Aggiornamenti in Epatologia :Update Epatite C Belgirate Hotel Villa Carlotta 9 giugno 2012 Terapia antivirale : gestione degli eventi avversi Dr. Piero Zaninetti, MMG Crevoladossola

Evolution of hepatitis C treatment Discovery of HCV genome Treatment with IFN alfa for 24 or 48 weeks – 3x weekly dosing – Poor outcomes Addition of RBV to IFN alfa improved outcomes Peg-IFN mono – once-weekly dosing Peg-IFN alfa plus RBV becomes gold standard Response-guided therapy emerging New antivirals enter development 1989 2010

Pegylated interferon and ribavirin Peginterferon alfa-2a (40KD) Ribavirin Slide 35. Pegylated interferon and ribavirin In randomised clinical trials, the highest overall sustained virological response (SVR) rates have been achieved with the combination of weekly subcutaneous injections of long-acting pegylated interferon and oral ribavirin, which represents the current standard of care. Pegylated interferons are produced by binding of the inert polyethylene glycol (PEG) moiety to interferon molecules, thus decreasing renal clearance, altering metabolism, and increasing the half-life of the peginterferon molecule. There are two currently licensed products, peginterferon alfa-2a (40KD) (PEGASYS) and pegylated interferon alfa-2b (12KD) (Pegatron). They are administered once weekly. Subcutaneous injection, once weekly By mouth, twice daily

HCV Antiviral Treatment efficacy IFN Pegylated IFN IFN & ribavirin Peg-IFN & ribavirin tolerability

Impatto dell’infezione sull’attività lavorativa I pazienti affetti da epatite cronica HCV correlata perdono più giorni di attività lavorativa e hanno disabilità a breve termine maggiore rispetto ai loro colleghi esenti da patologia

Impatto della terapia sulla qualità di vita Esacerba la fatica che peggiora nel corso della terapia Comporta spesso irritabilità e depressione che fanno peggiorare le relazioni con familiari e amici Necessarie frequenti visite di follow-up che influenzano l’attività lavorativa

Ribavirin: Adverse events are common but manageable Side effects Haemolytic anaemia Significant teratogenicity Rash Fatigue Itching Sinusitis Management includes: Ribavirin dose reduction Strict contraception (for females)3 Slide 52. Ribavirin: adverse events are common but manageable In general, the incidence and types of side effects of pegylated interferon alfa plus ribavirin are similar to those identified for interferon plus ribavirin. Side effects are common but, importantly, do not usually require discontinuation of treatment. However, patients on treatment do require significant support and encouragement throughout treatment. Specialists and nurses are best placed to manage side effects. Side effects associated with ribavirin include: haemolytic anaemia, fatigue, itching, rash, sinusitis, birth defects, or gout. Because of the concern of birth defects from the use of ribavirin, it is important that persons who receive the drug use strict contraception methods both during treatment and for a period of 6 months after treatment. This listing is by no means comprehensive; complete prescribing information should be thoroughly reviewed by anyone responsible for patients undergoing pegylated interferon plus ribavirin therapy. Management includes: ribavirin dose reduction, analgesics such as paracetamol or NSAIDs, growth factors and strict contraception.

Schema di riduzione del dosaggio della ribavirina

Pegylated interferon: Adverse events are common but manageable Side effects Flu-like symptoms Weight loss Depression Neutropenia Concentration/memory disturbance Insomnia Thrombocytopenia Hypo/hyperthirodism Management includes: Pegylated interferon dose reduction Antidepressants such as SSRIs Slide 51. Pegylated interferon: adverse events are common but manageable In general, the incidence and types of side effects of pegylated interferon alfa plus ribavirin are similar to those identified for interferon plus ribavirin. Side effects are common but, importantly, do not usually require discontinuation of treatment. However, patients on treatment do require significant support and encouragement throughout treatment. Specialists and nurses are best placed to manage side effects. Side effects associated with interferon alfa include: “Flu-like” symptoms, neutropenia, thrombocytopenia, depression, hypothyroidism and hyperthyroidism, irritability, concentration/memory disturbances, visual disturbances, fatigue, muscle aches, headaches, nausea and vomiting, skin irritation, low-grade fever, weight loss, insomnia, hearing loss, tinnitus, interstitial fibrosis and hair thinning. This listing is by no means comprehensive; complete prescribing information should be thoroughly reviewed by anyone responsible for patients undergoing pegylated interferon plus ribavirin therapy. Management includes: interferon dose reduction, analgesics such as paracetamol or NSAIDs, antidepressants such as SSRIs and growth factors.

Telaprevir Approval - FDA Approved May 23, 2011 Indications - In combination with Peginterferon-alfa and Ribavirin (PR) - Chronic HCV genotype 1 infection - Adults (> 18 years of age) with compensated liver disease, including cirrhosis - Treatment-naïve or prior interferon-based treatment Dosing - 750 mg (two 375-mg tablets) three times daily with food (not low fat) - Treat with PR for 12 weeks (followed by additional 12 or 36 weeks PR) Adverse Effects - Rash, anemia, nausea, fatigue, headache, diarrhea, pruritus, and anal or rectal irritation and pain Source: Telaprevir (Incivek) Prescribing Information. Vertex Pharmaceuticals.

Telaprevir Adverse Effects

Telaprevir Adverse Effects Adverse Clinical Symptom with > 5% Frequency Symptom Telaprevir + Peg-IFN + RBV Peg-IFN + RBV Rash (any) 56% 34% Fatigue 50% Pruritus 47% 28% Nausea 39% Anemia 36% 17% Diarrhea 26% Vomiting 13% 8% Hemorrhoids 12% 3% Anorectal Discomfort 11% Dysgeusia 10% Anal Pruritus 6% 1% Source: Telaprevir (Incivek) Prescribing Information and Vertex Pharmaceuticals.

RASH CUTANEO

Telaprevir Good Skin Care for Telaprevir-Associated Rash Apply skin moisturizers at least twice a day Avoid perfumes and other scented skin care products Use hypoallergenic products Keep hydrated Wear loose-fitted clothing Avoid scratching Use unscented and mild laundry detergent Avoid using dryer sheets with clothes in dryer Limit sun exposure and use sun screen when out in sun Avoid hot showers and hot baths Consider using a nonsoap cleanser Apply skin moisturizers after bathing (before drying off) Source: Vertex Pharmaceuticals.

Percentage of Patients with Rash HEPATITIS C: TREATMENT Telaprevir for Chronic Untreated HCV Infection ADVANCE Study: Adverse Effects Percentage of Patients with Rash T = Telaprevir; PR = Peginterferon + Ribavirin Source: Jacobson IM, et. al. N Engl J Med. 2011;364:2405-16.

Telaprevir Mild Skin Rash Source: Photograph Courtesy of John Scott, MD, University of Washington

Telaprevir Mild Skin Rash Assessment - Localized rash and/or rash with limited distribution - With or without associated pruritus Management - Continue all medications for HCV therapy - Use good skin care practices - Consider oral antihistamine + topical corticosteroid - Monitor and re-assess if progression occurs* *Stop telaprevir if becomes severe or systemic symptoms develop; OK to continue Peginterferon and Ribavirin, but if rash persists within 7 days of stopping Telaprevir, consider sequential or simultaneous discontinuation of Peginterferon and Ribavirin Source: Telaprevir (Incivek) Prescribing Information and Vertex Pharmaceuticals.

Telaprevir Moderate Skin Rash Source: Photograph Courtesy of John Scott, MD, University of Washington

Telaprevir Moderate Skin Rash Assessment - Diffuse rash and/or rash with limited distribution - With or without superficial skin peeling, pruritus, or mucous membrane involvement with no ulceration Management - Continue all medications for HCV therapy - Use good skin care practices - Consider oral antihistamine + topical corticosteroid - Monitor and re-assess if progression occurs* *Stop telaprevir if becomes severe or systemic symptoms develop; OK to continue Peginterferon and Ribavirin, but if does not improve within 7 days after stopping Telaprevir, consider sequential or simultaneous discontinuation of Peginterferon and Ribavirin Source: Telaprevir (Incivek) Prescribing Information and Vertex Pharmaceuticals.

Telaprevir Severe Skin Rash Source: Photograph Courtesy of John Scott, MD, University of Washington

Telaprevir Severe Skin Rash Assessment - Generalized rash with or without pruritus OR - Rash with vesicles, bullae, or ulcerations (other than SJS) Management - Stop Telaprevir (do not restart) - May continue Peginterferon + Ribavirin - Use good skin care practices - Consider oral antihistamine + topical corticosteroid - Monitor and re-assess* *If rash does not improve within 7 days of stopping Telaprevir, consider sequential or simultaneous discontinuation of Peginterferon and Ribavirin Source: Telaprevir (Incivek) Prescribing Information. Vertex Pharmaceuticals.

Telaprevir Serious Skin Rash (DRESS or SJS) HEPATITIS C: TREATMENT Telaprevir Serious Skin Rash (DRESS or SJS) Assessment - Stevens-Johnson Syndrome (SJS): Generalized rash with symptoms that may include fever, target lesions, and mucosal erosions or ulcerations OR - Drug Rash with Eosinophilia and Systemic Symptoms (DRESS): Presenting signs and systemic symptoms may include rash, fever, facial edema, and evidence of internal organ involvement (eg. hepatitis, nephritis). May occur with or without eosinophilia. Management - Stop all drugs immediately - Promptly refer for urgent medical care - Do NOT restart Telaprevir at any time in future Source: Telaprevir (Incivek) Prescribing Information and Vertex Pharmaceuticals.

Piroxicam 25 Reports della FDA per reazioni cutanee gravi ( sindrome di Stevens Jonhson e necrolisi Epidermica Tossica ) 8 casi mortali per reazioni dermatologiche tossiche DEAR DOCTOR LETTER dell’EMEA del 25.6.2007

Paracetamolo 29 reazioni avverse gravi in pz < 18 aa dal 4 Sindromi di Stevens Jonhson 3 Sindromi di Lyell fonte : Rete Nazionale di Farmacovigilanza

Dear Doctor Letter EMEA 25.7.2008 Moxifloxacina : Sindrome di Stevens Jonhson- Necrolisi Epidermica Tossica Ranelato di Stronzio : Sindrome di Stevens Jonhson e DRESS Dal 2004 al 2007 16 casi gravi ( 2 mortali ) di DRESS Cefaclor : Shock anafilattico

Sintomi anorettali e Telaprevir Interessano il 29% dei pazienti Emorroidi, prurito e bruciore rettale;, la diarrea può esacerbare i sintomi precedenti Sono solitamente lievi e di rado possono portare alla sospensione della terapia Compaiono dopo la prima settimana di terapia e possono perdurare per 2 mesi Utili i lubrificanti topici come vaselina e aloe vera; creme al cortisone e talora anestetici topici come la lidocaina Ricordare al paziente che i sintomi scompaiono al termine dell’assunzione del telaprevir

Gestione dei sintomi anorettali Steroidi topici Anestetici topici Antistaminici serali per attutire il prurito Trattare la diarrea con loperamide

Anemia

Anemia TELAPREVIR has been shown to have an additive but reversible effect on the incidence and severity of anemia compared to PR alone. In placebo controlled Phase 2 and 3 trials, anemia (all grades) was reported in 32.1% of patients who received TELAPREVIR combination treatment and in 14.8% of patients who received peginterferon alfa and ribavirin alone Ribavirin dose reductions were used for management of anemia Erythropoïesis-stimulating agents (ESAs) were generally not permited and used in only 1% of patients in the Phase 2 and 3 clinical trials INCIVO European Summary of Product Characteristics

Anemia data from Phase II and III placebo-controlled studies Incidence and severity of anemia increased with telaprevir combination treatment compared with PR alone Hemoglobin <10 g/dL Hemoglobin <8.5 g/dL Patients (%) T12PR PR48 T12PR PR48 T12/PR: INCIVO® (750 mg q8h) for 12 weeks in combination with any duration of peginterferon alfa-2a and ribavirin. Placebo/PR48: Placebo in combination with 48 weeks of peginterferon alfa-2a and ribavirin. INCIVO European Summary of Product Characteristics

Guidance for Management of Anemia Hemoglobin should be monitored at regular intervals prior to and during TELAPREVIRcombination treatment: hemoglobin monitoring is recommended at Weeks 2, 4, 8 and 12 and as clinically appropriate thereafter. Baseline hemoglobin values of ≥12 g/dL (females) and ≥13 g/dL (males) are recommended prior to initiation of combination therapy in adults. For the management of anemia, refer to the Summary of Product Characteristics for ribavirin for its dose reduction guidelines. If ribavirin is permanently discontinued due to anemia TELAPREVIR must also be stopped permanently. Treatment with peginterferon alfa and ribavirin may be continued if TELAPREVIR is discontinued due to anemia. The dose of TELAPREVIR must not be reduced. TELAPREVIR must not be restarted if discontinued due to anemia. INCIVO European Summary of Product Characteristics

Expert Rev Anti Infect Ther 2011 Dec ;9(12) :1105-14 Telaprevir for the treatment of chronic hepatitis C infection Drugs 2012 mar 26 ; 72(5): 619:41 Telaprevir : a review of its use in the management of genotype 1 chronic hepatitis C

“ gli effetti collaterali della terapia sono dovuti soprattutto a PEF IFN e RBV , tuttavia sono più frequenti nei regimi di combinazione con telaprevir : fatigue,rash , prurito , anemia e nausea “

Boceprevir Approval - FDA Approved May 13, 2011 Indications - In combination with Peginterferon-alfa and Ribavirin - Chronic HCV genotype 1 infection - Adults (> 18 years of age) with compensated liver disease, including cirrhosis - Treatment-naïve or failed prior interferon and ribavirin therapy Boceprevir Dosing - 800 mg (four 200-mg capsules) 3 times daily with food (meal or light snack) - Boceprevir given for 24-44 weeks - Treat with PR for 28-48 weeks based on HCV RNA results (week 8 & 24) Adverse Effects Attributable to Boceprevir - Anemia, nausea, and dysgeusia Source: Boceprevir (Victrelis) Prescribing Information. Merck & Co.

Boceprevir Adverse Effects

Eventi avversi con Boceprevir + PR Maggiore incidenza di anemia, neutropenia, e disgeusia Eventi avversi, % Boceprevir + PR RGT/48 (n = 1225) PR48 (n = 467) Anemia* 50 30 Neutropenia 25 19 Disgeusia 35 16 *Anemia è stata gestita con la riduzione della dose di RBV con o senza l’introduzione di epoetin alfa (43% di boceprevir + PR e 24% PR) Boceprevir [package insert]. May 2011.

Liver Int 2012 Feb ; 32 Suppl 1:27-31 Phase III results of Boceprevir in treatment naive patients with chronic hepatitis C genotype 1. “ L’anemia è stata il principale effetto collaterale e ha richiesto la riduzione della dose di RBV nel 21 % dei casi “

Eventi avversi %

Interazioni farmacologiche

Valutazione delle interazioni farmacologiche Telaprevir è metabolizzato dal CYP3A4 Boceprevir è metabolizzato principalmente dalla aldo- keto reduttasi e parzialmente da CYP3A4 Quasi la metà dei farmaci sono metabolizzati dal CYP3A4 La lista dei farmaci con possibile interazione è lunga Cautela quando si introduce un nuovo farmaco Ricercare l’eventule uso di prodotti di erboristeria

Come valutare l’interazione fra farmaci

Farmaci controindicati con BOC e TVR Drug Class Contraindicated With BOC[1] Contraindicated With TVR[2] Alpha 1-adrenoreceptor antagonist Alfuzosin Anticonvulsants Carbamazepine, phenobarbital, phenytoin N/A Antimycobacterials Rifampin Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine GI motility agents Cisapride Herbal products Hypericum perforatum (St John’s wort) Hypericum perforatum HMG CoA reductase inhibitors Lovastatin, simvastatin Atorvastatin, lovastatin, simvastatin Oral contraceptives Drospirenone Neuroleptic Pimozide PDE5 inhibitor Sildenafil or tadalafil when used for tx of pulmonary arterial HTN Sedatives/hypnotics Triazolam; orally administered midazolam Orally administered midazolam, triazolam *Studies of drug-drug interactions incomplete 1. Boceprevir [package insert]. May 2011. 2. Telaprevir [package insert]. May 2011.

Telaprevir Drug-Drug Interactions: Contraindicated Medications Medications Contraindicated for use with Telaprevir Drug Class Medication and Interaction Medications Contraindicated because they May Decrease Telaprevir Levels Antimycobacterials Rifampin Herbal Products St John’s wort (Hypericum perforatum) Medications Contraindicated because Levels May be Increased by Telaprevir Alpha-1 Adrenoreceptor Antagonist Alfuzosin Ergot Derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine Gastrointestinal Motility Agent Cisapride HMG CoA-Reductase Inhibitors Atorvastatin, lovastatin, simvastatin Neuroleptic Pimozide PDE5 Inhibitor Sildenafil or Tadalafil (dose levels for treatment of pulmonary hypertension) Sedatives/hypnotics Orally administered midazolam, triazolam

TVR: conseguenze sui livelli plasmatici dei farmaci cosomministrati Farmaco Dose AUC Alprazolam 0.5 mg 1.35 Amlodipina 5 mg 2.79 Atorvastatina 20 mg 7.88 Escitalopram 10 mg 0.65 Etinilestradiolo 0.035 mg 0.72 Ketoconazolo 200 mg 2.25 Metadone 40-120 mg 0.71 Tacrolimus 2 mg 17.6 Ciclosporina 100 mg 4.64 Efavirenz 600 mg 0.93 Tenofovir 300 mg 1.30 Tramadolo 50 mg ? Domperidone NO Prednisone

Telaprevir Aritmie gravi ( amiodarone,chinidina,terfenadina,sildenafil, tadalafil) Rabdomiolisi ( atorvastatina,lovastatina,simvastatina) Ischemia periferica ( diidroergotamina ) Ridotta efficacia degli estroprogestinici

Induttori enzimatici che riducono la attività di telaprevir Fenobarbital,carbamazepina, fenitoina Rifampicina, rifabutina Corticosteroidi Ritonavir,darunavir,atazanavir,efavirenz

Boceprevir è un potente inibitore del CYP3A4 Midazolam ,triazolam,alprazolam Diidroergotaminici Drospirenone\etinil estradiolo Simvastatina,atorvastatina

Farmaci che richiedono una modifica posologica Alprazolam: lieve aumento di efficacia (1.35), ridurre la dose Amlodipina: aumento di efficacia (2.79), dimezzare la dose Digossina: aumento di efficacia (1.85), ridurre la dose Atorvastatina: aumento di efficacia (7.88), evitare somministrazione, max 5 mg a dì alterni Escitalopram: significativa riduzione di efficacia (0.65), aumentare la dose Pillola anticoncezionale: ridotta efficacia, meglio associare metodi di barriera Telaprevir must not be administered concurrently with medicinal products with a narrow therapeutic window that are substrates of CYP3A. Co-administration of telaprevir may increase the plasma concentration of these medicinal products, which may lead to serious and / or lifethreatening adverse reactions such as cardiac arrhythmia (i.e., amiodarone, astemizole, bepridil, cisapride, flecainide, pimozide, propafenone, quinidine, terfenadine) or peripheral vasospasm or ischemia (i.e., dihydroergotamine, ergonovine, ergotamine, methylergonovine), or myopathy, including rhabdomyolysis (i.e., atorvastatin, lovastatin, simvastatin), or prolonged or increased sedation or respiratory depression (i.e., orally administered midazolam, triazolam), or hypotension or cardiac arrhythmia (i.e., alfuzosin and sildenafil or tadalafil for pulmonary arterial hypertension). This list is not exhaustive. Telaprevir must not be administered concurrently with any Class I or III antiarrhythmics (including but not limited to quinidine, flecainide, propafenone, and amiodarone). Rifampicin reduces the telaprevir plasma AUC by approximately 92%. Therefore, telaprevir must not be co-administered with rifampicin. St. John’s wort (Hypericum perforatum) - Plasma concentrations of telaprevir can be reduced by concomitant use of the herbal preparation St. John’s wort (Hypericum perforatum). Therefore, herbal preparations containing St. John’s wort should not be combined with telaprevir.

FARMACI DA EVITARE ANTIARITMICI (AMIODARONE, BEPRIDIL, CHINIDINA) ANTIBATTERICI (RIFAMPICINA) ANTIEPILETTICI (CARBAMAZEPINA, BARBITURICI, FENITOINA) ANTIEMICRANICI PIMOZIDE, MIDAZOLAM, TRIAZOLAM DROSPIRENONE, CISAPRIDE, VIAGRA, CIALIS, STATINE, ALFUZOSINA ERBA DI SAN GIOVANNI

Liver Int 2012 Feb; 32 Suppl 1: 54-60 Triple therapy for HCV genotype 1 infection : telaprevir or boceprevir ? “La scelta deve considerare lo schema terapeutico , la durata della terapia ….”

Regimi di Trattamento dei Pz Naive a confronto Telaprevir ha un regime di trattamento dei pazienti HCV G1 Naïve più compliante rispetto a Boceprevir (12 settimane vs 24/32 settimane nei pz senza Cirrosi e 12 settimane vs 44 settimane nei pz con cirrosi) Nei Pazienti Naïve eRVR positivi la durata di trattamento con la Triplice con Telaprevir si dimezza rispetto a quella con PR (24 settimane) mentre con la Triplice con Boceprevir si riduce a 28 settimane

Contraccezione durante terapia PI possono ridurre l’efficacia della pillola anticoncezionale Per le donne che assumono la pillola, sono richiesti due metodi di barriera Per i maschi in trattamento che abbiano una partner sessuale fertile sono richieste 2 forme di contraccezione 2 settimane dopo il termine del trattamento con telaprevir, la pillola anticoncezionale può ritenersi sufficiente se associata ad altro metodo di barriera per chi assuma ribavirina 2 metodi anticoncezionali devono essere utilizzati sino a 6 mesi dopo la fine della terapia Un test di gravidanza deve essere effettuato mensilmente durante il trattamento e sino a 6 mesi dopo Contraccettivi ormonali potrebbero non essere affidabili in corso di terapia con Telaprevir. Pertanto, si devono utilizzare 2 metodi supplementari di controllo delle nascite durante terapia e nei 2 mesi dopo l'ultima assunzione di Telaprevir. Si possono usare un preservativo per il maschio e un diaframma con spermicida nella donna. Dopo 2 mesi dal completamento del trattamento con Telaprevir, i contraccettivi ormonali possono essere nuovamente utilizzati come uno dei 2 metodi richiesti per il controllo delle nascite.

Conclusioni 1 Controindicazioni all’uso di PI Precedenti eventi avversi che hanno portato alla precoce interruzione di pegIFN/RBV Donne in gravidanza o uomini la cui partner sia in gravidanza Ghany MG, et al. Hepatology. 2011;54:1433-1444.

Conclusioni 2 Precauzioni nell’uso di PI Cosomministrazione di altri farmaci dipendenti per la clearance dal CYP3A4/5 Cosomministrazione di potenti induttori del CYP3A4/5 che possono ridurre i livelli plasmatici di BOC o TVR comportando una loro ridotta efficacia

Conclusioni 3 Sicurezza Sicurezza e profilo farmacocinetico non sono stati sufficientemente studiati nella cirrosi scompensata, nel setting del trapianto, nei coinfetti con HBV o HIV, o nei pazienti di età inferiore a 18 anni

Conclusioni 4 Gestione eventi avversi Informare il paziente degli eventi avversi prima di iniziare Valutare le interazioni farmacologiche prima di iniziare la terapia Vedere il paziente ogni 10 giorni nei primi due mesi Trattare gli eventi avversi prima che diventino critici Creare un team dedicato

grazie per l’attenzione