Viraferon 1 million IU/ml powder and solvent for solution for injection
One vial of powder contains 1 million IU of interferon alfa-2b produced in E.coli by recombinant DNA technology. After reconstitution, 1 ml contains 1 million IU of interferon alfa-2b. For a full list of excipients, see section 6.1.
Powder and solvent for solution for injection White to cream coloured powder. Clear and colourless solvent.
Chronic Hepatitis B
: Treatment of adult patients with chronic hepatitis B associated with evidence of hepatitis B viral replication (presence of HBV-DNA and HBeAg), elevated alanine aminotransferase (ALT) and histologically proven active liver inflammation and/or fibrosis.
Chronic Hepatitis C:
Adult patients:
Viraferon is indicated for the treatment of adult patients with chronic hepatitis C who have elevated transaminases without liver decompensation and who are positive for serum HCV-RNA or anti-HCV (see section 4.4). The best way to use Viraferon in this indication is in combination with ribavirin.
Chidren and adolescents:
Viraferon is intended for use, in a combination regimen with ribavirin, for the treatment of children and adolescents 3 years of age and older, who have chronic hepatitis C, not previously treated, without liver decompensation, and who are positive for serum HCV-RNA. The decision to treat should be made on a case by case basis, taking into account any evidence of disease progression such as hepatic inflammation and fibrosis, as well as prognostic factors for response, HCV genotype and viral load. The expected benefit of treatment should be weighed against the safety findings observed for paediatric subjects in the clinical trials (see sections 4.4, 4.8 and 5.1).
Treatment must be initiated by a physician experienced in the management of the disease. Not all dosage forms and strengths are appropriate for some indications. Please make sure to select an appropriate dosage form and strength.
If adverse events develop during the course of treatment with Viraferon for any indication, modify the dosage or discontinue therapy temporarily until the adverse events abate. If persistent or recurrent intolerance develops following adequate dosage adjustment, or disease progresses, discontinue treatment with Viraferon. At the discretion of the physician, the patient may self-administer the dose for maintenance dosage regimens administered subcutaneously.
Chronic Hepatitis B
: The recommended dosage 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 Viraferon therapy.
Chronic Hepatitis C
: Viraferon 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: Interferon alfa-2b 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 capsule SPC for dose of ribavirin capsules and dosage modification guidelines for combination therapy. For paediatric patients who weigh < 47 kg or cannot swallow capsules, see ribavirin oral solution SPC).
Relapse patients (adults):
Viraferon 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 Viraferon in combination with ribavirin for 6 months.
Naive patients:
Adults:
The efficacy of Viraferon is enhanced when given in combination with ribavirin. Viraferon should be given alone mainly in case of intolerance or contraindication to ribavirin.
Viraferon 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 Viraferon 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). Viraferon alone:
The optimal duration of therapy with Viraferon 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 Viraferon 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.
Children and adolescents:
The efficacy and safety of Viraferon in combination with ribavirin has been studied in children and adolescents who have not been previously treated for chronic hepatitis C.
Genotype 1:
The recommended duration of treatment is one year. Patients who fail to achieve virological response at 12 weeks are highly unlikely to become sustained virological responders (negative predictive value 96 %). Virological response is defined as absence of detectable HCV-RNA at Week 12. Treatment should be discontinued in these patients.
Genotype 2/3
: The recommended duration of treatment is 24 weeks.
Virological responses after 1 year of treatment and 6 months of follow-up were 36 % for genotype 1 and 81 % for genotype 2/3/4. Viraferon may be administered using either glass or plastic disposable injection syringes.
Hypersensitivity to the active substance or to any of the excipients.
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.
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 interferon alfa-2b is to be administered in combination with ribavirin in patients with chronic hepatitis C.
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 naive 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 | |
| System Organ Class | Adverse Reactions |
| Infections and infestations Very common: Common: Rarely: | Pharyngitis *, infection viral * Bronchitis, sinusitis, herpes simplex (resistance), rhinitis Pneumonia SS |
| Blood and lymphatic system disorders Very common: Common: Very rarely:Not known : | Leukopaenia Thrombocytopaenia, lymphadenopathy, lymphopenia Aplastic anaemia Pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura |
| Immune system disorders SS Very rarely: Not known: | Sarcoidosis, exacerbation of sarcoidosis Systemic lupus erythematosus, vasculitis, rheumatoid arthritis (new or aggravated), Vogt-Koyanagi-Harada syndrome, acute hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, anaphylaxis SS |
| Endocrine disorders Common: Very rarely: | Hypothyroidism SS , hyperthyroidism SS Diabetes, aggravated diabetes |
| Metabolism and nutrition disorders Very common: Common: Very rarely: | Anorexia Hypocalcaemia, dehydration, hyperuricemia, thirst Hyperglycaemia, hypertriglyceridaemia SS , increased appetite |
| Psychiatric disorders SS | |
| Very common: Common: Rarely: Very rarely: Not known: | Depression, insomnia, anxiety, emotional lability *, agitation, nervousness Confusion, sleep disorder, libido decreased Suicide ideation Suicide, suicide attempts, aggressive behaviour (sometimes directed against others), psychosis including hallucinations Mental status change SS |
| Nervous system disorders SS Very common: Common: Very rarely: Not known: | Dizziness, headache, concentration impaired, mouth dry Tremor, paresthesia, hypoesthesia, migraine, flushing, somnolence, taste perversion Cerebrovascular haemorrhage, cerbrovascular ischaemia, seizure, impaired consciousness, encephalopathy, neuropathy, polyneuropathy Mononeuropathies, coma SS |
| Eye disorders Very common: Common: Rarely: | Vision blurred Conjunctivitis, vision abnormal, lacrimal gland disorder, eye pain Retinal haemorrhages SS , retinopathies (including macular oedema), retinal artery or vein obstruction SS , optic neuritis, papilloedema, loss of visual acuity or visual field, cotton- wool spots SS |
| Ear and labyrinth Common: Very rarely: | Vertigo, tinnitus Hearing loss, hearing disorder |
| Cardiac disorders Common: Rarely: Very rarely: Not known: | Palpitation, tachycardia Cardiomyopathy Myocardial infarction, cardiac ischaemia Arrhythmia |
| Vascular disorders Common: Very rarely: | Hypertension Peripheral ischaemia, hypotension SS |
| Respiratory, thoracic and mediastinal disorders Very common: Common: Very rarely: | Dyspnoea *, coughing * Epistaxis, respiratory disorder, nasal congestion, rhinorrhea, cough nonproductive Pulmonary infiltrates SS , pneumonitis SS |
| Gastrointestinal disorders Very common: Common: Very rarely: Not known: | Nausea/vomiting, abdominal pain, diarrhoea, stomatitis, dyspepsia Stomatitis ulcerative, right upper quadrant pain, glossitis, gingivitis, constipation, loose stools Pancreatitis, ischaemic colitis, ulcerative colitis, gingival bleeding Periodontal disorder NOS, dental disorder NOS SS |
| Hepatobiliary disorders Common: Very rarely: | Hepatomegaly Hepatotoxicity, (including fatality) |
| Skin and subcutaneous tissue disorders Very common: Common: | Alopecia, pruritus *, skin dry *, rash *, sweating increased Psoriasis (new or aggravated) SS , rash maculopapular, rash |
| Very rarely: | erythematous, eczema, erythema, skin disorder Stevens Johnson syndrome, toxic epidermal necrolysis, erythema multiforme |
| Musculoskeletal and connective tissue disorders Very common: Common: Very rarely: | Myalgia, arthralgia, musculoskeletal pain Arthritis Rhabdomyolysis, myositis, leg cramps, back pain |
| Renal and urinary disorders Common: Very rarely: | Micturition frequency Renal failure, renal insufficiency, nephrotic syndrome |
| Reproductive system and breast disorders Common: | Amenorrhea, breast pain, dysmenorrhea, menorrhagia, menstrual disorder, vaginal disorder |
| General disorders and administration site conditions Very common: Common: Very rarely: | Injection site inflammation, injection site reaction *, fatigue, rigors, fever SS , flu-like symptoms SS , asthenia, irritability, chest pain, malaise Injection site pain Injection site necrosis, face oedema |
| Investigations Very common: | Weight decrease |
*These events were only common with Viraferon alone
SS
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) | |
| System Organ Class | Adverse Reactions |
| Infection and infestations Very common: Common: | Viral infection, pharyngitis Fungal infection, bacterial infection, pulmonary infection, otitis media, tooth abscess, herpes simplex, urinary tract infection, vaginitis, gastroenteritis |
| Neoplasms benign, malignant and unspecified (including cysts and polyps) Common: | Neoplasm (unspecified) |
| Blood and lymphatic system disorders Very common: Common: | Anaemia, neutropaenia Thrombocytopaenia, lymphadenopathy |
| Endocrine disorders Very common: Common: | Hypothyroidism SS , Hyperthyroidism SS , virilism |
| Metabolism and nutrition disorders Very common: Common: | Anorexia Hypertriglyceridemia SS , hyperuricemia, increased appetite |
| Psychiatric disorders SS Very common: Common: | Depression, emotional lability, insomnia Suicidal ideation, aggressive reaction, confusion, behaviour disorder, agitation, somnambulism, anxiety, nervousness, sleep disorder, abnormal dreaming, apathy |
| Nervous system disorders SS Very common: Common: | Headache, dizziness Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, hyperaesthesia, concentration impaired, somnolence |
| Eye disorders Common: | Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder |
| Vascular disorders Common: | Raynaud's disease, flushing, pallor |
| Respiratory, thoracic and mediastinal disorders Common: | Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal irritation, rhinorrhea, sneezing |
| Gastrointestinal disorders | |
| Very common: Common: | Diarrhoea, vomiting, nausea, abdominal pain Mouth ulceration, stomatitis ulcerative, stomatitis, right upper quadrant pain, dyspepsia, glossitis, gastroesophogeal reflux, rectal disorder, gastrointestinal disorder, constipation, loose stools, toothache, tooth disorder |
| Hepatobiliary disorders Common: | Hepatic function abnormal |
| Skin and subcutaneous tissue disorders Very common: Common: | Alopecia, rash Photosensitivity reaction, maculopapular rash, eczema, acne, skin disorder, nail disorder, skin discolouration, pruritus, dry skin, erythema, bruise, sweating increased |
| Musculoskeletal and connective tissue disorders Very common: | Arthralgia, myalgia, musculoskeletal pain |
| Renal and urinary disorders Common: | Enuresis, micturition disorder, urinary incontinence |
| Reproductive system and breast disorders Common: | Female : amenorrhea, menorrhagia, menstrual disorder, vaginal disorder Male : testicular pain |
| General disorders and administration site conditions Very common: Common: | Injection site inflammation, injection site reaction, fatigue, rigors, fever SS , influenza-like symptoms SS , malaise, irritability Chest pain, asthenia, oedema, injection site pain |
| Investigations Very common: | Growth rate decrease (height and/or weight decrease for age) SS |
| Injury and poisoning Common: | Skin laceration |
SS
See section 4.4
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.
Pharmacotherapeutic group: Immunostimulants, cytokines and immunomodulators, interferons, interferon alfa-2b, ATC code: L03A B05 Viraferon 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 Viraferon 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. Viraferon 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 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 naive patients with a ribavirin dose > 10.6 mg/kg, p < 0.01). Adult patients: Viraferon alone or in combination with ribavirin has been studied in 4 randomised Phase III clinical trials in 2,552 interferon-naive patients with chronic hepatitis C. The trials compared the efficacy of Viraferon 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. Viraferon 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 Viraferon alone or in combination with ribavirin (from two studies) are shown in Table 3. Co-administration of Viraferon with ribavirin increased the efficacy of Viraferon by at least two fold for the treatment of chronic heptatitis C in naive 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 Viraferon + ribavirin, compared with Viraferon alone, is maintained across all subgroups. The relative benefit of combination therapy with Viraferon + 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 Viraferon 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).
| Table 3 Sustained virologic response rates with Viraferon + ribavirin (one year of treatment) by genotype and viral load | |||
| HCV Genotype | I N=503 C95-132/I95-143 | I/R N=505 C95-132/I95-143 | I/R N=505 C/I98-580 |
| All Genotypes | 16 % | 41 % | 47 % |
| Genotype 1 | 9 % | 29 % | 33 % |
| Genotype 1 <= 2 million copies/ml | 25 % | 33 % | 45 % |
| Genotype 1 > 2 million copies/ml | 3 % | 27 % | 29 % |
| Genotype 2/3 | 31 % | 65 % | 79 % |
I Viraferon (3 MIU 3 times a week)
I/R Viraferon (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 Viraferon 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 ug/kg/week) plus ribavirin (800 mg/day) or Viraferon (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 ug /week based on weight) plus ribavirin (800-1,200 mg/day based on weight) or Viraferon (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 Viraferon in combination with ribavirin versus pegylated interferon alfa-2b in combination with ribavirin in HCV/HIV co-infected patients | ||||||
| Study 1 1 | Study 2 2 | |||||
| pegylated interferon alfa-2b (1.5 ug/kg/ week) + ribavirin (800 mg) | Viraferon (3 MIU TIW) + ribavirin (800 mg) | p value a | pegylated interferon alfa-2b (100 or 150 c ug/week) + ribavirin (800- 1,200 mg) d | Viraferon (3 MIU TIW) + ribavirin (800- 1,200 mg) d | p value b | |
| All | 27 % (56/205) | 20 % (41/205) | 0.047 | 44 % (23/52) | 21 % (9/43) | 0.017 |
| Genotype 1, 4 | 17 % (21/125) | 6 % (8/129) | 0.006 | 38 % (12/32) | 7 % (2/27) | 0.007 |
| Genotype 2, 3 | 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 ug/week pegylated interferon alfa-2b and subjects >= 75 kg received 150 ug/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.
Carrat F, Bani-Sadr F, Pol S et al. JAMA 2004; 292(23): 2839-2848.
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 Viraferon monotherapy or in combination with ribavirin. In these patients, the addition of ribavirin to Viraferon increased by as much as 10-fold the efficacy of Viraferon 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).
Clinical trials in paediatric patients with chronic hepatitis C:
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 Viraferon 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. Sustained virological response rates in children and adolescents
were similar to those in adults. 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 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.
| Table 5. Virological response in previously untreated paediatric patients | |
| Viraferon 3 MIU/m 2 3 times a week + ribavirin 15 mg/kg/day | |
| Overall Response 1 (n=118) | 54 (46 %) * |
| Genotype 1 (n=92) | 33 (36 %) * |
| Genotype 2/3/4 (n=26) | 21 (81 %) * |
*Number (%) of patients
1. Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up period
The pharmacokinetics of Viraferon 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. Children and adolescents: Multiple-dose pharmacokinetic properties for Viraferon injection and ribavirin capsules in children and adolescents with chronic hepatitis C, between 5 and 16 years of age, are summarized in Table 6. The pharmacokinetics of Viraferon and ribavirin (dose-normalized) are similar in adults and children or adolescents.
| Table 6. Mean (% CV) multiple-dose pharmacokinetic parameters for Viraferon and ribavirin capsules when administered to children or adolescents with chronic hepatitis C | ||
| Parameter | Ribavirin 15 mg/kg/day as 2 divided doses (n = 17) | Viraferon 3 MIU/m 2 3 times a week (n = 54) |
| T m ax (hr) | 1.9 (83) | 5.9 (36) |
| C m ax (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 Viraferon Interferon neutralising factor assays were performed on serum samples of patients who received Viraferon 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.
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 x 106 IU/kg/day for 3 months caused no remarkable toxicity. Toxicity was demonstrated in monkeys 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 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. 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 (see section 4.4 and Rebetol SPC if Viraferon is to be administered in combination with ribavirin).
Glycine, Disodium phosphate anhydrous,
Sodium dihydrogen phosphate monohydrate, Human albumin solution. Solvent: water for injections
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
3 years After reconstitution: An immediate use is recommended. However, the chemical and physical in-use stability has been demonstrated for 24 hours at 25oC.
Store in a refrigerator (2degC - 8degC). Do not freeze. Within its shelf-life, for the purpose of transport and/or to facilitate ambulatory use the non-reconstituted product can be kept at or below 25degC for a period up to four weeks before use. If the product is not reconstituted during the four-week period, it cannot be put back in the refrigerator for a new storage period and must be discarded.
24 mg of powder (corresponding to 1 MIU) in a vial (type I glass), with a stopper (butyl rubber) in a flip-off seal (aluminium) with a bonnet (polypropylene) and 1 ml water for injections in an ampoule (type I glass) with 1 injection syringe, 2 injection needles and 1 cleansing swab. Pack sizes of 1. Not all pack sizes may be marketed.
Not all dosage forms and strengths are appropriate for some indications. Please make sure to select an appropriate dosage form and strength. Reconstitution of Viraferon, powder for solution for injection, for parenteral administration: Viraferon is supplied as a powder at strengths of 1 million IU/ml for single-dose use. Vials must be reconstituted with 1 ml of water for injections. The reconstituted solutions are isotonic for parenteral administration. Proper precautions should be taken during reconstitution to prevent microbial contamination (refer to package leaflet). Using a sterilised injection syringe and injection needle, inject 1 ml water for injections into the vial of Viraferon. Agitate gently to facilitate complete dissolution of the powder. The appropriate dose can then be withdrawn with a sterile injection syringe and injected. As for all parenteral medicinal products, inspect the reconstituted solution visually for particulate matter and discoloration prior to administration. The reconstituted solution should be clear and colourless.
Detailed instructions for the subcutaneous use of the product are provided with the package leaflet (refer to "How to self inject Viraferon"). Any unused product must be discarded after withdrawal of the dose.
SP Europe 73, rue de Stalle B-1180 Bruxelles Belgium
EU/1/99/128/001
Date of first authorisation : 9 March 2000 Date of last renewal : 23 May 2005
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/