Disclosures. IPF Medications: Practical Experience. Prednisone, Azathioprine, N acyetylcysteine. Case 1. Brett Ley, MD, MAS Assistant Professor, UCSF

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1 IPF Medications: Practical Experience Disclosures Received speakers bureau honorarium from Roche/Genentech (makers of pirfenidone). Brett Ley, MD, MAS Assistant Professor, UCSF 67 y/o man 1 year cough and dyspnea PMH: GERD, HTN Exposures: former smoker HRCT: definite UIP pattern PFTs: FVC 68% DLCO 45% Case 1 What treatment would you offer? A. Prednisone, azathioprine, & NAC B. NAC only C. Nintedanib D. Pirfenidone E. PPI only F. No pharmacotherapy 26% 49% 15% 9% 2% 0% P r e d n i s o n e, a z a t h i o p... N A C o n l y N i n t e d a n i b P i r f e n i d o n e P P I o n l y N o p h a r m a c o t h e r a p y Prednisone, Azathioprine, N acyetylcysteine Triple therapy arm stopped early for harm Increased risk of death and hospitalizations NAC arm completed No effect on disease progression or death 1

2 Prednisone, Azathioprine, N acyetylcysteine Prednisone, Azathioprine, N acyetylcysteine Triple therapy arm stopped early for harm Increased risk of death and hospitalizations NAC arm completed No effect on disease progression or death Triple therapy arm stopped early for harm Increased risk of death and hospitalizations NAC arm completed No effect on disease progression or death Acid Suppression Therapy Antifibrotics Retrospective studies mixed (no RCTs) Less disease progression and longer survival 1,2 No difference in disease progression or mortality and possibly increased risk of infections 3 1. AJRCCM 2011;184(12):1390; 2. Lancet Respir Med. 2013;1(5):369; 3. Lancet Respir Med 2016;4(5):381. 2

3 Nintedatib: INPULSIS Study design INPULSIS: 1 Endpoint IPF/ likely IPF n = 1066 nintedanib n = 638 Placebo n = wks 1 : FVC 2 : acute exacerbation; QOL; death Mean difference (71.3, 148.6) P value < % Relative Reduction NEJM 2014;370:2071 NEJM 2014;370:2071 INPULSIS: 2 Endpoints INPULSIS I INPULSIS II Nintedanib Placebo Nintedanib Placebo Change in SGRQ * 5.48 Any death Pooled 5.5% 7.8% Respiratory death Time to acute exacerbation Pooled 3.8% 5.0% HR 1.15 (0.54, 2.42) HR 0.38* (0.19, 0.77) Acute Exacerbation (pooled) Survival (pooled) NEJM 2014;370:2071 * Statistically significant difference 3

4 INPULSIS: Safety No difference in SAEs 3x LFT increase 5.1% vs 0.7% Not recommended in moderate-severe hepatic impairment Non-sig. increase in arterial thromboembolic events (2.5% vs 08% including non-fatal MI - 1.5% vs 0.4%) Use with caution in patients with high cardiovascular risk, including known CAD Theoretical increase risk of bleeding based on MOA (10% vs 7%) Caution in known risk of bleeding, including anticoagulation Gastrointestinal Perforation (theoretic based on MOA) Caution after recent abdominal surgery NEJM 2014;370:2071 FDA Insert INPULSIS: tolerability Adverse event Nintedanib Placebo Diarrhea 62%, 63% 19%, 18% Nausea 23%, 26% 6%, 7% Decreased appetite 8%, 13% 7%, 5% Vomiting 13%, 10% 2%, 3% Weight loss 8%, 11% 6%, 1% Discontinuation ~24% ~19 NEJM 2014;370:2071 Pirfenidone: CAPACITY Trials Pirfenidone: ASCEND study design IPF (highly selected) n = 555 Pirfenidone n = 278 Placebo n = wks 1 : FVC 2 : 6MWT distance; PFS; dyspnea; death Lancet 2011;377:1760. NEJM 2014;370:2083 4

5 ASCEND: 1 Endpoint ASCEND: 2 Endpoints Relative difference = 48% P value < Decreased walk distance or death 50 meter decline from baseline Progression free survival 10% FVC decline; 50 meter 6MWT decline; death NEJM 2014;370:2083 ASCEND: 2 Endpoints Pirfenidone: mortality Worsened dyspnea Death from any cause Death related to IPF Pirfenidone Placeb o HR (CI) P value 29.1% 36.1% NP % 7.2% 0.55 (0.26, 1.15) 1.1% 2.5% 0.44 (0.11, 1.72) NEJM 2014;370:2083 5

6 Pirfenidone: Safety No difference in SAEs 3x LFT increase 3.7% vs 0.8% Not recommended in severe hepatic impairment NEJM 2014;370:2083 ASCEND: tolerability Adverse event Pirfenidone Placebo Nausea 36.0% 13.4% Rash 28.1% 8.7% Fatigue 21% 17% Dizziness 17.6% 13.0% Dyspepsia 17.6% 6.1% Anorexia 15.8% 6.5% Vomiting 12.9% 8.7% Decrease in weight 12.6% 7.9% Gastroesophageal reflux 11.9% 6.5% Insomnia 11.2% 6.5% Discontinuation 14.4% 10.8% NEJM 2014;370:2083 Nintedanib Pirfenidone Efficacy 45% FVC decline 48% 10% FVC decline/death Administration 150 mg pill BID With Food (100 mg pill available) 267 mg tablets 3 tabs TID (9 daily) titrated over 2 w With Food Laboratory monitoring (LFTs) Yes Yes Nausea/ Vomiting 24% vs 7% 12% vs 3% 36% vs 13% 13% vs 9% Diarrhea 62% vs 18% 22% vs 22% Skin -- 28% vs 9% Weight loss 10% vs 3% 13% vs 8% Fatigue -- 21% vs 17% Cardiac (MI) 1.5% (0.5%) -- Hepatotoxicity (> 3 ULN) ~5% vs 1% 3.7% vs 0.8% Discontinuation 19% vs 11-15% 14% vs 11% Drug Interactions P-gp > CYP3A4 inhibitors (ketoconazole, erythromycin) CYP1A2 inhibitors (fluvoxamine, ciprofloxacin) Cost per year $96,000 $94, y/o man 1 year cough and dyspnea PMH: GERD, HTN Former smoker, no exposures HRCT: definite UIP pattern PFTs: FVC 68% DLCO 45% Case 1 What treatment would you offer? A. Prednisone, azathioprine, & NAC B. NAC only C. Nintedanib D. Pirfenidone E. PPI only F. No pharmacotherapy 6

7 Take Home #1 Most patients should be offered treatment with nintedanib or pirfenidone upon diagnosis. Unless there are specific contraindications to one of the medications, I help the patient make an informed decision about which medication to choose after review of benefits, safety, side effects, and administration details. 73 man with IPF, started on nintedanib 150 mg bid After two weeks therapy, he begins having 3-4 watery stools per day with mild abdominal cramping He denies incontinence, reports normal PO intake Case 2a What would you do? A. Discontinue nintedanib B. Temporarily stop nintedanib and restart once symptoms resolve C. Switch to pirfenidone D. Reduce dose to 100 mg bid E. Provide loperamide as 0% 6% needed D i s c o n t i n u e n i n t e d a n i b T e m p o r a r i l y s t o p n i n... S w i t c h t o p i r f e n i d o n e 8% P r o v i d e l o p e r a m i d e a... R e d u c e d o s e t o m... 38% 48% Nintedanib: Diarrhea Almost all who reported diarrhea reported mild to moderate (95%), characterized as watery with or without formed stool 79% resolved without need for dose reduction or interruption 55% used anti-diarrheals as needed (loperamide) ~10% needed dose reduction 4.4% discontinued for diarrhea Respir Res 2015;16:116 FDA insert Respir Res 2015;16:116 FDA insert Nintedanib: Diarrhea < 4 extra stools per day and able to maintain PO hydration Loperamide as needed 4-6 extra stools and able to maintain PO hydration Loperamide as needed If >8 days, discontinue or reduce medication until less than 4 extra stools per day >6 stools, incontinence, IV fluids, hospitalization or decreased ADLs Discontinue medication until < 4 extra stools per day Restart at reduced dose 7

8 73 man with IPF, started on nintedanib 150 mg bid After two weeks therapy, he begins having 3-4 watery stools per day with mild abdominal cramping He denies incontinence, reports normal PO intake Case 2a What would you do? A. Discontinue nintedanib B. Temporarily stop nintedanib and restart once symptoms resolve C. Switch to pirfenidone D. Reduce dose to 100 mg bid E. Provide loperamide as needed Case 2b What would you do next? 75 woman with IPF started on pirfenidone. A. Discontinue pirfenidone Did fine through B. Stop pirfenidone for 2 second week on 2 weeks and restart once capsules TID symptoms resolve, On 3 capsules TID, titrating to full dose over began to have nausea, 2 weeks heartburn, and decreased appetite Nausea is worst in the late morning, she typically skips breakfast C. Switch to nintedanib D. Reduce back 1 cap. TID, ensure all doses with meals, extend up titrations, and start PPI D i s c o n t i n u e p i r f e n i d o n e 0% 0% 4% S t o p p i r f e n i d o n e f o r... S w i t c h t o n i n t e d a n i b R e d u c e b a c k 1 c a p. T I.. 96% Adv Ther 2014;31:375 FDA insert Pirfenidone: GI side effects Prevention Take pirfenidone during or after a meal Take each of the three capsules separately throughout the meal (rather than simultaneously) Dose titration can be spread out over 4 weeks instead of 2 weeks Management If side effects are not tolerable, dose reductions may be helpful with reescalation to recommended daily dose as tolerated If side effects persist despite dose reduction, temporary treatment discontinuation can be done until symptoms become tolerable (typically 1-2 weeks). Re-introduce the medication with a slower re-escalation scheme Prokinetic agents (e.g. metoclopramide) may help mitigate treatment related GI side effects. Dosing is 10 mg three times daily for a maximum of 5 days Proton pump inhibitors may be helpful for managing indigestion 75 woman with IPF started on pirfenidone. Did fine through second week on 2 capsules TID On 3 capsules TID, began to have nausea, heartburn, and decreased appetite Nausea is worst in the late morning, she typically skips breakfast Case 2b What would you do next? A. Discontinue pirfenidone B. Stop pirfenidone for 2 weeks and restart once symptoms resolve, titrating to full dose over 2 weeks C. Switch to nintedanib D. Reduce back 1 cap. TID, ensure all doses with meals, extend up titrations, and start PPI 8

9 Adv Ther 2014;31:375 FDA insert Pirfenidone: rash Prevention Avoid direct sun, use sunscreen SPF 50+ with both UVA and UVB, wear protective clothing, and avoid other meds with photosensitivity Mild-moderate photosensitivity reaction or rash reduce dose (1 cap TID x 7 days or resolution) If persists > 7 days, discontinue for 15 days After resolved, re-introduce/re-escalate, as tolerated Severe photosensitivity reaction Discontinue medication Nintedanib and pirfenidone: LFT elevations AST/ALT > 3 to < 5 ULN without symptoms or elevated bilirubin Interrupt or dose reduce until LFTs return to baseline, then resume full dose Respir Res 2015;16:116; FDA prescribing information for Esbriet and Ofev AST/ALT > 5 or > 3 ULN with symptoms or elevated bilirubin Discontinue After discontinuation for intolerance Try the other medication Intolerance to one does mean the patient will not tolerate the other medication Take Home #2 Discuss common side effects with patient Anticipate and manage side effects to keep patients on initial therapy if symptoms are mild-moderate Monitor liver function tests Discontinue or dose reduce for more severe side effects or significant LFT elevations Try the alternative if intolerant to first choice 9

10 Case 3 67 y/o woman with 3 years of dry cough PMH: none Exposures: 10ppy former smoker FH: Mother died of IPF at age 70 HRCT: mild peripheral reticulation in a possible UIP pattern SLB: usual interstitial pneumonia PFTs: FVC 106% DLCO 80% What would you do? A. Reassure B. Observe with serial PFTs, treat for worsening symptoms or decline in PFTs 47%48% C. Start nintedanib or pirfenidone D. Refer for lung transplant 2% 3% R e a s s u r e O b s e r v e w i t h s e r i a l P... S t a r t n i n t e d a n i b o r p i... R e f e r f o r l u n g t r a n s p l a n t AJRCCM 2016;194(6) :711 Treat Mild/Early IPF? Treat Mild/Early IPF? Treat Mild/Early IPF? ERJ 2016;48:843 Thorax 2016;epub Sept 26,

11 Treat Mild/Early IPF? Acute exacerbation incidence ~ 10% per year High mortality 50% in hospital 90% if intubated Median survival ~ 3-4 months Treat Mild/Early IPF? Family history is important Most have telomere-associated gene mutation May have faster progression and shorter survival compared to the average sporadic IPF patient AJRCCM 2011;183(4):431 AJRCCM 2016;194(3):265 Eur Respir J 2016;epub Case 3 Take Home #3 67 y/o woman with 3 years of dry cough PMH: none Exposures: 10ppy former smoker FH: Mother died of IPF at age 70 HRCT: mild peripheral reticulation in a possible UIP pattern SLB: usual interstitial pneumonia PFTs: FVC 106% DLCO 80% What would you do? A. Reassure B. Observe with serial PFTs, treat for worsening symptoms or decline in PFTs C. Start nintedanib or pirfenidone D. Refer for lung transplant IPF patients with early/mild disease were included in the landmark anti-fibrotic trials and derived the same benefits as the overall study cohorts. I believe most patients with early/mild IPF should be offered treatment with nintedanib or pirfenidone rather than observation alone without treatment. 11

12 Patient A: 79 woman with IPF dx for 3 years, severe dyspnea confining her to the home, has poor appetite and weight loss, uses O2 4LPM at rest and up to 8LPM with any exertion, FVC 48%, DLCO can t perform Patient B: 78 woman with IPF dx for 3 years, limiting dyspnea at 3-4 blocks, able to perform all daily activities, RA at rest, up to 3LPM with activity, FVC 48%, DLCO 30% Case 4 Which patient would you offer nintedanib or pirfenidone to? A. Patient A only B. Patient B only C. Both patient A and B D. Neither patient P a t i e n t A o n l y 2% P a t i e n t B o n l y 51% 43% B o t h p a t i e n t A a n d B N e i t h e r p a t i e n t 5% Case 4 Phase III trials excluded patients for severe impairment in FVC and DLCO % predicted FVC < 50% DLCO < 30 or 35% Problem with numeric cut-offs Take into account functional status and quality of life 120% 100% 80% 50% 0% Patient A Patient B 70% decline 30% decline Case 4 Case 4 Lung 2016;194:739 Unpublished data from CAPACITY and ASCEND trials. GAP Stage III Patient A: 79 woman with IPF dx for 3 years, severe dyspnea confining her to the home, has poor appetite and weight loss, uses O2 4LPM at rest and up to 8LPM with any exertion, FVC 48%, DLCO can t perform Patient B: 78 woman with IPF dx for 3 years, limiting dyspnea at 3-4 blocks, able to perform all daily activities, RA at rest, up to 3LPM with activity, FVC 48%, DLCO 30% Which patient would you offer nintedanib or pirfenidone to? A. Patient A only B. Patient B only C. Both patient A and B D. Neither patient 12

13 Take Home #4 Patients with physiologically severe disease were not included in landmark anti-fibrotic trials, so benefits (and harms) in this sub-group are unknown. I don t use numeric cut-offs for treatment. Rather, for those with reasonable quality of life and functional status, I offer therapy. But I manage expectations and make it clear that treatment will not make them feel better, and might make them feel overall worse. 66 man with new diagnosis of IPF Needs O2 2LPM with exertion FVC 72%, DLCO 54% Started on drug A After 6 months, reports more dyspnea, notices he needs up to 4LPM to keep sats > 88% with walking Repeat FVC 12% lower, DLCO 15% lower Case 5 In addition to referring for lung transplant evaluation, what would you do next? A. Stop drug A, don t start drug B B. Continue drug A C. Stop drug A and switch to drug B S t o p d r u g A, d o n t s t a r... 7% C o n t i n u e d r u g A 27% 66% S t o p d r u g A a n d s w i t c... Thorax 2016;71:429 Case 5 66 man with new diagnosis of IPF Needs O2 2LPM with exertion FVC 72%, DLCO 54% Started on drug A After 6 months, reports more dyspnea, notices he needs up to 4LPM to keep sats > 88% with walking Repeat FVC 12% lower, DLCO 15% lower Case 5 In addition to referring for lung transplant evaluation, what would you do next? A.Stop drug A, don t start drug B B.Continue drug A C.Stop drug A and switch to drug B 13

14 Take Home #5 For IPF patients that experience a significant decline on anti-fibrotic therapy, the next best step in pharmacologic management is unclear. I favor either continuing the initial medication or switching to the alternative over stopping treatment all-together, unless palliative care seems more appropriate, and these patients should be referred for urgent lung transplant evaluation if appropriate. Take Home Points 1. Anti-fibrotic therapy should be offered to most patients upon diagnosis of IPF 2. Anticipate and manage side effects 3. Early/mild disease was included in the landmark anti-fibrotic trials with same observed benefit 4. Physiologically severe disease was not represented in landmark anti-fibrotic trials, so benefits (and harms) in this sub-group are unknown. 5. For IPF patients that experience a significant decline on anti-fibrotic therapy, the next best step in pharmacologic management is unclear. 14