Showing posts with label side effects-direct-acting antivirals. Show all posts
Showing posts with label side effects-direct-acting antivirals. Show all posts

Sunday, October 28, 2012

Watch - Management of Hepatitis C Virus in the New Era: Small Molecules Bring Big Changes

 CME Webcast

When new education-related information on hepatitis C becomes available this blog provides readers with background information, links and a few tips for navigating the website.

A few days ago IAS-USA published a new CME webcast, "Management of Hepatitis C Virus in the New Era: Small Molecules Bring Big Changes, discussing the rapid advances in HCV treatment." headed up by the one and only Douglas T Dieterich MD, Susanna Naggie MD, John Webb Ward MD, George M. Shaw MD, PhD, FACP, Kimberly A Workowski MD, FACP, FIDSA, Michael S Saag MD, Jennifer J Kiser PharmD, and Kenneth E Sherman MD, PhD.

The live activity includes case studies discussing the following topics; who should begin therapy, treatment regimens, resistance, current direct-acting antivirals, investigational direct-acting antivirals and interferon alfa-free regimens, effects of HCV on the liver, drug-drug interactions, and managing the adverse-effects of therapy.

Naviatgating The CME Webcast

Links are provided below to each presentation.

*The webcast will take only a few minutes to load, its worth the wait. Each presentation is approximately thirty minutes to an hour.

No registration is required

1-Click on a presentation below - after landing on the index page click "Watch the Webcast"
2-Scroll to the bottom of the page and click on “I have read these instructions and understand them,” to begin activity.

Presentations

Tuesday, September 4, 2012

Adding Telaprevir to HCV Regimen Worthwhile

VOL. 6 • NO. 9 • SEPTEMBER 2012
GI& HEPATOLOGY NEWS

Adding Telaprevir to HCV Regimen Worthwhile

BY DIANA MAHONEY
IMNG Medical News
SAN DIEGO

"When considered in the context of the improved SVR, “the burden of the increased incidence of anemia and rash associated with telaprevir, of which few cases are severe, appears to be outweighed by the overall treatment response.” Addition of telaprevir to peginterferon/ribavirin therapy for chronic hepatitis C can exacerbate treatment- related side effects, but the triple combination does not diminish patient quality of life relative to the peginterferon/ ribavirin regimen alone, a study has shown."

Adding the protease inhibitor telaprevir “does not further diminish patient quality of life,” lead investigator Dr. Zobair Younossi, AGAF, explained at the annual Digestive Disease Week.

“The most important contributor to the quality of life measurement in interferon therapy is interferon itself, which is so overwhelming in terms of side effects, especially grade 4 and 5 effects, that it probably overshadows everything else.

” Studies have shown that addition of telaprevir to standard peginterferon alfa- 2a/ribavirin (PR) significantly improves treatment efficacy in treatment-naive patients with genotype 1 hepatitis C virus (HCV), but there is a perception that the additional side effect burden from telaprevir is prohibitive in some patients, said Dr. Younossi, chairman of the department of medicine at Inova Health System in Falls Church, Va.

Dr. Younossi and colleagues conducted post hoc analyses of data from the ADVANCE trial, in which adding telaprevir to the treatment mix significantly improved patients’ sustained virologic response compared with standard PR therapy.

In the ADVANCE study, 1,088 treatment- naive HCV genotype 1 patients were assigned to one of three treatment arms: 48 weeks of standard PR therapy; 12 weeks of telaprevir plus 24 weeks PR; or 12 weeks of telaprevir plus 48 weeks of PR.

Nearly 80% of patients in both telaprevir groups achieved sustained virologic response, compared with 46% of patients in the standard PR treatment group (N. Engl. J. Med. 2011; 364:2405-16). In terms of side effects, “across all phase III studies, the incidence of rash and anemia (which are the effects we’re talking about with the protease inhibitors) was 56% and 34%, respectively, among telaprevir-treated patients, and 36% and 17% in patients receiving standard treatment,” Dr. Younossi said.

To assess whether and to what degree these increases played a role in patient quality of life, Dr. Younossi and colleagues analyzed the results of EQ-5D quality of life questionnaires completed at baseline and at weeks 4, 12, 24, 36, 48, and 72 by 722 patients.

The investigators derived a summary index by calculating the percentages of patients reporting problems for each of the five health-related quality of life dimensions measured (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression).

After adjustment for age and sex, the baseline mean index values for the EQ- 5D were 0.92 for the telaprevir plus 24- week PR group, 0.90 for the telaprevir plus 48-week PR group, and 0.91 for the 48-week PR-only group.

The percentages of patients reporting any problems in each of the five qualitative dimensions at baseline were 8.2% for mobility, 2.0% for self-care, 12.9% for usual activities, 25.7% for pain/discomfort, and 25.6% for anxiety/depression, he said.

Across all the treatment groups, the EQ-5D index scores worsened during the first 12 weeks of treatment initiation. Specifically, mean values were 0.80 for the pooled-telaprevir groups and 0.83 for the PR-only group, according to Dr. Younossi.

Also, the respective percentages of patients in the pooled-telaprevir and PR-only groups reporting any problems at week 12 were 56% and 50% for usual activities, 51% and 42% for anxiety/depression, and 60% and 63% for pain/discomfort, he said.

Change from baseline in terms of reported impact on mobility and self-care were small and not reported.

At week 48, the corresponding mean EQ-5D values were 0.93 for the telaprevir plus 24-week PR group, 0.83 for the telaprevir plus 48-week PR group, and 0.84 for the PR-only group.

By week 72 the EQ-5D index values returned to baseline levels, Dr. Younossi said.

Adjusted for age and sex, the mean EQ-5D index at week 72 was higher among the patients achieving sustained virologic response (SVR) compared with those who did not, with respective values of 0.90 and 0.86. “The 4% difference is within the range of published values for the minimal clinically important difference for the EQ-5D,” he said.

Furthermore, at week 72, there were fewer patients among those who experienced SVR and reported problems in each dimension, compared with those who did not experience SVR.

At week 72, after adjustment for the index at baseline, patient age, sex, race, advanced liver disease, self-reported comorbidities, and the number of adverse events during treatment, only SVR was a positive predictor of the EQ-5D index.

“We saw that [SVR] was a statistically significant and meaningful predictor of health-related quality of life,” he said. The study findings are consistent with the published research on the impacts of interferon-based regimens on health-related quality of life in this patient population, “and support the value of shorter treatment duration and [SVR] from a patient- reported outcomes perspective,” said Dr. Younossi. “We certainly cannot say that adding telaprevir causes fewer side effects.

It’s clear there are more side effects, but it appears that the most troublesome side effects are related to the interferon therapy,” he explained.

When considered in the context of the improved SVR, “the burden of the increased incidence of anemia and rash associated with telaprevir, of which few cases are severe, appears to be outweighed by the overall treatment response.”

This study was sponsored by Vertex. Dr. Younossi disclosed relationships with Biolex, Vertex, Salix, GlaxoSmithKline, and Tibotec.

GI & Hepatology News is the official newspaper of the AGA Institute and provides the gastroenterologist with timely and relevant news and commentary about clinical developments and about the impact of health-care policy. The newspaper is led by an internationally renowned board of editors.

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Drug-Drug Interactions Added to Boceprevir Label

VOL. 6 • NO. 9 • SEPTEMBER 2012
GI& HEPATOLOGY NEWS

BY ELIZABETH MECHCATIE
IMNG Medical News

Drug-Drug Interactions Added to Boceprevir Label

New information about interactions between boceprevir and several other drugs has been added to the prescribing information for the antiviral drug, the Food and Drug Administration announced on Aug. 1.

Boceprevir (Victrelis), a protease inhibitor approved for treating hepatitis C in 2011, interacts with cyclosporine, tacrolimus (Prograf ), escitalopram (Lexapro), atorvastatin (Lipitor), and pravastatin (Pravachol), according to the FDA statement. The new information states that exposure to atorvastatin increases when given with boceprevir.

If the two drugs are used together, the lowest effective dose of atorvastatin should be used, not to exceed a daily dose of 40 mg, according to the FDA.

Dose adjustments of cyclosporine should be expected when it is given with boceprevir. Cyclosporine dosage “should be guided by close monitoring of cyclosporine blood concentrations and frequent assessments of renal function and cyclosporine-related side effects.” When administered with boceprevir, exposure of escitalopram “was slightly decreased,” the statement said. Although selective serotonin reuptake inhibitors such as escitalopram have a wide therapeutic index, it may be necessary to adjust the dosage when it is administered with boceprevir.

Coadministration of boceprevir with pravastatin increases exposure to pravastatin, but pravastatin can be started at the recommended dosage when coadministered with boceprevir. “Close clinical monitoring is warranted,” the statement said. Giving tacrolimus and boceprevir together “requires significant dose reduction and prolongation of the dosing interval for tacrolimus, with close monitoring of tacrolimus blood concentrations and frequent assessments of renal function and tacrolimus-related side effects,” the statement said.

Boceprevir is manufactured in a capsule formulation by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., and is taken by mouth three times a day.

The drug-drug interaction data are from in vivo drug interaction trials, which the company conducted as part of its postmarketing commitments.

At a meeting in April 2011, an FDA advisory panel enthusiastically supported the approval of boceprevir for treating hepatitis C infection because of the antiviral’s efficacy, but emphasized that postmarketing studies on interactions with other drugs, including antidepressants, were needed. ■

The revised prescribing information is available at www.accessdata.fda . gov/drugsatfda_docs/label/2012/ 202258s001lbl.pdf ?source= govdelivery .

Serious adverse events associated with boceprevir should be reported to MedWatch at 800- 332-1088 or www.fda.gov/ medwatch
.
GI & Hepatology News is the official newspaper of the AGA Institute and provides the gastroenterologist with timely and relevant news and commentary about clinical developments and about the impact of health-care policy. The newspaper is led by an internationally renowned board of editors.

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Monday, July 23, 2012

So You Think You’re A Hepatitis C Expert? 35 questions answered by 9 hepatology experts

Hello folks,
A few days ago Clinical Care Options released an online quiz containing 35 questions on treating hepatitis C, answered by nine world-renowned hepatology experts.

Check out these two questions offered in the quiz, with expert analysis by Stefan Zeuzem, MD.

Patient Case: Management of Rash

A 45-year-old female patient chronically infected with genotype 1b HCV relapsed following previous therapy with peginterferon/ribavirin. During previous therapy, treatment was well tolerated and she responded to peginterferon/ribavirin rapidly and had undetectable HCV RNA by Week 8. She is interested in retreatment with triple therapy and favors telaprevir-based therapy because of the 12-week period of triple therapy and hopes that this will minimize potential for adverse events. She is a TV moderator and is, therefore, particularly worried about a potential telaprevir-associated rash and specifically asks whether the rash is likely to occur in the face. How should this patient be counseled?

Analysis by Stefan Zeuzem, MD:
The typical telaprevir-associated rash can be described as an eczematous dermatitis, associated with pruritus and xerosis.[21,22] High-volume treaters have seen that telaprevir-associated rash is typically located on the trunk, arms, and legs, and only rarely affects the face. Grade 1 and 2 rash can be treated using emollients, moisturizers, and topical steroids.[21] Grade 3, or severe, rash requires immediate discontinuation of telaprevir.[21] Systemic steroids are not recommended during concomitant telaprevir administration and should be given only for severe rash after discontinuation of telaprevir.[1

Patient Case: Management of Rash

A 58-year-old male Hispanic patient with chronic genotype 1a HCV infection was started on triple therapy with peginterferon/ribavirin and telaprevir. After 4 weeks of therapy, HCV RNA was no longer detectable in serum. During Week 6 of triple therapy, he develops skin itching and a maculopapular rash on his trunk sparing the face, arms, and legs. He has a strong hair growth both on the front and the back of his trunk, which makes the rash difficult to visualize. Should telaprevir be discontinued?

Analysis by Stefan Zeuzem, MD:
The management strategy for telaprevir rash depends on its severity, with treatment discontinuation indicated only for grade 3 or “severe” rashes that cover > 50% of the body surface area. According to the “rule of nines,” each arm and leg comprises 9% and 18% of body surface area, respectively (in total 54%).[24] Rash affecting the complete trunk but sparing arms and legs is calculated to comprise approximately 36% of the body surface area (18% for the chest and abdomen, 18% for the back), that is, < 50% of total body surface area. Therefore, this patient’s rash would be classified as grade 2,[21] and treatment with telaprevir can be continued. Pruritus should be treated with cetirizine or other antihistamines without relevant drug–drug interactions with telaprevir.[21] Despite strong hair growth on the patient’s trunk, emollients/moisturizers and topical steroids should also be used in the treatment of the rash. Coadministration of systemic steroids and telaprevir is not recommended.

Are you ready to take the quiz?

Provided below is a look at the 35 questions. If you haven't registered with CCO, click here to register, and here to take the quiz. Thanks CCO !

Part 1 - ClinicalQuiz: So You Think You’re A Hepatitis C Expert?
By: Nezam H. Afdhal, MD, FRCPI, Donald M. Jensen, MD, Paul Y. Kwo, MD, Andrew J. Muir, MD, MHS, David R. Nelson, MD, Paul J. Pockros, MD, Fred Poordad, MD, Mark S. Sulkowski, MD, Stefan Zeuzem, MD

Introduction
Hepatitis C is a rapidly evolving field with 2 newly available medications, recently updated treatment guidelines, and several investigational therapies in late stages of development. New therapies available for the treatment of patients infected with genotype 1 hepatitis C virus (HCV) have unique features that have changed the way clinicians treat the disease.

At the same time, management of non–genotype 1 HCV has evolved as new data have highlighted strategies for optimizing treatment in these patients. To help clinicians better apply current treatment guidelines and best management practices for hepatitis C, Raymond T. Chung, MD, and Jordan J. Feld, MD, together with 9 world-renowned hepatology experts, developed the educational program, “ClinicalQuiz: So You Think You’re a, Hepatitis C Expert,” an online and mobile game application designed to test knowledge and competence in treating hepatitis C.

This CME-certified educational activity includes important recommendations and clinical pearls from the first 35 questions of the HCV ClinicalQuiz.

Applying Response-Guided Paradigms for Treatment With Protease Inhibitor–Based Therapy
1-Patient Case: Telaprevir Regimen in Cirrhotic
2-Patient Case: Telaprevir Regimen in Previous Relapser
3-Patient Case: Telaprevir Regimen in Treatment-Experienced
4-Patient Patient Case: Use of Lead-in With Telaprevir
5-Patient Case: Qualifying for Shortened Therapy With Telaprevir
6-Patient Case: Boceprevir Regimen in Treatment-Experienced
7-Patient Patient Case: Telaprevir Futility Rules
8-Patient Case: Management of Missed Virologic Time Point
9-Patient Case: Assessing Response to Lead-in With Boceprevir Therapy
10-Patient Case: Response-Guided Therapy With Boceprevir in Treatment-Naive
11-Patient Patient Case: Qualifying for Shortened Therapy With Boceprevir
12-Patient Case: Futility Rules With Boceprevir
13-Patient Case: Interpretation of HCV RNA Assay Results

Adverse Event Management
14-Patient Case: Management of Anemia
15-Patient Case: Counseling Regarding Anemia
16-Patient Case: Counseling Regarding Neutropenia
17-Patient Case: Management of Thrombocytopenia
18-Patient Case: Management of Depression
19-Patient Case: Management of Rash
20-Patient Case: Management of Rash
21-Patient Case: Management of Dysgeusia

Strategies for Management of Special Populations With HCV Infection
22-Patient Case: Protease Inhibitor Therapy in Women of Childbearing Age
23-Patient Case: Management of Acute HCV Infection
24-Patient Case: Selection of Therapy in Patient With Renal Impairment
25-Patient Case: Management of HCV Posttransplant

Applying Best Practices to the Management of Genotype 2/3 Patients
26-Patient Case: Selection of Therapy in Genotype 3
27-Patient Patient Case: Pretreatment Counseling in Genotype 3 Patient
28-Patient Case: Treatment Duration in Genotype 2 Patient Cases and Strategies for Additional Management Considerations

Cases and Strategies for Additional Management Considerations
29-Patient Case: Food Requirements With Telaprevir
30-Patient Case: Posttreatment Monitoring of Patients
31-Patient Case: Interpretation of Assay Results
32-Patient Case: Treatment Options in Treatment-Experienced Genotype 1
33-Patient Patient Case: Treatment Options in Treatment-Experienced Genotype 2 Patient
34-Patient Case: Food Requirements With Boceprevir Therapy
35-Patient Case: Managing a Missed Dose of Boceprevir

Coming Soon!
ClinicalQuiz:
Answer Case-Based Questions Online Or On Your Mobile Device

CME-Certified Modules:
ClinicalQuiz: So You Think You’re a Hepatitis C Expert, Educational Material, Part 2
ClinicalQuiz: So You Think You’re a Hepatitis C Expert, Educational Material, Part 3

Monday, July 2, 2012

Exanthematous Drug Eruptions:Prescription and over-the-counter medications

Telaprevir approved by the FDA for the treatment of hepatitis C has been reported to cause cutaneous (skin) adverse events. Skin disorders in the triple therapy - (telaprevir plus PegIFN/RBV) has been reported more frequently and more severe than with PEG-IFN/RBV alone.

According to commentary in the - Journal Options-Hepatitis @ CCO, in clinical trials of telaprevir rash was experienced in 56% of patients, although as a rash management plan was implemented discontinuation of therapy in future trials improved.

An excerpt from CCO:

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

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.

 Read more here....

Last April Reuters reported on telaprevir-associated rash with information published in the 2012 March issue of  the Journal of Hepatology.  In the paper physicians reported during therapy with telaprevir, peginterferon, and ribavirin three patients out of 56, or 5 %  developed probable or definite DRESS.  According to the report; All cases managed successfully with discontinuation of medications, topical class I corticosteroids, and systemic antihistamines.

Excerpt;
In phase II and III clinical trials involving over 3,800 patients, 3.7% of telaprevir-treated patients developed severe cutaneous adverse events, the researchers note. The U.S. Food and Drug Administration approved telaprevir for treating HCV infection on May 23, 2011 and included DRESS among its warnings and precautions.
"The most feared complication of DRESS is end-organ damage, which in extreme cases can be life-threatening," Dr. Wu said, "so it is important to identify the syndrome early to stop the offending medications and monitor the disease."
"These are observations from a single institution during a finite amount of time," she added. "More information is needed to determine the true incidence of DRESS in telaprevir-treated patients, their prognosis, risk factors, and optimal treatment."
At this point there are no standard measures for preventing DRESS, according to Dr. Wu. "Future studies may involve genotyping those who have DRESS on telaprevir-based therapy and screening patients with associated HLA type or slow metabolism prior to receiving the medication," she said. "Although testing for human herpes virus 6 reactivation is not commonly done in this country, its association with DRESS has been made in other countries, and it may be worth screening for in the future."
Read more here....

Today on the blog is a case vignette from The New England Journal of Medicine which highlights cutaneous reactions from prescription and over-the-counter medications. The article discusses
the rare and more serious Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS). Hepatitis C patients, telaprevir, interferon alfa, and ribavirin is briefly mentioned.

Clinical Practice
Exanthematous Drug Eruptions
Robert S. Stern, M.D.
N Engl J Med 2012; 366:2492-2501

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations.

A 50-year-old woman with bipolar depression presents with a widespread pruritic rash of 1 day's duration. She is afebrile and otherwise well. She has a history of childhood eczema and is allergic to sulfonamide antibiotics. Her medications include thyroxine daily, naproxen intermittently, and lamotrigine, which she began taking 3 weeks earlier. How should this case be evaluated and treated?
.
The Clinical Problem
In the United States, patients fill more than 300 million drug prescriptions and purchase millions of over-the-counter medications each month.1 In many cases patients are using these medications for the first time. Cutaneous reactions are among the most common adverse effects of drugs, including penicillins, cephalosporins, sulfonamide antimicrobial agents, and allopurinol (with an incidence of up to 50 cases per 1000 new users), and particularly the aromatic amine antiseizure medications, including carbamazepine, phenytoin, and lamotrigine (with an incidence of up to 100 cases per 1000 new users).2-7 Drug-related rash is reported for nearly all prescription medications, usually at rates exceeding 10 cases per 1000 new users. These reactions can range from asymptomatic mild eruptions to life-threatening conditions. Cutaneous reactions may be difficult to distinguish from common rashes that are unrelated to medication use, particularly viral exanthems.

Exanthematous drug eruptions (also called morbilliform or maculopapular drug eruptions) are the most common drug-induced eruptions.2,7 They and the much rarer and more serious Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS) are idiosyncratic, T-cell–mediated, delayed (type IV) hypersensitivity reactions.8-11 Classically, antigen-presenting cells present haptens, composed of the drug or its metabolite bound to a protein or peptide, to naive T cells. These antigen-specific T cells proliferate, infiltrate the skin, and release cytokines, chemokines, and other proinflammatory mediators that are responsible for the signs and symptoms of the drug-related rash.12-15 According to an alternative theory known as the p-i (pharmacologic interaction of drugs with immune receptors) concept, small-molecule drugs or their metabolites, which are not complete antigens, activate T cells directly by binding to T-cell receptors.12,13 Irrespective of the mechanism that elicits a T-cell response to a drug, it is not known why only a minority of patients receiving a given drug have a clinical reaction to it, whereas others have immunologic reactivity without a rash.

Alterations in a patient's immune status, as well as genetic factors related to immune response, affect the risk of these drug reactions. Patients with human immunodeficiency virus (HIV) infection, bone marrow transplants, or certain infections for which they are taking particular medications are at especially high risk. 16,17 For example, most patients with infectious mononucleosis who are being treated with aminopenicillins have exanthematous eruptions, as compared with about 5% of patients without this disorder who are taking these drugs. Certain HLA alleles confer a much higher risk of some T-cell–mediated hypersensitivity reactions. Most often described in cases of severe cutaneous reactions, these associations are generally specific to the type of reaction, causative drug, and ethnic group (see Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org).18 In Europeans taking carbamazepine, HLA-A*3101 is reported to be associated with an increased risk of maculopapular exanthems.19

Most rashes due to medications are self-limited and only mildly symptomatic. The majority of skin events attributed to drugs are either exanthematous (maculopapular or morbilliform) eruptions (>80%) or urticaria (5 to 10%), but these percentages vary among medications and among patient groups.2,5,20 Among patients who are not immunologically compromised, severe cutaneous reactions to medications are rare (with an incidence of <1 case per 1000 new users), even with high-risk medications.8-11,20-23

Exanthematous eruptions present as a widespread, symmetrically distributed rash composed of pink-to-red macules and papules that may coalesce to form plaques (Figure 1A, 1B, and 1C 

Figure 1

Clinical Presentations of Common Drug Reactions and Measles.). Although mucous membranes are usually spared, redness without blistering may occur at these sites. Pruritus is frequent but highly variable in severity, and low-grade fever (temperature of <38.5°C) is common.

Urticaria (Figure 1D), photosensitivity, and fixed drug eruptions account for most of the remaining drug-associated eruptions in ambulatory patients. Urticaria shares pathophysiologic features with anaphylaxis and angioedema, both of which may be life-threatening. With most drugs, urticaria is an IgE–mediated, immediate (type I) hypersensitivity reaction. Urticaria due to nonsteroidal antiinflammatory drugs (NSAIDs) or angiotensin-converting–enzyme inhibitors usually reflects the pharmacologic effects of these medications rather than an immunologic reaction.24-26

Photosensitivity eruptions that accompany the use of systemic medications are almost always a consequence of ultraviolet- or visible-light activation of a drug, resulting in phototoxic injury to cells in the skin and a sunburn-like reaction that may blister in exposed areas27 (Figure 1E). Drugs commonly associated with phototoxicity include tetracyclines (particularly doxycycline), thiazide diuretics, quinolones, voriconazole, vemurafenib, amiodarone, and psoralens.28

Fixed drug eruptions present as small (usually <8 cm in diameter), red, round plaques that may sting, usually result in long-lasting pigmentation, particularly in persons with more skin pigment, and typically recur at the same sites (lips, genitalia, and acral skin) on reexposure to the causative medication (Figure 1F).29 Commonly responsible drugs include penicillins, NSAIDs, and acetaminophen.30

Strategies and Evidence
Evaluation and Diagnosis
In evaluating a patient with a new rash, the clinician should attempt to determine whether the rash is drug-related, whether it is likely to become severe, which medication or medications are most likely to be responsible, which medications can be discontinued, how the eruption should be treated, and what the patient should be told about future medication use. The appearance of the rash (its distribution and morphologic features and whether mucous membranes are involved), the time of its onset relative to the use of drugs, and an assessment of the patient for the presence of fever and other associated symptoms and signs (indicating involvement of other organs) and past reactions to medications, as well as other characteristics of the patient and any coexisting disorders, should guide decision making.

Any new, symmetric exanthematous eruption may be related to medication. Viral exanthems are often difficult to differentiate from drug-induced exanthems (Figure 1G). Viral illnesses are often characterized by the rapid onset of widespread, symmetric eruptions of pink-to-red macules and papules that may coalesce, with fever, malaise, sore throat, and conjunctivitis; however, these features may also be seen with a drug eruption. Viral exanthems are more common in children than in adults and are usually self-limited and mildly symptomatic.31 Table 1


Table 1

Selected Infections and Other Conditions that Often Include an Exanthem and Characteristics that Help Differentiate Them from an Exanthematous Drug Eruption. describes the characteristic features of some common viral exanthems that help distinguish them from drug eruptions. Patients with fever, sore throat, or malaise due to infections use many medications (particularly antibiotics and NSAIDs) that also cause exanthematous rash. Because of the time required for hypersensitivity to develop in a patient not previously sensitized to a particular drug, a rash that appears within 3 days after the drug has been initiated for these indications is more likely to be due to infection than to the drug.2,14,22
Most drug-induced exanthematous eruptions evolve rapidly, are symmetric and widespread, reach the maximal extent within 2 days after the elimination of the causative drug, and fade within a week after the drug is eliminated. Some drug eruptions start to fade even while the patient is still taking the causative agent.

The character of the individual lesions frequently varies according to the body site (e.g., confluent red plaques on the trunk and discrete pink macules and papules on the extremities). The rash is likely to be a deeper red and may even become purpuric in dependent areas. With the exception of patients who bleed easily, one should be able to cause blanching of the rash in nondependent areas. Skin eruptions that differ in appearance from exanthematous drug eruptions are common in patients treated with tyrosine kinase inhibitors (papulopustular eruptions) and patients with hepatitis C who are treated with telaprevir, interferon alfa, and ribavirin (eczematous eruptions).32,33

First-time exanthematous drug eruptions and T-cell–mediated severe cutaneous reactions typically begin to appear 4 to 21 days after the start of treatment with the responsible medication but may develop later in DRESS (Table 2

Table 2

Features of Selected Severe Cutaneous Adverse Reactions to Drugs.).2,11,22,23 Therefore, assessment of the timing of drug administration relative to the onset of rash and other symptoms is a key step. Resolution after a medication is stopped (known as a “dechallenge”) also helps identify the causative agent.

Since the likelihood of a drug-induced rash varies according to the medication, the population treated, and the indication for use, such factors should be considered in assessing the probability that the patient's rash is due to a specific drug. Aside from the genetic and disease factors discussed above, some groups of patients are at greatly increased risk for unknown reasons. For example, the rate of drug-related rash among young women treated with the antibiotic gemifloxacin (>20%) is about 10 times as high as the rate among other patients treated for the same indications.34 Organ-specific algorithms rather than algorithms that assess drug causality irrespective of the affected organ system may improve interrater reliability in the assessment of the cause of drug eruptions.35 Table S2 in the Supplementary Appendix provides an algorithm, adapted from one validated for SJS–TEN (another T-cell–mediated drug reaction), that may help identify the causative drug in cases of exanthematous drug eruptions,36 although it has not been validated for exanthematous reactions.

Assessing the Likelihood of a Severe Reaction
It is important to determine whether an exanthematous drug-induced rash is likely to be an early sign of a severe cutaneous reaction. Determining whether DRESS will develop in a patient with a widespread eruption and fever is particularly challenging. Table 2 summarizes the signs and symptoms associated with medication use for the three severe cutaneous reactions that together account for more than 90% of such reactions: DRESS (Figure 2A


Figure 2

Clinical Presentations of Severe Cutaneous Reactions to Drugs.), SJS–TEN (Figure 2B), and AGEP (Figure 2C). Table S1 in the Supplementary Appendix lists selected medications commonly associated with these reactions, as well as genetic risk factors.

Cutaneous leukocytoclastic vasculitis is characterized by erythematous and purpuric papules predominantly on the lower extremities (Figure 2D). Although most cases are associated with infection or autoimmune disorders, about 20% are due to drugs.37 More than 100 drugs have been implicated, particularly propylthiouracil.38
Serum sickness–like reactions have a variety of cutaneous manifestations, including exanthematous and urticarial eruptions, as well as fever, lymphadenopathy, arthralgia, and inflammation of other organs. Foreign proteins, including biologic agents, minocycline, and cephalosporins, have been associated with these reactions.

Further Evaluation
In most cases of exanthematous drug reactions, a structured clinical evaluation will identify the most likely causative drug (or drugs), which can be withdrawn and avoided in the future (Table S2 in the Supplementary Appendix). Occasionally, greater certainty is needed to establish the causative drug. Whereas in vitro detection of specific IgE antibodies may assist in identifying cases of urticaria, angioedema, and anaphylaxis due to beta-lactam antibiotics and some other drugs, these tests are not relevant to T-cell–mediated drug eruptions, including DRESS and SJS–TEN.39
Various tests have been advocated for establishing the causative drug in cases of exanthematous eruption, but all the tests have limitations. Patch testing has long been used to document the cause of allergic contact dermatitis, a T-cell–mediated delayed hypersensitivity reaction. However, standardized reagents for patch testing are lacking, and sensitivities below 10% have been reported.40 The lymphocyte transformation test attempts to quantify in vitro activation of T cells in response to a drug or its metabolites, but the test is cumbersome and not sufficiently standardized for clinical decision making.40 Drug provocation testing relies on the controlled readministration of a suspected drug to determine causality. Such testing is rarely used in clinical practice because it is not well standardized, may have false positive or false negative results, and carries a risk of triggering a new and possibly more serious drug reaction.
Skin biopsy may help identify SJS–TEN or AGEP in their early phases, but specific histopathological features that would distinguish exanthematous eruptions from DRESS and viral exanthems early in their course are lacking. 41 Phototoxic reactions have characteristic features on biopsy.

Management
Whenever feasible, identification and prompt withdrawal of the suspected drug constitute the cornerstone of management for drug-induced eruptions. This is particularly important for drugs with a short half-life (<24 hours) when an exanthematous rash may represent the early sign of SJS–TEN, since prompt withdrawal of drugs with a short (but not long) half-life has been associated with reduced mortality.42 Patients with signs and symptoms suggesting that the rash may be an early manifestation of a severe reaction should be closely monitored and are often hospitalized until a severe reaction can be ruled out. If the drug is essential and the reaction is not severe, desensitization after recovery may be attempted, but this process is rarely required and is cumbersome.
Sedating antihistamines such as diphenhydramine and hydroxyzine may provide symptomatic relief from pruritus. Potent topical glucocorticoids (which should not be used on the face or in intertriginous areas) may reduce signs and symptoms of the rash, but data from randomized trials of their efficacy in this setting are lacking. Data from a retrospective review and an open-label study, respectively, suggest that early treatment of SJS–TEN with systemic glucocorticoids or cyclosporine is associated with reduced mortality.43,44 The role of intravenous immune globulin in the treatment of SJS–TEN is controversial. The benefits of systemic glucocorticoids relative to their risks in the treatment of exanthematous drug reactions are not clear.

Subsequent Care of Patients with a History of an Exanthematous Drug Reaction
Although in many patients, rechallenge with a drug thought to be responsible for a prior drug-related rash does not result in a new eruption, it should generally be avoided because an eruption on reexposure to the drug may be more severe than the previous eruption. The exception is infectious mononucleosis; if a rash develops in association with the use of aminopenicillin in a patient with this disorder, the risk associated with readministration is only slightly higher than it is for first-time users of the drug.
Exposure to chemically related compounds is also a concern among patients with a prior drug exanthem. However, in many cases, the related drug is tolerated. Among patients who have had an exanthematous (non-IgE–mediated) rash in association with a penicillin antibiotic, the risk of a reaction to a beta-lactam antibiotic is probably less than 10%, and cross-reactivity between cephalosporins with different side chains is infrequent.45 Sulfonamide antimicrobial agents are frequent causes of drug eruptions. The structures of nonantimicrobial sulfonamides, including diuretics, some NSAIDs, and antidiabetic agents, differ sufficiently from the structures of sulfonamide antibiotics that cross-reactivity with sulfonamide antibiotics is unlikely.46 Cross-reactivity is frequent among aromatic amine antiepileptic agents.47 Irrespective of the agent causing an initial drug reaction, persons with a history of drug hypersensitivity are about twice as likely to have hypersensitivity reactions to any other medication as are those without such a history.46

Areas of Uncertainty
Limited information suggests that HLA haplotypes and other genetic factors may be useful in predicting the risk of exanthematous reactions to certain drugs, but more data are needed to improve the identification of persons at high risk for such reactions. In addition, a better understanding is needed of factors that mediate differences in the extent and severity of exanthematous drug reactions among affected patients exposed to the same medication. Finally, the usefulness of systemic glucocorticoids and other treatments for exanthematous drug reactions remains uncertain.

Guidelines
Guidelines for the identification and management of cutaneous drug reactions have been published by the American Academy of Dermatology (most recently in 1996)48; the American Academy of Allergy, Asthma, and Immunology49; and the British Society for Allergy and Clinical Immunology.50 The British guidelines put greater emphasis on skin testing to determine causative drugs than do the recommendations presented here, which are otherwise consistent with these guidelines.

Conclusions and Recommendations
The patient described in the vignette almost certainly has an exanthematous drug eruption due to lamotrigine. Fortunately, she has no signs or symptoms suggestive of a severe cutaneous reaction, but she should be informed that if fever, mucosal symptoms, blisters, or malaise develops, she should seek immediate medical attention. She should also be advised to stop taking lamotrigine and to ask her psychiatrist to prescribe an alternative agent that is not an aromatic amine. Since lamotrigine has a long half-life, the patient should be informed that the eruption may take a week or longer to fade. I would recommend that she apply emollients and take sedating antihistamines at bedtime. If the rash is very itchy, I would recommend treatment with a potent topical glucocorticoid for 1 week; although data from randomized trials are lacking, clinical experience suggests that this treatment should reduce secondary skin inflammation and pruritus. Oral glucocorticoids are not indicated, and no further tests are necessary. She should be counseled to avoid this drug and other aromatic amines, including phenytoin and carbamazepine.

Dr. Stern reports receiving consulting fees for the assessment of skin reactions associated with drugs under development from Vertex, InterMune, Johnson & Johnson, Boehringer Ingelheim, and Takeda and its Millennium Division, and for serving on a drug-safety panel for Takeda and as an expert witness in product liability litigation relating to skin reactions for Johnson & Johnson and Mutual, as a consultant to Audet Partners in litigation unrelated to cutaneous drug reactions, and as an expert in patent litigation for Nycomed. No other potential conflict of interest relevant to this article was reported.
Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

I thank Drs. E. Hawryluk and S. Huang for their helpful comments and clinical photographs, Drs. T. Nijsten and Gail A. Howrigan for their helpful comments, and Drs. R.A. Johnson and P.A. Wu for clinical photographs.

Source Information
From the Department of Dermatology, Beth Israel Deaconess Medical Center, Boston.
Address reprint requests to Dr. Stern at the Dermatology Department, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., Gryzmish 522A, Boston, MA 02215, or at .


Key Clinical Points

EXANTHEMATOUS DRUG ERUPTIONS
• Exanthematous drug eruptions, also called morbilliform or maculopapular drug rashes, occur in 1 to 5% of first-time users of most drugs.
• These often pruritic skin reactions typically appear 4 to 21 days after a person starts taking the causative medication and are characterized by symmetrically distributed, pink-to-red macules and papules that spread rapidly and may coalesce.
• Patients with human immunodeficiency virus infection or bone marrow transplants are at increased risk.
• Identifying and discontinuing the causative drug are the most important steps in management; symptomatic treatment with antipruritic agents and potent topical glucocorticoids may be helpful.
• Signs and symptoms that should alert the clinician to the possibility of a severe cutaneous reaction include mucous-membrane involvement, temperature above 38.5°C, blisters, facial edema and erythema, and lymphadenopathy.

 http://www.nejm.org/doi/full/10.1056/NEJMcp1104080

Tuesday, April 24, 2012

Telaprevir May Cause Severe Cutaneous Eruptions NEW YORK (Reuters Health)

From Reuters Health Information
Telaprevir May Cause Severe Cutaneous Eruptions
NEW YORK (Reuters Health)

Apr 19 - The antiviral agent telaprevir (Incivek) has been associated with severe cutaneous eruptions, including the DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), a new report warns.

"I would like physicians to be aware of DRESS occurring in patients on telaprevir-based therapy, as its effectiveness in hepatitis C is sure to make its use more ubiquitous in the future," Dr. Peggy A. Wu from Beth Israel Deaconess Medical Center, Boston, Massachusetts, told Reuters Health in an email. "Presentation tends to be later, around 3-12 weeks, and common symptoms include fever and extensive rash."

In the March 1 online issue of the Journal of Hepatology, Dr. Wu and Dr. Steven T. Chen reported on three patients out of 56 patients at risk (5%) who developed probable or definite DRESS during therapy with telaprevir, peginterferon, and ribavirin.
The three patients were a 60-year-old man in week seven of treatment, a 56-year-old woman who had completed seven weeks of treatment, and a 55-year-old woman who presented a week after completing 12 weeks of telaprevir therapy.

All three cases were managed successfully with discontinuation of medications, topical class I corticosteroids, and systemic antihistamines.

In phase II and III clinical trials involving over 3,800 patients, 3.7% of telaprevir-treated patients developed severe cutaneous adverse events, the researchers note. The U.S. Food and Drug Administration approved telaprevir for treating HCV infection on May 23, 2011 and included DRESS among its warnings and precautions.

"The most feared complication of DRESS is end-organ damage, which in extreme cases can be life-threatening," Dr. Wu said, "so it is important to identify the syndrome early to stop the offending medications and monitor the disease."

"These are observations from a single institution during a finite amount of time," she added. "More information is needed to determine the true incidence of DRESS in telaprevir-treated patients, their prognosis, risk factors, and optimal treatment."

At this point there are no standard measures for preventing DRESS, according to Dr. Wu. "Future studies may involve genotyping those who have DRESS on telaprevir-based therapy and screening patients with associated HLA type or slow metabolism prior to receiving the medication," she said. "Although testing for human herpes virus 6 reactivation is not commonly done in this country, its association with DRESS has been made in other countries, and it may be worth screening for in the future."

SOURCE: http://bit.ly/HJbDoq
J Hepatol 2012.
http://www.medscape.com/viewarticle/762337

Thursday, April 19, 2012

EASL-Anemia Management Strategies Used With VICTRELIS® (boceprevir) Combination Therapy

Merck Reports Phase III Study Results Evaluating Anemia Management Strategies Used With VICTRELIS® (boceprevir) Combination Therapy

businesswire.com

Merck (NYSE: MRK), known as MSD outside of the United States and Canada, announced final results from a Phase III, open-label study designed to compare the impact of two anemia management strategies on sustained virologic response (SVR)1 in patients with chronic hepatitis C virus (HCV) genotype 1 infection treated with VICTRELIS® (boceprevir) in combination with PEGINTRON® (peginterferon alfa-2b) and ribavirin (P/R). The rates of SVR were 71 percent for both groups: those patients whose anemia was managed by ribavirin dose reduction (178/249) and those patients whose anemia was managed by the addition of erythropoietin (EPO) (178/251). The rates of relapse were identical at 10 percent in both groups. These results were presented today for the first time as part of a late breaker poster session [poster #1419] at The International Liver Congress™ / 47th European Association for the Study of the Liver (EASL) annual meeting.

"Chronic hepatitis C treatment regimens with peginterferon alfa and ribavirin are commonly associated with the development of anemia, and this effect is further increased with the addition of VICTRELIS,' said Fred Poordad, M.D., chief of hepatology and liver transplantation, Cedars-Sinai Medical Center, Los Angeles. "The results of this study show there was no difference in SVR rates among these anemia management strategies and that ribavirin dose reduction should be the primary strategy for managing anemia in patients taking VICTRELIS combination therapy.'

Indications and usage for VICTRELIS
VICTRELIS is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 (G1) infection, in combination with peginterferon alfa and ribavirin (P/R), in adult patients (18 years and older) with compensated liver disease, including cirrhosis, who are previously untreated or who have failed previous interferon and ribavirin therapy.
The following points should be considered when initiating VICTRELIS for treatment of chronic HCV infection:
  • VICTRELIS must not be used as monotherapy and should only be used in combination with peginterferon alfa and ribavirin.
  • VICTRELIS efficacy has not been studied in patients who have previously failed therapy with a treatment regimen that includes VICTRELIS or other HCV NS3/4A protease inhibitors.
  • VICTRELIS in combination with peginterferon alfa and ribavirin has not been studied in patients documented to be historical null responders (less than a 2 log HCV-RNA decline by treatment week 12) during prior therapy with peginterferon alfa and ribavirin. The clinical studies included patients who were poorly interferon responsive. Patients with less than 0.5 log HCV-RNA decline in viral load at treatment week 4 with peginterferon alfa plus ribavirin alone are predicted to have a null response (less than a 2 log viral load decline by treatment week 12) to peginterferon alfa and ribavirin therapy.
  • Poorly interferon responsive patients who were treated with VICTRELIS in combination with peginterferon alfa and ribavirin have a lower likelihood of achieving a sustained virologic response (SVR), and a higher rate of detection of resistance-associated substitutions upon treatment failure, compared to patients with a greater response to peginterferon alfa and ribavirin.
.
About the Study
In this study, 687 treatment-naïve adult patients with chronic HCV genotype 1 who had baseline hemoglobin levels of less than or equal to 15 g/dL were enrolled in a multinational, open-label trial and monitored for the development of anemia. Patients were treated with a 4-week lead-in of peginterferon alfa-2b (1.5 mcg/kg/week) and an investigational dose of ribavirin (600-1,400 mg/day), followed by the addition of VICTRELIS (800 mg three times a day) after week 4 for 24 or 44 weeks based on HCV-RNA levels at treatment week 8. Sixteen (16) percent (111/687) of patients were enrolled in Cohort 1 and assigned a fixed-dose regimen that included the 4-week lead-in of P/R followed by the addition of VICTRELIS for 44 weeks. A protocol amendment was then added to allow the use of the response-guided therapy (RGT) paradigm, consistent with findings in the pivotal clinical studies for VICTRELIS, and the rest of the patients were enrolled in Cohort 2. The results for patients receiving the fixed-dose regimen (Cohort 1) versus the RGT paradigm (Cohort 2) did not differ and have been combined in the presentation of these data. Patients with a less than 2-log10 decline in HCV-RNA at week 12, or a greater than or equal to lower limit of quantification of HCV-RNA at week 24 were considered treatment failures and were discontinued from the studies.
A total of 500 patients developed anemia, defined by having hemoglobin of less than or equal to 10 g/dL (or less than 11 g/dL and were expected to reach less than or equal to 10 g/dL before the next visit). These patients were randomized to receive either ribavirin dose reduction (by 200 to 400 mg/d) or the addition of EPO (40,000 IU/week). A secondary method of anemia management, such as the addition of EPO, ribavirin dose reduction or transfusion, was later permitted if a patient's hemoglobin reached less than or equal to 8.5 g/dL. Treatment was discontinued if hemoglobin levels reached less than or equal to 7.5 g/dL. If the initial hemoglobin measurement qualifying a patient as anemic was less than or equal to 8.5 g/dL, that patient was not randomized to one of the anemia management strategies.

The primary endpoint of the study was the comparison of SVR in patients who were randomized to receive ribavirin dose reduction or the addition of EPO.

Safety Findings
The safety profiles were similar regardless of anemia management strategy. The most common adverse events (occurring in 30 percent or more of patients in either group) were anemia, neutropenia, diarrhea, dysgeusia, nausea, chills, fatigue, headache, insomnia and alopecia. There was no difference in the incidence of adverse events between the ribavirin dose reduction and EPO treatment arms, including influenza-like symptoms (27 percent each), fatigue (70 percent vs. 71 percent), depression (20 percent vs. 21 percent), anxiety (12 percent each), shortness of breath (19 percent vs. 21 percent) and cardiovascular events (14 percent vs. 13 percent), respectively.

Serious adverse events occurred in 16 percent of patients in the ribavirin dose reduction arm and 13 percent of patients in the EPO arm. The discontinuation rates were 11 and 13 percent, due to any adverse event, and 2.0 and 2.4 percent due to anemia, respectively. There was one death in the ribavirin dose reduction arm that occurred three weeks following the end of treatment, with cause of death reported as "sudden cardiac death'.

Important safety information about VICTRELIS
All contraindications to peginterferon alfa and ribavirin also apply since VICTRELIS must be administered with peginterferon alfa and ribavirin. Because ribavirin may cause birth defects and fetal death, VICTRELIS in combination with peginterferon alfa and ribavirin is contraindicated in pregnant women and in men whose female partners are pregnant. Avoid pregnancy in female patients and female partners of male patients. Patients must have a negative pregnancy test prior to therapy; have monthly pregnancy tests; and use two or more forms of effective contraception, including intrauterine devices and barrier methods, during treatment and for at least 6 months after treatment has concluded. Systemic hormonal contraceptives may not be as effective in women while taking VICTRELIS and concomitant ribavirin.

VICTRELIS is contraindicated in coadministration with drugs that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events. VICTRELIS also is contraindicated in coadministration with potent CYP3A4/5 inducers where significantly reduced VICTRELIS plasma concentrations may be associated with reduced efficacy. Drugs that are contraindicated with VICTRELIS include: alfuzosin, carbamazepine, phenobarbital, phenytoin, rifampin, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, St. John's Wort (hypericum perforatum), lovastatin, simvastatin, drosperinone, Revatio® (sildenafil) or Adcirca® (tadalafil) (when used for the treatment of pulmonary arterial hypertension), pimozide, triazolam, and orally administered midazolam.

Anemia and/or Neutropenia -- The addition of VICTRELIS to peginterferon alfa and ribavirin is associated with an additional decrease in hemoglobin concentrations compared to peginterferon alfa and ribavirin alone and/or may result in worsening of neutropenia associated with peginterferon alfa and ribavirin therapy alone. If hemoglobin is less than 10 g/dL, a decrease in dosage or interruption of ribavirin is recommended. If hemoglobin is less than 8.5 g/dL, discontinuation of ribavirin is recommended. Decreases in neutrophil counts also may require dose reduction or discontinuation of PR. Dose reduction or discontinuation of peginterferon alfa and/or ribavirin may be required. Dose reduction of VICTRELIS is not recommended. VICTRELIS must not be administered in the absence of peginterferon alfa and ribavirin.

In the pivotal clinical trials, the proportion of patients who experienced hemoglobin values less than 10 g/dL and less than 8.5 g/dL was higher in subjects treated with the combination of VICTRELIS plus P/R than in those treated with P/R alone, respectively.
-- Treatment-naïve patients experienced hemoglobin levels less than 10 g/dL and less than 8.5 g/dL in 49 percent and six percent of patients treated with VICTRELIS plus P/R, compared to 29 percent and three percent of patients treated with P/R alone, respectively.

-- Patients who previously failed P/R therapy experienced levels less than 10 g/dL and less than 8.5 d/L in 49 percent and 10 percent of patients treated with VICTRELIS plus P/R, compared to 25 percent and 1 percent of patients treated with P/R alone, respectively.
Complete blood counts (with white blood cell differential counts) must be conducted in all patients prior to initiating combination therapy with VICTRELIS. Complete blood counts should be obtained at treatment weeks 4, 8 and 12, and should be monitored closely at other time points, as clinically appropriate.

The most commonly reported adverse reactions (greater than 35 percent) in clinical trials in adult patients receiving the combination of VICTRELIS with peginterferon alfa and ribavirin were fatigue, anemia, nausea, headache and dysgeusia. Of these commonly reported adverse reactions, fatigue, anemia, nausea, and dysgeusia occurred at rates greater than or equal to 5 percent above the rates for peginterferon alfa and ribavirin alone in either clinical study. The incidence of these adverse reactions in previously untreated patients who were treated with combination therapy with VICTRELIS compared with peginterferon and ribavirin alone were: fatigue (58 vs. 59 percent), anemia (50 vs. 30 percent), nausea (46 vs. 42 percent) and dysgeusia (35 vs. 16 percent), respectively. The incidence of these adverse reactions in previous treatment-failure patients who were treated with combination therapy with VICTRELIS compared with peginterferon and ribavirin alone were: fatigue (55 vs. 50 percent), anemia (45 vs. 20 percent), nausea (43 vs. 38 percent) and dysgeusia (44 vs. 11 percent), respectively.

VICTRELIS is a strong inhibitor of CYP3A4/5 and is partly metabolized by CYP3A4/5. The potential for drug-drug interactions must be considered prior to and during therapy.
Please see U.S. prescribing information at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf.

Merck's global commitment to advancing hepatitis therapy
Merck is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver vaccines and medicines to help prevent and treat viral hepatitis. In hepatitis C, company researchers developed the first approved therapy for chronic HCV in 1991 and the first combination therapy in 1998. In addition to ongoing studies with VICTRELIS, extensive research efforts are underway to develop additional innovative oral therapies for viral hepatitis treatment.

About Merck
Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement
This news release includes 'forward-looking statements' within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Such statements may include, but are not limited to, statements about the benefits of the merger between Merck and Schering-Plough, including future financial and operating results, the combined company's plans, objectives, expectations and intentions and other statements that are not historical facts. Such statements are based upon the current beliefs and expectations of Merck's management and are subject to significant risks and uncertainties. Actual results may differ from those set forth in the forward-looking statements.

The following factors, among others, could cause actual results to differ from those set forth in the forward-looking statements: the possibility that all of the expected synergies from the merger of Merck and Schering-Plough will not be realized, or will not be realized within the expected time period; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; Merck's ability to accurately predict future market conditions; dependence on the effectiveness of Merck's patents and other protections for innovative products; and the exposure to litigation and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck's 2011 Annual Report on Form 10-K and the company's other filings with the Securities and Exchange Commission (SEC) available at the SEC's Internet site (www.sec.gov).

Please see Prescribing Information for VICTRELIS at http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf and Medication Guide for VICTRELIS at http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_mg.pdf.
1 SVR, the protocol specified primary efficacy endpoint of the study, is defined as achievement of undetectable HCV-RNA at 24 weeks after the end of treatment in all randomized patients treated with any study medication. Per protocol, if a patient did not have a 24-week post-treatment assessment, the patient's 12-week post-treatment assessment was utilized.

VICTRELIS® and PEGINTRON® are trademarks of Schering Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, N.J., USA.
Revatio® and Adcirca® are trademarks of their respective owners and are not trademarks of Merck & Co., Inc., Whitehouse Station, N.J., USA.

Saturday, April 14, 2012

HCV Weekend Reading-What you need to know about Direct-Acting Antiviral (DAA) Therapy for hepatitis C



Weekend Reading

Most weekends this blog offers up a few substantial links to relevant HCV information, click here for previous "Weekend Reading" articles.


First up from CAP is the April "Pubmed Review" of the most relevant research on hepatitis C.



Next offered at -"Projects In Knowledge" are six chapters on what you need to know about "Direct-Acting Antiviral (DAA) Therapy" for hepatitis C. The site is a great source for easy to understand information, although like any site offering continuing medical education - CME, it requires a free quick registration.

The six chapters listed below can be a useful learning tool for anyone considering hepatitis C therapy. The last chapter "Neuropsychiatric Adverse Effects" has been made available on the blog below. Once you register at "Projects In Knowledge"  view all eHandbook Chapters -- here.

Release date: October 31, 2011

Chapter 1
Getting Ready for Direct-Acting Antiviral (DAA) Therapy
Chapter 2
What You Need to Know About the New Direct-Acting Antiviral (DAA) Regimens
Chapter 3
Hematologic Adverse Effects
Chapter 4
Dermatologic Adverse Effects
Chapter 5
Gastrointestinal Adverse Effects

Chapter 6
Neuropsychiatric Adverse Effects
Release date: October 31, 2011
Introduction
Depression
Irritability and Anxiety

Related:View List-FDA Alert-Statins and HIV or Hepatitis C Drugs
Protease inhibitors and statins taken together may raise the blood levels of statins and increase the risk of myopathy, kidney damage, and kidney failure, which can be fatal.
View the list of HIV or HCV Drugs which interact with statins Here or Here.
..
Hepatitis C — Neuropsychiatric Adverse Effects –  eHandbook Chapter
  • Depression, irritability, and anxiety are common in HCV patients receiving peginterferon/ribavirin treatment. The addition of direct-acting antiviral (DAA) therapy to peginterferon/ribavirin does not appear to further increase the incidence of these neuropsychiatric events, but drug-drug interactions limit the treatment options for depression and anxiety. In the sixth chapter of this eHandbook, HCV Care and Guidance: Practical Education and Resources for Nurse Practitioners and Physician Assistants, Jill Y. Chang, PA-C outlines management strategies for these adverse effects that may help improve patient outcomes


  • Introduction

  • Interferon/ribavirin therapy for chronic hepatitis C virus (HCV) infection is associated with neuropsychiatric effects, including depression, irritability, and anxiety; other effects, such as mania or suicidal ideation and behavior, may also occur.1-3 While the direct-acting antivirals (DAAs) boceprevir and telaprevir do not appear to add to the incidence of these adverse effects, they complicate management because they are associated with drug-drug interactions with several commonly prescribed psychotropic medications, including antidepressants and sedatives/hypnotics.


  • Important Take-Away Points

    • Clinicians need to be aware of drug-drug interactions between the DAAs and drugs used to treat neuropsychiatric adverse effects.
    • Patients should be screened for depression and assessed for history of other psychiatric disorders prior to initiating anti-HCV therapy and should be monitored for symptoms during and after therapy.
    • If interferon therapy is discontinued due to neuropsychiatric or other adverse effects, it is also necessary to discontinue ribavirin and the protease inhibitor.
    .
    Neuropsychiatric Adverse Effects

    Depression
    Major depression is estimated to affect at least 25% of patients with chronic HCV infection compared with approximately 7% of the general population.4,5 Interferon treatment is associated with depression, and a prevalence of 23% to 44% has been shown in chronic HCV patients receiving interferon monotherapy.2 Moreover, patients initiating therapy for chronic HCV commonly have pre-existing psychiatric disorders, including depression, and this may predispose them to new or worsened interferon-associated depression.1,2 The postulated physiologic mechanisms responsible for the increase in depression with interferon include monoamine dysfunction (in particular, decreased serotonin levels), hypothalamic-pituitary-adrenocortical axis activation, proinflammatory cytokine activation, decreased peptidase levels, increased levels of intracellular adhesion molecule-1 in tissues and in its soluble form in serum, and increased nitric oxide levels.2

    Although interferon treatment has been associated with depression in other disease settings, such as cancer, it appears that patients with chronic HCV may be more susceptible, possibly because of lower baseline levels of serotonin.2 Studies with ribavirin either alone or in combination with interferon or peginterferon have indicated that it too may play a role in the increase in depression seen with interferon.2 However, studies of triple therapy with DAA therapy in combination with peginterferon/ribavirin for the treatment of chronic HCV infection have provided no evidence that the addition of a DAA increases the risk of depression.6-9

    Boceprevir Triple-Therapy Data

    In two phase III clinical trials, the rate of depression was not significantly different between patients receiving boceprevir triple therapy and patients receiving peginterferon/ribavirin combination therapy. In the treatment-naive trial, depression occurred in 22% of patients in the peginterferon/ribavirin group compared with 23% and 19% in the two triple-therapy groups (P = .86 and .36, respectively).6 In the treatment-experienced trial, depression occurred in 15.0% of patients in the peginterferon/ribavirin group compared with 12.3% and 16.8% in the two triple-therapy groups (P = not significant for both).7

    Telaprevir Triple-Therapy Data

    The incidence of depression was similar between patients receiving telaprevir triple therapy and patients receiving peginterferon/ribavirin therapy in two phase III clinical trials. Depression occurred in 22% of patients in the peginterferon/ribavirin group compared with 18% and 17% in the two telaprevir triple-therapy groups in the treatment-naive trial.8 Depression occurred in 14% of patients in the peginterferon/ribavirin group compared with 9% and 13% in the two telaprevir triple-therapy groups in the treatment-experienced trial.9

    Management Strategies

    Given the risk of worsening depression, interferon-based therapy should be used with extreme caution in patients with a history of depression, and clinicians should monitor all patients for evidence of depression. In addition, mood and anxiety symptoms prior to treatment are important risk factors for developing interferon-induced depression.10 Clinicians treating patients with chronic HCV infection should be familiar with the various depression screening tools, and all patients should receive a pretreatment assessment for pre-existing depression or risk factors and follow-up assessments throughout therapy.2,11,12 The key is not which tool to use, but rather to be consistent in your practice and use the same tool for both baseline screening and follow-ups. In addition, it is important that clinicians are extremely vigilant for the symptoms associated with major depressive syndrome, as sometimes the symptoms are subtle and may be missed. The clinician should educate all patients and their families about the individual risk for depression, the symptoms of depression, and a plan to address the development of depression.1 There are many preventive strategies that a clinician can implement to avoid significant depression, as noted in Table 1.
    .
    Table 1. Management of Depression
    Note: Strategies included within this table are based on expert opinion and experience.
    .
    Symptoms2
    • Depressed mood
    • Diminished interest or pleasure in activities
    • Significant weight loss/gain or decrease/increase in appetite
    • Insomnia or hypersomnia
    • Psychomotor agitation or retardation
    • Fatigue or loss of energy
    • Feelings of worthlessness or excessive guilt
    • Diminished ability to think or concentrate; indecisiveness
    • Recurrent thoughts of death or suicidal ideation
    Screening tools2,12
    • Center for Epidemiologic Studies-Depressed Mood Scale (CES-D) - preferred screening tool
    • Beck Depression Inventory (BDI) - good for patients with physical complaints
    • Zung Self-Rating Depression Scale (ZSDS)
    • Hospital Anxiety and Depression Scale (HADS)
    • Montgomery-Asberg Depression Rating Scale (MADRS)
    Preventive strategies
    Most important strategies:
    • Treat/stabilize pre-existing depression before starting anti-HCV therapy*
    • Consider prophylactic antidepressant therapy for those deemed high risk for depression*
    • Educate patient/family regarding risk of depression; encourage early reporting of depressive symptoms
    • Refer patient to a local hepatitis C support group, or online support programs, if available
    • Provide positive feedback/reinforcement for proactive side-effect management efforts
    • Patients infected with HCV with history of injection drug addiction: subcutaneous injection may trigger feelings of drug hunger, anxiety, depression, or provoke posttraumatic stress disorder.13 Reassure the patient and arrange for outpatient injection or family member administration
    Additional strategies that may be helpful:
    • The patient may benefit from the practice of stress reduction, including relaxation periods (yoga, meditation, etc)
    • Encourage regular exercise
    • Encourage patient to recognize and "reroute" negative thinking patterns; eg, use a journal to record thoughts and daily activities
    • Maintain adequate hydration. Limit caffeine, alcohol, and processed-food intake

    *See product labeling for drug-drug interactions between DAAs and drugs that may be used to treat neuropsychiatric adverse effects.

    Often, depression will require medical intervention; this is especially true in patients with previous history or active depression. Patients with symptoms of moderate depression should be considered for antidepressant therapy and may benefit from a temporary interferon dose reduction as outlined in the peginterferon product labeling.14,15 Patients experiencing severe depression or suicidal ideation should discontinue therapy and be followed closely with appropriate medical management and psychiatric intervention.11 It is important to note that if interferon is discontinued, the protease inhibitor and ribavirin also must be discontinued.16-18 In general, psychiatric adverse events resolve on cessation of therapy; however, in some cases resolution may take several months or longer and psychiatric medications may be required. Commonly used medications for depression are listed in Table 2, with selective serotonin reuptake inhibitors often being used as first-line therapy. Clinicians need to be aware of drug-drug interactions with DAAs when treating patients with antidepressants or sedatives/hypnotics, as outlined in the boceprevir and telaprevir product labeling.

    Table 2. Treatment Options for the Pharmacologic Management of Interferon-Induced Depression1

    Class
    Agents
    SSRIs
    • Citalopram
    • Escitalopram (has drug-drug interactions with DAAs: boceprevir - interaction not studied, an interaction is predicted based on drug metabolic profiles; telaprevir - escitalopram concentrations may decrease, may need to adjust escitalopram dose)
    • Sertraline
    • Fluoxetine
    • Paroxetine
    • Fluvoxamine
    SNRIs
    • Venlafaxine
    • Desvenlafaxine
    • Duloxetine
    DNRIs
    • Bupropion
    Mixed-receptor
    • Mirtazapine
    • Nefazodone
    TCAs
    • Nortriptyline
    • Imipramine
    D2/5HT2 agents*
    • Risperidone
    • Paliperidone
    • Olanzapine
    • Quetiapine
    • Ziprasidone
    • Aripiprazole

    *No evidence regarding use of these agents in patients receiving interferon-alfa; none of these agents are approved for the treatment of unipolar major depressive disorder.

    Abbreviations: DNRIs, dopamine/norepinephrine reuptake inhibitors; SNRIs, serotonin/norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.

    Disclaimer: Drug-drug interaction information in this table is correct as of the time of writing, but testing for potential interactions between the approved protease inhibitors and other drugs and supplements is ongoing. Clinicians should always check the most recent product labeling for all known drug-drug interactions before prescribing any drug in combination with either boceprevir triple therapy or telaprevir triple therapy.

    One of the most important decisions during the treatment of depression is when to refer a patient for a psychiatric consultation, as this will not be required for all patients.1 If further psychiatric evaluation is warranted based on initial screening, it should include an assessment of any current psychiatric disorders, whether they have been stable for the preceding 3 to 6 months, any barriers to adherence (either for psychiatric or antiviral treatments), and whether the current level of depressive symptoms warrants antidepressants.1 A signed informed consent form allowing communication between the psychiatrist and the hepatologist or other clinicians helps to ensure coordination of the patient's care.1 Regular follow-up should be available, especially for patients at an increased risk of developing depression.1 Based on the outcome of this initial assessment, some patients may require additional psychiatric treatment, monitoring, or education prior to initiating anti-HCV therapy.1 It may also be necessary to address any barriers to adherence or to defer anti-HCV therapy if necessary.1 Any clinical decisions should involve both the hepatologist and psychiatrist, and should take into consideration the patient's liver disease, comorbidities, and any other patient-specific requirements.1
    Often, patients may not display depressive symptoms until after anti-HCV therapy is discontinued; these are most likely not related to interferon and are instead due to an underlying or pre-existing condition. Clinicians should also consider the patient's psychologic/emotional issues, history (including alcohol or drug abuse), and social situation when these symptoms occur. It is important to continue to follow these patients clinically posttherapy as well.
    .
    Neuropsychiatric Adverse Effects

    Irritability and Anxiety
    A syndrome of irritability/labile anger that is distinct from major depressive disorder has been reported in up to 25% of patients receiving interferon therapy and has also been linked to ribavirin.1,2 In patients taking interferon, the underlying physiologic mechanisms responsible for this syndrome may include decreased tryptophan levels as well as a polymorphism in tumor necrosis factor-alpha.19,20
    Interferon and ribavirin are also associated with anxiety, which has been reported in 10% to 20% of patients taking interferon.2,3,21 It is not clear, however, that the anxiety associated with interferon/ribavirin is distinct from depression.21 Interferon-associated anxiety is related to increased levels of proinflammatory cytokines and reductions in tryptophan levels.21 Studies with triple therapy have reported that adding a DAA to peginterferon/ribavirin has little effect on the incidence of irritability or anxiety except for an increase in irritability with boceprevir triple therapy in previously treated patients.8,9,17

    Boceprevir Triple-Therapy Data
    In combined safety data from a phase II and a phase III trial in treatment-naive patients, the incidence of irritability was 23% in the peginterferon/ribavirin group and 22% in the boceprevir triple-therapy group in treatment-naive patients.17 In the phase III trial in previously treated patients, irritability occurred in 13% of patients in the peginterferon/ribavirin group and 21% in the boceprevir triple-therapy group.17
    The incidence of anxiety did not meet the threshold for reporting in the boceprevir prescribing information (incidence 10% or greater with boceprevir triple therapy and at least 5% greater with triple therapy compared with peginterferon/ribavirin therapy).17 Anxiety frequency also did not meet the threshold for reporting in the two phase III trials (incidence 15% or greater in any treatment group).6,7

    Telaprevir Triple-Therapy Data
    The incidence of irritability in the treatment-naive phase III trial was 18% in the peginterferon/ribavirin group and 22% and 19% in the two telaprevir triple-therapy groups.8 In the treatment-experienced trial, irritability occurred in 16% of patients in the peginterferon/ribavirin group compared with 14% and 14% in the two telaprevir triple-therapy groups.9
    Anxiety did not meet the threshold for reporting in the telaprevir prescribing information (incidence in the telaprevir triple-therapy group at least 5% greater than in the peginterferon/ribavirin group).18 Anxiety was reported in 12% of patients in the peginterferon/ribavirin group compared with 10% and 9% in the two telaprevir triple-therapy groups in the treatment-naive trial, but did not meet the threshold for reporting in the treatment-experienced trial (incidence 10% or greater of patients in any study group).8,9

    Management Strategies
    Note: Strategies included within this section are based on expert opinion and experience as well as published studies.

    The recommendations for screening and psychiatric consultation outlined in the section on depression also apply to other psychiatric disorders, including irritability and anxiety. In particular, clinicians should be aware that some patients may minimize or deny neuropsychiatric symptoms because of embarrassment22 or fear of dose reduction or treatment cessation. Various preventive, nonpharmacologic, and pharmacologic strategies for managing patients with irritability or anxiety are listed in Tables 3 and 4. As with the pharmacologic treatment of depression, it is important to recognize the potential for drug-drug interactions between the DAAs and any antidepressants or anxiolytics used to treat irritability or anxiety. For patients resistant to single-drug interventions for the treatment of irritability, combining two antidepressants or reducing the interferon dose may be effective. If these strategies are not successful, interferon treatment should be discontinued, keeping in mind that when interferon is discontinued it is also necessary to discontinue the protease inhibitor and ribavirin.16-18


    Table 3. Management of Irritability/Labile Anger
    Note: Strategies included within this table are based on expert opinion and experience.

    Nonpharmacologic treatment strategies
    Encourage patients to:
    • Engage in mild to moderate aerobic and/or anaerobic exercise, as a mechanism to channel anger and irritability
    • Try meditation/relaxation techniques (yoga, biofeedback, imagery, massage)
    • Maintain good sleep habits (consistent times for sleeping; avoid caffeine; consume tryptophan-containing foods, such as warm milk, turkey, and salmon)
    • Avoid overstimulating environments (crowds, heavy traffic, loud noise)
    • Ensure adequate hydration
    • Enjoy small pleasures (movies, music, friends, pets, laughter, positive reminiscence)
    • Recognize and report warning signs (early detection and intervention are crucial)
    Providers should:
    • Educate and support families to help them cope with unpredictable, difficult personality changes and mood swings
    Pharmacologic treatment strategies
    SSRIs
    • Citalopram*
    • Escitalopram* (has drug-drug interactions with DAAs: boceprevir - interaction not studied, an interaction is predicted based on drug metabolic profiles; telaprevir - escitalopram concentrations may decrease, may need to adjust escitalopram dose)
    • Sertraline*
    SNRIs
    • Venlafaxine* (has a sedating effect, reducing irritability and combative behavior)
    Mixed-receptor
    • Mirtazapine*
    • Nefazodone* (has a sedating effect, reducing irritability and combative behavior)
    • Trazodone* (useful adjunct for sleep disturbance and is well tolerated; has drug-drug interactions with DAAs: use with caution with telaprevir and boceprevir, adverse events such as nausea, dizziness, hypotension, and syncope may occur, trazodone concentrations may increase, consider lower dose of trazodone)
    DNRIs
    • Bupropion* (has a sedating effect, reducing irritability and combative behavior)
    Anticonvulsant
    • Gabapentin* (may prove useful for mild to moderate irritability or impulsivity in the absence of depressive symptoms)

    *Not approved for the treatment of irritability/labile anger.

    Abbreviations: DNRIs, dopamine/norepinephrine reuptake inhibitors; SNRIs, serotonin/norephinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors.
    Disclaimer: Drug-drug interaction information in this table is correct as of the time of writing, but testing for potential interactions between the approved protease inhibitors and other drugs and supplements is ongoing. Clinicians should always check the most recent product labeling for all known drug-drug interactions before prescribing any drug in combination with either boceprevir triple therapy or telaprevir triple therapy.

    Table 4. Management of Anxiety
    Note: Strategies included within this table are based on expert opinion and experience.

    Preventive strategies
    Encourage patients to:
    • Reduce or eliminate alcohol, caffeine, nicotine, and other stimulants, and to eat smaller, more frequent meals
    • Keep a food diary to detect correlation between attacks and foods consumed
    • Consider stress management/biofeedback interventions, including relaxation exercises and tapes, guided imagery, and meditation. Talking with family or friends can diffuse anxiety
    • Exercise: walking, swimming, yoga, aerobics, etc. Conversely, assess for and ensure adequate sleep and rest
    Providers should:
    • Educate the patient regarding disease, treatment, subcutaneous injection, side effects, and symptom management to allay concerns and anxiety level
    • Provide contact numbers of office nurse, local hepatitis C support group, and "buddy," if available
    • Perform pretreatment assessment for current/past history of anxiety or panic disorder, and/or depression. Consider prescription antidepressants prior to or concomitantly with therapy to prevent progression of the disorder. See "Depression" section for further information
    • Discuss expectations of therapy, including side effects and management, and make specific plans for behavior modification in individuals with prior psychiatric history. This may prevent onset of symptoms or prompt reporting of the development of new symptoms
    • Involve family members in education and treatment planning to minimize "sick role"
    Nonpharmacologic treatment strategies
    Encourage patients to:
    • Create relaxation times throughout the day and evening, exercise, and limit daily tasks and pressure situations
    Providers should:
    • Instruct the patient how to manage panic attacks: Inhale to a count of four, exhale slowly to a count of four, do nothing to a count of four; repeat until the attack subsides. Patient should remind self that attacks are time-limited and will pass
    • Be aware that graded exposure (desensitization) may be required to treat panic attacks
    Anxiolytics
    • Buspirone
    • Meprobamate
    • Hydroxyzine
    Benzodiazepines
    • Alprazolam (has drug-drug interactions with DAAs: alprazolam concentrations may increase with boceprevir and telaprevir, clinical monitoring is warranted, alprazolam dose reduction should be considered)
    • Chlordiazepoxide
    • Clorazepate
    • Diazepam
    • Lorazepam
    • Oxazepam
    • Clonazepam*
    TCAs
    • Doxepin
    Antidepressants may also be used
    • SSRIs
    • TCAs
    • Mixed-receptor
    • Some antidepressants have drug-drug interactions with DAAs, see product labeling

    Abbreviations: SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.

    Disclaimer: Drug-drug interaction information in this table is correct as of the time of writing, but testing for potential interactions between the approved protease inhibitors and other drugs and supplements is ongoing. Clinicians should always check the most recent product labeling for all known drug-drug interactions before prescribing any drug in combination with either boceprevir triple therapy or telaprevir triple therapy.

    Conclusion
    Recognizing and addressing neuropsychiatric problems in chronic HCV patients increases the likelihood of positive outcomes.1 It is essential to assess all patients prior to treatment for any psychiatric concerns and to follow with ongoing close psychiatric monitoring during treatment. With the addition of DAAs, clinicians need to be well versed in drug-drug interactions with antidepressants in order to ensure patient safety. Prompt initiation and adjustment of antidepressants and continuing bidirectional communication between the psychiatrist and other clinicians are essential for overall treatment success.
    .
    References
    1.Lotrich F. Management of psychiatric disease in hepatitis C treatment candidates. Curr Hepat Rep. 2010;9:113-118.
    2.Asnis GM, De La Garza R II. Interferon-induced depression in chronic hepatitis C: a review of its prevalence, risk factors, biology, and treatment approaches. J Clin Gastroenterol. 2006;40:322-335.
    3.Sockalingam S, Links PS, Abbey SE. Suicide risk in hepatitis C and during interferon-alpha therapy: a review and clinical update. J Viral Hepat. 2011;18:153-160.
    4.Evon DM, Simpson KM, Esserman D, Verma A, Smith S, Fried MW. Barriers to accessing care in patients with chronic hepatitis C: the impact of depression. Aliment Pharmacol Ther. 2010;32:1163-1173.
    5.Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:617-627.
    6.Poordad F, McCone J Jr, Bacon BR, et al. Supplementary materials for: Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206.
    7.Bacon BR, Gordon SC, Lawitz E, et al. Supplementary materials for: Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207-1217.
    8.Jacobson IM, McHutchison JG, Dusheiko G, et al. Supplementary materials for: Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416.
    9.Zeuzem S, Andreone P, Pol S, et al. Supplementary materials for: Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417-2428.
    10.Raison CL, Demetrashvili M, Capuron L, Miller AH. Neuropsychiatric adverse effects of interferon-alpha: recognition and management. CNS Drugs. 2005;19:105-123.
    11.Valentine AD, Meyers CA, Kling MA, Richelson E, Hauser P. Mood and cognitive side effects of interferon-alpha therapy. Semin Oncol. 1998;25(suppl 1):39-47.
    12.Zdilar D, Franco-Bronson K, Buchler N, Locala JA, Younossi ZM. Hepatitis C, interferon alfa, and depression. Hepatology. 2000;31:1207-1211.
    13.Maunder RG, Hunter JJ, Feinman SV. Interferon treatment of hepatitis C associated with symptoms of PTSD.
    Psychosomatics. 1998;39:461-464.
    14.Pegasys [package insert]. Nutley, NJ: Hoffman-La Roche, Inc; 2011.
    15.PegIntron [package insert]. Whitehouse Station, NJ: Schering Corp; 2011.
    16.Copegus [package insert]. South San Francisco, CA: Genentech, Inc; 2010.
    17.Victrelis [package insert]. Whitehouse Station, NJ: Schering Corp; 2011.
    18.Incivek [package insert]. Cambridge, MA: Vertex Pharmaceuticals Inc; 2011.
    19.Russo S, Kema IP, Haagsma EB, et al. Irritability rather than depression during interferon treatment is linked to increased tryptophan catabolism. Psychosom Med. 2005;67:773-777.
    20.Lotrich FE, Ferrell RE, Rabinovitz M, Pollock BG. Labile anger during interferon alfa treatment is associated with a polymorphism in tumor necrosis factor alpha. Clin Neuropharmacol. 2010;33:191-197.
    21.Crone CC, Gabriel GM, Wise TN. Managing the neuropsychiatric side effects of interferon-based therapy for hepatitis C. Cleve Clin J Med. 2004;71(suppl 3):S27-S32.
    22.Renault PF, Hoofnagle JH, Park Y, et al. Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med. 1987;147:1577-1580.