Roferon (Interferon alfa-2a)

ROFERON®-A

Roche

Interferon alfa-2a

Biological Response Modifier

Action And Clinical Pharmacology: The mechanisms by which interferon alfa-2a, or any other interferon, exerts antitumor activity are not clearly understood. However, it is believed that the direct antiproliferative action against tumor cells and modulation of the host immune response play important roles in the antitumor activity.

Interferon alfa-2a has been shown to exert antiproliferative activity against a variety of human tumors in vitro and to inhibit the growth of some human tumor xenografts in immuno-compromised (nude) mice.

The serum concentrations of recombinant interferon alfa-2a exhibited a large intersubject variation in both healthy volunteers and patients with disseminated cancer.

In healthy people, recombinant interferon alfa-2a exhibited an elimination half-life of 3.7 to 8.5 hours (mean 5.1 hours), volume of distribution at steady-state of 0.223 to 0.748 L/kg (mean 0.4 L/kg) and a total body clearance of 2.14 to 3.62 mL/min/kg (mean 2.79 mL/min/kg) after a 36 million IU (2.2´10pg) i.v. infusion. After i.m. and s.c. administrations of 36 million IU, peak serum concentrations ranged from 1 500 to 2 580 pg/mL (mean 2 020 pg/mL) at a mean time to peak of 3.8 hours and from 1 250 to 2 320 pg/mL (mean 1 730 pg/mL) at a mean time to peak of 7.3 hours, respectively. The apparent fraction of the dose absorbed after i.m. or s.c. injection was greater than 80%.

The pharmacokinetics of recombinant interferon alfa-2a after single i.m. doses to patients with disseminated cancer were similar to those found in healthy volunteers. Dose proportional increases in serum concentrations were observed after single doses up to 198 million IU. There were no changes in the distribution or elimination of recombinant interferon alfa-2a during twice daily (0.5 to 36 million IU), once daily (1 to 54 million IU), or 3 times weekly (1 to 136 million IU) dosing regimens up to 28 days of dosing. Multiple i.m. doses of recombinant interferon alfa-2a resulted in an accumulation of 2 to 4 times the single dose serum concentrations. Pharmacokinetic information in patients with hairy cell leukemia is presently unknown.

Indications And Clinical Uses: For use in the treatment of hairy cell leukemia, Kaposi’s sarcoma in patients with AIDS (Acquired Immune Deficiency Syndrome), chronic active hepatitis B, chronic myelogenous leukemia (CML), and thrombocytosis associated with CML, renal cell carcinoma, cutaneous T-cell lymphoma (CTCL) and chronic hepatitis C.

Contra-Indications: In patients with known hypersensitivity to the drug, its components or other interferon preparations; in patients with chronic hepatitis associated with advanced, decompensated cirrhosis of the liver and in patients with chronic hepatitis who are being or have recently been treated with immunosuppressive agents, excluding short-term “steroid withdrawal”.

Roferon-A Albumin (Human) Free which contains benzyl alcohol as a preservative, is contraindicated in patients with hypersensitivity to benzyl alcohol (also see Precautions, Children).

Manufacturers’ Warnings In Clinical States: Initial therapy with interferon alfa-2a should be conducted under the guidance of a qualified physician experienced in the use of cancer chemotherapeutic agents, in a unit having adequate facilities for monitoring of the relevant clinical and laboratory parameters. Treatment with interferon alfa-2a is not recommended in patients with severe pre-existing cardiac disease or severe renal or hepatic dysfunction as the benefit-risk ratio may not warrant therapy.

Precautions: General: If acute hypersensitivity reactions to interferon alfa-2a develop, the drug should be discontinued.

Moderate to severe adverse reactions may require modification of the patient’s dosage regimen, or in some cases, termination of drug therapy.

CNS adverse reactions have been reported. These reactions included confusion, somnolence, dizziness and depression. Seizures and coma have been rarely observed. Most of these abnormalities were mild and were reversible within a few days to a few weeks upon dose reduction or discontinuation of therapy. Interferon alfa-2a should be used with caution in patients with seizure disorders and/or compromised CNS functions. Periodic examination of the neuropsychiatric status of all patients is recommended.

Interferon alfa-2a should be administered with caution to patients with cardiac disease or with any history of cardiac illness. No direct cardiotoxic effect has been demonstrated, but it is likely that acute self-limiting toxicities (i.e., fever, chills), frequently associated with interferon alfa-2a administration may exacerbate pre-existing cardiac conditions. Myocardial infarction occurred rarely in patients receiving interferon alfa-2a.

Those patients who have pre-existing cardiac abnormalities and/or are in advanced stages of cancer should have ECGs taken prior to and during the course of treatment.

When mild to moderate renal or hepatic impairment is present, close monitoring of these functions is required.

Hyperglycemia has been observed rarely in patients treated with interferon alfa-2a. Symptomatic patients should have their blood glucose measured and followed-up accordingly. Patients with diabetes mellitus should have their blood glucose measured and adjusted according to their antidiabetic regimen.

Careful periodic monitoring of all patients is recommended. Suicidal behavior has been observed rarely in patients receiving interferon alfa-2a. Therapy should be discontinued in patients exhibiting suicidal behavior.

The development of auto-antibodies may play a role in the development of autoimmune disorders. Autoimmune phenomena such as vasculitis, arthritis, hemolytic anemia, thyroid dysfunction and lupus erythematosus syndrome have been observed rarely in patients receiving interferon alfa-2a.

Pregnancy: Safe use in human pregnancy has not been established. As with other anticancer drugs, interferon alfa-2a should not be administered to fertile persons of either sex not practising effective contraception. In pregnancy, interferon alfa-2a should be administered only if the benefit to the woman justifies the potential risk to the fetus. 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 Albumin (Human) Free immediately prior to birth or Cesarean section.

Lactation: 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, a decision should be made whether to discontinue nursing or to postpone treatment, taking into account the importance of the drug to the mother.

Children: Safety and effectiveness in patients under 18 years of age have not been established. Roferon-A Albumin (Human) Free is not recommended for use in the newborn or children under the age of 2 years since it contains benzyl alcohol as a preservative.

Patients with Special Diseases: Caution should be exercised when administering interferon alfa-2a to patients with severe myelosuppression.

Drug Interactions: Interactions between interferon alfa-2a and other drugs have not been fully evaluated.

As interferon alfa-2a may affect central nervous functions, interactions could occur following concurrent administration of centrally acting drugs.

Alfa-Interferons may affect the oxidative metabolic process by reducing the activity of 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. Reduced clearance of theophylline following the concomitant administration of alfa-interferons has been reported.

It has been observed that 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.

Caution should be exercised when interferon alfa-2a is used in combination with other agents that are known to cause myelosuppression. Synergistic toxicity has been observed when interferon alfa-2a is administered in combination with zidovudine (AZT). The effects of interferon alfa-2a when combined with other drugs used in the treatment of AIDS-related diseases are not known.

Laboratory Tests: Periodic complete blood counts and liver function tests should be performed during the course of interferon alfa-2a treatment. They should be performed prior to therapy and at appropriate periods during therapy. Interferon has suppressive effects on the bone marrow, leading to a fall in the white blood count, particularly the granulocytes, the platelet count and commonly the hemoglobin concentration.

Information for the Patient: Patients should be informed not only of the potential benefits and risks of therapy, but also that they will probably experience adverse reactions.

Patients should be well hydrated, especially during the initial stages of treatment.

Adverse Reactions: The following data on adverse reactions are based on information derived from the treatment of patients with a wide variety of malignancies including patients with hairy cell leukemia, AIDS related Kaposi’s sarcoma and chronic active hepatitis B and patients with chronic hepatitis C. Most patients suffered from advanced forms of the diseases. Also, most patients received doses that were significantly higher than the doses now recommended and this probably affected the frequency and severity of adverse reactions.

General Symptoms: The majority of the patients experienced flu-like symptoms such as fatigue, fever, chills, anorexia, myalgia, headache, arthralgias and diaphoresis. Dose attenuation usually decreased the severity of the adverse effects.

Gastrointestinal: Slightly more than half of the patients studied experienced anorexia and/or nausea. Emesis, diarrhea and mild to moderate abdominal pain were less frequently observed. Constipation, flatulence, hypermotility or heartburn occurred rarely. Reactivation of peptic ulcer and nonlife-threatening gastrointestinal bleeding have also been reported.

Alterations of hepatic function shown by an elevation of AST, alkaline phosphatase, LDH and bilirubin have been observed and generally did not require dose adjustment. Hepatitis was rarely reported.

CNS: Dizziness, vertigo, decreased mental status, depression, drowsiness, confusion, behavioral disturbances such as anxiety and nervousness and sleep disturbances were reported. Severe somnolence, convulsions, coma, seizures and encephalopathy and suicidal behavior are rare complications.

Peripheral Nervous System: Paresthesias, sleep disturbances, visual disturbances, numbness, neuropathy and tremor occurred occasionally, ischemic retinopathy rarely.

Cardiovascular: Reactions were seen in less than a fifth of the patients and consisted of transient hypotensive or hypertensive episodes, edema, chest pain, cyanosis, arrhythmias and palpitations. Rare cases of pulmonary edema, congestive heart failure, cardiorespiratory arrest and myocardial infarction have been reported.

Skin and Appendages: Rash, pruritus, mild to moderate hair loss, dryness of skin, rhinorrhea, urticaria, epistaxis and reactivation of herpes labialis were reported.

Renal and Urinary: Abnormalities consisted primarily of proteinuria and increased red and white cell counts in sediment. Elevations of BUN, serum creatinine and uric acid have been rarely observed. Rare cases of acute renal failure have been reported, mainly in cancer patients with renal disease and/or nephrotoxic comedications as concomitant risk factors.

Hematopoietic: Transient leukopenia occurred in about one third of the patients, but rarely required dosage reduction.

Thrombocytopenia was less frequently seen. Decreased hemoglobin and hematocrit occurred rarely. Recovery of severe hematological deviations to pretreatment levels usually occurred within 7 to 10 days after stopping interferon alfa-2a treatment.

Other: Weight loss, change in taste, and dryness or inflammation of the oropharynx have been reported, bleeding gums, ecchymosis and pneumonia rarely. Hyperglycemia has been observed rarely in patients treated with interferon alfa-2a.

Neutralizing antibodies to interferon alfa-2a were detected in 14.6 to 38% of patients in clinical trials with hairy cell leukemia, AIDS related Kaposi’s sarcoma, chronic active hepatitis B, renal cell carcinoma, chronic myelogenous leukemia and chronic hepatitis C.

No data on neutralizing antibodies yet exist from clinical trials in which the presently marketed material, which is stored at 4°C, has been used. In a mouse model, however, the relative immunogenicity of interferon alfa-2a increases with time when the material is stored at 25°C – no such increase in immunogenicity is observed when interferon alfa-2a is stored at 4°C, the presently recommended storage conditions.

In general, the higher the cumulative dose of interferon alfa-2a received, the more likely a patient will produce antibodies to interferon alfa-2a. Antibodies to human leukocyte interferon may occur spontaneously in certain clinical conditions (cancer, systemic lupus erythematosus, herpes zoster) in patients who have never received exogenous interferon.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There are no reports of overdosage but repeated large doses of interferon are associated with profound lethargy, fatigue, prostration, and coma. Such patients should be hospitalized for observation and appropriate supportive treatment given. tag_DosageDosage

Dosage And Administration: The following dosage schedules are recommended and should not be exceeded: Adults: Hairy Cell Leukemia: Induction dose of 3 million IU daily for 16 to 24 weeks administered as an i.m. injection. Maintenance 3 million IU 3 times/week. S.C. administration may be utilized in thrombocytopenic patients (platelet count
AIDS related Kaposi’s Sarcoma: Induction dose of 36 million IU daily for 4 to 10 weeks as a s.c. or i.m. injection. Maintenance dose of 36 million IU 3 times/week.

Patients with Kaposi’s sarcoma should be treated for 30 to 90 days before the physician determines the possible benefits of continued therapy in patients whose disease did not progress.

Chronic Active Hepatitis B: Recommended dose is 4.5 million IU administered s.c. 3 times/week for 6 months.

If markers for viral replication or HBeAg do not decrease after 1 month of therapy, the dose can be escalated. The dosage may be further adjusted to the patient’s tolerance to medication. If no improvement has been observed after 3 to 4 months of treatment, discontinuation of therapy should be considered.

Therapeutic trials in patients with chronic active hepatitis B show that interferon alfa-2a therapy at doses equivalent to ³4.5 million IU 3 times weekly for 6 months is associated with inhibition of viral replication, development of a specific humoral immune response and a reduction or disappearance of necroinflammatory disease of the liver. Response to therapy is generally signalled by a transient asymptomatic acute hepatitis “flare” with a serum transaminase peak accompanied by a fall in the level of genomic and antigenic (especially HBe) markers of viral replication. Loss or reduction of HBs antigenemia usually occurs over a period of many months. The appearance of anti-HBe and in some patients anti-HBs antibody in the serum signals antiviral immunity. Maximal response to therapy often occurs weeks or months after the end of treatment. Patients with active disease respond better to therapy than those with hypoactive disease as defined by liver biopsy and/or serum ALT levels. Doses £1.5 million IU 3 times weekly for 16 weeks are suboptimally effective. Some patients may require doses up to the equivalent of 18 million IU for 6 months to benefit from therapy.

Chronic Myelogenous Leukemia: It is recommended that interferon alfa-2a should be given by s.c. or i.m. injection for 8 to 12 weeks to patients 18 years or more. The recommended schedule is: days 1 to 3: 3 million IU daily; days 4 to 6: 6 million IU daily; days 7 to 84: 9 million I.U. daily.

Duration of Treatment: Patients should be treated for a minimum of 8 weeks, preferably for at least 12 weeks before the physician decides whether or not to continue treatment in responding patients or to discontinue treatment in patients not showing any changes in hematological parameters. Responding patients should be treated until complete hematological response is achieved or for a maximum of 18 months. All patients with complete hematologic responses should continue treatment with 9 million IU daily (optimum) or 9 million IU 3 times/week (minimum) in order to achieve a cytogenic response in the shortest possible time. The optimal duration of interferon alfa-2a treatment for a chronic myelogenous leukemia has not been determined, although cytogenic responses have been observed 2 years after treatment started.

Thrombocytosis associated with CML: Thrombocytosis is a frequent concomitant phenomenon in CML. The morbid nature of severe thrombocytosis is reflected by the frequent manifestation of a serious thrombotic or hemorrhagic diathesis. In a large Phase 3 clinical trial, when 206 interferon alfa-2a treated CML patients were available for hematologic response assessment, 75 subjects had a baseline thrombocyte count of >450´10L. Platelet control was achieved in 73 patients (97%).

Therefore, therapy is recommended with interferon alfa-2a for the treatment of patients with excessive thrombocytosis in CML, even in the absence of cytogenetic response.

The recommended dosage for thrombocytosis in CML is the same as that recommended above for the treatment of CML.

Renal Cell Carcinoma: Induction dose of at least 18´ 10IU daily as a s.c. or i.m. injection and if possible, 36´ 10IU daily for 8 to 12 weeks using the recommended escalation schedules: 3´ 10IU daily, days 1 to 3; 9´ 10IU daily, days 4 to 6; 18´ 10IU daily, days 7 to 9 and if tolerated, increase to: 36´ 10IU daily, days 10 to 84.

Maintenance doses should be given to those patients responding to induction therapy. The maintenance dose should be identical to the maximum tolerated dose but should not exceed 36´10IU 3 times/week.

Interferon alfa-2a has also shown to be effective in combination with vinblastine. 18´ 10IU of interferon alfa-2a given i.m. 3 times/week for 8 to 12 weeks with concurrent vinblastine i.v. injected with doses of 0.1 mg/kg body weight, once every 3 weeks has shown increased effectiveness over interferon alfa-2a alone at these relatively lower doses. However, the objective response rate of the combination was similar to the response rate under optimal conditions for treatment of interferon alfa-2a alone.

Cutaneous T-Cell Lymphoma: Induction dose of at least 18 x 10IU daily for 8 to 12 weeks administered by s.c. or i.m. injections. The recommended escalation schedule is as follows: 3´ 10IU daily, days 1 to 3; 9´ 10IU daily, days 4 to 6; 18´ 10IU daily, days 7 to 84.

Maintenance dose of 18´10IU 3 times/week. Patients should be treated for a minimum of 8 weeks and preferably for at least 12 weeks before the physician decides whether to continue treatment in responding patients or to discontinue treatment in nonresponding patients. Minimum treatment duration for patients who respond is suggested to be 12 months in order to maximize the chance of achieving a complete response and improve the chance of a prolonged response. Patients have been treated for up to 40 consecutive months.

Chronic Hepatitis C: Interferon alfa-2a is indicated for the treatment of adult patients with chronic hepatitis C who are positive for HCV antibodies and have elevated ALT without liver decompensation (Child’s Class A).

Initial Dosage: Interferon alfa-2a should be administered at a dose of 6 million IU by s.c. or i.m. injection 3 times/week for 3 months as induction therapy.

Maintenance Dosage: Patients whose serum ALT has normalized require maintenance therapy with 3 million IU interferon alfa-2a 3 times/week for an additional 3 months to consolidate the complete response.

Patients whose serum ALT has not normalized should stop treatment.

Note: The majority of patients who relapse after adequate treatment do so within 4 months of the end of treatment.

Special Dosage Instructions: Dosage should be modified to take into account the constitutional symptoms, the myelosuppressive effects, and the other clinical or laboratory test abnormalities caused by interferon alfa-2a therapy.

Dosage adjustments may be more important when administering interferon alfa-2a to patients receiving concomitant therapies or who may have compromised bone marrow reserve due to prior x-ray treatment or chemotherapy.

Geriatrics: Elderly patients may be more susceptible to the side effects and caution is recommended in the treatment of such patients.

Children: Safety and efficacy in patients under 18 years of age have not been established.

Administration: The s.c. or i.m. routes of administration should be used. S.C. administration is particularly suggested for, but not limited to, patients who are thrombocytopenic (platelet count
Stability and Storage: Solutions: See expiration date on the outer package. Store in a refrigerator at 2 to 8°C. Do not freeze or shake.

Availability And Storage: Alluman (Human) Free: 3 million IU: Each mL contains: interferon alfa-2a 3 million IU. Nonmedicinal ingredients: sodium chloride 7.21 mg, ammonium acetate 0.77 mg, polysorbate 80 0.2 mg with benzyl alcohol 10 mg as preservative and sodium hydroxyde or glacial acetic acid to adjust pH. Vials of 1 mL.

4.5 million IU: Each mL contains: interferon alfa-2a 4.5 million IU. Nonmedicinal ingredients: sodium chloride 7.21 mg, ammonium acetate 0.77 mg, polysorbate 80 0.2 mg with benzyl alcohol 10 mg as preservative and sodium hydroxide or glacial acetic acid to adjust pH. Vials of 1 mL.

6 million IU: Each mL contains: interferon alfa-2a 6 million IU. Nonmedicinal ingredients: sodium chloride 7.21 mg, ammonium acetate 0.77 mg, polysorbate 80 0.2 mg with benzyl alcohol 10 mg as preservative and sodium hydroxide or glacial acetic acid to adjust pH. Vials of 1 mL.

9 million IU: Each mL contains: interferon alfa-2a 9 million IU. Nonmedicinal ingredients: sodium chloride 7.21 mg, ammonium acetate 0.77 mg, polysorbate 80 0.2 mg with benzyl alcohol 10 mg as preservative and sodium hydroxide or glacial acetic acid to adjust pH. Vials of 1 mL.

18 million IU: Each mL contains: interferon alfa-2a 6 million IU. Nonmedicinal ingredients: sodium chloride 7.21 mg, ammonium acetate 0.77 mg, polysorbate 80 0.2 mg with benzyl alcohol 10 mg as preservative and sodium hydroxide or glacial acetic acid to adjust pH. Vials of 3 mL.

See expiration date on the outer package. Store in a refrigerator at 2 to 8°C. Do not freeze or shake.

ROFERON®-A Roche Interferon alfa-2a Biological Response Modifier

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