Papo de Índio Entrevista Francisco Pianko, Secretário Dos Povos Indígenas (Parte III)
Simone Strasser Stephen Pianko Adverse events and drug interactions.
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Transcript of Simone Strasser Stephen Pianko Adverse events and drug interactions.
Simone StrasserStephen Pianko
Adverse events and drug interactions
Learning objectives
• Discuss management of AEs in patients treated with protease inhibitors
• Anaemia• Skin rash
• Discuss drug interactions with direct acting antiviral agents (DAAs)
Gary
• First seen in 2001• HCV genotype 1a, cirrhosis• History of IDU; on methadone• Cannabis 3-4 days/week• Alcohol: 12 cans beer/day for many years
Antiviral treatment history2002 – Rebetron (interferon alfa-2b + RBV)• Multiple RBV dose reductions for anaemia• Multiple AEs including fatigue, mood swings, insomnia• HCV RNA positive week 24 – stopped
2003 – Pegasys/RBV (peg-IFN alfa-2a + RBV)• Dose reductions peg-IFN and RBV from week 10• GCSF from week 12• Poorly tolerated• 48 weeks Rx, pEVR, ETR but relapse week 4 FU
Gary• GT 1a; cirrhosis• Non-responder to Rebetron• Relapser to Pegasys RBV
• No further antiviral treatment offered
• 2012 – He is very anxious about his disease and wants maximal treatment
• Any recommendations?
REALIZE: Treatment-experienced patients with advanced fibrosis or cirrhosis
• Previous relapsers with liver disease had high SVR rates following treatment with telaprevir plus peg-IFN/RBV
– For previous null responders with cirrhosis, SVR rates similar to peg-IFN/RBV alone
Zeuzem S, et al. EASL 2011. Abstract 5.
Previous Relapsers Previous Partial Responders Previous Null Responders
2/15n/N= 53/
62144/167
12/38 0/5
10/18
34/47
3/17 0/9
15/38
11/32
1/5
No, minimal, or
portal fibrosis
CirrhosisStage
Pooled T12/PR 48Pbo/PR 48
2/15
48/57
24/59
1/18 7/50
1/10
Bridgingfibrosis
No, minimal, or
portal fibrosis
CirrhosisBridgingfibrosis
No, minimal, or
portal fibrosis
CirrhosisBridgingfibrosis
100
0
60
SVR
(%)
80
40
20
86
32
85
13
84
13
72
18
56
0
34
20
41
6
39
014 10
Clinical Care Options: Hepatitis
Treatment-experienced patients with advanced fibrosis or cirrhosis
• Package inserts for both boceprevir and telaprevir recommend fixed duration therapy rather than response-guided approach in cirrhotics– Supported by RESPOND-2 study data evaluating impact of response-guided
therapy on SVR in cirrhotic patients
Bacon BR, et al. N Engl J Med 2011;364:1207-1217.
100
80
60
40
20
0
23
F0-2 F3-4
SV
R (
%)
14/61
PR BOC RGT BOC PR 48
Advanced fibrosis Cirrhosis
66
77/117
68
81/119
13
2/15
44
14/32
68
21/31
100
80
60
40
20
0
24
No cirrhosis Cirrhosis
SV
R (
%)
16/66
64
85/132
66
85/128
0
0/10
35
6/17
77
17/22n/N = n/N =
Clinical Care Options: Hepatitis
Gary
• Decision made to proceed to treatment with boceprevir
Baseline investigations5/9/11
Week B/L
Bilirubin 10
Albumin 38
AST 98
ALT 72
Hb 124
WCC / ANC 2.6 / 1.3
Platelets 135
Gary – Current medications
• Candesartan 16 mg/day • Pantoprazole 40 mg/day• Methadone 22 mL (110 mg)/day
• What issues do you anticipate?
• Any planning ahead of treatment?
Questions
Anaemia in controlled clinical trials of TVR and BOC
Hezode C. Liver Int 2012 Feb;32 Suppl 1:32-8.
Relatively few patients with cirrhosis included in phase III clinical trials of boceprevir (n=115) and telaprevir (n=247)
Patients, % TVR Phase II/III trials BOC phase III trials
TVR Control BOC Control
Anaemia 32 15 49 29
RBV dose reductions 22 9 26 13
EPO use* 1 0 43 24
Blood transfusion 4.6 1.6 3 <1
* EPO use not permitted in TPV trials
The CUPIC study
• HCV genotype 1 patients, n=455• Compensated cirrhosis (Child Pugh A) genotype 1
• Non-responders– Relapsers– Partial responders ( >2 log10 HCV RNA decline at Week 12)– Null responders theoretically excluded
• Treated in the French ATU
• Safety data available; SVR data awaited
Real-life safety of telaprevir or boceprevir in combination with peg-IFN alfa/RBV in cirrhotic non-responders.
First results of the French early access program (ANRS CO20-CUPIC)
CUPIC: BOC and TVR – Safety findings (EASL 2012)Patients, % Boceprevir (n=159) Telaprevir (n=296)
Serious AEs 38.4 48.6
Discontinuation due to serious AE 7.4 14.5
Death n (%) 2 (1.3%) 6 (2%)
Rash Grade 3 SCAR
00
7.50
Infection 2.5 8.8Anaemia Grade 2 (8.0 – <10.0 g/dL) Grade 3/4 (<8.0 g/dL) EPO use Transfusion
22.610.166
10.7
19.610.156.815.2
Neutropenia Grade 3/4 (<500 – <1000/mm3) G-CSF use
53.8
4.72.4
Thrombocytopenia Grade 3/4 (<25,000 – <50,000) Use of thrombopoietin
6.91.9
13.11.7
Deaths: TPV – sepsis (2); pneumopathy (1); BOV (1); HE (1); Ca lung (1) BOC – pneumonia (1); sepsis (1)
• 4 week peg-IFN/RBV lead-in phase
• Expect 48 weeks total treatment duration with BOC plus peg-IFN/RBV
• Will stop if detectable HCV RNA week 12 or week 24
Anticipated treatment duration
On-treatment investigationsB/L Wk 4
Dose 180/1000
Bilirubin 10 20Albumin 38 40AST 98 50ALT 72 30
Hb 124 110WCC / ANC 2.6 / 1.3 5.9/4.7Platelets 135 71HCV RNA 230,000 341Support GSF x3/wk
Weeklyblood tests
Commenced wk2
Symptoms• Fatigue• Insomnia• Bone pain since starting GCSF
Discussion prior to commencing BOC• Management plan for side-effects• Education re. drug interactions with BOC• Correspondence with GP re. treatment
Week 4 peg-IFN/RBV
On-treatment investigationsB/L Wk 4 Wk 5
Dose 180/1000 180/1000BOC 800 tds
Bilirubin 10 20 25
Albumin 38 40 35
AST 98 50 39
ALT 72 30 22
Hb 124 110 97
WCC / ANC 2.6 / 1.3 5.9/4.7 7.8/6.5
Platelets 135 71 61
HCV RNA 230,000 341
Support GSF x3/wk GSF x3/wk
?
Weeklyblood tests
Gary – Anaemia at week 5
What options?
1. Observe and monitor?2. Dose reduce peg-IFN?3. Dose reduce RBV?4. Dose reduce boceprevir?5. Blood transfusion?6. Erythropoietin?
1.
2.
Poordad F et al. EASL 2012
Hb every 2 weeks from TW 0 to 20; then every 4 to 8 weeksRBV DR 200-400 mg/day then further 2 x DR of 200 mg/day
A randomised trial comparing RBV dose reduction vs EPO for anaemia in treatment-naïve patients receiving BOC + peg-IFN/RBV
Poordad F et al. EASL 2012
A randomised trial comparing RBV dose reduction vs EPO for anaemia in treatment-naïve patients receiving BOC + peg-IFN/RBV
(73%)
n (%)
RA
ND
OM
ISA
TIO
N
®ns
Poordad F et al. EASL 2012
®
n (%)
ns
A randomised trial comparing RBV dose reduction vs EPO for anaemia in treatment-naïve patients receiving BOC + peg-IFN/RBV
(73%)
Gary – Anaemia at week 5
What options?1. Observe and monitor?2. Dose reduce peg-IFN?3. Dose reduce RBV?4. Dose reduce boceprevir?5. Blood transfusion?6. Erythropoietin?
Decision to reduce RBV by 200 mg to 800 mg/wk
On-treatment investigationsB/L Wk 4 Wk 5 Wk 6
Dose 180/1000 180/1000BOC 800 tds
180/800BOC 800 tds
Bilirubin 10 20 25 13
Albumin 38 40 35 34
AST 98 50 39 35
ALT 72 30 22 19
Hb 124 110 97 88
WCC / ANC 2.6 / 1.3 5.9/4.7 7.8/6.5 6.2/5.3
Platelets 135 71 61 56
HCV RNA 230,000 341
Support GSF x3/wk GSF x3/wk GSF x3/wk
Weeklyblood tests
• Pale • SOBOE• Fatigue• Nausea• Insomni
a
Symptoms
Gary – Worsening anaemia at week 6 despite RBV dose reduction
What options?1. Observe and monitor?2. Dose reduce peg-IFN?3. Dose reduce RBV?4. Dose reduce boceprevir?5. Blood transfusion?6. Erythropoietin?
Decision to reduce RBV to 600 mg/wk
On-treatment investigationsWk 4 Wk 5 Wk 6 Wk 8
Dose 180/1000 180/1000BOC 800 tds
180/800BOC 800 tds
180/600BOC 800 tds
Bilirubin 20 25 13 12
Albumin 40 35 34 35
AST 50 39 35 40
ALT 30 22 19 22
Hb 110 97 88 88
WCC / ANC 5.9/4.7 7.8/6.5 6.2/5.3 13.6/12.4
Platelets 71 61 56 55
HCV RNA 341 Not det
Support GSF x3/wk GSF x3/wk GSF x3/wk GSF x2/wk
Weeklyblood tests
• SOBOE• Fatigue
Symptoms
Gary – Remains anaemic at week 8 despite RBV dose reduction to 600 mg daily
What options?
1. Further RBV dose reduction?2. Blood transfusion?3. Erythropoietin?4. Other?
Secondary interventionImpact on SVR
• 18% of patients randomly assigned to RBV DR and 38% of patients randomly assigned to EPO received secondary anaemia management intervention
SV
R
• Patients who received additional secondary intervention had a numerically higher SVR rate than those who only received primary intervention
Poordad F et al. EASL 2012
Use of EPO for early anaemia may prevent treatment discontinuation
The IDEAL trial
Sulkowski M et al. Gastroenterology 2010;139:1602–1611
Early anaemia/No ESA
Early anaemia/ESALate anaemia
Tre
atm
ent
Dis
cont
inua
tion
Gary – Progress
• Commenced darbepoetin 60 mcg/wk from week 8
• Maintained RBV 600 mg/day
d
On-treatment investigationsWk 6 Wk 8 Wk 12
Dose 180/800BOC 800 tds
180/600BOC 800 tds
180/600BOC 800 tds
Bilirubin 13 12 14
Albumin 34 35 33
AST 35 40 37
ALT 19 22 17
Hb 88 88 81
WCC / ANC 6.2/5.3 13.6/12.4 6.3/5.2
Platelets 56 55 27
HCV RNA Not det Not det
Support GSF x3/wk GSF x2/wkAranesp 60/wk
GSF x2/wkAranesp 60/wk
Weeklyblood tests
• Dysgeusia
• SOBOE• Fatigue• Nausea• Dry skin• 5 kg wt
loss
Symptoms
Gary – Worsening anaemia at Week 12 despite RBV dose reduction and EPO; marked thrombocytopenia
What options?
1. Observe and monitor?2. Dose reduce peg-IFN?3. Dose reduce/omit RBV?4. Dose reduce/stop boceprevir?5. Blood transfusion?6. Erythropoietin?
Omitted RBV and reduced peg-IFN
Gary – Progress to Week 18• Peg-IFN reduced to 90 mcg/wk for 2 weeks
then increased to 135mcg weekly
• Blood transfusion (2 units) at week 14 (Hb 77)
• Darbepoetin increased to 60 mcg twice weekly
• RBV restarted after 1 week off at 400 mg/day
• Dietician review – ENSURE 2-3/day
On-treatment investigationsWk 6 Wk 8 Wk 12 Wk 18
Dose 180/800BOC 800 tds
180/600BOC 800 tds
180/600BOC 800 tds
180/400BOC 800 tds
Bilirubin 13 12 14 10
Albumin 34 35 33 29
AST 35 40 37 42
ALT 19 22 17 20
Hb 88 88 81 100
WCC / ANC 6.2/5.3 13.6/12.4 6.3/5.2 5.9/5.2
Platelets 56 55 27 39
HCV RNA Not det Not det
Support GSF x3/wk GSF x2/wkEPO 60/wk
GSF x2/wkEPO 60/wk
GSF x2/wkEPO 60 x2/wk
Weeklyblood tests
• Dysgeusia
• SOBOE• Fatigue• Nausea• Dry skin• 10 kg wt
loss
Symptoms
Gary – Progress to Week 24
• Weekly blood tests
• Peg-IFN at varying doses 90/135/180 mcg/wk according to platelet count (27-40)
• Darbepoetin continued at 60 mcg twice weekly
• RBV maintained at 600 mg daily
• Oedema, no ascites or HE, Fatigue
On-treatment investigationsWk 8 Wk 12 Wk 18 Wk 24
Dose 180/600BOC 800 tds
180/600BOC 800 tds
180/400BOC 800 tds
90-180/600BOC 800 tds
Bilirubin 12 14 10 9
Albumin 35 33 29 31
AST 40 37 42 40
ALT 22 17 20 19
Hb 88 81 100 99
WCC / ANC 13.6/12.4 6.3/5.2 5.9/5.2 2/1.2
Platelets 55 27 39 36
HCV RNA Not det Not det Not det
Support GSF x2/wkEPO 60/wk
GSF x2/wkEPO 60/wk
GSF x2/wkEPO 60 x2/wk
GSF x2/wkEPO 60 x2/wk
Weeklyblood tests
• Dysgeusia
• SOBOE• Fatigue• Nausea• Oedema
on Ensure
Symptoms
Gary – Progress to-date (Week 32)
• Weekly blood tests
• Continues to struggle with symptoms
• Seeing psychologist and dietician regularly
• Keen to continue therapy
• Aim to continue triple therapy to week 48
• Treatment with PI in cirrhotics is complex. Requires significant clinic resources including nurse and doctor time, blood tests, growth factors, BTx etc.
• SVR rates with PI higher among anaemic vs non-anaemic patients
• RBV dose reduction does not impair efficacy and should be initial management for anaemia
• Use of ESA for early anaemia may maintain patients on treatment, but availability limited in Australia
Summary
Worth it for an SVR?
Telaprevir rash
• Who has seen it?
Adverse Event, % Telaprevir + peg-IFN/RBV(n=1797)
peg-IFN/RBV(n=493)
Rash 56 % 34 %
Grading telaprevir rashGrade Severity Features
Grade 1 Mild Localised or limited distribution
Grade 2 Moderate Diffuse, up to 50% body surface area. Mucosal inflammation without ulceration. No epidermal detachment or target lesions. May have fever, eosinophilia, joint pain.
Grade 3 Severe Over 50% body surface area ± vesicles/bullae, superficial mucosal ulceration, DRESS, EM, AGEP
Grade 4 Life-threatening Generalised bullous eruption, SJS, TEN
Management of telaprevir rash
• Grade 1 and 2: – Limit sun exposure, oatmeal baths, loose fitting clothing, topical/systemic
antihistamines, topical urea/corticosteroid creams, consider stopping telaprevir if rash progresses/does not improve
• Grade 3: – As above, may require oral CS. Cease telaprevir and do not recommence.
Dermatology consultation. May need to stop peg-IFN/RBV if not improving within 7 days
• Grade 4:– As above, stop all medications. Management as indicated.
Recommendation: Ensure access to dermatologist
Drug interactions
Learning objectives
• To consider drug interactions with DAAs when treating HCV
• Peg-IFN/RBV – minimal drug-drug interactions
• DAAs – many potential interactions with commonlyprescribed drugs
• Previously treated in USA with peg-IFN/RBV for 48 weeks (breakthrough-non-responder)
• 2010 – Enrolled in a study of DEB025 A2210 cyclophilin inhibitor (Alisporivir) for prior IFN/RBV non-response
• peg-IFN/RBV + DEB/placebo
Alison
Concomitant Medications:
• Lamotrigine• Venlafaxine • Oral Contraceptive
Alison
Consider potential drug interactions
1. Alisporivir (Debio 025)
2. Lamotrigine(Lamictal)
3. Venlafaxine (Efexor)
4. Oral contraceptive
What resources are available to help with drug interactions?
What resources are available to help with drug interactions?
• Pharmacists• Websites• Product Information • Pharmaceutical companies• Understanding of how drug is metabolised
Potential drug interactions
www.drugs.com/drug-interactions/
• Lamotrigine dosing:• peg-IFN/RBV/Deb started 11/10 • Initial dose of lamotrigine 150 mg/day
• 1/11 dose 300 mg/d• 4/11 dose 500 mg/d• 7/11 dose 600 mg/d
Alison
• HCV treatment ceased week 4 per protocol due to non-response
For reduction inserum drug levels
• Any concerns?
Alison
Any concerns?• What to do with lamotrigine dosing?
Alison
Lamotrigine dosing:• On cessation of therapy, bipolar disorder
became unstable; lamotrigine drug levels became toxic
• Cessation of peg-IFN and toxicity from lamotrigine
• Dose of lamotrigine reduced by private psychiatrist
Alison
Lamotrigine dosing:• Lamotrigine (antiepileptic drug of the
phenyltriazine class) is metabolised predominantly by glucuronidation
• Drug interaction had not been anticipated
Alison
What about drug-drug interactions with protease inhibitors?
Drug CYP P-glycoprotein Non-CYP metabolism
Telaprevir CYP 3A4• Substrate• Inhibitor
• Substrate• Inhibitor
Boceprevir CYP 3A4/5• Substrate• Inhibitor
• Substrate • Substrate (aldo-keto reductase 1C2/1C3)
Pharmacologic characteristics of TVR and BOC
Magnitude of drug interaction cannot be predicted and must be studied
Hezode C. Liver International 2012
How will drug-drug interaction management change with approval of TVR and BOC?
• Potential for increased PK interactions between HCV PIs and other medications
• TPV and BOC may be primarily metabolised by CYP3A• Suggests many interactions with HIV PIs and NNRTIs, other
CYP3A inducers/inhibitors• Concomitant drugs may reduce or potentially enhance
efficacy of PIs• Potential for overlapping toxicities• Other agents associated with anemia, rash, etc.• Toxicity of the concomitant drugsSeden K, et al. J Antimicrob Chemother 2010;65:1079-1085.
Drug interactions – Conclusions
• Consider all drugs as having potential for interactions with PIs
• Mechanism of concomitant drug metabolism needs to be understood
• Utilise pharmacists and Web-based help
• Remember dose adjustments both on and after cessation of therapy of concomitant medications