Management of adverse effects of triple therapy

Transcription

1 Management of adverse effects of triple therapy Giovanni Battista Gaeta Cattedra di Malattie Infettive UOC Epatiti Virali Seconda Università di Napoli

2 Disclosures Advisory board: BMS, Gilead, Janssen Speaker: BMS, Gilead, Roche, Janssen, Merck

3 Factors influencing the safety profile of a drug Number of treated patients More frequent ADR/AE (both serious and trivial) are usually detected in premarket studies conducted for drug approval. There are not enough subjects to reliably detect a type of ADR that occurs only once in 2,500-5,000 or more exposures Registrative trials are sized to detect efficacy not safety Once a drug is approved, it may be administered to millions of people Circumstances of use Once a drug is marketed, its use is quite different from the premarket testing. Drugs may be used in different populations i.e. in patients with comorbiditiesor in combinations of different drugs Learning curve

4 Telaprevir placebo-controlled Phase II/III studies: summary of AEs during telaprevir/placebo phase Patients, % T12/PR (750 mg q8h) N=1346 Skin and subcutaneous tissue disorders Placebo/PR48 N=764 Leading to discontinuation of all study drugs*(%) Pruritus (SSC) % Rash (SSC) % Gastrointestinal disorders Nausea <0.5 Diarrhea <0.5 Hemorrhoids 12 3 <0.5 Anorectal discomfort 8 2 <0.5 Anal pruritus 6 1 <0.5 Blood and lymphatic system disorders Anemia (SSC) % *Discontinuation of all study drugs in the T12/PR arms (analyzed within SSC for rash and anemia) SSC: special search category Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf

5 Boceprevir Phase III studies: summary of AEs over course of therapy Patients, % BOC RGT BOC44/PR48 PR SPRINT-2 (naïve) 1 N=368 N=366 N=363 Anemia* Dysgeusia* Grade 3-4 neutropenia (500 to <750/mm 3 and <500/mm 3 ) RESPOND-2 (experienced) 2 N=162 N=161 N=80 Anemia* Dysgeusia* Dry skin** Grade 3-4 neutropenia (500 to <750/mm 3 and <500/mm 3 ) Rash *p<0.001 for boceprevir arms versus PR **p=0.009 (BOC RGT) and p=0.004 (BOC44/PR48) versus PR p=0.01 (BOC RGT) and p=0.05 (BOC44/PR48) versus PR 1. Poordad F, et al. N Engl J Med 2011;364: Bacon BR, et al. N Engl J Med 2011;364:

6 Summary of anemiadata TELAPREVIR Hemoglobin <10 g/dl Hemoglobin <8.5 g/dl Patients (%) T12/PR Placebo/ PR48 T12/PR Placebo/ PR48 Patients (%) Hemoglobin <10 to 8.5 g/dl BOCEPREVIR Hemoglobin <8.5 g/dl BOC RGT BOC44/ PR48 Control BOC RGT BOC44/ PR48 Control Poordad F, et al. Hepatology 2010;52(Suppl.):402A; Telaprevir EU SmPC

7 How to handle anemia? Erythropoetin Regulatory limits Possible side effects Ribavirin dose reduction Risk of lower SVR? Blood transfusions Patients refusal Transfusion-related risks 1. Telaprevir EU SmPC; 2. Boceprevir EU SmPC

8 Management of anemia observed with telaprevir and boceprevir Ribavirin dose reductions due to anemia EPO use Transfusions Discontinuation clinical Telaprevir trials Phase II/III placebo-controlled trials % (telaprevir arms) vs 9.4% (control) Not permitted (1% use) Telaprevir/placebo dosing phase: 2.5% (telaprevir arms) vs 0.7% (control) Overall study period: 4.6% (telaprevirarms) vs 1.6% (control) Telaprevir alone: 1.9% vs 0.5% control All treatment at the same time: 0.9% (telaprevir arm) vs 0.5% (control) Boceprevir trials % (boceprevir arms) vs 13% (control) 43% (boceprevir arms) vs 24% (control) 3% (boceprevir arms) vs <1%(control) 0 3% (boceprevir arms) vs 0 1% (control) 3,4 1. Telaprevir EU SmPC; 2. Boceprevir EU SmpC 3. Poordad F, et al. N Engl J Med 2011;364: ; 4. Bacon BR, et al. N Engl J Med 2011;364:

9 Telaprevir studies: SVR rates by anemia status and RBV dose reduction 100 Anemia No anemia RBV dose reduction No RBV dose reduction SVR (%) PR T12PR PR T12PR PR T12PR PR T12PR n/n= 46/92 267/ / /524 37/69 243/ / /565 ADVANCE and ILLUMINATE pooled data; Erythropoietin alfa (EPO) was not allowed Sulkowski M, et al. J Hepatol 2011;54(Suppl. 1):S195

10 Boceprevir: SVR rates by EPO use and RBV dose reduction No anemia Anemia SVR (%) n/n= 212/363 95/129 29/37 109/153 30/44 SPRINT-2 Study; Data of pooled boceprevir arms Sulkowski M, et al. J Hepatol 2011;54(Suppl. 1):S194

11 Gestione dell anemia Cosa NON fare: ridurre dose di telaprevir o boceprevir Cosa fare: considerare riduzione dose ribavirina nei pazienti già HCV-RNA negativi EPO in casi selezionati Trasfusione

12 Anemia in a patient treated with telaprevir-based therapy OC, woman, age 56, no cirrhosis, naive HCV-RNA (log) 6.1 Undetectable 16 Hb g/dl T= transfusion RBV dose reduction Stop telaprevir DAYS Stop all drugs 6.6 T T Malattie Infettive, Napoli

13 Incidence of rash during telaprevir phase vs. standard therapy

14 Patient: grading of skin eruption severity Mild: localized skin eruption and/or a skin eruption with limited distribution (up to several isolated sites on the body) Moderate: diffuse rash 50% of body surface area Severe: Extent of rash >50% of body surface area or associated with significant systemic symptoms, mucous membrane ulceration, target lesions, epidermal detachment SCAR*: generalized bullous eruption, drug rash with eosinophilia and systemic symptoms (DRESS), Stevens- Johnson Syndrome/toxic epidermal necrolysis, acute generalized exanthematous pustulosis, erythema multiforme *systemic cutaneous adverse reaction Telaprevir EU SmPC

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16 Rash in 5 giornata di terapia con telaprevir Malattie Infettive, Napoli

17 Estensione al dorso in 6 giornata Malattie Infettive, Napoli

18 Estimatingbody surface area (BSA) 9% 9% Front 18% Back 18% 9% Adult body BSA Perineum 1% Arm 9% Head (front and back) 9% 18% 18% Leg 18% Chest 18% Back 18% Hettiaratchy S, et al. BMJ 2004;329:101 3

19 Checking list for criteria of rash severity Rash 50% of body surface area No prolonged fever No facial edema No mucosal involvement No enlarged lymph nodes No dyspnea No need to check for biological alterations (eosinophilia, raised ALT, Alk Ph, creatinine) MONITOR Bocquet H, et al. Semin Cutan Med Surg 1996;15:250 57

20 Treating Patients with Mild or Moderate Rash Limitexposuretosun Topical corticosteroids Systemic antihistaminic* Systemic steroids not allowed Regular follow-up is mandatory * diphenhydramine; hydroxyzine; levocetirizine; desloratadine

21 Administrationoftopicalsteroids The fingertip rule A fingertip= 0.5 g ofsteroid Sufficient to treat an area equivalent to two palms From: CacoubP etal. J Hepatolo2012; 56:455-63

22 Summary of rash data from placebo-controlled Phase II/III trials: telaprevir treatment phase Incidence of rash (%) T12/PR (N=1346) 33 Placebo/PR48 (N=764) >90% of all rash = mild/moderate Features: Typically pruritic and eczematous, and involving <30% BSA Progression was infrequent (<10% of cases) Incidence of rash (%) T12/PR arm Reported within a special search category Telaprevir EU SmPC Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf

23 Anorectal signs and symptoms First reported with telaprevir in PROVE1 as hemorrhoids Subsequently reported under various terms such as anal pruritus, anorectal discomfort as well as hemorrhoids Onset is most commonly in the first 2 weeks of treatment Mechanism is unknown Telaprevir is extensively metabolized and metabolites primarily excreted in the feces No rectal findings in any of the toxicology studies No evident association with either generalized pruritus or skin rash Treatment: local corticosteroids, anaesthetics McHutchison JG, et al. New Engl J Med 2009;360:

24 CUPIC cohort: HCV gen1, cirrhosis 430 patients included; in this analysis Hezode, HepDart 2011

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26 Hezode, HepDart 2011

27 Summary& Conclusions Triple therapy for HCV is associated with significant adverse events. An intense on-therapy monitoring is required Adherence to updated management plans is important Post-marketing surveillance and cohort studies will design the safety profileofdaasin realworld settings

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29 Boceprevir Phase III studies: summary of AEs over course of therapy BOC RGT BOC44/ PR48 PR SPRINT-2 (naïve) 1,2 N=368 N=366 N=363 Deaths N=1 N=1 N=4 Serious AEs 11% 12% 9% Discontinued due to AEs 12% 16% 16% RESPOND-2 (experienced) 3 N=162 N=161 N=80 Deaths N=1 N=0 N=0 Serious AEs 10% 14% 5% Discontinued due to AE 8% 12% 2% 1. Poordad F, et al. N Engl J Med 2011;364: ; 2. Poordad F, et al. N Engl J Med 2011;364: (supplementary appendix); 3. Bacon BR, et al. N Engl J Med 2011;364:

30 Anorectal disorders* during the telaprevir treatment period in Phase II and III studies Proportion (%) of patients with: 1 T12/PR (750 mg q8h) N=1346 Placebo/PR48 N=764 AE AE of at least Grade AE leading to permanent discontinuation of telaprevir/placebo In clinical trials, the majority of these events (e.g., haemorrhoids, anorectal discomfort, anal pruritus, and rectal burning) were mild to moderate, very few led to treatment discontinuation and resolved after completion of telaprevir dosing 2 *Reported within a special search category 1. Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf 2. Telaprevir EU SmPC

31 Telaprevir placebo-controlled Phase II/III studies: summary of AEs during telaprevir/placebo phase T12/PR (750 mg q8h) N=1346 Placebo/PR48 N=764 Deaths N=0 a N=1 a,b Serious AEs 7% 3% AEs leading to permanent discontinuation of Telaprevir/Placebo AEs leading to permanent discontinuation of all study drugs at same time 14% 4% 8% 4% a Refers to the number of patients who died as a result of an AE with onset during the telaprevir/placebo treatment phase b This includes 1 patient who had a life-threatening AE that was not resolved at his last study visit. The patient died afterwards due to this AE Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf

32 Severe rash and SCAR* Rash Severe Discontinue telaprevir immediately. Consultation with a specialist in dermatology is recommended Monitor for progression or systemic symptoms until the rash is resolved. If no improvement within 7 days of stopping telaprevir (or earlier if rash worsens), sequential or simultaneous interruption or discontinuation of ribavirin and/or peginterferon should be considered SCAR? Permanent and immediate discontinuation of telaprevir, peginterferon and ribavirin is required Consult with a specialist in dermatology TELAPREVIR must not be restarted if discontinued *systemic cutaneous adverse reaction Telaprevir EU SmPC