DESCRIPTION
PEG-IntronTM, peginterferon alfa-2b Powder for Injection, is a covalent conjugate of recombinant alfa-2b
interferon with monomethoxy polyethylene glycol (PEG). The average molecular weight of the PEG
portion of the molecule is 12,000 daltons. The average molecular weight of the PEG-Intron molecule is
approximately 31,000 daltons. The specific activity of peginterferon alfa-2b is approximately 0.7 x 108
IU/mg protein.
Interferon alfa-2b, is a water-soluble protein with a molecular weight of 19,271 daltons produced by
recombinant DNA techniques. It is obtained from the bacterial fermentation of a strain of Escherichia
coli bearing a genetically engineered plasmid containing an interferon gene from human leukocytes.
PEG-Intron is a white to off-white lyophilized powder supplied in 2-mL vials for subcutaneous use.
Each vial contains either 74 µg, 118.4 µg;, 177.6 µg;, or 222 µg; of PEG-Intron, and 1.11 mg dibasic sodium
phosphate anhydrous, 1.11 mg monobasic sodium phosphate dihydrate, 59.2 mg sucrose and
0.074 mg polysorbate 80. Following reconstitution with 0.7 mL of the supplied diluent (Sterile Water for
Injection, USP), each vial contains PEG-Intron at strengths of either 50 µg; per 0.5 mL, 80 µg; per .05 mL,
120 µg; per 0.5 mL, or 150 µg; per 0.5 mL.
CLINICAL PHARMACOLOGY
General:
The biological activity of PEG-Intron is derived from its interferon alfa-2b moiety. Interferons
exert their cellular activities by binding to specific membrane receptors on the cell surface and initiate
a complex sequence of intracellular events. These include the induction of certain enzymes, suppression
of cell proliferation, immunomodulating activities such as enhancement of the phagocytic activity
of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells, and inhibition
of virus replication in virus-infected cells. Interferon alfa upregulates the Th1 T-helper cell subset
in in vitro studies. The clinical relevance of these findings is not known.
Pharmacodynamics:
PEG-Intron raises concentrations of effector proteins such as serum neopterin
and 2..5..oligoadenylate synthetase, raises body temperature, and causes reversible decreases in leukocyte
and platelet counts. The correlation between the in vitro and in vivo pharmacologic and pharmacodynamic
and clinical effects is unknown.
Pharmacokinetics:
Following a single subcutaneous (SC) dose of PEG-Intron, the mean absorption
half-life (t 1 /2 ka) was 4.6 hours. Maximal serum concentrations (Cmax) occur between 15-44 hours post-dose,
and are sustained for up to 48-72 hours. The Cmax and AUC measurements of PEG-Intron increase
in a dose-related manner. After multiple dosing, there is an increase in bioavailability of PEG-Intron.
Week 48 mean trough concentrations (320 pg/mL; range 0, 2960) are approximately 3-fold higher than
Week 4 mean trough concentrations (94 pg/mL; range 0, 416). The mean PEG-Intron elimination half-life
is approximately 40 hours (range 22 to 60 hours) in patients with HCV infection. The apparent
clearance of PEG-Intron is estimated to be approximately 22.0 mL/hrokg. Renal elimination accounts for
30% of the clearance. Single dose peginterferon alfa-2b pharmacokinetics following a subcutaneous
1.0 µg;/kg dose suggest the clearance of peginterferon alfa-2b is reduced by approximately half in subjects
with impaired renal function (creatinine clearance <50 mL/minute).
Pegylation of interferon alfa-2b produces a product (PEG-Intron) whose clearance is lower than that
of non-pegylated interferon alfa-2b. When compared to INTRON A, PEG-Intron (1.0 µg/kg) has approximately
a seven-fold lower mean apparent clearance and a five-fold greater mean half-life permitting a
reduced dosing frequency. At effective therapeutic doses, PEG-Intron has approximately tenfold
greater Cmax and 50-fold greater AUC than interferon alfa-2b.
The pharmacokinetics of geriatric subjects (>65 years of age) treated with a single subcutaneous
dose of 1.0 µg;/kg of PEG-Intron were similar in Cmax, AUC, clearance, or elimination half-life as compared
to younger subjects (28 to 44 years of age).
During the 48 week treatment period with PEG-Intron, no differences in the pharmacokinetic profiles
were observed between male and female patients with chronic hepatitis C infection.
Effect of Food on Absorption of Ribavirin Both AUCtf and Cmax increased by 70% when
REBETOL Capsules were administered with a high-fat meal (841 kcal, 53.8 g fat, 31.6 g protein, and
57.4 g carbohydrate) in a single-dose pharmacokinetic study. (See DOSAGE AND ADMINISTRATION).
Drug Interactions:
It is not known if PEG-Intron therapy causes clinically significant drug-drug interactions
with drugs metabolized by the liver in patients with hepatitis C. In 12 healthy subjects known to
be CYP2D6 extensive metabolizers, a single subcutaneous dose of 1 µg;/kg PEG-Intron did not inhibit
CYP1A2, 2C8/9, 2D6, hepatic 3A4 or N-acetyltransferase; the effects of PEG-Intron on CYP2C19 were
not assessed.
CLINICAL STUDIES
PEG-Intron Monotherapy-Study 1
A randomized study compared treatment with PEG-Intron (0.5, 1.0, or 1.5 µg/kg once weekly SC) to
treatment with INTRON A, (3 million units three times weekly SC) in 1219 adults with chronic hepatitis
from HCV infection. The patients were not previously treated with interferon alfa, had compensated liver
disease, detectable HCV RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis.
Patients were treated for 48 weeks and were followed for 24 weeks post-treatment. Seventy percent of
all patients were infected with HCV genotype 1, and 74 percent of all patients had high baseline levels
of HCV RNA (more than 2 million copies per mL of serum), two factors known to predict poor response
to treatment.
Response to treatment was defined as undetectable HCV RNA and normalization of ALT at
24 weeks post-treatment. The response rates to the 1.0 and 1.5 µg/kg PEG-Intron doses were similar
(approximately 24%) to each other and were both higher than the response rate to INTRON A (12%).
(See Table 1)
| Table 1. Rates of Response to Treatment |
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Patients with both viral genotype 1 and high serum levels of HCV RNA at baseline were less likely to
respond to treatment with PEG-Intron. Among patients with the two unfavorable prognostic variables,
8% (12/157) responded to PEG-Intron treatment and 2% (4/169) responded to INTRON A. Doses of
PEG-Intron higher than the recommended dose did not result in higher response rates in these patients.
Patients receiving PEG-Intron with viral genotype 1 had a response rate of 14% (28/199) while
patients with other viral genotypes had a 45% (43/96) response rate.
Ninety-six percent of the responders in the PEG-Intron groups and 100% of responders in the
INTRON A group first cleared their viral RNA by week-24 of treatment. See DOSAGE AND ADMINISTRATION.
The treatment response rates were similar in men and women. Response rates were lower in African
American and Hispanic patients and higher in Asians compared to Caucasians. Although African
Americans had a higher proportion of poor prognostic factors compared to Caucasians the number of
non-Caucasians studied (9% of the total) was insufficient to allow meaningful conclusions about differences
in response rates after adjusting for prognostic factors.
Liver biopsies were obtained before and after treatment in 60% of patients. A modest reduction in
inflammation compared to baseline that was similar in all four treatment groups was observed.
PEG-Intron/REBETOL Combination Therapy-Study 2
A randomized study compared treatment with two PEG-Intron/REBETOL regimens [PEG-Intron
1.5 µg/kg SC once weekly (QW)/REBETOL 800 mg PO daily (in divided doses); PEG-Intron
1.5 µg/kg SC QW for 4 weeks then 0.5 µg/kg SC QW for 44 weeks/REBETOL 1000/1200 mg PO daily
(in divided doses)] with INTRON A (3 MIU SC thrice weekly (TIW)/REBETOL 1000/1200 mg PO daily
(in divided doses) in 1530 adults with chronic hepatitis C. Interferon na�ve patients were treated for
48 weeks and followed for 24 weeks post-treatment. Eligible patients had compensated liver disease,
detectable HCV RNA, elevated ALT, and liver histopathology consistent with chronic hepatitis.
Response to treatment was defined as undetectable HCV RNA at 24 weeks post-treatment. The
response rate to the PEG-Intron 1.5 µg/kg plus ribavirin 800 mg dose was higher than the response rate
to INTRON A/REBETOL (See Table 2). The response rate to PEG-Intron 1.5 -> 0.5µg/kg/REBETOL was
essentially the same as the response to INTRON A/REBETOL (data not shown).
| Table 2. Rates of Response to Treatment-Study 2 |
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Patients with viral genotype 1, regardless of viral load, had a lower response rate to PEG-Intron
(1.5 µg/kg)/REBETOL compared to patients with other viral genotypes. Patients with both poor prognostic
factors (genotype 1 and high viral load) had a response rate of 30% (78/256) compared to a
response rate of 29% (71/247) with INTRON A/REBETOL.
Patients with lower body weight tended to have higher adverse event rates (see ADVERSE REACTIONS)
and higher response rates than patients with higher body weights. Differences in response rates
between treatment arms did not substantially vary with body weight.
Treatment response rates with PEG-Intron/REBETOL were 49% in men and 56% in women. Response
rates were lower in African American and Hispanic patients and higher in Asians compared to
Caucasians. Although African Americans had a higher proportion of poor prognostic factors compared
to Caucasians the number of non-Caucasians studied (11% of the total) was insufficient to allow meaningful
conclusions about differences in response rates after adjusting for prognostic factors.
Liver biopsies were obtained before and after treatment in 68% of patients. Compared to baseline
approximately 2/3 of patients in all treatment groups were observed to have a modest
reduction in inflammation.
INDICATIONS AND USAGE
PEG-Intron, peginterferon alfa-2b, is indicated for use alone or in combination with REBETOL (ribavirin,
USP) for the treatment of chronic hepatitis C in patients with compensated liver disease who have not
been previously treated with interferon alpha and are at least 18 years of age.
CONTRAINDICATIONS
PEG-Intron is contraindicated in patients with:
hypersensitivity to PEG-Intron or any other component of the product
autoimmune hepatitis
decompensated liver disease
PEG-Intron/REBETOL combination therapy is additionally contraindicated in:
patients with hypersensitivity to ribavirin or any other component of the product
women who are pregnant
men whose female partners are pregnant
patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia)
WARNINGS
Patients should be monitored for the following serious conditions, some of which may become life
threatening. Patients with persistently severe or worsening signs or symptoms should be withdrawn
from therapy.
Neuropsychiatric events
Life-threatening or fatal neuropsychiatric events, including suicide, suicidal and homicidal ideation,
depression, relapse of drug addiction/overdose, and aggressive behavior have occurred in patients with
and without a previous psychiatric disorder during PEG-Intron treatment and follow-up. Psychoses,
hallucinations, bipolar disorders, and mania have been observed in patients treated with alpha interferons.
PEG-Intron should be used with extreme caution in patients with a history of psychiatric disorders.
Patients should be advised to report immediately any symptoms of depression and/or suicidal ideation
to their prescribing physicians. Physicians should monitor all patients for evidence of depression and
other psychiatric symptoms. In severe cases, PEG-Intron should be stopped immediately and psychi-atric
intervention instituted. (See DOSAGE AND ADMINISTRATION: Dose Reduction.)
Bone marrow toxicity
PEG-Intron suppresses bone marrow function, sometimes resulting in severe cytopenias.
PEG-Intron should be discontinued in patients who develop severe decreases in neutrophil
or platelet counts. (See DOSAGE AND ADMINISTRATION: Dose Reduction). Ribavirin may potentiate
the neutropenia induced by interferon alpha. Very rarely alpha interferons may be associated with aplastic
anemia.
Endocrine disorders
PEG-Intron causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia has been
observed in patients treated with PEG-Intron. Diabetes mellitus has been observed in patients treated
with alpha interferons. Patients with these conditions who cannot be effectively treated by medication
should not begin PEG-Intron therapy. Patients who develop these conditions during treatment and cannot
be controlled with medication should not continue PEG-Intron therapy.
Cardiovascular events
Cardiovascular events, which include hypotension, arrhythmia, tachycardia, cardiomyopathy, angina
pectoris, and myocardial infarction, have been observed in patients treated with PEG-Intron. PEG-Intron
should be used cautiously in patients with cardiovascular disease. Patients with a history of myocardial
infarction and arrhythmic disorder who require PEG-Intron therapy should be closely monitored (see
Laboratory Tests). Patients with a history of significant or unstable cardiac disease should not be treated
with PEG-Intron/REBETOL combination therapy. [See REBETOL package insert.]
Pulmonary disorders
Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis and sarcoidosis
some resulting in respiratory failure and/or patient deaths, may be induced or aggravated by
PEG-Intron or alpha interferon therapy. Recurrence of respiratory failure has been observed with interferon
rechallenge. PEG-Intron combination treatment should be suspended in patients who develop
pulmonary infiltrates or pulmonary function impairment. Patients who resume interferon treatment
should be closely monitored.
Colitis
Fatal and nonfatal ulcerative or hemorrhagic/ischemic colitis have been observed within
12 weeks of the start of alpha interferon treatment. Abdominal pain, bloody diarrhea, and fever are the
typical manifestations. PEG-Intron treatment should be discontinued immediately in patients who
develop these symptoms and signs. The colitis usually resolves within 1-3 weeks of discontinuation of
alpha interferons.
Pancreatitis
Fatal and nonfatal pancreatitis has been observed in patients treated with alpha interferon.
PEG-Intron therapy should be suspended in patients with signs and symptoms suggestive of pancreatitis
and discontinued in patients diagnosed with pancreatitis.
Autoimmune disorders
Development or exacerbation of autoimmune disorders (e.g. thyroiditis, thrombocytopenia, rheumatoid
arthritis, interstitial nephritis, systemic lupus erythematosus, psoriasis) have been observed in patients
receiving PEG-Intron. PEG-Intron should be used with caution in patients with autoimmune disorders.
Ophthalmologic disorders
Decrease or loss of vision, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool
spots, optic neuritis, and papilledema are induced or aggravated by treatment with PEG-Intron or other
alpha interferons. All patients should receive an eye examination at baseline. Patients with preexisting
ophthalmologic disorders (e.g. diabetic or hypertensive retinopathy) should receive periodic ophthalmologic
exams during interferon alpha treatment. Any patient who develops ocular symptoms should
receive a prompt and complete eye examination. PEG-interferon treatment should be discontinued in
patients who develop new or worsening ophthalmologic disorders.
Hypersensitivity
Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction,
anaphylaxis) have been rarely observed during alpha interferon therapy. If such a reaction develops
during treatment with PEG-Intron, discontinue treatment and institute appropriate medical therapy
immediately. Transient rashes do not necessitate interruption of treatment.
Use with Ribavirin-(See also REBETOL Package Insert)
REBETOL may cause birth defects and/or death of the unborn child. REBETOL 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 forms of contraception and have monthly
pregnancy tests (See BOXED WARNING, CONTRAINDICATIONS and PRECAUTIONS: Information for
Patients and REBETOL package insert).
Anemia
Ribavirin caused hemolytic anemia in 10% of PEG-Intron/REBETOL treated patients within
1-4 weeks of initiation of therapy. Complete blood counts should be obtained pretreatment and at week
2 and week 4 of therapy or more frequently if clinically indicated. Anemia associated with REBETOL ther
apy may result in a worsening of cardiac disease. Decrease in dosage or discontinuation of REBETOL
may be necessary. (See DOSAGE AND ADMINISTRATION: Dose Reduction.)
PRECAUTIONS
PEG-Intron alone or in combination with REBETOL has not been studied in patients who have failed other alpha interferon treatments.
The safety and efficacy of PEG-Intron alone or in combination with REBETOL for the treatment of hepatitis C in liver or other organ transplant recipients have not been studied.
The safety and efficacy of PEG-Intron/REBETOL for the treatment of patients with HCV co-infected with HIV or HBV have not been established.
Patients with renal failure: Patients with impairment of renal function should be closely monitored for
signs and symptoms of interferon toxicity and doses of PEG-Intron should be adjusted accordingly.
PEG-Intron should be used with caution in patients with creatinine clearance <50 mL/min. See DOSAGE
AND ADMINISTRATION: Dose Modification.
Immunogenicity: Approximately 2% of patients receiving PEG-Intron (32/1759) or INTRON A (11/728)
with or without REBETOL developed low-titer (<160) neutralizing antibodies to PEG-Intron or INTRON A.
The clinical and pathological significance of the appearance of serum neutralizing antibodies is unknown.
No apparent correlation of antibody development to clinical response or adverse events was observed.
The incidence of post-treatment binding antibody ranged from 8 to 15 percent. The data reflect
the percentage of patients whose test results were considered positive for antibodies to
PEG-Intron in a Biacore assay that is used to measure binding antibodies, and in an antiviral neutralization
assay, which measures serum-neutralizing antibodies. The percentage of patients whose test results
were considered positive for antibodies is highly dependent on the sensitivity and specificity of the
assays. Additionally the observed incidence of antibody positivity in these assays may be influenced by
several factors including sample timing and handling, concomitant medications, and underlying disease.
For these reasons, comparison of the incidence of antibodies to PEG-Intron with the incidence of anti-bodies
to other products may be misleading.
Laboratory Tests: PEG-Intron alone or in combination with ribavirin may cause severe decreases in
neutrophil and platelet counts, and hematologic, endocrine (e.g.TSH) and hepatic abnormalities.
Transient elevations in ALT (2-5 fold above baseline) were observed in 10% of patients treated with
PEG-Intron, and was not associated with deterioration of other liver functions.
Patients on PEG-Intron or PEG-Intron/REBETOL combination therapy should have hematology and
blood chemistry testing before the start of treatment and then periodically thereafter. In the clinical trial
CBC (including hemoglobin, neutrophil and platelet counts) and chemistries (including AST, ALT, bilirubin,
and uric acid) were measured during the treatment period at weeks 2, 4, 8, 12, and then at 6-week
intervals or more frequently if abnormalities developed. TSH levels were measured every 12 weeks during
the treatment period.
HCV RNA should be measured at 6 months of treatment. PEG-Intron or PEG-Intron/REBETOL combination
therapy should be discontinued in patients with persistent high viral levels.
Patients who have pre-existing cardiac abnormalities should have electrocardiograms administered
before treatment with PEG-Intron/REBETOL.
Information for Patients: Patients receiving PEG-Intron alone or in combination with REBETOL should be
directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred
to the MEDICATION GUIDES for PEG-Intron and, if applicable, REBETOL (ribavirin, USP).
Patients must be informed that REBETOL may cause birth defects and/or death of the unborn child.
Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients
taking combination PEG-Intron/REBETOL therapy. Combination PEG-Intron/REBETOL therapy should
not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation
of therapy. It is recommended that patients undergo monthly pregnancy tests during therapy and for
6 months post-therapy. (See CONTRAINIDICATIONS and REBETOL package insert).
A puncture-resistant container for the disposal of used syringes and needles should be supplied to
the patient for at home use. Patients should be thoroughly instructed in the importance of proper disposal
and cautioned against any reuse of needles and syringes. The full container should be disposed
of according to the directions provided by the physician (see MEDICATION GUIDE).
Patients should be informed that there are no data regarding whether PEG-Intron therapy will prevent
transmission of HCV infection to others. Also, it is not known if treatment with PEG-Intron will cure hepatitis
C or prevent cirrhosis, liver failure, or liver cancer that may be the result of infection with the
hepatitis C virus.
Patients should be advised that laboratory evaluations are required before starting therapy and periodically
thereafter (see Laboratory Tests). It is advised that patients be well-hydrated, especially during the
initial stages of treatment. "Flu-like" symptoms associated with administration of PEG-Intron may be
minimized by bedtime administration of PEG-Intron or by use of antipyretics.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis and Mutagenesis: PEG-Intron has not been tested for its carcinogenic potential.
Neither PEG-Intron, nor its components interferon or methoxypolyethylene glycol caused damage to
DNA when tested in the standard battery of mutagenesis assays, in the presence and absence of metabolic
activation.
Use with Ribavirin: Ribavirin is genotoxic and mutagenic and should be considered a potential
carcinogen. See REBETOL package insert for additional warnings relevant to PEG-Intron therapy in
combination with ribavirin.
Impairment of Fertility: PEG-Intron may impair human fertility. Irregular menstrual cycles were
observed in female cynomolgus monkeys given subcutaneous injections of 4239 µg/m 2 PEG-Intron
alone every other day for one month, (approximately 345 times the recommended weekly human dose
based upon body surface area). These effects included transiently decreased serum levels of estradiol
and progesterone, suggestive of anovulation. Normal menstrual cycles and serum hormone levels
resumed in these animals 2 to 3 months following cessation of PEG-Intron treatment. Every other day
dosing with 262 µg/m 2 (approximately 21 times the weekly human dose) had no effects on cycle duration
or reproductive hormone status. The effects of PEG-Intron on male fertility have not been studied.
Pregnancy Category C: PEG-Intron monotherapy: Non-pegylated Interferon alfa-2b, has been shown
to have abortifacient effects in Macaca mulatta (rhesus monkeys) at 15 and 30 million IU/kg (estimated
human equivalent of 5 and 10 million IU/kg, based on body surface area adjustment for a 60 kg
adult). PEG-Intron should be assumed to also have abortifacient potential. There are no adequate and
well-controlled studies in pregnant women. PEG-Intron therapy is to be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus. Therefore, PEG-Intron is recommended for
use in fertile women only when they are using effective contraception during the treatment period.
Pregnancy Category X : Use with Ribavirin
Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species
exposed to ribavirin. REBETOL therapy is contraindicated in women who are pregnant and in the
male partners of women who are pregnant. See CONTRAINDICATIONS and the REBETOL Package
Insert.
If pregnancy occurs in a patient or partner of a patient during treatment with PEG-Intron and
REBETOL during the 6 months after treatment cessation, physicians should report such cases by
calling (800) 727-7064.
Pediatric. Safety and effectiveness in pediatric patients below the age of 18 years have not been
established.
Geriatric. In general, younger patients tend to respond better than older patients to interferon-based
therapies. Clinical studies of PEG-Intron alone or in combination with REBETOL did not include sufficient
numbers of subjects aged 65 and over, however, to determine whether they respond differently
than younger subjects. Treatment with alpha interferons, including PEG-Intron, is associated with neuropsychiatric,
cardiac, pulmonary, GI and systemic (flu-like) adverse effects. Because these adverse
reactions may be more severe in the elderly, caution should be exercised in use of PEG-Intron in this
population. This drug is known to be substantially excreted by the kidney. Because elderly patients are
more likely to have decreased renal function, the risk of toxic reactions to this drug may be greater in
patients with impaired renal function. REBETOL should not be used in patients with creatinine clearance
<50 mL/min. When using PEG-Intron/REBETOL therapy, refer also to the REBETOL Medication Guide.
ADVERSE REACTIONS
Nearly all study patients in clinical trials experienced one or more adverse events. In the PEG monotherapy
trial the incidence of serious adverse events was similar (about 12%) in all treatment groups. In the
PEG-Intron/REBETOL combination trial the incidence of serious adverse events was 17% in the
PEG-Intron/REBETOL groups compared to 14% in the INTRON A/REBETOL group.
In many but not all cases, adverse events resolved after dose reduction or discontinuation of therapy.
Some patients experienced ongoing or new serious adverse events during the 6-month follow-up
period. In the PEG-Intron/REBETOL trial 13 patients experienced life-threatening psychiatric events
(suicidal ideation or attempt) and one patient accomplished suicide.
There have been five patient deaths which occurred in clinical trials: one suicide in a patient receiving
PEG-Intron monotherapy and one suicide in a patient receiving PEG-Intron/REBETOL combination therapy;
two deaths among patients receiving INTRON A monotherapy (1 murder/suicide and 1 sudden
death) and one patient death in the INTRON A/REBETOL group (motor vehicle accident).
Overall 10-14% of patients receiving PEG-Intron, alone or in combination with REBETOL, discontinued
therapy compared with 6% treated with INTRON A alone and 13% treated with INTRON A in
combination with REBETOL. The most common reasons for discontinuation of therapy were related to
psychiatric, systemic (e.g. fatigue, headache), or gastrointestinal adverse events.
In the combination therapy trial, dose reductions due to adverse reactions occurred in 42% of patients
receiving PEG-Intron (1.5 µg/kg)/REBETOL and in 34% of those receiving INTRON A/REBETOL. The
majority of patients (57%) weighing 60 kg or less receiving PEG-Intron (1.5 µg/kg)/REBETOL required
dose reduction. Reduction of interferon was dose related (PEG-Intron 1.5 µg/kg > PEG-Intron 0.5 µg/kg
or INTRON A), 40%, 27%, 28%, respectively. Dose reduction for REBETOL was similar across all three
groups, 33-35%. The most common reasons for dose modifications were neutropenia (18%), or anemia
(9%). (see Laboratory Values). Other common reasons included depression, fatigue, nausea, and
thrombocytopenia.
In the PEG-Intron/REBETOL combination trial the most common adverse events were
psychiatric which occurred among 77% of patients and included most commonly depression, irritability,
and insomnia, each reported by approximately 30-40% of subjects in all treatment groups. Suicidal
behavior (ideation, attempts, and suicides) occurred in 2% of all patients during treatment or during
follow-up after treatment cessation (see WARNINGS).
PEG-Intron induced fatigue or headache in approximately two-thirds of patients, and induced fever or
rigors in approximately half of the patients. The severity of some of these systemic symptoms (e.g.
fever and headache) tended to decrease as treatment continues. The incidence tends to be higher with
PEG-Intron than with INTRON A therapy alone or in combination with REBETOL.
Application site inflammation and reaction (e.g. bruise, itchiness, irritation) occurred at approximately
twice the incidence with PEG-Intron therapies (in up to 75% of patients) compared with INTRON A.
However injection site pain was infrequent (2-3%) in all groups.
Other common adverse events in the PEG-Intron/REBETOL group included myalgia (56%), arthralgia
(34%), nausea (43%), anorexia (32%), weight loss (29%), alopecia (36%), and pruritus (29%).
In the PEG-Intron monotherapy trial the incidence of severe adverse events was 13% in the INTRON A
group and 17% in the PEG-Intron groups. In the PEG-Intron/REBETOL combination therapy trial the incidence
of severe adverse events was 23% in the INTRON A/REBETOL group and 31-34% in the
PEG-Intron/REBETOL groups. The incidence of life-threatening adverse events was =1% across all
groups in the monotherapy and combination therapy trials.
Adverse events that occurred in the clinical trial at >5% incidence are provided in Table 3 by treatment
group. Due to potential differences in ascertainment procedures, adverse event rate comparisons
across studies should not be made.
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| Table 3. Adverse Events Occurring in >5% of Patients |
Percentage of Patients Reporting Adverse Events* |
|
Study 1 |
Study 2 |
| Adverse Events |
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PEG-Intron
1.0 µg/kg
(n=297)
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INTRON A
3 MIU
(n=303)
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PEG-Intron
1.5 µg/kg/
REBETOL (n=511)
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INTRON A
3 MIU/
REBETOL (n=505)
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| Application Site Disorders |
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| Autonomic Nervous System Disorders |
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| Body as a Whole |
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Central and Periph.
Nerv. Sys. |
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| Endocrine Disorders |
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| Gastrointestinal |
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| Hemotologic Disorders |
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| Liver and Biliary System Disorders |
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| Musculoskeletal |
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| Psychiatric |
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| Reproductive, Female |
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| Resistance Mechanism |
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| Respiratory System |
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| Skin and Appendages |
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| Special Senses Other |
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| Vision Disorders |
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Many patients continued to experience adverse events several months after discontinuation of therapy.
By the end of the 6-month follow-up period the incidence of ongoing adverse events by body class in the
PEG-Intron 1.5/REBETOL group was 33% (psychiatric), 20% (musculoskeletal), and 10% (for endocrine
and for GI). In approximately 10-15% of patients weight loss, fatigue and headache had not resolved.
Individual serious adverse events occurred at a frequency <1% and included suicide attempt, suicidal
ideation, severe depression; psychosis, aggressive reaction, relapse of drug addiction/overdose; nerve
palsy (facial, oculomotor); cardiomyopathy, myocardial infarction, 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, phototoxicity.
Laboratory Values
Changes in selected laboratory values during treatment with PEG-Intron alone or in combination with
REBETOL treatment are described below. Decreases in hemoglobin, neutrophils, and platelets may
require dose reduction or permanent discontinuation from therapy. (See DOSAGE AND ADMINISTRA-TION-
Dose Reduction)
Hemoglobin. REBETOL induced a decrease in hemoglobin levels in approximately two thirds of patients.
Hemoglobin levels decreased to <11g/dL in about 30% of patients. Severe anemia (<8 g/dL) occurred in
<1% of patients. Dose modification was required in 9 and 13% of patients in the PEG-Intron/REBETOL
and INTRON A/REBETOL groups. Hemoglobin levels become stable by treatment week 4-6 on average.
Hemoglobin levels return to baseline between 4 and 12 weeks posttreatment. In the PEG-Intron
monotherapy trial hemoglobin decreases were generally mild and dose modifications were rarely necessary.
(See DOSAGE AND ADMINISTRATION: Dose Modification).
Neutrophils. Decreases in neutrophil counts were observed in a majority of patients treated with
PEG-Intron alone (70%) or as combination therapy with REBETOL (85%) and INTRON A/
REBETOL (60%). Severe potentially life-threatening neutropenia (<0.5 x 109/L) occurred in 1% of
patients treated with PEG-Intron monotherapy, 2% of patients treated with INTRON A/
REBETOL and in 4% of patients treated with PEG-Intron/REBETOL. Two percent of patients receiving
PEG-Intron monotherapy and 18% of patients receiving PEG-Intron/REBETOL required modification of
interferon dosage. Few patients (<1%) required permanent discontinuation of treatment. Neutrophil
counts generally return to pre-treatment levels within 4 weeks of cessation of therapy. (See DOSAGE
AND ADMINISTRATION: Dose Modification).
Platelets. Platelet counts decrease in approximately 20% of patients treated with PEG-Intron alone or
with REBETOL and in 6% of patients treated with INTRON A/REBETOL. Severe decreases in platelet
counts (<50,000/mm3) occur in <1% of patients. Patients may require discontinuation or dose modification
as a result of platelet decreases. (See DOSAGE AND ADMINISTRATION: Dose Modification). In
the PEG-Intron/REBETOL combination therapy trial 1% or 3% of patients required dose modification of
INTRON A or PEG-Intron respectively. Platelet counts generally returned to pretreatment levels within
4 weeks of the cessation of therapy.
Thyroid Function. Development of TSH abnormalities, with and without clinical manifestations, are
associated with interferon therapies. Clinically apparent thyroid disorders occur among patients treated
with either INTRON A or PEG-Intron (with or without REBETOL) at a similar incidence (5% for
hypothyroidism and 3% for hyperthyroidism). Subjects developed new onset TSH abnormalities while
on treatment and during the follow-up period. At the end of the follow-up period 7% of subjects still
had abnormal TSH values.
Bilirubin and uric acid. In the PEG-Intron/REBETOL trial 10-14% of patients developed hyperbilirubinemia
and 33-38% developed hyperuricemia in association with hemolysis. Six patients developed mild to moderate gout.
OVERDOSAGE
There is limited experience with overdosage. In the clinical studies, a few patients accidentally received
a dose greater than that prescribed. There were no instances in which a participant in the monotherapy
or combination therapy trials received more than 10.5 times the intended dose of PEG-Intron. The
maximum dose received by any patient was 3.45 µg/kg weekly over a period of approximately 12 weeks.
The maximum known overdosage of REBETOL was an intentional ingestion of 10 g (fifty 200 mg
capsules). There were no serious reactions attributed to these overdosages. In cases of overdosing,
symptomatic treatment and close observation of the patient are recommended.
DOSAGE AND ADMINISTRATION
There are no safety and efficacy data on treatment for longer than one year. A patient should self-inject
PEG-Intron only if the physician determines that it is appropriate and the patient agrees to medicalfollow-up as necessary and training in proper injection technique has been given to him/her. (See illus-trated
MEDICATION GUIDE for instructions.)
It is recommended that patients receiving PEG-Intron, alone or in combination with ribavirin, be
discontinued from therapy if HCV viral levels remain high after 6 months of therapy.
PEG-Intron Monotherapy
The recommended dose of PEG-Intron regimen is 1.0 µg/kg/week for one year.
The volume of PEG-Intron to be injected depends on the vial strength used and the patient's weight (see Table 4 below).
| TABLE 4. Recommended PEG-Intron Monotherapy Dosing |
Body
weight
(kg) |
PEG-Intron
Vial Strength
|
Amount of
PEG-Intron
(µg)
to Administer |
Volume (mL)* of
PEG-Intron*
to Administer |
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PEG-Intron/REBETOL Combination Therapy
When administered in combination with REBETOL, the recommended dose of PEG-Intron is
1.5 micrograms/kg/week. The volume of PEG-Intron to be injected depends on the vial strength of
PEG-Intron and patient's body weight. (See Table 5 below).
| TABLE 5. Recommended PEG-Intron Combination Therapy Dosing |
Body
weight
(kg) |
PEG-Intron
Vial Strength
|
Amount of
PEG-Intron
(µg)
to Administer |
Volume (mL)* of
PEG-Intron*
to Administer |
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The recommended dose of REBETOL is 800 mg/day in 2 divided doses: two capsules (400 mg) with
breakfast and two capsules (400 mg) with dinner. REBETOL should not be used in patients with creatinine
clearance <50 mL/min.
Dose Reduction
If a serious adverse reaction develops during the course of treatment (See WARNINGS) discontinue or
modify the dosage of PEG-Intron and/or REBETOL until the adverse event abates or decreases in severity.
If persistent or recurrent serious adverse events develop despite adequate dosage adjustment,
discontinue treatment. For guidelines for dose modifications and discontinuation based on laboratory
parameters, see Tables 6 and 7. In the combination therapy trial dose reductions occurred among 42%
of patients receiving PEG-Intron 1.5 µg/kg/REBETOL 800 mg daily including 57% of those patients
weighing 60 kg or less (see ADVERSE REACTIONS).
| TABLE 6. Guidelines for Modification or Discontinuation of PEG-Intron or PEG-Intron/REBETOL and for Scheduling Visits for Patients with Depression
|
| Depression Severity1 |
Initial Management |
Depression |
| Dose modification |
Visit schedule |
Remains stable |
Improves |
Worsens |
Two Safety-Lok* syringes are provided in the package; one syringe is for the reconstitution steps and one
for the patient injection. There is a plastic safety sleeve to be pulled over the needle after use. The syringe
locks with an audible click when the green stripe on the safety sleeve covers the red stripe on the needle.
Brief instructions for the preparation and administration of PEG-Intron Powder for Injection are provided
below. Please refer to the Medication Guide for detailed, step-by-step instructions.
Reconstitute the PEG-Intron lyophilized product with only 0.7 mL of supplied diluent (Sterile Water
for Injection, USP). The diluent vial is for single use only. The remaining diluent should be discarded.
No other medications should be added to solutions containing PEG-Intron, and PEG-Intron should
not be reconstituted with other diluents. Swirl gently to hasten complete dissolution of the powder. The
reconstituted solution should be clear and colorless. Visually inspect the solution for particulate matter
and discoloration prior to administration. The solution should not be used if discolored or cloudy, or if
particulates are present (see MEDICATION GUIDE for detailed instructions).
The reconstituted solution should be used immediately and cannot be stored for more than
24 hours at 2�-8�C (See Storage). The appropriate PEG-Intron dose should be withdrawn and injected
subcutaneously. (See MEDICATION GUIDE for detailed instructions). The PEG-Intron vial is a single use
vial and does not contain a preservative. DO NOT REENTER VIAL. DISCARD UNUSED PORTION. Once
the dose from a single dose vial has been withdrawn, the sterility of any remaining product can no
longer be guaranteed. Pooling of unused portions of some medications has been linked to bacterial
contamination and morbidity.
After preparation and administration of the PEG-Intron injection, it is essential to follow the procedure
for proper disposal of syringes and needles. A puncture-resistant container should be used for disposal
of syringes. Patients should be instructed in the technique and importance of proper syringe disposal
and be cautioned against reuse of these items (See MEDICATION GUIDE for detailed instructions.)
Storage
PEG-Intron should be stored at 25�C (77�F): excursions permitted to 15�-30�C (59�-86�F)[see USP
Controlled Room Temperature]. After reconstitution with supplied Diluent the solution should be used
immediately, but may be stored up to 24 hours at 2� to 8�C (36� to 46�F). The reconstituted solution
contains no preservative, is clear and colorless. Do not freeze.
HOW SUPPLIED
PEG-Intron is a white to off-white lyophilized powder supplied in 2-mL vials. The PEG-Intron Powder
for Injection should be reconstituted with 0.7 mL of the supplied Diluent (Sterile Water for Injection,
USP) prior to use.
| Each PEG-Intron Package Contains: |
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