HCV New Drug Research

Also See;Side effects-direct-acting antivirals

Related Sept 26 2011; Hepatitis News Ticker-Video; Treatment Side Effects


In the past this blog has posted a few articles relating to the side effects experienced when treating with standard therapy, you can read them here. Today we will cover the possible side effects from the newly FDA approved drug Incivek (telaprevir).

A wide array of side effects have been encountered using telaprevir in several large trials. These side effects were discussed during the "FDA April Advisory Committee meeting", you can read those transcripts for both drugs; Telaprevir "INCIVEK" and Boceprevir "VICTRELIS" here

The side effects of standard therapy comes with more then a few side effects of their own, ribavirin is associated with anemia and rash. Patients who experience anemia may have weakness, trouble sleeping, and feel fatigued. In the most severe cases of anemia a blood transfusion may be required. The drug can be extremely harmful and cause birth defects in an unborn baby. Female patients and the female partners of male patients should avoid getting pregnant until 6 months after treatment ends. Pegylated interferon can cause fatal or make life-threatening problems worse (like mental, immune system, heart, liver, lung, intestinal and infections).

From About.com
Pegylated interferon, usually called peginterferon, is a chemically modified form of the standard interferon that treats Hepatitis C. The difference between interferon and peginterferon is the PEG, which stands for a molecule called polyethylene glycol. The PEG does nothing to fight the virus. But by attaching it to the interferon (which does fight the virus), the interferon will stay in the body (specifically the blood) much longer.

Side Effects: Pegylated interferon and Ribavirin

The common side effects are;Flu-like symptoms (including fever, chills, muscle aches, joint pain, headaches, tiredness)Upset stomach (like nausea, vomiting, taste changes, diarrhea)
Skin problems (like rash, dry or itchy skin, or redness and swelling at injection site)
Hair thinning or loss (temporary)
Mental health problems (such as depression, difficulty sleeping, irritability, and anxiety)Anorexia or loss of appetite leading to weight loss
Dehydration

Serious side effects are;
Eye problems (blurred, loss of vision, retinal detachment, and corneal ulcers related to intestinal inflammation)Autoimmune problems (sarcoidosis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and thyroid problems, such as hyperthyroidism and hypothyroidism)Rash with fever or blisters
Lung problems (like trouble breathing, pneumonia, inflammation of lung tissue, and high lung blood pressure), sometimes requiring a machine to breathe for you and/or causing death

See Medication Guides; Peginterferon alfa Ribavirin

Please keep in mind the severity of these side effects range from mild to manageable and are rarely severe. During therapy the importance of understanding these adverse reactions will enable you to expedite your recovery.

Incivek (telaprevir) Side Effects

Recently and in the past, this blog has received numerous emails from readers treating with Incivek asking for information about these three specific side effects; rash, anal burning itching sensation, and anemia. This blog entry will cover those topics and more. The information today will come from a variety of sources but mainly from the FDA April Advisory Committee meeting.

From FDA April Advisory Committee meeting

Telaprevir's safety profile

Telaprevir's safety profile is based on exposure in more than 3,800 patients. Addition of telaprevir to peginterferon and ribavirin increased the incidence of specific adverse events. The majority occurred in the first 12 weeks, were mild to moderate, and did not lead to treatment discontinuation.
Rash and anemia were identified as key telaprevir-associated adverse events. Addition of telaprevir resulted in an increased incidence and severity of these events, as well as treatment discontinuations.
Rash and anemia were well characterized during the development program, and both were reversible and manageable. Early recognition of these key events helped us characterize them and develop management strategies that were tested in Phase 3.

Blog Note;
As mentioned during triple therapy (telaprevir, peginterferon alfa, and ribavirin) skin rashes are common. The rash is often mild and not serious in most cases. The advisory committee members were concerned about the three cases of Stevens Johnson Syndrome (SJS) which appeared during the telaprevir clinical trials. Keep in mind that there were approximately 2,200 trial participants. The serious skin reactions included a drug rash with eosinophilia and systemic symptoms known as (DRESS) and Stevens Johnson Syndrome (SJS). In the telaprevir trial the serious adverse reactions were reported in less then 1% , that is compared to none in the trial participants who received peginterferon alfa and ribavirin alone.

From FDA April Advisory Committee meeting

Rash, SJS And Pruritus

Blog Note;

SCAR- Severe Cutaneous Adverse Reactions

Cutaneous drug reactions occur when your skin has a reaction to a drug.

DRESS-(Drug Reaction with Eosinophilia and Systemic Symptoms)
Japanese Dermatologists call this syndrome DIHS (Drug Induced Hypersensitivity Syndrome) while European and American dermatologists suggested the acronym of DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms)

DRESS is one of several terms that has been used to describe a severe idiosyncratic reaction to a drug that is characterized by a long latency of onset after exposure to the offending medication, a rash, involvement of internal organs, hematologic abnormalities and systemic illness.

FDA – Russell Fleischer; @ the FDA April Advisory Committee meeting

Rash and pruritus you've heard a lot about. It was identified in the Phase2 trials. A detailed monitoring and management plan was put into place for Phase3. You've heard about the rash special search criteria. Severe rashes and rashes that led to discontinuation were considered events of special interest. And there was a dermatology expert panel convened to retrospectively adjudicate cases.

Rash events: 56 percent for telaprevir subjects versus 34 percent for peg/ribavirin. There were more grade 3 severe rash at 4 percent versus less than1 percent. About 1 percent of telaprevir subjects had a serious adverse event of rash compared to no subjects treated with peg and ribavirin. The rash event of special interest was 7 percent compared to less than 1 percent.
Pruritus by itself was reported in about 47 percent of subjects compared to 28 treated with peg and ribavirin. And when you looked at rash and/or pruritus, it was 73percent for telaprevir versus 48 percent for peg and ribavirin.Rash was managed a number of ways, as you've already heard. About 7 percent of subjects actually discontinued telaprevir due to rash compared to less than 1 percent who discontinued placebo. Just under 1 percent discontinued the entire regimen compared to no subjects in peg and ribavirin.

Use of oral antihistamines, topical steroids, and systemic steroids were higher for treatment of severe rash among subjects who were treated with telaprevir. And in this group, there were a number of subjects who received more than one intervention.You heard about the dermatology expert panel.

And their conclusions were that this rash was clinically and histologically similar to peg and ribavirin. It was a pruritic, eczematous, spongiform dermatitis with lymphocytic perivascular infiltration. However, it was more severe and more extensive, and did occur at a higher incidence.

The majority of evaluable rashes by the expert panel involved less than or equal to 30 percent of the body surface area, but investigators frequently estimated the extent of body surface area to be greater.In general, the rash improved after discontinuation of telaprevir, but it could take up to weeks to resolve.

And less than 1 percent of subjects experienced suspected -- I'm going to induce another new term -- SCAR, which is severe cutaneous adverse reactions.

And those are things like SJS, TEN, and DRESS. And as you heard, there were no cases of TEN.

Blog Note;Toxic epidermal necrolysis (TEN) begins with fever, cough, and other nonspecific symptoms, and is soon followed by purplish, bloody-looking lesions on the skin and mucous membranes. These early lesions, typically found on the head, neck, and upper chest, soon merge and blister. Sheets of epidermis then begin to detach from the skin layers below. In time, the entire surface of the skin may be involved, with detachment of 100% of the epidermis.

And among the cases of SJS or DRESS, there were no fatal outcomes. All subjects recovered.We obtained a consult from our colleagues in the dermatology division, and some of the issues that were identified include that there needs to be a distinction between severe rash and SCAR, and that distinction is important because SCAR has implications for morbidity and mortality that may not attach to severe. So, for example, someone could have severe acne, but it's not necessarily a SCAR event

Most SCAR events, particularly as they relate to DRESS, were suspected on case review, retrospective case review by the expert panel and not by investigators, which may actually suggest under-reporting and under-diagnosis of these events in the field. And the detection of suspected SCAR cases may be noteworthy given that SCAR are generally considered to be rare, and the sample size of clinical trials intended to support marked improvement are generally not powered to detect such rare events.

We also feel that the expert panel review may have been biased towards characterizing only the more severe events, given the definition of "event of special interest." So the extent to which the conclusions about eruptions from the expert panel review might apply to the broader population of telaprevir-treated subjects who experienced cutaneous eruptions is unclear. And most of the ESI events had what we considered an eczematous component, so it's not clear that this translates to a general characterization of the rash as being primarily eczematous.So in summary, telaprevir-related rash and pruritus occur frequently.

They can be severe and treatment-limiting. SCAR events occur infrequently but may be significant. They may have been under-diagnosed by investigators. It's important to recall that not all severe rash were SCAR events. And in the subjects who had SCAR events, there were no deaths. Rash may take weeks to resolve. The effect of antihistamines and steroids remain unclear. And as you also heard, the etiology of this rash remains undetermined.

Distinction between severe rash and SCAR; How do you define SCAR?

DR. STRADER: My last question, you talked about dermatologic issues thatneeded to be identified, and you said distinction between severe rash and SCAR,but you don't tell us what that distinction should be, how do you define this SCAR. Because if you don't tell us, how are we going to know?Have you decided yet, or it's something --

MR. FLEISCHER: Well, SCAR events, maybe Dr. Bigby can say something. But SCAR is sort of a specific definition that's associated with morbidity and mortality. Things like the DRESS is a SCAR. SJS is a SCAR. TEN is a SCAR.

DR. STRADER: But there have to be some distinctions, something that you find, bullae, something that tells me this is SCAR as opposed to just amaculopapular rash.

DR. CARGILL: I think perhaps we can ask Dr. Bigby to clarify that forus.

DR. BIGBY: I think that the rashes that would be considered severe and sometimes life-threatening would be toxic epidermal necrolysis; Stevens-Johnson syndrome, which most people think those two are related and only depend on extent.
The big thing about those two are that they lead to epidermal detachment,so that if there's more than 30 percent epidermal detachment, you would call it TEN. If the epidermal detachment is less than 10 percent, it's SJS. And if it's somewhere in between, there's an overlap syndrome.

Then patients that have what's referred to here as DRESS have actually an exanthematous eruption that usually covers more than 50 percent of the body,associated with eosinophilia and systemic symptoms, the most common one being fever. And they can also have internal involvement of other organs like liver and kidneys. It, too, has a mortality associated with it.So those are the ones that I think he is referring to when he says SCAR.

DR. STRADER: So anything else is a severe rash. TEN, SJS, and DRESS, and the overlap thing would be considered SCAR, but everything else would be considered regular rash or severe rash?

DR. BIGBY: That's usually the case

Clarify; How Long Until The Rash Resolves Completely

From FDA April Advisory Committee meeting

Question;
DR. STRADER: Two more quick questions. One of them, there's a slide CS-17 where you're showing the rash with telaprevir and with placebo. And it appears that you indicate that the rash continues even though the telaprevir dose is discontinued, and for a long period of time.But I was under the impression that once the telaprevir dose was discontinued, the rash resolved. So can you just clarify that slide for me, please?

DR. SINGHAL: Yes. I can clarify that. The point here was that, in general, we have noted that there is a background rate of rash, mild and moderate rash, with peginterferon and ribavirin, to the rate of about 34 percent. When we added telaprevir to that regimen, there was an increase in the rate of mild and moderate rash. And then there was a severe rash that wasn't really noted at all in the placebo/peginterferon/ribavirin group. It was only noted in the telaprevir groups, as we demonstrated.

So when telaprevir was discontinued by the rules that we had established, remember, the patients were still on peginterferon and ribavirin, so they had the underlying peginterferon and ribavirin. We believe that that may be contributing to an increased time to resolution.
In general, the severe rash could take about 4 to 6 weeks to resolve completely. That was the median time to resolution, which is why I wanted to make the point that it doesn't go away immediately.

From FDA April Advisory Committee meeting

Prior Rash In Patients; Are they more susceptible?

MS. DEE: Okay. I'm not sure if this is for the sponsor or for the agency. I know I heard somebody mention prior rash in patients before, but I didn't really hear an answer about whether people who had had a rash situation in the past might be more susceptible to getting a rash with this drug.

DR. SINGHAL: We did not collect information on baseline experience with rash. For example, in the treatment failure trial, C216, we did not exclude any subjects who had previously had rash.However, when we collected the data on the rash events that patients experienced during the study, we did collect information as to whether they had had an event previously. And the rates that we observed in C216 were really no different from rates in the 108 study. So we don't believe that there's an impact on prior rash. But to be really sure, we are collecting prospective information in ongoing studies, so we are looking at that in further depth.


Management Of Telaprevir Rash

MS. VALBH: Okay. And, I'm sorry, I have one more question. On one of the slides there was a mention that there was guidance on symptomatic management of rash. Can you tell me a little bit about what that guidance was? Did you have an algorithm that, if a rash presented itself, start with a topic corticosteroid, or you start with an antihistamine? What was that guidance?

DR. KAUFFMAN: Yes. I'll ask Dr. Singhal to come up and tell you about that.

DR. SINGHAL: A very specific guidance was included in all the Phase 3 protocols, and let me begin by the general principles that were included. So the general principles were that physicians needed to follow the general management principles and use systemic antihistamines as required for pruritus or rash, as well as topical corticosteroids. There was a specific mention that if they needed to use topical corticosteroids for more than two weeks, they needed to connect with a medical monitor to allow whether it was going to be systemically absorbed.Very specifically, systemic corticosteroids were to be used only as indicated and if required when other modalities had failed because systemic corticosteroids, once they were used, we required telaprevir and other drugs to be discontinued. So that was the specific management.
Now, this was a general principle management across all grades of rash. So I just want to go back to the management that I provided. This was the general management as well as the symptomatic treatment. We do have the details of how many patients used these treatments, and if you like, I can share that with you.

With regards to study action, it was really very clear. Mild and moderate rash did not require any discontinuation, and that was more than 93 percent, as we saw. And then the severe rash required discontinuation of telaprevir alone.

From FDA April Advisory Committee meeting

Rash Photosensitization

Photosensitization; development of abnormally heightened reactivity of the skin or eyes to sunlight

DR. KORMAN: Just quickly, about photosensitization, did you make any recommendations?

DR. SINGHAL: Right. So we did examine that from a nonclinical perspective, the photosensitization, and we do not believe that it contributes to the rash in any great way. From a clinical perspective, the dermatology expert panel also examined this based on about 150 cases with photographs that they examined, and there did not seem to be any indication of it being photosensitive.

From FDA April Advisory Committee meeting

Anal Itch; Burning sensation or an itching sensation

DR. VAN DYKE: Great. Super. My other question is, could you give us moreclinical details on the anorectal symptoms in terms of what they were, what didthey look like clinically, and how long did they last, and how much of a problem really were they for the subjects? Because they were quite common, like 29percent.

DR. KAUFFMAN: Yes. We first became aware of this in Phase 2 with increased reports of hemorrhoids. And, frankly, I don't think it was really hemorrhoids, but hemorrhoids are present very commonly, so when you take a look, you often will find hemorrhoids, even if they're not really related to the phenomenon.We have really only anecdotal reports. But I have spoken to many investigators about this phenomenon. Upon examination, there is no inflammation. Either externally or on anoscopy, there's been no inflammation. And I'll just point out parenthetically that in all of our nonclinical studies, there is no inflammation or other findings related to the colon with telaprevir.

It's described as a burning sensation or an itching sensation. It occurs relatively rapidly after the beginning of administration of telaprevir. It actually often resolves either during the period of dosing or very rapidly thereafter. And as we pointed out, it's almost never associated with treatment discontinuation. It is an annoying side effect, but it really doesn't have any serious consequences in terms of compliance with the treatment regimen.

From RX List
There were anorectal events in 29% of subjects treated with Incivek™ combination treatment (compared to 7% being treated with just peginterferon alfa and ribavirin). The majority of these anorectal events included hemorrhoids, anorectal discomfort, anal pruritus and rectal burning which were mild to moderate in severity. Less than 1% of these events led to treatment discontinuation and all resolved during or after Incivek™ dosing.

From FDA April Advisory Committee meeting

Do treatment-experienced patients that have more advanced liver disease have a different side effect profile ?

DR. KORMAN: I wanted to ask a question about the side effect profile. You pooled the data for the treatment-experienced and treatment-naive patients, I think; that's all that I saw. I'd be interested in knowing whether the treatment-experienced patients that have more advanced liver disease have a different side effect profile and whether the rash can be predicted by treatment-experienced patients having had skin reactions of either mild, moderate, or severe characteristics.

At least in my experience, many of the patients, particularly the female patients, complain of hair loss, and I notice that that's not included. I wondered if that actually is also something that other hepatologists see, and whether you can comment on seeing that during this process. It's clearly a very disturbing symptom.

DR. KAUFFMAN: Yes. Just overall, the adverse event profile in the treatment-experienced patients was very similar to the treatment-naive patients, and that's why we were able to pool those groups together. I'll ask Dr. Singhal to come up and address your other questions in more detail.

DR. SINGHAL: Okay. No, I just wanted to mention that the alopecia, which is actually commonly noted with peginterferon and ribavirin, we did not see any increased rates with telaprevir at all, which is why it was not mentioned as part of -- and it's below 20 percent, so it didn't make it to the most common AEs, either.

Anemia

From RX List

While anemia has been reported with peginterferon alfa and ribavirin therapy, adding Incivek™ to this treatment created an additional decrease in hemoglobin concentrations. Of those subjects who received Incivek™ combination treatment, 36% had hemoglobin values less than or equal to 10 g/dL compared to 17% of those in the study receiving just peginterferon alfa and ribavirin. Furthermore, hemoglobin values less than 8.5 g/dL were reported in 14% of those receiving Incivek™ combination therapy versus 5% of those being treated in the study with just peginterferon alfa and ribavirin.

Of the participants of the study arm receiving Incivek™ combination therapy, 4% discontinued just Incivek™, 1% discontinued the entire Incivek™ triple therapy and 32% had a ribavirin dose modification (reduction, interruption or discontinuation) due to anemia.

For those subjects of the study arm receiving just peginterferon alfa and ribavirin, 2 people discontinued and 12% had a ribavirin dose modification.Vertex recommends that hemoglobin should be monitored prior to treatment with Incivek™ and at least every 4 weeks during Incivek ™ combination therapy.

To manage anemia it is recommended that ribavirin dose reductions be used based on ribavirin dose reduction guidelines. If ribavirin dose reductions are not working, discontinuation of Incivek™ should be considered. However, if ribavirin is permanently discontinued for the management of anemia, Incivek™ must be permanently discontinued as well and not restarted

Anemia had No Effect on Efficacy Outcomes in Treatment-naïve Patients Who Received Telaprevir-based Regimen in the ADVANCE and ILLUMINATE Phase 3 Studies

Bilirubin

From FDA April Advisory Committee meeting

Bilirubin elevations were much higher in telaprevir versuspeg/ribavirin at 41 versus 30 percent. Elevations to above grade 3 levels, whichwas greater than about 2.6 times the upper limit of normal using the date scale,were 4 percent for telaprevir, 2 percent for peg and ribavirin. Again, thesteepest increase very early, then there was stabilization, and by weeks 12 to16, they were back to baseline levels.

About 1 percent of subjects in both treatment groups had a "clinicalevent." Again, this could have been an isolated lab abnormality. And 14 of thesetelaprevir subjects only listed -- the only thing that was listed was eitherelevated bilirubin or hyperbilirubinemia. Thirteen of the 14 actually occurred after the telaprevir dosing period was completed.

RX List

Bilirubin: Forty one percent of INCIVEK-treated subjects compared to 28% of peginterferon alfa and ribavirin-treated subjects had all grade elevations in bilirubin levels; 4% and 2% of subjects, respectively, had greater than or equal to 2.6 x ULN elevations. Bilirubin levels increased most steeply during the first 1 to 2 weeks of INCIVEK dosing, stabilized and between Weeks 12 and 16 were at baseline levels.

Uric Acid

Uric Acid: During the INCIVEK combination treatment period, 73% of subjects had elevated uric acid levels compared to 29% for those treated with peginterferon alfa and ribavirin alone. Shifts to greater than or equal to 12.1 mg/dL from baseline in uric acid levels were also more frequent among subjects treated with INCIVEK (7%) compared to peginterferon alfa and ribavirin (1%). Less than 1% of subjects had clinical events of gout/gouty arthritis; none were serious and none resulted in treatment discontinuation.

Table from RX list

INCIVEK was administered in combination with peginterferon alfa and ribavirin. The following table lists adverse drug reactions that occurred in INCIVEK-treated subjects with an incidence at least 5% greater than in subjects receiving peginterferon alfa and ribavirin alone (Table 4).





Possible side effects of Telaprevir:
All medicines may cause side effects, but many people have no, or minor, side effects.

Check with your doctor if any of these most COMMON side effects persist or become bothersome:
Anal or rectal problems (eg, burning, discomfort, itching, hemorrhoids); change in taste; diarrhea; nausea; tiredness; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); change in the amount of urine produced; dark, tarry, or bloody stools; dizziness; fast or irregular heartbeat; feeling cold, especially in the hands or feet; fever, chills, or sore throat; joint pain (especially in the big toe); mouth sores or ulcers; pale skin; rash (with or without itching); red or irritated eyes; red, swollen, blistered, or peeling skin; severe or prolonged nausea or vomiting; shortness of breath; swelling of the face; unusual tiredness or weakness; yellowing of the skin or eyes.

For More Information See
Telaprevir/Incivek Prescribing Information
Medication Guide
Incivek Warnings & Precautions
Also; FDA Transcripts Telaprevir/Boceprevir April Advisory Committee Meeting