Depressive illness and suicidal behavior, including suicidal ideation, suicide
attempt, 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 (interferon alfa-2a, recombinant) , were mostly mild to moderate in
severity and manageable without the need for discontinuation of therapy. A 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 (interferon alfa-2a, recombinant) .
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 (interferon alfa-2a, recombinant) 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.
Triglyceride levels were not evaluated in the clinical trials. However, hypertriglyceridemia
has been reported postmarketing in patients receiving Roferon-A (interferon alfa-2a, recombinant) therapy for
chronic hepatitis C.
For Patients With Chronic Myelogenous Leukemia
For patients with chronic myelogenous leukemia, the percentage of adverse events,
whether related to drug therapy or not, experienced by patients treated with
rIFNα-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 (interferon alfa-2a, recombinant) , 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
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
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
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%).
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.
In Other Investigational Studies of Roferon-A (interferon alfa-2a, recombinant)
The following infrequent adverse events have been reported with the investigational
use of Roferon-A (interferon alfa-2a, recombinant) .
Gastrointestinal: Pancreatitis, colitis, gastrointestinal hemorrhage,
stomatitis ( < 5%); constipation ( < 3%); hepatitis, abdominal fullness,
hypermotility, excessive salivation, gastric distress ( < 1%).
Cardiovascular: Palpitations ( < 3%); myocardial infarction, congestive
heart failure, ischemic retinopathy, Raynaud's phenomenon, hot flashes ( <
Pulmonary: Pneumonitis, some cases responded to interferon cessation
and corticosteroid therapy ( < 5%); chest congestion ( < 3%); tachypnea
( < 1%).
Central Nervous System and Psychiatric: Stroke, coma, encephalopathy,
transient ischemic attacks, dysphasia, hallucinations, gait disturbance, psychomotor
retardation, apathy, sedation, irritability, hyperactivity, claustrophobia,
loss of libido, ataxia, neuropathy, poor coordination, dysarthria, aphasia,
aphonia, amnesia ( < 1%).
Autoimmune Disease: Vasculitis, arthritis, hemolytic anemia and lupus
erythematosus syndrome ( < 3%).
Other: Thyroid dysfunction including hypothyroidism and hyperthyroidism,
diabetes requiring insulin therapy in some patients ( < 5%); anaphylactic
reactions, eye irritation, earache, cyanosis, flushing of skin ( < 1%).
Abnormal Laboratory Test Values
The percentage of patients with chronic hepatitis C, hairy cell leukemia, 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 (interferon alfa-2a, recombinant) is shown in Table 2:
Table 2 - Significant Abnormal Laboratory Test Values
||Chronic Hepatitis C
||Chronic Myelogenous Leukemia‡
||Hairy Cell Leukemia (n=218)
|(n=203) 3 MIU tiw
||US Study (n=91)
||Non-US Study (n=219)
|| < 1%
| *In the majority of patients, initial hematologic
laboratory test values were abnormal due to their underlying disease.
† ed a proteinuria > 1+ at least once.Ten percent of the patients
‡ es receiving at least one dose of Roferon-A (interferon alfa-2a, recombinant) .Patients enrolled
in the two
NAP = Not applicable.
NA = Not assessed.
Elevated triglyceride levels have been observed in patients receiving interferon
therapy, including Roferon-A (interferon alfa-2a, recombinant) .
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 rIFNα-2a in clinical studies. Severe cytopenias led to discontinuation
of therapy in 4% of all Roferon-A (interferon alfa-2a, recombinant) 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 (interferon alfa-2a, recombinant) . 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%
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.
Central and Peripheral Nervous System: Somnolence, hearing impairment,
Vision: Retinopathy including retinal hemorrhages and cotton-wool spots,
papilledema, retinal artery and vein thrombosis and optic neuropathy.
Skin: Injection site necrosis.
Blood: Idiopathic thrombocytopenic purpura, cyanosis.
Renal and Urinary System: Increased blood urea and serum creatinine,
decreased renal function and acute renal failure.
Immune System Disorder: Sarcoidosis.
Respiratory: Pulmonary edema.
Metabolic and Nutritional: Cases of hypertriglyceridemia/hyperlipidemia
have been reported including some occurring in association with pancreatitis.