A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Roferon-A Warnings, Precautions, Pregnancy, Nursing, Abuse - Interferon alfa-2a, Recombinant
Roferon-A Warnings, Precautions, Pregnancy, Nursing, Abuse - Interferon alfa-2a, Recombinant
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
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.
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 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
See PATIENT INFORMATION section.
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
See DRUG INTERACTIONS section.
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 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
).
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