Thursday, February 2, 2012

Strategies for Success: Management of Telaprevir-Associated Rash and Anorectal Symptoms

Scott Cotler , M.D.
Strategies for Success: Management of Telaprevir-Associated Rash and Anorectal Symptoms
Editor’s note: In this edition of Journal Options Hepatitis, we feature the 5 pivotal phase III studies that led to the approval in 2011 of boceprevir and telaprevir for the treatment of chronic hepatitis C. Each commentary in this series addresses a key issue or question of clinical relevance related to the use of these agents in clinical practice.

Despite increased sustained virologic response (SVR) rates associated with protease inhibitor–based therapy, challenges exist, including adverse events. Rash and anorectal symptoms are among the more common adverse events associated with telaprevir,[1] although the mechanism of action resulting in these adverse effects is currently unknown. Although there is an increase in adverse events associated with telaprevir, these events are rarely serious, may be managed, and should not dissuade clinicians from giving patients the best possible treatment for hepatitis C virus (HCV) infection to increase the chance of SVR.
This commentary reviews what is known about telaprevir-associated rash and anorectal symptoms and how these events can be managed to help patients successfully complete a course of treatment. 

Data from controlled clinical trials of telaprevir indicate that approximately 56% of patients experienced rash.[1] Telaprevir-associated rash is eczematous, associated with dry skin and pruritus, and in some cases has a maculopapular component. The rash is similar in appearance and histology to that observed with peginterferon/ribavirin but can be more extensive or severe. Rash onset typically occurs within the first 4 weeks of telaprevir treatment, with a median time to onset of 25 days; however, it is important to recognize that rash can develop any time during telaprevir therapy.[1,2] In most cases the rash does not progress and it tends to resolve gradually over weeks after telaprevir is discontinued. At our center, my colleagues and I have seen some transient cases of telaprevir-associated rash that resolved while patients continued to take telaprevir.
Severe rash, which is generalized and covers more than 50% of body surface area or which shows evidence of skin breakdown (eg, vesicles, ulcerations), was reported in 4% of patients receiving telaprevir in controlled clinical trials.[1] Potentially life-threatening events, including Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) syndrome and Stevens-Johnson syndrome, were rarely reported. An analysis of more than 1200 patients treated with telaprevir during the clinical development program identified 11 cases of DRESS (< 1%) and 2 cases of Stevens-Johnson syndrome (< 0.2%).[2] These diagnoses were judged as probable or possible by a dermatology expert panel. On a positive note, these syndromes resolved with telaprevir discontinuation in all cases. Thus, although severe events can occur, they are quite rare. Nevertheless, clinicians need to remain vigilant for the development of these syndromes.

Clear guidance for managing telaprevir-associated rash is detailed in the prescribing information.[1,2] Management of rash that is mild (localized) or moderate (more diffuse, but covering < 50% body surface area) involves continuing all medication, monitoring for progression, and using symptomatic therapy consisting of topical corticosteroids and/or oral antihistamines. Systemic corticosteroids are contraindicated given the potential for drug-drug interactions with telaprevir. For severe rash, the management approach is to discontinue telaprevir, continue peginterferon/ribavirin, and monitor patients closely over the course of 7 days. If the rash does not improve or worsens, consideration should be given to discontinuing ribavirin and/or peginterferon. If a patient shows evidence of either DRESS or Stevens-Johnson syndrome, all treatment should be immediately stopped, with favor given to patient hospitalization and consultation from a dermatologist. It is very important not to reduce the dose of telaprevir in response to rash—or any adverse event, for that matter—as dose reduction may result in the emergence of telaprevir-resistant HCV variants.

This rash management plan was implemented in the phase III studies of telaprevir with success.[2] Although the overall incidence of rash remained similar in the phase III trials to that seen in the phase II trials, the rate of discontinuation of all medications due to rash fell to 1.1% in the phase III trials compared with a rate of 6.2% in the phase II trials. Thus, by using this management plan, most cases of rash can be effectively handled, allowing patients to remain on telaprevir therapy and maximizing the potential response to treatment. 

Anorectal Symptoms
In the controlled trials of telaprevir, anorectal symptoms consisted primarily of hemorrhoids, anorectal discomfort, anal pruritus, and rectal burning.[1] Some patients experience diarrhea while taking telaprevir, which can exacerbate these symptoms. Overall, 29% of patients treated with telaprevir experienced anorectal symptoms. Most events were mild, and it was rare that they were treatment limiting. The median time to onset was 9 days, and the median duration was 57 days.[3] My colleagues and I have found in our practice that these symptoms are troubling or annoying to patients, but tolerable. Moreover, it is very rare that patients need to discontinue treatment due to these events.
Management of anorectal adverse events should target the symptoms through use of topical lubricants (eg, petroleum jelly, aloe vera), topical hydrocortisone cream, and in some cases, topical anesthetics (eg, lidocaine). The underlying approach is to get patients through treatment and to remind them that these symptoms will resolve when the course of telaprevir is complete. 

Please review the remaining 4 commentaries in this series on the use of boceprevir and telaprevir in clinical practice:
Free registration is required to view the below links

  • To review strategies for management of telaprevir-associated rash and anorectal symptoms, click here.
  • For a better understanding of futility rules and their importance with boceprevir and telaprevir, click here.
  • To review the impact of the occurrence and management of anemia with boceprevir and telaprevir, click here.
  • To review rules for following response-guided therapy guidelines with telaprevir and boceprevir, click here.
1. Incivek [package insert]. Cambridge, Mass: Vertex Pharmaceuticals Inc.; 2011.
2. Cacoub P, Bourlière M, Lübbe J, et al. Dermatological side effects of hepatitis C and its treatment: patient management in the era of direct-acting antivirals. J Hepatol. 2011;[Epub ahead of print].
3. US Food and Drug Administration, Center for Drug Evaluation and Research. Drug approval package, Incivek (telaprevir) film-coated tablets. Application number: 201917Orig1s000, medical review(s). Available at: Accessed December 12, 2011.

No comments:

Post a Comment