"SILVER SPRING, MD â€” The US Food and Drug Administration (FDA) is updating labeling information for the hepatitis C antivirals ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) and sofosbuvir (Sovaldi, Gilead Sciences) after th"...
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:
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 (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%).
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%).
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%).
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)|
| *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 experienc
‡ 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% 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.
Central and Peripheral Nervous System: Somnolence, hearing impairment, hearing loss.
Skin: Injection site necrosis.
Blood: Idiopathic thrombocytopenic purpura, cyanosis.
Immune System Disorder: Sarcoidosis.
Respiratory: Pulmonary edema.
Metabolic and Nutritional: Cases of hypertriglyceridemia/hyperlipidemia have been reported including some occurring in association with pancreatitis.
Read the Roferon-A (interferon alfa-2a, recombinant) Side Effects Center for a complete guide to possible side effects
Roferon-A (interferon alfa-2a, recombinant) has been reported to reduce the clearance of theophylline10,11. The clinical relevance of this interaction is presently unknown. Caution should be exercised when administering Roferon-A (interferon alfa-2a, recombinant) in combination with other potentially myelosuppressive agents. Synergistic toxicity has been observed when Roferon-A (interferon alfa-2a, recombinant) is administered in combination with zidovudine (AZT) (see WARNINGS: Bone Marrow Toxicity).
In transplant recipients, therapeutic immunosuppression may be weakened because interferons also exert an immunostimulatory action.
Alpha-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 administration of centrally acting drugs. Use of Roferon-A (interferon alfa-2a, recombinant) in conjunction with interleukin-2 may potentiate risks of renal failure.
Last reviewed on RxList: 11/25/2008
This monograph has been modified to include the generic and brand name in many instances.
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