Compressor + Pari LC+ nebulizer 300mg/4ml nebulized BID 28days on/off via Pari VIOS Air Compressor + Pari LC+ nebulizer 300mg/5ml nebulized BID 28days on/off via DeVilbiss Pulmo- Aide Compressor + Pari LC+ nebulizer (co-packaged) 112 mg (4 x 28 mg capsules) inhaled BID BID 28days on/off Voice alteration, tinnitus FEV 1, rales, dysphonia cough, pharyngitis, sputum cough, lung disorder, productive, dyspnea, pyrexia, oropharyngeal pain, dysphonia, hemoptysis, and headache Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; June

13 Module #2: Chronic Medications: Changing the Course of Tobramycin (TOBI, TOBI Podhaler, Bethkis,Kitabis ) TOBI, Bethkis,Kitabis Storage/Stability refrigeration at 2 C to 8 C (36 F to 46 F). May be stored in foil pouch (opened or unopened) at room temperature of 25 C (77 F) for up to 28 days. Protect from light. The colorless to pale yellow solution may darken over time if not stored under refrigeration; however, the color change does not affect product quality. Do not use if solution has been stored at room temperature for >28 days. TOBI Podhaler Storage/Stability Store in original package at 25 C (77 F); excursions permitted to 15 C to 30 C (59 F to 86 F). Protect from moisture. Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; June 2016 Tobramycin solution Evidence Trial Treatment/ Study Design Outcomes Ramsey BW et al n=520 pts Tobramycin 300 mg BID 28 days on and 28 off for 24 wks RDBPCT, Multicenter FEV-1 (p<0.001); in density of P. aeruginosa (p<0.001), hospitalizations (26% reduction) MacLusky IB et al n=27 pts Ramsey BW et al n=71 pts Gibson RL et al n=21 pts (age 6mo-6yrs) Murphy TD et al n=400 pts (age 6-15yrs) Treggiari MM et al n=304 (age 1-12yrs) Tobramycin 80 mg TID for 32 mo; RPBPCT Tobramycin 600 mg TID 28 days on and 2x28 days off (or 28 days off and 2x28 days on); RDBPCT 3 period crossover; Multicenter Tobramycin 300 mg BID for 28 days; RDBPCT; Multicenter Tobramycin 300 mg BID for 28 days on 28 days off; RCT; Multicenter Tobramycin 300 mg BID 28 days on and PO Ciprofloxacin 15-20mg/kg BID - 14 days for 18 mo; RPCT, Multicenter PF in 6/15 in tx group and 11/12 in control; resistance in 4/12 in tx and 0/12 in placebo FEV1 (p<0.001) by 9.7% and in sputum density of P. aeruginosa (p<0.001) Eradication of colonization in 8/8 tx (5 with mucoid strain) and 1/13 of placebo; no difference in markers of inflammation Study terminated early 2.42-fold risk of hospitalization study terminated early; Abx (p=0.009) No difference in exacerbation rates or prevalence of P. aeruginosa 13

14 Module #2: Chronic Medications: Changing the Course of Tobramycin powder Evidence Trial Treatment/ Study Design Outcomes Galeva I et al n=62 (6-21yrs) TIP 112mg BID 28 days on and 28days off; RDBCT, Multicenter FEV-1 (p<0.05); in density of P. aeruginosa (p=0.002) Konstan M et al n=95 (6-21yrs) TIP 112mg BID 28 days on and 28days off for 3 cycles; RDBCT, Multicenter FEV-1 (p<0.002) ; in density of P. aeruginosa, hospitalizations, and need for IV ABX Konstan M et al n=517 (>6yrs) TIP 112mg or TIS 300 mg BID 28 days on and 28days off for 3 cycles; Rand, Open-label, Multicenter No difference in FEV-1 or sputum density of P. aeruginosa; Administration time significantly less with TIP (5.6min vs. 19.7min; p<0.0001) Tobramycin inhaled Ramsey B, et al (OPTIMIZing) Currently enrolling phase 3 study pts 6mo-18yrs TIS +/- Azithromycin in pts with early isolation of P. aeruginosa Nichols D, et al (TEACH-IP-15) Currently enrolling phase 2 study pts >12yrs TIS + Azithromycin P. aeruginosa w/ FEV % Ramsey B, et al. ClinicalTrials.gov Identifier: NCT Nichols D, et al. ClinicalTrials.gov Identifier:NCT

15 Module #2: Chronic Medications: Changing the Course of Tobramycin Evidence Summary Yes Pts > 6yrs with moderate to severe dx with chronic P. aeruginosa Yes? Pts > 6mo with mild dx with chronic P. aeruginosa Pts > 6mo with early P. aeruginosa Future? Pts > 6mo-18yrs with early P. aeruginosa TIS +/- Azithromycin (Phase 3) Pts > 12yrs TIS + Azithromycin P. aeruginosa w/ FEV % TIS + Azithromycin (Phase 2) Aztreonam solution Guideline Dose Dose Interval (hrs) Comments CFF (Mogayzel et al.) 75mg TID 28days on/28 days off UK CF Trust N/A European Consensus (Heijerman et al.) 75mg TID 28days on/28 days off CFF, 1994; Mogayzel et al. 2013; UK CF Trust 2009; Doring et al. 2000; Heijerman et al

16 Module #2: Chronic Medications: Changing the Course of Aztreonam (Cayston ) Indicated for management of CF patients (>7yrs) with P. aeruginosa (FEV 1 >25%<75%) 75mg/1ml nebulized TID via Cayston Altera for 28 days; Then OFF 28 days Adverse effects Cough, nasal congestion, wheezing, oropharyngeal pain, pyrexia, chest discomfort, abdominal pain and vomiting Storage/Stability In refrigerator (2-8 C or F) or until expiration date. Opened or unopened pouches at room temperature (up to 25 C/77 F) for up to 28 days. Avoid exposing ampules to intense light. You should not use Cayston if it is cloudy, if there are particles in the solution, or if it has been stored at room temperature for more than 28 days. You should not use Cayston beyond the expiration date stamped on the ampule. Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; June 2016 Aztreonam solution Evidence Trial Treatment/ Study Design Outcomes McCoy et al n=211 (>6yrs) AZLI 75mg BID or TID 28 days on and monitored for 56days; RDBCT, Multicenter Time to next abx (p=0.007); FEV- 1 (p=0.001); in density of P. aeruginosa (p=0.006) Retsch-Bogart et al n=164 (>6yrs) AZLI 75mg TID 28 days on and monitored for 14days; RDBCT, Multicenter FEV-1 (p<0.001); in density of P. aeruginosa (p<0.001) Assael BM et al n=273 (>6yrs) Wainright CE et al n=157 (>6yrs; FEV-1 >75%) AZLI 75mg TID vs. TIS TID 28 days on/28 days off for 3 cycles; RDBCT, Multicenter AZLI 75mg TID vs. TIS TID 28 days on/28 days off for 3 cycles; RDBCT, Multicenter Mean change in FEV-1 >AZLI (p=0.002); in hospitalizations, need for abx (p=0.044; p=0.004) FEV-1 (p<0.021); in density of P. aeruginosa (p<0.001) 32 16

17 Module #2: Chronic Medications: Changing the Course of Aztreonam inhaled Tiddens H, et al (ALPINE) 3 mo-18yrs w/ new onset P. aeruginosa w/fev 1 >80% AZLI 75mg neb TID 28-day 89.1% (n=90) were free of Pa at the end of treatment and 75.2% (n=76) were free of Pa 4 weeks after the end of treatment Tullis E, et al >6yrs w/ chronic B. cepacia w/fev 1 >80% AZLI 75mg neb TID 24-weeks No significant treatment differences (AZLI vs. placebo) were observed at week 24 for any endpoints, including FEV1% predicted, number of respiratory exacerbations requiring systemic/inhaled antibiotics, or hospitalizations Tiddens H, et al. J Cyst Fibros Jan;14(1): Tullis E, et al. J Cyst Fibros 2014;13(3): Aztreonam Evidence Summary Yes Yes? Future? Pts > 6yrs with moderate to severe dx with chronic P. aeruginosa infection Pts > 6yrs with mild dx with chronic P. aeruginosa infection Pts 3mo<18yrs with new onset P. aeruginosa w/fev 1 >80% Pt > 6yrs with P. aeruginosa w/fev % continuous alternating therapy (Phase 3) 34 17

18 Module #2: Chronic Medications: Changing the Course of Colistimethate sodium (CMS) Guideline CMS Dose (mg) Dose Interval (hrs) Comments CFF (Mogayzel et al.) N/A UK CF Trust (>2 yrs) mg BID Initial treatment should be nebulized colistin European Consensus (Doring et al.) mg QD-BID Max 320mg/day CFF, 1994; Mogayzel et al. 2013; UK CF Trust 2009; Doring et al. 2000; Heijerman et al Colistimethate sodium (CMS) Currently not FDA approved Colistin DPI (Colobreathe, Tadim ) currently in Europe, United Kingdom, Australia 18

19 Module #2: Chronic Medications: Changing the Course of Colistimethate sodium powder (Colobreathe,Tadim ) Medication Indication Dosage Adverse effects Colobreathe >6yrs with P. aeruginosa (FEV1<25%>75%) 1,662,500 IU (125mg CMS) BID via Turbospin DPI inhaler; Treatment may be continued as long as the physician considers the patient is obtaining benefit Cough, throat irritation, dyspnea, dysphonia Tadim >2yrs with P. aeruginosa (FEV1<25%>75%) 1-2 million IU (80-160mg CMS) neb soln two or three times daily Chest tightness CMS Evidence Trial Treatment Outcomes Valerius NH et al n=26 pts Taccetti G et al n=47 pts Frederiksen B et al n=48 CMS 80mg BID with PO Cipro for 3wk; RPCT CMS mg BID with PO cipro; CMS 80mg BID 160mg TID with PO cipro Tx pts were 88% less likely to be colonized with Pseudomonas at 24 mo post tx; clinical outcomes not measured Median time to recolonization 18 mo after eradication; FEV-1 less than in pts with chronic infx (p<0.05) Tx prevented or delayed chronic infx by 78% over 3.5 yrs (p<0.005) 19

20 Module #2: Chronic Medications: Changing the Course of CMS Evidence Trial Treatment Outcomes Hodson ME et al n=115 pts (age 7-50 yrs) TIS 300 mg BID or CMS 80 mg BID for 4 wks; RCOL, multicenter Tobramycin (n=53) had FEV1 compared to colistin (n=62) 6.7% vs. 0.37% (p=0.006); Did not reach target sample size of 60 pts per group Jensen T et al n=40 pts (age 7-35 yrs) CMS 80mg BID; RDBPCT In FVC at 90 days with tx (7 vs 18); no difference in FEV1 btwn groups Schuster A et al n=380 (>6yrs) CMS DPI 125mg BID 24- weeks vs. TIS 300mg BID 28 days on 28 days off for 3 cycles. No difference in mean change in FEV1 (-0.56%; 95% CI %); Ease of use 91% vs. 54% (p<0.001) 39 CMS powder Evidence Summary Yes Pts > 6yrs with moderate to severe dx with chronic P. aeruginosa infection for 24-weeks (FEV1<25%>75%) >2yrs with moderate to severe dx with chronic P. aeruginosa (FEV1<25%>75%) Yes? Pts with early colonization with P. aeruginosa in combo with PO cipro Only one trial was prospective, randomized, and PC Future Showing non-inferiority vs TIS; Need trial comparing CMS DPI vs TIP 20

21 Module #2: Chronic Medications: Changing the Course of Future Inhaled antibiotics Levofloxacin solution (Aeroquin ) Liposomal Amikacin solution (Arikace ) Vancomycin powder (AeroVanc ) Targets of Existing Therapy Thick viscous secretions Infection Anti-inflammatory Ibuprofen, Azithromycin, Inhaled corticosteroids Bronchial Obstruction Inflammation Bronchiectasis Activation of airway inflammatory cells (PMNs) 21

22 Module #2: Chronic Medications: Changing the Course of Anti-inflammatory Therapy Ibuprofen Inhibits cyclooxygenase and lipoxygenase (at high doses) Via inhibition of lipooxygenase = migration & function of neutrophils is Ages 6-17 years FEV-1>60% predicted Use mg/kg twice daily Peak plasma mcg/ml Draw levels 60, 120,180minutes after taking dose Mogayzel P et al. Am J Respir Crit Care Med (7): Anti-inflammatory Therapy Azithromycin (Macrolide antibiotic) Long tissue half life--accumulates in sputum & lungs Potent anti-inflammatory Exact mechanism unknown Inhibits production of proinflammatory cytokines Exhibits anti-biofilm effects May improve pulmonary function & decrease hospitalizations Flume P et al. Am J Respir Crit Care Med. 2007;176(10):

23 Module #2: Chronic Medications: Changing the Course of Anti-inflammatory Therapy Patient selection >6 years Persistent P. aeruginosa (net benefit high) Without Persistent P. aeruginosa (net benefit moderate) Azithromycin Dosing <18 kg: 10 mg/kg/dose M, W, F kg: 250 mg M, W, F >37.5 kg: 500 mg M, W, F <40kg: 250mg daily >40kg: 500mg daily Mogayzel P et al. Am J Respir Crit Care Med (7): Anti-inflammatory Evidence Summary Yes Ibuprofen 6 and 17 years of age, with an FEV1 > 60% predicted Azithromycin >6yrs with chronic P. aeruginosa Azithromycin >6yrs w/o chronic P. aeruginosa Yes? Inhaled steroids in pts with asthma or abpa Future? 23

24 Module #2: Chronic Medications: Changing the Course of Targets of Existing Therapy Infection CFTR Modulators Ivacaftor, lumacaftor/ivacaftor Bronchial Obstruction Inflammation Thick viscous secretions Activation of airway inflammatory cells (PMNs) Bronchiectasis Ivacaftor (Kalydeco ) CFTR potentiator for G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P,G1349D, and R117H mutations Dosage 6 yrs: 150 mg (1 tablet) twice daily 2-6yrs: <14 kg: 50 mg packet twice daily; 14 kg: 75 mg packet twice daily Reduce dose moderate/severe hepatic impairment Increase absorption with high-fat meal 2.5 to 4-fold Pregnancy category B Mogayzel P et al. Am J Respir Crit Care Med (7):

25 Module #2: Chronic Medications: Changing the Course of Ivacaftor (Kalydeco ) Adverse effects headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, nasopharyngitis, diarrhea, rash, nausea, and dizziness Must monitor LFT quarterly 1 st year then annual Ophthalmological exams at baseline and yearly eye exams (pediatric patients) Interactions CYP3A4 inducers (rifampin) Avoid concomitant use CYP3A4 inhibitors (azole antifungals) Reduce dose to 150mg twice weekly (ketoconazole) Reduce dose to 150mg daily (fluconazole) Avoid grapefruit or Seville oranges Lumacaftor + Ivacaftor (Orkambi ) Homozygous F508del Dosage (lumacaftor/ivacaftor) 6-11yrs: 100 mg/125mg (2 tablets) twice daily Approved 9/28/16 12 yrs: 200 mg/125mg (2 tablets) twice daily Reduce dose moderate/severe hepatic impairment Increase absorption with high-fat meal 2 to 3-fold Pregnancy category? 25

26 Module #2: Chronic Medications: Changing the Course of Lumacaftor + Ivacaftor (Orkambi ) Adverse effects dyspnea, nasopharyngitis, nausea, diarrhea, upper respiratory tract infection, fatigue, respiration abnormal, blood creatinine phosphokinase increased, rash, flatulence, rhinorrhea, influenza Must monitor LFT quarterly 1 st year then annual Ophthalmological exams at baseline and yearly eye exams (pediatric patients) Lumacaftor + Ivacaftor (Orkambi ) Interactions CYP3A4 inducers (rifampin) Avoid concomitant use CYP3A4 inhibitors (azole antifungals) Reduce dose to 200/120mg daily x7d then 400/250mg BID (ketoconazole) No dosage adjustment is required for patients already maintained on lumacaftor/ivacaftor who begin therapy with a CYP3A inhibitor. No dosage adjustment of ivacaftor/lumacaftor with: azithromycin, aztreonam, budesonide, ceftazidime, cetirizine, ciprofloxacin, colistimethate, colistin, dornase alfa, fluticasone, ipratropium, levofloxacin, pancreatin, pancrelipase, salbutamol, salmeterol, sulfamethoxazole and trimethoprim, tiotropium, and tobramycin Avoid grapefruit or Seville oranges 26

27 Module #2: Chronic Medications: Changing the Course of CFTR Modulator Evidence Summary Yes >2yrs for G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P,G1349D, and R117H mutations >12yrs for homozygous F508del mutations Yes? Ivacaftor >6yrs non-g551d mutations Future >2-5yrs ivacaftor PK/PD with >1 gating mutation 0-2yrs ivacaftor PK/PD with G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P, or G1349D.G1349D mutation >6-11yrs for homozygous F508del mutations w/fev % Conclusions Cystic fibrosis is a genetic disorder that affects multiple organ systems The complexity of chronic medications to treat and alleviate symptoms of CF has dramatically increased. Pharmacists can play a key role in the management chronic medications in the treatment of patients with cystic fibrosis 27