1. Name Of The Medicinal Product
Roferon-A 3 million international units (MIU) solution for injection in pre-filled syringe
Roferon-A 4.5 million international units (MIU) solution for injection in pre-filled syringe
Roferon-A 6 million international units (MIU) solution for injection in pre-filled syringe
Roferon-A 9 million international units (MIU) solution for injection in pre-filled syringe
2. Qualitative And Quantitative Composition
Each pre-filled syringe contains:
3 Million International Units interferon alfa-2a* per 0.5 millilitres**(3MIU/0.5ml).
4.5 Million International Units interferon alfa-2a* per 0.5 millilitres**(4.5MIU/0.5ml).
6 Million International Units interferon alfa-2a* per 0.5 millilitres**(6MIU/0.5ml).
9 Million International Units interferon alfa-2a* per 0.5 millilitres**(9MIU/0.5ml).
* produced in Escherichia coli by recombinant DNA technology
**Contains volume overages
For a full list of excipients, see section 6.1.
Excipients recognised to have a known effect:
Benzyl alcohol (10mg/1ml)
3. Pharmaceutical Form
Solution for injection in pre-filled syringe.
Solution is clear and colourless to light yellow.
4. Clinical Particulars
4.1 Therapeutic Indications
Roferon-A is indicated for the treatment of:
- Hairy cell leukaemia.
- AIDS patients with progressive, asymptomatic Kaposi's sarcoma who have a CD4 count > 250/mm3.
- Chronic phase Philadelphia-chromosome positive chronic myelogenous leukaemia. Roferon-A is not an alternative treatment for CML patients who have an HLA-identical relative and for whom allogeneic bone marrow transplantation is planned or possible in the immediate future. It is still unknown whether Roferon-A can be considered as a treatment with a curative potential in this indication.
- Cutaneous T-cell lymphoma. Interferon alfa-2a (Roferon-A) may be active in patients who have progressive disease and who are refractory to, or unsuitable for, conventional therapy.
- Adult patients with histologically proven chronic hepatitis B who have markers for viral replication, i.e., those who are positive for HBV DNA or HBeAg.
- Adult patients with histologically proven chronic hepatitis C who are positive for HCV antibodies or HCV RNA and have elevated serum alanine aminotransferase (ALT) without liver decompensation.
The efficacy of interferon alfa-2a in the treatment of hepatitis C is enhanced when combined with ribavirin. Roferon-A should be given alone mainly in case of intolerance or contraindication to ribavirin.
- Follicular non-Hodgkin's lymphoma.
- Advanced renal cell carcinoma.
- Patients with AJCC stage II malignant melanoma (Breslow tumour thickness > 1.5 mm, no lymph node involvement or cutaneous spread) who are free of disease after surgery.
4.2 Posology And Method Of Administration
Not all available Roferon-A strengths can be used for all indications mentioned in section 4.1 Therapeutic indications. The prescribed strength should correspond with the recommended dose for each individual indication.
- HAIRY CELL LEUKAEMIA
Initial dosage:
Three million IU daily, given by subcutaneous injection for 16 - 24 weeks. If intolerance develops, either the daily dose should be lowered to 1.5 million IU or the schedule changed to three times per week, or both.
Maintenance dosage:
Three million IU, given three times per week by subcutaneous injection. If intolerance develops, the dose should be lowered to 1.5 million IU three times per week.
Duration of treatment:
Patients should be treated for approximately six months before the physician decides whether to continue treatment in responding patients or to discontinue treatment in non-responding patients. Patients have been treated for up to 20 consecutive months. The optimal duration of Roferon-A treatment for hairy cell leukaemia has not been determined.
The minimum effective dose of Roferon-A in hairy cell leukaemia has not been established.
- AIDS-RELATED KAPOSI'S SARCOMA
Roferon-A is indicated for the treatment of AIDS patients with progressive, asymptomatic Kaposi's sarcoma who have a CD4 count > 250/mm3. AIDS patients with CD4 counts < 250/mm3, or those with a history of opportunistic infections or constitutional symptoms, are unlikely to respond to Roferon-A therapy and therefore should not be treated. The optimal posology has not yet been well established.
Roferon-A should not be used in conjunction with protease inhibitors. With the exception of zidovudine, there is a lack of safety data for the combination of Roferon-A with reverse transcriptase inhibitors.
Initial dosage:
Roferon-A should be given by subcutaneous injection, and escalated to at least 18 million IU daily and if possible to 36 million IU daily for a total of ten to twelve weeks in patients of 18 years or older. The recommended escalation schedule is as follows:
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Maintenance dosage:
Roferon-A should be given by subcutaneous injection three times per week at the maximum dose which is acceptable to the patient, but not exceeding 36 million IU.
Patients with AIDS-related Kaposi's sarcoma treated with 3 million IU of Roferon-A given daily showed a lower response rate than those treated with the recommended dosage.
Duration of treatment:
The evolution of lesions should be documented to determine response to therapy. Patients should be treated for a minimum of 10 weeks and preferably for at least twelve weeks before the physician decides whether to continue treatment in responding patients or to discontinue treatment in non-responding patients. Patients generally showed evidence of response after approximately three months of therapy. Patients have been treated for up to 20 consecutive months. If a response to treatment occurs, treatment should continue at least until there is no further evidence of tumour. The optimal duration of Roferon-A treatment for AIDS-related Kaposi's sarcoma has not been determined.
Note:
Lesions of Kaposi's sarcoma frequently reappear when Roferon-A treatment is discontinued.
- CHRONIC MYELOGENOUS LEUKAEMIA
Roferon-A is indicated for the treatment of patients with chronic phase Philadelphia-chromosome positive chronic myelogenous leukaemia. Roferon-A is not an alternative treatment for CML patients who have an HLA-identical relative and for whom allogeneic bone marrow transplantation is planned or possible in the immediate future.
Roferon-A produces haematological remissions in 60% of patients with chronic phase CML, independent of prior treatment. Two thirds of these patients have complete haematological responses which occur as late as 18 months after treatment start.
In contrast to cytotoxic chemotherapy, interferon alfa-2a is able to generate sustained, ongoing cytogenetic responses beyond 40 months. It is still unknown whether Roferon-A can be considered as a treatment with a curative potential in this indication.
Dosage:
It is recommended that Roferon-A should be given by subcutaneous injection for eight to 12 weeks to patients 18 years or more. The recommended schedule is:
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Duration of treatment:
Patients should be treated for a minimum of eight weeks, preferably for at least twelve 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 haematological parameters. Responding patients should be treated until complete haematological response is achieved or for a maximum of 18 months. All patients with complete haematologic responses should continue treatment with 9 million IU daily (optimum) or 9 million IU three times a week (minimum) in order to achieve a cytogenetic response in the shortest possible time. The optimal duration of Roferon-A treatment for chronic myelogenous leukaemia has not been determined, although cytogenetic responses have been observed two years after treatment start.
The safety, efficacy and optimal dosage of Roferon-A in children with CML has not yet been established.
- CUTANEOUS T-CELL LYMPHOMA (CTCL)
Interferon alfa-2a (Roferon-A) may be active in patients with progressive cutaneous T-cell lymphoma and who are refractory to, or unsuitable for conventional therapy.
The optimal dosage has not been established.
Initial dosage:
Roferon-A should be given by subcutaneous injection, and escalated to 18 million IU daily for a total of 12 weeks in patients of 18 years or older. The recommended escalation schedule is as follows:
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Maintenance dosage:
Roferon-A should be given by subcutaneous injection three times per week at the maximum dose which is acceptable to the patient, but not exceeding 18 million IU.
Duration of treatment:
Patients should be treated for a minimum of eight weeks and preferably for at least twelve weeks before the physician decides whether to continue treatment in responding patients or to discontinue treatment in non-responding patients. Minimum treatment duration in responding patients should be 12 months in order to maximise the chance to achieve a complete response and improve the chance for a prolonged response. Patients have been treated for up to 40 consecutive months. The optimal duration of Roferon-A treatment for cutaneous T-cell lymphoma has not been determined.
Warning:
Objective tumor responses have not been observed in approximately 40% of patients with CTCL. Partial responses are usually seen within 3 months and complete responses within 6 months, although it may occasionally take more than one year to reach the best response.
- CHRONIC HEPATITIS B
Roferon-A is indicated for the treatment of adult patients with histologically proven chronic hepatitis B who have markers for viral replication, i.e., those who are positive for HBV DNA or HBeAg.
Dosage recommendation:
The optimal schedule of treatment has not been established yet. The dose is usually in the range of 2.5 million IU to 5.0 million IU/m2 body surface administered subcutaneously three times per week for a period of 4 to 6 months.
The dosage may be adjusted according to the patient's tolerance to the medication. If no improvement has been observed after 3-4 months of treatment, discontinuation of therapy should be considered.
Children: up to 10 million IU/m2 has been safely administered to children with chronic hepatitis B. However efficacy of therapy has not been demonstrated.
- CHRONIC HEPATITIS C
ROFERON-A IN COMBINATION WITH RIBAVIRIN
RELAPSED PATIENTS
Roferon-A is given in combination with ribavirin for adult patients with chronic hepatitis C who have previously responded to interferon alpha monotherapy, but who have relapsed after treatment was stopped.
Dosage:
Roferon-A: 4.5 MIU 3 times per week by subcutaneous injection for a period of 6 months.
Dosage of Ribavirin:
Ribavirin dose: 1000 mg to 1200 mg/day in two divided doses (once in the morning with breakfast and once with the evening meal). Please refer to the SmPC for ribavirin for further details on the posology and method of administration of ribavirin.
NAÏVE PATIENTS
The efficacy of interferon alfa-2a in the treatment of hepatitis C is enhanced when combined with ribavirin. Roferon-A should be given alone mainly in case of intolerance or contraindication to ribavirin.
Dosage:
Roferon-A: 3 to 4.5 MIU 3 times per week by subcutaneous injection for a period of at least 6 months. Treatment should be continued for an additional 6 months in patients who have negative HCV RNA at month 6, and are infected with genotype 1 and have high pretreatment viral load.
Dosage of Ribavirin: see above
Other negative prognostic factors (age > 40 years, male gender, bridging fibrosis) should be taken into account in order to extend therapy to 12 months.
Patients who failed to show a virologic response after 6 months of treatment (HCV-RNA below lower limit of detection) do generally not become sustained virologic responders (HCV-RNA below lower limit of detection six months after withdrawal of treatment).
ROFERON-A MONOTHERAPY
Roferon-A monotherapy should be given mainly in case of intolerance or contraindication to ribavirin.
Initial dosage:
Roferon-A should be administered at a dose of 3 to 6 million IU by subcutaneous injection three times a week for six months as induction therapy, patient tolerance permitting. In patients who fail to respond after three to four months of treatment, discontinuation of Roferon-A should be considered.
Maintenance dosage:
Patients whose serum ALT has normalised and/or HCV RNA has become undetectable require maintenance therapy with 3 million IU Roferon-A three times a week for an additional six months or longer to consolidate the complete response. The optimal duration of treatment has not yet been determined but a therapy of at least 12 months is advised.
Note:
The majority of patients who relapse after adequate treatment with Roferon-A alone do so within four months of the end of treatment.
- FOLLICULAR NON-HODGKINS LYMPHOMA
Roferon-A prolongs disease-free and progression-free survival when used as adjunctive treatment to CHOP-like chemotherapy regimens in patients with advanced (high tumour burden) follicular non-Hodgkin's lymphoma. However, the efficacy of adjunctive interferon alfa-2a treatment on overall long-term survival of these patients has not yet been established.
Dosage Recommendation:
Roferon-A should be administered concomitantly to a conventional chemotherapy regimen (such as the combination of cyclophosphamide, prednisone, vincristine and doxorubicin) according to a schedule such as 6 million IU/m2 given subcutaneously from day 22 to day 26 of each 28-day cycle.
- ADVANCED RENAL CELL CARCINOMA
COMBINATION WITH VINBLASTINE
Therapy with Roferon-A in combination with vinblastine induces overall response rates of approximately 17-26%, delays disease progression, and prolongs overall survival in patients with advanced renal cell carcinoma.
Dosage recommendation:
Roferon-A should be given by subcutaneous injection at a dose of 3 million IU three times weekly for one week, 9 million IU three times weekly for the following week and 18 million IU three times weekly thereafter. Concomitantly vinblastine should be given intravenously according to the manufacturer's instructions at a dose of 0.1 mg/kg once every 3 weeks.
If the Roferon-A dosage of 18 million IU three times per week is not tolerated the dose may be reduced to 9 million IU three times per week.
Treatment should be given for a minimum of three months, up to a maximum of 12 months or until the development of progressive disease. Patients who achieve a complete response may stop treatment three months after the response is established.
COMBINATION WITH BEVACIZUMAB (AVASTIN)
Dosage recommendations:
9 MIU sc three times weekly until disease progression or up to 12 months.
Roferon-A therapy may be initiated with a lower dose (3 or 6 MIU), the recommended dose of 9 MIU should however be reached within the first 2 weeks of treatment.
If the Roferon-A dosage of 9MIU three times per week is not tolerated, the dosage may be reduced to a minimum dosage of 3 MIU three times per week.
Roferon-A injections are given after completion of the Avastin infusion. For more information on the combination use with Avastin, refer to the Avastin SmPC.
- SURGICALLY RESECTED MALIGNANT MELANOMA.
Adjuvant therapy with a low dose of Roferon-A prolongs disease-free interval in patients with no nodal or distant metastases following resection of a melanoma (tumour thickness > 1.5 mm).
Dosage recommendation:
Roferon-A should be administered subcutaneously at a dose of 3 million IU three times a week for 18 months, starting no later than six weeks post surgery. If intolerance develops, the dose should be lowered to 1.5 million IU three times a week.
4.3 Contraindications
Roferon-A is contraindicated in patients with:
1) A history of hypersensitivity to recombinant interferon alfa-2a or to any of the excipients,
2) Patients with severe pre-existing 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 administration of Roferon-A may exacerbate pre-existing cardiac conditions,
3) Severe renal, hepatic or myeloid dysfunction,
4) Uncontrolled seizure disorders and/or compromised central nervous system function (see section 4.4.),
5) Chronic hepatitis with advanced, decompensated hepatic disease or cirrhosis of the liver,
6) Chronic hepatitis who are being or have recently been treated with immunosuppressive agents,
7) Benzyl alcohol, which is an excipient in Roferon-A solution for injection has on rare occasions been associated with potentially fatal toxicities and anaphylactoid reactions in children up to 3 years old. Therefore, Roferon-A solution for injection should not be used in premature babies, neonates, infants or children up to 3 years old Roferon-A solution contains 10 mg / ml Benzyl alcohol.
Combination therapy with ribavirin: Also see ribavirin labelling if interferon alfa-2a is to be administered in combination with ribavirin in patients with chronic hepatitis C.
4.4 Special Warnings And Precautions For Use
Roferon-A should be administered under the supervision of a qualified physician experienced in the management of the respective indication. Appropriate management of the therapy and its complications is possible only when adequate diagnostic and treatment facilities are readily available.
Patients should be informed not only of the benefits of therapy but also that they will probably experience adverse reactions.
Hypersensitivity: If a hypersensitivity reaction occurs during treatment with Roferon-A or in the combination therapy with ribavirin, treatment has to be discontinued and appropriate medical therapy has to be instituted immediately. Transient rashes do not necessitate interruption of treatment.
In transplant patients (e.g., kidney or bone marrow transplant) therapeutic immunosuppression may be weakened because interferons also exert an immunostimulatory action. As with other alpha interferons, graft rejections have been reported in patients taking Roferon-A.
Fever/Infections: While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent fever, particularly serious infections (bacterial, viral, fungal) must be ruled out, especially in patients with neutropenia. Serious infections (bacterial, viral, fungal) have been reported during treatment with alfa interferons including Roferon-A. Appropriate anti-infective therapy should be started immediately and discontinuation of therapy should be considered.
Psychiatric: Severe psychiatric adverse reactions may manifest in patients receiving therapy with interferons, including Roferon-A. Depression, suicidal ideation, suicidal attempt, and suicide may occur in patients with and without previous psychiatric illness. Physicians should monitor all patients treated with Roferon-A for evidence of depression. Physicians should inform patients of the possible development of depression prior to initiation of therapy, and patients should report any sign or symptom of depression immediately. Psychiatric intervention and/or drug discontinuation should be considered in such cases.
Ophthalmologic: As with other interferons, retinopathy including retinal haemorrhages, cotton wool spots, papilloedema, retinal artery or vein thrombosis and optic neuropathy which may result in loss of vision, have been reported after treatment with Roferon-A. Any patient complaining of decrease or loss of vision must have an eye examination. Because these ocular events may occur in conjunction with other disease states, a visual examination prior to initiation of Roferon-A monotherapy or in the combination therapy with ribavirin is recommended in patients with diabetes mellitus or hypertension. Roferon-A monotherapy or the combination therapy with ribavirin should be discontinued in patients who develop new or worsening ophthalmologic disorders.
Endocrine: Hyperglycaemia has been observed rarely in patients treated with Roferon-A. All patients who develop symptoms of hyperglycaemia should have their blood glucose measured and followed-up accordingly. Patients with diabetes mellitus may require adjustment of their antidiabetic regimen.
When mild to moderate renal, hepatic or myeloid dysfunction is present, close monitoring of these functions is required.
Hepatic function: In rare cases interferon alpha has been suspected of causing an exacerbation of an underlying autoimmune disease in hepatitis patients. Therefore, when treating hepatitis patients with a history of autoimmune disease caution is recommended. If a deterioration in liver function in these patients develops a determination of autoimmune antibodies should be considered. If necessary treatment should be discontinued.
Bone marrow suppression: Extreme caution should be exercised when administering Roferon-A to patients with severe myelosuppression as it has a suppressive effect on the bone marrow, leading to a fall in the white blood count, particularly granulocytes, platelet count and, less commonly, haemoglobin concentration. This can lead to an increased risk of infection or of haemorrhage. It is important to monitor closely these events in patients and periodic complete blood counts should be performed during the course of Roferon-A treatment, both prior to therapy and at appropriate periods during therapy.
Autoimmune: The development of different auto-antibodies has been reported during treatment with alpha interferons. Clinical manifestations of autoimmune disease during interferon therapy occur more frequently in subjects predisposed to the development of autoimmune disorders. In patients with an underlying or clinical history of auto-immune disorders, monitoring of symptoms suggestive of these disorders, as well as measurement of auto antibodies and TSH level, is recommended.
The use of Roferon-A in children is not recommended as the safety and effectiveness of Roferon-A in children have not been established.
Efficacy in patients with chronic hepatitis B or C who are on haemodialysis or have haemophilia or are coinfected with human immunodeficiency virus has not been demonstrated.
This product contains less than 1 mmol sodium (23 mg) per 0.5 ml, i.e. essentially 'sodium-free'.
Combination therapy with ribavirin: Also see ribavirin labelling if interferon alfa-2a is to be administered in combination with ribavirin in patients with chronic hepatitis C.
Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of developing lactic acidosis. Caution should be used when adding Roferon-A and ribavirin to HAART therapy (see ribavirin SPC).
Co-infected patients with advanced cirrhosis receiving HAART may be at increased risk of hepatic decompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirin may increase the risk in this patient subset.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Since alpha-interferons alter cellular metabolism, the potential to modify the activity of other drugs exists. In a small study, Roferon-A was shown to have an effect on specific microsomal enzyme systems. The clinical relevance of these findings is unknown.
Alpha-interferons may affect the oxidative metabolic process; this should be borne in mind when prescribing concomitant therapy with drugs metabolised by this route. However, as yet no specific information is available.
Roferon-A has been reported to reduce the clearance of theophylline.
As Roferon-A may affect central nervous system functions, interactions could occur following concurrent administration of centrally-acting drugs. The neurotoxic, haematotoxic or cardiotoxic effects of previously or concurrently administered drugs may be increased by interferons.
Combination therapy with ribavirin: Also see ribavirin labelling if interferon alfa-2a is to be administered in combination with ribavirin in patients with chronic hepatitis C.
Results from a controlled clinical study in renal cancer patients demonstrated no significant effect of bevacizumab (Avastin) on the pharmacokinetics of interferon alfa-2a (Roferon-A).
4.6 Pregnancy And Lactation
Men and women receiving Roferon-A should practise effective contraception. There are no adequate data on the use of Roferon-A in pregnant women. When doses greatly in excess of the recommended clinical dose were administered to pregnant rhesus monkeys in the early to mid-foetal period, an abortifacient effect was observed (see section 5.3). Although animal tests do not indicate that Roferon-A is a teratogen, harm to the foetus from use during pregnancy cannot be excluded. In pregnancy, Roferon-A should be administered only if the benefit to the woman justifies the potential risk to the foetus.
It is not known whether this drug is excreted in human milk. A decision must be taken whether to suspend breast feeding or to discontinue the drug, taking into account the importance of the drug to the mother.
Use with ribavirin in patients with chronic hepatitis C
Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Ribavirin therapy is contraindicated in women who are pregnant. Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking Roferon-A in combination with ribavirin. Female patients of childbearing potential and their partners must each use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients and their female partners must each use an effective contraception during treatment and for 7 months after treatment has been concluded. Please refer to the ribavirin SPC.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed. However depending on dose and schedule as well as the sensitivity of the individual patient, Roferon-A may have an effect on the speed of reaction which could impair certain operations, e.g., driving, operation of machinery etc.
4.8 Undesirable Effects
Combination therapy with ribavirin: Also see ribavirin labeling if interferon alfa-2a is to be administered in combination with ribavirin in patients with chronic hepatitis C.
The following data on adverse reactions are based on information derived from the treatment of cancer patients with a wide variety of malignancies and often refractory to previous therapy and suffering from advanced disease, patients with chronic hepatitis B, and patients with chronic hepatitis C.
Approximately two thirds of cancer patients experienced anorexia and one half nausea. Cardiovascular and pulmonary disorders were seen in about one fifth of cancer patients and consisted of transient hypotension, hypertension, oedema, cyanosis, arrhythmias, palpitations and chest pain. Most cancer patients received doses that were significantly higher than the dose now recommended and may explain the higher frequency and severity of adverse reactions in this patient group compared with patients with hepatitis B where adverse reactions are usually transient, and patients return to pre-treatment status within 1 to 2 weeks after the end of therapy. Cardiovascular disorders were very rarely seen in patients with hepatitis B. In hepatitis B patients, changes in transaminases usually signal an improvement in the clinical state of the patient.
The majority of the patients experienced flu-like symptoms such as fatigue, pyrexia, rigors, decreased appetite, myalgia, headache, arthralgia and diaphoresis. These acute side-effects can usually be reduced or eliminated by concurrent administration of paracetamol and tend to diminish with continued therapy or dose modification although continuing therapy can lead to lethargy, asthenia and fatigue.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness:
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