Sylatron

Overdose

Doses up to 10.5 times the intended dose have been reported. The maximum daily dose reported is 1,200 µg for one day. In general, the adverse events seen in overdose cases involving Sylatron are consistent with the known safety profile for Sylatron; however, the severity of the events may be increased. Standard methods to increase elimination of the medicinal product, e.g., dialysis, have not been shown to be useful. No specific antidote for Sylatron is available; therefore, symptomatic treatment and close observation of the patient are recommended in cases of overdose. If available, prescribers are advised to consult with a poison control centre (PCC).

Contraindications

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

- A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in the previous six months ;

- Severe, debilitating medical conditions;

- Autoimmune hepatitis or a history of autoimmune disease;

- Severe hepatic dysfunction or decompensated cirrhosis of the liver;

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

- Epilepsy and/or compromised central nervous system (CNS) function;

- HCV/HIV patients with cirrhosis and a Child-Pugh score > 6.

- Combination of Sylatron with telbivudine.

Paediatric population

- Existence of, or history of severe psychiatric condition, particularly severe depression, suicidal ideation or suicidal attempt.

Combination therapy

Also see SmPCs for ribavirin and boceprevir if Sylatron is to be administered in combination therapy in patients with chronic hepatitis C.

Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Undesirable effects

Adults

Tritherapy

Refer to the SmPC for boceprevir.

Bitherapy and monotherapy

Summary of the safety profile

The most common treatment-related adverse reactions reported during clinical trials with Sylatron in combination with ribavirin in adults, seen in more than half of the study subjects, were fatigue, headache, and injection site reaction. Additional adverse reactions reported in more than 25 % of subjects included nausea, chills, insomnia, anaemia, pyrexia, myalgia, asthenia, pain, alopecia, anorexia, weight decreased, depression, rash and irritability. The most frequently reported adverse reactions were mostly mild to moderate in severity and were manageable without the need for modification of doses or discontinuation of therapy. Fatigue, alopecia, pruritus, nausea, anorexia, weight decreased, irritability and insomnia occur at a notably lower rate in patients treated with Sylatron monotherapy compared to those treated with combination therapy (see Table 6).

Tabulated summary of adverse reactions

The following treatment-related adverse reactions were reported in adults in clinical trials or through post-marketing surveillance in patients treated with peginterferon alfa-2b, including Sylatron monotherapy or Sylatron/ribavirin. These reactions are listed in table 6 by system organ class and frequency (very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000) or not known (cannot be estimated from the available data).

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

Table 6 Adverse reactions reported in adults in clinical trials or through post-marketing surveillance in patients treated with peginterferon alfa-2b, including Sylatron monotherapy or Sylatron + ribavirin

*These adverse reactions were common (>1/100 to < 1/10) in clinical trials in patients treated with Sylatron monotherapy.

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

Description of selected adverse reactions in adults

Most cases of neutropenia and thrombocytopenia were mild (WHO grades 1 or 2). There were some cases of more severe neutropenia in patients treated with the recommended doses of Sylatron in combination with ribavirin (WHO grade 3: 39 of 186 [21 %]; and WHO grade 4: 13 of 186 [7 %]).

In a clinical trial, approximately 1.2 % of patients treated with Sylatron or interferon alfa-2b in combination with ribavirin reported life-threatening psychiatric events during treatment. These events included suicidal ideation and attempted suicide.

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.

Ophthalmological disorders that have been reported rarely with alpha interferons include retinopathies (including macular oedema), retinal haemorrhages, retinal artery or vein occlusion, retinal exudates, loss of visual acuity or visual field, optic neuritis, and papilloedema.

HCV/HIV co-infected patients

Summary of the safety profile

For HCV/HIV co-infected patients receiving Sylatron in combination with ribavirin, other undesirable effects (that were not reported in mono-infected patients) which have been reported in the larger studies with a frequency > 5 % were: oral candidiasis (14 %), lipodystrophy acquired (13 %), CD4 lymphocytes decreased (8 %), appetite decreased (8 %), gamma-glutamyltransferase increased (9 %), back pain (5 %), blood amylase increased (6 %), blood lactic acid increased (5 %), cytolytic hepatitis (6 %), lipase increased (6 %) and pain in limb (6 %).

Description of selected adverse reactions

Mitochondrial toxicity

Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI regimen and associated ribavirin for co-HCV infection.

Laboratory values for HCV/HIV co-infected patients

Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HCV/HIV co-infected patients, the majority could be managed by dose modification and rarely required premature discontinuation of treatment. Haematological abnormalities were more frequently reported in patients receiving Sylatron in combination with ribavirin when compared to patients receiving interferon alfa-2b in combination with ribavirin. In Study 1 , decrease in absolute neutrophil count levels below 500 cells/mm3 was observed in 4 % (8/194) of patients and decrease in platelets below 50,000/mm3 was observed in 4 % (8/194) of patients receiving Sylatron in combination with ribavirin. Anaemia (hemoglobin < 9.4 g/dl) was reported in 12 % (23/194) of patients treated with Sylatron in combination with ribavirin.

CD4 lymphocytes decrease

Treatment with Sylatron in combination with ribavirin was associated with decreases in absolute CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. The decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. The use of Sylatron in combination with ribavirin had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data (N= 25) are available in co-infected patients with CD4+ cell counts < 200/µl.

Please refer to the respective SmPCs of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with Sylatron in combination with ribavirin.

Paediatric population

Summary of the safety profile

In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated with combination therapy of Sylatron and ribavirin, dose modifications were required in 25 % of patients, most commonly for anaemia, neutropenia and weight loss. In general, the adverse reactions profile in children and adolescents was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition. During combination therapy for up to 48 weeks with Sylatron and ribavirin, growth inhibition was observed that resulted in reduced height in some patients. Weight loss and growth inhibition were very common during the treatment (at the end of treatment, mean decrease from baseline in weight and height percentile were of 15 percentiles and 8 percentiles, respectively) and growth velocity was inhibited (< 3rd percentile in 70 % of the patients).

At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height percentiles were still of 3 percentiles and 7 percentiles respectively, and 20 % of the children continued to have inhibited growth (growth velocity < 3rd percentile). Ninety-four of 107 subjects enrolled in the 5 year long-term follow-up trial. The effects on growth were less in those subjects treated for 24 weeks than those treated for 48 weeks. From pre-treatment to end of long-term follow-up among subjects treated for 24 or 48 weeks, height-for-age percentiles decreased 1.3 and 9.0 percentiles, respectively. Twenty-four percent of subjects (11/46) treated for 24 weeks and 40 % of subjects (19/48) treated for 48 weeks had a > 15 percentile height-for-age decrease from pre-treatment to the end of the 5 year long-term follow-up compared to pre-treatment baseline percentile. Eleven percent of subjects (5/46) treated for 24 weeks and 13 % of subjects (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline of > 30 height-for-age percentiles to the end of the 5 year long-term follow-up. For weight, pre-treatment to end of long-term follow-up, weight-for-age percentiles decreased 1.3 and 5.5 percentiles among subjects treated for 24 weeks or 48 weeks, respectively. For BMI, pre-treatment to end of long-term follow-up, BMI-for-age percentiles decreased 1.8 and 7.5 percentiles among subjects treated for 24 weeks or 48 weeks, respectively.

Decrease in mean height percentile at year 1 of long-term follow-up was most prominent in prepubertal age children. The decline of height, weight and BMI Z scores observed during the treatment phase in comparison to a normative population did not fully recover at the end of long-term follow-up period for children treated with 48 weeks of therapy.

In the treatment phase of this study, the most prevalent adverse reactions in all subjects were pyrexia (80 %), headache (62 %), neutropenia (33 %), fatigue (30 %), anorexia (29 %) and injection-site erythema (29 %). Only 1 subject discontinued therapy as the result of an adverse reaction (thrombocytopenia). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7 % (8/107) of all subjects and included injection site pain (1 %), pain in extremity (1 %), headache (1 %), neutropenia (1 %), and pyrexia (4 %). Important treatment-emergent adverse reactions that occurred in this patient population were nervousness (8 %), aggression (3 %), anger (2 %), depression/depressed mood (4 %) and hypothyroidism (3 %) and 5 subjects received levothyroxine treatment for hypothyroidism/elevated TSH.

Tabulated summary of adverse reactions

The following treatment-related adverse reactions were reported in the study in children and adolescent patients treated with Sylatron in combination with ribavirin. These reactions are listed in Table 7 by system organ class and frequency (very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000) or not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 7 Adverse reactions very commonly, commonly and uncommonly reported in the clinical trial in children and adolescent patients treated with Sylatron in combination with ribavirin

§class effect of interferon-alfa containing products - reported with standard interferon therapy in adult and paediatric patients; with Sylatron reported in adult patients.

Description of selected adverse reactions in children and adolescents

Most of the changes in laboratory values in the Sylatron/ribavirin clinical trial were mild or moderate. Decreases in haemoglobin, white blood cells, platelets, neutrophils and increase in bilirubin may require dose reduction or permanent discontinuation from therapy. While changes in laboratory values were observed in some patients treated with Sylatron used in combination with ribavirin in the clinical trial, values returned to baseline levels within a few weeks after the end of therapy.

Reporting of

Preclinical safety data

Sylatron

Adverse events not observed in clinical trials were not seen in toxicity studies in monkeys. These studies were limited to four weeks due to the appearance of anti-interferon antibodies in most monkeys.

Reproduction studies of Sylatron have not been performed.). Sylatron showed no genotoxic potential.

The relative non-toxicity of monomethoxy-polyethylene glycol (mPEG), which is liberated from Sylatron by metabolism in vivo has been demonstrated in preclinical acute and subchronic toxicity studies in rodents and monkeys, standard embryo-foetal development studies and in in vitro mutagenicity assays.

Sylatron plus ribavirin

When used in combination with ribavirin, Sylatron did not cause any effects not previously seen with either active substance alone. The major treatment-related change was a reversible, mild to moderate anaemia, the severity of which was greater than that produced by either active substance alone.

No studies have been conducted in juvenile animals to examine the effects of treatment with Sylatron on growth, development, sexual maturation, and behaviour.).

Therapeutic indications

Adults (tritherapy)

Sylatron in combination with ribavirin and boceprevir (tritherapy) is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 infection in adult patients (18 years of age and older) with compensated liver disease who are previously untreated or who have failed previous therapy.

Please refer to the ribavirin and boceprevir Summary of Product Characteristics (SmPCs) when Sylatron is to be used in combination with these medicines.

Adults (bitherapy and monotherapy)

Sylatron is indicated for the treatment of adult patients (18 years of age and older) with CHC who are positive for hepatitis C virus RNA (HCV-RNA), including patients with compensated cirrhosis and/or co-infected with clinically stable HIV.

Sylatron in combination with ribavirin (bitherapy) is indicated for the treatment of CHC infection in adult patients who are previously untreated including patients with clinically stable HIV co-infection and in adult patients who have failed previous treatment with interferon alpha (pegylated or nonpegylated) and ribavirin combination therapy or interferon alpha monotherapy.

Interferon monotherapy, including Sylatron, is indicated mainly in case of intolerance or contraindication to ribavirin.

Please refer to the ribavirin SmPC when Sylatron is to be used in combination with ribavirin.

Paediatric population (bitherapy)

Sylatron is indicated in a combination regimen with ribavirin for the treatment of children 3 years of age and older and adolescents, who have chronic hepatitis C, previously untreated, without liver decompensation, and who are positive for HCV-RNA.

When deciding not to defer treatment until adulthood, it is important to consider that the combination therapy induced a growth inhibition that may be irreversible in some patients. The decision to treat should be made on a case by case basis.

Please refer to the ribavirin SmPC for capsules or oral solution when Sylatron is to be used in combination with ribavirin.

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB10.

Recombinant interferon alfa-2b is covalently conjugated with monomethoxy polyethylene glycol at an average degree of substitution of 1 mole of polymer/mole of protein. The average molecular mass is approximately 31,300 daltons of which the protein moiety constitutes approximately 19,300.

Mechanism of action

In vitro and in vivo studies suggest that the biological activity of Sylatron is derived from its interferon alfa-2b moiety.

Interferons exert their cellular activities by binding to specific membrane receptors on the cell surface. Studies with other interferons have demonstrated species specificity. However, certain monkey species, e.g., Rhesus monkeys are susceptible to pharmacodynamic stimulation upon exposure to human type 1 interferons.

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 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.

Pharmacodynamic effects

Sylatron pharmacodynamics were assessed in a rising single-dose trial in healthy subjects by examining changes in oral temperature, concentrations of effector proteins such as serum neopterin and 2'5'-oligoadenylate synthetase (2'5'-OAS), as well as white cell and neutrophil counts. Subjects treated with Sylatron showed mild dose-related elevations in body temperature. Following single doses of Sylatron between 0.25 and 2.0 micrograms/kg/week, serum neopterin concentration was increased in a dose-related manner. Neutrophil and white cell count reductions at the end of week 4 correlated with the dose of Sylatron.

Clinical efficacy and safety - Adults

Tritherapy with Sylatron, ribavirin and boceprevir

Refer to the SmPC for boceprevir.

Monotherapy with Sylatron and bitherapy with Sylatron and ribavirin

Naïve patients

Two pivotal trials have been conducted, one (C/I97-010) with Sylatron monotherapy; the other (C/I98-580) with Sylatron in combination with ribavirin. Eligible patients for these trials had chronic hepatitis C confirmed by a positive HCV-RNA polymerase chain reaction (PCR) assay (> 30 IU/ml), a liver biopsy consistent with a histological diagnosis of chronic hepatitis with no other cause for the chronic hepatitis, and abnormal serum ALT.

In the Sylatron monotherapy trial, a total of 916 naïve chronic hepatitis C patients were treated with Sylatron (0.5, 1.0 or 1.5 micrograms/kg/week) for one year with a follow-up period of six months. In addition, 303 patients received interferon alfa-2b (3 million International Units [MIU] three times a week) as a comparator. This study showed that Sylatron was superior to interferon alfa-2b (Table 8).

In the Sylatron combination trial, 1,530 naïve patients were treated for one year with one of the following combination regimens:

- Sylatron (1.5 micrograms/kg/week) + ribavirin (800 mg/day), (n = 511).

- Sylatron (1.5 micrograms/kg/week for one month followed by 0.5 microgram/kg/week for 11 months) + ribavirin (1,000/1,200 mg/day), (n = 514).

- Interferon alfa-2b (3 MIU three times a week) + ribavirin (1,000/1,200 mg/day) (n = 505).

In this trial, the combination of Sylatron (1.5 micrograms/kg/week) and ribavirin was significantly more effective than the combination of interferon alfa-2b and ribavirin (Table 8), particularly in patients infected with Genotype 1 (Table 9). Sustained response was assessed by the response rate six months after the cessation of treatment.

HCV genotype and baseline virus load are prognostic factors which are known to affect response rates. However, response rates in this trial were shown to be dependent also on the dose of ribavirin administered in combination with Sylatron or interferon alfa-2b. In those patients that received > 10.6 mg/kg ribavirin (800 mg dose in typical 75 kg patient), regardless of genotype or viral load, response rates were significantly higher than in those patients that received ≤ 10.6 mg/kg ribavirin (Table 9), while response rates in patients that received > 13.2 mg/kg ribavirin were even higher.

Table 8 Sustained virological response (% patients HCV negative)

Table 9 Sustained response rates with Sylatron + ribavirin (by ribavirin dose, genotype and viral load)

In the Sylatron monotherapy study, the Quality of Life was generally less affected by 0.5 microgram/kg of Sylatron than by either 1.0 microgram/kg of Sylatron once weekly or 3 MIU of interferon alfa-2b three times a week.

In a separate trial, 224 patients with genotype 2 or 3 received Sylatron, 1.5 micrograms/kg subcutaneously, once weekly, in combination with ribavirin 800 mg -1,400 mg p.o. for 6 months (based on body weight, only three patients weighing > 105 kg, received the 1,400 mg dose) (Table 10). Twenty-four % had bridging fibrosis or cirrhosis (Knodell 3/4).

Table 10 Virologic response at end of treatment, Sustained Virologic Response and relapse by HCV Genotype and viral load*

* Any subject with an undetectable HCV-RNA level at the follow-up week 12 visit and missing data at the follow-up week 24 visit was considered a sustained responder. Any subject with missing data in and after the follow-up week 12 window was considered to be a non-responder at week 24 of follow-up.

The 6 month treatment duration in this trial was better tolerated than one year of treatment in the pivotal combination trial; for discontinuation 5 % vs. 14 %, for dose modification 18 % vs. 49 %.

In a non-comparative trial, 235 patients with genotype 1 and low viral load (< 600,000 IU/ml) received Sylatron, 1.5 micrograms/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. The overall sustained response rate after a 24-week treatment duration was 50 %. Forty-one percent of subjects (97/235) had nondetectable plasma HCV-RNA levels at week 4 and week 24 of therapy. In this subgroup, there was a 92 % (89/97) sustained virological response rate. The high sustained response rate in this subgroup of patients was identified in an interim analysis (n=49) and prospectively confirmed (n=48).

Limited historical data indicate that treatment for 48 weeks might be associated with a higher sustained response rate (11/11) and with a lower risk of relapse (0/11 as compared to 7/96 following 24 weeks of treatment).

A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two Sylatron/ribavirin regimens [Sylatron 1.5 µg/kg and 1 µg/kg subcutaneously once weekly both in combination with ribavirin 800 to 1,400 mg p.o. daily (in two divided doses)] and peginterferon alfa-2a 180 µg subcutaneously once weekly with ribavirin 1,000 to 1,200 mg p.o. daily (in two divided doses) in 3,070 treatment-naïve adults with chronic hepatitis C genotype 1. Response to the treatment was measured by Sustained Virologic Response (SVR) which is defined as undetectable HCV-RNA at 24 weeks post-treatment (see Table 11).

Table 11 Virologic response at treatment week 12, end of treatment response, relapse rate *and Sustained Virologic Response (SVR)

* (HCV-RNA PCR assay, with a lower limit of quantitation of 27 IU/ml)

Lack of early virologic response by Treatment week 12 (detectable HCV-RNA with a < 2 log10 reduction from baseline) was a criterion for discontinuation of treatment.

In all three treatment groups, sustained virologic response rates were similar. In patients of African American origin (which is known to be a poor prognostic factor for HCV eradication), treatment with Sylatron (1.5 µg/kg)/ribavirin combination therapy resulted in a higher sustained virologic response rate compared to Sylatron 1 µg/kg dose. At the Sylatron 1.5 µg/kg plus ribavirin dose, sustained virologic response rates were lower in patients with cirrhosis, in patients with normal ALT levels, in patients with a baseline viral load > 600,000 IU/ml, and in patients > 40 years old. Caucasian patients had a higher sustained virologic response rate compared to the African Americans. Among patients with undetectable HCV-RNA at the end of treatment, the relapse rate was 24 %.

Predictability of sustained virological response - Naïve patients: Virological response by week 12 is defined as at least 2-log viral load decrease or undetectable levels of HCV-RNA.Virological response by week 4 is defined as at least 1-log viral load decrease or undetectable levels of HCV-RNA. These time points (treatment week 4 and treatment week 12) have been shown to be predictive for sustained response (Table 12).

Table 12 Predictive value of in-treatment Virologic Response while on Sylatron 1.5 µg/kg/ribavirin 800-1,400 mg combination therapy

*Genotype 1 receive 48 weeks treatment

**Genotype 2, 3 receive 24 weeks treatment

***The presented results are from a single point of time. A patient may be missing or have had a different result for week 4 or week 12.

†These criteria were used in the protocol: If week 12 HCV-RNA is positive and < 2log10 decrease from baseline, patients to stop therapy. If week 12 HCV-RNA is positive and decreased > 2log10 from baseline, then retest HCV-RNA at week 24 and if positive, patients to stop therapy.

The negative predictive value for sustained response in patients treated with Sylatron in monotherapy was 98 %.

HCV/HIV Co-infected patients

Two trials have been conducted in patients co-infected with HIV and HCV. The response to treatment in both of these trials is presented in Table 13. 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 Sylatron (1.5 µg/kg/week) plus ribavirin (800 mg/day) or interferon alfa-2b (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 Sylatron (100 or 150 µg/week based on weight) plus ribavirin (800-1,200 mg/day based on weight) or interferon alfa-2b (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 13 Sustained virological response based on genotype after Sylatron in combination with Ribavirin in HCV/HIV Co-infected patients

Histological response: Liver biopsies were obtained before and after treatment in Study 1 and were available for 210 of the 412 subjects (51 %). Both the Metavir score and Ishak grade decreased among subjects treated with Sylatron in combination with ribavirin. This decline was significant among responders (-0.3 for Metavir and -1.2 for Ishak) and stable (-0.1 for Metavir and -0.2 for Ishak) among non-responders. In terms of activity, about one-third of sustained responders showed improvement and none showed worsening. There was no improvement in terms of fibrosis observed in this study. Steatosis was significantly improved in patients infected with HCV Genotype 3.

Sylatron/ribavirin retreatment of prior treatment failures

In a non-comparative trial, 2,293 patients with moderate to severe fibrosis who failed previous treatment with combination alpha interferon/ribavirin were retreated with Sylatron, 1.5 micrograms/kg subcutaneously, once weekly, in combination with weight adjusted ribavirin. Failure to prior therapy was defined as relapse or non-response (HCV-RNA positive at the end of a minimum of 12 weeks of treatment).

Patients who were HCV-RNA negative at treatment week 12 continued treatment for 48 weeks and were followed for 24 weeks post-treatment. Response week 12 was defined as undetectable HCV-RNA after 12 weeks of treatment. Sustained Virologic Response (SVR) is defined as undetectable HCV-RNA at 24 weeks post-treatment (Table 14).

Table 14 Rates of response to retreatment in prior treatment failures

Pharmacokinetic properties

Sylatron is a well characterized polyethylene glycol-modified (“pegylated”) derivative of interferon alfa-2b and is predominantly composed of monopegylated species. The plasma half-life of Sylatron is prolonged compared with nonpegylated interferon alfa-2b. Sylatron has a potential to depegylate to free interferon alfa-2b. The biologic activity of the pegylated isomers is qualitatively similar, but weaker than free interferon alfa-2b.

Following subcutaneous administration, maximal serum concentrations occur between 15-44 hours post-dose, and are sustained for up to 48-72 hours post-dose.

Sylatron Cmax and AUC measurements increase in a dose-related manner. Mean apparent volume of distribution is 0.99 l/kg.

Upon multiple dosing, there is an accumulation of immunoreactive interferons. There is, however, only a modest increase in biologic activity as measured by a bioassay.

Mean (SD) Sylatron elimination half-life is approximately 40 hours (13.3 hours), with apparent clearance of 22.0 ml/hr/kg. The mechanisms involved in clearance of interferons in man have not yet been fully elucidated. However, renal elimination may account for a minority (approximately 30 %) of Sylatron apparent clearance.

Renal impairment

Renal clearance appears to account for 30 % of total clearance of Sylatron. In a single dose study (1.0 microgram/kg) in patients with impaired renal function, Cmax, AUC, and half-life increased in relation to the degree of renal impairment.

Following multiple dosing of Sylatron (1.0 microgram/kg subcutaneously administered every week for four weeks) the clearance of Sylatron is reduced by a mean of 17 % in patients with moderate renal impairment (creatinine clearance 30-49 ml/minute) and by a mean of 44 % in patients with severe renal impairment (creatinine clearance 15-29 ml/minute) compared to subjects with normal renal function. Based on single dose data, clearance was similar in patients with severe renal impairment not on dialysis and in patients who were receiving hemodialysis. The dose of Sylatron for monotherapy should be reduced in patients with moderate or severe renal impairment. Patients with creatinine clearance < 50 ml/minute must not be treated with Sylatron in combination with ribavirin (bitherapy or tritherapy).

Because of marked inter-subject variability in interferon pharmacokinetics, it is recommended that patients with severe renal impairment be closely monitored during treatment with Sylatron

Hepatic impairment

The pharmacokinetics of Sylatron have not been evaluated in patients with severe hepatic dysfunction.

Elderly (> 65 years of age)

The pharmacokinetics of Sylatron following a single subcutaneous dose of 1.0 microgram/kg were not affected by age. The data suggest that no alteration in Sylatron dosage is necessary based on advancing age.

Paediatric population

Multiple-dose pharmacokinetic properties for Sylatron and ribavirin (capsules and oral solution) in children and adolescent patients with chronic hepatitis C have been evaluated during a clinical study. In children and adolescent patients receiving body surface area-adjusted dosing of Sylatron at 60 μg/m2/week, the log transformed ratio estimate of exposure during the dosing interval is predicted to be 58 % (90 % CI: 141-177 %) higher than observed in adults receiving 1.5 μg/kg/week.

Interferon neutralising factors

Interferon neutralising factor assays were performed on serum samples of patients who received Sylatron in the clinical trial. Interferon neutralising factors are antibodies which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors in patients who received Sylatron 0.5 micrograms/kg is 1.1 %.

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.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

More significant obtundation and coma, including cases of encephalopathy, have been observed in some patients, usually elderly, treated at higher doses for oncology indications. 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 interferon alpha.

All patients in the selected 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.

Acute hypersensitivity

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

Cardiovascular system

As with interferon alfa-2b, adult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders, receiving Sylatron therapy require close monitoring. It is recommended that patients who have pre-existing cardiac abnormalities 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 Sylatron therapy. There are no data in children or adolescents with a history of cardiac disease.

Hepatic Failure

Sylatron increases the risk of hepatic decompensation and death in patients with cirrhosis. As with all interferons, discontinue treatment with Sylatron in patients who develop prolongation of coagulation markers which might indicate liver decompensation. Liver enzymes and hepatic function should be closely monitored in cirrhotic patients.

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.

Hydration

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

Pulmonary changes

Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alpha treated patients. 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. Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear to be associated with resolution of pulmonary adverse events.

Autoimmune disease

The development of auto-antibodies and autoimmune disorders has been reported during treatment with alpha interferons.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.

Ocular changes

Ophthalmologic disorders, including retinal haemorrhages, retinal exudates, serous retinal detachment, and retinal artery or vein occlusion have been reported in rare instances after treatment with alpha interferons. All patients should have a baseline eye examination. Any patient complaining of ocular symptoms, including loss of visual acuity or visual field must have a prompt and complete eye examination. Periodic visual examinations are recommended during Sylatron therapy, particularly in patients with disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of Sylatron should be considered in patients who develop new or worsening ophthalmological disorders.

Thyroid changes

Infrequently, adult patients treated for chronic hepatitis C with interferon alpha have developed thyroid abnormalities, either hypothyroidism or hyperthyroidism. Approximately 21 % of children treated with Sylatron/ribavirin combination therapy developed increase in thyroid stimulating hormone (TSH). Another approximately 2 % had a transient decrease below the lower limit of normal. Prior to initiation of Sylatron therapy, TSH levels must be evaluated and any thyroid abnormality detected at that time must be treated with conventional therapy. Determine TSH levels if, during the course of therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the presence of thyroid dysfunction, Sylatron treatment may be continued if TSH levels can be maintained in the normal range by medicine. Children and adolescents should be monitored every 3 months for evidence of thyroid dysfunction (e.g. TSH).

Metabolic disturbances

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

HCV/HIV Co-infection

Mitochondrial toxicity and lactic acidosis

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 Sylatron and ribavirin to HAART therapy (see ribavirin SmPC).

Hepatic decompensation in HCV/HIV co-infected patients with advanced cirrhosis

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. Other baseline factors in co-infected patients that may be associated with a higher risk of hepatic decompensation include treatment with didanosine and elevated bilirubin serum concentration.

Co-infected patients receiving both antiretroviral (ARV) and anti-hepatitis treatment should be closely monitored, assessing their Child-Pugh score during treatment. Patients progressing to hepatic decompensation should have their anti-hepatitis treatment immediately discontinued and the ARV treatment reassessed.

Haematological abnormalities in HCV/HIV co-infected patients

Patients treated with Sylatron and ribavirin combination therapy and zidovudine are at increased risk of developing anaemia and therefore the concomitant use of this combination with zidovudine is not recommended.

Patients with low CD4 counts

In patients co-infected with HCV/HIV, limited efficacy and safety data (N = 25) are available in subjects with CD4 counts less than 200 cells/µl. Caution is therefore warranted in the treatment of patients with low CD4 counts.

Please refer to the respective SmPCs of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with Sylatron and ribavirin.

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 Sylatron 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 Sylatron 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.

Organ transplant recipients

The safety and efficacy of Sylatron alone or in combination with ribavirin for the treatment of hepatitis C in liver or other organ transplant recipients have not been studied. Preliminary data indicate that interferon alpha therapy may be associated with an increased rate of kidney graft rejection. Liver graft rejection has also been reported.

Other

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

Laboratory tests

Standard haematologic tests, blood chemistry and a test of thyroid function must be conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline prior to initiation of Sylatron therapy are:

Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as clinically appropriate. HCV-RNA should be measured periodically during treatment.

Long term maintenance monotherapy

It has been demonstrated in a clinical study that peginterferon alfa-2b at low-dose (0.5 μg/kg/week) is not effective in long term maintenance monotherapy (for a mean duration of 2.5 years) for the prevention of disease progression in non responders with compensated cirrhosis. No statistically significant effect on the time to development of the first clinical event (liver decompensation, hepatocellular carcinoma, death and/or liver transplantation) was observed as compared to the absence of treatment. Sylatron should therefore not be used as long term maintenance monotherapy.

Important information about some of the ingredients of Sylatron

Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

This medicinal product contains less than 1 mmol sodium (23 mg) per 0.7 ml, i.e., essentially "sodium-free".

Effects on ability to drive and use machines

Patients who develop fatigue, somnolence or confusion during treatment with Sylatron are cautioned to avoid driving or operating machines.

Dosage (Posology) and method of administration

Treatment should be initiated and monitored only by a physician experienced in the management of patients with hepatitis C.

Posology

Sylatron should be administered as a once weekly subcutaneous injection. The dose administered in adults depends on whether it is used in combination therapy (bitherapy or tritherapy) or as monotherapy.

Sylatron combination therapy (bitherapy or tritherapy)

Bitherapy (Sylatron with ribavirin): applies to all adult and paediatric patients 3 years of age and older.

Tritherapy (Sylatron with ribavirin and boceprevir): applies to adult patients with genotype 1 CHC.

Adults - Dose to be administered

Sylatron 1.5 micrograms/kg/week in combination with ribavirin capsules.

The intended dose of 1.5 μg/kg of Sylatron to be used in combination with ribavirin may be delivered in weight categories with the Sylatron strengths according to Table 1. Ribavirin capsules are to be administered orally each day in two divided doses with food (morning and evening).

Table 1 Dosing for combination therapy*

a: 2 morning, 2 evening

b: 2 morning, 3 evening

c: 3 morning, 3 evening

d: 3 morning, 4 evening

* Refer to the SmPC of boceprevir for details about the dose of boceprevir to be administered in tritherapy.

Adults - Duration of treatment - Naïve patients

Tritherapy: Refer to the SmPC for boceprevir.

- Genotype 1:

- Patients who have undetectable HCV-RNA at treatment week 12, treatment should be continued for another nine month period (i.e., a total of 48 weeks).

- Patients with detectable but > 2 log decrease in HCV-RNA level from baseline at treatment week 12 should be reassessed at treatment week 24 and, if HCV-RNA is undetectable, they should continue with full course of therapy (i.e. a total of 48 weeks). However, if HCV-RNA is still detectable at treatment week 24, discontinuation of therapy should be considered.

- In the subset of patients with genotype 1 infection and low viral load (< 600,000 IU/ml) who become HCV-RNA negative at treatment week 4 and remain HCV-RNA negative at week 24, the treatment could either be stopped after this 24 week treatment course or pursued for an additional 24 weeks (i.e. overall 48 weeks treatment duration). However, an overall 24 weeks treatment duration may be associated with a higher risk of relapse than a 48 weeks treatment duration.

- Genotypes 2 or 3:

It is recommended that all patients be treated with bitherapy for 24 weeks, except for HCV/HIV co-infected patients who should receive 48 weeks of treatment.

- Genotype 4:

In general, patients infected with genotype 4 are considered harder to treat and limited study data (n=66) indicate they are compatible with a duration of treatment with bitherapy as for genotype 1.

Adults - Duration of treatment - HCV/HIV co-infection

Bitherapy: The recommended duration of treatment for HCV/HIV co-infected patients is 48 weeks with bitherapy, regardless of genotype.

Predictability of response and non-response in HCV/HIV co-infection - Early virological response by week 12, defined as a 2 log viral load decrease or undetectable levels of HCV-RNA, has been shown to be predictive for sustained response. The negative predictive value for sustained response in HCV/HIV co-infected patients treated with Sylatron in combination with ribavirin was 99 % (67/68; Study 1). A positive predictive value of 50 % (52/104; Study 1) was observed for HCV/HIV co-infected patients receiving bitherapy.

Adults - Duration of treatment - Retreatment

Tritherapy: Refer to the SmPC for boceprevir.

Bitherapy: Predictability of sustained virological response - All patients, irrespective of genotype, who have demonstrated serum HCV-RNA below the limits of detection at week 12 should receive 48 weeks of bitherapy.).

Retreatment duration greater than 48 weeks in non-responder patients with genotype 1 has not been studied with pegylated interferon alfa-2b and ribavirin combination therapy.

Paediatric population (bitherapy only) - Dose to be administered

Dosing for children 3 years of age and older and adolescent patients is determined by body surface area for Sylatron and by body weight for ribavirin. The recommended dose of Sylatron is 60 μg/m2/week subcutaneously in combination with ribavirin 15 mg/kg/day orally in two divided doses with food (morning and evening).

Paediatric population (bitherapy only) - Duration of treatment

- Genotype 1:

The recommended duration of treatment with bitherapy is 1 year. By extrapolation from clinical data on combination therapy with standard interferon in paediatric patients (negative predictive value 96 % for interferon alfa-2b/ribavirin), patients who fail to achieve virological response at 12 weeks are highly unlikely to become sustained virological responders. Therefore, it is recommended that children and adolescent patients receiving Sylatron/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 or 3:

The recommended duration of treatment with bitherapy is 24 weeks.

- Genotype 4:

Only 5 children and adolescents with Genotype 4 were treated in the Sylatron/ribavirin clinical trial. The recommended duration of treatment with bitherapy is 1 year. It is recommended that children and adolescent patients receiving Sylatron/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.

Sylatron monotherapy - Adults

Dose to be administered

As monotherapy the Sylatron regimen is 0.5 or 1.0 μg/kg/week. The lowest Sylatron strength available is 50 μg/0.5 ml; therefore for patients prescribed 0.5 μg/kg/week, doses must be adjusted by volume as shown in Table 2. For the 1.0 μg/kg dose, similar volume adjustments can be made or alternate strengths can be used as shown in Table 2. Sylatron monotherapy was not studied in HCV/HIV co-infected patients.

Table 2 Monotherapy dosing

Minimum delivery for pen is 0.2 ml.

* Must use vial.

** For patients > 120 kg, the Sylatron dose should be calculated based on the individual patient weight. This may require combinations of various Sylatron dose strengths and volumes.

Duration of treatment

For patients who exhibit virological response at week 12, treatment should be continued for at least another three-month period (i.e., a total of six months). The decision to extend therapy to one year of treatment should be based on prognostic factors (e.g., genotype, age > 40 years, male gender, bridging fibrosis).

Dose modification for all patients (monotherapy and combination therapy)

If severe adverse reactions or laboratory abnormalities develop during treatment with Sylatron monotherapy or combination therapy, the dosages of Sylatron and/or ribavirin must be modified as appropriate, until the adverse reactions abate. Dose reduction of boceprevir is not recommended. Boceprevir must not be administered in the absence of Sylatron and ribavirin.

As adherence might be of importance for outcome of therapy, the dose of Sylatron and ribavirin should be kept as close as possible to the recommended standard dose. Guidelines were developed in clinical trials for dose modification.

Combination therapy dose reduction guidelines

Table 2a Dose modification guidelines for combination therapy based on laboratory parameters

* Upper limit of normal

Note 1: In adult patients 1st dose reduction of ribavirin is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2nd dose reduction of ribavirin is by an additional 200 mg/day. Patients whose dose of ribavirin is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening.

In children and adolescent patients 1st dose reduction of ribavirin is to 12 mg/kg/day, 2nd dose reduction of ribavirin is to 8 mg/kg/day.

Note 2: In adult patients 1st dose reduction of Sylatron is to 1 µg/kg/week. If needed, 2nd dose reduction of Sylatron is to 0.5 µg/kg/week. For patients on Sylatron monotherapy: refer to monotherapy dose reduction guidelines section for dose reduction.

In children and adolescent patients 1st dose reduction of Sylatron is to 40 μg/m2/week, 2nd dose reduction of Sylatron is to 20 μg/m2/week.

Dose reduction of Sylatron in adults may be accomplished by reducing the prescribed volume or by utilizing a lower dose strength as shown in Table 2b. Dose reduction of Sylatron in children and adolescents is accomplished by modifying the recommended dose in a two-step process from the original starting dose of 60 μg/m2/week, to 40 μg/m2/week, then to 20 μg/m2/week, if needed.

Table 2b Two-step dose reduction of Sylatron in combination therapy in adults

Sylatron monotherapy dose reduction guidelines in adults

Dose modification guidelines for adult patients who use Sylatron monotherapy are shown in Table 3a.

Table 3a Dose modification guidelines for Sylatron monotherapy in adults based on laboratory parameters

For adult patients who use 0.5 μg/kg Sylatron monotherapy, dose reduction may be accomplished by reducing the prescribed volume by one-half as shown in Table 3b.

Table 3b Reduced Sylatron dose (0.25 μg/kg) for the 0.5 μg/kg monotherapy regimen in adults

Minimum delivery for pen is 0.2 ml.

* Must use vial.

** For patients > 120 kg, the Sylatron dose should be calculated based on the individual patient weight. This may require combinations of various Sylatron dose strengths and volumes.

For adult patients who use 1.0 μg/kg Sylatron monotherapy, dose reduction may be accomplished by reducing the prescribed volume by one-half or by utilizing a lower dose strength as shown in Table 3c.

Table 3c Reduced Sylatron dose (0.5 μg/kg) for the 1.0 μg/kg monotherapy regimen in adults

Minimum delivery for pen is 0.2 ml.

* Must use vial.

** For patients > 120 kg, the Sylatron dose should be calculated based on the individual patient weight. This may require combinations of various Sylatron dose strengths and volumes.

Special populations

Renal impairment

Monotherapy

Sylatron should be used with caution in patients with moderate to severe renal impairment. In patients with moderate renal dysfunction (creatinine clearance 30-50 ml/minute), the starting dose of Sylatron should be reduced by 25 %. Patients with severe renal dysfunction (creatinine clearance 15-29 ml/minute) should have the starting dose of Sylatron reduced by 50 %. Data are not available for the use of Sylatron in patients with creatinine clearance < 15 ml/minute. Patients with severe renal impairment, including those on hemodialysis, should be closely monitored. If renal function decreases during treatment, Sylatron therapy should be discontinued.

Combination therapy

Patients with creatinine clearance < 50 ml/minute must not be treated with Sylatron in combination with ribavirin (see ribavirin SmPC). When administered in combination therapy, patients with impaired renal function should be more carefully monitored with respect to the development of anaemia.

Hepatic impairment

The safety and efficacy of Sylatron therapy has not been evaluated in patients with severe hepatic dysfunction, therefore Sylatron must not be used for these patients.

Elderly (> 65 years of age)

There are no apparent age-related effects on the pharmacokinetics of Sylatron. Data from elderly patients treated with a single dose of Sylatron suggest no alteration in Sylatron dose is necessary based on age.

Paediatric population

Sylatron can be used in combination with ribavirin in paediatric patients 3 years of age and older.

Method of administration

Sylatron should be administered as a subcutaneous injection. Patients may self-inject Sylatron if their physician determines that it is appropriate and with medical follow-up as necessary.

Special precautions for disposal and other handling

Sylatron pre-filled pen is to be removed from the refrigerator before administration to allow the solvent to reach room temperature (not more than 25°C).

Sylatron 50 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chamber cartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lost during preparation of Sylatron for injection when the dose is measured and injected. Therefore, each pre-filled pen contains an excess amount of solvent and Sylatron powder to ensure delivery of the labelled dose in 0.5 ml of Sylatron, solution for injection. The reconstituted solution has a concentration of 50 micrograms in 0.5 ml.

Sylatron 80 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chamber cartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lost during preparation of Sylatron for injection when the dose is measured and injected. Therefore, each pre-filled pen contains an excess amount of solvent and Sylatron powder to ensure delivery of the labelled dose in 0.5 ml of Sylatron, solution for injection. The reconstituted solution has a concentration of 80 micrograms in 0.5 ml.

Sylatron 100 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chamber cartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lost during preparation of Sylatron for injection when the dose is measured and injected. Therefore, each pre-filled pen contains an excess amount of solvent and Sylatron powder to ensure delivery of the labelled dose in 0.5 ml of Sylatron, solution for injection. The reconstituted solution has a concentration of 100 micrograms in 0.5 ml.

Sylatron 120 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chamber cartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lost during preparation of Sylatron for injection when the dose is measured and injected. Therefore, each pre-filled pen contains an excess amount of solvent and Sylatron powder to ensure delivery of the labelled dose in 0.5 ml of Sylatron, solution for injection. The reconstituted solution has a concentration of 120 micrograms in 0.5 ml.

Sylatron 150 micrograms powder and solvent for solution for injection in pre-filled pen

Each pre-filled pen (CLEARCLICK) is reconstituted with the solvent provided in the two-chamber cartridge (water for injections) for administration of up to 0.5 ml of solution. A small volume is lost during preparation of Sylatron for injection when the dose is measured and injected. Therefore, each pre-filled pen contains an excess amount of solvent and Sylatron powder to ensure delivery of the labelled dose in 0.5 ml of Sylatron, solution for injection. The reconstituted solution has a concentration of 150 micrograms in 0.5 ml.

Sylatron is injected subcutaneously after reconstituting the powder as instructed, attaching a needle and setting the prescribed dose. A complete and illustrated set of instructions is provided in the Annex to the Package Leaflet.

As for all parenteral medicinal products, the reconstituted solution is to be inspected visually prior to administration. The reconstituted solution should be clear and colourless. If discolouration or particulate matter is present, the reconstituted solution should not be used. After administering the dose, the Sylatron pre-filled pen and any unused solution contained in it is to be disposed of in accordance with local requirements.