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