Boceprevir; Four-Week Lead-In Response and IL28B Status Helped Define Likelihood of Achieving SVR

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Boceprevir; Four-Week Lead-In Response and IL28B Status Helped Define Likelihood of Achieving SVR

New Data Analyses with VICTRELIS (boceprevir), Merck's Investigational Medicine, Examined Possible Predictors of Sustained Virologic ResponseFour-Week Lead-In Response and IL28B Status Helped Define Likelihood of Achieving SVR With VICTRELIS Added to Standard Therapy for Chronic Hepatitis C Genotype 1BERLIN--(BUSINESS WIRE)--Mar 31, 2011 - Merck (NYSE: MRK), knownas MSD outside of the United States and Canada, announced resultsfrom several new data analyses from the pivotal Phase III studiesevaluating the addition of its investigational oral proteaseinhibitor VICTRELISâ„¢ (boceprevir) to peginterferon alfa-2band ribavirin (PR) in adult patients with chronic hepatitis C virus(HCV) genotype 1 infection. The new data analyses identifiedpotential predictors for the likelihood of achieving sustainedvirologic response (SVR)1 based on a patient's responseduring a four-week

lead-in period with PR alone prior to theaddition of VICTRELIS, as well as the genetic marker IL28B. Theresults were presented today at The International LiverCongress™ / 46th European Association for the Study of theLiver (EASL) annual meeting."In the pivotal studies using a four-week lead-in strategy, theaddition of VICTRELIS to current standard therapy achieved higherSVR rates compared to standard therapy alone in patients withchronic hepatitis C genotype 1," said Fred Poordad, M.D., chief ofhepatology and liver transplantation, Cedars-Sinai Medical Center,Los Angeles, and lead author for the HCV SPRINT-2 study intreatment-naïve patients. "Based on new analyses of thesestudies, identification of a patient's IL28B status prior totreatment, used in conjunction with a patient's response after thefour-week lead-in period, provided information on the likelihood ofachieving SVR when

VICTRELIS was added to standard therapy."The presentation of these new analyses coincide with thepublication of the primary data from the pivotal Phase III studiesof VICTRELIS in today's edition of The New England Journal ofMedicine. These results showed that the addition of VICTRELISsignificantly improved SVR in adult patients who failed previoustreatment (HCV-RESPOND-2 study) or who were new to treatment(HCV-SPRINT-2 study) for chronic HCV genotype 1 compared to PRalone, the primary endpoint of the studies.In these studies, all patients receiving VICTRELIS were treatedwith a 4-week lead-in of PEGINTRON® (peginterferonalfa-2b) (1.5 mcg/kg/week) and an investigational dose of ribavirin(600-1,400 mg/day) prior to the addition of VICTRELIS (800 mg threetimes daily).Primary results from these two studies, which each achievedstatistical significance of p<0.0001 based on

intent-to-treatanalyses, were:

In treatment-failure patients: theaddition of VICTRELIS to PR resulted in approximately a three-foldincrease in SVR rates to 59 percent for the RGT arm (95/162) and 66percent for the 48-week treatment arm (107/161) compared to 21percent for control (17/80).

In treatment-naïve patients: theaddition of VICTRELIS to PR resulted in an increase in SVR rates to63 percent for the RGT arm (233/368) and 66 percent for the 48-weektreatment arm (242/366), compared to 38 percent for control(137/363).

HCV-RNA decline after 4-week PR lead-in period helped predictlikelihood of SVRIn pre-specified analyses [Poster #481], researchers evaluatedthe relationship between decline in levels of virus (HCV-RNA) afterthe 4-week PR lead-in period to overall SVR.In the HCV SPRINT-2 treatment-naïve study, patientsreceiving VICTRELIS who had good response after the 4-week lead-inperiod, defined by a greater than or equal to 1.0-log10decline in HCV-RNA , achieved SVR rates of 81 percent (203/252) inthe RGT arm and 79 percent (200/254) in the 48-week treatment armcompared to 51 percent (133/260) in the PR control arm. Patientswith poor response after the 4-week lead-in, defined by a less than1.0-log10 decline in HCV-RNA, achieved SVR rates of 28percent (27/97) in the RGT arm and 38 percent (36/95) in the48-week treatment arm compared to 4 percent (3/83) in the PRcontrol

arm.Similarly, in the HCV RESPOND-2 treatment-failure study,patients receiving VICTRELIS who had good response after thelead-in achieved SVR rates of 73 percent (80/110) in the RGT armand 79 percent (90/114) in the 48-week treatment arm compared to 25percent (17/67) in the PR control arm. Patients with poor responseafter the 4-week lead-in achieved SVR rates of 33 percent (15/46)in the RGT arm and 34 percent (15/44) in the 48-week treatment armcompared to 0 percent (0/12) in the PR control arm.These analyses showed that 4-week lead-in response helpedpredict SVR in all three treatment groups, and the addition ofVICTRELIS to the treatment regimen improved SVR rates regardless ofwhether patients had good or poor response during the lead-inperiod.IL28B genotype helped predict likelihood of treatmentresponseIn pre-specified analyses of the pivotal Phase III studies

[Oralpresentation Parallel Session: HCV Therapy], researchers found thatIL28B status (CC, CT or TT) was a strong baseline predictor ofviral response at treatment week 4, week 8 and SVR among patientsreceiving VICTRELIS. Among those carrying the CC gene allele, 89percent of treatment-naïve patients and 82 percent oftreatment-failure patients had an early response, defined byundetectable virus (HCV-RNA) at treatment week 8, and were eligiblefor a shorter duration of therapy. Among those with the lessfavorable gene allele (CT or TT), 52 percent oftreatment-naïve patients and 48 percent of treatment-failurepatients had an early response and were eligible for a shorterduration of therapy. The analyses also showed that response afterthe 4-week lead-in was a stronger predictor of SVR than any singlebaseline variable, including IL28B status.The analyses included data from 63 percent of

patients(912/1442) in the pivotal Phase III studies who received at leastone dose of VICTRELIS or standard therapy and consented to genomicanalysis to test for IL28B polymorphisms. In total, 28 percent oftested patients carried the CC allele, while 54 percent carried theCT allele and 18 percent carried TT.Data on resistance-associated variants also presentedTo better understand resistance-associated variants whenVICTRELIS was added to standard therapy, researchers analyzed bloodsamples from 343 patients who did not achieve SVR in the HCVSPRINT-2 and HCV RESPOND-2 studies. Samples were obtained atvarious time points of virologic failure (breakthrough, incompletevirologic response, relapse and nonresponse), andresistance-associated variants were detected by populationsequencing.Results of this analysis [Oral presentation Parallel Session:HCV Therapy] showed that

resistance-associated variants were highlyassociated with those patients not achieving SVR, and that themajority of patients with virologic breakthrough or incompletevirologic response had viruses with detectableresistance-associated variants.When analyzed as a function of poor response after the 4-weeklead-in (less than 1-log10 viral load decrease) versusgood response (greater than or equal to 1-log10 viralload decrease), resistance-associated variants were more frequentin patients with a poor lead-in response (68 percent) compared withpatients with a good lead-in response (31 percent). Additionalanalyses are ongoing, with a 3.5-year long-term follow-up studyunderway to evaluate the persistence of resistance-associatedvariants over time.Tolerability profile in the pivotal studies ofVICTRELISIn the HCV SPRINT-2 study in treatment-naïve patients, thefive

most common treatment-related adverse events reported forpatients receiving VICTRELIS in RGT, VICTRELIS in a 48-weektreatment regimen and control, respectively, were: fatigue (53, 57and 60 percent), headache (46, 46 and 42 percent), nausea (48, 43and 42 percent), anemia (49, 49 and 29 percent) and dysgeusia (badtaste) (37, 43 and 18 percent). Serious adverse events werereported in 11, 12 and 9 percent of patients in the study arms,respectively. There were six deaths during the study: four patientsin the control group died, as did two patients in the VICTRELISgroups. Two suicides (one patient in the control group and onepatient receiving VICTRELIS in RGT) were judged to have possiblybeen related to peginterferon. No other deaths were considered tobe drug-related.In HCV SPRINT-2, treatment discontinuations due to adverseevents over the total course of all treatment were 12 percent and16

percent for patients receiving VICTRELIS in RGT and VICTRELIS ina 48-week treatment regimen, respectively, compared to 16 percentfor control. Treatment discontinuations due to anemia were 2percent for each of the treatment groups receiving VICTRELIScompared to 1 percent for control. EPO for management of anemia wasallowed at the discretion of the investigator per the studyprotocol, and was used by 43 percent of patients in each of thetreatment groups receiving VICTRELIS compared to 24 percent forcontrol.In the HCV RESPOND-2 study in treatment-failure patients, thefive most common treatment-related adverse events reported forpatients receiving VICTRELIS in RGT, VICTRELIS in a 48-weektreatment regimen and control, respectively, were: fatigue (54, 57,and 50 percent), headache (41, 39 and 48 percent), nausea (44, 39and 38 percent), anemia (43, 46 and 20) and chills (35, 30 and 30percent).

Serious adverse events were reported in 10, 14 and 5percent of patients in the study arms, respectively. There was onedeath in the study, a suicide in the group receiving VICTRELIS inRGT, which occurred 18 weeks after the end of the study treatmentand was considered to be unrelated to the study treatment.In HCV RESPOND-2, treatment discontinuations due to adverseevents over the total course of all treatment were 8 percent and 12percent for patients receiving VICTRELIS in RGT and VICTRELIS in a48-week treatment regimen, respectively, compared to 2 percent forcontrol. Treatment discontinuations due to anemia were 0 percentand 3 percent for the treatment groups receiving VICTRELIS,respectively, compared to 0 percent for control. Erythropoietin(EPO) for management of anemia was allowed at the discretion of theinvestigator per the study protocol, and was used by 41 and 46percent of patients receiving

VICTRELIS in RGT and VICTRELIS in a48-week treatment regimen, respectively, compared to 21 percent forcontrol.Merck's global commitment to advancing hepatitistherapyMerck is committed to building on its strong legacy in the fieldof viral hepatitis by continuing to discover, develop and delivervaccines and medicines to help prevent and treat viral hepatitis.In hepatitis C, company researchers developed the first approvedtherapy for chronic HCV in 1991 and the first combination therapyin 1998. 2011 marks the 10-year anniversary of the introduction ofPEGINTRON and ribavirin in combination therapy, a current standardtherapy for chronic HCV worldwide. In addition to ongoing studieswith VICTRELIS, extensive research efforts are underway to developadditional innovative oral therapies for viral hepatitis care.About PEGINTRONPEGINTRON is indicated for use in combination with

ribavirin forthe treatment of chronic hepatitis C in patients 3 years of age andolder with compensated liver disease.The following points should be considered when initiatingtherapy with PEGINTRON in combination with ribavirin: (1) Theseindications are based on achieving undetectable HCV-RNA aftertreatment for 24 or 48 weeks and maintaining a Sustained VirologicResponse (SVR) 24 weeks after the last dose. (2) Patients with thefollowing characteristics are less likely to benefit fromre-treatment after failing a course of therapy: previousnonresponse, previous pegylated interferon treatment, significantbridging fibrosis or cirrhosis, and genotype 1 infection. (3) Nosafety and efficacy data are available for treatment of longer thanone year.PEGINTRON is also indicated for use alone for the treatment ofchronic hepatitis C in patients with compensated liver diseasepreviously untreated with

interferon alpha and who are at least 18years of age.The following points should be considered when initiatingtherapy with PEGINTRON alone: Combination therapy with ribavirin ispreferred over PEGINTRON monotherapy unless there arecontraindications to, or significant intolerance of, ribavirin.Combination therapy provides substantially better response ratesthan monotherapy.Selected Safety Information on PEGINTRONWARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATEDEFFECTSAlpha interferons, including PEGINTRON, may cause oraggravate fatal or life-threatening neuropsychiatric, autoimmune,ischemic, and infectious disorders. Patients should bemonitored closely with periodic clinical and laboratoryevaluations. Patients with persistently severe or worseningsigns or symptoms of these conditions should be withdrawn fromtherapy. In many, but not all cases,

these disorders resolve afterstopping PEGINTRON therapy.Use with Ribavirin:Ribavirin may cause birth defects and death of the unbornchild. Extreme care must be taken to avoid pregnancy infemale patients and in female partners of male patients.Ribavirin causes hemolytic anemia. The anemia associatedwith ribavirin therapy may result in a worsening of cardiacdisease. Ribavirin is genotoxic and mutagenic and should beconsidered a potential carcinogen.ContraindicationsPEGINTRON is contraindicated in patients with knownhypersensitivity reactions such as urticaria, angioedema,bronchoconstriction, anaphylaxis, s- syndrome andtoxic epidermal necrolysis to interferon alpha or any othercomponent of the product, autoimmune hepatitis, and hepaticdecompensation (Child-Pugh score greater than 6 [class B and

C]) incirrhotic CHC patients before or during treatment.PEGINTRON/ribavirin combination therapy is additionallycontraindicated in women who are pregnant or may become pregnant,men whose female partners are pregnant, patients withhemoglobinopathies (e.g., thalassemia major, sickle-cell anemia),and patients with creatinine clearance less than 50 mL per min.PregnancyRibavirin therapy should not be started until a report of anegative pregnancy test has been obtained immediately prior toplanned initiation of therapy. Patients should use at leasttwo effective forms of contraception and have monthly pregnancytests during therapy and for six months after completion oftherapy. If this drug is used during pregnancy, or if a patientbecomes pregnant, the patient should be apprised of the potentialhazard to a fetus. A Ribavirin Pregnancy Registry has beenestablished to monitor

maternal-fetal outcomes of pregnancies infemale patients and female partners of male patients exposed toribavirin during treatment, and for six months following cessationof treatment. Physicians and patients are encouraged to report suchcases by calling 1-800-593-2214.Patients with the following conditions should be closelymonitored and may require dose reduction or discontinuation oftherapy:

Hemolytic anemia with ribavirin

Neuropsychiatric events

History of significant or unstablecardiac disease

Hypothyroidism, hyperthyroidism,hyperglycemia, diabetes mellitus that cannot be effectively treatedby medication

New or worsening ophthalmologicdisorders

Ischemic and hemorrhagiccerebrovascular events

Severe decreases in neutrophil orplatelet counts

History of autoimmune disorders

Pancreatitis and ulcerative orhemorrhagic/ischemic colitis and pancreatitis

Pulmonary infiltrates or pulmonaryfunction impairment

Child-Pugh score greater than 6 (ClassB and C)

Increased creatinine levels in patientswith renal insufficiency

Serious, acute hypersensitivityreactions and cutaneous eruptions

Dental/periodontal disorders reportedwith combination therapy

Hypertriglyceridemia may result inpancreatitis (e.g., triglycerides greater than1000 mg/dL)

Weight loss and growth inhibitionreported with combination therapy in pediatric patients.

Life-threatening or fatal neuropsychiatric events, includingsuicidal and homicidal ideation, depression, relapse of drugaddiction/overdose, and aggressive behavior, sometimes directedtowards others, have occurred in patients with and without aprevious psychiatric disorder during PEGINTRON treatment andfollow-up.Adverse EventsSerious adverse reactions have occurred in approximately 12percent of subjects in clinical trials. The most common seriousevents occurring in subjects treated with PEGINTRON and ribavirinwere depression and suicidal ideation, each occurring at afrequency of less than 1 percent. The most common fatal eventsoccurring in subjects treated with PEGINTRON and ribavirin werecardiac arrest, suicidal ideation, and suicide attempt, alloccurring in less than 1 percent of subjects.The incidence of serious adverse reactions was comparablebetween PEGINTRON monotherapy

(about 12 percent) andPEGINTRON/ribavirin combination therapy weight-based (12 percent)or flat-dose (17 percent). In many but not all cases, adversereactions resolved after dose reduction or discontinuation oftherapy. Some patients experienced ongoing or new serious adversereactions during the 6-month follow-up period. In a study withPEGINTRON/ribavirin (weight-based) combination therapy in adultpatients, anemia with weight-based dosing occurred at an increasedrate (29 percent vs. 19 percent); however, the majority of thesecases were mild and responded to dose reductions. The incidence ofserious adverse reactions reported for the weight-based ribaviringroup was 12 percent. There were 31 deaths in clinical trials whichoccurred during treatment or during follow-up. Of the deaths, 19were patients on either PEGINTRON or PEGINTRON/ribavirincombination therapy and three occurred during the follow-up

periodbut had been on PEGINTRON/ribavirin combination therapy.Additional serious adverse reactions seen in clinical trials ata frequency of equal to or less than 1 percent included psychosis,aggressive reaction, relapse of drug addiction/overdose; nervepalsy (facial, oculomotor); cardiomyopathy, angina, pericardialeffusion, retinal ischemia, retinal artery or vein thrombosis,blindness, decreased visual acuity, optic neuritis, transientischemic attack, supraventricular arrhythmias, loss ofconsciousness; neutropenia, infection (sepsis, pneumonia, abscess,cellulitis); emphysema, bronchiolitis obliterans, pleural effusion,gastroenteritis, pancreatitis, gout, hyperglycemia, hyperthyroidismand hypothyroidism, autoimmune thrombocytopenia with or withoutpurpura, rheumatoid arthritis, interstitial nephritis, lupus-likesyndrome, sarcoidosis, aggravated psoriasis, urticaria, injectionsite necrosis,

vasculitis, and phototoxicity.Greater than 96 percent of all subjects in clinical trialsexperienced one or more adverse events. Most common adversereactions (greater than 40 percent) in adult patients receivingeither PEGINTRON or PEGINTRON/ribavirin are injection siteinflammation/reaction, fatigue/asthenia, headache, rigors, fevers,nausea, myalgia, and anxiety/emotional lability/irritability.The adverse reaction profile was similar between weight-basedand flat-dose PEGINTRON/ribavirin therapies. Weight-basedPEGINTRON/ribavirin dosing resulted in increased rates of anemia.Most common adverse reactions with PEGINTRON/ribavirin(weight-based) therapy were psychiatric, which occurred among 68-69percent of patients and included depression, irritability, andinsomnia, each reported by approximately 30-40 percent of subjectsin all treatment groups. Suicidal behavior (ideation, attempts, andsuicides)

occurred in 2 percent of all patients during treatment orduring follow-up after treatment cessation. Other common reactionsincluded injection site reactions, fatigue/ asthenia, headache,rigors, fever, nausea, myalgia, anxiety/emotionallability/irritability. The severity of some of these systemicsymptoms tends to decrease as treatment continues.Subjects receiving PEGINTRON/ribavirin as re-treatment afterfailing a previous interferon combination regimen reported adversereactions similar to previous treatment-naïve patientsreceiving this regimen.In general, the adverse reaction profile in the pediatricpopulation was similar to that observed in adults. Most commonadverse reactions (greater than 25 percent) in pediatric patientsreceiving PEGINTRON/ribavirin are pyrexia, headache, neutropenia,fatigue, anorexia, injection site erythema, abdominal pain, andvomiting.Please see full prescribing

information at http://www.spfiles.com/pipeg-intron.pdf.About MerckToday's Merck is a global healthcare leader working to help theworld be well. Merck is known as MSD outside the United States andCanada. Through our prescription medicines, vaccines, biologictherapies, and consumer care and animal health products, we workwith customers and operate in more than 140 countries to deliverinnovative health solutions. We also demonstrate our commitment toincreasing access to healthcare through far-reaching policies,programs and partnerships. For more information, visit www.merck.com.Forward-Looking StatementThis news release includes “forward-lookingstatements†within the meaning of the

safe harbor provisionsof the United States Private Securities Litigation Reform Act of1995. Such statements may include, but are not limited to,statements about the benefits of the merger between Merck andSchering-Plough, including future financial and operating results,the combined company's plans, objectives, expectations andintentions and other statements that are not historical facts. Suchstatements are based upon the current beliefs and expectations ofMerck's management and are subject to significant risks anduncertainties. Actual results may differ from those set forth inthe forward-looking statements.The following factors, among others, could cause actual resultsto differ from those set forth in the forward-looking statements:the possibility that the expected synergies from the merger ofMerck and Schering-Plough will not be realized, or will not berealized within the expected time

period; the impact ofpharmaceutical industry regulation and health care legislation; therisk that the businesses will not be integrated successfully;disruption from the merger making it more difficult to maintainbusiness and operational relationships; Merck's ability toaccurately predict future market conditions; dependence on theeffectiveness of Merck's patents and other protections forinnovative products; the risk of new and changing regulation andhealth policies in the U.S. and internationally and the exposure tolitigation and/or regulatory actions.Merck undertakes no obligation to publicly update anyforward-looking statement, whether as a result of new information,future events or otherwise. Additional factors that could causeresults to differ materially from those described in theforward-looking statements can be found in Merck's 2010 AnnualReport on Form 10-K and the company's other

filings with theSecurities and Exchange Commission (SEC) available at the SEC'sInternet site (http://www.sec.gov/).Please see attached Prescribing Information, MedicationGuide, and Instructions for Use including Boxed Warning forPEGINTRON. The Prescribing Information, Medication Guide,and Instructions for Use are also available at http://www.spfiles.com/pipeg-intron.pdf,http://www.spfiles.com/mgpeg-intron.pdf andhttp://www.spfiles.com/ifupeg-intron.pdf.1 SVR, the protocol specified primary efficacyendpoint of the studies, is defined as achievement of undetectableHCV-RNA at 24 weeks after the end of treatment in all randomizedpatients

treated with any study medication. Per protocol, if apatient did not have a 24-week post-treatment assessment, thepatient's 12-week post-treatment assessment was utilized.AINF-1003633-0000HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed tousePegIntron safely and effectively. See full prescribinginformation for PegIntron.PegIntron (Peginterferon alfa-2b) Injection, Powder forSolution for Subcutaneous UseInitial U.S. Approval: 2001WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATEDEFFECTSSee full prescribing information for complete boxedwarning.

May cause or aggravate fatal orlife-threatening neuropsychiatric, autoimmune, ischemic, andinfectious disorders. Monitor closely and withdraw therapy withpersistently severe or worsening signs or symptoms of the abovedisorders. (5)

Use with Ribavirin

Ribavirin may cause birth defectsand fetal death; avoid pregnancy in female patients and femalepartners of male patients. (5.1)

Ribavirin is a potential carcinogen.(5.1, 13.1)

RECENT MAJOR CHANGESWarnings and Precautions, Pulmonary Disorders (5.11)[2/2011]INDICATIONS AND USAGEPegIntron is an antiviral indicated for

Combinationtherapy with REBETOL (ribavirin):Chronic Hepatitis C (CHC) in patients ‰¥3 years withcompensated liver disease. (1.1)Patients with the following characteristics are less likely tobenefit from re-treatment after failing a course of therapy:previous nonresponse, previous pegylated interferon treatment,significant bridging fibrosis or cirrhosis, and genotype 1infection. (1.1)

Monotherapy: CHC in patients (‰¥18years) with compensated liver disease previously untreated withinterferon alpha. (1.1)

DOSAGE AND ADMINISTRATION

PegIntron is administered bysubcutaneous injection.

PegIntronDose (Adults)*

PegIntronDose (Pediatric Patients)

REBETOLDose* (Adults)

REBETOLDose (Pediatric Patients)

PegIntron/REBETOL Combination Therapy (2.1)

1.5mcg/kg/ week

60mcg/m2/ week

800-1400mg orally daily with food

15mg/kg/day orally with food in 2 divided doses* Refer to Tables 1-7 of the full Prescribing Information.

Dose reduction is recommended inpatients experiencing certain adverse reactions or renaldysfunction. (2.3, 2.5)

DOSAGE FORMS AND STRENGTHSSingle-use vial (with 1.25 mL diluent) and REDIPEN®(3):

50 mcg per 0.5 mL,80 mcg per 0.5 mL, 120 mcg per 0.5 mL,150 mcg per 0.5 mL.

CONTRAINDICATIONS

Known hypersensitivity reactions, suchas urticaria, angioedema, bronchoconstriction, anaphylaxis,s- syndrome, and toxic epidermal necrolysis tointerferon alpha or any other product component. (4)

Autoimmune hepatitis. (4)

Hepatic decompensation (Child-Pughscore >6 [class B and C]) in cirrhotic CHC patients before orduring treatment. (4)

Additional contraindications for combination therapy withribavirin:

Pregnant women and men whose femalepartners are pregnant. (4, 8.1)

Hemoglobinopathies (e.g., thalassemiamajor, sickle-cell anemia). (4)

Creatinine clearance<50 mL/min. (4)

WARNINGS AND PRECAUTIONS

Birth defects and fetal death withribavirin: Patients must have a negative pregnancy test prior totherapy, use at least 2 forms of contraception, and undergo monthlypregnancy tests. (5.1)

Patients exhibiting the following conditions should be closelymonitored and may require dose reduction or discontinuation oftherapy:

Hemolytic anemia with ribavirin.(5.1)

Neuropsychiatric events. (5.2)

History of significant or unstablecardiac disease. (5.3)

Hypothyroidism, hyperthyroidism,hyperglycemia, diabetes mellitus that cannot be effectively treatedby medication. (5.4)

New or worsening ophthalmologicdisorders. (5.5)

Ischemic and hemorrhagiccerebrovascular events. (5.6)

Severe decreases in neutrophil orplatelet counts. (5.7)

History of autoimmune disorders.(5.8)

Pancreatitis and ulcerative orhemorrhagic/ischemic colitis and pancreatitis. (5.9, 5.10)

Pulmonary infiltrates or pulmonaryfunction impairment. (5.11)

Child-Pugh score >6 (class B and C).(4, 5.12)

Increased creatinine levels in patientswith renal insufficiency. (5.13)

Serious, acute hypersensitivityreactions and cutaneous eruptions. (5.14)

Dental/periodontal disorders reportedwith combination therapy. (5.16)

Hypertriglyceridemia may result inpancreatitis (e.g., triglycerides >1000 mg/dL). (5.17)

Weight loss and growth inhibitionreported with combination therapy in pediatric patients.(5.18)

Peripheral neuropathy when used incombination with telbivudine. (5.19)

ADVERSE REACTIONSMost common adverse reactions (>40%) in adult patientsreceiving eitherPegIntron or PegIntron/REBETOL are injection siteinflammation/reaction, fatigue/asthenia, headache, rigors, fevers, nausea,myalgia and anxiety/emotional lability/irritability (6.1). Mostcommon adverse reactions (>25%) in pediatric patients receivingPegIntron/REBETOL are pyrexia, headache, neutropenia, fatigue,anorexia, injection-site erythema, vomiting (6.1).To report SUSPECTED ADVERSE REACTIONS, contact ScheringCorporation, a subsidiary of Merck & Co., Inc., at1-800-526-4099 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.DRUG INTERACTIONS

Drug metabolized by CYP450: Cautionwith drugs metabolized by CYP2C8/9 (e.g., warfarin, phenytoin) orCYP2D6 (e.g., flecainide). (7.1)

Methadone: Monitor for increasednarcotic effect. (7.2)

Nucleoside analogues: Closely monitorfor toxicities. Discontinue nucleoside reverse transcriptaseinhibitors or reduce dose or discontinue interferon, ribavirin, orboth with worsening toxicities. (7.3)

Didanosine: Concurrent use with REBETOLis not recommended. (7.3)

USE IN SPECIFIC POPULATIONS

Ribavirin Pregnancy Registry:1-800-593-2214 (8.1)

Pediatrics: safety and efficacy inpediatrics <3 years old have not been established (8.4)

Geriatrics: neuropsychiatric, cardiac,pulmonary, GI, and systemic (flu-like) adverse reactions may bemore severe (8.5)

Organ transplant: safety and efficacyhave not been studied (8.6)

HIV or HBV co-infection: safety andefficacy have not been established (8.7)

See 17 for PATIENT COUNSELING INFORMATION and MedicationGuide.Revised: 02/2011FULL PRESCRIBING INFORMATION: CONTENTS*WARNING – RISK OF SERIOUS DISORDERS ANDRIBAVIRIN-ASSOCIATED EFFECTS1 INDICATIONS AND USAGE1.1 Chronic Hepatitis C2 DOSAGE AND ADMINISTRATION2.1 PegIntron/REBETOL Combination Therapy2.2 PegIntron Monotherapy2.3 Dose Reduction2.4 Discontinuation of Dosing2.5 Renal Function2.6 Preparation and Administration3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Use with Ribavirin5.2 Neuropsychiatric Events5.3 Cardiovascular Events5.4 Endocrine Disorders5.5 Ophthalmologic Disorders5.6 Cerebrovascular Disorders5.7 Bone Marrow Toxicity5.8 Autoimmune Disorders5.9 Pancreatitis5.10 Colitis5.11 Pulmonary

Disorders5.12 Hepatic Failure5.13 Patients with Renal Insufficiency5.14 Hypersensitivity5.15 Laboratory Tests5.16 Dental and Periodontal Disorders5.17 Triglycerides5.18 Impact on Growth- Pediatric Use5.19 Peripheral Neuropathy6 ADVERSE REACTIONS6.1 Clinical Trials Experience6.2 Immunogenicity6.3 Postmarketing Experience7 DRUG INTERACTIONS7.1 Drugs Metabolized by Cytochrome P-4507.2 Methadone7.3 Use with Ribavirin (Nucleoside Analogues)8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Organ Transplant Recipients8.7 HIV or HBV Co-infection10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics12.4 Microbiology13 NONCLINICAL TOXICOLOGY13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility14 CLINICAL STUDIES14.1 Chronic Hepatitis C in Adults14.2 Chronic Hepatitis C in Pediatrics16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION17.1 Pregnancy17.2 HCV Transmission17.3 Laboratory Evaluations, Hydration, “Flu-likeâ€Symptoms17.4 Instructions for Use*Sections or subsections omitted from the full prescribinginformation are not listed.FULL PRESCRIBING INFORMATIONWARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATEDEFFECTSAlpha interferons, including PegIntron, may cause oraggravate fatal or life-threatening neuropsychiatric, autoimmune,ischemic, and infectious disorders. Patients should bemonitored closely with periodic clinical and laboratoryevaluations. Patients with persistently severe or worseningsigns or symptoms of these

conditions should be withdrawn fromtherapy. In many, but not all cases, these disorders resolveafter stopping PegIntron therapy [see Warnings andPrecautions (5) and Adverse Reactions(6.1)].Use with RibavirinRibavirin may cause birth defects and death of the unbornchild. Extreme care must be taken to avoid pregnancy infemale patients and in female partners of male patients. Ribavirincauses hemolytic anemia. The anemia associated with REBETOLtherapy may result in a worsening of cardiac disease.Ribavirin is genotoxic and mutagenic and should be considered apotential carcinogen. [see REBETOL packageinsert]1 INDICATIONS AND USAGE1.1 Chronic Hepatitis CCombination therapy:PegIntron® in combination with REBETOL® (ribavirin)

isindicated for the treatment of chronic hepatitis C in patients 3years of age and older with compensated liver disease.The following points should be considered when initiatingtherapy with PegIntron in combination with REBETOL:

These indications are based onachieving undetectable HCV-RNA after treatment for 24 or 48 weeksand maintaining a Sustained Virologic Response (SVR) 24 weeks afterthe last dose.

Patients with the followingcharacteristics are less likely to benefit from retreatment afterfailing a course of therapy: previous nonresponse, previouspegylated interferon treatment, significant bridging fibrosis orcirrhosis, and genotype 1 infection [see Clinical Studies(14)].

No safety and efficacy data areavailable for treatment of longer than 1 year.

Monotherapy (for patients who areintolerant to ribavirin):PegIntron (peginterferon alfa-2b) is indicated for use alone forthe treatment of chronic hepatitis C in patients with compensatedliver disease previously untreated with interferon alpha and whoare at least 18 years of age.The following point should be considered when initiating therapywith PegIntron alone:

Combination therapy with REBETOL ispreferred over PegIntron monotherapy unless there arecontraindications to or significant intolerance of REBETOL.

Combination therapy provides substantially better response ratesthan monotherapy [see Clinical Studies (14)].2 DOSAGE AND ADMINISTRATION2. 1 PegIntron/REBETOL Combination TherapyREBETOL should be taken with food. REBETOL should not be used inpatients with creatinine clearance <50 mL/min.AdultsThe recommended dose of PegIntron is 1.5 mcg/kg/weeksubcutaneously in combination with 800 to 1400 mg of REBETOL orallybased on patient body weight. The volume of PegIntron to beinjected depends on the strength of PegIntron and patient's bodyweight (see Table 1).Duration of Treatment – Interferon Alpha-naïvePatientsThe treatment duration for patients with genotype 1 is 48 weeks.Discontinuation of therapy should be considered in patients who donot achieve at least a 2 log10 drop or loss of

HCV-RNAat 12 weeks, or if HCV-RNA remains detectable after 24 weeks oftherapy. Patients with genotype 2 and 3 should be treated for 24weeks.Duration of Treatment – Re-treatment withPegIntron/REBETOL of Prior Treatment FailuresThe treatment duration for patients who previously failedtherapy is 48 weeks, regardless of HCV genotype. Re-treatedpatients who fail to achieve undetectable HCV-RNA at Week 12 oftherapy, or whose HCV-RNA remains detectable after 24 weeks oftherapy, are highly unlikely to achieve SVR and discontinuation oftherapy should be considered [see Clinical Studies(14.1)].

TABLE 1Recommended PegIntron Combination Therapy Dosing(Adults)

Bodyweightkg (lbs)

PegIntron REDIPEN® or VialStrength to Use

Amountof PegIntron (mcg) to Administer

Volume(mL)* of PegIntron to Administer

REBETOLDaily Dose

REBETOLNumber of Capsules

<40(<88)

50 mcg per0.5 mL

50

0.5

800mg/day

2 x 200 mgcapsules A.M. 2 x 200 mg capsules P.M.

40 – 50 (88 – 111)

80 mcg per 0.5 mL

64

0.4

800 mg/day

2x 200 mg capsules A.M. 2 x 200 mg capsules P.M.

51– 60 (112 – 133)

80

0.5

800mg/day

2 x 200 mgcapsules A.M. 2 x 200 mg capsules P.M.

61 – 65 (134 – 144)

120 mcg per 0.5 mL

96

0.4

800 mg/day

2x 200 mg capsules A.M. 2 x 200 mg capsules P.M.

66– 75 (145 – 166)

96

0.4

1000mg/day

2 x 200 mgcapsules A.M. 3 x 200 mg capsules P.M.

76 – 80 (167 – 177)

120

0.5

1000 mg/day

2x 200 mg capsules A.M. 3 x 200 mg capsules P.M.

81– 85 (178 – 187)

1200mg/day

3 x 200 mgcapsules A.M. 3 x 200 mg capsules P.M.

86– 105 (188 – 231)

150 mcgper 0.5 mL

150

0.5

1200mg/day

3 x 200 mgcapsules A.M. 3 x 200 mg capsules P.M.

>105(>231)

**

**

**

1400mg/day

3 x 200 mgcapsules A.M. 4 x 200 mg capsules P.M.* When reconstituted as directed.** For patients weighing >105 kg (>231 pounds), thePegIntron dose of 1.5 mcg/kg/week should be calculated based on theindividual patient weight. Two vials of PegIntron may be necessaryto provide the dose.Pediatric PatientsDosing for pediatric patients is determined by body surface areafor PegIntron and by body weight for REBETOL. The recommended doseof PegIntron is 60mcg/m2/week subcutaneously incombination with 15 mg/kg/day of REBETOL orally in 2 divided doses(see Table 2) for pediatric patients ages 3 to 17 years.Patients who reach their 18th birthday while receivingPegIntron/REBETOL, should

remain on the pediatric dosing regimen.The treatment duration for patients with genotype 1 is 48 weeks.Patients with genotype 2 and 3 should be treated for 24 weeks.

TABLE 2Recommended REBETOL* Dosing inCombination Therapy (Pediatrics)

Bodyweightkg (lbs)

REBETOLDaily Dose

REBETOLNumber of Capsules

less then;47(less then;103)

15mg/kg/day

UseREBETOL Oral Solution**

47– 59(103-131)

800mg/day

2 x200 mg capsules A.M. 2 x 200 mg capsules P.M.

60– 73 (132-162)

1000mg/day

2 x200 mg capsules A.M. 3 x 200 mg capsules P.M.

more then 73(less then162)

1200mg/day

3 x200 mg capsules A.M. 3 x 200 mg capsules P.M.*REBETOL to be used in combination with PegIntron 60mcg/m2 weekly.** REBETOL Oral Solution may be used for any patientregardless of body weight.2.2 PegIntron MonotherapyThe recommended dose of PegIntron regimen is 1 mcg/kg/weeksubcutaneously for 1 year administered on the same day of the week.Discontinuation of therapy should be considered in patients who donot achieve at least a 2 log10 drop or loss of HCV-RNAat 12 weeks of therapy, or whose HCV-RNA levels remain detectableafter 24 weeks of therapy. The volume of PegIntron to be injecteddepends on patient weight (see Table 3).

TABLE 3Recommended PegIntron Monotherapy Dosing

Bodyweightkg (lbs)

PegIntron REDIPEN or Vial Strength to Use

AmountofPegIntron (mcg) to Administer

Volume(mL)* of PegIntron to Administer

‰¤45(‰¤100)

50 mcg per 0.5 mL

40

0.4

46– 56 (101 – 124)

50

0.5

57 – 72 (125 – 159)

80 mcg per 0.5 mL

64

0.4

73– 88 (160 – 195)

80

0.5

89 – 106 (196 – 234)

120 mcg per 0.5 mL

96

0.4

107– 136 (235 – 300)

120

0.5

137– 160 (301 – 353)

150 mcgper 0.5 mL

150

Also See; Boceprevir; Difficult Hepatitis C Type Responds to Novel Protease Inhibitor

http://Hepatitis Cnewdrugs.blogspot.com/2011/04/boceprevir-four-week-lead-in-response.html