Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Treatment of adult patients with chronic hepatitis B associated with evidence of hepatitis B viral replication (presence of DNA of hepatitis B virus (HBV-DNA) and hepatitis B antigen (HBeAg), elevated alanine aminotransferase (ALT) and histologically proven active liver inflammation and/or fibrosis.
Before initiating treatment with IntronA, consideration should be given to the results from clinical trials comparing IntronA with pegylated interferon (see section 5.1).
IntronA is indicated for the treatment of adult patients with chronic hepatitis C who have elevated transaminases without liver decompensation and who are positive for hepatitis C virus RNA (HCV-RNA) (see section 4.4).
The best way to use IntronA in this indication is in combination with ribavirin.
IntronA is indicated, in a combination regimen with ribavirin, for the treatment of children 3 years of age and older and adolescents, who have chronic hepatitis C, not previously treated, without liver decompensation, and who are positive for HCV-RNA.
When deciding not to defer treatment until adulthood, it is important to consider that the combination therapy induced a growth inhibition that resulted in reduced final adult height in some patients. The decision to treat should be made on a case by case basis (see section 4.4).
Treatment of patients with hairy cell leukaemia.
Treatment of adult patients with Philadelphia chromosome or bcr/abl translocation positive chronic myelogenous leukaemia.
Clinical experience indicates that a haematological and cytogenetic major/minor response is obtainable in the majority of patients treated. A major cytogenetic response is defined by <34% Ph+ leukaemic cells in the bone marrow, whereas a minor response is ≥34%, but <90% Ph+ cells in the marrow.
The combination of interferon alfa-2b and cytarabine (Ara-C) administered during the first 12 months of treatment has been demonstrated to significantly increase the rate of major cytogenetic responses and to significantly prolong the overall survival at three years when compared to interferon alfa-2b monotherapy.
As maintenance therapy in patients who have achieved objective remission (more than 50% reduction in myeloma protein) following initial induction chemotherapy. Current clinical experience indicates that maintenance therapy with interferon alfa-2b prolongs the plateau phase; however, effects on overall survival have not been conclusively demonstrated.
Treatment of high tumour burden follicular lymphoma as adjunct to appropriate combination induction chemotherapy such as a CHOP-like regimen. High tumour burden is defined as having at least one of the following: bulky tumour mass (>7 cm), involvement of three or more nodal sites (each >3 cm), systemic symptoms (weight loss >10%, pyrexia >38°C for more than 8 days, or nocturnal sweats), splenomegaly beyond the umbilicus, major organ obstruction or compression syndrome, orbital or epidural involvement, serous effusion, or leukaemia.
Treatment of carcinoid tumours with lymph node or liver metastases and with “carcinoid syndrome”.
As adjuvant therapy in patients who are free of disease after surgery but are at high risk of systemic recurrence, e.g. patients with primary or recurrent (clinical or pathological) lymph node involvement.
Treatment must be initiated by a physician experienced in the management of the disease.
Not all dose forms and strengths are appropriate for some indications. Appropriate dose form and strength must be selected.
If adverse events develop during the course of treatment with IntronA for any indication, modify the dose or discontinue therapy temporarily until the adverse events abate. If persistent or recurrent intolerance develops following adequate dose adjustment, or disease progresses, discontinue treatment with IntronA. At the discretion of the physician, the patient may self-administer the dose for maintenance dose regimens administered subcutaneously.
The recommended dose is in the range 5 to 10 million IU administered subcutaneously three times a week (every other day) for a period of 4 to 6 months.
The administered dose should be reduced by 50% in case of occurrence of haematological disorders (white blood cells <1,500/mm³, granulocytes <1,000/mm³, thrombocytes <100,000/mm³). Treatment should be discontinued in case of severe leukopaenia (<1,200/mm³), severe neutropaenia (<750/mm³) or severe thrombocytopaenia (<70,000/mm³).
For all patients, if no improvement on serum HBV-DNA is observed after 3 to 4 months of treatment (at the maximum tolerated dose), discontinue IntronA therapy.
IntronA is administered subcutaneously at a dose of 3 million IU three times a week (every other day) to adult patients, whether administered as monotherapy or in combination with ribavirin.
IntronA 3 MIU/m² is administered subcutaneously 3 times a week (every other day) in combination with ribavirin capsules or oral solution administered orally in two divided doses daily with food (morning and evening).
(See ribavirin capsules SPC for dose of ribavirin capsules and dose modification guidelines for combination therapy. For paediatric patients who weigh < 47 kg or cannot swallow capsules, see ribavirin oral solution SPC.)
IntronA is given in combination with ribavirin. Based on the results of clinical trials, in which data are available for 6 months of treatment, it is recommended that patients be treated with IntronA in combination with ribavirin for 6 months.
The efficacy of IntronA is enhanced when given in combination with ribavirin. IntronA should be given alone mainly in case of intolerance or contraindication to ribavirin.
Based on the results of clinical trials, in which data are available for 12 months of treatment, it is recommended that patients be treated with IntronA in combination with ribavirin for at least 6 months.
Treatment should be continued for another 6-month period (i.e., a total of 12 months) in patients who exhibit negative HCV-RNA at month 6, and with viral genotype 1 (as determined in a pre-treatment sample) and high pre-treatment viral load.
Other negative prognostic factors (age > 40 years, male gender, bridging fibrosis) should be taken into account in order to extend therapy to 12 months.
During clinical trials, patients who failed to show a virologic response after 6 months of treatment (HCV-RNA below lower limit of detection) did not become sustained virologic responders (HCV- RNA below lower limit of detection six months after withdrawal of treatment).
The optimal duration of therapy with IntronA alone is not yet fully established, but a therapy of between 12 and 18 months is advised.
It is recommended that patients be treated with IntronA alone for at least 3 to 4 months, at which point HCV-RNA status should be determined. Treatment should be continued in patients who exhibit negative HCV-RNA.
The efficacy and safety of IntronA in combination with ribavirin has been studied in children and adolescents who have not been previously treated for chronic hepatitis C.
Genotype 1: The recommended duration of treatment is one year. Patients who fail to achieve virological response at 12 weeks are highly unlikely to become sustained virological responders (negative predictive value 96%). Therefore, it is recommended that children and adolescent patients receiving IntronA/ribavirin combination be discontinued from therapy if their week 12 HCV-RNA dropped <2 log10 compared to pretreatment, or if they have detectable HCV-RNA at treatment week 24.
Genotype 2/3: The recommended duration of treatment is 24 weeks.
The recommended dose is 2 million IU/m² administered subcutaneously three times a week (every other day) for both splenectomised and non-splenectomised patients. For most patients with hairy cell leukaemia, normalisation of one or more haematological variables occurs within one to two months of IntronA treatment. Improvement in all three haematological variables (granulocyte count, platelet count and haemoglobin level) may require six months or more. This regimen must be maintained unless the disease progresses rapidly or severe intolerance is manifested.
The recommended dose of IntronA is 4 to 5 million IU/m² administered daily subcutaneously. Some patients have been shown to benefit from IntronA 5 million IU/m² administered daily subcutaneously in association with cytarabine (Ara-C) 20 mg/m² administered daily subcutaneously for 10 days per month (up to a maximum daily dose of 40 mg). When the white blood cell count is controlled, administer the maximum tolerated dose of IntronA (4 to 5 million IU/m 2 daily) to maintain haematological remission.
IntronA treatment must be discontinued after 8 to 12 weeks of treatment if at least a partial haematological remission or a clinically meaningful cytoreduction has not been achieved.
In patients who are in the plateau phase (more than 50% reduction of myeloma protein) following initial induction chemotherapy, interferon alfa-2b may be administered as monotherapy, subcutaneously, at a dose of 3 million IU/m 2 three times a week (every other day).
Adjunctively with chemotherapy, interferon alfa-2b may be administered subcutaneously, at a dose of 5 million IU three times a week (every other day) for a duration of 18 months. CHOP-like regimens are advised, but clinical experience is available only with CHVP (combination of cyclophosphamide, doxorubicin, teniposide and prednisolone).
The usual dose is 5 million IU (3 to 9 million IU) administered subcutaneously three times a week (every other day). Patients with advanced disease may require a daily dose of 5 million IU. The treatment is to be temporarily discontinued during and after surgery. Therapy may continue for as long as the patient responds to interferon alfa-2b treatment.
As induction therapy, interferon alfa-2b is administered intravenously at a dose of 20 million IU/m² daily for five days a week for a four-week period; the calculated interferon alfa-2b dose is added to sodium chloride 9 mg/mL (0.9%) solution for injection and administered as a 20-minute infusion (see section 6.6). As maintenance treatment, the recommended dose is 10 million IU/m² administered subcutaneously three days a week (every other day) for 48 weeks.
If severe adverse events develop during interferon alfa-2b treatment, particularly if granulocytes decrease to <500/mm³ or alanine aminotransferase/aspartate aminotransferase (ALT/AST) rises to >5 x upper limit of normal, discontinue treatment temporarily until the adverse event abates. Interferon alfa-2b treatment is to be restarted at 50% of the previous dose. If intolerance persists after dose adjustment or if granulocytes decrease to <250/mm³ or ALT/AST rises to >10 x upper limit of normal, discontinue interferon alfa-2b therapy.
Although the optimal (minimum) dose for full clinical benefit is unknown, patients must be treated at the recommended dose, with dose reduction for toxicity as described.
IntronA may be administered using either glass or plastic disposable injection syringes.
No case of overdose has been reported that has led to acute clinical manifestations. However, as for any pharmacologically active compound, symptomatic treatment with frequent monitoring of vital signs and close observation of the patient is indicated.
Shelf life: 18 months.
Within its shelf-life, for the purpose of transport, the solution can be kept at or below 25°C for a period up to seven days before use. IntronA can be put back in the refrigerator at any time during this seven-day period. If the product is not used during the seven-day period, it cannot be put back in the refrigerator for a new storage period and must be discarded.
Store in a refrigerator (2°C-8°C).
Do not freeze.
For storage conditions of the medicinal product, see section 6.3.
1 mL of solution (corresponding to 10 MIU) is contained in a single dose vial (type I glass) with a stopper (halobutyl rubber) in a flip-off seal (aluminium) with a bonnet (polypropylene).
IntronA is supplied as:
Not all pack sizes may be marketed.
Not all dose forms and strengths are appropriate for some indications. Please make sure to select an appropriate dose form and strength.
IntronA solution for injection or infusion may be injected directly after withdrawal of the appropriate doses from the vial with a sterile injection syringe.
Detailed instructions for the subcutaneous use of the product are provided with the package leaflet (refer to “How to self inject IntronA”).
Preparation of IntronA for intravenous infusion: The infusion is to be prepared immediately prior to use. Any size vial may be used to measure the required dose; however, final concentration of interferon in sodium chloride solution must be not less than 0.3 million IU/mL. The appropriate dose of IntronA is withdrawn from the vial(s), added to 50 mL of 9 mg/mL (0.9%) sodium chloride solution for injection in a PVC bag or glass bottle for intravenous use and administered over 20 minutes.
No other medicinal product can be infused concomitantly with IntronA.
As with all parenteral medicinal products, prior to administration inspect IntronA, solution for injection or infusion, visually for particulate matter and discolouration. The solution should be clear and colourless.
Any unused medicinal product must be discarded after withdrawal of the dose and in accordance with local requirements.
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