Urifron

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.

Contraindications

- 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.

- 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 Urifron 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 Urifron is to be administered in combination with ribavirin in patients with chronic hepatitis C.

Undesirable effects

See ribavirin SPC for ribavirin-related undesirable effects if Urifron 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 Urifron alone or in combination with ribavirin for one year. All patients in these trials received 3 MIU of Urifron 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 Urifron alone

§

#Class label for interferon products, see below Pulmonary arterial hypertension

These undesirable effects have also been reported with Urifron alone.

The undesirable effects seen with hepatitis C are representative of those reported when Urifron is administered in other indications, with some anticipated dose-related increases in incidence. For example, in a trial of high-dose adjuvant Urifron treatment in patients with melanoma, incidences of fatigue, pyrexia, myalgia, neutropaenia/anaemia, anorexia, nausea and vomiting, diarrhoea, chills, flu-like symptoms, depression, alopecia, altered taste, and dizziness were greater than in the hepatitis 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. Cardiomyopathy, that may be reversible upon discontinuation of interferon alpha, has been reported rarely in patients without prior evidence of cardiac disease.

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.

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 Urifron 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 long-term follow-up was most prominent in prepubertal age children.

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). 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.

§

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 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.

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.

Urifron plus ribavirin

Pharmacotherapeutic group

Pharmacodynamic properties

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

Urifron 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 Urifron 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. Urifron 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).

Urifron 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 Urifron 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.

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

Co-administration of Urifron with ribavirin increased the efficacy of Urifron 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 Urifron + ribavirin, compared with Urifron alone, is maintained across all subgroups. The relative benefit of combination therapy with Urifron + 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 Urifron 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 Urifron (3 MIU 3 times a week)

I/R Urifron (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 Urifron 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 µg/kg/week) plus ribavirin (800 mg/day) or Urifron (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 µg /week based on weight) plus ribavirin (800-1,200 mg/day based on weight) or Urifron (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.

Relapse patients

A total of 345 interferon alpha relapse patients were treated in two clinical trials with Urifron monotherapy or in combination with ribavirin. In these patients, the addition of ribavirin to Urifron increased by as much as 10-fold the efficacy of Urifron 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 Urifron 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 Urifron 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.

Study results are summarized in Table 5.

*Number (%) of patients

a Defined as HCV-RNA below limit of detection using a research based RT-PCR assay at end of treatment and during follow-up 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 μg/m2 plus ribavirin 15 mg/kg per day once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load.). The study results are summarized in Table 6.

Pharmacokinetic properties

The pharmacokinetics of Urifron 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 Urifron 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 Urifron 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 Urifron and ribavirin (dose-normalized) are similar in adults and children or adolescents.

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

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.

Special warnings and precautions for use

Hypersensitivity reactions

Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) to interferon alfa-2b have been observed rarely during Urifron 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 Urifron therapy. Urifron increases the risk of liver decompensation and death in patients with cirrhosis.

Discontinue treatment with Urifron 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 Urifron 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 Urifron 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 Urifron 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

Urifron 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 Urifron. 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. 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 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 Urifron, must have a prompt and complete eye examination. Periodic visual examinations during Urifron therapy are recommended particularly in patients with disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of Urifron 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 Urifron.

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 Urifron 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 Urifron 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 Urifron 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

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.

Concomitant chemotherapy

Administration of Urifron 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 Urifron and for the concomitant chemotherapeutic agents. When Urifron 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 Urifron 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 Urifron developed thyroid abnormalities, either hypothyroidism or hyperthyroidism. In clinical trials using Urifron therapy, 2.8 % patients overall developed thyroid abnormalities. The abnormalities were controlled by conventional therapy for thyroid dysfunction. The mechanism by which Urifron may alter thyroid status is unknown. Prior to initiation of Urifron 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. Urifron treatment may be initiated if TSH levels can be maintained in the normal range by medication. Determine TSH levels if, during the course of Urifron therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the presence of thyroid dysfunction, Urifron treatment may be continued if TSH levels can be maintained in the normal range by medication. Discontinuation of Urifron 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 Urifron therapy, TSH levels must be evaluated and any thyroid abnormality detected at that time must be treated with conventional therapy. Urifron 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 Urifron and ribavirin to HAART therapy (see ribavirin SPC). Patients treated with Urifron 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 co-infected 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 Urifron 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 Urifron 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 Urifron.

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 Urifron therapy to greater than or equal to 2 times baseline, Urifron 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.

Important information about some of the ingredients of Urifron

Urifron 10 million IU/mL solution for injection or infusion

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

Urifron 25 million IU/2.5 mL solution for injection or infusion

This medicinal product contains less than 1 mmol sodium (23 mg) per 2.5 mL, i.e., essentially “sodium-free”.

Effects on ability to drive and use machines

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

Dosage (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 Urifron 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 Urifron. 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 Urifron therapy.

Chronic hepatitis C

Adults

Urifron 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

Urifron 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)

Urifron 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 Urifron in combination with ribavirin for 6 months.

Naïve patients (adults)

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

- Urifron 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 Urifron 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).

- Urifron alone

The optimal duration of therapy with Urifron 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 Urifron 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 Urifron 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 Urifron/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 Urifron 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 Urifron is 4 to 5 million IU/m2 administered daily subcutaneously. Some patients have been shown to benefit from Urifron 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 Urifron (4 to 5 million IU/m2 daily) to maintain haematological remission.

Urifron 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. 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.

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

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.

Urifron 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 Urifron”).

Preparation of Urifron 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 Urifron 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 Urifron.

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

Urifron 10 million IU/mL solution for injection or infusion

Any unused medicinal product must be discarded after withdrawal of the dose and in accordance with local requirements.