Telaprevir is a protease inhibitor approved to treat genotype 1 chronic hepatitis C in combination with peginterferon and ribavirin. It works by inhibiting the HCV NS3/4A protease to prevent viral replication. Several clinical trials found telaprevir combination therapy resulted in higher rates of undetectable HCV RNA levels and sustained virologic response compared to peginterferon-ribavirin alone. The most common side effects were rash, pruritis, fatigue, and gastrointestinal issues. Though telaprevir is associated with more side effects, its ability to shorten treatment duration and improve outcomes outweighs the increased costs. As such, the

1. Purdue University Formulary Evaluation
Incivek® (telaprevir)
TITLE:
Generic Name (Trade Name®): 1 Telaprevir (Incivek®)
Manufacturer: 1 Vertex Pharmaceuticals, Inc.
Dosage Form (NDC Number):2 375-mg tablet (511670-100-01)
AHFS Classification:3 Protease Inhibitor: 8:18.40
Storage: 1 Keep at 25ºC (77ºF) with excursions permitted to 15-30ºC (59-86ºF). Use within 28
days after opening package. Keep bottle tightly closed.
SUMMARY:
Telaprevir is a protease inhibitor that prevents the replication of HCV. 2,3 By preventing the
HCV NS3/4A serine protease, proteins that are encoded by the virus necessary for HCV
replication are unable to be cleaved into their mature forms. 2 Telaprevir is indicated for the
treatment of genotype 1 chronic hepatitis C in adults with compensated liver disease who have
not received prior treatment or have been previously treated only with interferon-based
therapy. Telaprevir is only indicated for use as an adjunct to PegIntron® (peginterferon-alpha
2b) and Rebetol® (ribavirin) combination therapy and should never be prescribed alone. 1,2,4
Current formulary agents for the treatment of chronic hepatitis C include peginterferon-alpha
2b for use as a single agent or as a dual therapy with ribavirin. Peginterferon-ribavirin
combination therapy is indicated for use in patients over 3 years old with chronic hepatitis C
and compensated liver disease. 5 Peginterferon-alpha 2b limits the replication of HCV by
inducing the antiviral immune response through the activation of the type 1 interferon
receptor.5 Ribavirin acts as a purine analog that has direct antiviral activity; however, the
overall mechanism of combination therapy is not completely understood. 6
Several clinical studies have shown an increased virological response to telaprevir combination
therapy compared to peginterferon-alpha 2b and ribavirin dual therapy alone. In one clinical
study, 1088 previously untreated subjects were divided into groups receiving telaprevir
combination treatment for 12 weeks, 8 weeks, and an active control using dual therapy only.
Undetectable HCV RNA levels were observed in 75% (p<0.001), 69% (p<0.001), and 44% of
subjects respectively, when measured 24 weeks after the last treatment. 7 Another study
divided subjects who had been previously treated for HCV into groups receiving telaprevir
combination therapy for 12 weeks followed by 12 weeks of dual therapy, telaprevir for 24
weeks followed by 24 weeks of dual therapy, telaprevir for 24 weeks, and a control group
using dual therapy for 48 weeks. The amount of patients achieving a sustained virologic
response was 53% (p<0.001), 54% (p<0.001), 54% (p=0.02), and 14% respectively. 8 Another
study demonstrated the effect of telaprevir on patients who relapsed with previous
peginterferon-ribavirin treatments. Patients who were given telaprevir combination therapy for
12 weeks had a sustained viral response in 83% (p<0.001), and patients with peginterferon-
ribavirin treatment for 4 weeks before 12 weeks of telaprevir combination therapy achieved
88% with a sustained response (p<0.001). Comparatively, the patients in the control who were
not given telaprevir showed 24% with a sustained response. 9
The most commonly reported side effects associated with the use of telaprevir were pruritis
(56%), rash (56%), fatigue (56%), anemia (36%), nausea (39%), diarrhea (26%), vomiting
(13%), hemorrhoids (12%), anorectal pain (11%), altered taste (10%), and pruritis (6%).
Several serious side effects were reported as severe skin hypersensitivity reactions (<1%),
Stevens-Johnson syndrome (<1%), and severe anemia. 1,2,4 The tolerability of these effects
appears to be somewhat questionable, as 14% of subjects discontinued telaprevir due to
1

2. negative side effects. 2 Since telaprevir is indicated as a combination therapy, patients will also
be subjected to the adverse effects of the additional medications. Patients undergoing
treatment with peginterferon-alpha 2b and ribavirin therapy experienced similar types of side
effects as caused by telaprevir, but the addition of telaprevir increased the incidence of these
side effects. 1,2,5 There are no black box warnings associated with telaprevir or significant errors
reported through ISMP.1,2,10
The cost of telaprevir is significantly more than the cost of peginterferon-alpha 2b and ribavirin
therapy. A 12 week course of treatment with telaprevir costs $59,040 plus the cost of
peginterferon at $8,303.04 and ribavirin at $4,170.60. 4,6,11
RECOMMENDATION:
Telaprevir should be added to the formulary. This conclusion is based on several factors
including decreased time to demonstrate a virologic response and an increased proportion of
patients achieving a sustained virologic response. A shorter duration of treatment also
influenced the recommendation to add telaprevir. This increase in positive outcomes
outweighs the increased cost associated with adding the drug to formulary. While telaprevir is
associated with a greater incidence of side effects, those side effects are similar to those
experienced by patients receiving only the current therapy. 7,8,9 Peginterferon alpha and
ribavirin should still be included on the formulary because telaprevir is only indicated for use as
an adjunct with these two medications. 1,2
DESCRIPTION AND PHARMACOLOGY4-6,12:
Telaprevir is a direct-acting antiviral agent that is an inhibitor of the HCV NS3/4A serine
protease enzyme. This protease is responsible for cleavage of HCV polyprotein into active
forms of the NS4A, NS4B, NS5A, and NS5B proteins necessary for the replication of the virus
particle. In a biochemical assay, telaprevir had an IC50 of 10 nM for inhibition of the
recombinant HCV NS3 protease domain. 4
Peginterferon alpha-2b induces the antiviral response of the innate immune system. It binds to
and activates the human type 1 interferon receptor, activating multiple signal transduction
pathways including regulation of transcription. The recommended dose for peginterferon
alpha-2b monotherapy is 1 mcg/kg/wk for one year. It is often used in combination with
ribavirin, whose mechanism of action is not fully established but is known to possess antiviral
activity. In the case of combination therapy with ribavirin, the duration of therapy is 48 weeks
(for HCV genotypes 1 and 4) and 24 weeks (for genotypes 2 and 3). Telaprevir is only
approved for co-therapy with peginterferon alpha-2b and ribavirin. In the Protease Inhibition for
Viral Evaluation 1 trial (PROVE 1) and PROVE 2 trials involving HCV genotype 1 patients with
no previous treatment, the rates of prolonged virologic response were 61% and 69%,
respectively for PROVE 1 and PROVE 2 after a 12-week course of
telaprevir/ribavirin/peginterferon followed by peginteferon-ribavirin therapy continuing for an
additional 12 weeks. The addition of telaprevir reduced the median time to achieve an
undetectable (<50 units/mL) HCV level (<30 days rather than 113 days). This may be one
advantage of addition of telaprevir. Telaprevir is administered during the first twelve weeks of
therapy only, followed by twelve or thirty-six weeks of ribavirin-peginterferon therapy,
depending on detectable levels of HCV RNA at weeks four and twelve. Giving telaprevir with
peginterferon and ribavirin will decrease the total duration of therapy associated with telaprevir
monotherapy (from one year to twenty-four or forty-eight weeks). However, telaprevir is given
three times daily in contrast to peginterferon montherapy during which medication is
administered once a week. A disadvantage of telaprevir may be the increased prevalence of
side effects. In patients receiving the three-drug combination therapy, the most common side
2

3. effects experienced are as follows: rash (56%), pruritis (47%), anemia (36%), fatigue (56%),
nausea (39%), and vomiting (13%). These side effects are similar to those experienced with
ribavirin-peginterferon dual therapy, although addition of telaprevir increased the percentage of
patients reporting these side effects. Responsiveness to treatment regardless of therapy used
requires monitoring by measuring HCV RNA levels among other clinical methods of
assessment.
PHARMACOKINETICS:
telaprevir1,13 peginteferon alpha- ribavirin6
2b5,14
Absorption When given orally with After subcutaneous When given orally,
peginteferon-alpha injection, peak serum ribavirin is best
and ribavirin levels are achieved within absorbed when
concomitantly, 15 to 44 hours. The half- taken with a high
telaprevir is absorbed life for absorption is 4.6 fat meal.
primarily in the small hours.
intestine and reaches
peak concentrations
after 4 to 5 hours. It
should be taken within
30 minutes of a fatty
meal (≥ 20g of fat).
Distribution Between 59% to 76% Peak plasma levels are It is not bound by
of telaprevir is bound upheld for 48 to 72 hours plasma proteins
to proteins in the following administration. and is transported
plasma. Protein The bioavailability is by an es-type
binding is increased with multiple equilibrative
concentration doses (3 times higher in nucleoside
dependent. week 48 than week 4). transporter which
is found on all cell
types.
Metabolism Upon oral There is no information The tablet form is
administration, the about any pathways or not metabolized by
majority of metabolism enzymes that metabolize CYP-450
occurs via CYP3A4 peginterferon-alpha 2b. enzymes. The
enzymes in the liver. solution/capsule
The resulting form is
metabolites are either metabolized to a
inactive or less active triazole carboxylic
than telaprevir and acid or reversibly
can be found in the phosphorylated.
urine, bile, and
plasma.
Excretion The half-life of The average half-life of The average half-
elimination is 4 to 4.7 elimination is 40 hours. life of elimination is
hours for a single About 30% of 120 to 170 hours.
dose of telaprevir and peginterferon-alpha 2b is Metabolites are
9 to 11 hours for eliminated via the excreted renally.
stable dosing. The kidneys. The relative
primary elimination amount excreted by other
route is through the routes is not specified.
3

4. feces (82%) followed
by expired air (9%)
and urine (1%).
Renal impairment: For patients with CrCl < 30mL/min, the C max of telaprevir was reduced by
3%, and the AUC was reduced by 21%. 2
Hepatic impairment: The steady-state exposure of telaprevir was reduced 15% in patients
with mild hepatic dysfunction (Child-Pugh class A) and 46% in patients with moderate
hepatic dysfunction (Child-Pugh class B). 2
INDICATIONS1,14: According to the package insert, “telaprevir is a hepatitis C virus (HCV)
NS3/4A protease inhibitor indicated, in combination with peginterferon alfa and ribavirin, for the
treatment of genotype 1 chronic hepatitis C (CHC) in adult patients with compensated liver
disease, including cirrhosis, who are treatment-naïve or who have been previously treated with
interferon-based treatment, including prior null responders, partial responders, and relapsers.
Telaprevir must not be used as monotherapy and must only be used in combination with
peginterferon alfa and ribavirin. A high proportion of previous null responders (particularly
those with cirrhosis) did not achieve Sustained Virologic Response (SVR) and had telaprevir
resistance-associated substitutions emerge on treatment with INCIVEK. Telaprevir efficacy
has not been established for patients who have previously failed therapy with a treatment
regimen that includes telaprevir or other HCV NS3/4A protease inhibitors.” 1 Comparatively,
peginterferon alpha 2-b used in combination with ribavirin is indicated for treatment of chronic
hepatitis C and is not limited to genotype 1 HCV infection.
CLINICAL TRIALS:
CITATION:7 Jacbson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously
untreated chronic hepatisis C virus infection. N Engl J Med 2011; 364: 2405-16.
OBJECTIVE: To compare the efficacy and safety of telaprevir in combination with
peginterferon-ribavirin to peginterferon-ribavirin therapy alone for the treatment of HCV in
previously untreated patients.
METHODS: The study was a phase 3, randomized, double-blind, placebo-controlled trial that
lasted either 24 or 48 weeks, depending on patients’ HCV RNA plasma concentrations at
weeks 4 and 12. The trial assessed 1088 patients who had not been previously treated for
HCV. Patients were included in the study if they were between 18 and 70 years of age, had
HCV genotype 1 infection with evidence of chronic hepatitis, compensated liver cirrhosis,
seronegativity for hepatitis B surface antigen, absence of antibodies against human
immunodeficiency virus types 1 and 2, absolute neutrophil counts of 1500 or more per cubic
millimeter, platelet counts of 90,000 or more per cubic millimeter, and hemoglobin levels of at
least 12 g per deciliter in women or 13 g per deciliter in men. Exclusion criteria were
decompensated liver disease, liver disease from other causes, and hepatocellular carcinoma.
Participants in the active treatment groups were given oral doses of 750mg telaprevir every 8
hours with food. In addition, participants were also given 180mcg peginterferon alfa-2a
subcutaneously every week and oral doses of either 1000mg or 1200mg ribavirin daily
depending on patient weight.
PR group (control): 361patients received only peginterferon-ribavirin treatment and placebo
throughout the study duration.
4

5. T12PR group: 363 patients received telaprevir and peginterferon-ribavirin treatment for the
first 12 weeks.
T8PR group: 364 patients received telaprevir for 8 weeks followed by 4 weeks of placebo and
peginterferon-ribavirin for the first 12 weeks.
Following the initial 12 week treatment period, participants in both active groups that had
undetectable HCV RNA plasma concentrations at weeks 4 and 12 received additional
treatment with peginterferon-ribavirin therapy alone for 12 weeks. Participants that had
detectable HCV RNA levels were given peginterferon-ribavirin therapy alone for an additional
36 weeks. The primary endpoint of the trial was the proportion of participants whose plasma
concentrations of HCV RNA was undetectable 24 weeks after the last treatment dose.
RESULTS: When HCV RNA levels were assessed 24 weeks after the last treatment dose,
undetectable levels were observed in 75% of the T12PR group, 69% of the T8PR group, and
44% of the PR group (p<0.001). The most common side effects occurring in T8PR, T12PR,
and PR were nausea (40,43,31%), diarrhea (32,28,22%), pruritus (45,50,36%), rash
(35,37,24%), and anemia (37,39,19%). Rash and anemia were the greatest causes in
discontinuation of telaprevir treatment. Development of a serious rash caused discontinuation
of 7% in T12PR and 5% in T8PR, and anemia caused discontinuation of treatment in 4% of
T12PR and 2% of T8PR. One case of Stevens-Johnson syndrome was reported.
CONCLUSION: The data suggests the addition of telaprevir to peginterferon-ribavirin therapy
is more effective at treating chronic hepatitis C infections, as evidenced by decreased HCV
RNA levels. Because it has shown to increase the rate at which patients respond to treatment,
it may be possible to shorten treatment duration compared to peginterferon-ribavirin alone.
Treatment with telaprevir for 12 weeks appears to be more efficacious than treatment for 8
weeks, and a 12 week treatment course only slightly increases the amount of adverse effects
over an 8 week treatment. In addition to being a more effective treatment method, telaprevir
was shown to cause a decreased occurrence of relapse throughout the trial duration compared
to the control group. Treatment with telaprevir increased the risk for anemia and relatively
serious skin reactions which should be considered before starting therapy.
COMMENTS: The study is limited to patients who have not received prior treatment for HCV
which could limit the generalizability of the results. The clinical trial does not provide efficacy
data beyond 72 weeks, so there is limited knowledge about the long-term benefits of therapy
with telaprevir or the need for re-treatment. Since post-telaprevir therapy was determined by
HCV RNA levels at weeks 4 and 12, a potential confounding variable is that patients did not
have a uniform duration of treatment even within the same treatment groups. Sustained low
HCV concentrations could be contributed to longer treatment with peginterferon-ribavirin than
telaprevir itself. In addition, the authors did not discuss the strengths and limitations of their
study design.
CITATION8,15: McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously
treated chronic HCV infection. N Engl J Med 2010;362:1292-303.
OBJECTIVE: Assess the efficacy and safety of telaprevir therapy in patients previously treated
for HCV infection who did not have a sustained virologic response to a full-course regimen of
peginterferon alfa-2a and ribavirin therapy.
METHODS: The study design was a randomized, multi-center stratified, 72-week, partially
placebo-controlled, partially double-blind, phase 2 clinical trial. After screening for criteria
requirements, a total of 465 patients underwent randomization into four treatment groups.
Patients eligible for the study were 18 to 70 years old, suffered from HCV genotype 1 infection,
and had received previous treatment for HCV infection with peginterferon alfa and and ribavirin
but did not have achieve a sustained virologic response. Sustained virologic response was
5

6. defined as never achieving undetectable HCV RNA levels during the course of therapy,
relapse of infection after treatment has ended, or breakthrough (i.e., undetectable RNA levels
during the course of treatment but appearance of detectable levels before the end of
treatment). Other inclusion criteria were: Negative results from plasma test for hepatitis B
surface antigen and antibodies against HIV type 1 and 2 viruses, an absolute neutrophil count
of 1500 or more/cubic mL, a platelet count of 100,000 or more/cubic mL, and normal bilirubin
values. In addition, patients need to have had a liver biopsy within 3 years of study
commencement. Exclusion criteria included decompensated liver disease, hepatocellular
carcinoma, or any other clinical liver disease. Patients were divided into four groups. Dosage
of individual medications is as follows: Telaprevir was administered at an initial dose of 1125
mg by mouth followed by a 750 mg dose every eight hours thereafter. Peginterferon alfa-2a
was administered subcutaneously at a dose of 180 mcg per week. Ribavirin was given orally
twice daily at a dose of 1000 mg per day for patients weighing less than 75 kg. Patients
weighing greater than 75 kg received ribavirin twice a day at a dose of 1200 mg per day.
T12PR24 group: 116 patients received telaprevir and peginterferon with ribavirin for 12
weeks, followed by placebo and peginterferon and ribavirin for the following 12 weeks.
T24PR48 group: 117 patients were given telaprevir plus peginterferon and ribavirin for 24
weeks, followed by peginterferon and ribavirin for the following 24 weeks.
T24P24 group: 115 patients assigned to this group received telaprevir and peginterferon for
24 weeks.
PR48 group (control): The remaining 117 patients received a placebo plus peginterferon and
ribavirin for 24 weeks, followed up with peginterferon and ribavirin for the remaining 24 weeks.
The primary endpoint was a sustained virologic response defined as an undetectable plasma
HCV RNA concentration at the conclusion of 24 weeks following the final study drug dose.
RESULTS: The results for the primary endpoint of percentage of patients achieving a
sustained virologic response for each group compared to control were as follows: For the
T12PR24 group (53%, P<0.001), T24PR48 group (53%, P<0.001), T23P24 group (54%,
P=0.02). The control group had a sustained virologic response incidence of 14%. The
difference in side effects worth noting between certain groups was as follows: Fatigue (67% in
T12PR24, 61% in T24PR48, 46% in T24P24, and 56% in the control group), pyrexia (24% in
T24PR48 versus 12% in the control group), nausea (48% in T24PR48 versus 34% in the
control group), diarrhea (32% in T12PR24, 43% in T24PR48, 26% in T24P24, and 19% for the
control), hemorrhoids (13%-17% in telaprevir groups versus 3% in the control group), pruritis
(34%-44% in telaprevir groups compared to 15% in the control group), rash-related event
(41%-60% in telaprevir groups versus 20% for control), alopecia (21% in T12PR24, 14% in
T24PR48, 13% in T24P24, compared to 11% for control), insomnia (18%-29% in telaprevir
groups versus 17% for control), and anemia (26% for T12PR24, 27% for T25PR48, 8% for
T24P24, and 8% for control).
CONCLUSION: Based on the study results, the addition of telaprevir to ribavirin plus
peginterferon therapy could be beneficial in achieving a sustained virologic response.
However, among all groups, there was a decrease in the percentage of patients experiencing
a sustained virologic response from the end of the treatment period until 24 weeks after the
end of treatment, which warrants consideration of long-term effectiveness after the treatment
period has ended. The decrease in the percentage of patients having a sustained virologic
response from the time of end of treatment until 24 weeks after treatment was as follows for
the T12PR24, T24PR48, T24P24, PR48 groups respectively: 25%, 14%, 30%, and 16%.
Telaprevir groups were associated with an increased rate of side effects. The amount of
patients dropping out of the study due to adverse events attests to the severity of the side
effects.
COMMENTS: Patients included in the study were similar to patients who would likely receive
therapy. Exclusion criteria included liver disease, and HCV treatment is contraindicated in
6

7. patients with decompensated liver disease. 15 218 of 465 patients dropped out of the study due
to meeting predefined stopping rules due to nonresponse, adverse effects, consent
withdrawal, or other reasons. A 72-week trial is not sufficient to assess the effects of long-term
telaprevir use. Results were interpreted with an intention-to-treat analysis of all patients
receiving at least one dose of study drug. The fact that the primary endpoint is surrogate
rather than clinical may be a limitation of the study, although eradication of HCV infection is the
goal of HCV therapy. Baseline characteristics among groups were similar with two exceptions.
29% of patients in the control group had no or minimal fibrosis while 15%-23% of patients in
the telaprevir groups had none or minimal fibrosis. This reduced percentage could affect the
ability to obtain a sustained response to therapy. In addition, 11% of patients in the control
group had cirrhosis compared to 17%-20% in the telaprevir groups. The variable measured for
the primary endpoint, sustained virologic response was not continuous, and was recorded as
an all-or-none response. Stratification of patients by ethnic group (black versus nonblack) and
previous response to treatment (achievement or no achievement of undetectable RNA levels)
controlled for potential confounding variables. The partially double-blind and partially placebo-
controlled study design used increases the potential for bias, which could have influenced
study results.
CITATION9: Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV
infection. N Engl J Med 2011;364:2417-28.
OBJECTIVE: Assess the efficacy and safety of adding telaprevir to peginterferon and ribavirin
combination treatment in patients with chronic HCV genotype 1 infection who did not have a
sustained virologic response to previous treatment with peginterferon and telprevir.
METHODS: Design: Randomized, double-blind, placebo-controlled, multi-center phase 3
clinical trial. This trial took place over a period of 72 weeks following an enrollment period of
23 months. Patients included in the study were between the ages of 18 and 70 years, had
chronic HCV genotype 1 infection, had no virologic response to a previous peginterferon and
ribavirin treatment regimen despite receiving at least 80% of the dose intended, and had well-
characterized data on previous treatment results. Patients who were eligible for inclusion had
detectable HCV RNA, had undergone a liver biopsy within 18 months prior to screening, and
had an absolute neutrophil count of at least 1200 per cubic milliliter. Other inclusion criteria
were a platelet count of at least 1200 per cubic milliliter and a hemoglobin level of at least 12
g/dL for women and at least 13 g/dL for men. Exclusion criteria were the presence of
decompensated liver disease, other causes of significant liver disease, or active cancer. 883
patients were initially screened and 663 were deemed qualified and subsequently underwent
randomization into one of three treatment groups (Telaprevir, when administered, was
administered orally as a dose of 750 mg every 8 hours, peginterferon alfa-2a was given
subcutaneously at a dose of 180 mcg per week, and ribavirin was administered orally at a
dose of 1000 to 1200 mg daily.
Group 1: 266 patients were assigned to be administered telaprevir, peginterferon, and ribavirin
for 12 weeks, followed by placebo plus peginterferon and ribaivirin for 4 weeks, and finally
peginterferon and ribavirin alone for 32 weeks.
Group 2: 264 patients received a lead-in phase consisting of placebo, peginterferon, and
ribavirin for 4 weeks, followed by telaprevir plus interferon and ribavirin therapy for 12 weeks,
and then peginterferon plus riabavirin alone for 32 weeks.
Group 3 (control group): 132 patients were anticipated to receive placebo, peginterferon, and
ribavirin for 16 weeks, followed by peginterferon plus ribavirin for 32 weeks. The primary end
point was the proportion of patients with either a previous relapse or a lack of previous
response who had a sustained virologic response following study treatment. The virologic
7

8. response was defined as an undetectable plasma HCV RNA 24 weeks after the last planned
administration of study drug. This was a surrogate endpoint.
Patients were stratified according to baseline viral load (HCV RNA <800,000 or ≥800,000 IU
per milliliter) and type of previous resonse to peginterferon and ribavirin therapy (no response,
some response, or relapse). No response was defined as a reduction of less than 2 log 10 or
more in HCV RNA after 12 weeks of therapy. Partial response was defined as a reduction of
at least 2 log10 or greater in HCV RNA following 12 weeks of therapy. Finally, relapse was
defined as detection of HCV after the patient had an undetectable level of HCV RNA following
a previous course of treatment.
RESULTS: At 24 weeks after the last planned administration of study drug, 83% of patients in
group 1 who had experienced a previous relapse exhibited a sustained virologic response.
88% of patients in group 2 had a sustained virologic response. These percentages are
compared to 24% for the control group. For those patients with a lack of a previous virologic
response, percentages of sustained virologic response for the three treatment groups were as
follows for groups 1, 2, and control respectively: (41%, 41%, and 9%). The previous
percentages include patients with a partial previous virologic response or no response. The P-
value for all comparisons is <0.001 which provides statistically significant evidence that
addition of telaprevir is effective in increasing the proportion of patients with a sustained
virologic response. Overall, the groups receiving telaprevir were associated with a greater
proportion of patients experiencing any adverse event. There was a higher percentage of
patients achieving a sustained virologic response that also had a previous virologic response
compared to patients with no previous response to patients. Rash was an adverse event of
interest because is caused the largest amount of patients to discontinue therapy. In the two
telaprevir groups, 4% of patients discontinued telaprevir and 1% of patients discontinued all
drugs because of rash. No patients in the control group discontinued due to rash. Anemia
was more frequent in both telaprevir groups than the control group (2%, 3%, 1% for groups 1,
2, and 3 respectively). In both telaprevir groups, 1% and 3% experienced neoplasm compared
to 0% in the control group. Cardiac disorder of any type were slightly more frequent in the two
telaprevir groups (2% and 1%) than in the control group (1%). It is difficult to determine if this
is caused by telaprevir since the difference between groups is not very large and no patient
data on existing cardiac disorders were discussed in the trial. The frequency of adverse
events appears to be of no significant difference between the peginterferon and ribavirin lead-
in group and the non-lead-in group.
CONCLUSION: The addition of telaprevir to ribavirin and peginterferon therapy in patients with
relapse or lack of previous response to previous treatment appears to reduce the HCV RNA
levels to undetectable levels in more patients as compared to ribavirin and peginterferon
alone. Although this is a surrogate endpoint, eradication of infection is commonly used to
assess HCV infection therapy. Overall, failure rates of virologic response were lower in
patients with previous a relapse of partial response than in those patients with no response to
previous treatment. Because the primary endpoint was measured in patients with no previous
response or only a partial response the previous therapy, it is not known how previous
exposure to these agents may have affected individual patients’ responses. HCV RNA levels
are a surrogate endpoint and may not reflect clinical significance of adding telaprevir.
Telaprevir may be associated with rash, pruritis, and more severe adverse events such as
anemia and neoplasms.
COMMENTS: The length of the trial is not adequate for monitoring long-term response to
treatment. 24-week follow up after treatment provided more information on the absence or
presence of undetectable HCV RNA levels, but is still not sufficient to detect long-term effects.
A strength of the study is that patients were stratified into groups based on viral load and type
of previous response to therapy. The clinical trial was double-blinded, which reduces bias.
Randomization eliminates variability in patients due to factors other than chance. This acts as
8

9. a form of control for confounding variables. Intention-to-treat analysis provides conservative
results. P-values were not reported for all comparisons of undetectable viral levels between
groups in a clear table format. This can be misleading. Including patients with different
baseline HCV RNA levels revealed that there was no significant association between the
baseline viral load and sustained virologic response. On the other hand, fine print in the study
revealed the patient’s stage of liver fibrosis had a significant effect on the primary endpoint,
specifically for patients who had no response or a partial response to previous treatment. The
end-point of undetectable viral load is all-or-none. Previous cardiac conditions of patients
were not mentioned, and cardiac disorders occurred in both telaprevir as well as control
groups. The study only included patients who have failed previous treatment but no newly
diagnosed patients. Previous treatment may have an unknown influence on cure rates
presented in the study. The presence of IL-28B gene polymorphisms has been demonstrated
to be a predictor of response to peginterferon and ribavirin therapy. Patients were not grouped
according to the presence of this gene because this association was now known at the time of
enrollment.
SAFETY AND TOLERABILITY:
CONTRAINDICATIONS: Telaprevir in conjunction with inteferon-alpha and ribavirin should not
be used in female patients who are either pregnant or have a chance of becoming pregnant,
and it is also contraindicated in men who have female partners that are currently pregnant. 1,13
Telaprevir combination therapy is also contraindicated with the use of other drugs that
significantly utilize or induce the CYP3A4 enzyme which includes the following drugs:
alfuzosin, cisapride, dihydroergotamine, ergonovine, ergotamine, methylergonovine,
atorvastatin, lovastatin, simvastatin, midazolam, pimozide, sildenafil or tadalafil (when used for
treatment of pulmonary arterial hypertension), triazolam, rifampin, and St. John’s wort. 1,13
WARNINGS AND PRECAUTIONS: Telepravir/peginterferon-alfa/ribavirin combination therapy
carries a pregnancy category X label, and a fetus exposed to the drug has an increased risk
for birth defects and death. Because of the high teratogenic effects, females and male
partners taking telaprevir have to take added precautions to avoid pregnancy. 1,13 Two non-
hormonal contraceptive techniques should be used during the duration of drug treatment and
at least six months after therapy concludes. Hormonal contraceptives may be uneffective
during telaprevir combination treatment until two weeks after discontinuation. 2 In addition,
females should present a negative pregnancy test before starting telaprevir and take monthly
pregnancy tests until six months after stopping the drug. 1,13
Patients should be monitored for symptoms of serious skin reactions such as Stevens-
Johnson sydrome. If a patient exhibits symptoms that appear to be systemic in nature or show
signs of eosinophilia, the patient should be immediately hospitalized for treatment and
discontinue telaprevir combination therapy. 1,13 In addition, 56% of studied patients developed
less serious rashes. Patients who experience rash-like symptoms should be monitored for
worsening of symptoms into severe conditions or systemic effects. 1,13 If the rash becomes
severe, the patient should immediately seek treatment and discontinue telaprevir.
Peginteferon-alpha and ritonavir can be continued unless rash symptoms do not improve after
seven days of discontinuing telaprevir.1 Rash-like symptoms can be present at any time during
treatment but commonly first appear in the first 4 weeks of treatment. 2
Treatment with telaprevir causes an increased risk of anemia compared to treatment with
peginteferon-alpha and ribavirin alone. Patients should have their hemoglobin levels assessed
every 4 weeks during combination therapy. 1 In patients who experience anemia, reduce the
9

10. dose of ribavirin, but if improvement is not sufficient, the discontinuation of telaprevir is
recommended. Ribavirin cannot be discontinued for the treatment of anemia without also
stopping telaprevir simultaneously. 1
Blood tests monitoring HCV-RNA concentrations should be completed on weeks 4 and 12 of
therapy to determine treatment response and optimal further treatment methods after the
completion of telaprevir. The recommended lower limit of the test monitoring HCV-RNA is 25
IU/mL, and the detection range should be pre-set between 10-15 IU/mL. A test result that is
below the suggested range but is still detectable should not be considered as undetectable
when assessing treatment response. 1
Caution should be exercised in patients with hepatic dysfunction (See Dosing). Telaprevir
should never be given without also prescribing peginterferon-alfa and ribavirin, so it is
suggested to also look over their prescribing information before beginning treatment. 1
ADVERSE DRUG EFFECTS: Patients receiving treatment with telaprevir experience similar
side effects to patients taking peginterferon-alpha 2b and ribavirin; however, telaprevir appears
to increase the frequency of these adverse reactions. The most commonly reported adverse
effects in telaprevir combination therapy are pruritus (56%), rash (56%), and fatigue (56%)
compared to 28%, 34%, and 50% respectively, when compared to peginterferon-alpha 2b and
ribavirin dual treatment. 1,2,4 Other common adverse effects of telaprevir compared to
peginterferon and ribavirin include gastrointestinal effects such as anorectal pain (11%,3%),
diarrhea (26%,17%), hemorrhoids (12%,3%), nausea (39%, 28%), anal pruritus (6%,1%),
altered taste (10%,3%), and vomiting (13%, 8%). 1,2,4 While no subjects taking only
peginterferon-alpha 2b and ribiavirin therapy experienced serious side effects, 3% of patients
on telaprevir combination therapy experienced serious side effects. 2 Serious side effects of
telaprevir are hypersensitivity skin reactions (<1%), Stevens-Johnson syndrome (<1%), and
anemia (36%).2,4 Patients on peginterferon and ribavirin also experienced anemia (17%), but
telaprevir increased the severity of the anemia in addition to the incidence. 1
DRUG INTERACTIONS: The following drugs result in unsafe elevations in plasma
concentrations when co-administered with telaprevir. They are contraindicated with telaprevir
and should be discontinued:1,2
• Alfuzosin
• Cisapride
• Ergot derivatives (ergonovine, ergotamine, methylergonovine, dihydroergotamine)
• HMG CoA recuctase inhibitors (atorvastatin, lovastatin, simvastatin)
• Sedative-hypnotics (midazolam, triazolam)
• Pimozide
• PDE5 inhibitors (sildenafil, tadalafil) when used for treatment of pulmonary arterial
hypertension
• Rifampin
• St. John’s wort.
The following drugs are not contraindicated with telaprevir, but it is recommended that they
should be discontinued or replaced with an alternate therapy: 1,2
• Corticosteroids (budesonide, fluticasone, dexamethasone, methylprednisolone, and
prednisone) have elevated plasma levels. Dexamethasone can decrease plasma
concentrations of telaprevir.
• Darunavir/ritonavir and fosamprenavir/ritonavir reduce the steady-state exposure of
telaprevir.
• Lopinavir and ritonavir reduce the steady-state exposure of telaprevir.
10

11. • Rifabutin has an increased plasma concentration and reduces the plasma
concentration of telaprevir.
• Salemeterol has elevated plasma concentrations.
The therapeutic concentrations of the following drugs when co-administered with telaprevir
should be monitored and potentially adjusted as stated: 1,2
• Antiarrhythmic agents (amiodarone, bepridil, flecainide, lidocaine, propafenone, and
quinidine) have elevated plasma concentrations.
• Anticonvulsants (carbamazepine, phenobarbital, and phenytoin) have varied plasma
concentrations and decrease the concentration of telaprevir.
• Antidepressants (desipramine and trazodone) have elevated plasma concentrations. A
lower dose of the antidepressant may be necessary.
• Atazanavir and ritonavir reduce the steady-state exposure of telaprevir.
• Azole antifungal agents (itraconazole, ketoconazole, posaconazole, and voriconazole)
have varied plasma concentrations and increase the plasma concentration of telaprevir.
Doses of ketoconazole and itraconazole are not recommended to exceed 200mg/day.
• Benzodiazepines (alprazolam) has elevated plasma concentrations.
• Calcium channel blockers (amlodipine, diltiazem, felodipine, nicardipine, nifedipine,
nisoldipine, and verapamil) have elevated plasma concentrations.
• Colchicine has elevated plasma concentrations. A dose reduction is recommended,
and avoid use in renally and hepatically compromised patients.
• Digoxin has elevated plasma concentrations. Begin digoxin therapy with the lowest
dose and titrate up while observing plasma concentrations.
• Efavirnez reduces the steady-state exposure of telaprevir.
• Escitalopram has reduced plasma concentrations. Adjust the dose as clinically
necessary.
• Hormone contraceptives have reduced efficacy.
• Immunosuppressive agents (cyclosporine, sirolimus, and tacrolimus) have increased
plasma concentrations. Dose reductions and increased time between administration
may be required.
• Macrolide antibiotics (clarithromycin, erythromycin, and telithromycin) have elevated
plasma concentrations and increase the plasma concentrations of telaprevir.
• Methadone has reduced plasma concentrations.
• PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) when used for the treatment of
erectile dysfunction should not exceed 25mg/48hrs for sildenail, 10mg/72hrs for
tadalafil, and 2.5mg/72hrs in vardenafil.
• Tenofovir disoproxil fumarate may cause an increased risk for tenovir toxicity.
Discontinue if toxicity develops.
• Warfarin plasma concentrations may be altered. Dose adjustments may be necessary
according to INR results.
• Zolpidem has reduced plasma concentrations.
MEDICATION ERROR POSSIBILITY10,13:
Telaprevir could potentially be mistakenly prescribed as monotherapy for treatment of chronic
HCV. No medication error related ADEs have been reported through ISMP or Lexi-Comp. 10,13
DOSING:
11

12. The recommended oral dose of telaprevir in adults is 750mg given three times daily, and
treatment should be given simultaneously with inteferon-alpha and ribaviron therapy over a
period of 12 weeks. 1,2,13 Doses of telaprevir should be taken within 30 minutes of a fatty meal
(≥ 20g of fat) to be most effective. 13 Throughout the 12 week treatment duration, the dose of
telaprevir should not be decreased or altered to ensure treatment success, but discontinuation
should be considered when HCV-RNA levels reach or exceed 1000 IU/mL . Once
discontinued, telaprevir should not be restarted. 1
Special Populations:
Pediatric: Telaprevir is not approved for use in pediatric patients. 1
Geriatric: There is no recommended adjustment from the usual adult dose, but caution
and careful observation is suggested. 1
Renal dysfunction: There is no recommended adjustment for renal impairment. 1
Hepatic dysfunction: For patients with mild hepatic dysfunction (Child-Pugh A), the dose of
telaprevir does not need to be adjusted. Telaprevir has not been studied in individuals with
more severe hepatic dysfunction (Child-Pugh class B-C), and its use should be avoided in
these patients.1,13
Lactation: Before initiation of treatment, breast-feeding should be stopped. 2
Co-infection: Safety of use in patients who are co-infected with HCV/HIV or HCV/HBV has
not been sufficiently determined. 1
BUDGET IMPACT: 4,6,11
Telaprevir Peginterferon alpha-2b and
Ribavirin*
AWP (unit price) $117.14 (350 mg) peginterferon: $691.92 (120
mcg)**
ribavirin ***: $9.93 (200 mg)
Recommended Dosing 750 mg every 7-9 hours for 12 peginterferon: 1.5 mcg/kg/week
weeks ribavirin: 200 mg 4-7 times daily
depending on body weight
Average cost for 12 $59,040 peginterferon: $8,303.04
weeks of therapy ribavirin: $4,170.60
** Based on a body weight of 76-85 kg for which recommended dose of peginterferon
per week is 120 mcg.
*** Telaprevir is only recommended for use with ribavirin and peginterferon. The cost of
telaprevir would be added to the cost of ribavirin and peginterferon.
REFERENCES:
1. Incivek®. [package insert]. Cambridge, MA: Vertex Pharmaceuticals Inc; 2011.
2. Telaprevir. Drug Facts and Comparisons. Drug Facts and Comparisons eAnswers.
Wolters Kluwer Health, Inc. St. Louis, MO. Available at:
http://www.factsandcomparisons.com. Accessed October 10, 2011.
12

13. 3. AHFS Drug Information. New Drug Assignments and Reassignments for 2011.
Available at: http://www.ahfsdruginformation.com/class/changes.aspx. Accessed
October 15, 2011.
4. Telaprevir. Micromedex 2.0. Thomson Micromedex. Greenwood Village, CO.
Available at: http://www.thomsonhc.com.
5. Peginterferon alfa-2b. Drug Facts and Comparisons. Drug Facts and Comparisons
eAnswers. Wolters Kluwer Health, Inc. St. Louis, MO. Available at:
http://www.factsandcomparisons.com. Accessed October 16, 2011.
6. Ribavirin. Drug Facts and Comparisons. Drug Facts and Comparisons eAnswers.
Wolters Kluwer Health, Inc. St. Louis, MO. Available at:
http://www.factsandcomparisons.com. Accessed October 16, 2011.
7. Jacbson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated
chronic hepatisis C virus infection. N Engl J Med 2011; 364: 2405-16.
8. McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previously treated chronic
HCV infection. N Engl J Med 2010;362:1292-303.
9. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N
Engl J Med 2011;364:2417-28.
10. Institute for Safe Medication Practices. ISMP’s List of Confused Drug Names.
Available at: http://www.ismp.org. Accessed November 6, 2011.
11. Red Book® Online Search Results. Red Book® Online. Thomson Micromedex.
Greenwood Village, CO. Available at: http://www.thomsonhc-com. Accessed
November 6, 2011.
12. Hezode C, Forestier N, Dusheiko, G, et al. Telaprevir and peginterferon with or without
ribavirin for chronic HCV infection. N Engl J Med 2009; 360:1839-50.
13. Telaprevir. Lexi-Drugs Online. Lexi-Comp Online. Lexi-Comp Inc. Hudson, OH.
Available at: http://online.lexi.com. Accessed November 6, 2011.
14. Pegintron®. [package insert]. Whitehouse Station, NJ: Schering Corporation; 2011.
15. Deming P. Viral Hepatitis. In: Pharmacotherapy: A Pathophysiologic Approach. 8th
Ed. DiPiro JT, Talbert RL, Yee GC, et. al, eds. Chicago, IL: McGraw Hill Companies,
Inc; 2011.
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