VIRAFERON Powder and solvent for solution for injection Ref.[50279] Active ingredients: Interferon, alfa-2b

For all patients

Psychiatric and central nervous system (CNS): Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during Viraferon therapy, and even after treatment discontinuation mainly during the 6-month follow-up periodand in the follow-up period. Among children and adolescents treated with Viraferon 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), 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 ideation is identified, it is recommended that treatment with Viraferon be discontinued, and the patient followed, with psychiatric intervention as appropriate.

Patients with existence of or history of severe psychiatric conditions

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

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

Moderate to severe adverse experiences may require modification of the patient’s dosage regimen, or in some cases, termination of Viraferon therapy. Any patient developing liver function abnormalities during treatment with Viraferon must be monitored closely and treatment discontinued if signs and symptoms progress.

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

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

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

Viraferon 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 infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alpha treated patients, including those treated with Viraferon. 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 fever, 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 (see section 4.8) including retinal haemorrhages, cotton wool spots, and retinal artery or vein obstruction have been reported in rare instance 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 Viraferon, must have a prompt and complete eye examination. Periodic visual examinations during Viraferon therapy are recommended particularly in patients with disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of Viraferon should be considered in patients who develop new or worsening ophthalmological disorders.

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 Viraferon.

Adult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders, who require Viraferon 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 Viraferon therapy. There are no data in children or adolescents with a history of cardiac disease.

Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed. Monitoring of lipid levels is, therefore, recommended.

Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of Viraferon in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies the potential risk.

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.

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).

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

Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma-derived albumin.

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

There are no reports of virus transmissions with albumin manufactured to European Pharmacopoeia specifications by established processes.

It is strongly recommended that every time that Viraferon is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Chronic Hepatitis C

Combination therapy with ribavirin: Also see ribavirin SPC if Viraferon 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 Viraferon developed thyroid abnormalities, either hypothyroidism or hyperthyroidism. In clinical trials using Viraferon therapy, 2.8% patients overall developed thyroid abnormalities. The abnormalities were controlled by conventional therapy for thyroid dysfunction. The mechanism by which Viraferon may alter thyroid status is unknown. Prior to initiation of Viraferon 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. Viraferon treatment may be initiated if TSH levels can be maintained in the normal range by medication. Determine TSH levels if, during the course of Viraferon therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the presence of thyroid dysfunction, Viraferon treatment may be continued if TSH levels can be maintained in the normal range by medication. Discontinuation of Viraferon therapy has not reversed thyroid dysfunction occurring during treatment (also see Children and adolescents, Thyroid monitoring).

Supplemental monitoring specific for children and adolescents

Thyroid Monitoring: Approximately 12% of children treated with interferon alfa-2b and ribavirin developed increase in TSH. Another 4% had a transient decrease below the lower limit of normal. Prior to initiation of Viraferon therapy, TSH levels must be evaluated and any thyroid abnormality detected at that time must be treated with conventional therapy. Viraferon 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).

Growth and Development: During a 1-year course of therapy there was a decrease in the rate of linear growth (mean percentile decrease of 9%) and a decrease in the rate of weight gain (mean percentile decrease of 13%). A general reversal of these trends was noted during the 6 months follow-up post treatment. However, based on interim data from a long-term follow-up study, 12 (14%) of 84 children had a >15 percentile decrease in rate of linear growth, of whom 5 (6%) children had a >30 percentile decrease despite being off treatment for more than 1 year. In addition, preclicinal juvenile toxicity results have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with ribavirin (see section 5.3). Therefore, the risk/benefit of the combined use of interferon alfa-2b and ribavirin should be assessed in young children prior to the initiation of therapy. Physicians are advised to monitor the growth of children taking ribavirin in combination with interferon alfa-2b. There are no data on long term effects on growth and development and on sexual maturation.

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 Viraferon and ribavirin to HAART therapy (see ribavirin SPC). Patients treated with Viraferon 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.

Dental and periodontal disorders: Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving Viraferon 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 Viraferon 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 Tests

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 Viraferon.

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 Viraferon therapy to greater than or equal to 2 times baseline, Viraferon therapy may be continued unless signs and symptoms of liver failure are observed. During ALT flare, liver function tests: ALT, prothrombin time, alkaline phosphatase, albumin and bilirubin must be monitored at two-week intervals.

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

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

Interactions between Viraferon and other medicinal products have not been fully evaluated. Caution must be exercised when administering Viraferon 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 dosage 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 Viraferon. 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).

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

Women of childbearing potential have to use effective contraception during treatment. Viraferon must be used with caution in fertile men. Decreased serum estradiol and progesterone concentrations have been reported in women treated with human leukocyte interferon.

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. Viraferon is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

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.

Combination therapy with ribavirin: Ribavirin causes serious birth defects when administered during pregnancy. Ribavirin therapy is contraindicated in women who are pregnant. Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking Viraferon in combination with ribavirin. Females of childbearing potential and their partners must each use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients and their female partners must each use an effective contraceptive during treatment and for 7 months after treatment has been concluded (see ribavirin SPC).

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

See ribavirin SPC for ribavirin-related undesirable effects if Viraferon 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 fever, fatigue, headache and myalgia. Fever and fatigue were often reversible within 72 hours of interruption or cessation of treatment.

In clinical trials conducted in the hepatitis C population, patients were treated with Viraferon alone or in combination with ribavirin for one year. All patients in these trials received 3 MIU of Viraferon 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, <1/10); rarely (≥1/10,000, <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 Viraferon alone or in combination with ribavirin:

^* These events were only common with Viraferon alone
^§ See section 4.4

These undesirable effects have also been reported with Viraferon alone.

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).

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. 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.

For safety with respect to transmissible agents, see section 4.4.

Paediatric population

Children and adolescents – Chronic Hepatitis C

In clinical trials of 118 children or adolescents 3 to 16 years of age, 6% discontinued therapy due to adverse events. In general, the adverse event profile in the limited paediatric population studied was similar to that observed in adults, although there is a paediatric specific concern regarding growth inhibition as decrease in height (mean percentile decrease of growth velocity of 9%) and weight (mean percentile decrease of 13%) percentile were observed during treatment (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, fever, 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 paediatric 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.

Table 2. Adverse reactions very commonly and commonly reported in paediatric clinical trials Very common (≥1/10) - Common (≥1/100, <1/10):

^§ See section 4.4

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