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Drug Monograph


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Drug formulary monograph describing basic information, dosing, pharmacology, clinical trials, warnings/precuations, cost analysis, and recommendations concerning Telaprevir, an oral antiretroviral medication.

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Drug Monograph

  1. 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: 8:18.40Storage: 1 Keep at 25ºC (77ºF) with excursions permitted to 15-30ºC (59-86ºF). Use within 28days after opening package. Keep bottle tightly closed.SUMMARY:Telaprevir is a protease inhibitor that prevents the replication of HCV. 2,3 By preventing theHCV NS3/4A serine protease, proteins that are encoded by the virus necessary for HCVreplication are unable to be cleaved into their mature forms. 2 Telaprevir is indicated for thetreatment of genotype 1 chronic hepatitis C in adults with compensated liver disease who havenot received prior treatment or have been previously treated only with interferon-basedtherapy. Telaprevir is only indicated for use as an adjunct to PegIntron® (peginterferon-alpha2b) and Rebetol® (ribavirin) combination therapy and should never be prescribed alone. 1,2,4Current formulary agents for the treatment of chronic hepatitis C include peginterferon-alpha2b for use as a single agent or as a dual therapy with ribavirin. Peginterferon-ribavirincombination therapy is indicated for use in patients over 3 years old with chronic hepatitis Cand compensated liver disease. 5 Peginterferon-alpha 2b limits the replication of HCV byinducing the antiviral immune response through the activation of the type 1 interferonreceptor.5 Ribavirin acts as a purine analog that has direct antiviral activity; however, theoverall mechanism of combination therapy is not completely understood. 6Several clinical studies have shown an increased virological response to telaprevir combinationtherapy compared to peginterferon-alpha 2b and ribavirin dual therapy alone. In one clinicalstudy, 1088 previously untreated subjects were divided into groups receiving telaprevircombination 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% ofsubjects respectively, when measured 24 weeks after the last treatment. 7 Another studydivided subjects who had been previously treated for HCV into groups receiving telaprevircombination therapy for 12 weeks followed by 12 weeks of dual therapy, telaprevir for 24weeks followed by 24 weeks of dual therapy, telaprevir for 24 weeks, and a control groupusing dual therapy for 48 weeks. The amount of patients achieving a sustained virologicresponse was 53% (p<0.001), 54% (p<0.001), 54% (p=0.02), and 14% respectively. 8 Anotherstudy demonstrated the effect of telaprevir on patients who relapsed with previouspeginterferon-ribavirin treatments. Patients who were given telaprevir combination therapy for12 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 achieved88% with a sustained response (p<0.001). Comparatively, the patients in the control who werenot given telaprevir showed 24% with a sustained response. 9The 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 effectsappears to be somewhat questionable, as 14% of subjects discontinued telaprevir due to 1
  2. 2. negative side effects. 2 Since telaprevir is indicated as a combination therapy, patients will alsobe subjected to the adverse effects of the additional medications. Patients undergoingtreatment with peginterferon-alpha 2b and ribavirin therapy experienced similar types of sideeffects as caused by telaprevir, but the addition of telaprevir increased the incidence of theseside effects. 1,2,5 There are no black box warnings associated with telaprevir or significant errorsreported through ISMP.1,2,10The cost of telaprevir is significantly more than the cost of peginterferon-alpha 2b and ribavirintherapy. A 12 week course of treatment with telaprevir costs $59,040 plus the cost ofpeginterferon at $8,303.04 and ribavirin at $4,170.60. 4,6,11RECOMMENDATION:Telaprevir should be added to the formulary. This conclusion is based on several factorsincluding decreased time to demonstrate a virologic response and an increased proportion ofpatients achieving a sustained virologic response. A shorter duration of treatment alsoinfluenced the recommendation to add telaprevir. This increase in positive outcomesoutweighs the increased cost associated with adding the drug to formulary. While telaprevir isassociated with a greater incidence of side effects, those side effects are similar to thoseexperienced by patients receiving only the current therapy. 7,8,9 Peginterferon alpha andribavirin should still be included on the formulary because telaprevir is only indicated for use asan adjunct with these two medications. 1,2DESCRIPTION AND PHARMACOLOGY4-6,12:Telaprevir is a direct-acting antiviral agent that is an inhibitor of the HCV NS3/4A serineprotease enzyme. This protease is responsible for cleavage of HCV polyprotein into activeforms of the NS4A, NS4B, NS5A, and NS5B proteins necessary for the replication of the virusparticle. In a biochemical assay, telaprevir had an IC50 of 10 nM for inhibition of therecombinant HCV NS3 protease domain. 4Peginterferon alpha-2b induces the antiviral response of the innate immune system. It binds toand activates the human type 1 interferon receptor, activating multiple signal transductionpathways including regulation of transcription. The recommended dose for peginterferonalpha-2b monotherapy is 1 mcg/kg/wk for one year. It is often used in combination withribavirin, whose mechanism of action is not fully established but is known to possess antiviralactivity. 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 onlyapproved for co-therapy with peginterferon alpha-2b and ribavirin. In the Protease Inhibition forViral Evaluation 1 trial (PROVE 1) and PROVE 2 trials involving HCV genotype 1 patients withno previous treatment, the rates of prolonged virologic response were 61% and 69%,respectively for PROVE 1 and PROVE 2 after a 12-week course oftelaprevir/ribavirin/peginterferon followed by peginteferon-ribavirin therapy continuing for anadditional 12 weeks. The addition of telaprevir reduced the median time to achieve anundetectable (<50 units/mL) HCV level (<30 days rather than 113 days). This may be oneadvantage of addition of telaprevir. Telaprevir is administered during the first twelve weeks oftherapy 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 withpeginterferon and ribavirin will decrease the total duration of therapy associated with telaprevirmonotherapy (from one year to twenty-four or forty-eight weeks). However, telaprevir is giventhree times daily in contrast to peginterferon montherapy during which medication isadministered once a week. A disadvantage of telaprevir may be the increased prevalence ofside effects. In patients receiving the three-drug combination therapy, the most common side 2
  3. 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 withribavirin-peginterferon dual therapy, although addition of telaprevir increased the percentage ofpatients reporting these side effects. Responsiveness to treatment regardless of therapy usedrequires monitoring by measuring HCV RNA levels among other clinical methods ofassessment.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. 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). 2INDICATIONS1,14: 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 thetreatment of genotype 1 chronic hepatitis C (CHC) in adult patients with compensated liverdisease, including cirrhosis, who are treatment-naïve or who have been previously treated withinterferon-based treatment, including prior null responders, partial responders, and relapsers.Telaprevir must not be used as monotherapy and must only be used in combination withpeginterferon alfa and ribavirin. A high proportion of previous null responders (particularlythose with cirrhosis) did not achieve Sustained Virologic Response (SVR) and had telaprevirresistance-associated substitutions emerge on treatment with INCIVEK. Telaprevir efficacyhas not been established for patients who have previously failed therapy with a treatmentregimen 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 chronichepatitis C and is not limited to genotype 1 HCV infection.CLINICAL TRIALS:CITATION:7 Jacbson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previouslyuntreated chronic hepatisis C virus infection. N Engl J Med 2011; 364: 2405-16.OBJECTIVE: To compare the efficacy and safety of telaprevir in combination withpeginterferon-ribavirin to peginterferon-ribavirin therapy alone for the treatment of HCV inpreviously untreated patients. METHODS: The study was a phase 3, randomized, double-blind, placebo-controlled trial thatlasted either 24 or 48 weeks, depending on patients’ HCV RNA plasma concentrations atweeks 4 and 12. The trial assessed 1088 patients who had not been previously treated forHCV. Patients were included in the study if they were between 18 and 70 years of age, hadHCV genotype 1 infection with evidence of chronic hepatitis, compensated liver cirrhosis,seronegativity for hepatitis B surface antigen, absence of antibodies against humanimmunodeficiency virus types 1 and 2, absolute neutrophil counts of 1500 or more per cubicmillimeter, platelet counts of 90,000 or more per cubic millimeter, and hemoglobin levels of atleast 12 g per deciliter in women or 13 g per deciliter in men. Exclusion criteria weredecompensated liver disease, liver disease from other causes, and hepatocellular carcinoma.Participants in the active treatment groups were given oral doses of 750mg telaprevir every 8hours with food. In addition, participants were also given 180mcg peginterferon alfa-2asubcutaneously every week and oral doses of either 1000mg or 1200mg ribavirin dailydepending on patient weight.PR group (control): 361patients received only peginterferon-ribavirin treatment and placebothroughout the study duration. 4
  5. 5. T12PR group: 363 patients received telaprevir and peginterferon-ribavirin treatment for thefirst 12 weeks.T8PR group: 364 patients received telaprevir for 8 weeks followed by 4 weeks of placebo andpeginterferon-ribavirin for the first 12 weeks.Following the initial 12 week treatment period, participants in both active groups that hadundetectable HCV RNA plasma concentrations at weeks 4 and 12 received additionaltreatment with peginterferon-ribavirin therapy alone for 12 weeks. Participants that haddetectable HCV RNA levels were given peginterferon-ribavirin therapy alone for an additional36 weeks. The primary endpoint of the trial was the proportion of participants whose plasmaconcentrations 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, and44% 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 indiscontinuation of telaprevir treatment. Development of a serious rash caused discontinuationof 7% in T12PR and 5% in T8PR, and anemia caused discontinuation of treatment in 4% ofT12PR and 2% of T8PR. One case of Stevens-Johnson syndrome was reported.CONCLUSION: The data suggests the addition of telaprevir to peginterferon-ribavirin therapyis more effective at treating chronic hepatitis C infections, as evidenced by decreased HCVRNA 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 8weeks, and a 12 week treatment course only slightly increases the amount of adverse effectsover an 8 week treatment. In addition to being a more effective treatment method, telaprevirwas shown to cause a decreased occurrence of relapse throughout the trial duration comparedto the control group. Treatment with telaprevir increased the risk for anemia and relativelyserious skin reactions which should be considered before starting therapy.COMMENTS: The study is limited to patients who have not received prior treatment for HCVwhich could limit the generalizability of the results. The clinical trial does not provide efficacydata beyond 72 weeks, so there is limited knowledge about the long-term benefits of therapywith telaprevir or the need for re-treatment. Since post-telaprevir therapy was determined byHCV RNA levels at weeks 4 and 12, a potential confounding variable is that patients did nothave a uniform duration of treatment even within the same treatment groups. Sustained lowHCV concentrations could be contributed to longer treatment with peginterferon-ribavirin thantelaprevir itself. In addition, the authors did not discuss the strengths and limitations of theirstudy design.CITATION8,15: McHutchison JG, Manns MP, Muir AJ, et al. Telaprevir for previouslytreated chronic HCV infection. N Engl J Med 2010;362:1292-303.OBJECTIVE: Assess the efficacy and safety of telaprevir therapy in patients previously treatedfor HCV infection who did not have a sustained virologic response to a full-course regimen ofpeginterferon alfa-2a and ribavirin therapy.METHODS: The study design was a randomized, multi-center stratified, 72-week, partiallyplacebo-controlled, partially double-blind, phase 2 clinical trial. After screening for criteriarequirements, 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 ribavirinbut did not have achieve a sustained virologic response. Sustained virologic response was 5
  6. 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 levelsduring the course of treatment but appearance of detectable levels before the end oftreatment). Other inclusion criteria were: Negative results from plasma test for hepatitis Bsurface antigen and antibodies against HIV type 1 and 2 viruses, an absolute neutrophil countof 1500 or more/cubic mL, a platelet count of 100,000 or more/cubic mL, and normal bilirubinvalues. In addition, patients need to have had a liver biopsy within 3 years of studycommencement. Exclusion criteria included decompensated liver disease, hepatocellularcarcinoma, or any other clinical liver disease. Patients were divided into four groups. Dosageof individual medications is as follows: Telaprevir was administered at an initial dose of 1125mg by mouth followed by a 750 mg dose every eight hours thereafter. Peginterferon alfa-2awas administered subcutaneously at a dose of 180 mcg per week. Ribavirin was given orallytwice daily at a dose of 1000 mg per day for patients weighing less than 75 kg. Patientsweighing 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 12weeks, followed by placebo and peginterferon and ribavirin for the following 12 weeks.T24PR48 group: 117 patients were given telaprevir plus peginterferon and ribavirin for 24weeks, followed by peginterferon and ribavirin for the following 24 weeks.T24P24 group: 115 patients assigned to this group received telaprevir and peginterferon for24 weeks.PR48 group (control): The remaining 117 patients received a placebo plus peginterferon andribavirin 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 plasmaHCV 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 asustained virologic response for each group compared to control were as follows: For theT12PR24 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%. Thedifference in side effects worth noting between certain groups was as follows: Fatigue (67% inT12PR24, 61% in T24PR48, 46% in T24P24, and 56% in the control group), pyrexia (24% inT24PR48 versus 12% in the control group), nausea (48% in T24PR48 versus 34% in thecontrol group), diarrhea (32% in T12PR24, 43% in T24PR48, 26% in T24P24, and 19% for thecontrol), 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% inT24PR48, 13% in T24P24, compared to 11% for control), insomnia (18%-29% in telaprevirgroups versus 17% for control), and anemia (26% for T12PR24, 27% for T25PR48, 8% forT24P24, and 8% for control).CONCLUSION: Based on the study results, the addition of telaprevir to ribavirin pluspeginterferon therapy could be beneficial in achieving a sustained virologic response.However, among all groups, there was a decrease in the percentage of patients experiencinga sustained virologic response from the end of the treatment period until 24 weeks after theend of treatment, which warrants consideration of long-term effectiveness after the treatmentperiod has ended. The decrease in the percentage of patients having a sustained virologicresponse from the time of end of treatment until 24 weeks after treatment was as follows forthe T12PR24, T24PR48, T24P24, PR48 groups respectively: 25%, 14%, 30%, and 16%.Telaprevir groups were associated with an increased rate of side effects. The amount ofpatients dropping out of the study due to adverse events attests to the severity of the sideeffects.COMMENTS: Patients included in the study were similar to patients who would likely receivetherapy. Exclusion criteria included liver disease, and HCV treatment is contraindicated in 6
  7. 7. patients with decompensated liver disease. 15 218 of 465 patients dropped out of the study dueto meeting predefined stopping rules due to nonresponse, adverse effects, consentwithdrawal, or other reasons. A 72-week trial is not sufficient to assess the effects of long-termtelaprevir use. Results were interpreted with an intention-to-treat analysis of all patientsreceiving at least one dose of study drug. The fact that the primary endpoint is surrogaterather than clinical may be a limitation of the study, although eradication of HCV infection is thegoal 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 inthe telaprevir groups had none or minimal fibrosis. This reduced percentage could affect theability to obtain a sustained response to therapy. In addition, 11% of patients in the controlgroup had cirrhosis compared to 17%-20% in the telaprevir groups. The variable measured forthe primary endpoint, sustained virologic response was not continuous, and was recorded asan all-or-none response. Stratification of patients by ethnic group (black versus nonblack) andprevious 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 influencedstudy results.CITATION9: Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCVinfection. N Engl J Med 2011;364:2417-28.OBJECTIVE: Assess the efficacy and safety of adding telaprevir to peginterferon and ribavirincombination treatment in patients with chronic HCV genotype 1 infection who did not have asustained virologic response to previous treatment with peginterferon and telprevir.METHODS: Design: Randomized, double-blind, placebo-controlled, multi-center phase 3clinical trial. This trial took place over a period of 72 weeks following an enrollment period of23 months. Patients included in the study were between the ages of 18 and 70 years, hadchronic HCV genotype 1 infection, had no virologic response to a previous peginterferon andribavirin 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 haddetectable HCV RNA, had undergone a liver biopsy within 18 months prior to screening, andhad an absolute neutrophil count of at least 1200 per cubic milliliter. Other inclusion criteriawere a platelet count of at least 1200 per cubic milliliter and a hemoglobin level of at least 12g/dL for women and at least 13 g/dL for men. Exclusion criteria were the presence ofdecompensated liver disease, other causes of significant liver disease, or active cancer. 883patients were initially screened and 663 were deemed qualified and subsequently underwentrandomization into one of three treatment groups (Telaprevir, when administered, wasadministered orally as a dose of 750 mg every 8 hours, peginterferon alfa-2a was givensubcutaneously at a dose of 180 mcg per week, and ribavirin was administered orally at adose of 1000 to 1200 mg daily.Group 1: 266 patients were assigned to be administered telaprevir, peginterferon, and ribavirinfor 12 weeks, followed by placebo plus peginterferon and ribaivirin for 4 weeks, and finallypeginterferon and ribavirin alone for 32 weeks.Group 2: 264 patients received a lead-in phase consisting of placebo, peginterferon, andribavirin 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, andribavirin for 16 weeks, followed by peginterferon plus ribavirin for 32 weeks. The primary endpoint was the proportion of patients with either a previous relapse or a lack of previousresponse who had a sustained virologic response following study treatment. The virologic 7
  8. 8. response was defined as an undetectable plasma HCV RNA 24 weeks after the last plannedadministration of study drug. This was a surrogate endpoint.Patients were stratified according to baseline viral load (HCV RNA <800,000 or ≥800,000 IUper 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 ormore in HCV RNA after 12 weeks of therapy. Partial response was defined as a reduction ofat least 2 log10 or greater in HCV RNA following 12 weeks of therapy. Finally, relapse wasdefined as detection of HCV after the patient had an undetectable level of HCV RNA followinga previous course of treatment.RESULTS: At 24 weeks after the last planned administration of study drug, 83% of patients ingroup 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 arecompared to 24% for the control group. For those patients with a lack of a previous virologicresponse, percentages of sustained virologic response for the three treatment groups were asfollows for groups 1, 2, and control respectively: (41%, 41%, and 9%). The previouspercentages 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 thataddition of telaprevir is effective in increasing the proportion of patients with a sustainedvirologic response. Overall, the groups receiving telaprevir were associated with a greaterproportion of patients experiencing any adverse event. There was a higher percentage ofpatients achieving a sustained virologic response that also had a previous virologic responsecompared to patients with no previous response to patients. Rash was an adverse event ofinterest because is caused the largest amount of patients to discontinue therapy. In the twotelaprevir groups, 4% of patients discontinued telaprevir and 1% of patients discontinued alldrugs because of rash. No patients in the control group discontinued due to rash. Anemiawas 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 comparedto 0% in the control group. Cardiac disorder of any type were slightly more frequent in the twotelaprevir groups (2% and 1%) than in the control group (1%). It is difficult to determine if thisis caused by telaprevir since the difference between groups is not very large and no patientdata on existing cardiac disorders were discussed in the trial. The frequency of adverseevents 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 withrelapse or lack of previous response to previous treatment appears to reduce the HCV RNAlevels to undetectable levels in more patients as compared to ribavirin and peginterferonalone. Although this is a surrogate endpoint, eradication of infection is commonly used toassess HCV infection therapy. Overall, failure rates of virologic response were lower inpatients with previous a relapse of partial response than in those patients with no response toprevious treatment. Because the primary endpoint was measured in patients with no previousresponse or only a partial response the previous therapy, it is not known how previousexposure to these agents may have affected individual patients’ responses. HCV RNA levelsare 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 asanemia and neoplasms.COMMENTS: The length of the trial is not adequate for monitoring long-term response totreatment. 24-week follow up after treatment provided more information on the absence orpresence 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 typeof 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. 9. a form of control for confounding variables. Intention-to-treat analysis provides conservativeresults. P-values were not reported for all comparisons of undetectable viral levels betweengroups in a clear table format. This can be misleading. Including patients with differentbaseline HCV RNA levels revealed that there was no significant association between thebaseline viral load and sustained virologic response. On the other hand, fine print in the studyrevealed 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. Theend-point of undetectable viral load is all-or-none. Previous cardiac conditions of patientswere not mentioned, and cardiac disorders occurred in both telaprevir as well as controlgroups. The study only included patients who have failed previous treatment but no newlydiagnosed patients. Previous treatment may have an unknown influence on cure ratespresented in the study. The presence of IL-28B gene polymorphisms has been demonstratedto be a predictor of response to peginterferon and ribavirin therapy. Patients were not groupedaccording to the presence of this gene because this association was now known at the time ofenrollment.SAFETY AND TOLERABILITY:CONTRAINDICATIONS: Telaprevir in conjunction with inteferon-alpha and ribavirin should notbe 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. 1,13Telaprevir combination therapy is also contraindicated with the use of other drugs thatsignificantly 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 fortreatment of pulmonary arterial hypertension), triazolam, rifampin, and St. John’s wort. 1,13WARNINGS AND PRECAUTIONS: Telepravir/peginterferon-alfa/ribavirin combination therapycarries a pregnancy category X label, and a fetus exposed to the drug has an increased riskfor birth defects and death. Because of the high teratogenic effects, females and malepartners 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 andat least six months after therapy concludes. Hormonal contraceptives may be uneffectiveduring telaprevir combination treatment until two weeks after discontinuation. 2 In addition,females should present a negative pregnancy test before starting telaprevir and take monthlypregnancy tests until six months after stopping the drug. 1,13Patients 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 showsigns of eosinophilia, the patient should be immediately hospitalized for treatment anddiscontinue telaprevir combination therapy. 1,13 In addition, 56% of studied patients developedless serious rashes. Patients who experience rash-like symptoms should be monitored forworsening of symptoms into severe conditions or systemic effects. 1,13 If the rash becomessevere, the patient should immediately seek treatment and discontinue telaprevir.Peginteferon-alpha and ritonavir can be continued unless rash symptoms do not improve afterseven days of discontinuing telaprevir.1 Rash-like symptoms can be present at any time duringtreatment but commonly first appear in the first 4 weeks of treatment. 2Treatment with telaprevir causes an increased risk of anemia compared to treatment withpeginteferon-alpha and ribavirin alone. Patients should have their hemoglobin levels assessedevery 4 weeks during combination therapy. 1 In patients who experience anemia, reduce the 9
  10. 10. dose of ribavirin, but if improvement is not sufficient, the discontinuation of telaprevir isrecommended. Ribavirin cannot be discontinued for the treatment of anemia without alsostopping telaprevir simultaneously. 1Blood tests monitoring HCV-RNA concentrations should be completed on weeks 4 and 12 oftherapy to determine treatment response and optimal further treatment methods after thecompletion of telaprevir. The recommended lower limit of the test monitoring HCV-RNA is 25IU/mL, and the detection range should be pre-set between 10-15 IU/mL. A test result that isbelow the suggested range but is still detectable should not be considered as undetectablewhen assessing treatment response. 1Caution should be exercised in patients with hepatic dysfunction (See Dosing). Telaprevirshould never be given without also prescribing peginterferon-alfa and ribavirin, so it issuggested to also look over their prescribing information before beginning treatment. 1ADVERSE DRUG EFFECTS: Patients receiving treatment with telaprevir experience similarside effects to patients taking peginterferon-alpha 2b and ribavirin; however, telaprevir appearsto increase the frequency of these adverse reactions. The most commonly reported adverseeffects 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 andribavirin dual treatment. 1,2,4 Other common adverse effects of telaprevir compared topeginterferon 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 onlypeginterferon-alpha 2b and ribiavirin therapy experienced serious side effects, 3% of patientson telaprevir combination therapy experienced serious side effects. 2 Serious side effects oftelaprevir are hypersensitivity skin reactions (<1%), Stevens-Johnson syndrome (<1%), andanemia (36%).2,4 Patients on peginterferon and ribavirin also experienced anemia (17%), buttelaprevir increased the severity of the anemia in addition to the incidence. 1DRUG INTERACTIONS: The following drugs result in unsafe elevations in plasmaconcentrations when co-administered with telaprevir. They are contraindicated with telaprevirand 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 theyshould 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. 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 telaprevirshould 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 chronicHCV. No medication error related ADEs have been reported through ISMP or Lexi-Comp. 10,13DOSING: 11
  12. 12. The recommended oral dose of telaprevir in adults is 750mg given three times daily, andtreatment should be given simultaneously with inteferon-alpha and ribaviron therapy over aperiod 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 oftelaprevir should not be decreased or altered to ensure treatment success, but discontinuationshould be considered when HCV-RNA levels reach or exceed 1000 IU/mL . Oncediscontinued, 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. 1BUDGET 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: Accessed October 10, 2011. 12
  13. 13. 3. AHFS Drug Information. New Drug Assignments and Reassignments for 2011. Available at: Accessed October 15, 2011.4. Telaprevir. Micromedex 2.0. Thomson Micromedex. Greenwood Village, CO. Available at: Peginterferon alfa-2b. Drug Facts and Comparisons. Drug Facts and Comparisons eAnswers. Wolters Kluwer Health, Inc. St. Louis, MO. Available at: Accessed October 16, 2011.6. Ribavirin. Drug Facts and Comparisons. Drug Facts and Comparisons eAnswers. Wolters Kluwer Health, Inc. St. Louis, MO. Available at: 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: 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: 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. 13