INTRON A 18 MUI/3ml solution for injection / infusion medication leaflet

IntronA 18 million IU/3 mL solution for injection or infusion

One vial of solution for injection or infusion contains 18 million IU of recombinant interferon alfa-2bproduced in E. coli by recombinant DNA technology, in 3 mL of solution.

One mL of solution contains 6 million IU of interferon alfa-2b.

For the full list of excipients, see section 6.1.

Solution for injection or infusion.

Clear and colourless solution.

Chronic hepatitis B

Treatment of adult patients with chronic hepatitis B associated with evidence of hepatitis B viralreplication (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/orfibrosis.

Chronic hepatitis C

Before initiating treatment with IntronA, consideration should be given to the results from clinicaltrials comparing IntronA with pegylated interferon (see section 5.1).

Adult patients

IntronA is indicated for the treatment of adult patients with chronic hepatitis C who have elevatedtransaminases 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.

Children 3 years of age and older and adolescents

IntronA is indicated, in a combination regimen with ribavirin, for the treatment of children 3 years ofage and older and adolescents, who have chronic hepatitis C, not previously treated, without liverdecompensation, and who are positive for HCV-RNA.

When deciding not to defer treatment until adulthood, it is important to consider that the combinationtherapy 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).

Hairy cell leukaemia

Treatment of patients with hairy cell leukaemia.

Chronic myelogenous leukaemia

Treatment of adult patients with Philadelphia chromosome or bcr/abl translocation positive chronicmyelogenous leukaemia.

Clinical experience indicates that a haematological and cytogenetic major/minor response isobtainable 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 themarrow.

The combination of interferon alfa-2b and cytarabine (Ara-C) administered during the first 12 monthsof treatment has been demonstrated to significantly increase the rate of major cytogenetic responsesand to significantly prolong the overall survival at three years when compared to interferon alfa-2bmonotherapy.

As maintenance therapy in patients who have achieved objective remission (more than 50 % reductionin myeloma protein) following initial induction chemotherapy.

Current clinical experience indicates that maintenance therapy with interferon alfa-2b prolongs theplateau phase; however, effects on overall survival have not been conclusively demonstrated.

Treatment of high tumour burden follicular lymphoma as adjunct to appropriate combination inductionchemotherapy such as a CHOP-like regimen. High tumour burden is defined as having at least one ofthe 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 orepidural involvement, serous effusion, or leukaemia.

Carcinoid tumour

Treatment of carcinoid tumours with lymph node or liver metastases and with 'carcinoid syndrome'.

Malignant melanoma

As adjuvant therapy in patients who are free of disease after surgery but are at high risk of systemicrecurrence, 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 andstrength must be selected.

If adverse events develop during the course of treatment with IntronA for any indication, modify thedose or discontinue therapy temporarily until the adverse events abate. If persistent or recurrentintolerance develops following adequate dose adjustment, or disease progresses, discontinue treatmentwith IntronA. At the discretion of the physician, the patient may self-administer the dose formaintenance dose regimens administered subcutaneously.

Chronic hepatitis B

The recommended dose is in the range 5 to 10 million IU administered subcutaneously three times aweek (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). Treatmentshould 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.

Chronic hepatitis C

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.

Children 3 years of age or older and adolescents

IntronA 3 MIU/m2 is administered subcutaneously 3 times a week (every other day) in combinationwith 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 forcombination therapy. For paediatric patients who weigh < 47 kg or cannot swallow capsules, seeribavirin oral solution SPC.)

Relapse patients (adults)

IntronA is given in combination with ribavirin. Based on the results of clinical trials, in which data areavailable for 6 months of treatment, it is recommended that patients be treated with IntronA incombination with ribavirin for 6 months.

Naïve patients (adults)

The efficacy of IntronA is enhanced when given in combination with ribavirin. IntronA should begiven alone mainly in case of intolerance or contraindication to ribavirin.

- IntronA in combination with ribavirin

Based on the results of clinical trials, in which data are available for 12 months of treatment, it isrecommended 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 whoexhibit negative HCV-RNA at month 6, and with viral genotype 1 (as determined in a pre-treatmentsample) and high pre-treatment viral load.

Other negative prognostic factors (age > 40 years, male gender, bridging fibrosis) should be taken intoaccount 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).

- IntronA alone

The optimal duration of therapy with IntronA alone is not yet fully established, but a therapy ofbetween 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 exhibitnegative HCV-RNA.

Naïve patients (children and adolescents)

The efficacy and safety of IntronA in combination with ribavirin has been studied in children andadolescents who have not been previously treated for chronic hepatitis C.

Duration of treatment for children and adolescents

- Genotype 1: The recommended duration of treatment is one year. Patients who fail to achievevirological response at 12 weeks are highly unlikely to become sustained virological responders(negative predictive value 96 %). Therefore, it is recommended that children and adolescentpatients 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-RNAat treatment week 24.

- Genotype 2/3: The recommended duration of treatment is 24 weeks.

Hairy cell leukaemia

The recommended dose is 2 million IU/m2 administered subcutaneously three times a week (everyother day) for both splenectomised and non-splenectomised patients. For most patients with hairy cellleukaemia, normalisation of one or more haematological variables occurs within one to two months of

IntronA treatment. Improvement in all three haematological variables (granulocyte count, plateletcount and haemoglobin level) may require six months or more. This regimen must be maintainedunless the disease progresses rapidly or severe intolerance is manifested.

Chronic myelogenous leukaemia

The recommended dose of IntronA is 4 to 5 million IU/m2 administered daily subcutaneously. Somepatients have been shown to benefit from IntronA 5 million IU/m2 administered daily subcutaneouslyin association with cytarabine (Ara-C) 20 mg/m2 administered daily subcutaneously for 10 days permonth (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/m2 daily) to maintainhaematological remission.

IntronA treatment must be discontinued after 8 to 12 weeks of treatment if at least a partialhaematological 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) followinginitial induction chemotherapy, interferon alfa-2b may be administered as monotherapy,subcutaneously, at a dose of 3 million IU/m2 three times a week (every other day).

Adjunctively with chemotherapy, interferon alfa-2b may be administered subcutaneously, at a dose of5 million IU three times a week (every other day) for a duration of 18 months. CHOP-like regimensare advised, but clinical experience is available only with CHVP (combination of cyclophosphamide,doxorubicin, teniposide and prednisolone).

Carcinoid tumour

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. Thetreatment is to be temporarily discontinued during and after surgery. Therapy may continue for as longas the patient responds to interferon alfa-2b treatment.

Malignant melanoma

As induction therapy, interferon alfa-2b is administered intravenously at a dose of 20 million IU/m2daily for five days a week for a four-week period; the calculated interferon alfa-2b dose is added tosodium chloride 9 mg/mL (0.9 %) solution for injection and administered as a 20-minute infusion (seesection 6.6). As maintenance treatment, the recommended dose is 10 million IU/m2 administeredsubcutaneously three days a week (every other day) for 48 weeks.

If severe adverse events develop during interferon alfa-2b treatment, particularly if granulocytesdecrease 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 afterdose adjustment or if granulocytes decrease to < 250/mm3 or ALT/AST rises to > 10 x upper limit ofnormal, discontinue interferon alfa-2b therapy.

Although the optimal (minimum) dose for full clinical benefit is unknown, patients must be treated atthe recommended dose, with dose reduction for toxicity as described.

IntronA may be administered using either glass or plastic disposable injection syringes.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- A history of severe pre-existing cardiac disease, e.g., uncontrolled congestive heart failure,recent myocardial infarction, severe arrhythmic disorders.

- Severe renal or hepatic dysfunction; including that caused by metastases.

- Epilepsy and/or compromised central nervous system (CNS) function (see section 4.4).

- Chronic hepatitis with decompensated cirrhosis of the liver.

- Chronic hepatitis in patients who are being or have been treated recently withimmunosuppressive agents excluding short term corticosteroid withdrawal.

- Autoimmune hepatitis; or history of autoimmune disease; immunosuppressed transplantrecipients.

- Pre-existing thyroid disease unless it can be controlled with conventional treatment.

- Combination of IntronA with telbivudine.

Children and adolescents

- Existence of, or history of severe psychiatric condition, particularly severe depression, suicidalideation or suicide attempt.

Combination therapy with ribavirin

Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients withchronic hepatitis C.

Psychiatric and central nervous system (CNS)

Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have beenobserved in some patients during IntronA therapy, and even after treatment discontinuation mainlyduring the 6-month follow-up period. Among children and adolescents treated with IntronA incombination with ribavirin, suicidal ideation or attempts were reported more frequently compared to adultpatients (2.4 % vs 1 %) during treatment and during the 6-month follow-up after treatment. As in adultpatients, children and adolescents experienced other psychiatric adverse events (e.g., depression,emotional lability, and somnolence). Other CNS effects including aggressive behaviour (sometimesdirected against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations ofmental status have been observed with alpha interferons. Patients should be closely monitored for anysigns or symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness ofthese undesirable effects must be borne in mind by the prescribing physician and the need for adequatetherapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidalor homicidal ideation is identified, it is recommended that treatment with IntronA be discontinued, andthe patient followed, with psychiatric intervention as appropriate.

Patients with existence of, or history of severe psychiatric conditions:

If treatment with interferon alfa-2b is judged necessary in adult patients with existence or history of severepsychiatric conditions, this should only be initiated after having ensured appropriate individualiseddiagnostic and therapeutic management of the psychiatric condition.

- The use of interferon alfa-2b in children and adolescents with existence of or history of severepsychiatric conditions is contraindicated (see section 4.3).

Patients with substance use/abuse:

HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at anincreased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorderswhen treated with alpha interferon. If treatment with alpha interferon is judged necessary in these patients,the presence of psychiatric co-morbidities and the potential for other substance use should be carefullyassessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approachincluding a mental health care provider or addiction specialist should be considered to evaluate, treat andfollow the patient. Patients should be closely monitored during therapy and even after treatmentdiscontinuation. Early intervention for re-emergence or development of psychiatric disorders andsubstance use is recommended.

Children and adolescent population: Growth and development (chronic hepatitis C)

During the course of interferon (standard and pegylated)/ribavirin combination therapy lasting up to48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common (seesections 4.8 and 5.1). The longer term data available in children treated with the combination therapywith standard interferon/ribavirin are also indicative of substantial growth retardation (> 15 percentiledecrease in height percentile as compared to baseline) in 21 % of children (n=20) despite being offtreatment for more than 5 years. Final adult height was available for 14 of those children anddemonstrated that 12 continued to show height deficits > 15 percentiles, 10 to 12 years after the end oftreatment.

Case by case benefit/risk assessment in children

The expected benefit of treatment should be carefully weighed against the safety findings observed forchildren and adolescents in the clinical trials (see sections 4.8 and 5.1).

- It is important to consider that the combination therapy induced a growth inhibition that resultedin reduced final adult height in some patients.

- This risk should be weighed against the disease characteristics of the child, such as evidenceof disease progression (notably fibrosis), co-morbidities that may negatively influence thedisease progression (such as HIV co-infection), as well as prognostic factors of response, (HCVgenotype and viral load).

Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce therisk of growth inhibition. There are no data on long term effects on sexual maturation.

Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) tointerferon alfa-2b have been observed rarely during IntronA therapy. If such a reaction develops,discontinue the medicine and institute appropriate medical therapy. Transient rashes do not necessitateinterruption of treatment.

Adverse experiences including prolongation of coagulation markers and liver abnormalities

Moderate to severe adverse experiences may require modification of the patient's dose regimen, or insome cases, termination of IntronA therapy. IntronA increases the risk of liver decompensation anddeath in patients with cirrhosis.

Discontinue treatment with IntronA in patients with chronic hepatitis who develop prolongation ofcoagulation markers which might indicate liver decomposition.

Any patient developing liver function abnormalities during treatment with IntronA must be monitoredclosely and treatment discontinued if signs and symptoms progress.

Liver enzymes and hepatic function should be closely monitored in cirrhotic patients.

Hypotension may occur during IntronA therapy or up to two days post-therapy and may requiresupportive treatment.

Need for adequate hydration

Adequate hydration must be maintained in patients undergoing IntronA therapy since hypotensionrelated to fluid depletion has been seen in some patients. Fluid replacement may be necessary.

While pyrexia may be associated with the flu-like syndrome reported commonly during interferontherapy, other causes of persistent pyrexia must be ruled out.

Patients with debilitating medical conditions

IntronA must be used cautiously in patients with debilitating medical conditions, such as those with ahistory of pulmonary disease (e.g., chronic obstructive pulmonary disease) or diabetes mellitus proneto ketoacidosis. Caution must be observed also in patients with coagulation disorders (e.g.,thrombophlebitis, pulmonary embolism) or severe myelosuppression.

Pulmonary conditions

Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have beenobserved rarely in interferon alpha treated patients, including those treated with IntronA. Theaetiology has not been defined. These symptoms have been reported more frequently when shosaikoto,a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.5). Anypatient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-raytaken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary functionimpairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alpha.

While this has been reported more often in patients with chronic hepatitis C treated with interferonalpha, it has also been reported in patients with oncologic diseases treated with interferon alpha.

Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear tobe associated with resolution of pulmonary adverse events.

Ocular adverse events

Ocular adverse events (see section 4.8) including retinal haemorrhages, cotton wool spots, serousretinal detachment, and retinal artery or vein obstruction have been reported in rare instances aftertreatment with alpha interferons. All patients should have a baseline eye examination. Any patientcomplaining of changes in visual acuity or visual fields, or reporting other ophthalmologic symptomsduring treatment with IntronA, must have a prompt and complete eye examination. Periodic visualexaminations during IntronA therapy are recommended particularly in patients with disorders that maybe associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of IntronAshould be considered in patients who develop new or worsening ophthalmological disorders.

Obtundation, coma and encephalopathy

More significant obtundation and coma, including cases of encephalopathy, have been observed insome patients, usually elderly, treated at higher doses. While these effects are generally reversible, in afew patients full resolution took up to three weeks. Very rarely, seizures have occurred with highdoses of IntronA.

Patients with pre-existing cardiac abnormalities

Adult patients with a history of congestive heart failure, myocardial infarction and/or previous orcurrent arrhythmic disorders, who require IntronA therapy, must be closely monitored. It isrecommended that those patients who have pre-existing cardiac abnormalities and/or are in advancedstages of cancer have electrocardiograms taken prior to and during the course of treatment. Cardiacarrhythmias (primarily supraventricular) usually respond to conventional therapy but may requirediscontinuation of IntronA therapy. There are no data in children or adolescents with a history of cardiacdisease.

Hypertriglyceridemia

Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed.

Monitoring of lipid levels is, therefore, recommended.

Patients with psoriasis and sarcoidosis

Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of

IntronA in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifiesthe potential risk.

Kidney and liver graft rejection

Preliminary data indicates that interferon alpha therapy may be associated with an increased rate ofkidney graft rejection. Liver graft rejection has also been reported.

Auto-antibodies and autoimmune disorders

The development of auto-antibodies and autoimmune disorders has been reported during treatmentwith alpha interferons. Patients predisposed to the development of autoimmune disorders may be atincreased risk. Patients with signs or symptoms compatible with autoimmune disorders should beevaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see alsosection 4.4 Chronic hepatitis C, Monotherapy (thyroid abnormalities) and section 4.8).

Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronichepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affectingthe eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatmentshould be withdrawn and corticosteroid therapy discussed (see section 4.8).

Concomitant chemotherapy

Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C,cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity andduration), which may be life-threatening or fatal as a result of the concomitantly administeredmedicinal product. The most commonly reported potentially life-threatening or fatal adverse eventsinclude mucositis, diarrhoea, neutropaenia, renal impairment, and electrolyte disturbance. Because ofthe risk of increased toxicity, careful adjustments of doses are required for IntronA and for theconcomitant chemotherapeutic agents (see section 4.5). When IntronA is used with hydroxyurea, thefrequency and severity of cutaneous vasculitis may be increased.

Chronic hepatitis C

Combination therapy with ribavirin

Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients withchronic hepatitis C.

All patients in the chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases(i.e. patients with genotype 2 and 3), treatment may be possible without histological confirmation.

Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior tocommencing treatment.

Infrequently, adult patients treated for chronic hepatitis C with IntronA developed thyroidabnormalities, either hypothyroidism or hyperthyroidism. In clinical trials using IntronA therapy,2.8 % patients overall developed thyroid abnormalities. The abnormalities were controlled byconventional therapy for thyroid dysfunction. The mechanism by which IntronA may alter thyroidstatus is unknown. Prior to initiation of IntronA therapy for the treatment of chronic hepatitis C,evaluate serum thyroid-stimulating hormone (TSH) levels. Any thyroid abnormality detected at thattime must be treated with conventional therapy. IntronA treatment may be initiated if TSH levels canbe maintained in the normal range by medication. Determine TSH levels if, during the course of

IntronA therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In thepresence of thyroid dysfunction, IntronA treatment may be continued if TSH levels can be maintainedin the normal range by medication. Discontinuation of IntronA therapy has not reversed thyroiddysfunction occurring during treatment (also see Thyroid supplemental monitoring specific forchildren and adolescents).

Thyroid supplemental monitoring specific for children and adolescents

Approximately 12 % of children treated with interferon alfa-2b and ribavirin combination therapydeveloped increase in thyroid stimulating hormone (TSH). Another 4 % had a transient decreasebelow the lower limit of normal. Prior to initiation of IntronA therapy, TSH levels must be evaluatedand any thyroid abnormality detected at that time must be treated with conventional therapy. IntronAtherapy may be initiated if TSH levels can be maintained in the normal range by medication. Thyroiddysfunction during treatment with interferon alfa-2b and ribavirin has been observed. If thyroidabnormalities are detected, the patient’s thyroid status should be evaluated and treated as clinicallyappropriate. Children and adolescents should be monitored every 3 months for evidence of thyroiddysfunction (e.g. TSH).

HCV/HIV Coinfection

Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be atincreased risk of developing lactic acidosis. Caution should be used when adding IntronA and ribavirin to

HAART therapy (see ribavirin SPC). Patients treated with IntronA and ribavirin combination therapyand zidovudine could be at increased risk of developing anaemia.

Co-infected patients with advanced cirrhosis receiving HAART may be at increased risk of hepaticdecompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirinmay increase the risk in this patient subset.

HCV/HBV Coinfection

Cases of hepatitis B re-activation (some with severe consequences) have been reported in patients co-infected with hepatitis B and C viruses treated with interferon. The frequency of such re-activationappears to be low.

All patients should be screened for hepatitis B before starting treatment with interferon for hepatitis C;patients co-infected with hepatitis B and C must then be monitored and managed according to currentclinical guidelines.

Dental and periodontal disorders

Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patientsreceiving IntronA and ribavirin combination therapy. In addition, dry mouth could have a damagingeffect on teeth and mucous membranes of the mouth during long-term treatment with the combinationof IntronA and ribavirin. Patients should brush their teeth thoroughly twice daily and have regulardental examinations. In addition some patients may experience vomiting. If this reaction occurs, theyshould be advised to rinse out their mouth thoroughly afterwards.

Laboratory Tests

Standard haematological tests and blood chemistries (complete blood count and differential, plateletcount, electrolytes, liver enzymes, serum protein, serum bilirubin and serum creatinine) are to beconducted in all patients prior to and periodically during systemic treatment with IntronA.

During treatment for hepatitis B or C the recommended testing schedule is at weeks 1, 2, 4, 8, 12, 16,and every other month, thereafter, throughout treatment. If ALT flares during IntronA therapy togreater than or equal to 2 times baseline, IntronA therapy may be continued unless signs andsymptoms of liver failure are observed. During ALT flare, the following liver function tests must bemonitored at two-week intervals: ALT, prothrombin time, alkaline phosphatase, albumin and bilirubin.

In patients treated for malignant melanoma, liver function and white blood cell (WBC) count anddifferential must be monitored weekly during the induction phase of therapy and monthly during themaintenance phase of therapy.

Effect on fertility

Interferon may impair fertility (see section 4.6 and section 5.3).

Important information about some of the ingredients of IntronA

This medicinal product contains less than 1 mmol sodium (23 mg) per 3 mL, i.e., essentially 'sodium-free'.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Interaction studies have only been performed in adults.

Narcotics, hypnotics or sedatives must be administered with caution when used concomitantly with

IntronA.

Interactions between IntronA and other medicinal products have not been fully evaluated. Cautionmust be exercised when administering IntronA in combination with other potentiallymyelosuppressive agents.

Interferons may affect the oxidative metabolic process. This must be considered during concomitanttherapy with medicinal products metabolised by this route, such as the xanthine derivativestheophylline or aminophylline. During concomitant therapy with xanthine agents, serum theophyllinelevels must be monitored and dose adjusted if necessary.

Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have beenobserved rarely in interferon alpha treated patients, including those treated with IntronA. Theaetiology has not been defined. These symptoms have been reported more frequently when shosaikoto,a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.4).

Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C,cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity andduration) (see section 4.4).

Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients withchronic hepatitis C.

A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferonalfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combinationis associated with an increased risk of developing peripheral neuropathy. The mechanism behind theseevents is not known (see sections pct. 4.3, pct. 4.4 and 4.5 of the telbivudine SPC). Moreover, the safety andefficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has notbeen demonstrated. Therefore, the combination of IntronA with telbivudine is contraindicated (seesection 4.3).

Women of childbearing potential/contraception in males and females

Women of childbearing potential have to use effective contraception during treatment. Decreasedserum estradiol and progesterone concentrations have been reported in women treated with humanleukocyte interferon.

IntronA must be used with caution in fertile men.

Combination therapy with ribavirin

Ribavirin causes serious birth defects when administered during pregnancy. Extreme care must betaken to avoid pregnancy in female patients or in partners of male patients taking IntronA incombination with ribavirin. Females of childbearing potential must use an effective contraceptiveduring treatment and for 4 months after treatment has been concluded. Male patients or their femalepartners must use an effective contraceptive during treatment and for 7 months after treatment hasbeen concluded (see ribavirin SPC).

There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animalshave shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. IntronAis to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Combination therapy with ribavirin

Ribavirin therapy is contraindicated in women who are pregnant.

It is not known whether the components of this medicinal product are excreted in human milk.

Because of the potential for adverse reactions in nursing infants, nursing should be discontinued priorto initiation of treatment.

Patients are to be advised that they may develop fatigue, somnolence, or confusion during treatmentwith IntronA, and therefore it is recommended that they avoid driving or operating machinery.

See ribavirin SPC for ribavirin-related undesirable effects if IntronA is to be administered incombination with ribavirin in patients with chronic hepatitis C.

In clinical trials conducted in a broad range of indications and at a wide range of doses (from6 MIU/m2/week in hairy cell leukaemia up to 100 MIU/m2/week in melanoma), the most commonlyreported undesirable effects were pyrexia, fatigue, headache and myalgia. Pyrexia and fatigue wereoften reversible within 72 hours of interruption or cessation of treatment.

In clinical trials conducted in the hepatitis C population, patients were treated with IntronA alone or incombination with ribavirin for one year. All patients in these trials received 3 MIU of IntronA threetimes a week. In Table 1 the frequency of patients reporting (treatment related) undesirable effects ispresented from clinical trials in naïve patients treated for one year. Severity was generally mild tomoderate. The adverse reactions listed in Table 1 are based on experience from clinical trials andpost-marketing. Within the organ system classes, adverse reactions are listed under headings offrequency using the following categories: very common (≥1/10); common (≥1/100 to <1/10);uncommon (≥1/1,000 to <1/100); rarely (≥1/10,000 to <1/1,000); very rarely (<1/10,000); not known.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1 Adverse reactions reported during clinical trials or following the marketing use of

IntronA alone or in combination with ribavirin

System Organ Class Adverse Reactions

Very common: Pharyngitis*, infection viral*

Common: Bronchitis, sinusitis, herpes simplex (resistance), rhinitis

Uncommon: Bacterial infection

Rarely: Pneumonia§, sepsis

Not known: Hepatitis B reactivation in HCV/HBV co-infected patients

Very common: Leukopaenia

Common: Thrombocytopaenia, lymphadenopathy, lymphopenia

Very rarely: Aplastic anaemia

Not known: Pure red cell aplasia, idiopathic thrombocytopenicpurpura, thrombotic thrombocytopenic purpura

Immune system disorders§

Very rarely: Sarcoidosis, exacerbation of sarcoidosis

Not known: Systemic lupus erythematosus, vasculitis, rheumatoidarthritis (new or aggravated), Vogt-Koyanagi-Haradasyndrome, acute hypersensitivity reactions includingurticaria, angioedema, bronchoconstriction, anaphylaxis§

Common: Hypothyroidism§, hyperthyroidism§

Very rarely: Diabetes, aggravated diabetes

Very common: Anorexia

Common: Hypocalcaemia, dehydration, hyperuricemia, thirst

Very rarely: Hyperglycaemia, hypertriglyceridaemia§, increasedappetite

Psychiatric disorders§

Very common: Depression, insomnia, anxiety, emotional lability*,agitation, nervousness

Common: Confusion, sleep disorder, libido decreased

Rarely: Suicide ideation

Very rarely: Suicide, suicide attempts, aggressive behaviour(sometimes directed against others), psychosis including

Not known: hallucinations

Homicidal ideation, mental status change§, mania, bipolardisorders

Nervous system disorders§

Very common: Dizziness, headache, concentration impaired, mouth dry

Common: Tremor, paresthesia, hypoesthesia, migraine, flushing,somnolence, taste perversion

Uncommon: Peripheral neuropathy

Very rarely: Cerebrovascular haemorrhage, cerebrovascular ischaemia,seizure, impaired consciousness, encephalopathy

Not known: Mononeuropathies, coma§

Very common: Vision blurred

Common: Conjunctivitis, vision abnormal, lacrimal gland disorder,eye pain

Rarely: Retinal haemorrhages§, retinopathies (including macularoedema), retinal artery or vein obstruction§, optic neuritis,papilloedema, loss of visual acuity or visual field, cotton-wool spots§

Not known: Serous retinal detachment

Ear and labyrinth

Common: Vertigo, tinnitus

Very rarely: Hearing loss, hearing disorder

Common: Palpitation, tachycardia

Uncommon: Pericarditis

Rarely: Cardiomyopathy

Very rarely: Myocardial infarction, cardiac ischaemia

Not known: Congestive heart failure, pericardial effusion, arrhythmia

Common: Hypertension

Very rarely: Peripheral ischaemia, hypotension§

Respiratory, thoracic and mediastinaldisorders

Very common: Dyspnoea*, coughing*

Common: Epistaxis, respiratory disorder, nasal congestion,rhinorrhea, cough nonproductive

Very rarely: Pulmonary infiltrates§, pneumonitis§

Not known: Pulmonary fibrosis, pulmonary arterial hypertension#

Very common: Nausea/vomiting, abdominal pain, diarrhoea, stomatitis,dyspepsia

Common: Stomatitis ulcerative, right upper quadrant pain, glossitis,gingivitis, constipation, loose stools

Very rarely: Pancreatitis, ischaemic colitis, ulcerative colitis, gingivalbleeding

Not known: Periodontal disorder NOS, dental disorder NOS, tonguepigmentation §

Common: Hepatomegaly

Very rarely: Hepatotoxicity, (including fatality)

Skin and subcutaneous tissuedisorders Alopecia, pruritus*, skin dry*, rash*, sweating increased

Very common: Psoriasis (new or aggravated)§, rash maculopapular, rash

Common: erythematous, eczema, erythema, skin disorder

Stevens Johnson syndrome, toxic epidermal necrolysis,

Very rarely: erythema multiforme

Musculoskeletal and connective tissuedisorders

Very common: Myalgia, arthralgia, musculoskeletal pain

Common: Arthritis

Very rarely: Rhabdomyolysis, myositis, leg cramps, back pain

Common: Micturition frequency

Very rarely: Renal failure, renal insufficiency, nephrotic syndrome

Reproductive system and breastdisorders

Common: Amenorrhea, breast pain, dysmenorrhea, menorrhagia,menstrual disorder, vaginal disorder

General disorders and administrationsite conditions

Very common: Injection site inflammation, injection site reaction*,fatigue, rigors, pyrexia§, flu-like symptoms§, asthenia,irritability, chest pain, malaise

Common: Injection site pain

Very rarely: Injection site necrosis, face oedema

Very common: Weight decrease

*These events were only common with IntronA alone.§See section 4.4#Class label for interferon products, see below Pulmonary arterial hypertension.

These undesirable effects have also been reported with IntronA alone.

The undesirable effects seen with hepatitis C are representative of those reported when IntronA isadministered in other indications, with some anticipated dose-related increases in incidence. Forexample, in a trial of high-dose adjuvant IntronA treatment in patients with melanoma, incidences offatigue, pyrexia, myalgia, neutropaenia/anaemia, anorexia, nausea and vomiting, diarrhoea, chills, flu-like symptoms, depression, alopecia, altered taste, and dizziness were greater than in the hepatitis Ctrials. Severity also increased with high dose therapy (WHO Grade 3 and 4, in 66 % and 14 % ofpatients, respectively), in comparison with the mild to moderate severity usually associated with lowerdoses. Undesirable effects were usually managed by dose adjustment.

Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly withpre-existing CVS disease and prior therapy with cardiotoxic agents (see section 4.4). Cardiomyopathy,that may be reversible upon discontinuation of interferon alpha, has been reported rarely in patientswithout prior evidence of cardiac disease (see section 4.4).

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products,notably in patients with risk factors for PAH (such as portal hypertension, HIV-infection, cirrhosis).

Events were reported at various time points typically several months after starting treatment withinterferon alfa.

A wide variety of autoimmune and immune-mediated disorders have been reported with alphainterferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new oraggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies includingmononeuropathies (see also section 4.4).

Clinically significant laboratory abnormalities, most frequently occurring at doses greater than10 million IU daily, include reduction in granulocyte and white blood cell counts; decreases inhaemoglobin level and platelet count; increases in alkaline phosphatase, LDH, serum creatinine andserum urea nitrogen levels. Moderate and usually reversible pancytopenia has been reported. Increasein serum ALT/AST (SGPT/SGOT) levels have been noted as an abnormality in some non-hepatitissubjects and also in some patients with chronic hepatitis B coincident with clearance of viral DNAp.

Children and adolescent population

Chronic Hepatitis C - Combination therapy with ribavirin

In clinical trials of 118 children and adolescents (3 to 16 years of age), 6 % discontinued therapy dueto adverse reactions. In general, the adverse reaction profile in the limited children and adolescentpopulation studied was similar to that observed in adults, although there is a paediatric- specificconcern regarding growth inhibition as decrease in height percentile (mean percentile decrease of9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed duringtreatment. Within the 5 years follow-up post-treatment period, the children had a mean height of44th percentile, which was below the median of the normative population and less than their meanbaseline height (48th percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in heightpercentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile fromthe start of treatment to the end of long-term follow-up (up to 5 years). Final adult height wasavailable for 14 of those children and demonstrated that 12 continued to show height deficits > 15percentiles, 10 to 12 years after the end of treatment. During combination therapy for up to 48 weekswith IntronA and ribavirin, growth inhibition was observed that resulted in reduced final adult heightin some patients. In particular, decrease in mean height percentile from baseline to the end of the long-term follow-up was most prominent in prepubertal age children (see section 4.4).

Furthermore, suicidal ideation or attempts were reported more frequently compared to adult patients(2.4 % vs 1 %) during treatment and during the 6 month follow-up after treatment. As in adultpatients, children and adolescents also experienced other psychiatric adverse events (e.g., depression,emotional lability, and somnolence) (see section 4.4). In addition, injection site disorders, pyrexia,anorexia, vomiting, and emotional lability occurred more frequently in children and adolescentscompared to adult patients. Dose modifications were required in 30 % of patients, most commonly foranaemia and neutropaenia.

The adverse reactions listed in Table 2 are based on experience from the two multicentre children andadolescent clinical trials. Within the organ system classes, adverse reactions are listed under headingsof frequency using the following categories: very common (≥1/10); common (≥1/100, <1/10). Withineach frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2 Adverse reactions very commonly and commonly reported during clinical trials inchildren and adolescent patients treated with IntronA in combination with ribavirin

System Organ Class Adverse Reactions

Infection and infestations

Very common: Viral infection, pharyngitis

Common: Fungal infection, bacterial infection, pulmonary infection, otitismedia, tooth abscess, herpes simplex, urinary tract infection,vaginitis, gastroenteritis

Neoplasms benign, malignantand unspecified (includingcysts and polyps)

Common: Neoplasm (unspecified)

Blood and lymphatic systemdisorders

Very common: Anaemia, neutropaenia

Common: Thrombocytopaenia, lymphadenopathy

Very common: Hypothyroidism§,

Common: Hyperthyroidism§, virilism

Metabolism and nutritiondisorders

Very common: Anorexia

Common: Hypertriglyceridemia§, hyperuricemia, increased appetite

Psychiatric disorders§

Very common: Depression, emotional lability, insomnia

Common: Suicidal ideation, aggressive reaction, confusion, behaviourdisorder, agitation, somnambulism, anxiety, nervousness, sleepdisorder, abnormal dreaming, apathy

Nervous system disorders§

Very common: Headache, dizziness

Common: Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia,hyperaesthesia, concentration impaired, somnolence

Common: Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder

Common: Flushing, pallor

Respiratory, thoracic andmediastinal disorders

Common: Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasalirritation, rhinorrhea, sneezing

Very common: Diarrhoea, vomiting, nausea, abdominal pain

Common: Mouth ulceration, stomatitis ulcerative, stomatitis, right upperquadrant pain, dyspepsia, glossitis, gastroesophageal reflux, rectaldisorder, gastrointestinal disorder, constipation, loose stools,toothache, tooth disorder

Common: Hepatic function abnormal

Skin and subcutaneous tissuedisorders

Very common: Alopecia, rash

Common: Photosensitivity reaction, maculopapular rash, eczema, acne, skindisorder, nail disorder, skin discolouration, pruritus, dry skin,erythema, bruise, sweating increased

Musculoskeletal andconnective tissue disorders

Very common: Arthralgia, myalgia, musculoskeletal pain

Common: Enuresis, micturition disorder, urinary incontinence

Reproductive system andbreast disorders

Common: Female: amenorrhea, menorrhagia, menstrual disorder, vaginaldisorder

Male: testicular pain

General disorders andadministration siteconditions

Very common: Injection site inflammation, injection site reaction, fatigue, rigors,pyrexia§, influenza-like symptoms§, malaise, irritability

Common: Chest pain, asthenia, oedema, injection site pain

Very common: Growth rate decrease (height and/or weight decrease for age)§

Injury and poisoning

Common: Skin laceration§See section 4.4

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No case of overdose has been reported that has led to acute clinical manifestations. However, as forany pharmacologically active compound, symptomatic treatment with frequent monitoring of vitalsigns and close observation of the patient is indicated.

Pharmacotherapeutic group: interferon alfa-2b, ATC code: L03A B05

IntronA is a sterile, stable, formulation of highly purified interferon alfa-2b produced by recombinant

DNA techniques. Recombinant interferon alfa-2b is a water-soluble protein with a molecular weight ofapproximately 19,300 daltons. It is obtained from a clone of E. coli, which harbours a geneticallyengineered plasmid hybrid encompassing an interferon alfa-2b gene from human leukocytes.

The activity of IntronA is expressed in terms of IU, with 1 mg of recombinant interferon alfa-2bprotein corresponding to 2.6 x l08 IU. International Units are determined by comparison of the activityof the recombinant interferon alfa-2b with the activity of the international reference preparation ofhuman leukocyte interferon established by the World Health Organisation.

The interferons are a family of small protein molecules with molecular weights of approximately15,000 to 21,000 daltons. They are produced and secreted by cells in response to viral infections orvarious synthetic and biological inducers. Three major classes of interferons have been identified:alpha, beta and gamma. These three main classes are themselves not homogeneous and may containseveral different molecular species of interferon. More than 14 genetically distinct human alphainterferons have been identified. IntronA has been classified as recombinant interferon alfa-2b.

Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface.

Human interferon receptors, as isolated from human lymphoblastoid (Daudi) cells, appear to be highlyasymmetric proteins. They exhibit selectivity for human but not murine interferons, suggesting speciesspecificity. Studies with other interferons have demonstrated species specificity. However, certainmonkey species, eg, rhesus monkeys, are susceptible to pharmacodynamic stimulation upon exposureto human type 1 interferons.

The results of several studies suggest that, once bound to the cell membrane, interferon initiates acomplex sequence of intracellular events that include the induction of certain enzymes. It is thoughtthat this process, at least in part, is responsible for the various cellular responses to interferon,including inhibition of virus replication in virus-infected cells, suppression of cell proliferation andsuch immunomodulating activities as enhancement of the phagocytic activity of macrophages andaugmentation of the specific cytotoxicity of lymphocytes for target cells. Any or all of these activitiesmay contribute to interferon's therapeutic effects.

Recombinant interferon alfa-2b has exhibited antiproliferative effects in studies employing bothanimal and human cell culture systems as well as human tumour xenografts in animals. It hasdemonstrated significant immunomodulatory activity in vitro.

Recombinant interferon alfa-2b also inhibits viral replication in vitro and in vivo. Although the exactantiviral mode of action of recombinant interferon alfa-2b is unknown, it appears to alter the host cellmetabolism. This action inhibits viral replication or if replication occurs, the progeny virions areunable to leave the cell.

Chronic hepatitis B

Current clinical experience in patients who remain on interferon alfa-2b for 4 to 6 months indicatesthat therapy can produce clearance of serum HBV-DNA. An improvement in liver histology has beenobserved. In adult patients with loss of HBeAg and HBV-DNA, a significant reduction in morbidityand mortality has been observed.

Interferon alfa-2b (6 MIU/m2 3 times a week for 6 months) has been given to children with chronicactive hepatitis B. Because of a methodological flaw, efficacy could not be demonstrated. Moreoverchildren treated with interferon alfa-2b experienced a reduced rate of growth and some cases ofdepression were observed.

Chronic hepatitis C in adult patients

In adult patients receiving interferon in combination with ribavirin, the achieved sustained responserate is 47 %. Superior efficacy has been demonstrated with the combination of pegylated interferonwith ribavirin (sustained response rate of 61 % achieved in a study performed in naïve patients with aribavirin dose > 10.6 mg/kg, p < 0.01).

IntronA alone or in combination with ribavirin has been studied in 4 randomised Phase III clinicaltrials in 2,552 interferon-naïve patients with chronic hepatitis C. The trials compared the efficacy of

IntronA used alone or in combination with ribavirin. Efficacy was defined as sustained virologicresponse, 6 months after the end of treatment. Eligible patients for these trials had chronic hepatitis Cconfirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 100 copies/mL), a liverbiopsy consistent with a histologic diagnosis of chronic hepatitis with no other cause for the chronichepatitis, and abnormal serum ALT.

IntronA was administered at a dose of 3 MIU 3 times a week as monotherapy or in combination withribavirin. The majority of patients in these clinical trials were treated for one year. All patients werefollowed for an additional 6 months after the end of treatment for the determination of sustainedvirologic response. Sustained virologic response rates for treatment groups treated for one year with

IntronA alone or in combination with ribavirin (from two studies) are shown in Table 3.

Co-administration of IntronA with ribavirin increased the efficacy of IntronA by at least two fold forthe treatment of chronic hepatitis C in naïve patients. HCV genotype and baseline virus load areprognostic factors which are known to affect response rates. The increased response rate to thecombination of IntronA + ribavirin, compared with IntronA alone, is maintained across all subgroups. Therelative benefit of combination therapy with IntronA + ribavirin is particularly significant in the mostdifficult to treat subgroup of patients (genotype 1 and high virus load) (Table 3).

Response rates in these trials were increased with compliance. Regardless of genotype, patients whoreceived IntronA in combination with ribavirin and received  80 % of their treatment had a highersustained response 6 months after 1 year of treatment than those who took < 80 % of their treatment(56 % vs. 32 % in trial C/I98-580).

Table 3 Sustained virologic response rates with IntronA + ribavirin (one year of treatment) bygenotype and viral load

HCV Genotype I I/R I/R

N=503 N=505 N=505

C95-132/I95-143 C95-132/I95-143 C/I98-580

All Genotypes 16 % 41 % 47 %

Genotype 1 9 % 29 % 33 %

Genotype 1 2 million 25 % 33 % 45 %copies/mL

Genotype 1> 2 million 3 % 27 % 29 %copies/mL

Genotype 2/3 31 % 65 % 79 %

I IntronA (3 MIU 3 times a week)

I/R IntronA (3 MIU 3 times a week) + ribavirin (1,000/1,200 mg/day)

HCV/HIV Co-infected patients

Two trials have been conducted in patients co-infected with HIV and HCV. Overall, in both studies,patients who received IntronA plus ribavirin, were less likely to respond than patients who receivedpegylated interferon alfa-2b with ribavirin. The response to treatment in both of these trials ispresented in Table 4. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study whichenrolled 412 previously untreated adult patients with chronic hepatitis C who were co-infected with

HIV. Patients were randomized to receive either pegylated interferon alfa-2b (1.5 µg/kg/week) plusribavirin (800 mg/day) or IntronA (3 MIU TIW) plus ribavirin (800 mg/day) for 48 weeks with afollow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled95 previously untreated adult patients with chronic hepatitis C who were co-infected with HIV.

Patients were randomized to receive either pegylated interferon alfa-2b (100 or 150 µg /week based onweight) plus ribavirin (800-1,200 mg/day based on weight) or IntronA (3 MIU TIW) plus ribavirin(800-1,200 mg/day based on weight). The duration of therapy was 48 weeks with a follow-up periodof 6 months except for patients infected with genotypes 2 or 3 and viral load < 800,000 IU/mL(Amplicor) who were treated for 24 weeks with a 6-month follow-up period.

Table 4 Sustained virological response based on genotype after IntronA in combination withribavirin versus pegylated interferon alfa-2b in combination with ribavirin in

HCV/HIV co-infected patients

Study 11 Study 22pegylatedinterferonpegylated alfa-2b (100interferon alfa- or IntronA2b (1.5 µg/kg/ IntronA 150c µg/week) (3 MIU TIW)week) + (3 MIU TIW) + + ribavirin + ribavirinribavirin ribavirin p (800- (800- p(800 mg) (800 mg) valuea 1,200 mg)d 1,200 mg)d valueb

All 27 % (56/205) 20 % (41/205) 0.047 44 % (23/52) 21 % (9/43) 0.017

Genotype 1, 17 % (21/125) 6 % (8/129) 0.006 38 % (12/32) 7 % (2/27) 0.007

Genotype 2, 44 % (35/80) 43 % (33/76) 0.88 53 % (10/19) 47 % (7/15) 0.730

MIU = million international units; TIW = three times a week.a: p value based on Cochran-Mantel Haenszel Chi square test.b: p value based on chi-square test.c: subjects < 75 kg received 100 µg/week pegylated interferon alfa-2b and subjects ≥ 75 kg received 150 µg/week pegylatedinterferon alfa-2b.d: ribavirin dosing was 800 mg for patients < 60 kg, 1,000 mg for patients 60-75 kg, and 1,200 mg for patients > 75 kg.

1Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848.2 Laguno M, Murillas J, Blanco J.L et al. AIDS 2004; 18(13): F27-F36.

Relapse patients

A total of 345 interferon alpha relapse patients were treated in two clinical trials with IntronAmonotherapy or in combination with ribavirin. In these patients, the addition of ribavirin to IntronAincreased by as much as 10-fold the efficacy of IntronA used alone in the treatment of chronichepatitis C (48.6 % vs. 4.7 %). This enhancement in efficacy included loss of serum HCV(< 100 copies/mL by PCR), improvement in hepatic inflammation, and normalisation of ALT, and wassustained when measured 6 months after the end of treatment.

Long-Term efficacy data

In a large study, 1,071 patients were enrolled after treatment in a prior non-pegylated interferon alfa-2b or non-pegylated interferon alfa-2b/ribavirin study to evaluate the durability of sustained virologicresponse and assess the impact of continued viral negativity on clinical outcomes. 462 patientscompleted at least 5 years of long-term follow-up and only 12 sustained responders' out of492 relapsed during this study.

The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 97 % witha 95 % Confidence Interval of [95 %, 99 %].

SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b (with or without ribavirin)results in long-term clearance of the virus providing resolution of the hepatic infection and clinical'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patientswith cirrhosis (including hepatocarcinoma).

Chronic hepatitis C in children and adolescent population

Three clinical trials have been conducted in children and adolescents; two with standard interferon andribavirin and one with pegylated interferon and ribavirin. Patients who received IntronA plus ribavirinwere less likely to respond than patients who received pegylated interferon alfa-2b and ribavirin.

Children and adolescents 3 to 16 years of age with compensated chronic hepatitis C and detectable

HCV-RNA (assessed by a central laboratory using a research-based RT-PCR assay) were enrolled intwo multicentre trials and received IntronA 3 MIU/m2 3 times a week plus ribavirin 15 mg/kg per dayfor 1 year followed by 6 months follow-up after-treatment. A total of 118 patients were enrolled: 57 %male, 80 % Caucasian, and 78 % genotype 1,64 %  12 years of age. The population enrolled mainlyconsisted in children with mild to moderate hepatitis C. In the two multicentre trials sustainedvirological response rates in children and adolescents were similar to those in adults. Due to the lackof data in these two multicentre trials for children with severe progression of the disease, and thepotential for undesirable effects, the benefit/risk of the combination of ribavirin and interferon alfa-2bneeds to be carefully considered in this population (see sections 4.1, pct. 4.4 and 4.8).

Study results are summarized in Table 5.

Table 5 Sustained virological response in previously untreated children and adolescents

IntronA 3 MIU/m2 3 times a week+ribavirin 15 mg/kg/day

Overall Responsea (n=118) 54 (46 %)*

Genotype 1 (n=92) 33 (36 %)*

Genotype 2/3/4 (n=26) 21 (81 %)*

*Number (%) of patientsa Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and duringfollow-up period

Long-term efficacy data

A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis Cpatients after treatment in the standard interferon multicentre trials. Seventy percent (68/97) of allenrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purposeof the study was to annually evaluate the durability of sustained virologic response (SVR) and assessthe impact of continued viral negativity on clinical outcomes for patients who were sustainedresponders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All butone of the paediatric subjects remained sustained virologic responders during long-term follow-upafter completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate forcontinued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patientstreated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels atfollow-up week 24 maintained normal ALT levels at their last visit.

SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with ribavirin results inlong-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' fromchronic HCV. However, this does not preclude the occurrence of hepatic events in patients withcirrhosis (including hepatocarcinoma).

Results from the clinical trial conducted with pegylated interferon alfa-2b and ribavirin

In a multicentre trial children and adolescents 3 to 17 years of age with compensated chronichepatitis C and detectable HCV-RNA were treated with peginterferon alfa-2b 60 g/m2 plus ribavirin15 mg/kg per day once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load.

All patients were to be followed for 24 weeks post-treatment. A total of 107 patients receivedtreatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and63 % < 12 years of age. The population enrolled mainly consisted of children with mild to moderatehepatitis C. Due to the lack of data in children with severe progression of the disease, and the potentialfor undesirable effects, the benefit/risk of the combination of peginterferon alfa-2b with ribavirinneeds to be carefully considered in this population (see peginterferon alfa-2b and ribavirin SPCssection 4.4). The study results are summarized in Table 6.

Table 6 Sustained virological response rates (na,b (%)) in previously untreated children andadolescents by genotype and treatment duration - All subjectsn = 10724 weeks 48 weeks

All Genotypes 26/27 (96 %) 44/80 (55 %)

Genotype 1 - 38/72 (53 %)

Genotype 2 14/15 (93 %) -

Genotype 3c 12/12 (100 %) 2/3 (67 %)

Genotype 4 - 4/5 (80 %)a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment, lower limit ofdetection=125 IU/mL.

b: n = number of responders/number of subjects with given genotype, and assigned treatment duration.

c: Patients with genotype 3 low viral load (< 600,000 IU/mL) were to receive 24 weeks of treatment while those withgenotype 3 and high viral load (≥ 600,000 IU/mL) were to receive 48 weeks of treatment.

The pharmacokinetics of IntronA were studied in healthy volunteers following single 5 million IU/m2and 10 million IU doses administered subcutaneously, at 5 million IU/m2 administered intramuscularlyand as a 30-minute intravenous infusion. The mean serum interferon concentrations followingsubcutaneous and intramuscular injections were comparable. Cmax occurred three to 12 hours after thelower dose and six to eight hours after the higher dose. The elimination half-lives of interferoninjections were approximately two to three hours, and six to seven hours, respectively. Serum levelswere below the detection limit 16 and 24 hours, respectively, post-injection. Both subcutaneous andintramuscular administration resulted in bioavailabilities greater than 100 %.

After intravenous administration, serum interferon levels peaked (135 to 273 IU/mL) by the end of theinfusion, then declined at a slightly more rapid rate than after subcutaneous or intramuscularadministration of medicinal product, becoming undetectable four hours after the infusion. Theelimination half-life was approximately two hours.

Urine levels of interferon were below the detection limit following each of the three routes ofadministration.

Interferon neutralising factor assays were performed on serum samples of patients who received

IntronA in Schering-Plough monitored clinical trials. Interferon neutralising factors are antibodieswhich neutralise the antiviral activity of interferon. The clinical incidence of neutralising factorsdeveloping in cancer patients treated systemically is 2.9 % and in chronic hepatitis patients is 6.2 %.

The detectable titres are low in almost all cases and have not been regularly associated with loss ofresponse or any other autoimmune phenomenon. In patients with hepatitis, no loss of response wasobserved apparently due to the low titres.

Children and adolescent population

Multiple-dose pharmacokinetic properties for IntronA injection and ribavirin capsules in children andadolescents with chronic hepatitis C, between 5 and 16 years of age, are summarized in Table 7. Thepharmacokinetics of IntronA and ribavirin (dose-normalized) are similar in adults and children oradolescents.

Table 7 Mean (% CV) multiple-dose pharmacokinetic parameters for IntronA and ribavirincapsules when administered to children or adolescents with chronic hepatitis C

Parameter Ribavirin IntronA15 mg/kg/day as 2 divided doses 3 MIU/m2 3 times a week(n = 17) (n = 54)

Tmax (hr) 1.9 (83) 5.9 (36)

Cmax (ng/mL) 3,275 (25) 51 (48)

AUC* 29,774 (26) 622 (48)

Apparent clearance L/hr/kg 0.27 (27) Not done

*AUC12 (ng.hr/mL) for ribavirin; AUC0-24 (IU.hr/mL) for IntronA

Transfer into seminal fluid

Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid isapproximately two-fold higher compared to serum. However, ribavirin systemic exposure of a femalepartner after sexual intercourse with a treated patient has been estimated and remains extremelylimited compared to therapeutic plasma concentration of ribavirin.

Although interferon is generally recognised as being species specific, toxicity studies in animals wereconducted. Injections of human recombinant interferon alfa-2b for up to three months have shown noevidence of toxicity in mice, rats, and rabbits. Daily dosing of cynomolgus monkeys with20 x 106 IU/kg/day for 3 months caused no remarkable toxicity. Toxicity was demonstrated inmonkeys given 100 x 106 IU/kg/day for 3 months.

In studies of interferon use in non-human primates, abnormalities of the menstrual cycle have beenobserved (see section 4.4).

Results of animal reproduction studies indicate that recombinant interferon alfa-2b was not teratogenicin rats or rabbits, nor did it adversely affect pregnancy, foetal development or reproductive capacity inoffspring of treated rats. Interferon alfa-2b has been shown to have abortifacient effects in Macacamulatta (rhesus monkeys) at 90 and 180 times the recommended intramuscular or subcutaneous doseof 2 million IU/m2. Abortion was observed in all dose groups (7.5 million, 15 million and30 million IU/kg), and was statistically significant versus control at the mid- and high-dose groups(corresponding to 90 and 180 times the recommended intramuscular or subcutaneous dose of2 million IU/m2). High doses of other forms of interferons alpha and beta are known to produce dose-related anovulatory and abortifacient effects in rhesus monkeys.

Mutagenicity studies with interferon alfa-2b revealed no adverse events.

IntronA plus ribavirin

No studies have been conducted in juvenile animals to examine the effects of treatment with interferonalfa-2b on growth, development, sexual maturation, and behaviour. Preclinical juvenile toxicity resultshave demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed withribavirin (see section 5.3 of Rebetol SPC if IntronA is to be administered in combination withribavirin).

Disodium phosphate anhydrous

Sodium dihydrogen phosphate monohydrate

Edetate disodium

Sodium chloride

M-cresol

Polysorbate 80

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

2 years.

After first opening the container: Chemical and physical in-use stability has been demonstrated for28 days at 2ºC - 8ºC.

From a microbiological point of view, once opened, the product may be stored for a maximum of28 days at 2ºC - 8ºC. Other in-use storage times and conditions are the responsibility of the user.

Within its shelf-life, for the purpose of transport, the solution can be kept at or below 25ºC for a periodup 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 therefrigerator 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.

3 mL of solution (corresponding to 18 MIU) is contained in a multidose vial (type I glass) with astopper (halobutyl rubber) in a flip-off seal (aluminium) with a bonnet (polypropylene).

IntronA is supplied as:

- Pack of 1 vial

- Pack of 1 vial, 6 injection syringes of 1 mL, 6 injection needles and 12 cleansing swabs

- Pack of 1 vial, 6 injection syringes with attached needle and needle protection device of 1 mLand 12 cleansing swabs

- Pack of 2 vials

- Pack of 2 vials, 12 injection syringes of 1 mL, 12 injection needles and 24 cleansing swabs

- Pack of 2 vials, 12 injection syringes with attached needle and needle protection device of 1 mLand 24 cleansing swabs

- Pack of 12 vials

- Pack of 12 vials, 72 injection syringes of 1 mL, 72 injection needles and 144 cleansing swabs

- Pack of 12 vials, 72 injection syringes with attached needle and needle protection device of1 mL and 144 cleansing swabs

Not all pack sizes may be marketed.

Not all dose forms and strengths are appropriate for some indications. Please make sure to select anappropriate dose form and strength.

IntronA solution for injection or infusion may be injected directly after withdrawal of the appropriatedoses 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 touse. Any size vial may be used to measure the required dose; however, final concentration ofinterferon in sodium chloride solution must be not less than 0.3 million IU/mL. The appropriate doseof IntronA is withdrawn from the vial(s), added to 50 mL of 9 mg/mL (0.9 %) sodium chloridesolution for injection in a PVC bag or glass bottle for intravenous use and administered over20 minutes.

No other medicinal product can be infused concomitantly with IntronA.

As with all parenteral medicinal products, prior to administration inspect IntronA, solution forinjection or infusion, visually for particulate matter and discolouration. The solution should be clearand colourless.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/99/127/023

EU/1/99/127/024

EU/1/99/127/025

EU/1/99/127/026

EU/1/99/127/041

EU/1/99/127/042

EU/1/99/127/045

EU/1/99/127/046

EU/1/99/127/047

Date of first authorisation: 9 March 2000

Date of latest renewal: 9 March 2010

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.