Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group:        Immunostimulants, interferons, ATC Code L03AB04 
Roferon-A has been shown to possess many of the activities of the so-called natural human alpha-interferon preparations. Roferon-A exerts its antiviral effects by inducing a state of resistance to viral infections in cells and by modulating the effector arm of the immune system to neutralize viruses or eliminate virus infected cells. The essential mechanism for the antitumour action of Roferon-A is not yet known. However, several changes are described in human tumoural cells treated with Roferon-A: HT 29 cells show a significant reduction of DNA, RNA and protein synthesis. Roferon-A has been shown to exert antiproliferative activity against a variety of human tumours in vitro and to inhibit the growth of some human tumour xenografts in nude mice. A limited number of human tumour cell lines grown in vivo in immunocompromised nude mice has been tested for the susceptibility to Roferon-A. In vivo antiproliferative activity of Roferon-A has been studied on tumours including breast mucoid carcinoma, adenocarcinoma of the caecum, colon carcinoma and prostatic carcinoma. The degree of antiproliferative activity is variable.


Unlike other human proteins, many of the effects of interferon alfa-2a are partially or completely suppressed when it is tested in other animal species. However, significant antivaccinia virus activity was induced in rhesus monkeys pre-treated with interferon alfa-2a.

Clinical efficacy and safety

Hairy Cell Leukaemia
The therapeutic efficacy of Roferon-A in the treatment of hairy cell leukaemia has been demonstrated in a large trial of 218 patients, of whom 174 were evaluable for efficacy after 16-24 weeks of therapy.
Response was observed in 88% of patients (complete response 33%, partial response 55%).

AIDS-related Kaposi’s Sarcoma
The efficacy of Roferon-A in the treatment of Kaposi’s sarcoma was assessed in 364 patients receiving of 3 to 54 million IU per day. Objective response rates were dose-related, ranging from 14% to 50%, with a daily dose of 36 million IU producing the best overall therapeutic benefit (13.3% complete response, 12.2% partial response). High baseline CD4 lymphocyte count was a favourable prognostic factor for response, with 46% of patients with a CD4 count > 400/mm³ responding to Roferon-A. Response to Roferon-A therapy was the strongest prognostic factor for survival.

Chronic Myelogenous Leukaemia (CML)
The efficacy of Roferon-A was assessed in 226 patients with chronic phase CML, and compared with 109 patients receiving chemotherapy (hydroxyurea or busulfan). Both groups had favourable features at diagnosis (less than 10% blasts in the blood) and treatment was initiated with interferon within 6 months of diagnosis. Treatment of patients with CML in the chronic phase leads to the same proportion of patients (85-90%) achieving a hematologic response as treatment with the standard chemotherapy regimens. In addition patients treated with Roferon-A resulted in 8% complete cytogenetic response and 38% partial cytogenetic response versus 9% partial cytogenetic response during chemotherapy. Time to progression from the chronic phase of leukaemia to an accelerated or a blastic phase was longer in the Roferon-A group (69 months) than in the conventional chemo-therapy group (46 months) (p < 0.001) as was median overall survival (72.8 months versus 54.5 months, p=0.002).

Chronic Hepatitis B
The efficacy of Roferon-A in the treatment of chronic hepatitis B was assessed in trials involving over 900 patients. In the pivotal controlled study 238 patients were randomised into four groups: patients received either 2.5 million IU/m2, 5.0 million IU/m2, 10 million IU/m2, 3 times per week of Roferon-A or no treatment. Treatment duration was 12-24 weeks depending on response, i.e., clearance of HBeAg and HBV DNA from serum. Patients were followed for up to 12 months after treatment was discontinued. There was a statistically significant difference in sustained response [clearance of hepatitis B e antigen (HBeAg) and hepatitis B viral DNA (HBV DNA)] between treated and untreated patients (37% versus 13%). Response differences between various dose groups did not reach statistical significance (33%, 34% and 43% for the 2.5, 5.0 and 10.0 million IU/m2 groups). Serological and virological responses were associated with marked improvement in liver histology after 12 months of treatment free-follow up.

Chronic Hepatitis C
The efficacy of Roferon-A in the treatment of chronic hepatitis C has been assessed in 1701 patients, with 130 untreated or placebo treated controls. At recommended doses, Roferon-A induces complete biochemical response in up to 85% of patients, with response rates maintained for at least 6 months after treatment ranging from 11 to 44% depending on pre-treatment disease characteristics, IFN dose and treatment duration. Biochemical response to Roferon-A is associated with significant improvement of liver disease as shown by evaluation of pre-and post-liver biopsies. For those patients who have a sustained response 3-6 months after end of therapy, response has been reported to be maintained for up to 4 years.

The therapeutic efficacy of Interferon alfa-2a alone and in combination with ribavirin was compared in a double-blind randomised clinical trial in naive (previously untreated) and relapsed patients with virologically, biochemically and histologically documented chronic hepatitis C. Six months after end of treatment sustained biochemical and virological response as well as histological improvement were assessed.

A statistically significant 10-fold increase (from 4% to 43%; p  0.01) in sustained virological and biochemical response was observed in relapsed patients. The favourable profile of the combination therapy was also reflected in the response rates relative to HCV genotype or baseline viral load.

Although the sustained response rates in patients with HCV genotype-1 were lower than in the overall population (approx. 30% versus 0% in the monotherapy arm) the relative benefit of ribavirin in combination with interferon alfa-2a is particularly significant in this group of patients. In addition the histological improvement favoured the combination therapy.
Supportive favourable results from a small study in naïve patients were reported using interferon alfa- 2a (3 million IU 3 times per week) with ribavirin.

For other information on pharmacodynamic properties please refer to the Prescribing Information for Ribavirin.

Follicular Non-Hodgkin's lymphoma
The efficacy of Roferon-A in addition to cytotoxic chemotherapy (CHOP-like regimen of cyclophosphamide, vincristine, prednisone and doxorubicin) was assessed in 122 patients with clinically aggressive low-grade or intermediate-grade non-Hodgkin’s lymphoma and compared with 127 controls receiving the same chemotherapy regimen. The two regimens produced comparable objective responses, but the regimen including Roferon-A had a greater effect in prolonging the time to treatment failure (p< 0.001), the duration of complete response (p < 0.003).

Renal Cell Carcinoma
Combination with vinblastine
The efficacy of Roferon-A, given in combination with vinblastine, was compared with vinblastine alone.
The combination of Roferon-A plus vinblastine is superior to vinblastine alone in the treatment of patients with locally advanced or metastatic renal cell carcinoma. Median survival was 67.8 weeks for the 79 patients receiving Roferon-A plus vinblastine and 37.8 weeks for the 81 patients treated with vinblastine (p=0.0049). Overall response rates were 16.5% for patients treated Roferon-A plus vinblastine and 2.5% for patients treated with vinblastine alone (p=0.0025).


Combination with bevacizumab (Avastin)
The pivotal phase III study compared bevacizumab in combination with interferon alfa-2a (N=327) to placebo plus interferon alfa-2a (N=322) as first-line therapy of nephrectomised patients with advanced and/or metastatic renal cell carcinoma.

Table 1: Efficacy results for study BO17705
Parameter                          Pbo + IFN            Bv + IFN         Hazard Ratioα          p-value (median value)                      N = 322             N = 327
Overall survival                    21.3 mo.            23.3 mo.              0.91            p = 0.3360 β (0.76 – 1.10)
Progression-free survival           5.4 mo.             10.2 mo.              0.63            p < 0.0001 β (0.52 – 0.75)
Overall response rate               12.8%               31.4%                N/A             p < 0.0001  

α - determined with a 95% CI.
β - p-value was obtained using Log-Rank Test
 - populations for reference are those patients with measurable disease at baseline [ITT N =289/306]  - p-value was obtained using 2 Test

Surgically Resected Malignant Melanoma
The efficacy of Roferon-A in patients with primary cutaneous melanoma thicker than 1.5 mm and without clinically detectable node metastasis was assessed in a large randomised study involving 253 patients receiving Roferon-A at a dose of 3 million IU three times a week for 18 months, compared with 246 untreated controls. After a median follow-up of 4.4 years a significant extension of relapse- free interval (p=0.035) but no statistically significant difference in overall survival (p=0.059) in Roferon- A treated patients compared with controls have been shown. The overall treatment effect was a 25% reduction in the risk of relapse.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

The serum concentrations of interferon alfa-2a reflected a large intersubject variation in both healthy volunteers and patients with disseminated cancer. The pharmacokinetics of Roferon-A in animals (monkey, dog and mouse) were similar to those seen in man. The pharmacokinetics of Roferon-A in man were linear over a 3 million to 198 million IU dose range. In healthy man, interferon alfa-2a exhibited an elimination half-life of 3.7-8.5 hours (mean: 5.1 hours), a volume of distribution at steady state of 
0.223-0.748 l/kg (mean: 0.4 l/kg) and a total body clearance of 2.14-3.62 ml/min/kg (mean: 2.79 ml/min/kg) after a 36 million IU intravenous infusion. After intramuscular administration 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 after subcutaneous administration of 36 million IU from 1,250 to 2,320 pg/ml (mean: 1,730 pg/ml) at a mean time to peak of 7.3 hours.

The apparent fraction of the dose absorbed after intramuscular or subcutaneous injection is greater than 80%.

The pharmacokinetics of interferon alfa-2a after single intramuscular doses to patients with disseminated cancer and chronic hepatitis B 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 interferon alfa-2a during twice daily (0.5-36 million IU), once daily (1-54 million IU), or three times weekly (1-136 million IU) dosing regimens up to 28 days of dosing.
Renal catabolism is the major pathway for Roferon-A elimination. Biliary excretion and liver metabolism are considered to be minor pathways of elimination of Roferon-A.

Intramuscular administration of Roferon-A one or more times daily for up to 28 days to some patients with disseminated cancer resulted in peak plasma concentrations of two to four times greater than those seen after single doses. However, multiple dosing caused no changes in its distribution or elimination parameters during several dosage regimens studied.

For other information on pharmacokinetic properties please refer to the Prescribing Information for Ribavirin.