Incivek (telaprevir) product labeling revised...

Posted at FDA.gov on 6/26. The FDA revised the product labeling for Incivek. The changes were a combination of DDI, warnings, clinical trial data revisions and corrections. See below for full list of changes. 

Incivek (telaprevir) product labeling revised

The Incivek (telaprevir) product labeling was recently revised to include the following changes:

1. Update the clinical comment for neuroleptic drug pimozide in Section 4 Contraindications to state: "Potential for serious and/or life-threatening adverse reactions such as cardiac arrhythmias"

2. Update Section 5 Warnings and Precautions subsection 5.4 Anemia to state: "Hemoglobin should be monitored prior to and at least at weeks 2, 4, 8 and 12 during INCIVEK combination treatment and as clinically appropriate."

3. Update Section 5 Warnings and Precautions subsection 5.6 Laboratory Tests to state the following: Use of a sensitive real-time RT-PCR assay for monitoring HCV-RNA levels during treatment is recommended. The assay should have a lower limit of HCV-RNA quantification equal to or less than 25 IU per mL and a limit of HCV-RNA detection of approximately 10-15 IU per mL.

4. Update Section 7 Drug Interactions to remove desipramine from Table 5: Established and Other Potentially Significant Interactions. Also added to Section 7 was a statement that no dose adjustment is needed for Incivek when given with either raltegravir or buprenorphine. The corresponding results from the drug-drug interaction trial with raltegravir and buprenorphine are included in Section 12 Pharmacokinetics.

5. Update Section 14 Clinical Studies to include revisions to the definition of sustained virologic response (SVR) and to correct the SVR rates for African American and Cirrhotic subpopulations as follows:

SVR was defined as HCV RNA less than 25 IU per mL at last observation within the SVR visit window (i.e., weeks 32-78 for patients assigned to 24 weeks of treatment and weeks 56-78 for patients assigned to 48 weeks of treatment).

Trial 108 (ADVANCE)

Twenty-six subjects were Black/African Americans. The overall SVR among Black/African American subjects was 62% (16/26). Among these subjects, 35% (9/26) were assigned to 24 weeks of treatment and of those 89% (8/9)achieved SVR.

Twenty-one subjects had cirrhosis at baseline and the overall SVR in these subjects was 71% (15/21). Among subjects with cirrhosis, 43% (9/21)were assigned to 24 weeks of treatment and of those 78% (7/9)achieved SVR.
Trial 111 (ILLUMINATE)

Sixty-one (11%) of subjects had cirrhosis at baseline. Among subjects with cirrhosis, 30 (49%) achieved an eRVR: 18 were randomized to T12/PR24 and 12 to T12/PR48. The SVR rates were 61% (11/18) for the T12/PR24 group and 92% (11/12) for the T12/PR48 group.
Blacks/African Americans comprised 14% (73/540) of trial subjects. Thirty-four (47%) Black/African American subjects achieved an eRVR and were randomized to T12/PR24 or T12/PR48. The respective SVR rates were 88% (15/17) and 88% (15/17), compared to 92% (244/266) for Caucasians among randomized subjects.
Trial C216

Twenty-six percent (139/530) of INCIVEK-treated subjects had cirrhosis at baseline. SVR rates among cirrhotic subjects who received INCIVEK combination treatment compared to Pbo/PR48 were: 84% (48/57) compared to 7% (1/15) for prior relapsers, 34% (11/32) compared to 20% (1/5) for prior partial responders, and 14% (7/50) compared to 10% (1/10) for prior null responders.
Four percent (19/530) of treatment experienced subjects who received INCIVEK combination treatment were Black/African Americans; the SVR rate for these subjects was 63% (12/19) compared to 66% (328/498) for Caucasians.

The complete revised label can be viewed on the FDA web site at Drugs@FDA.

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration

HCAB Position Statement: Hepatitis C Drug Development and Drug-Drug Interaction Studies...

This HCAB (Hepatitis C Community Advisory Board) position statement was published on 2/28/12 regarding Hepatitis C drug development and drug-drug interaction (DDI) studies. In short, the HCAB would like drug developers to be more proactive in doing DDI studies before the drugs come to market. They admonish Merck specifically for not doing DDI studies with commonly available antiretrovirals and their HCV antiviral drug, boceprevir. Further, they applaud the efforts of Vertex and J&J for doing full due diligence in DDI studies prior to the launch of Telaprevir. 

HCAB Position Statement: Hepatitis C Drug Development and Drug-Drug Interaction Studies

February 17, 2012 -- The Hepatitis C Community Advisory Board (HCAB) recognizes the value of more effective and less toxic treatment for hepatitis C virus (HCV). We believe that sponsors can conduct key drug-drug interaction (DDI) studies with direct-acting antivirals (DAAs) and other candidates in development and medications commonly used by people with hepatitis C and those coinfected with HIV/HCV prior to their approval, without delaying development of these important therapies.

DAAs may share metabolic pathways with drugs that are commonly used by populations with a high prevalence of hepatitis C, such as hormonal contraceptives, methadone, buprenorphine, lipid-lowering agents, immunosuppressive drugs, herbal remedies, and commonly prescribed psychiatric medications.

In recognition of the suboptimal efficacy and tolerability of [pegylated interferon] and ribavirin, rapid trajectory of liver disease progression, and increasing mortality from HCV-related complications among HIV/HCV coinfected patients, regulators in the US and the EU encourage sponsors to conduct trials in HIV/HCV coinfected patients prior to approval for HCV monoinfection. Sponsors have already opened, or plan to launch these trials.

The recent discovery of drug-drug interactions between boceprevir and boosted HIV protease inhibitors underscores the importance of DDI studies with DAAs. Although we commend the sponsor, Merck, for opening one of the first coinfection trials with a DAA, we were outraged that Merck chose not to conduct DDIs with commonly used antiretroviral agents prior to launching the trial, and prior to gaining approval for boceprevir. Vertex and Tibotec were able to bring telaprevir [Incivek] to market with a much fuller portfolio of DDI data, although both drugs were developed within the same timeframe.

HCAB asks FDA [the US Food and Drug Administration], EMA [European Medicines Agency] and pharmaceutical companies to work together to minimize potential harm to hepatitis C monoinfected and HIV/HCV coinfected patients from uncharacterized drug-drug interactions. Furthermore, we call upon sponsors to perform DDI studies (as indicated by metabolic profile of their drug or drugs) with DHHS [US Department of Health and Human Services], EACS [European AIDS Clinical Society] and WHO [World Health Organization]-recommended antiretroviral agents for first-line, and treatment-experienced HIV/HCV coinfected people prior to approval, and strongly encourage studies of hormonal contraceptives, methadone, buprenorphine, lipid-lowering agents, immunosuppressive drugs, herbal remedies, and commonly prescribed psychiatric medications.

2/28/12

Source

Hepatitis C Community Advisory Board. HCAB Position Statement: Hepatitis C Drug Development and Drug-Drug Interaction Studies. February 16, 2012.

University of Liverpool launches an iPhone app for HCV DAA drug interactions...

(Finally, an app that is immediately practical! The new HEP i-Chart app launched by University of Liverpool researchers assists patients and providers alike in keeping up to date with possible drug-drug interactions between the new Direct Acting Antivirals for Hepatitis C and other medications and herbs. More info at http://www.hep-druginteractions.org/ )

The University of Liverpool has launched an iphone app, HEP i-chart, that provides Hepatitis C (HCV) patients with quick and easy access to the latest information about drug interactions.

Hepatitis C was first discovered in the 1980s when it became apparent that there was a new virus (not the already known hepatitis A or B) causing liver damage. Hepatitis C causes inflammation and swelling of the liver. It is estimated that over 170million individuals – representing 3% of the world's population – are chronically infected with the Hepatitis C virus (HCV). Statistically, as many people are infected with HCV as are with HIV.

Since its identification, drug treatment to eradicate the virus has advanced greatly, especially in the last few years. Two new drugs have recently been licensed for treatment of HCV, and there are more drugs in development.

HEP i-chart is based on the website (http://www.hep-druginteractions.org/) developed at the University by Professor David Back and Professor Saye Khoo which provides a comprehensive online guide to the interactions between anti-hepatitis drugs and other drugs. It is a tool that provides Hepatitis C patients and healthcare professionals with immediate access to up-to-date information on potential drug interactions between HCV drugs, and other drugs that the patient may be prescribed as well as over-the-counter, recreational or herbal medications.

Existing HCV drugs, newly licensed drugs and drugs in development can have interactions with each other and with other drugs which can impact on their effectiveness – sometimes with serious consequences. For this reason, some drug combinations must not be used, whilst others must be given with caution, possibly requiring adjustment or monitoring.

Professor of Pharmacology, David Back, said: "We are delighted to launch with our partners – KnowledgePoint360, MSD and Janssen- this new i-phone application that provides Hepatitis C patients and healthcare professionals with instant and easy access to information about HCV drug interactions which is relevant and reliable and up-to-date. This resource is especially important as new HCV drug treatments are approved and come into use."

Professor Graham Foster, President of the British Association for the Study of the Liver (BASL) said: "This new app, HEP i-chart, is a timely and much-needed resource for HCV patients as the number of new drugs which are available to treat Hepatitis C increases."

Pharmacokinetic Interactions Between Antiretroviral Agents and the Investigational HCV Protease Inhibitor Telaprevir in Healthy Volunteers

Jules Levin reports on the DDIs between Telaprevir (TVR) and some of the current drugs to treat HIV. As you have probably read, the RVR rates for Telaprevir in co-infected patients ranged from 70 to 75% in a sample size of 60 randomized to patients not on treatment as well as patients currently on Viread or an Atazanavir regimen. No info was available on whether patients HIV was controlled during that four week period. Based on the data on DDIs between Telaprevir and ARTs presented by R van Heeswijk,et al, Telaprevir is both an inducer and inhibitor of CYP3A, which means it is likely to interact with most ARTs on the market. Indeed, they did see reduced exposure to Telaprevir and variable effects on HIV protease inhibitors and tenofovir.

Telaprevir AUC using the 750mg Q8h dose with Lopinavir, Durnavir, Atazanavir (ATV) and Fosamprenavir saw 54%, 20%, 35% and 32% reductions respectively. Looking at the HIV PI concentrations, Ritonavir boosted Lopinavir, Durnavir, Atazanavir and Fosamprenavir saw no change, 40% less, 17% increase and 47% decrease with Telaprevir 750mg q8h respectively.

These interactions prompted Vertex to choose regimens with the least effect on exposure for their co-infected trial. ATV/r 300/100mg qd + TVR 750mg q8h/P+r and Efavirenz 600mg qd + TVR 1125 q8h/P+r.

Despite the author conclusions below, there is cause for concern in regards to DDIs with common ARVs and TVR. The PK concentrations of drugs are highly variable in individuals due to a variety of reasons. Add DDIs to the mix and even the slightest change in drug concentrations can case a Cmin to dip below the IC50 of the virus, with potential to cause either HIV and/or HCVresistance. Because of this, we might see resurgence of Therapeutic Drug Monitoring (TDM)in an effort to prevent resistance - Chris

AUTHOR CONCLUSIONS

RTV-boosted HIV PIs + TVR 750 mg q8h
–(Mutual) drug interactions were observed
•Reduced exposure to TVR, variable effects on HIV PIs
–Protein displacement may play a role in reduction of total concentrations (in-vitro evaluation ongoing)
–Appropriate doses have not been established
–
EFV and Tenofovir + TVR 1125 mg q8h
–Small changes in TVR, EFV and tenofovir exposure
–Higher TVR dose (1125 mg q8h) partly offset interaction with EFV
–
Based on these results, a pilot study of TVR in HIV/HCV co-infection was initiated with ATV/r 300/100 mg qd + TVR 750 mg q8h or EFV 600 mg qd + TVR 1125 mg q8h (plus Peg-IFN and ribavirin)

From CROI: Clinical Pharmacology of Boceprevir: Metabolism, Excretion, and Drug-Drug Interactions

(Jules Levin of NATAP.org reports on a session at CROI looking at Boceprevir drug interactions. Fortunately, with the notable exception of Efavirenz, it looks like BOC is a pretty clean drug in terms of DDI's)

Clinical Pharmacology of Boceprevir: Metabolism, Excretion, and Drug-Drug Interactions - see attached full slide report

Reported by Jules Levin

CROI – March 1, 2011
Boston, MA

C Kasserra, E Hughes, M Treitel,
S Gupta, and E O'Mara


AUTHOR CONCLUSIONS
•Radiolabeled data support a primarily hepatic-mediated clearance of BOC
•CYP3A4 probes
–Marked ↑ in midazolam exposure in the presence of BOC indicates that BOC is a strong, reversible inhibitor of CYP3A4
–↑ exposure to BOC with ketoconazole suggests involvement of another non–CYP3A4-mediated pathway
•Metabolic inhibitors (even in combination) did not alter BOC PK profile substantially to change BOC’s dose or schedule
–Diflunisal (AKR inhibitor) did not alter BOC exposure
–Ritonavir (CYP 3A4 inhibitor) did not substantively affect exposure to BOC
–Clarithromycin (CYP3A4, P-gp inhibitor) did not affect exposure to BOC
•No dosage adjustment is needed for the coadministration of BOC with tenofovir or peginterferon
•Clinical implications of a ↓ mean BOC trough concentration when coadministered with efavirenz will be clearer as data from coinfected populations are obtained
•Boceprevir did not affect the exposure to drospirenone/ ethinylestradiol in a manner that would be anticipated to reduce contraceptive efficacy