Roferon-A Side Effects

Generic Name: interferon alfa-2a

Please note - some side effects for Roferon-A may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Roferon-A - for the Consumer

Roferon-A Solution

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Roferon-A Solution:

Anxiety; bone pain; coughing; diarrhea; dizziness; dry mouth, throat, or skin; hair loss; headache; increased sweating; irritability; loss of appetite; mild flu-like symptoms (eg, fever, chills, joint and muscle pain); nausea; pain, swelling, or redness at the site of injection; stomach pain; taste changes; tiredness or weakness; trouble sleeping; vomiting.

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); behavior changes; bloody or black, tarry stools; bloody vomit; change in amount of urine produced; chest pain; confusion; dark urine; fainting; fast or irregular heartbeat; heart attack symptoms (eg, chest, shoulder, jaw, or neck pain; numbness of an arm or leg; severe stomach pain, dizziness, or vomiting); memory problems; mental or mood changes (eg, depression, severe or persistent irritability or anxiety); numbness or tingling; pale, blue, or very cold fingers or toes; seizures; severe or persistent fever, chills, coughing, or sore throat; severe or persistent joint and muscle pain; severe or persistent stomach pain; severe or persistent tiredness or weakness; shortness of breath; suicidal thoughts or attempts; trouble concentrating or thinking; unexplained weight gain; unusual bleeding or bruising; vision loss or other vision problems; yellowing of the eyes or skin.

Roferon-A Side Effects - for the Professional

Roferon-A

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.

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 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.

Triglyceride levels were not evaluated in the clinical trials. However, hypertriglyceridemia has been reported postmarketing in patients receiving Roferon-A 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, 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%).

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

The following infrequent adverse events have been reported with the investigational use of Roferon-A.

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 (<1%).

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 is shown in Table 2:

Elevated triglyceride levels have been observed in patients receiving interferon therapy, including Roferon-A.

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 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.

Postmarketing

Central and Peripheral Nervous System: Somnolence, hearing impairment, hearing loss.

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.

Endocrine: Hyperglycemia.

Immune System Disorder: Sarcoidosis.

Respiratory: Pulmonary edema.

Metabolic and Nutritional: Cases of hypertriglyceridemia/hyperlipidemia have been reported including some occurring in association with pancreatitis.

Side Effects by Body System

Psychiatric

Depression has been reported to have sometimes continued after decreases in dosage or discontinuation of therapy.

Results of a recent study (n=14) of patients affected by chronic hepatitis C who received interferon alfa-2b suggests that the development of the interferon alfa-induced depressive symptoms may arise through depletion of central and peripheral 5-HT and reduction of tryptophan plasma levels.

Psychiatric side effects have included depression (16% to 28%) and suicidal behavior including suicidal ideation, suicide attempts, and suicides. Irritability (15%), insomnia (14%), anxiety (5% to 6%), and behavioral disturbances (3%) have also been reported. In a study of patients (n=25) with chronic myelogenous leukemia conducted to evaluate the neuropsychological symptoms related to the treatment with interferon alfa, a disproportionate number of these patients scored in the impaired range on tests of verbal memory, delayed visual memory, verbal fluency, visual scanning and sequencing, executive function, and motor dexterity for the preferred hand when compared to controls. Besides the mentioned cognitive deficits, the patients receiving interferon alfa also showed signs of personality and mood disturbances.

Other

Other side effects have included flu like symptoms such as fatigue (58% to 95%), fever (25% to 92%), myalgia (68% to 71%), headache (44% to 66%), chills (23% to 64%), arthralgia/bone pain (25% to 47%), asthenia (6%), sweating (5%), leg cramps (3%), and malaise (1%). Weight loss (25% to 33%), change in taste or smell (3% to 25%), pain (24%), back pain (16%), night sweats (8%), menstrual irregularity (4%), reversible hearing loss, and tinnitus have also been reported.

Flu like symptoms may be especially prevalent during the first week of therapy.

Gastrointestinal

Gastrointestinal (GI) side effects have included anorexia (14% to 65%), diarrhea (20% to 42%), nausea/vomiting (33% to 39%), abdominal pain (12% to 15%), flatulence (3%), liver pain (3%), impaired digestion (2%), gingival bleeding (2%), and GI hemorrhage.

Nervous system

Nervous system side effects have included headache (44% to 64%), dizziness (11% to 40%), decreased mental status (10% to 17%), paresthesias (7% to 12%), numbness (3% to 12%), sleep disturbances (10 % to 11%), confusion (5% to 8%), involuntary movements (7%), lethargy (6%), sleep disturbances (5%), and impaired concentration (4%). At least one case of myorhythmia has also been reported, in addition to a case of encephalopathy.

Most of the central nervous system adverse effects have been mild and reversible within a few days to 3 weeks after dose reduction or discontinuation of therapy.

A 49-year-old female with a history of chronic myeloid leukemia experienced myorhythmia coincident with interferon alfa-2a therapy. She was treated with increasing doses of subcutaneous interferon alfa-2a up to 6 megaunits daily, with good clinical and hematologic response. After 1.5 years on the interferon, she had a gradual onset of involuntary facial movements. Movements on her forehead and both sides of her lower face were noted by her family members. Brain magnetic resonance imaging (MRI) did not show any structural abnormality. The patient was asked to discontinue interferon. Within 2 weeks, she reported improvement of the facial movements, and at 1 month there was almost complete resolution of her symptoms.

A 44-year-old female with metastatic renal cell cancer experienced encephalopathy coincident with interferon alfa-2a therapy. She presented with progressive apathy and slight subjective memory loss as well as two seizures. Electroencephalogram showed multifocal epileptiform discharges. Lumbar puncture results were normal. MRI demonstrated hyperintensities in the basal ganglia and the adjacent white matter but no other significant lesions. After stopping interferon therapy, the patients clinical state normalized, as did MRI 3 weeks later.

Dermatologic

Dermatologic side effects have included skin rash (8% to 44%), injection site reaction (29%), diaphoresis (7% to 22%), partial alopecia (17% to 22%), dry skin (7% to 17%), pruritus (7% to 13%), hematoma (1%). Psoriasis, cutaneous eruptions, eczema, and seborrhea have also been reported in less than 1% of patients.

Respiratory

Respiratory side effects have included cough (19% to 27%), throat irritation (21%), coughing (16%), rhinorrhea (12%), dyspnea (8% to 12%), pneumonia (11%), sinusitis (greater than 1% to 11%), dryness or inflammation of the oropharynx (6%), epistaxis (4%), and rhinitis (3%).

Cardiovascular

Cardiovascular side effects have included hypertension (11%), edema (9% to 11%), chest pain (4% to 11%), dysrhythmia (7%), hypotension (4%), and arrhythmia (1%). Myocardial infarction has been reported rarely. Cases of cardiomyopathy have been reported rarely in patients treated with alpha interferons.

Ocular

Ocular side effects have included visual disturbance (5% to 6%) and conjunctivitis (4%).

Musculoskeletal

Musculoskeletal side effects have included arthritis or polyarthritis (5%).

Hepatic

Hepatic side effects have included transient increases of liver transaminase or alkaline phosphatase in up to 50% of studied patients diagnosed with chronic myelogenous leukemia receiving interferon alfa-2a. Other hepatic side effects rarely reported have included pancreatitis, hypertriglyceridemia, and hepatitis.

Severe chronic active hepatitis has been reported in a patient post completion of interferon alfa-2a therapy and successful treatment of chronic active hepatitis B.

Hematologic

The incidence of neutropenia (WHO grades III or IV) among chronic hepatitis C patients was over twice as high in those treated with 6 million international units thrice weekly (21%) as those treated with 3 million international units three times weekly (10%).

Hematologic side effects have included decreases in WBC (including neutropenia), hematocrit, and platelet counts.

Endocrine

Endocrine side effects have included thyroid disorders (hyperthyroidism or hypothyroidism).

Metabolic

Metabolic side effects have included hyperglycemia.

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