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, IN PATIENTS WITH AND WITHOUT PREVIOUS PSYCHIATRIC ILLNESS. Roferon-A should be used with extreme caution in patients who report a history of depression. Patients 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. Psychiatric intervention and/or 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 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 (i.e., 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 alpha interferons.
Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alfa-based therapies, including Roferon-A. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made and a causal relationship between interferon alfa-based therapies and these events is difficult to establish.
Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction and anaphylaxis), as well as skin rashes have been rarely observed during alpha-interferon therapy, including interferon alfa-2a. If a serious reaction develops during treatment with Roferon-A, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment.
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.
Infrequently, severe or fatal gastrointestinal hemorrhage has been reported in association with alpha-interferon therapy.
Ulcerative, and hemorrhagic/ischemic colitis, sometimes fatal, have been observed within 12 weeks of starting alpha interferon treatment. Abdominal pain, bloody diarrhea, and fever are the typical manifestations of colitis. Roferon-A should be discontinued immediately if these symptoms develop. The colitis usually resolves within 1 to 3 weeks of discontinuation of alpha interferon.
While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of high or persistent fever must be ruled out, particularly in patients with neutropenia. Serious and severe infections (bacterial, viral, fungal), some fatal, have been reported during treatment with alpha interferons including Roferon-A. Appropriate anti-infective therapy should be started immediately and discontinuation of therapy should be considered.
Bone Marrow Toxicity
Alpha-interferons suppress bone marrow function and may result in severe cytopenias and anemia including very rare events of aplastic anemia. Cytopenias (e.g., leukopenia, thrombocytopenia) can lead to an increased risk of infections or hemorrhage. 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 × 109/L) or platelet counts (<25 × 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 myelosuppression. Synergistic toxicity has been observed when Roferon-A is administered in combination with zidovudine (AZT).9
Roferon-A causes or aggravates hypothyroidism and hyperthyroidism. Hyperglycemia has been observed 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.
Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis and sarcoidosis, some resulting in respiratory failure and/or patient deaths, may be induced or aggravated by alpha interferon therapy. Patients who develop persistent or unexplained pulmonary infiltrates or pulmonary function impairment should discontinue treatment with Roferon-A.
Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots, optic neuritis, and papilledema are induced or aggravated by treatment with Interferon alfa-2a or other alpha interferons. All patients should receive an eye examination at baseline. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during interferon alpha treatment. Any patient who develops ocular symptoms should receive a prompt and complete eye examination. Interferon alfa-2a treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.
Pancreatitis has been observed in patients receiving alpha interferon treatment, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to Roferon-A has not been established, marked triglyceride elevation is a risk factor for development of pancreatitis. Roferon-A should be suspended if symptoms or signs suggestive of pancreatitis are observed. In patients diagnosed with pancreatitis, discontinuation of therapy with Roferon-A should be considered.
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 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.
The safety and efficacy of Roferon-A have not been established in organ transplant recipients.
Dose-limiting renal toxicities were unusual. Infrequently, severe renal toxicities, sometimes requiring renal dialysis, have been reported with alpha-interferon therapy alone or in combination with IL-2. In patients with impaired renal function, signs and symptomsof interferon toxicity should be closely monitored. Roferon-A should be used with caution in patients with creatinine clearance <50 mL/min.
Development or exacerbation of autoimmune diseases including idiopathic thrombocytopenic purpura, vasculitis, Raynaud's phenomenon, rheumatoid arthritis, psoriasis, interstitial nephritis, thyroiditis, lupus erythematosus, hepatitis, myositis 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 Patients
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 Medication Guide. Patients should be well hydrated, especially during the initial stages of treatment.
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 (see Medication Guide).
Patients should be advised that laboratory evaluations are required before starting therapy and periodically thereafter (see Laboratory Tests).
Patients receiving high-dose alpha-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.
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.
Complete blood counts with differential platelet counts and clinical chemistry tests should be performed before initiation of Roferon-A therapy and at appropriate periods during therapy. 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. Since responses of hairy cell leukemia, 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 developing liver function abnormalities during Roferon-A treatment should be closely monitored and if necessary treatment should be discontinued. Use of alpha-interferons has been rarely associated with severe hepatic dysfunction and liver failure.
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.
Elevated triglyceride levels have been observed in patients treated with interferons including Roferon-A therapy. Triglyceride levels should be monitored periodically during treatment and elevated levels should be managed as clinically appropriate. Hypertriglyceridemia may result in pancreatitis. Discontinuation of Roferon-A therapy should be considered for patients with persistently elevated triglycerides (e.g., triglycerides >1000 mg/dL) associated with symptoms of potential pancreatitis, such as abdominal pain, nausea, or vomiting.
Roferon-A has been reported to reduce the clearance of theophylline.10,11 The clinical relevance of this interaction is presently unknown. Caution should be exercised when administering Roferon-A in combination with other potentially myelosuppressive agents. Synergistic toxicity has been observed when Roferon-A 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 in conjunction with interleukin-2 may potentiate risks of renal failure.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Roferon-A has not been tested for its carcinogenic potential.
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 Category C
Roferon-A has been associated with statistically significant, dose-related increases in abortions in pregnant rhesus monkeys treated with 1, 5, or 25 MIU/kg/day (approximately 20 to 500 times the human weekly dose, when scaled by body surface area) during the early to midfetal period of organogenesis (gestation day 22 to 70). Abortifacient activity was also observed in 2/6 pregnant rhesus monkeys treated with 25 MIU/kg/day Roferon-A (500 times the human dose) during the period of late fetal development (days 79 to 100 of gestation). No teratogenic effects were seen in either study. However, the validity of extrapolating doses used in animal studies to human doses is not established. Therefore, no direct comparison of the doses that induced fetal death in monkeys to dose levels of Roferon-A used clinically can be made. There are no adequate and well-controlled studies of Roferon-A in pregnant women. Roferon-A is to be used during pregnancy only if the potential benefit to the woman justifies the potential risk to the fetus. Roferon-A is recommended for use in women of childbearing potential and in men only when they are using effectivecontraception during therapy.
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.
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.
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 observed8 (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 CONTRAINDICATIONS).
In clinical studies of Roferon-A in chronic hepatitis C, 101 patients were 65 years old or older. The numbers were insufficient to determine if antiviral responses differ from younger subjects. There were greater proportions of geriatric patients with serious adverse reactions (9% vs. 6%), withdrawals due to adverse reactions (11% vs. 6%), and WHO grade III neutropenia and thrombocytopenia.
Clinical studies of Roferon-A in chronic myelogenous leukemia or hairy cell leukemia did not include sufficient numbers of subjects aged 65 or older to determine whether they respond differently from younger subjects.
This drug is known to be excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, these patients should receive careful monitoring, including renal function.