IntronA - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

IntronA 3 million IU/0.5 mL solution for injection or infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial of solution for injection or infusion contains 3 million IU of recombinant interferon alfa-2b produced in E. coli by recombinant DNA technology, in 0.5 mL of solution.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection or infusion.

Clear and colourless solution.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Chronic hepatitis B

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.

Chronic hepatitis C

Before initiating treatment with IntronA, consideration should be given to the results from clinical trials 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 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.

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 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).

Hairy cell leukaemia

Treatment of patients with hairy cell leukaemia.

Chronic myelogenous leukaemia

Monotherapy

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.

Combination therapy

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.

Multiple myeloma

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.

Follicular lymphoma

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.

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 systemic recurrence, e.g., patients with primary or recurrent (clinical or pathological) lymph node involvement.

4.2 Posology and method of administration

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.

Chronic hepatitis B

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.

Chronic hepatitis C

Adults

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 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.)

Relapse patients (adults)

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.

Naïve patients (adults)

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.

• – IntronA in combination with 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).

• – IntronA alone

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.

Naïve patients (children and adolescents)

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.

Duration of treatment for children and adolescents

• • 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.

Hairy cell leukaemia

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.

Chronic myelogenous leukaemia

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/m2 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.

Multiple myeloma

Maintenance therapy

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/m2 three times a week (every other day).

Follicular lymphoma

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).

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. 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.

Malignant melanoma

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.

4.3 Contraindications

• – 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 with immunosuppressive agents excluding short term corticosteroid withdrawal.

• – Autoimmune hepatitis; or history of autoimmune disease; immunosuppressed transplant recipients.

• - 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, suicidal ideation or suicide attempt.

Combination therapy with ribavirin

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

4.4 Special warnings and precautions for use

Psychiatric and central nervous system (CNS)

Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during IntronA therapy, and even after treatment discontinuation mainly during the 6-month follow-up period. Among children and adolescents treated with IntronA in combination with ribavirin, 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 adult patients, children and adolescents experienced other psychiatric adverse events (e.g., depression, emotional lability, and somnolence). Other CNS effects including aggressive behaviour (sometimes directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of mental status have been observed with alpha interferons. Patients should be closely monitored for any signs or symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of these undesirable effects must be borne in mind by the prescribing physician and the need for adequate therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal or homicidal ideation is identified, it is recommended that treatment with IntronA be discontinued, and the 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 severe psychiatric conditions, this should only be initiated after having ensured appropriate individualised diagnostic and therapeutic management of the psychiatric condition.

• – The use of interferon alfa-2b in children and adolescents with existence of or history of severe psychiatric 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 an increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders when 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 carefully assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach including a mental health care provider or addiction specialist should be considered to evaluate, treat and follow the patient. Patients should be closely monitored during therapy and even after treatment discontinuation. Early intervention for re-emergence or development of psychiatric disorders and substance 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 to 48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common (see sections 4.8 and 5.1). The longer term data available in children treated with the combination therapy with standard interferon/ri­bavirin are also indicative of substantial growth retardation (> 15 percentile decrease in height percentile as compared to baseline) in 21 % of children (n=20) despite being off treatment for more than 5 years. Final adult height was available for 14 of those children and demonstrated that 12 continued to show height deficits > 15 percentiles, 10 to 12 years after the end of treatment.

Case by case benefit/risk assessment in children

The expected benefit of treatment should be carefully weighed against the safety findings observed for children 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 resulted in reduced final adult height in some patients.

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

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

Hypersensitivity reactions

Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstric­tion, anaphylaxis) to interferon 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 necessitate interruption 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 in some cases, termination of IntronA therapy. IntronA increases the risk of liver decompensation and death in patients with cirrhosis.

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

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

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

Hypotension

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

Need for adequate hydration

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

Pyrexia

While pyrexia may be associated with the flu-like syndrome reported commonly during interferon therapy, 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 a history of pulmonary disease (e.g., chronic obstructive pulmonary disease) or diabetes mellitus prone to 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 been observed rarely in interferon alpha treated patients, including those treated with IntronA. The aetiology 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). Any patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function impairment, 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 interferon alpha, 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 to be associated with resolution of pulmonary adverse events.

Ocular adverse events

Ocular adverse events (see section 4.8) including retinal haemorrhages, cotton wool spots, serous retinal detachment, and retinal artery or vein obstruction have been reported in rare instances after treatment with alpha interferons. All patients should have a baseline eye examination. Any patient complaining of changes in visual acuity or visual fields, or reporting other ophthalmologic symptoms during treatment with IntronA, must have a prompt and complete eye examination. Periodic visual examinations during IntronA therapy are recommended particularly in patients with disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of IntronA should 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 in some patients, usually elderly, treated at higher doses. While these effects are generally reversible, in a few patients full resolution took up to three weeks. Very rarely, seizures have occurred with high doses of IntronA.

Patients with pre-existing cardiac abnormalities

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

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 justifies the potential risk.

Kidney and liver graft rejection

Preliminary data indicates that interferon alpha therapy may be associated with an increased rate of kidney 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 treatment with alpha interferons. Patients predisposed to the development of autoimmune disorders may be at increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also section 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 chronic hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment should 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 and duration), which may be life-threatening or fatal as a result of the concomitantly administered medicinal product. The most commonly reported potentially life-threatening or fatal adverse events include mucositis, diarrhoea, neutropaenia, renal impairment, and electrolyte disturbance. Because of the risk of increased toxicity, careful adjustments of doses are required for IntronA and for the concomitant chemotherapeutic agents (see section 4.5). When IntronA is used with hydroxyurea, the frequency 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 with chronic 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 to commencing treatment.

Monotherapy

Infrequently, adult patients treated for chronic hepatitis C with IntronA developed thyroid abnormalities, either hypothyroidism or hyperthyroidism. In clinical trials using IntronA therapy, 2.8 % patients overall developed thyroid abnormalities. The abnormalities were controlled by conventional therapy for thyroid dysfunction. The mechanism by which IntronA may alter thyroid status 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 that time must be treated with conventional therapy. IntronA treatment may be initiated if TSH levels can be 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 the presence of thyroid dysfunction, IntronA treatment may be continued if TSH levels can be maintained in the normal range by medication. Discontinuation of IntronA therapy has not reversed thyroid dysfunction occurring during treatment (also see Thyroid supplemental monitoring specific for children and adolescents).

Thyroid supplemental monitoring specific for children and adolescents

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

HCV/HIV Coinfection

Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of developing lactic acidosis. Caution should be used when adding IntronA and ribavirin to HAART therapy (see ribavirin SPC). Patients treated with IntronA and ribavirin combination therapy and zidovudine could be at increased risk of developing anaemia.

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

HCV/HBV Coinfection

Cases of hepatitis B re-activation (some with severe consequences) have been reported in patients coinfected with hepatitis B and C viruses treated with interferon. The frequency of such re-activation appears 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 current clinical guidelines.

Dental and periodontal disorders

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

Laboratory T ests

Standard haematological tests and blood chemistries (complete blood count and differential, platelet count, electrolytes, liver enzymes, serum protein, serum bilirubin and serum creatinine) are to be conducted 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 to greater than or equal to 2 times baseline, IntronA therapy may be continued unless signs and symptoms of liver failure are observed. During ALT flare, the following liver function tests must be monitored 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 and differential must be monitored weekly during the induction phase of therapy and monthly during the maintenance 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 0.5 mL, i.e., essentially „sodium-free“.

Traceability

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

4.5 Interaction with other medicinal products and other forms of interaction

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. Caution must be exercised when administering IntronA in combination with other potentially myelosuppressive agents.

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

Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alpha treated patients, including those treated with IntronA. The aetiology 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 and duration) (see section 4.4).

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

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

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/con­traception in males and females

Women of childbearing potential have to use effective contraception during treatment. Decreased serum estradiol and progesterone concentrations have been reported in women treated with human leukocyte 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 be taken to avoid pregnancy in female patients or in partners of male patients taking IntronA in combination with ribavirin. Females of childbearing potential must use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients or their female partners must use an effective contraceptive during treatment and for 7 months after treatment has been concluded (see ribavirin SPC).

Pregnancy

There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. IntronA is 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.

Breast-feeding

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 prior to initiation of treatment.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

See ribavirin SPC for ribavirin-related undesirable effects if IntronA is to be administered in combination 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 (from 6 MIU/m2/week in hairy cell leukaemia up to 100 MIU/m2/week in melanoma), the most commonly reported undesirable effects were pyrexia, fatigue, headache and myalgia. Pyrexia and fatigue were often reversible within 72 hours of interruption or cessation of treatment.

Adults

In clinical trials conducted in the hepatitis C population, patients were treated with IntronA alone or in combination with ribavirin for one year. All patients in these trials received 3 MIU of IntronA three times a week. In Table 1 the frequency of patients reporting (treatment related) undesirable effects is presented from clinical trials in naïve patients treated for one year. Severity was generally mild to moderate. The adverse reactions listed in Table 1 are based on experience from clinical trials and post-marketing. Within the organ system classes, adverse reactions are listed under headings of frequency 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.

*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 is administered in other indications, with some anticipated dose-related increases in incidence. For example, in a trial of high-dose adjuvant IntronA treatment in patients with melanoma, incidences of fatigue, pyrexia, myalgia, neutropaenia/a­naemia, anorexia, nausea and vomiting, diarrhoea, chills, flulike symptoms, depression, alopecia, altered taste, and dizziness were greater than in the hepatitis C trials. Severity also increased with high dose therapy (WHO Grade 3 and 4, in 66 % and 14 % of patients, respectively), in comparison with the mild to moderate severity usually associated with lower doses. Undesirable effects were usually managed by dose adjustment.

Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with pre-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 patients without 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 with interferon alfa.

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

Clinically significant laboratory abnormalities, most frequently occurring at doses greater than 10 million IU daily, include reduction in granulocyte and white blood cell counts; decreases in haemoglobin level and platelet count; increases in alkaline phosphatase, LDH, serum creatinine and serum urea nitrogen levels. Moderate and usually reversible pancytopenia has been reported. Increase in serum ALT/AST (SGPT/SGOT) levels have been noted as an abnormality in some non-hepatitis subjects 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 due to adverse reactions. In general, the adverse reaction profile in the limited children and adolescent population studied was similar to that observed in adults, although there is a paediatric- specific concern regarding growth inhibition as decrease in height percentile (mean percentile decrease of 9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of 44th percentile, which was below the median of the normative population and less than their mean baseline height (48th percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from the start of treatment to the end of long-term follow-up (up to 5 years). Final adult height was available for 14 of those children and demonstrated that 12 continued to show height deficits > 15 percentiles, 10 to 12 years after the end of treatment. During combination therapy for up to 48 weeks with IntronA and ribavirin, growth inhibition was observed that resulted in reduced final adult height in some patients. In particular, decrease in mean height percentile from baseline to the end of the longterm 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 adult patients, 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 adolescents compared to adult patients. Dose modifications were required in 30 % of patients, most commonly for anaemia and neutropaenia.

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

§See section 4.4

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in

4.9 Overdose

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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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 of approximately 19,300 daltons. It is obtained from a clone of E. coli, which harbours a genetically engineered 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-2b protein corresponding to 2.6 x l08 IU. International Units are determined by comparison of the activity of the recombinant interferon alfa-2b with the activity of the international reference preparation of human leukocyte interferon established by the World Health Organisation.

The interferons are a family of small protein molecules with molecular weights of approximately 15,000 to 21,000 daltons. They are produced and secreted by cells in response to viral infections or various 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 contain several different molecular species of interferon. More than 14 genetically distinct human alpha interferons 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 highly asymmetric proteins. They exhibit selectivity for human but not murine interferons, suggesting species specificity. Studies with other interferons have demonstrated species specificity. However, certain monkey species, eg, rhesus monkeys, are susceptible to pharmacodynamic stimulation upon exposure to human type 1 interferons.

The results of several studies suggest that, once bound to the cell membrane, interferon initiates a complex sequence of intracellular events that include the induction of certain enzymes. It is thought that 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 and such immunomodulating activities as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells. Any or all of these activities may contribute to interferon's the­rapeutic effects.

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

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

Chronic hepatitis B

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

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

Chronic hepatitis C in adult patients

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

IntronA alone or in combination with ribavirin has been studied in 4 randomised Phase III clinical trials 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 virologic response, 6 months after the end of treatment. Eligible patients for these trials had chronic hepatitis C confirmed by a positive HCV-RNA polymerase chain reaction assay (PCR) (> 100 copies/mL), a liver biopsy consistent with a histologic diagnosis of chronic hepatitis with no other cause for the chronic hepatitis, and abnormal serum ALT.

IntronA was administered at a dose of 3 MIU 3 times a week as monotherapy or in combination with ribavirin. The majority of patients in these clinical trials were treated for one year. All patients were followed for an additional 6 months after the end of treatment for the determination of sustained virologic 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 for the treatment of chronic hepatitis C in naïve patients. HCV genotype and baseline virus load are prognostic factors which are known to affect response rates. The increased response rate to the combination of IntronA + ribavirin, compared with IntronA alone, is maintained across all subgroups. The relative benefit of combination therapy with IntronA + ribavirin is particularly significant in the most difficult 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 who received IntronA in combination with ribavirin and received > 80 % of their treatment had a higher sustained response 6 months after 1 year of treatment than those who took < 80 % of their treatment (56 % vs. 32 % in trial C/I98–580).

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 received pegylated interferon alfa-2b with ribavirin. The response to treatment in both of these trials is presented in Table 4. Study 1 (RIBAVIC; P01017) was a randomized, multicentre study which enrolled 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 pg/kg/week) plus ribavirin (800 mg/day) or IntronA (3 MIU TIW) plus ribavirin (800 mg/day) for 48 weeks with a follow-up period of 6 months. Study 2 (P02080) was a randomized, single centre study that enrolled 95 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 pg /week based on weight) 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 period of 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 with ribavirin versus pegylated interferon alfa-2b in combination with ribavirin in HCV/HIV co-infected patients

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 gg/week pegylated interferon alfa-2b and subjects > 75 kg received 150 gg/week pegylated interferon 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 IntronA monotherapy or in combination with ribavirin. In these patients, the addition of ribavirin to IntronA increased by as much as 10-fold the efficacy of IntronA used alone in the treatment of chronic hepatitis 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 was sustained 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 virologic response and assess the impact of continued viral negativity on clinical outcomes. 462 patients completed at least 5 years of long-term follow-up and only 12 sustained responders' out of 492 relapsed during this study.

The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 97 % with a 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 patients with 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 and ribavirin and one with pegylated interferon and ribavirin. Patients who received IntronA plus ribavirin were 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 in two multicentre trials and received IntronA 3 MIU/m2 3 times a week plus ribavirin 15 mg/kg per day for 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 mainly consisted in children with mild to moderate hepatitis C. In the two multicentre trials sustained virological response rates in children and adolescents were similar to those in adults. Due to the lack of data in these two multicentre trials for children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of ribavirin and interferon alfa-2b needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8).

Study results are summarized in Table 5.

Number (%) of patients

aDefined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during followup period

Long-term efficacy data

A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C patients after treatment in the standard interferon multicentre trials. Seventy percent (68/97) of all enrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but one of the paediatric subjects remained sustained virologic responders during long-term follow-up after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at follow-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 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 patients with cirrhosis (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 chronic hepatitis C and detectable HCV-RNA were treated with peginterferon alfa-2b 60 pg/m2 plus ribavirin 15 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 received treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and

63 % < 12 years of age. The population enrolled mainly consisted of children with mild to moderate hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of peginterferon alfa-2b with ribavirin needs to be carefully considered in this population (see peginterferon alfa-2b and ribavirin SPCs section 4.4). The study results are summarized in Table 6.

a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment, lower limit of

detection=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 with genotype 3 and high viral load (> 600,000 lU/mL) were to receive 48 weeks of treatment.

5.2 Pharmacokinetic properties

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

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

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

Interferon neutralising factor assays were performed on serum samples of patients who received IntronA in Schering-Plough monitored clinical trials. Interferon neutralising factors are antibodies which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors developing 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 of response or any other autoimmune phenomenon. In patients with hepatitis, no loss of response was observed apparently due to the low titres.

Children and adolescent population

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

*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 is approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female partner after sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentration of ribavirin.

5.3 Preclinical safety data

Although interferon is generally recognised as being species specific, toxicity studies in animals were conducted. Injections of human recombinant interferon alfa-2b for up to three months have shown no evidence of toxicity in mice, rats, and rabbits. Daily dosing of cynomolgus monkeys with 20 × 10 IU/kg/day for 3 months caused no remarkable toxicity. Toxicity was demonstrated in monkeys given 100 × 10 IU/kg/day for 3 months.

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

Results of animal reproduction studies indicate that recombinant interferon alfa-2b was not teratogenic in rats or rabbits, nor did it adversely affect pregnancy, foetal development or reproductive capacity in offspring of treated rats. Interferon alfa-2b has been shown to have abortifacient effects in Macaca mulatta (rhesus monkeys) at 90 and 180 times the recommended intramuscular or subcutaneous dose of 2 million IU/m2. Abortion was observed in all dose groups (7.5 million, 15 million and 30 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 of 2 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 interferon alfa-2b on growth, development, sexual maturation, and behaviour. Preclinical juvenile toxicity results have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with ribavirin (see section 5.3 of Rebetol SPC if IntronA is to be administered in combination with ribavirin).

Sodium chloride

M-cresol

Polysorbate 80

Water for injections

6.2 Incompatibilities

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

6.3 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 sevenday 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.

6.4 Special precautions for storage

Store in a refrigerator (2°C – 8°C).

Do not freeze.

For storage conditions of the medicinal product, see section 6.3.

6.5 Nature and contents of container

0.5 mL of solution (corresponding to 3 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: - Pack of 1 vial - Pack of 1 vial, 1 injection syringe of 1 mL, 1 injection needle and 1 cleansing swab

• - Pack of 6 vials, 6 injection syringes of 1 mL, 6 injection needles and 6 cleansing swabs

• - Pack of 12 vials, 12 injection syringes of 1 mL, 12 injection needles and 12 cleansing swabs Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme B.V.

Waarderweg 39

2031 BN Haarlem

The Netherlands

8. MARKETING AUTHORISATION NUMBERS

EU/1/99/127/011

EU/1/99/127/012

EU/1/99/127/013

EU/1/99/127/014

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 9 March 2000

Date of latest renewal: 9 March 2010