Transcript www.msdonline.com.au

Adverse events
and drug interactions
Simone Strasser
Stephen Pianko
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 history
2002 – 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
Previous Relapsers
100
86
85
Previous Partial Responders
84
SVR (%)
80
Pooled T12/PR 48
Pbo/PR 48
72
56
60
40
32
0
Stage
13
144/
167
12/
38
41
34
20
n/N=
Previous Null Responders
53/
62
2/
15
No,
Bridging
minimal, or
fibrosis
portal fibrosis
Zeuzem S, et al. EASL 2011. Abstract 5.
48/
57
2/
15
Cirrhosis
20
18
13
34/
47
3/
17
No,
minimal, or
portal fibrosis
39
10/
18
0
0/5
Bridging
fibrosis
6
11/
32
1/
5
Cirrhosis
24/
59
1/18
No,
minimal, or
portal fibrosis
15/
38
0
0/9
Bridging
fibrosis
14 10
7/
50
1/
10
Cirrhosis
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
PR
BOC RGT
BOC PR 48
Advanced fibrosis
Cirrhosis
100
100
66
68
60
13
40
20
n/N =
0
23
14/ 77/ 81/
61 117 119
F0-2
2/
15
44
14/
32
F3-4
Bacon BR, et al. N Engl J Med 2011;364:1207-1217.
21/
31
77
80
68
64
SVR (%)
SVR (%)
80
66
60
35
40
20
n/N =
0
24
0
16/ 85/ 85/
66 132 128
0/
10
No cirrhosis
Clinical Care Options: Hepatitis
6/
17
17/
22
Cirrhosis
Gary
• Decision made to proceed to treatment with
boceprevir
Baseline investigations
5/9/11
Week
B/L
Bilirubin
10
Albumin
38
AST
98
ALT
72
Hb
124
WCC / ANC
Platelets
2.6 / 1.3
135
Gary – Current medications
• Candesartan
• Pantoprazole
• Methadone
16 mg/day
40 mg/day
22 mL (110 mg)/day
Questions
• What issues do you anticipate?
• Any planning ahead of treatment?
Anaemia in controlled clinical trials of
TVR and BOC
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
4.6
1.6
3
<1
Blood transfusion
* EPO use not permitted in TPV trials
Hezode C. Liver Int 2012 Feb;32 Suppl 1:32-8.
The CUPIC study
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)
• 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
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
2 (1.3%)
6 (2%)
0
0
7.5
0
2.5
8.8
22.6
10.1
66
10.7
19.6
10.1
56.8
15.2
5
3.8
4.7
2.4
6.9
1.9
13.1
1.7
Death n (%)
Rash
Grade 3
SCAR
Infection
Anaemia
Grade 2 (8.0 – <10.0 g/dL)
Grade 3/4 (<8.0 g/dL)
EPO use
Transfusion
Neutropenia
Grade 3/4 (<500 – <1000/mm3)
G-CSF use
Thrombocytopenia
Grade 3/4 (<25,000 – <50,000)
Use of thrombopoietin
Deaths: TPV – sepsis (2); pneumopathy (1); BOV (1); HE (1); Ca lung (1) BOC – pneumonia (1); sepsis (1)
Anticipated treatment duration
• 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
On-treatment investigations
B/L
Dose
Bilirubin
Weekly
blood
tests
Wk 4
180/1000
10
38
98
72
20
40
50
30
Hb
WCC / ANC
124
2.6 / 1.3
110
5.9/4.7
Platelets
HCV RNA
Support
135
230,000
71
341
GSF x3/wk
Albumin
AST
ALT
Commenced wk2
Week 4 peg-IFN/RBV
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
On-treatment investigations
B/L
Dose
Weekly
blood
tests
Wk 4
Wk 5
180/1000
180/1000
BOC 800 tds
Bilirubin
10
20
25
Albumin
38
40
35
AST
98
50
39
ALT
72
30
22
Hb
124
110
97
2.6 / 1.3
5.9/4.7
7.8/6.5
Platelets
135
71
61
HCV RNA
230,000
341
WCC / ANC
Support
GSF x3/wk
GSF x3/wk
?
Gary – Anaemia at week 5
What options?
1.
2.
3.
4.
5.
6.
Observe and monitor?
Dose reduce peg-IFN?
Dose reduce RBV?
Dose reduce boceprevir?
Blood transfusion?
Erythropoietin?
A randomised trial comparing RBV dose reduction vs EPO for anaemia in
treatment-naïve patients receiving BOC + peg-IFN/RBV
1.
2.
Hb every 2 weeks from TW 0 to 20; then every 4 to 8 weeks
RBV DR 200-400 mg/day then further 2 x DR of 200 mg/day
Poordad F et al. EASL 2012
RANDOMISATION
A randomised trial comparing RBV dose reduction vs EPO for
anaemia in treatment-naïve patients receiving BOC + peg-IFN/RBV
(73%)
®
ns
n (%)
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%)
®
ns
n (%)
Poordad F et al. EASL 2012
Gary – Anaemia at week 5
What options?
1.
2.
3.
4.
5.
6.
Observe and monitor?
Dose reduce peg-IFN?
Dose reduce RBV?
Dose reduce boceprevir?
Blood transfusion?
Erythropoietin?
Decision to reduce RBV by 200 mg to 800 mg/wk
On-treatment investigations
B/L
Dose
Weekly
blood
tests
Symptoms
•Pale
•SOBOE
•Fatigue
•Nausea
•Insomnia
Wk 4
Wk 5
Wk 6
180/1000
180/1000
BOC 800 tds
180/800
BOC 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
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
GSF x3/wk
GSF x3/wk
WCC / ANC
Support
GSF x3/wk
Gary – Worsening anaemia at week 6 despite
RBV dose reduction
What options?
1.
2.
3.
4.
5.
6.
Observe and monitor?
Dose reduce peg-IFN?
Dose reduce RBV?
Dose reduce boceprevir?
Blood transfusion?
Erythropoietin?
Decision to reduce RBV to 600 mg/wk
On-treatment investigations
Wk 4
Wk 5
Wk 6
Wk 8
180/1000
180/1000
BOC 800 tds
180/800
BOC 800 tds
180/600
BOC 800 tds
Bilirubin
20
25
13
12
Albumin
40
35
34
35
AST
50
39
35
40
ALT
30
22
19
22
Symptoms Hb
110
97
88
88
5.9/4.7
7.8/6.5
6.2/5.3
13.6/12.4
Platelets
71
61
56
55
HCV RNA
341
Support
GSF x3/wk
Dose
Weekly
blood
tests
•SOBOE
•Fatigue
WCC / ANC
Not det
GSF x3/wk
GSF x3/wk
GSF x2/wk
Gary – Remains anaemic at week 8 despite
RBV dose reduction to 600 mg daily
What options?
1.
2.
3.
4.
Further RBV dose reduction?
Blood transfusion?
Erythropoietin?
Other?
Secondary intervention
Impact on SVR
18% of patients randomly assigned to RBV DR and 38% of patients randomly
assigned to EPO received secondary anaemia management intervention
SVR
•
•
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
The IDEAL trial
Treatment Discontinuation
Use of EPO for early anaemia may prevent treatment discontinuation
Early anaemia/No ESA
Early anaemia/ESA
Late anaemia
Sulkowski M et al. Gastroenterology 2010;139:1602–1611
Gary – Progress
• Commenced darbepoetin 60 mcg/wk
from week 8
• Maintained RBV 600 mg/day
On-treatment investigations
Wk 6
Wk 8
Wk 12
180/800
BOC 800 tds
180/600
BOC 800 tds
180/600
BOC 800 tds
Bilirubin
13
12
14
Albumin
34
35
33
AST
35
40
37
ALT
19
22
17
Hb
88
88
81
6.2/5.3
13.6/12.4
6.3/5.2
56
55
27
Not det
Not det
GSF x2/wk
GSF x2/wk
Aranesp 60/wk
Aranesp 60/wk
Dose
Weekly
blood
tests
Symptoms
•Dysgeusia
•SOBOE
•Fatigue
•Nausea
•Dry skin
•5 kg wt
loss
WCC / ANC
Platelets
HCV RNA
Support
GSF x3/wk
d
Gary – Worsening anaemia at Week 12 despite RBV
dose reduction and EPO; marked thrombocytopenia
What options?
1.
2.
3.
4.
5.
6.
Observe and monitor?
Dose reduce peg-IFN?
Dose reduce/omit RBV?
Dose reduce/stop boceprevir?
Blood transfusion?
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 investigations
Wk 6
Wk 8
Wk 12
Wk 18
180/800
BOC 800 tds
180/600
BOC 800 tds
180/600
BOC 800 tds
180/400
BOC 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
6.2/5.3
13.6/12.4
6.3/5.2
5.9/5.2
56
55
27
39
Not det
Not det
GSF x2/wk
GSF x2/wk
GSF x2/wk
EPO 60/wk
EPO 60/wk
EPO 60 x2/wk
Dose
Weekly
blood
tests
Symptoms
•Dysgeusia
•SOBOE
•Fatigue
•Nausea
•Dry skin
•10 kg wt
loss
WCC / ANC
Platelets
HCV RNA
Support
GSF x3/wk
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 investigations
Wk 8
Wk 12
Wk 18
Wk 24
180/600
BOC 800 tds
180/600
BOC 800 tds
180/400
BOC 800 tds
90-180/600
BOC 800 tds
Bilirubin
12
14
10
9
Albumin
35
33
29
31
AST
40
37
42
40
Symptoms ALT
22
17
20
19
•Dysgeusia
•SOBOE
•Fatigue
•Nausea
•Oedema
on Ensure
88
81
100
99
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
Support
GSF x2/wk
GSF x2/wk
GSF x2/wk
GSF x2/wk
EPO 60/wk
EPO 60/wk
EPO 60 x2/wk
EPO 60 x2/wk
Dose
Weekly
blood
tests
Hb
WCC / ANC
Not det
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
Summary
• 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 nonanaemic 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
Worth it for an SVR?
Telaprevir rash
Adverse Event, %
Telaprevir + peg-IFN/RBV
peg-IFN/RBV
(n=1797)
(n=493)
56 %
34 %
Rash
• Who has seen it?
Grading telaprevir rash
Grade
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
Recommendation: Ensure access to dermatologist
• 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.
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 commonly
prescribed drugs
Alison
•
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
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/
Alison
•
•
•
Lamotrigine dosing:
peg-IFN/RBV/Deb started 11/10
Initial dose of lamotrigine 150 mg/day
• 1/11 dose 300 mg/d
For reduction in
• 4/11 dose 500 mg/d
serum drug levels
• 7/11 dose 600 mg/d
•
HCV treatment ceased week 4 per protocol
due to non-response
Alison
• 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
What about drug-drug interactions with
protease inhibitors?
Pharmacologic characteristics of TVR and BOC
Drug
CYP
Telaprevir
CYP 3A4
• Substrate
• Inhibitor
Boceprevir
CYP 3A4/5
• Substrate
• Inhibitor
P-glycoprotein
Non-CYP metabolism
• Substrate
• Inhibitor
• Substrate
• Substrate
(aldo-keto reductase
1C2/1C3)
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 drugs
Seden 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