Objectives - ProCEs3.proce.com/res/pdf/CF/CF2Handout.pdf · Objectives • Discuss current...
Transcript of Objectives - ProCEs3.proce.com/res/pdf/CF/CF2Handout.pdf · Objectives • Discuss current...
Cystic Fibrosis Module #2: Chronic Medications: Changing the Course of Cystic Fibrosis
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Chronic Medications: Changing the Course of Cystic Fibrosis
Dr. Jeffery T. Zobell, Pharm.D., BCPPSDr. 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
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Areas Where Drug Therapy Exists
Cystic Fibrosis
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; 180:802–808
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Thick viscous secretions
Bronchial Obstruction
Activation of airway inflammatory cells (PMNs)
Infection
Inflammation
Bronchiectasis
Targets of Existing Therapy
NonpharmacologicChest physiotherapy, Vest
• 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. 2004 Jan;125(1 Suppl):1S-39S.
Non-pharmacologic
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Chronic CF Therapies – Recommended Order
Aerosolized antibiotics
Airway clearance
Dornase alfa
Hypertonic saline
Bronchodilator
Mogayzel PJ, et al. Am J Respir Crit Care Med. 2013;187(7):680-689.
Thick viscous secretions
Bronchial Obstruction
Activation of airway inflammatory cells (PMNs)
Infection
Inflammation
Bronchiectasis
Targets of Existing TherapyBronchodilators
Albuterol, Levalbuterol, Salmeterol, Formoterol, Arformoterol, Indacaterol, Olodaterol, Ipratropium, Tiotropium
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Chronic Inhaled Beta2 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 2013 187(7):680–689
Chronic Inhaled Anticholinergics(ipratropium, tiotropium)
• Insufficient evidence to recommend for or against chronic, daily use in CF pts > 6 yrs
• Ratjen et al. 2015– ↑ FEV1 AUC0–4 h of 2.62% in pooled phase 2/3
trial tiotropium vs placebo CF pt >5yrs
• Brandt et al. 2016– Adult CF pt w/FEV1 >70% improvement annual
FEV1 decline (3.5%)
Brandt C et al. PLoS One. 2016 Jun 28;11(6):e0158193Mogayzel P et al. Am J Respir Crit Care Med 2013 187(7):680–689Ratjen F et al. J Cyst Fibros. 2015 Sep;14(5):608-14
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Inhaled Bronchodilators Evidence Summary
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?• Insufficient evidence to
recommend for or against chronic, daily use in CF pts > 6 yrs
Future • Chronic, daily use in CF pts > 6 yrs
Thick viscous secretions
Bronchial Obstruction
Activation of airway inflammatory cells (PMNs)
Infection
Inflammation
Bronchiectasis
Targets of Existing Therapy
MucolyticsDornase alfa, Hypertonic saline
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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
– ↑ FEV1 (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 2007 176:957–969Mogayzel P et al. Am J Respir Crit Care Med 2013 187(7):680–689
• Rosenfeld, et al. 2012 – No change in APE in pts 4-60months
• Rosenfeld, et al. 2015– Currently enrolling phase 2 study hypertonic
saline in pts 3-5yrs
Hypertonic saline
Rosenfeld M, et al. JAMA 2012;307(21):2269-2277ClinicalTrials.gov Identifier: NCT02378467
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• 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%)
Dornase alfa (Pulmozyme®)
Flume P et al. Am J Respir Crit Care Med 2007 176:957–969Mogayzel P et al. Am J Respir Crit Care Med 2013 187(7):680–689
• Yang, et al. 2016 – ↑ 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. 2016– “Timing of dornase alfa inhalation (before or after
airway clearance or the time of day) can be based on practical reasons or individual preference “
Dornase alfa (Pulmozyme®)
Yang C, Chilvers M, et al. Cochrane Database of Systematic Reviews 2016Dentice R, Elkins M. Cochrane Database of Systematic Reviews 2016
Cystic Fibrosis Module #2: Chronic Medications: Changing the Course of Cystic Fibrosis
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Chronic CF Therapies – Recommended Order
Aerosolized antibiotics
Airway clearance
Dornase alfa
Hypertonic saline
Bronchodilator
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 2016
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• Aitken, et al. 2012 – Double-blind, randomized, controlled– >6yrs; FEV1 30-89%; N=318– 400mg 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/ FEV1 40-90%
Inhaled Dry Powdered Mannitol
Aitken M et al. Am J Respir Crit Care Med. 2012 Mar 15;185(6):645-52ClinicalTrials.gov identifier: NCT02134353
Mucolytics Evidence Summary
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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 FEV1 <99% (Phase 2)
• Inhaled dry powdered mannitol in pts >18yrs w/ FEV1 40-90% (Phase 3)
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Thick viscous secretions
Bronchial Obstruction
Activation of airway inflammatory cells (PMNs)
Infection
Inflammation
Bronchiectasis
Targets of Existing Therapy
Antimicrobials
Inhaled tobramycin;
Inhaled aztreonam;
IV antibiotics
Aerosolized ABX in CFAminoglycosides β-Lactams Quinolone Others
Amikacin Aztreonam Levofloxacin Colistimethatesodium
Tobramycin Ciprofloxacin Vancomycin
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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 treatmentshould 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. 2009
Tobramycin (TOBI®, TOBI Podhaler®, Bethkis®,Kitabis®)Medication Indication Dosage Adverse effectsTobi® >6yrs with
P. aeruginosa (FEV1 25%-75%)
300mg/5ml nebulized BID 28days on/off via DeVilbiss Pulmo-Aide Compressor + Pari LC+ nebulizer
Voice alteration, tinnitus
Bethkis® >6yrs with P. aeruginosa (FEV1 40%-80%)
300mg/4ml nebulized BID 28days on/off via Pari VIOS Air Compressor + Pari LC+ nebulizer
↓ FEV1, rales, dysphonia
Kitabis® >6yrs with P. aeruginosa (FEV1 25%-75%)
300mg/5ml nebulized BID 28days on/off via DeVilbiss Pulmo-Aide Compressor + Pari LC+ nebulizer (co-packaged)
cough, pharyngitis, ↑ sputum
Tobi Podhaler® >6yrs with P. aeruginosa (FEV1 25%-80%)
112 mg (4 x 28 mg capsules) inhaledBID BID 28days on/off
cough, lung disorder, productive, dyspnea, pyrexia, oropharyngeal pain, dysphonia, hemoptysis, and headache
Lexi-Drugs Online. Hudson, Ohio: Lexi-Comp, Inc.; June 2016
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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 EvidenceTrial Treatment/ Study Design Outcomes
Ramsey BW et al. 1999n=520 pts
Tobramycin 300 mg BID – 28 days on and 28 off for 24 wksRDBPCT, Multicenter
FEV-1 (p<0.001); in density of P. aeruginosa (p<0.001), hospitalizations (26% reduction)
MacLusky IB et al. 1989n=27 pts
Tobramycin 80 mg TID for 32 mo;RPBPCT
PF in 6/15 in tx group and 11/12 in control; resistance in 4/12 in tx and 0/12 in placebo
Ramsey BW et al. 1993n=71 pts
Tobramycin 600 mg TID – 28 days on and 2x28 days off (or 28 days off and 2x28 days on); RDBPCT 3 period crossover; Multicenter
FEV1 (p<0.001) by 9.7% and in sputum density of P. aeruginosa (p<0.001)
Gibson RL et al. 2003n=21 pts (age 6mo-6yrs)
Tobramycin 300 mg BID for 28 days; RDBPCT; Multicenter
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
Murphy TD et al. 2004n=400 pts (age 6-15yrs)
Tobramycin 300 mg BID for 28 days on 28 days off; RCT; Multicenter
2.42-fold risk of hospitalization– study terminated early; Abx (p=0.009)
Treggiari MM et al. 2011n=304 (age 1-12yrs)
Tobramycin 300 mg BID – 28 days on and PO Ciprofloxacin 15-20mg/kg BID -14 days for 18 mo; RPCT, Multicenter
No difference in exacerbation rates or prevalence of P. aeruginosa
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Tobramycin powder EvidenceTrial Treatment/ Study Design Outcomes
Galeva I et al. 2013n=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. 2010 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. 2011n=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)
• Ramsey B, et al. 2014 (OPTIMIZing)– Currently enrolling phase 3 study pts 6mo-18yrs– TIS +/- Azithromycin in pts with early isolation of
P. aeruginosa• Nichols D, et al. 2016 (TEACH-IP-15)
– Currently enrolling phase 2 study pts >12yrs– TIS + Azithromycin P. aeruginosa w/ FEV125-
100%
Tobramycin inhaled
Ramsey B, et al. ClinicalTrials.gov Identifier: NCT02054156Nichols D, et al. ClinicalTrials.gov Identifier:NCT02677701
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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/ FEV125-100% TIS +
Azithromycin (Phase 2)
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. 2009
Aztreonam solution
Cystic Fibrosis Module #2: Chronic Medications: Changing the Course of Cystic Fibrosis
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Aztreonam (Cayston®)• Indicated for management of CF patients (>7yrs) with P. aeruginosa
(FEV1>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 36-46°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
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Trial Treatment/ Study Design Outcomes
McCoy et al. 2008n=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. 2009n=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. 2012n=273 (>6yrs)
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)
Wainright CE et al. 2011n=157 (>6yrs; FEV-1>75%)
AZLI 75mg TID vs. TIS TID– 28 days on/28 days off for 3 cycles; RDBCT, Multicenter
FEV-1 (p<0.021); in density of P. aeruginosa (p<0.001)
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• Tiddens H, et al. 2015 (ALPINE)– 3 mo-18yrs w/ new onset P. aeruginosa w/FEV1>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. 2014– >6yrs w/ chronic B. cepacia w/FEV1>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
Aztreonam inhaled
Tiddens H, et al. J Cyst Fibros. 2015 Jan;14(1):111-9.Tullis E, et al. J Cyst Fibros 2014;13(3):296-305
Aztreonam Evidence Summary
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Yes• Pts > 6yrs with moderate to severe dx with chronic
P. aeruginosa infection
Yes?• Pts > 6yrs with mild dx with chronic P. aeruginosa
infection
Future ?
• Pts 3mo<18yrs with new onset P. aeruginosa w/FEV1>80%
• Pt > 6yrs with P. aeruginosa w/FEV1 25-75% continuous alternating therapy (Phase 3)
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Colistimethate sodium (CMS)Guideline CMS Dose
(mg)Dose Interval (hrs)
Comments
CFF (Mogayzel et al.) N/A
UK CF Trust (>2 yrs) 80-160mg BID Initial treatmentshould be nebulized colistin
European Consensus (Doring et al.)
80-160mg QD-BID Max 320mg/day
CFF, 1994; Mogayzel et al. 2013; UK CF Trust 2009; Doring et al. 2000; Heijerman et al. 2009
Colistimethate sodium (CMS)
• Currently not FDA approved• Colistin DPI (Colobreathe ®, Tadim ®) currently
in Europe, United Kingdom, Australia
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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 EvidenceTrial Treatment Outcomes
Valerius NH et al. 1991n=26 pts
CMS 80mg BID with PO Cipro for 3wk; RPCT
Tx pts were 88% less likely to be colonized with Pseudomonas at 24 mo post tx; clinical outcomes not measured
Taccetti G et al. 2005n=47 pts
CMS 80-160mg BID with PO cipro;
Median time to recolonization 18 mo after eradication; FEV-1 less than in pts with chronic infx (p<0.05)
Frederiksen B et al. 1997n=48
CMS 80mg BID –160mg TID with PO cipro
Tx prevented or delayed chronic infx by 78% over 3.5 yrs (p<0.005)
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CMS Evidence
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Trial Treatment Outcomes
Hodson ME et al. 2002n=115 pts (age 7-50 yrs)
TIS 300 mg BID or CMS 80 mg BID for 4 wks; RCOL,multicenter
Tobramycin (n=53) hadFEV1 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. 1987n=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. 2013n=380 (>6yrs)
CMS DPI 125mg BID 24-weeks vs. TIS 300mg BID 28 days on 28 days off for 3 cycles.
No difference in meanchange in FEV1 (-0.56%; 95% CI -2.71-1.70%); Ease of use 91% vs. 54% (p<0.001)
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
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Future Inhaled antibiotics
• Levofloxacin solution (Aeroquin®)• Liposomal Amikacin solution (Arikace®)• Vancomycin powder (AeroVanc®)
Thick viscous secretions
Bronchial Obstruction
Activation of airway inflammatory cells (PMNs)
Infection
Inflammation
Bronchiectasis
Targets of Existing Therapy
Anti-inflammatoryIbuprofen, Azithromycin, Inhaled corticosteroids
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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 20-30 mg/kg twice daily– Peak plasma 50-100 mcg/mL
• Draw levels 60, 120,180minutes after taking dose
Mogayzel P et al. Am J Respir Crit Care Med 2013 187(7):680–689
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):957-69
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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– 18-37.5 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 2013 187(7):680–689
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• ?
Cystic Fibrosis Module #2: Chronic Medications: Changing the Course of Cystic Fibrosis
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Thick viscous secretions
Bronchial Obstruction
Activation of airway inflammatory cells (PMNs)
Infection
Inflammation
Bronchiectasis
Targets of Existing Therapy
CFTR ModulatorsIvacaftor, lumacaftor/ivacaftor
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 2013 187(7):680–689
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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 1st 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 ?
Cystic Fibrosis Module #2: Chronic Medications: Changing the Course of Cystic Fibrosis
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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 1st 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
Cystic Fibrosis Module #2: Chronic Medications: Changing the Course of Cystic Fibrosis
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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/FEV1 70-105%
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