Posology : מינונים

4.2    Posology and method of administration

Not all available Roferon-A strengths can be used for all indications mentioned in section 4.1. The prescribed strength should correspond with the recommended dose for each individual indication.
Substitution of Roferon-A by any other similar biological medicinal product requires the consent of the prescribing physician.

-     CONDYLOMATA ACUMINATA (GENITAL WARTS)

A total daily dose of 3 million IU should be given either as one subcutaneous injection or devided into 1 to 5 intralesional injections. The dose may be reduced if side effects are not tolerated, but 1 million IU is the minimum effective dose.
ROFERON-A should be administered three times weekly for at least three weeks. If intralesional injections are to be given, the lesions should first be cleaned with a sterile alcohol pad. The injections should be made at the base of the lesion using a fine (30 gauge) needle.

-      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:
 days 1-3             3 million IU daily days 4-6             9 million IU daily days 7-9            18 million IU daily - and, if tolerated, increase to: days 10-84          36 million IU daily

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:

Days 1-3     3 million IU daily
Days 4-6     6 million IU daily
Days 7-84    9 million IU daily

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 hematologic 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.

-     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 million IU 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 Prescribing Information 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 million IU 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 normalized 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 recommendation:
9 million IU by subcutaneous injection three times weekly until disease progression or up to 12 months. The safety and efficacy of Roferon-A therapy after 12 months have not been evaluated.


Roferon-A therapy may be initiated with a lower dose (3 or 6 million IU), the recommended dose of 9 million IU should however be reached within the first 2 weeks of treatment.
If the Roferon-A dosage of 9 million IU three times per week is not tolerated, the dosage may be reduced to a minimum dosage of 3 million IU three times per week.

Roferon-A injections are given after completion of the Avastin infusion. For more information on combination use with Avastin, refer to the Avastin Prescribing Information.

-     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.