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Interferon alfa-2a,
recombinant = Roferon-A
Central nervous system adverse reactions have been reported in a number of
patients. These reactions included decreased mental status, dizziness,
impaired memory, agitation, manic behavior and psychotic reactions. More
severe obtundation and coma have been rarely observed. Most of these
abnormalities were mild and reversible within a few days to 3 weeks upon
dose reduction or discontinuation of Roferon-A therapy. Careful periodic
neuropsychiatric monitoring of all patients is recommended.
Roferon-A should be used with caution in patients with preexisting cardiac
disease, renal or hepatic disease, seizure disorders and/or compromised
central nervous system function.
Roferon-A should be administered with caution to patients with cardiac
disease or with any history of cardiac illness. Acute, self-limited
toxicities (ie, fever, chills) frequently associated with Roferon-A
administration may exacerbate preexisting cardiac conditions. Rarely,
myocardial infarction has occurred in patients receiving Roferon-A. Cases
of cardiomyopathy have been
observed on rare occasions in patients treated with alfa interferons.
HLR 03/20/01
ROFERON®-A
(Interferon alfa-2a, recombinant)
Alpha interferons, including Interferon alfa-2a, 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signs or symptoms of these conditions should be withdrawn from therapy.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 Interferon
alfa-2a therapy (see WARNINGS and ADVERSE REACTIONS).
DESCRIPTION: Roferon-A (Interferon alfa-2a, recombinant) is a sterile
protein product for use by injection. Roferon-A is manufactured by
recombinant DNA technology that employs a genetically engineered
Escherichia coli bacterium containing DNA that codes for the human
protein. Interferon alfa-2a, recombinant is a highly purified protein
containing 165 amino acids, and it has an approximate molecular weight of
19,000 daltons. Fermentation is carried out in a defined nutrient medium
containing the antibiotic tetracycline hydrochloride, 5 mg/L. However, the
presence of the antibiotic is not detectable in the final product. Roferon-A
is supplied as an injectable solution in a vial or a prefilled syringe.
Each glass syringe barrel contains 0.5 mL of product. In addition, there
is a needle which is ˝ inch in length.
Single Use Injectable Solution:
3 million IU (11.1 mcg/mL) Roferon-A per vial - The solution is colorless
and each mL
contains 3 MIU of Interferon alfa-2a, recombinant, 7.21 mg sodium
chloride, 0.2 mg
polysorbate 80, 10 mg benzyl alcohol as a preservative and 0.77 mg
ammonium acetate.
6 million IU (22.2 mcg/mL) Roferon-A per vial - The solution is colorless
and each mL
contains 6 MIU of Interferon alfa-2a, recombinant, 7.21 mg sodium
chloride, 0.2 mg
polysorbate 80, 10 mg benzyl alcohol as a preservative and 0.77 mg
ammonium acetate.
9 million IU (33.3 mcg/0.9 mL) Roferon-A per vial - The solution is
colorless and each
0.9 mL contains 9 MIU of Interferon alfa-2a, recombinant, 6.49 mg sodium
chloride, 0.18
mg polysorbate 80, 9 mg benzyl alcohol as a preservative and 0.69 mg
ammonium
acetate. For single dose administration, withdraw 0.9 mL using a 1 mL
syringe. Also can
be used as a multidose vial.
36 million IU (133.3 mcg/mL) Roferon-A per vial - The solution is
colorless and each
mL contains 36 MIU of Interferon alfa-2a, recombinant, 7.21 mg sodium
chloride, 0.2 mg
polysorbate 80, 10 mg benzyl alcohol as a preservative and 0.77 mg
ammonium acetate.
Single Use Prefilled Syringes: 1
Roferon®-A (Interferon alfa-2a, recombinant)
3 million IU (11.1 mcg/0.5 mL) Roferon-A per syringe - The solution is
colorless and
each 0.5 mL contains 3 MIU of Interferon alfa-2a, recombinant, 3.605 mg
sodium
chloride, 0.1 mg polysorbate 80, 5 mg benzyl alcohol as a preservative and
0.385 mg
ammonium acetate.
6 million IU (22.2 mcg/0.5 mL) Roferon-A per syringe - The solution is
colorless and
each 0.5 mL contains 6 MIU of Interferon alfa-2a, recombinant, 3.605 mg
sodium
chloride, 0.1 mg polysorbate 80, 5 mg benzyl alcohol as a preservative and
0.385 mg
ammonium acetate.
9 million IU (33.3 mcg/0.5 mL) Roferon-A per syringe - The solution is
colorless and
each 0.5 mL contains 9 MIU of Interferon alfa-2a, recombinant, 3.605 mg
sodium
chloride, 0.1 mg polysorbate 80, 5 mg benzyl alcohol as a preservative and
0.385 mg
ammonium acetate.
Multidose Injectable Solution:
9 million IU (33.3 mcg/0.9 mL) Roferon-A per vial - The solution is
colorless and each
0.9 mL contains 9 MIU of Interferon alfa-2a, recombinant, 6.49 mg sodium
chloride, 0.18
mg polysorbate 80, 9 mg benzyl alcohol as a preservative and 0.69 mg
ammonium
acetate. Also can be used as a single use vial.
18 million IU (66.7 mcg/3 mL) Roferon-A per vial - The solution is
colorless and each
mL contains 6 MIU of Interferon alfa-2a, recombinant, 7.21 mg sodium
chloride, 0.2 mg
polysorbate 80, 10 mg benzyl alcohol as a preservative and 0.77 mg
ammonium acetate.
Each 0.5 mL contains 3 MIU of Interferon alfa-2a, recombinant.
Based on the specific activity of 2.7x108IU/mg protein, the corresponding
quantities of Interferon
alfa-2a, recombinant in the vials described above are approximately 3 MIU
(11.1 mcg/mL), 6
MIU (22.2 mcg/mL), 9 MIU (33.3 mcg/0.9 mL), 18 MIU (66.7 mcg/3 mL) and 36
MIU (133.3
mcg/mL).
The route of administration for the vial is subcutaneous or intramuscular;
the route of
administration for the prefilled syringe is subcutaneous only.
CLINICAL PHARMACOLOGY: The mechanism by which Interferon alfa-2a,
recombinant, or
any other interferon, exerts antitumor or antiviral activity is not
clearly understood. However, it is
believed that direct antiproliferative action against tumor cells,
inhibition of virus replication and
modulation of the host immune response play important roles in antitumor
and antiviral activity.
The biological activities of Interferon alfa-2a, recombinant are
species-restricted, ie, they are
expressed in a very limited number of species other than humans. As a
consequence, preclinical
evaluation of Interferon alfa-2a, recombinant has involved in vitro
experiments with human cells
and some in vivo experiments.1 Using human cells in culture, Interferon
alfa-2a, recombinant has
been shown to have antiproliferative and immunomodulatory activities that
are very similar to
those of the mixture of interferon alfa subtypes produced by human
leukocytes. In vivo,
2
Roferon®-A (Interferon alfa-2a, recombinant)
Interferon alfa-2a, recombinant has been shown to inhibit the growth of
several human tumors
growing in immunocompromised (nude) mice. Because of its
species-restricted activity, it has not
been possible to demonstrate antitumor activity in immunologically intact
syngeneic tumor
model systems, where effects on the host immune system would be
observable. However, such
antitumor activity has been repeatedly demonstrated with, for example,
mouse interferon-alfa in
transplantable mouse tumor systems. The clinical significance of these
findings is unknown.
The metabolism of Interferon alfa-2a, recombinant is consistent with that
of alfa interferons in
general. Alfa interferons are totally filtered through the glomeruli and
undergo rapid proteolytic
degradation during tubular reabsorption, rendering a negligible
reappearance of intact alfa
interferon in the systemic circulation. Small amounts of radiolabeled
Interferon alfa-2a,
recombinant appear in the urine of isolated rat kidneys, suggesting near
complete reabsorption of
Interferon alfa-2a, recombinant catabolites. Liver metabolism and
subsequent biliary excretion
are considered minor pathways of elimination for alfa interferons.
The serum concentrations of Interferon alfa-2a, recombinant reflected a
large intersubject
variation in both healthy volunteers and patients with disseminated
cancer.
In healthy people, Interferon alfa-2a, recombinant exhibited an
elimination half-life of 3.7 to 8.5
hours (mean 5.1 hours), volume of distribution at steady-state of 0.223 to
0.748 L/kg (mean 0.400
L/kg) and a total body clearance of 2.14 to 3.62 mL/min/kg (mean 2.79 mL/min/kg)
after a 36
MIU (2.2x108pg) intravenous infusion. After intramuscular and subcutaneous
administrations of
36 MIU, peak serum concentrations ranged from 1500 to 2580 pg/mL (mean
2020 pg/mL) at a
mean time to peak of 3.8 hours and from 1250 to 2320 pg/mL (mean 1730 pg/mL)
at a mean time
to peak of 7.3 hours, respectively. The apparent fraction of the dose
absorbed after intramuscular
injection was greater than 80%.
The pharmacokinetics of Interferon alfa-2a, recombinant after single
intramuscular doses to
patients with disseminated cancer were similar to those found in healthy
volunteers. Dose
proportional increases in serum concentrations were observed after single
doses up to 198 MIU.
There were no changes in the distribution or elimination of Interferon
alfa-2a, recombinant during
twice daily (0.5 to 36 MIU), once daily (1 to 54 MIU), or three times
weekly (1 to 136 MIU)
dosing regimens up to 28 days of dosing. Multiple intramuscular doses of
Interferon alfa-2a,
recombinant resulted in an accumulation of two to four times the single
dose serum
concentrations. There is no pharmacokinetic information in patients with
chronic hepatitis C,
hairy cell leukemia, AIDS-related Kaposi's sarcoma and chronic myelogenous
leukemia.
Serum neutralizing activity, determined by a highly sensitive enzyme
immunoassay, and a
neutralization bioassay, was detected in approximately 25% of all patients
who received Roferon-
A.2 Antibodies to human leukocyte interferon may occur spontaneously in
certain clinical
conditions (cancer, systemic lupus erythematosus, herpes zoster) in
patients who have never
received exogenous interferon.3 The significance of the appearance of
serum neutralizing activity
is not known.
CLINICAL STUDIES: Studies have shown that Roferon-A can normalize serum
ALT, improve
liver histology and reduce viral load in patients with chronic hepatitis
C. Other studies have
3
Roferon®-A (Interferon alfa-2a, recombinant)
shown that Roferon-A can produce clinically meaningful tumor regression or
disease stabilization
in patients with hairy cell leukemia or in patients with AIDS-related
Kaposi's sarcoma.4-6 In Ph-
positive Chronic Myelogenous Leukemia, Roferon-A supplemented with
intermittent
chemotherapy has been shown to prolong overall survival and to delay
disease progression
compared to patients treated with chemotherapy alone.7 In addition,
Roferon-A has been shown
to produce sustained complete cytogenetic responses in a small subset of
patients with CML in
chronic phase. The activity of Roferon-A in Ph-negative CML has not been
determined.
EFFECTS ON CHRONIC HEPATITIS C: The safety and efficacy of Roferon-A was
evaluated in
multiple clinical trials involving over 2000 patients 18 years of age or
older with hepatitis, with or
without cirrhosis, who had elevated serum alanine aminotransferase (ALT)
levels and tested
positive for antibody to hepatitis C. Roferon-A was given three times a
week (tiw) by
subcutaneous (SC) or intramuscular (IM) injection in a variety of dosing
regimens, including
dose escalation and de-escalation regimens. Normalization of serum ALT was
defined in all
studies as two consecutive normal serum ALT values at least 21 days apart.
A sustained response
(SR) was defined as normalization of ALT both at the end of treatment and
at the end of at least 6
months of treatment-free follow-up.
In trials in which Roferon-A was administered for 6 months, 6 MIU, 3 MIU,
and 1 MIU were
directly compared. Six MIU was associated with higher SR rates but greater
toxicity (see
ADVERSE REACTIONS). In studies in which the same dose of Roferon-A was
administered for
6 or 12 months, the longer duration was associated with higher SR rates
and adverse events were
no more severe or frequent in the second 6 months than in the first 6
months. Based on these
data, the recommended regimens are 3 MIU for 12 months or 6 MIU for the
first 3 months
followed by 3 MIU for the next 9 months (see Table 1 and DOSAGE AND
ADMINISTRATION). There are no direct comparisons of these two regimens.
Younger patients (eg, less than 35 years of age) and patients without
cirrhosis on liver biopsy
were more likely to respond completely to Roferon-A than those patients
greater than 35 years of
age or patients with cirrhosis on liver biopsy.
In the two studies in which Roferon-A was administered subcutaneously
three times weekly for
12 months, 20/173 (12%) patients experienced a sustained response to
therapy (see Table 1). Of
these patients, 15/173 (9%) maintained this sustained response during
continuous follow-up for
up to four years. Patients who have ALT normalization but who fail to have
a sustained response
following an initial course of therapy may benefit from retreatment with
higher doses of Roferon-
A (see DOSAGE AND ADMINISTRATION).
A subset of patients had liver biopsies performed both before and after
treatment with Roferon-
A. An improvement in liver histology as assessed by Knodell Histology
Activity Index was
generally observed.
A retrospective subgroup analysis of 317 patients from two studies
suggested a correlation
between improvement in liver histology, durable serum ALT response rates,
and decreased viral
load as measured by the polymerase chain reaction (PCR).
4
Roferon®-A (Interferon alfa-2a, recombinant)
Table 1. - ALT Normalization in Patients Receiving Therapy With Roferon-A
for 12
Months
Study No. Dose (MIU) N End of Treatment End of Observation
[% (95% CI)] (Sustained Response SR)
[% (95% CI)] *
1** 3 56 23 11
2 3 117 23 12
1 and 2 3 173 23 (17-30) 12 (7-17)
Combined
3 6-3 210 25 (19-31) 19 (14-25)
* All patients were followed for 6 months after end of treatment.
** EOT and SR rates for Placebo (study 1) were 0.
EFFECTS ON Ph-POSITIVE CHRONIC MYELOGENOUS LEUKEMIA (CML): Roferon-A was
evaluated in two trials of patients with chronic phase CML. Study DM84-38
was a single center
phase II study conducted at the MD Anderson Cancer Center, which enrolled
91 patients, 81%
were previously treated, 82% were Ph positive, and 63% received Roferon-A
within 1 year of
diagnosis. Study MI400 was a multicenter randomized phase III study
conducted in Italy by the
Italian Cooperative Study Group on CML in 335 patients; 226 Roferon-A and
109 chemotherapy.
Patients with Ph-positive, newly diagnosed or minimally treated CML were
randomized (ratio
2:1) to either Roferon-A or conventional chemotherapy with either
hydroxyurea or busulfan. In
study DM84-38, patients started Roferon-A at 9 MIU/day, whereas in study
MI400, it was
progressively escalated from 3 to 9 MIU/day over the first month. In both
trials, dose escalation
for insufficient hematologic response, and dose attenuation or
interruption for toxicity was
permitted. No formal guidelines for dose attenuation were given in the
chemotherapy arm of
study MI400. In addition, in the Roferon-A arm, the MI400 protocol allowed
the addition of
intermittent single agent chemotherapy for insufficient hematologic
response to Roferon-A alone.
In this trial, 44% of the Roferon-A treated patients also received
intermittent single agent
chemotherapy at some time during the study.
The two studies were analyzed according to uniform response criteria. For
hematologic response:
complete response (WBC <9x109/L, normalization of the differential with no
immature forms in
the peripheral blood, disappearance of splenomegaly), partial response
(>50% decrease from
baseline of WBC to <20%x109/L). For cytogenetic response: complete
response (0% Ph-positive
metaphases), partial response (1% to 34% Ph-positive metaphases).
In study DM84-38, the median survival from initiation of Roferon-A was 47
months. In study
MI400, the median survival for the patients on the interferon arm was 69
months, which was
significantly better than the 55 months seen in the chemotherapy control
group (48 patients in
study MI400 proceeded to BMT and in study DM84-38, 15 patients proceeded
to BMT).
Roferon-A treatment significantly delayed disease progression to blastic
phase as evidenced by a
median time to disease progression of 69 months to 46 months with
chemotherapy.
5
Roferon®-A (Interferon alfa-2a, recombinant)
By multivariate analysis of prognostic factors associated with all 335
patients entered into the
randomized study, treatment with Roferon-A (with or without intermittent
additional
chemotherapy; p=0.006), Sokal index8 (p=0.006) and WBC (p=0.023) were the
three variables
associated with an improved survival, independent of other baseline
characteristics (Karnofsky
performance status and hemoglobin being the other factors entered into the
model).
In study MI400, overall hematologic responses, [complete responses (CR)
and partial responses
(PR)], were observed in approximately 60% of patients treated with Roferon-A
(40% CR, 20%
PR), compared to 70% with chemotherapy (30% CR, 40% PR). The median time
to reach a
complete hematologic response was 5 months in the Roferon-A arm and 4
months in the
chemotherapy arm. The overall cytogenetic response rate (CR+PR), in
patients receiving
Roferon-A, was 10% and 12% in studies MI400 and DM84-38, respectively,
according to the
intent-to-treat principle. In contrast, only 2% of the patients in the
chemotherapy arm of study
MI400 achieved a cytogenetic response (with no complete responses).
Cytogenetic responses
were observed only in patients who had complete hematologic responses. In
study DM84-38,
hematologic and cytogenetic response rates were higher in the subset of
patients treated with
Roferon-A within 1 year of diagnosis (76% and 17%, respectively) compared
to the subset
initiating Roferon-A therapy more than 1 year from diagnosis (29% and 4%,
respectively). In an
exploratory analysis, patients who achieved a cytogenetic response lived
longer than those who
did not.
Severe adverse events were observed in 66% and 31% of patients on study
DM84-38 and MI400,
respectively. Dose reduction and temporary cessation of therapy was
required frequently.
Permanent cessation of Roferon-A, due to intolerable side effects, was
required in 15% and 23%
of patients on studies DM84-38 and MI400, respectively (see ADVERSE
REACTIONS).
Limited data are available on the use of Roferon-A in children with
Ph-positive, adult-type CML.
A published report on 15 children with CML suggests a safety profile
similar to that seen in adult
CML; clinical responses were also observed9 (see DOSAGE AND
ADMINISTRATION).
EFFECTS ON HAIRY CELL LEUKEMIA: A multicenter US phase II study (N2752)
enrolled 218
patients; 75 were evaluable for efficacy in a preliminary analysis; 218
patients were evaluable for
safety. Patients were to receive a starting dose of Roferon-A up to 6 MIU/m2/day,
for an
induction period of 4 to 6 months. Responding patients were to receive 12
months maintenance
therapy.
During the first 1 to 2 months of treatment of patients with hairy cell
leukemia, significant
depression of hematopoiesis was likely to occur. Subsequently, there was
improvement in
circulating blood cell counts. Of the 75 patients who were evaluable for
efficacy following at least
16 weeks of therapy, 46 (61%) achieved complete or partial response.
Twenty-one patients (28%)
had a minor remission, 8 (11%) remained stable, and none had worsening of
disease. All patients
who achieved either a complete or partial response had complete or partial
normalization of all
peripheral blood elements including hemoglobin level, white blood cell,
neutrophil, monocyte
and platelet counts with a concomitant decrease in peripheral blood and
bone marrow hairy cells.
Responding patients also exhibited a marked reduction in red blood cell
and platelet transfusion
requirements, a decrease in infectious episodes and improvement in
performance status. The
6
Roferon®-A (Interferon alfa-2a, recombinant)
probability of survival for 2 years in patients receiving Roferon-A (94%)
was statistically
increased compared to a historical control group (75%).
EFFECTS ON AIDS-RELATED KAPOSI'S SARCOMA: In six studies with Roferon-A,
doses of 3
to 54 MIU daily were evaluated for the treatment of AIDS-related Kaposi's
sarcoma in more than
350 patients. Four dosage regimens of Roferon-A were evaluated for initial
induction. Thirty-nine
patients received 3 MIU daily; 99 patients received an escalating regimen
of 3 MIU, 9 MIU and 18
MIU each daily for 3 days, followed by 36 MIU daily; 119 patients received
36 MIU daily; and 16
patients received doses greater than 36 MIU to a maximum of 54 MIU daily.
An additional 91
patients received Roferon-A in combination with vinblastine. The best
response rate associated
with acceptable toxicity was observed when Roferon-A was administered as a
single agent at a
dose of 36 MIU daily. The escalating regimen of 3 to 36 MIU daily provided
equivalent
therapeutic benefit with some amelioration of acute toxicity in some
patients. In AIDS-related
Kaposi's sarcoma, lower doses were less effective in inducing tumor
regression and doses higher
than 36 MIU daily were associated with unacceptable toxicity.
As summarized in Table 2, the likelihood of response to Roferon-A varied
with the clinical
manifestations of human immunodeficiency virus (HIV) infection. Patients
with prior
opportunistic infection or B symptoms are unlikely to respond to treatment
with Roferon-A.
Table 2.- Likelihood of Response to Roferon-A in Patients With
AIDS-Related Kaposi's
Sarcoma
CD4(T4) Lymphocyte Count Objective Response Rate (%)
No. Pts.* (cells/mm3) CR PR Total
83 0-200 3.6 3.6 7.2
51 201-400 15.7 11.8 27.5
33 >400 24.2 21.2 45.4
In the 28 patients evaluated who had prior opportunistic infection or B
symptoms, the response
rate was 3.6%.
*Patients had no prior opportunistic infection or B symptoms. B symptoms
include night sweats,
weight loss of greater than 10% of body weight or 15 lbs, or fever greater
than 100°F without an
identifiable source of infection.
Patients who were otherwise asymptomatic, with no prior opportunistic
infection and near-
normal levels of CD4 lymphocytes, experienced higher response rates.
Responding patients with
a baseline CD4 lymphocyte count greater than 200 cells/mm3 had a distinct
survival advantage
over both responding patients with a baseline CD4 lymphocyte count of 200
cells/mm3 or less
and nonresponding patients regardless of their baseline CD4 lymphocyte
count. Median survival
for responding patients with CD4 lymphocyte counts of greater than 200 to
400 cells/mm3 had
not been reached but was greater than 32.7 months from the initiation of
therapy. For responding
patients with CD4 lymphocyte counts of greater than 400 cells/mm3, the
median survival had not
been reached but was greater than 29.5 months.
7
Roferon®-A (Interferon alfa-2a, recombinant)
A classification system for staging AIDS-related Kaposi's sarcoma has been
described based on
location and extent of disease. In studies of Roferon-A, no difference was
noted in response rates
for patients with different stages of Kaposi's sarcoma. Likelihood of
response was related to
manifestations of HIV infection (baseline CD4 lymphocyte count, prior
opportunistic infection or
B symptoms) and not to extent of tumor involvement. The median time to
response was 2.7
months. The median duration of response for patients achieving a partial
or complete response
was 6.3 and 20.7 months, respectively. Complete and partial responses
lasting in excess of 3
years have been observed. Therapy was discontinued because of progression
of Kaposi's
sarcoma, development of severe opportunistic infection or severe adverse
effects. The median
time to discontinuation of treatment was 12.5 months for responding
patients and 2.3 months for
patients who did not respond.
INDICATIONS AND USAGE: Roferon-A is indicated for the treatment of chronic
hepatitis C,
hairy cell leukemia and AIDS-related Kaposi's sarcoma in patients 18 years
of age or older. In
addition, it is indicated for chronic phase, Philadelphia chromosome (Ph)
positive chronic
myelogenous leukemia (CML) patients who are minimally pretreated (within 1
year of diagnosis).
FOR PATIENTS WITH CHRONIC HEPATITIS C: Roferon-A is indicated for use in
patients
with chronic hepatitis C diagnosed by HCV antibody and/or a history of
exposure to hepatitis C
who have compensated liver disease and are 18 years of age or older. A
liver biopsy and a serum
test for the presence of antibody to HCV should be performed to establish
the diagnosis of
chronic hepatitis C. Other causes of hepatitis, including hepatitis B,
should be excluded prior to
therapy with Roferon-A.
FOR PATIENTS WITH AIDS-RELATED KAPOSI'S SARCOMA: Roferon-A is indicated
for the
treatment of AIDS-related Kaposi's sarcoma in a select group of patients.
In determining whether
a patient should be treated, the physician should assess the likelihood of
response based on the
clinical manifestations of HIV infection, including prior opportunistic
infections, presence of B
symptoms, and CD4 count, and the manifestations of Kaposi's sarcoma
requiring treatment (see
CLINICAL PHARMACOLOGY).
CONTRAINDICATIONS: Roferon-A is contraindicated in patients with known
hypersensitivity to alfa interferon or any component of the product. The
injectable solutions
contain benzyl alcohol and are contraindicated in any individual with a
known allergy to that
preservative.
WARNINGS: Roferon-A should be administered under the guidance of a
qualified physician
(see DOSAGE AND ADMINISTRATION). Appropriate management of the therapy and
its
complications is possible only when adequate facilities are readily
available.
DEPRESSION AND SUICIDAL BEHAVIOR INCLUDING SUICIDAL IDEATION,
SUICIDAL ATTEMPTS AND SUICIDES HAVE BEEN REPORTED IN ASSOCIATION WITH
TREATMENT WITH ALFA INTERFERONS, INCLUDING ROFERON-A. Patients to be
treated with Roferon-A should be informed that depression and suicidal
ideation may be side
effects of treatment and should be advised to report these side effects
immediately to the
prescribing physician. Patients receiving Roferon-A therapy should receive
close monitoring for
8
Roferon®-A (Interferon alfa-2a, recombinant)
the occurrence of depressive symptomatology. Cessation of treatment should
be considered for
patients experiencing depression. Although dose reduction or treatment
cessation may lead to
resolution of the depressive symptomatology, depression may persist and
suicides have occurred
after withdrawing therapy (see PRECAUTIONS and ADVERSE REACTIONS).
Central nervous system adverse reactions have been reported in a number of
patients. These
reactions included decreased mental status, dizziness, impaired memory,
agitation, manic
behavior and psychotic reactions. More severe obtundation and coma have
been rarely observed.
Most of these abnormalities were mild and reversible within a few days to
3 weeks upon dose
reduction or discontinuation of Roferon-A therapy. Careful periodic
neuropsychiatric monitoring
of all patients is recommended.
Roferon-A should be used with caution in patients with severe preexisting
cardiac disease, severe
renal or hepatic disease, seizure disorders and/or compromised central
nervous system function.
Roferon-A should be administered with caution to patients with cardiac
disease or with any
history of cardiac illness. Acute, self-limited toxicities (ie, fever,
chills) frequently associated with
Roferon-A administration may exacerbate preexisting cardiac conditions.
Rarely, myocardial
infarction has occurred in patients receiving Roferon-A. Cases of
cardiomyopathy have been
observed on rare occasions in patients treated with alfa interferons.
Patients with a history of autoimmune hepatitis or a history of autoimmune
disease and patients
who are immunosuppressed transplant recipients should not be treated with
Roferon-A.
Controlled studies of Roferon-A therapy in patients with advanced
cirrhosis and/or
decompensated liver disease have not been performed. In chronic hepatitis
C, initiation of alfa-
interferon therapy, including Roferon-A, has been reported to cause
transient liver abnormalities,
which in patients with poorly compensated liver disease can result in
increased ascites, hepatic
failure or death.
Leukopenia and elevation of hepatic enzymes occurred frequently but were
rarely dose-limiting.
Thrombocytopenia occurred less frequently. Proteinuria and increased cells
in urinary sediment
were also seen infrequently. Dose-limiting hepatic or renal toxicities
were unusual. Infrequently,
severe renal toxicities, sometimes requiring renal dialysis, have been
reported with alfa-interferon
therapy alone or in combination with IL-2 (see PRECAUTIONS).
Infrequently, severe or fatal gastrointestinal hemorrhage has been
reported in association with
alfa-interferon therapy.
Alpha interferons suppress bone marrow function and may result in severe
cytopenias including
very rare events of aplastic anemia. It is advised that complete blood
counts (CBC) be obtained
pretreatment and monitored routinely during therapy. Alpha interferon
therapy should be
discontinued in patients who develop severe decreases in neutrophil (<0.5
x 109/L) or platelet
counts (<25 x 109/L).
Caution should be exercised when administering Roferon-A to patients with
myelosuppression
or when Roferon-A is used in combination with other agents that are known
to cause
9
Roferon®-A (Interferon alfa-2a, recombinant)
myelosuppression. Synergistic toxicity has been observed when Roferon-A is
administered in
combination with zidovudine (AZT).10 The effects of Roferon-A when
combined with other
drugs used in the treatment of AIDS-related disease are not known.
Hyperglycemia has been observed rarely in patients treated with Roferon-A.
Symptomatic
patients should have their blood glucose measured and followed-up
accordingly. Patients with
diabetes mellitus may require adjustment of their anti-diabetic regimen.
Roferon-A should not be used for the treatment of visceral AIDS-related
Kaposi's sarcoma
associated with rapidly progressive or life-threatening disease.
The injectable solutions contain benzyl alcohol and should not be used by
patients with a known
allergy to benzyl alcohol. This product is not indicated for use in
neonates or infants and should
not be used by patients in that age group. There have been rare reports of
death in neonates and
infants associated with excessive exposure to benzyl alcohol. There have
been reports of
permanent neuropsychiatric deficits and multiple system organ failure
associated with benzyl
alcohol in neonates and infants. The amount of benzyl alcohol at which
toxicity or adverse
effects may occur in neonates or infants is not known (see
CONTRAINDICATIONS).
PRECAUTIONS: General: In all instances where the use of Roferon-A is
considered for
chemotherapy, the physician must evaluate the need and usefulness of the
drug against the risk
of adverse reactions. Most adverse reactions are reversible if detected
early. If severe reactions
occur, the drug should be reduced in dosage or discontinued and
appropriate corrective measures
should be taken according to the clinical judgment of the physician.
Reinstitution of Roferon-A
therapy should be carried out with caution and with adequate consideration
of the further need
for the drug and, alertness to possible recurrence of toxicity. The
minimum effective doses of
Roferon-A for treatment of hairy cell leukemia, AIDS-related Kaposi's
sarcoma and chronic
myelogenous leukemia have not been established.
Variations in dosage and adverse reactions exist among different brands of
Interferon. Therefore,
do not use different brands of Interferon in a single treatment regimen.
Rare cases of autoimmune diseases including thrombocytopenia, vasculitis,
Raynaud's
phenomenon, rheumatoid arthritis, lupus erythematosus, and rhabdomyolysis
have been
observed in patients treated with alpha interferons. Any patient
developing an autoimmune
disorder during treatment should be closely monitored and, if appropriate,
treatment should be
discontinued.
Information for Patient: Patients should be cautioned not to change brands
of Interferon
without medical consultation, as a change in dosage may result. Patients
should be informed
regarding the potential benefits and risks attendant to the use of Roferon-A.
If home use is
determined to be desirable by the physician, instructions on appropriate
use should be given,
including review of the contents of the enclosed Patient Information
Sheet. Patients should be
well hydrated, especially during the initial stages of treatment.
10
Roferon®-A (Interferon alfa-2a, recombinant)
Patients should be thoroughly instructed in the importance of proper
disposal procedures and
cautioned against reusing syringes and needles. If home use is prescribed,
a puncture-resistant
container for the disposal of used syringes and needles should be supplied
to the patient. The full
container should be disposed of according to directions provided by the
physician.
Patients receiving high-dose alfa interferon should be cautioned against
performing tasks that
require complete mental alertness such as operating machinery or driving a
motor vehicle.
Patients to be treated with Roferon-A should be informed that depression
and suicidal ideation
may be side effects of treatment and should be advised to report these
side effects immediately to
the prescribing physician.
Laboratory Tests: Complete blood with differential platelet counts and
clinical chemistry tests
should be performed before initiation of Roferon-A therapy and at
appropriate periods during
therapy. Since responses of hairy cell leukemia, AIDS-related Kaposi's
sarcoma, chronic hepatitis
C and chronic myelogenous leukemia are not generally observed for 1 to 3
months after initiation
of treatment, very careful monitoring for severe depression of blood cell
counts is warranted
during the initial phase of treatment.
Those patients who have preexisting cardiac abnormalities and/or are in
advanced stages of
cancer should have electrocardiograms taken before and during the course
of treatment.
For patients being treated for chronic hepatitis C, serum ALT should be
evaluated before therapy
to establish baselines and repeated at week 2 and monthly thereafter
following initiation of
therapy for monitoring clinical response. Patients with neutrophil count
<1500/mm3, platelet
count <75,000/mm3, hemoglobin <10 g/dL and creatinine >1.5 mg/dL were
excluded from
several major chronic hepatitis C studies; patients with these laboratory
abnormalities should be
carefully monitored if treated with Roferon-A.
Patients with preexisting thyroid abnormalities may be treated if normal
thyroid stimulating
hormone (TSH) levels can be maintained by medication. Testing of TSH
levels in these patients is
recommended at baseline and every 3 months following initiation of
therapy.
Drug Interactions: Roferon-A has been reported to reduce the clearance of
theophylline.11,12 The
clinical relevance of this interaction is presently unknown. Interactions
between Roferon-A and
other drugs have not been fully evaluated. Caution should be exercised
when administering
Roferon-A in combination with other potentially myelosuppressive agents
(see WARNINGS).
Other Drug Interactions: Alfa interferons may affect the oxidative
metabolic process by
reducing the activity of hepatic microsomal cytochrome enzymes in the P450
group. Although
the clinical relevance is still unclear, this should be taken into account
when prescribing
concomitant therapy with drugs metabolized by this route.
The neurotoxic, hematotoxic or cardiotoxic effects of previously or
concurrently administered
drugs may be increased by interferons. Interactions could occur following
concurrent
11
Roferon®-A (Interferon alfa-2a, recombinant)
administration of centrally acting drugs. Use of Roferon-A in conjunction
with interleukin-2 may
potentiate risks of renal failure.
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Carcinogenesis: Roferon-A has not been tested for its carcinogenic
potential.
Mutagenesis: A. Internal Studies - Ames tests using six different tester
strains, with and
without metabolic activation, were performed with Roferon-A up to a
concentration of 1920
µg/plate. There was no evidence of mutagenicity.
Human lymphocyte cultures were treated in vitro with Roferon-A at
noncytotoxic
concentrations. No increase in the incidence of chromosomal damage was
noted.
B. Published Studies - There are no published studies on the mutagenic
potential of Roferon-A.
However, a number of studies on the genotoxicity of human leukocyte
interferon have been
reported.
A chromosomal defect following the addition of human leukocyte interferon
to lymphocyte
cultures from a patient suffering from a lymphoproliferative disorder has
been reported.
In contrast, other studies have failed to detect chromosomal abnormalities
following treatment of
lymphocyte cultures from healthy volunteers with human leukocyte
interferon.
It has also been shown that human leukocyte interferon protects primary
chick embryo
fibroblasts from chromosomal aberrations produced by gamma rays.
Impairment of Fertility: Roferon-A has been studied for its effect on
fertility in Macaca mulatta
(rhesus monkeys). Nonpregnant rhesus females treated with Roferon-A at
doses of 5 and 25
MIU/kg/day have shown menstrual cycle irregularities, including prolonged
or shortened
menstrual periods and erratic bleeding; these cycles were considered to be
anovulatory on the
basis that reduced progesterone levels were noted and that expected
increases in preovulatory
estrogen and luteinizing hormones were not observed. These monkeys
returned to a normal
menstrual rhythm following discontinuation of treatment.
Pregnancy: Teratogenic Effects: Pregnancy Category C. Roferon-A has been
shown to
demonstrate a statistically significant increase in abortifacient activity
in rhesus monkeys when
given at approximately 20 to 500 times the human dose. A study in pregnant
rhesus monkeys
treated with 1, 5 or 25 MIU/kg/day of Roferon-A in their early to midfetal
period (days 22 to 70
of gestation) has failed to demonstrate teratogenic activity for Roferon-A.
There are no adequate and well-controlled studies in pregnant women.
Nonteratogenic Effects: Dose-related abortifacient activity was observed
in pregnant rhesus
monkeys treated with 1, 5 or 25 MIU/kg/day of Roferon-A in their early to
midfetal period (days
12
Roferon®-A (Interferon alfa-2a, recombinant)
22 to 70 of gestation). A late fetal period study (days 79 to 100 of
gestation) is in progress and as
yet there have been no reports of any increased rate of abortion.
Usage in Pregnancy: Safe use in human pregnancy has not been established.
Therefore,
Roferon-A should be used during pregnancy only if the potential benefit
justifies the potential
risk to the fetus. Information from primate studies showed dose-related
menstrual irregularities
and an increased incidence of spontaneous abortions. Decreases in serum
estradiol and
progesterone concentrations have been reported in women treated with human
leukocyte
interferon.13 Therefore, fertile women should not receive Roferon-A unless
they are using
effective contraception during the therapy period.
The injectable solution contains benzyl alcohol. The excipient benzyl
alcohol can be transmitted
via the placenta. The possibility of toxicity should be taken into account
in premature infants after
the administration of Roferon-A solution for injection immediately prior
to birth or Cesarean
section.
Male fertility and teratologic evaluations have yielded no significant
adverse effects to date.
Nursing Mothers: It is not known whether this drug is excreted in human
milk. Because many
drugs are excreted in human milk and because of the potential for serious
adverse reactions in
nursing infants from Roferon-A, a decision should be made whether to
discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to
the mother.
Pediatric Use: Use of Roferon-A in children with Ph-positive adult-type
CML is supported by
evidence from adequate and well-controlled studies of Roferon-A in adults
with additional data
from the literature on the use of alfa interferon in children with CML. A
published report on 15
children with Ph-positive adult-type CML suggests a safety profile similar
to that seen in adult
CML; clinical responses were also observed9 (see DOSAGE AND
ADMINISTRATION).
For all other indications, safety and effectiveness have not been
established in patients below the
age of 18 years.
The injectable solutions are not indicated for use in neonates or infants
and should not be used
by patients in that age group. There have been rare reports of death in
neonates and infants
associated with excessive exposure to benzyl alcohol (see
WARNINGS).ADVERSE
REACTIONS: Depressive illness and suicidal behavior, including suicidal
ideation and suicides,
have been reported in association with the use of alfa-interferon
products. The incidence of
reported depression has varied substantially among trials, possibly
related to the underlying
disease, dose, duration of therapy and degree of monitoring, but has been
reported to be 15% or
higher (see WARNINGS).
FOR PATIENTS WITH CHRONIC HEPATITIS C: The most frequent adverse
experiences were
reported to be possibly or probably related to therapy with 3 MIU tiw
Roferon-A, were mostly
mild to moderate in severity and manageable without the need for
discontinuation of therapy. A
13
Roferon®-A (Interferon alfa-2a, recombinant)
relative increase in the incidence, severity and seriousness of adverse
events was observed in
patients receiving doses above 3 MIU tiw.
Adverse reactions associated with the 3 MIU dose include:
Flu-like Symptoms: Fatigue (58%), myalgia/arthralgia (51%), flu-like
symptoms (33%), fever
(28%), chills (23%), asthenia (6%), sweating (5%), leg cramps (3%) and
malaise (1%).
Central and Peripheral Nervous System: Headache (52%), dizziness (13%),
paresthesia (7%),
confusion (7%), concentration impaired (4%) and change in taste or smell
(3%).
Gastrointestinal: Nausea/vomiting (33%), diarrhea (20%), anorexia (14%),
abdominal pain
(12%), flatulence (3%), liver pain (3%), digestion impaired (2%) and
gingival bleeding (2%).
Psychiatric: Depression (16%), irritability (15%), insomnia (14%), anxiety
(5%) and behavior
disturbances (3%).
Pulmonary and Cardiovascular: Dryness or inflammation of oropharynx (6%),
epistaxis (4%),
rhinitis (3%), arrhythmia (1%) and sinusitis (<1%).
Skin: Injection site reaction (29%), partial alopecia (19%), rash (8%),
dry skin or pruritus (7%),
hematoma (1%), psoriasis (<1%), cutaneous eruptions (<1%), eczema (<1%)
and seborrhea
(<1%).
Other: Conjunctivitis (4%), menstrual irregularity (2%) and visual acuity
decreased (<1%).
Patients receiving 6 MIU tiw experienced a higher incidence of severe
psychiatric events (9%)
than those receiving 3 MIU tiw (6%) in two large US studies. In addition,
more patients withdrew
from these studies when receiving 6 MIU tiw (11%) than when receiving 3
MIU tiw (7%). Up to
half of patients receiving 3 MIU or 6 MIU tiw withdrawing from the study
experienced
depression or other psychiatric adverse events. At higher doses anxiety,
sleep disorders, and
irritability were observed more frequently. An increased incidence of
fatigue, myalgia/arthralgia,
headache, fever, chills, alopecia, sleep disturbances and dry skin or
pruritus was also generally
observed during treatment with higher doses of Roferon-A.
Generally there were fewer adverse events reported in the second 6 months
of treatment than in
the first 6 months for patients treated with 3 MIU tiw. Patients tolerant
of initial therapy with
Roferon-A generally tolerate re-treatment at the same dose, but tend to
experience more adverse
reactions at higher doses.
Infrequent adverse events (>1% but <3% incidence) included: cold feeling,
cough, muscle
cramps, diaphoresis, dyspnea, eye pain, reactivation of herpes simplex,
lethargy, edema, sexual
dysfunction, shaking, skin lesions, stomatitis, tooth disorder, urinary
tract infection, weakness in
extremities.
FOR PATIENTS WITH CHRONIC MYELOGENOUS LEUKEMIA:
14
Roferon®-A (Interferon alfa-2a, recombinant)
For patients with chronic myelogenous leukemia, the percentage of adverse
events, whether
related to drug therapy or not, experienced by patients treated with rIFN
-2a is given below.
Severe adverse events were observed in 66% and 31% of patients on study
DM84-38 and MI400,
respectively. Dose reduction and temporary cessation of therapy were
required frequently.
Permanent cessation of Roferon-A, due to intolerable side effects, was
required in 15% and 23%
of patients on studies DM84-38 and MI400, respectively.
Flu-like Symptoms: Fever (92%), asthenia or fatigue (88%), myalgia (68%),
chills (63%),
arthralgia/bone pain (47%) and headache (44%).
Gastrointestinal: Anorexia (48%), nausea/vomiting (37 %) and diarrhea
(37%).
Central and Peripheral Nervous System: Headache (44%), depression (28%),
decreased mental
status (16%), dizziness (11%), sleep disturbances (11%), paresthesia (8%),
involuntary
movements (7%) and visual disturbance (6%).
Pulmonary and Cardiovascular: Coughing (19%), dyspnea (8%) and dysrhythmia
(7%).
Skin: Hair changes (including alopecia) (18%), skin rash (18%), sweating
(15%), dry skin (7%)
and pruritus (7%).
Uncommon adverse events (< 4%) reported in clinical studies included chest
pain, syncope,
hypotension, impotence, alterations in taste or hearing, confusion,
seizures, memory loss,
disturbances of libido, bruising and coagulopathy. Miscellaneous adverse
events that were rarely
observed included Coombs' positive hemolytic anemia, aplastic anemia,
hypothyroidism,
cardiomyopathy, hypertriglyceridemia and bronchospasm.
FOR PATIENTS WITH HAIRY CELL LEUKEMIA:
Constitutional (100%): Fever (92%), fatigue (86%), headache (64%), chills
(64%), weight loss
(33%), dizziness (21%) and flu-like symptoms (16%).
Integumentary (79%): Skin rash (44%), diaphoresis (22%), partial alopecia
(17%), dry skin (17%)
and pruritus (13%).
Musculoskeletal (73%): Myalgia (71%), joint or bone pain (25%) and
arthritis or polyarthritis
(5%).
Gastrointestinal (69%): Anorexia (43%), nausea/vomiting (39%) and diarrhea
(34%).
Head and Neck (45%): Throat irritation (21%), rhinorrhea (12%) and
sinusitis (11%).
Pulmonary (40%): Coughing (16%), dyspnea (12%) and pneumonia (11%).
15
Roferon®-A (Interferon alfa-2a, recombinant)
Central Nervous System (39%): Dizziness (21%), depression (16%), sleep
disturbance (10%),
decreased mental status (10%), anxiety (6%), lethargy (6%), visual
disturbance (6%) and
confusion (5%).
Cardiovascular (39%): Chest pain (11%), edema (11%) and hypertension
(11%).
Pain (34%): Pain (24%) and pain in back (16%).
Peripheral Nervous System (23%): Paresthesia (12%) and numbness (12%).
Rarely (<5%), central nervous system effects including gait disturbance,
nervousness, syncope
and vertigo, as well as cardiac adverse events including murmur,
thrombophlebitis and
hypotension were reported. Adverse experiences that occurred rarely, and
may have been related
to underlying disease, included ecchymosis, epistaxis, bleeding gums and
petechiae. Urticaria and
inflammation at the site of injection were also rarely observed.
FOR PATIENTS WITH AIDS-RELATED KAPOSI'S SARCOMA:
Flu-like Symptoms: Fatigue (95%), fever (74%), myalgia (69%), headache
(66%), chills (41%)
and arthralgia (24%).
Gastrointestinal: Anorexia (65%), nausea (51%), diarrhea (42%), emesis
(17%) and abdominal
pain (15%).
Central and Peripheral Nervous System: Dizziness (40%), decreased mental
status (17%),
depression (16%), paresthesia (8%), confusion (8%), diaphoresis (7%),
visual disturbances (5%),
sleep disturbances (5%) and numbness (3%).
Pulmonary and Cardiovascular: Coughing (27%), dyspnea (11%), edema (9%),
chest pain (4%)
and hypotension (4%).
Skin: Partial alopecia (22%), rash (11%) and dry skin or pruritus (5%).
Other: Weight loss (25%), change in taste (25%), dryness or inflammation
of the oropharynx
(14%), night sweats (8%) and rhinorrhea (4%).
Occasionally (<3%) nervous system effects including anxiety, nervousness,
emotional lability,
vertigo and forgetfulness, as well as cardiac adverse events, including
palpitations and
arrhythmia, were reported. Other adverse experiences that occurred
occasionally (<3%) and may
have been related to underlying disease, included sinusitis, constipation,
chest congestion,
pneumonia, urticaria and flatulence. Adverse experiences which occurred
rarely (<1%) included
ataxia, seizures, cyanosis, gastric distress, bronchospasm, pain at
injection site, earache, eye
irritation and rhinitis. Miscellaneous adverse experiences such as poor
coordination, lethargy,
muscle contractions, neuropathy, tremor, involuntary movement, syncope,
aphasia, aphonia,
dysarthria, amnesia, weakness and flushing of skin were observed in less
than 0.5% of patients.
16
Roferon®-A (Interferon alfa-2a, recombinant)
Cases of cardiomyopathy have been observed on rare occasions in patients
treated with alfa
interferons.
IN OTHER INVESTIGATIONAL STUDIES OF ROFERON-A:
The following infrequent adverse events have been reported in one or more
of the approved
clinical indications as well as with the investigational use of Roferon-A
(<5%): pancreatitis,
colitis, gastrointestinal hemorrhage, stomatitis, thyroid dysfunction
(including hypothyroidism
and hyperthyroidism), diabetes (in some patients requiring insulin
therapy), and pneumonitis
(some cases responding to interferon cessation and corticosteroid
therapy). In addition to the
adverse experiences noted above, other adverse experiences that occurred
included: abdominal
fullness, hypermotility, hepatitis, gait disturbance, hallucinations,
encephalopathy, psychomotor
retardation, coma, stroke, transient ischemic attacks, dysphasia,
sedation, apathy, irritability,
hyperactivity, claustrophobia, loss of libido, congestive heart failure,
myocardial infarction,
Raynaud's phenomenon, hot flashes, tachypnea, ischemic retinopathy,
excessive salivation and
anaphylactic reactions. These adverse experiences occurred rarely (<1%).
The following events have been rarely observed (<3%) in some patients
receiving Roferon-A:
autoimmune diseases, ie, vasculitis, arthritis, hemolytic anemia and lupus
erythematosus
syndrome. The mechanism by which these events develop and their
relationship to Roferon-A
therapy are unclear. Similar events have been reported for other types of
interferon.
ABNORMAL LABORATORY TEST VALUES: The percentage of patients with chronic
hepatitis C,
hairy cell leukemia, with AIDS-related Kaposi's sarcoma, and with chronic
myelogenous
leukemia who experienced a significant abnormal laboratory test value (NCI
or WHO grades III
or IV) at least once during their treatment with Roferon-A is shown in the
following table:
Table 3. - Significant Abnormal Laboratory Test Values
Chronic Chronic Myelogenous Hairy Cell AIDS-related
Hepatitis C Leukemia Leukemia Kaposi's
(n=203) (n=218) Sarcoma
3 MIU tiw US Study Non-US (n=241)
(n=91) Study
(n=219)
Leukopenia 1.5% 20% 3% 45%* 49%
Neutropenia 10% 22% 0% 68%* 52%
Thrombocytopenia 4.5% 27% 5% 62%* 35%
Anemia (Hb) 0% 15% 4% 31%* 27%
SGOT NAP 5% 1% 9% 46%
Alk. Phosphatase 0% 3% 1% 3% 11%
LDH NAP NA NA <1% 10%
Proteinuria 0% NA NA 10% <1%
* In the majority of patients, initial hematologic laboratory test values
were abnormal due to
their underlying disease.
Ten percent of the patients experienced a proteinuria >1+ at least once.
17
Roferon®-A (Interferon alfa-2a, recombinant)
Patients enrolled in the two clinical studies receiving at least one dose
of Roferon-A.
NAP = Not applicable.
NA = Not assessed.
CHRONIC HEPATITIS C: The incidence of neutropenia (WHO grades III or IV)
was over twice
as high in those treated with 6 MIU tiw (21%) as those treated with 3 MIU
tiw (10%).
CHRONIC MYELOGENOUS LEUKEMIA: In the two clinical studies, a severe or
life-threatening
anemia was seen in up to 15% of patients. A severe or life-threatening
leukopenia and
thrombocytopenia were observed in up to 20% and 27% of patients,
respectively. Changes were
usually reversible when therapy was discontinued. One case of aplastic
anemia and one case of
Coombs' positive hemolytic anemia were seen in 310 patients treated with
rIFN -2a in clinical
studies. Severe cytopenias led to discontinuation of therapy in 4% of all
Roferon-A treated
patients.
Transient increases in liver transaminases or alkaline phosphatase of any
intensity were seen in up
to 50% of patients during treatment with Roferon-A. Only 5% of patients
had a severe or life-
threatening increase in SGOT. In the clinical studies, such abnormalities
required termination of
therapy in less than 1% of patients.
HAIRY CELL LEUKEMIA: Increases in serum phosphorus ( 1.6 mmol/L) and serum
uric acid
( 9.1 mg/dL) were observed in 9% and 10% of patients, respectively. The
increase in serum uric
acid is likely to be related to the underlying disease. Decreases in serum
calcium ( 1.9 mmol/L)
and serum phosphorus ( 0.9 mmol/L) were seen in 28% and 22% of patients,
respectively.
OVERDOSAGE: There are no reports of overdosage, but repeated large doses
of interferon can
be associated with profound lethargy, fatigue, prostration, and coma. Such
patients should be
hospitalized for observation and appropriate supportive treatment given.
DOSAGE AND ADMINISTRATION: Roferon-A recommended dosing regimens are
different
for each of the following indications as described below.
Note: Parenteral drug products should be inspected visually for
particulate matter and
discoloration before administration, whenever solution and container
permit.
Roferon-A vials are administered either subcutaneously or intramuscularly.
The Roferon-A
prefilled syringe is administered subcutaneously only, due to the length
of the syringe needle (1/2
inch) provided in the packaging.
CHRONIC HEPATITIS C: The recommended dosage of Roferon-A for the treatment
of chronic
hepatitis C is 3 MIU three times a week (tiw) administered subcutaneously
or intramuscularly for
12 months (48 to 52 weeks). As an alternative, patients may be treated
with an induction dose of
6 MIU tiw for the first 3 months (12 weeks) followed by 3 MIU tiw for 9
months (36 weeks).
Normalization of serum ALT generally occurs within a few weeks after
initiation of treatment in
responders. Approximately 90% of patients who respond to Roferon-A do so
within the first 3
months of treatment; however, patients responding to Roferon-A with a
reduction in ALT should
18
Roferon®-A (Interferon alfa-2a, recombinant)
complete 12 months of treatment. Patients who have no response to Roferon-A
within the first 3
months of therapy are not likely to respond with continued treatment;
treatment discontinuation
should be considered in these patients.
Patients who tolerate and partially or completely respond to therapy with
Roferon-A but relapse
following its discontinuation may be re-treated. Re-treatment with either
3 MIU tiw or with 6
MIU tiw for 6 to 12 months may be considered. Please see ADVERSE REACTIONS
regarding
the increased frequency of adverse reactions associated with treatment
with higher doses.
Temporary dose reduction by 50% is recommended in patients who do not
tolerate the
prescribed dose. If adverse events resolve, treatment with the original
prescribed dose can be re-
initiated. In patients who cannot tolerate the reduced dose, cessation of
therapy, at least
temporarily, is recommended.
CHRONIC MYELOGENOUS LEUKEMIA: For patients with Ph-positive CML in chronic
phase:
Prior to initiation of therapy, a diagnosis of Philadelphia chromosome
positive CML in chronic
phase by the appropriate peripheral blood, bone marrow and other
diagnostic testing should be
made. Monitoring of hematologic parameters should be done regularly (eg,
monthly). Since
significant cytogenetic changes are not readily apparent until after
hematologic response has
occurred, and usually not until several months of therapy have elapsed,
cytogenetic monitoring
may be performed at less frequent intervals. Achievement of complete
cytogenetic response has
been observed up to 2 years following the start of Roferon-A treatment.
The recommended initial dose of Roferon-A is 9 MIU daily administered as a
subcutaneous or
intramuscular injection. Based on clinical experience,3 short-term
tolerance may be improved by
gradually increasing the dose of Roferon-A over the first week of
administration from 3 MIU
daily for 3 days to 6 MIU daily for 3 days to the target dose of 9 MIU
daily for the duration of the
treatment period.
The optimal dose and duration of therapy have not yet been determined.
Even though the median
time to achieve a complete hematologic response was 5 months in study
MI400, hematologic
responses have been observed up to 18 months after treatment start.
Treatment should be
continued until disease progression. If severe side effects occur, a
treatment interruption or a
reduction in either the dose or the frequency of injections may be
necessary to achieve the
individual maximally tolerated dose (see PRECAUTIONS).
Limited data are available on the use of Roferon-A in children with CML.
In one report of 15
children with Ph-positive, adult-type CML doses between 2.5 to 5 MIU/m2/day
given
intramuscularly were tolerated.9 In another study, severe adverse effects
including deaths were
noted in children with previously untreated, Ph-negative, juvenile CML,
who received interferon
doses of 30 MIU/m2/day.14
HAIRY CELL LEUKEMIA: Prior to initiation of therapy, tests should be
performed to quantitate
peripheral blood hemoglobin, platelets, granulocytes and hairy cells and
bone marrow hairy cells.
These parameters should be monitored periodically (eg, monthly) during
treatment to determine
whether response to treatment has occurred. If a patient does not respond
within 6 months,
19
Roferon®-A (Interferon alfa-2a, recombinant)
treatment should be discontinued. If a response to treatment does occur,
treatment should be
continued until no further improvement is observed and these laboratory
parameters have been
stable for about 3 months. Patients with hairy cell leukemia have been
treated for up to 24
consecutive months. The optimal duration of treatment for this disease has
not been determined.
The induction dose of Roferon-A is 3 MIU daily for 16 to 24 weeks,
administered as a
subcutaneous or intramuscular injection. Subcutaneous administration is
particularly suggested
for, but not limited to, thrombocytopenic patients (platelet count
<50,000) or for patients at risk
for bleeding. The recommended maintenance dose is 3 MIU, three times a
week (tiw). Dose
reduction by one-half or withholding of individual doses may be needed
when severe adverse
reactions occur. The use of doses higher than 3 MIU is not recommended in
hairy cell leukemia.
AIDS-RELATED KAPOSI'S SARCOMA: Roferon-A is useful for the treatment of
AIDS-related
Kaposi's sarcoma in a select group of patients. In determining whether a
patient should be
treated, the physician should assess the likelihood of response based on
the clinical
manifestations of HIV infection and the manifestations of Kaposi's sarcoma
requiring treatment
(see CLINICAL PHARMACOLOGY).
Indicator lesion measurements and total lesion count should be performed
before initiation of
therapy. These parameters should be monitored periodically (eg, monthly)
during treatment to
determine whether response to treatment or disease stabilization has
occurred. When disease
stabilization or a response to treatment occurs, treatment should continue
until there is no further
evidence of tumor or until discontinuation is required because of a severe
opportunistic infection
or adverse effects. The optimal duration of treatment for this disease has
not been determined.
The recommended induction dose of Roferon-A is 36 MIU daily for 10 to 12
weeks, administered
as an intramuscular or subcutaneous injection. Subcutaneous administration
is particularly
suggested for, but not limited to, patients who are thrombocytopenic
(platelet count <50,000) or
who are at risk for bleeding. The recommended maintenance dose is 36 MIU,
three times a week
(tiw). If severe reactions occur, the dose should be modified (50%
reduction) or therapy should
be temporarily discontinued until the adverse reactions abate. An
escalating schedule of 3 MIU, 9
MIU and 18 MIU each daily for 3 days followed by 36 MIU daily for the
remainder of the 10- to
12-week induction period has also produced equivalent therapeutic benefit
with some
amelioration of the acute toxicity in some patients.
HOW SUPPLIED:
Single Use Injectable Solution: (for subcutaneous or intramuscular
administration)
3 million IU Roferon-A per vial - Each 1 mL contains 3 MIU of Interferon
alfa-2a,
recombinant, 7.21 mg sodium chloride, 0.2 mg polysorbate 80, 10 mg benzyl
alcohol as a
preservative and 0.77 mg ammonium acetate. Boxes of 1 (NDC 0004-2009-09).
20
Roferon®-A (Interferon alfa-2a, recombinant)
6 million IU Roferon-A per vial - Each 1 mL contains 6 MIU of Interferon
alfa-2a,
recombinant, 7.21 mg sodium chloride, 0.2 mg polysorbate 80, 10 mg benzyl
alcohol as a
preservative and 0.77 mg ammonium acetate. Boxes of 1 (NDC 0004-2007-09).
9 million IU Roferon-A per vial - Each 0.9 mL contains 9 MIU of Interferon
alfa-2a,
recombinant, 6.49 mg sodium chloride, 0.18 mg polysorbate 80, 9 mg benzyl
alcohol as a
preservative and 0.69 mg ammonium acetate. For single dose administration,
withdraw
0.9 mL using a 1 mL syringe. Also can be used as a multidose vial. Boxes
of 1 (NDC
0004-2010-09).
36 million IU Roferon-A per vial - Each 1 mL contains 36 MIU of Interferon
alfa-2a,
recombinant, 7.21 mg sodium chloride, 0.2 mg polysorbate 80, 10 mg benzyl
alcohol as a
preservative and 0.77 mg ammonium acetate. Boxes of 1 (NDC 0004-2012-09).
Single Use Prefilled Syringes: (for subcutaneous administration only)
3 million IU Roferon-A per syringe - Each 0.5 mL contains 3 MIU of
Interferon alfa-2a,
recombinant, 3.605 mg sodium chloride, 0.1 mg polysorbate 80, 5 mg benzyl
alcohol as a
preservative and 0.385 mg ammonium acetate. Boxes of 1 (NDC 0004-2015-09);
Boxes of
6 (NDC 0004-2015-07).
6 million IU Roferon-A per syringe - Each 0.5 mL contains 6 MIU of
Interferon alfa-2a,
recombinant, 3.605 mg sodium chloride, 0.1 mg polysorbate 80, 5 mg benzyl
alcohol as a
preservative and 0.385 mg ammonium acetate. Boxes of 1 (NDC 0004-2016-09);
Boxes of
6 (NDC 0004-2016-07).
9 million IU Roferon-A per syringe - Each 0.5 mL contains 9 MIU of
Interferon alfa-2a,
recombinant, 3.605 mg sodium chloride, 0.1 mg polysorbate 80, 5 mg benzyl
alcohol as a
preservative and 0.385 mg ammonium acetate. Boxes of 1 (NDC 0004-2017-09);
Boxes of
6 (NDC 0004-2017-07).
Multidose Injectable Solution: (for subcutaneous or intramuscular
administration)
9 million IU Roferon-A per vial - Each 0.3 mL contains 3 MIU of Interferon
alfa-2a,
recombinant, 2.16 mg sodium chloride, 0.06 mg polysorbate 80, 3 mg benzyl
alcohol as a
preservative and 0.23 mg ammonium acetate. Also can be used as a single
use vial. Once
the vial is entered, it must be used within 30 days. The 9 MIU multidose
vial contains an
average of 13 MIU of Interferon alfa-2a, recombinant in order to provide
the delivery of
three 0.3 mL doses, each containing 3 MIU of Roferon-A Interferon alfa-2a,
recombinant
for injection. Boxes of 1 (NDC 0004-2010-09).
18 million IU Roferon-A per vial - Each 1 mL contains 6 MIU of Interferon
alfa-2a,
recombinant, 7.21 mg sodium chloride, 0.2 mg polysorbate 80, 10 mg benzyl
alcohol as a
preservative and 0.77 mg ammonium acetate. Each 0.5 mL contains 3 MIU of
Interferon
alfa-2a, recombinant. Once the vial is entered, it must be used within 30
days. The 18 MIU
multidose vial contains an average of 22.8 MIU of Interferon alfa-2a,
recombinant in order
21
Roferon®-A (Interferon alfa-2a, recombinant)
to provide the delivery of six 0.5 mL doses, each containing 3 MIU of
Roferon-A
Interferon alfa-2a, recombinant for injection. Boxes of 1 (NDC
0004-2011-09).
Storage: The injectable solution and the prefilled syringe should be
stored in the refrigerator at
36° to 46°F (2° to 8°C). Do not freeze or shake.
REFERENCES:
1. Trown PW, et al. Cancer. 1986; 57(suppl):1648-1656. 2. Itri LM, et al.
Cancer. 1987; 59:668-
674. 3. Jones GJ, Itri LM. Cancer. 1986; 57(suppl):1709-1715. 4. Foon KA,
et al. Blood. 1984;
64(suppl 1):164a. 5. Quesada Jr, et al. Cancer. 1986; 57(suppl):1678-1680.
6. Krown SE, et al. N
Eng J Med. 1984; 308:1071-1076. 7. The Italian Cooperative Study Group on
CML. N Engl J
Med. 1994; 330:820-825. 8. Sokal JE, et al. Blood. 1984; 63(4):789-799. 9.
Dow LW, et al.
Cancer. 1991; 68:1678-1684. 10. Krown SE, et al. Proc Am Soc Clin Oncol.
1988; 7:1. 11.
Williams SJ, et al. Lancet. 1987; 2:939-941. 12. Jonkman JHG, et al. Br J
Clin Pharmacol. 1989;
2(27):795-802. 13. Kauppila A, et al. Int J Cancer. 1982; 29:291-294. 14.
Maybee D, et al. Proc
Annu Meet Am Soc Clin Oncol. 1992; 11:A950.
Rx only
U.S. Govt. Lic. No. 136
27897830-0301
Revised: March 2001
Printed in USA
Copyright © 1999-2001 by Hoffmann-La Roche Inc. All rights reserved.
Bone
damage - more than just nukes involved
.....combination of the anti-hepatitis-C nuke ribavirin
with interferon-alpha had an increased risk of developing thinning bones
compared to other people with hepatitis C who used interferon only.
TreatmentUpdate 117 - 2001 May; Volume 13 Issue 1
Hosein SR
Read study
Ribavirin & Bone damage
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