Four-Week Lead-In Response and IL28B Status Helped Define Likelihood of Achieving SVR With VICTRELIS Added to Standard Therapy for Chronic Hepatitis C Genotype 1
BERLIN--(BUSINESS WIRE)--Mar 31, 2011 - Merck (NYSE: MRK), known
as MSD outside of the United States and Canada, announced results
from several new data analyses from the pivotal Phase III studies
evaluating the addition of its investigational oral protease
inhibitor VICTRELIS™ (boceprevir) to peginterferon alfa-2b
and ribavirin (PR) in adult patients with chronic hepatitis C virus
(HCV) genotype 1 infection. The new data analyses identified
potential predictors for the likelihood of achieving sustained
virologic response (SVR)1 based on a patient's response
during a four-week lead-in period with PR alone prior to the
addition of VICTRELIS, as well as the genetic marker IL28B. The
results were presented today at The International Liver
Congress™ / 46th European Association for the Study of the
Liver (EASL) annual meeting.
"In the pivotal studies using a four-week lead-in strategy, the
addition of VICTRELIS to current standard therapy achieved higher
SVR rates compared to standard therapy alone in patients with
chronic hepatitis C genotype 1," said Fred Poordad, M.D., chief of
hepatology and liver transplantation, Cedars-Sinai Medical Center,
Los Angeles, and lead author for the HCV SPRINT-2 study in
treatment-naïve patients. "Based on new analyses of these
studies, identification of a patient's IL28B status prior to
treatment, used in conjunction with a patient's response after the
four-week lead-in period, provided information on the likelihood of
achieving SVR when VICTRELIS was added to standard therapy."
The presentation of these new analyses coincide with the
publication of the primary data from the pivotal Phase III studies
of VICTRELIS in today's edition of The New England Journal of
Medicine. These results showed that the addition of VICTRELIS
significantly improved SVR in adult patients who failed previous
treatment (HCV-RESPOND-2 study) or who were new to treatment
(HCV-SPRINT-2 study) for chronic HCV genotype 1 compared to PR
alone, the primary endpoint of the studies.
In these studies, all patients receiving VICTRELIS were treated
with a 4-week lead-in of PEGINTRON® (peginterferon
alfa-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 three
times daily).
Primary results from these two studies, which each achieved
statistical significance of p<0.0001 based on intent-to-treat
analyses, were:
- In treatment-failure patients: the
addition of VICTRELIS to PR resulted in approximately a three-fold
increase in SVR rates to 59 percent for the RGT arm (95/162) and 66
percent for the 48-week treatment arm (107/161) compared to 21
percent for control (17/80). - In treatment-naïve patients: the
addition of VICTRELIS to PR resulted in an increase in SVR rates to
63 percent for the RGT arm (233/368) and 66 percent for the 48-week
treatment arm (242/366), compared to 38 percent for control
(137/363).
likelihood of SVR
In pre-specified analyses [Poster #481], researchers evaluated
the relationship between decline in levels of virus (HCV-RNA) after
the 4-week PR lead-in period to overall SVR.
In the HCV SPRINT-2 treatment-naïve study, patients
receiving VICTRELIS who had good response after the 4-week lead-in
period, defined by a greater than or equal to 1.0-log10
decline in HCV-RNA , achieved SVR rates of 81 percent (203/252) in
the RGT arm and 79 percent (200/254) in the 48-week treatment arm
compared to 51 percent (133/260) in the PR control arm. Patients
with poor response after the 4-week lead-in, defined by a less than
1.0-log10 decline in HCV-RNA, achieved SVR rates of 28
percent (27/97) in the RGT arm and 38 percent (36/95) in the
48-week treatment arm compared to 4 percent (3/83) in the PR
control arm.
Similarly, in the HCV RESPOND-2 treatment-failure study,
patients receiving VICTRELIS who had good response after the
lead-in achieved SVR rates of 73 percent (80/110) in the RGT arm
and 79 percent (90/114) in the 48-week treatment arm compared to 25
percent (17/67) in the PR control arm. Patients with poor response
after 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 arm
compared to 0 percent (0/12) in the PR control arm.
These analyses showed that 4-week lead-in response helped
predict SVR in all three treatment groups, and the addition of
VICTRELIS to the treatment regimen improved SVR rates regardless of
whether patients had good or poor response during the lead-in
period.
IL28B genotype helped predict likelihood of treatment
response
In pre-specified analyses of the pivotal Phase III studies [Oral
presentation Parallel Session: HCV Therapy], researchers found that
IL28B status (CC, CT or TT) was a strong baseline predictor of
viral response at treatment week 4, week 8 and SVR among patients
receiving VICTRELIS. Among those carrying the CC gene allele, 89
percent of treatment-naïve patients and 82 percent of
treatment-failure patients had an early response, defined by
undetectable virus (HCV-RNA) at treatment week 8, and were eligible
for a shorter duration of therapy. Among those with the less
favorable gene allele (CT or TT), 52 percent of
treatment-naïve patients and 48 percent of treatment-failure
patients had an early response and were eligible for a shorter
duration of therapy. The analyses also showed that response after
the 4-week lead-in was a stronger predictor of SVR than any single
baseline variable, including IL28B status.
The analyses included data from 63 percent of patients
(912/1442) in the pivotal Phase III studies who received at least
one dose of VICTRELIS or standard therapy and consented to genomic
analysis to test for IL28B polymorphisms. In total, 28 percent of
tested patients carried the CC allele, while 54 percent carried the
CT allele and 18 percent carried TT.
Data on resistance-associated variants also presented
To better understand resistance-associated variants when
VICTRELIS was added to standard therapy, researchers analyzed blood
samples from 343 patients who did not achieve SVR in the HCV
SPRINT-2 and HCV RESPOND-2 studies. Samples were obtained at
various time points of virologic failure (breakthrough, incomplete
virologic response, relapse and nonresponse), and
resistance-associated variants were detected by population
sequencing.
Results of this analysis [Oral presentation Parallel Session:
HCV Therapy] showed that resistance-associated variants were highly
associated with those patients not achieving SVR, and that the
majority of patients with virologic breakthrough or incomplete
virologic response had viruses with detectable
resistance-associated variants.
When analyzed as a function of poor response after the 4-week
lead-in (less than 1-log10 viral load decrease) versus
good response (greater than or equal to 1-log10 viral
load decrease), resistance-associated variants were more frequent
in patients with a poor lead-in response (68 percent) compared with
patients with a good lead-in response (31 percent). Additional
analyses are ongoing, with a 3.5-year long-term follow-up study
underway to evaluate the persistence of resistance-associated
variants over time.
Tolerability profile in the pivotal studies of
VICTRELIS
In the HCV SPRINT-2 study in treatment-naïve patients, the
five most common treatment-related adverse events reported for
patients receiving VICTRELIS in RGT, VICTRELIS in a 48-week
treatment regimen and control, respectively, were: fatigue (53, 57
and 60 percent), headache (46, 46 and 42 percent), nausea (48, 43
and 42 percent), anemia (49, 49 and 29 percent) and dysgeusia (bad
taste) (37, 43 and 18 percent). Serious adverse events were
reported in 11, 12 and 9 percent of patients in the study arms,
respectively. There were six deaths during the study: four patients
in the control group died, as did two patients in the VICTRELIS
groups. Two suicides (one patient in the control group and one
patient receiving VICTRELIS in RGT) were judged to have possibly
been related to peginterferon. No other deaths were considered to
be drug-related.
In HCV SPRINT-2, treatment discontinuations due to adverse
events over the total course of all treatment were 12 percent and
16 percent for patients receiving VICTRELIS in RGT and VICTRELIS in
a 48-week treatment regimen, respectively, compared to 16 percent
for control. Treatment discontinuations due to anemia were 2
percent for each of the treatment groups receiving VICTRELIS
compared to 1 percent for control. EPO for management of anemia was
allowed at the discretion of the investigator per the study
protocol, and was used by 43 percent of patients in each of the
treatment groups receiving VICTRELIS compared to 24 percent for
control.
In the HCV RESPOND-2 study in treatment-failure patients, the
five most common treatment-related adverse events reported for
patients receiving VICTRELIS in RGT, VICTRELIS in a 48-week
treatment regimen and control, respectively, were: fatigue (54, 57,
and 50 percent), headache (41, 39 and 48 percent), nausea (44, 39
and 38 percent), anemia (43, 46 and 20) and chills (35, 30 and 30
percent). Serious adverse events were reported in 10, 14 and 5
percent of patients in the study arms, respectively. There was one
death in the study, a suicide in the group receiving VICTRELIS in
RGT, which occurred 18 weeks after the end of the study treatment
and was considered to be unrelated to the study treatment.
In HCV RESPOND-2, treatment discontinuations due to adverse
events over the total course of all treatment were 8 percent and 12
percent for patients receiving VICTRELIS in RGT and VICTRELIS in a
48-week treatment regimen, respectively, compared to 2 percent for
control. Treatment discontinuations due to anemia were 0 percent
and 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 the
investigator per the study protocol, and was used by 41 and 46
percent of patients receiving VICTRELIS in RGT and VICTRELIS in a
48-week treatment regimen, respectively, compared to 21 percent for
control.
Merck's global commitment to advancing hepatitis
therapy
Merck is committed to building on its strong legacy in the field
of viral hepatitis by continuing to discover, develop and deliver
vaccines and medicines to help prevent and treat viral hepatitis.
In hepatitis C, company researchers developed the first approved
therapy for chronic HCV in 1991 and the first combination therapy
in 1998. 2011 marks the 10-year anniversary of the introduction of
PEGINTRON and ribavirin in combination therapy, a current standard
therapy for chronic HCV worldwide. In addition to ongoing studies
with VICTRELIS, extensive research efforts are underway to develop
additional innovative oral therapies for viral hepatitis care.
About PEGINTRON
PEGINTRON is indicated for use in combination with ribavirin for
the treatment of chronic hepatitis C in patients 3 years of age and
older with compensated liver disease.
The following points should be considered when initiating
therapy with PEGINTRON in combination with ribavirin: (1) These
indications are based on achieving undetectable HCV-RNA after
treatment for 24 or 48 weeks and maintaining a Sustained Virologic
Response (SVR) 24 weeks after the last dose. (2) Patients with the
following characteristics are less likely to benefit from
re-treatment after failing a course of therapy: previous
nonresponse, previous pegylated interferon treatment, significant
bridging fibrosis or cirrhosis, and genotype 1 infection. (3) No
safety and efficacy data are available for treatment of longer than
one year.
PEGINTRON is also indicated for use alone for the treatment of
chronic hepatitis C in patients with compensated liver disease
previously untreated with interferon alpha and who are at least 18
years of age.
The following points should be considered when initiating
therapy with PEGINTRON alone: Combination therapy with ribavirin is
preferred over PEGINTRON monotherapy unless there are
contraindications to, or significant intolerance of, ribavirin.
Combination therapy provides substantially better response rates
than monotherapy.
Selected Safety Information on PEGINTRON
WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED
EFFECTS
Alpha interferons, including PEGINTRON, may cause or
aggravate fatal or life-threatening neuropsychiatric, autoimmune,
ischemic, and infectious disorders. Patients should be
monitored closely with periodic clinical and laboratory
evaluations. Patients with persistently severe or worsening
signs or symptoms of these conditions should be withdrawn from
therapy. In many, but not all cases, these disorders resolve after
stopping PEGINTRON therapy.
Use with Ribavirin:
Ribavirin may cause birth defects and death of the unborn
child. Extreme care must be taken to avoid pregnancy in
female patients and in female partners of male patients.
Ribavirin causes hemolytic anemia. The anemia associated
with ribavirin therapy may result in a worsening of cardiac
disease. Ribavirin is genotoxic and mutagenic and should be
considered a potential carcinogen.
Contraindications
PEGINTRON is contraindicated in patients with known
hypersensitivity reactions such as urticaria, angioedema,
bronchoconstriction, anaphylaxis, Stevens-Johnson syndrome and
toxic epidermal necrolysis to interferon alpha or any other
component of the product, autoimmune hepatitis, and hepatic
decompensation (Child-Pugh score greater than 6 [class B and C]) in
cirrhotic CHC patients before or during treatment.
PEGINTRON/ribavirin combination therapy is additionally
contraindicated in women who are pregnant or may become pregnant,
men whose female partners are pregnant, patients with
hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia),
and patients with creatinine clearance less than 50 mL per min.
Pregnancy
Ribavirin therapy should not be started until a report of a
negative pregnancy test has been obtained immediately prior to
planned initiation of therapy. Patients should use at least
two effective forms of contraception and have monthly pregnancy
tests during therapy and for six months after completion of
therapy. If this drug is used during pregnancy, or if a patient
becomes pregnant, the patient should be apprised of the potential
hazard to a fetus. A Ribavirin Pregnancy Registry has been
established to monitor maternal-fetal outcomes of pregnancies in
female patients and female partners of male patients exposed to
ribavirin during treatment, and for six months following cessation
of treatment. Physicians and patients are encouraged to report such
cases by calling 1-800-593-2214.
Patients with the following conditions should be closely
monitored and may require dose reduction or discontinuation of
therapy:
- Hemolytic anemia with ribavirin
- Neuropsychiatric events
- History of significant or unstable
cardiac disease - Hypothyroidism, hyperthyroidism,
hyperglycemia, diabetes mellitus that cannot be effectively treated
by medication - New or worsening ophthalmologic
disorders - Ischemic and hemorrhagic
cerebrovascular events - Severe decreases in neutrophil or
platelet counts - History of autoimmune disorders
- Pancreatitis and ulcerative or
hemorrhagic/ischemic colitis and pancreatitis - Pulmonary infiltrates or pulmonary
function impairment - Child-Pugh score greater than 6 (Class
B and C) - Increased creatinine levels in patients
with renal insufficiency - Serious, acute hypersensitivity
reactions and cutaneous eruptions - Dental/periodontal disorders reported
with combination therapy - Hypertriglyceridemia may result in
pancreatitis (e.g., triglycerides greater than
1000 mg/dL) - Weight loss and growth inhibition
reported with combination therapy in pediatric patients.
suicidal and homicidal ideation, depression, relapse of drug
addiction/overdose, and aggressive behavior, sometimes directed
towards others, have occurred in patients with and without a
previous psychiatric disorder during PEGINTRON treatment and
follow-up.
Adverse Events
Serious adverse reactions have occurred in approximately 12
percent of subjects in clinical trials. The most common serious
events occurring in subjects treated with PEGINTRON and ribavirin
were depression and suicidal ideation, each occurring at a
frequency of less than 1 percent. The most common fatal events
occurring in subjects treated with PEGINTRON and ribavirin were
cardiac arrest, suicidal ideation, and suicide attempt, all
occurring in less than 1 percent of subjects.
The incidence of serious adverse reactions was comparable
between PEGINTRON monotherapy (about 12 percent) and
PEGINTRON/ribavirin combination therapy weight-based (12 percent)
or flat-dose (17 percent). In many but not all cases, adverse
reactions resolved after dose reduction or discontinuation of
therapy. Some patients experienced ongoing or new serious adverse
reactions during the 6-month follow-up period. In a study with
PEGINTRON/ribavirin (weight-based) combination therapy in adult
patients, anemia with weight-based dosing occurred at an increased
rate (29 percent vs. 19 percent); however, the majority of these
cases were mild and responded to dose reductions. The incidence of
serious adverse reactions reported for the weight-based ribavirin
group was 12 percent. There were 31 deaths in clinical trials which
occurred during treatment or during follow-up. Of the deaths, 19
were patients on either PEGINTRON or PEGINTRON/ribavirin
combination therapy and three occurred during the follow-up period
but had been on PEGINTRON/ribavirin combination therapy.
Additional serious adverse reactions seen in clinical trials at
a frequency of equal to or less than 1 percent included psychosis,
aggressive reaction, relapse of drug addiction/overdose; nerve
palsy (facial, oculomotor); cardiomyopathy, angina, pericardial
effusion, retinal ischemia, retinal artery or vein thrombosis,
blindness, decreased visual acuity, optic neuritis, transient
ischemic attack, supraventricular arrhythmias, loss of
consciousness; neutropenia, infection (sepsis, pneumonia, abscess,
cellulitis); emphysema, bronchiolitis obliterans, pleural effusion,
gastroenteritis, pancreatitis, gout, hyperglycemia, hyperthyroidism
and hypothyroidism, autoimmune thrombocytopenia with or without
purpura, rheumatoid arthritis, interstitial nephritis, lupus-like
syndrome, sarcoidosis, aggravated psoriasis, urticaria, injection
site necrosis, vasculitis, and phototoxicity.
Greater than 96 percent of all subjects in clinical trials
experienced one or more adverse events. Most common adverse
reactions (greater than 40 percent) in adult patients receiving
either PEGINTRON or PEGINTRON/ribavirin are injection site
inflammation/reaction, fatigue/asthenia, headache, rigors, fevers,
nausea, myalgia, and anxiety/emotional lability/irritability.
The adverse reaction profile was similar between weight-based
and flat-dose PEGINTRON/ribavirin therapies. Weight-based
PEGINTRON/ribavirin dosing resulted in increased rates of anemia.
Most common adverse reactions with PEGINTRON/ribavirin
(weight-based) therapy were psychiatric, which occurred among 68-69
percent of patients and included depression, irritability, and
insomnia, each reported by approximately 30-40 percent of subjects
in all treatment groups. Suicidal behavior (ideation, attempts, and
suicides) occurred in 2 percent of all patients during treatment or
during follow-up after treatment cessation. Other common reactions
included injection site reactions, fatigue/ asthenia, headache,
rigors, fever, nausea, myalgia, anxiety/emotional
lability/irritability. The severity of some of these systemic
symptoms tends to decrease as treatment continues.
Subjects receiving PEGINTRON/ribavirin as re-treatment after
failing a previous interferon combination regimen reported adverse
reactions similar to previous treatment-naïve patients
receiving this regimen.
In general, the adverse reaction profile in the pediatric
population was similar to that observed in adults. Most common
adverse reactions (greater than 25 percent) in pediatric patients
receiving PEGINTRON/ribavirin are pyrexia, headache, neutropenia,
fatigue, anorexia, injection site erythema, abdominal pain, and
vomiting.
Please see full prescribing information at
http://www.spfiles.com/pipeg-intron.pdf.
About Merck
Today's Merck is a global healthcare leader working to help the
world be well. Merck is known as MSD outside the United States and
Canada. Through our prescription medicines, vaccines, biologic
therapies, and consumer care and animal health products, we work
with customers and operate in more than 140 countries to deliver
innovative health solutions. We also demonstrate our commitment to
increasing access to healthcare through far-reaching policies,
programs and partnerships. For more information, visit
www.merck.com.
Forward-Looking Statement
This news release includes “forward-looking
statements” within the meaning of the safe harbor provisions
of the United States Private Securities Litigation Reform Act of
1995. Such statements may include, but are not limited to,
statements about the benefits of the merger between Merck and
Schering-Plough, including future financial and operating results,
the combined company's plans, objectives, expectations and
intentions and other statements that are not historical facts. Such
statements are based upon the current beliefs and expectations of
Merck's management and are subject to significant risks and
uncertainties. Actual results may differ from those set forth in
the forward-looking statements.
The following factors, among others, could cause actual results
to differ from those set forth in the forward-looking statements:
the possibility that the expected synergies from the merger of
Merck and Schering-Plough will not be realized, or will not be
realized within the expected time period; the impact of
pharmaceutical industry regulation and health care legislation; the
risk that the businesses will not be integrated successfully;
disruption from the merger making it more difficult to maintain
business and operational relationships; Merck's ability to
accurately predict future market conditions; dependence on the
effectiveness of Merck's patents and other protections for
innovative products; the risk of new and changing regulation and
health policies in the U.S. and internationally and the exposure to
litigation and/or regulatory actions.
Merck undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in Merck's 2010 Annual
Report on Form 10-K and the company's other filings with the
Securities and Exchange Commission (SEC) available at the SEC's
Internet site (http://www.sec.gov/).
Please see attached Prescribing Information, Medication
Guide, and Instructions for Use including Boxed Warning for
PEGINTRON. 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 and
http://www.spfiles.com/ifupeg-intron.pdf.
1 SVR, the protocol specified primary efficacy
endpoint of the studies, is defined as achievement of undetectable
HCV-RNA at 24 weeks after the end of treatment in all randomized
patients treated with any study medication. Per protocol, if a
patient did not have a 24-week post-treatment assessment, the
patient's 12-week post-treatment assessment was utilized.
AINF-1003633-0000
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to
use
PegIntron safely and effectively. See full prescribing
information for PegIntron.
PegIntron (Peginterferon alfa-2b) Injection, Powder for
Solution for Subcutaneous Use
Initial U.S. Approval: 2001
WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED
EFFECTS
See full prescribing information for complete boxed
warning.
- May cause or aggravate fatal or
life-threatening neuropsychiatric, autoimmune, ischemic, and
infectious disorders. Monitor closely and withdraw therapy with
persistently severe or worsening signs or symptoms of the above
disorders. (5)
- Ribavirin may cause birth defects
and fetal death; avoid pregnancy in female patients and female
partners of male patients. (5.1) - Ribavirin is a potential carcinogen.
(5.1, 13.1)
Warnings and Precautions, Pulmonary Disorders (5.11)
[2/2011]
INDICATIONS AND USAGE
PegIntron is an antiviral indicated for
- Combination
therapy with REBETOL (ribavirin):
Chronic Hepatitis C (CHC) in patients ‰¥3 years with
compensated liver disease. (1.1)
Patients with the following characteristics are less likely to
benefit from re-treatment after failing a course of therapy:
previous nonresponse, previous pegylated interferon treatment,
significant bridging fibrosis or cirrhosis, and genotype 1
infection. (1.1)
- Monotherapy: CHC in patients (‰¥18
years) with compensated liver disease previously untreated with
interferon alpha. (1.1)
- PegIntron is administered by
subcutaneous injection.
| PegIntron Dose (Adults)* | PegIntron Dose (Pediatric Patients) | REBETOL Dose* (Adults) | REBETOL Dose (Pediatric Patients) | |||||
| PegIntron/ REBETOL Combination Therapy (2.1) | 1.5 mcg/kg/ week | 60 mcg/m2/ week | 800-1400 mg orally daily with food | 15 mg/kg/day orally with food in 2 divided doses |
- Dose reduction is recommended in
patients experiencing certain adverse reactions or renal
dysfunction. (2.3, 2.5)
Single-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.
- Known hypersensitivity reactions, such
as urticaria, angioedema, bronchoconstriction, anaphylaxis,
Stevens-Johnson syndrome, and toxic epidermal necrolysis to
interferon alpha or any other product component. (4) - Autoimmune hepatitis. (4)
- Hepatic decompensation (Child-Pugh
score >6 [class B and C]) in cirrhotic CHC patients before or
during treatment. (4)
ribavirin:
- Pregnant women and men whose female
partners are pregnant. (4, 8.1) - Hemoglobinopathies (e.g., thalassemia
major, sickle-cell anemia). (4) - Creatinine clearance
<50 mL/min. (4)
- Birth defects and fetal death with
ribavirin: Patients must have a negative pregnancy test prior to
therapy, use at least 2 forms of contraception, and undergo monthly
pregnancy tests. (5.1)
monitored and may require dose reduction or discontinuation of
therapy:
- Hemolytic anemia with ribavirin.
(5.1) - Neuropsychiatric events. (5.2)
- History of significant or unstable
cardiac disease. (5.3) - Hypothyroidism, hyperthyroidism,
hyperglycemia, diabetes mellitus that cannot be effectively treated
by medication. (5.4) - New or worsening ophthalmologic
disorders. (5.5) - Ischemic and hemorrhagic
cerebrovascular events. (5.6) - Severe decreases in neutrophil or
platelet counts. (5.7) - History of autoimmune disorders.
(5.8) - Pancreatitis and ulcerative or
hemorrhagic/ischemic colitis and pancreatitis. (5.9, 5.10) - Pulmonary infiltrates or pulmonary
function impairment. (5.11) - Child-Pugh score >6 (class B and C).
(4, 5.12) - Increased creatinine levels in patients
with renal insufficiency. (5.13) - Serious, acute hypersensitivity
reactions and cutaneous eruptions. (5.14) - Dental/periodontal disorders reported
with combination therapy. (5.16) - Hypertriglyceridemia may result in
pancreatitis (e.g., triglycerides >1000 mg/dL). (5.17) - Weight loss and growth inhibition
reported with combination therapy in pediatric patients.
(5.18) - Peripheral neuropathy when used in
combination with telbivudine. (5.19)
Most common adverse reactions (>40%) in adult patients
receiving either
PegIntron or PegIntron/REBETOL are injection site
inflammation/
reaction, fatigue/asthenia, headache, rigors, fevers, nausea,
myalgia and anxiety/emotional lability/irritability (6.1). Most
common adverse reactions (>25%) in pediatric patients receiving
PegIntron/REBETOL are pyrexia, headache, neutropenia, fatigue,
anorexia, injection-site erythema, vomiting (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Schering
Corporation, a subsidiary of Merck & Co., Inc., at
1-800-526-4099 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
DRUG INTERACTIONS
- Drug metabolized by CYP450: Caution
with drugs metabolized by CYP2C8/9 (e.g., warfarin, phenytoin) or
CYP2D6 (e.g., flecainide). (7.1) - Methadone: Monitor for increased
narcotic effect. (7.2) - Nucleoside analogues: Closely monitor
for toxicities. Discontinue nucleoside reverse transcriptase
inhibitors or reduce dose or discontinue interferon, ribavirin, or
both with worsening toxicities. (7.3) - Didanosine: Concurrent use with REBETOL
is not recommended. (7.3)
- Ribavirin Pregnancy Registry:
1-800-593-2214 (8.1) - Pediatrics: safety and efficacy in
pediatrics <3 years old have not been established (8.4) - Geriatrics: neuropsychiatric, cardiac,
pulmonary, GI, and systemic (flu-like) adverse reactions may be
more severe (8.5) - Organ transplant: safety and efficacy
have not been studied (8.6) - HIV or HBV co-infection: safety and
efficacy have not been established (8.7)
Guide.
Revised: 02/2011
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING – RISK OF SERIOUS DISORDERS AND
RIBAVIRIN-ASSOCIATED EFFECTS
1 INDICATIONS AND USAGE
1.1 Chronic Hepatitis C
2 DOSAGE AND ADMINISTRATION
2.1 PegIntron/REBETOL Combination Therapy
2.2 PegIntron Monotherapy
2.3 Dose Reduction
2.4 Discontinuation of Dosing
2.5 Renal Function
2.6 Preparation and Administration
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Use with Ribavirin
5.2 Neuropsychiatric Events
5.3 Cardiovascular Events
5.4 Endocrine Disorders
5.5 Ophthalmologic Disorders
5.6 Cerebrovascular Disorders
5.7 Bone Marrow Toxicity
5.8 Autoimmune Disorders
5.9 Pancreatitis
5.10 Colitis
5.11 Pulmonary Disorders
5.12 Hepatic Failure
5.13 Patients with Renal Insufficiency
5.14 Hypersensitivity
5.15 Laboratory Tests
5.16 Dental and Periodontal Disorders
5.17 Triglycerides
5.18 Impact on Growth- Pediatric Use
5.19 Peripheral Neuropathy
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Immunogenicity
6.3 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Drugs Metabolized by Cytochrome P-450
7.2 Methadone
7.3 Use with Ribavirin (Nucleoside Analogues)
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Organ Transplant Recipients
8.7 HIV or HBV Co-infection
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Chronic Hepatitis C in Adults
14.2 Chronic Hepatitis C in Pediatrics
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Pregnancy
17.2 HCV Transmission
17.3 Laboratory Evaluations, Hydration, “Flu-like”
Symptoms
17.4 Instructions for Use
*Sections or subsections omitted from the full prescribing
information are not listed.
FULL PRESCRIBING INFORMATION
WARNING: RISK OF SERIOUS DISORDERS AND RIBAVIRIN-ASSOCIATED
EFFECTS
Alpha interferons, including PegIntron, may cause or
aggravate fatal or life-threatening neuropsychiatric, autoimmune,
ischemic, and infectious disorders. Patients should be
monitored closely with periodic clinical and laboratory
evaluations. Patients with persistently severe or worsening
signs or symptoms of these conditions should be withdrawn from
therapy. In many, but not all cases, these disorders resolve
after stopping PegIntron therapy [see Warnings and
Precautions (5) and Adverse Reactions
(6.1)].
Use with Ribavirin
Ribavirin may cause birth defects and death of the unborn
child. Extreme care must be taken to avoid pregnancy in
female patients and in female partners of male patients. Ribavirin
causes hemolytic anemia. The anemia associated with REBETOL
therapy may result in a worsening of cardiac disease.
Ribavirin is genotoxic and mutagenic and should be considered a
potential carcinogen. [See REBETOL package
insert]
1 INDICATIONS AND USAGE
1.1 Chronic Hepatitis C
Combination therapy:
PegIntron® in combination with REBETOL® (ribavirin) is
indicated for the treatment of chronic hepatitis C in patients 3
years of age and older with compensated liver disease.
The following points should be considered when initiating
therapy with PegIntron in combination with REBETOL:
- These indications are based on
achieving undetectable HCV-RNA after treatment for 24 or 48 weeks
and maintaining a Sustained Virologic Response (SVR) 24 weeks after
the last dose. - Patients with the following
characteristics are less likely to benefit from retreatment after
failing a course of therapy: previous nonresponse, previous
pegylated interferon treatment, significant bridging fibrosis or
cirrhosis, and genotype 1 infection [see Clinical Studies
(14)]. - No safety and efficacy data are
available for treatment of longer than 1 year.
intolerant to ribavirin):
PegIntron (peginterferon alfa-2b) is indicated for use alone for
the treatment of chronic hepatitis C in patients with compensated
liver disease previously untreated with interferon alpha and who
are at least 18 years of age.
The following point should be considered when initiating therapy
with PegIntron alone:
- Combination therapy with REBETOL is
preferred over PegIntron monotherapy unless there are
contraindications to or significant intolerance of REBETOL.
than monotherapy [see Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
2. 1 PegIntron/REBETOL Combination Therapy
REBETOL should be taken with food. REBETOL should not be used in
patients with creatinine clearance <50 mL/min.
Adults
The recommended dose of PegIntron is 1.5 mcg/kg/week
subcutaneously in combination with 800 to 1400 mg of REBETOL orally
based on patient body weight. The volume of PegIntron to be
injected depends on the strength of PegIntron and patient's body
weight (see Table 1).
Duration of Treatment – Interferon Alpha-naïve
Patients
The treatment duration for patients with genotype 1 is 48 weeks.
Discontinuation of therapy should be considered in patients who do
not achieve at least a 2 log10 drop or loss of HCV-RNA
at 12 weeks, or if HCV-RNA remains detectable after 24 weeks of
therapy. Patients with genotype 2 and 3 should be treated for 24
weeks.
Duration of Treatment – Re-treatment with
PegIntron/REBETOL of Prior Treatment Failures
The treatment duration for patients who previously failed
therapy is 48 weeks, regardless of HCV genotype. Re-treated
patients who fail to achieve undetectable HCV-RNA at Week 12 of
therapy, or whose HCV-RNA remains detectable after 24 weeks of
therapy, are highly unlikely to achieve SVR and discontinuation of
therapy should be considered [see Clinical Studies
(14.1)].
| TABLE 1 Recommended PegIntron Combination Therapy Dosing (Adults) | |||||||||
| Body weight kg (lbs) | PegIntron REDIPEN® or Vial Strength to Use | Amount of PegIntron (mcg) to Administer | Volume (mL)* of PegIntron to Administer | REBETOL Daily Dose | REBETOL Number of Capsules | ||||
| <40 (<88) | 50 mcg per 0.5 mL | 50 | 0.5 | 800 mg/day | 2 x 200 mg capsules 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 | 2 x 200 mg capsules A.M. 2 x 200 mg capsules P.M. | ||||
| 51 – 60 (112 – 133) | 80 | 0.5 | 800 mg/day | 2 x 200 mg capsules 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 | 2 x 200 mg capsules A.M. 2 x 200 mg capsules P.M. | ||||
| 66 – 75 (145 – 166) | 96 | 0.4 | 1000 mg/day | 2 x 200 mg capsules A.M. 3 x 200 mg capsules P.M. | |||||
76 – 80 (167 – 177) | 120 | 0.5 | 1000 mg/day | 2 x 200 mg capsules A.M. 3 x 200 mg capsules P.M. | |||||
| 81 – 85 (178 – 187) | 1200 mg/day | 3 x 200 mg capsules A.M. 3 x 200 mg capsules P.M. | |||||||
| 86 – 105 (188 – 231) | 150 mcg per 0.5 mL | 150 | 0.5 | 1200 mg/day | 3 x 200 mg capsules A.M. 3 x 200 mg capsules P.M. | ||||
| >105 (>231) | ** | ** | ** | 1400 mg/day | 3 x 200 mg capsules A.M. 4 x 200 mg capsules P.M. | ||||
** For patients weighing >105 kg (>231 pounds), the
PegIntron dose of 1.5 mcg/kg/week should be calculated based on the
individual patient weight. Two vials of PegIntron may be necessary
to provide the dose.
Pediatric Patients
Dosing for pediatric patients is determined by body surface area
for PegIntron and by body weight for REBETOL. The recommended dose
of PegIntron is 60mcg/m2/week subcutaneously in
combination 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 receiving
PegIntron/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 2 Recommended REBETOL* Dosing in Combination Therapy (Pediatrics) | ||||
| Body weight kg (lbs) | REBETOL Daily Dose | REBETOL Number of Capsules | ||
| less then;47 (less then;103) | 15 mg/kg/day | Use REBETOL Oral Solution** | ||
| 47 – 59 (103-131) | 800 mg/day | 2 x 200 mg capsules A.M. 2 x 200 mg capsules P.M. | ||
| 60 – 73 (132-162) | 1000 mg/day | 2 x 200 mg capsules A.M. 3 x 200 mg capsules P.M. | ||
| more then 73 (less then162) | 1200 mg/day | 3 x 200 mg capsules A.M. 3 x 200 mg capsules P.M. | ||
mcg/m2 weekly.
** REBETOL Oral Solution may be used for any patient
regardless of body weight.
2.2 PegIntron Monotherapy
The recommended dose of PegIntron regimen is 1 mcg/kg/week
subcutaneously for 1 year administered on the same day of the week.
Discontinuation of therapy should be considered in patients who do
not achieve at least a 2 log10 drop or loss of HCV-RNA
at 12 weeks of therapy, or whose HCV-RNA levels remain detectable
after 24 weeks of therapy. The volume of PegIntron to be injected
depends on patient weight (see Table 3).
| TABLE 3 Recommended PegIntron Monotherapy Dosing | |||||||||
| Body weight kg (lbs) | PegIntron REDIPEN or Vial Strength to Use | Amount of PegIntron (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 mcg per 0.5 mL | 150 | |||||||
Also See; Boceprevir; Difficult Hepatitis C Type Responds to Novel Protease Inhibitor
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