Presentation and Status in Health Basket
500 mcg/0.5 ml
The dose is titrated individually with a recommended starting dose of 100 micrograms (or 50 micrograms in patients under another cytoreductive therapy). The dose should be gradually increased by 50 micrograms every two weeks (in parallel, other cytoreductive therapy should be decreased gradually, as appropriate) until stabilisation of the haematological parameters is achieved (haematocrit <45%, platelets <400 x 109/L and leukocytes <10 x 109/L). The maximum recommended single dose is 500 micrograms injected every two weeks.
The dose at which stabilization of the hematological parameters is achieved should be maintained in a two-week administration interval for at least 1.5 years. After that, the dose may be adapted and/or the administration interval prolonged up to every four weeks, as appropriate for the patient.
If adverse events develop during therapy, the administered dose should be reduced or treatment discontinued temporarily until adverse events abate; further, treatment should be re-initiated with a lower dose than the dose that caused adverse events.
If an increase of hematological parameters (hematocrit, platelets, leukocytes) is observed, the dose and/or dosing interval needs to be adapted individually.
In patients with compensated cirrhosis (i.e. Child-Pugh A), another pegylated interferon alfa medicinal product (pegylated interferon alfa-2a) has been shown to be safe. No ropeginterferon alfa-2b dose adjustment is required for adult patients with mild liver impairment.
The use of interferon alfa has not been evaluated in patients with decompensated cirrhosis (i.e. Child-Pugh B or C) and is contraindicated in these patients.
Increased liver enzyme levels have been observed in patients treated with ropeginterferon alfa-2b. When the increase in liver enzyme levels is progressive and persistent, the dose should be reduced. If the increase in liver enzymes is progressive and clinically significant despite dose reduction, or if there is evidence of hepatic decompensation, therapy should be discontinued.
The pharmacokinetic profile of other interferon alfa medicinal products (pegylated interferon alfa-2a and pegylated interferon alfa-2b) was evaluated in renal impaired patients.
No dose adjustment for ropeginterferon alfa-2b is required for adult patients with mild (GFR 60-89 mL/min) or moderate (GFR 30-59 mL/min) renal impairment. A reduced starting dose for ropeginterferon alfa-2b of 50 micrograms is recommended for patients with severe (GFR 15-29 mL/min) renal impairment. Ropeginterferon alfa-2b is contraindicated in patients with end stage renal disease (GFR <15 mL/min).
Adjustments in the recommended dose for ropeginterferon alfa-2b are not necessary when starting therapy in elderly patients.
Obese or underweighted patients
The pharmacokinetic profile of ropeginterferon alfa-2b has not been determined in obese and underweighted patients. No recommendation on dose adjustment for ropeginterferon alfa-2b can be given for these patients.
The safety and efficacy of this drug in children and adolescents has not been established. No data are available.
Monotherapy in adults for the treatment of polycythaemia vera without symptomatic splenomegaly.
Hypersensitivity to the active substance or to any of the excipients
• Pre-existing thyroid disease unless it can be controlled with conventional treatment
• Existence of, or history of severe psychiatric disorders, particularly severe depression, suicidal ideation or suicide attempt
• Severe pre-existing cardiovascular disease, (i.e. uncontrolled hypertension, congestive heart failure (≥ NYHA class 2), serious cardiac arrhythmia, significant coronary artery stenosis, unstable angina) or recent stroke or myocardial infarction
• History or presence of autoimmune disease
• Immunosuppressed transplant recipients
• Combination with telbivudine
• Decompensated cirrhosis of the liver (Child-Pugh B or C)
• End stage renal disease (GFR <15 mL/min)
In order to improve the traceability of biological medicinal products, the name of the administered product should be clearly recorded. It is recommended to record the batch number as well.
Dose titration phase
The recommended posology for the titration phase of ropeginterferon alfa-2b results in a prolonged time to reach the individual optimal dose compared to hydroxycarbamide. In a clinical study in polycythaemia vera, the end of the mean individual titration phase for ropeginterferon alfa-2b was reached after approximately 3.7 months, for hydroxycarbamide after approximately 2.6 months of treatment. Thus, other products (e.g. hydroxycarbamide) may be preferred in patients for whom an early reduction in elevated blood counts is necessary to prevent thrombosis and bleeding.
During the titration phase the efficacy to reduce the cardiovascular and thromboembolic risk of the underlying disease may not be fully established. Patients should be closely monitored, particularly during the titration phase; complete blood counts including determination of hematocrit level, leukocyte and platelet counts should be performed regularly also after the individual optimal dose has been established. Phlebotomy as rescue treatment to normalize blood hyperviscosity may be necessary.
Before ropeginterferon alfa-2b therapy, any pre-existing thyroid disease needs to be treated and controlled with conventional therapy. Patients who develop symptoms indicative of a thyroid dysfunction during ropeginterferon alfa-2b therapy, should evaluate their thyroid stimulating hormone (TSH) levels. If TSH levels can be controlled within the normal range, the therapy can be continued.
Diabetes mellitus have been observed with other interferon alfa medicinal products. Patients with this condition who cannot be effectively controlled by medicinal products should not begin ropeginterferon alfa-2b therapy. Patients who develop this condition during treatment and cannot be controlled by medicinal products should discontinue ropeginterferon alfa-2b therapy.
Central nervous system (CNS)
CNS effects, particularly depression, have been observed in some patients treated with ropeginterferon alfa-2b during the clinical development program. Other CNS effects, including suicidal ideation, attempted suicide, aggression, bipolar disorder, mania and confusion have been observed with other interferon alfa medicinal products. Patients should be closely monitored for any symptoms of psychiatric disorders and therapeutic management should be considered by the treating physician if such symptoms emerge. If psychiatric symptoms worsen, it is recommended to discontinue ropeginterferon alfa-2b therapy. Ropeginterferon alfa-2b must not be administered in patients with existence of or history of severe psychiatric disorders, particularly severe depression, suicidal ideation or suicide attempt.
Cardiac events including cardiomyopathy, myocardial infarction, atrial fibrillation and ischaemic coronary artery disorders have been associated with interferon alfa treatment. Patients with pre-existing or a history of cardiovascular disorders should be closely monitored during ropeginterferon alfa-2b therapy. This medicinal product is contraindicated in patients with severe pre-existing cardiovascular disease or patients who had recently suffered from a stroke or myocardial infarction.
Respiratory disorders such as lung infiltration, pneumonitis, pneumonia or pulmonary arterial hypertension have been observed rarely in patients treated with interferon alfa. Patients who develop respiratory symptoms should be monitored closely and if necessary, ropeginterferon alfa-2b therapy should be discontinued.
Severe eye disorders such as retinopathy, retinal haemorrhage, retinal exudates, retinal detachment and retinal artery or vein occlusion which may result in blindness have been observed rarely in patients treated with interferon alfa. Patients should have eye examinations before and during ropeginterferon alfa-2b therapy, specifically in those patients with retinopathy associated disease such as diabetes mellitus or hypertension. Any patient reporting a decrease or loss of vision or reporting other eye symptoms should have an immediate eye examination. Discontinuation of ropeginterferon alfa-2b should be considered in patients who develop new or worsening eye disorders.
Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been rarely observed with other interferon alfa medicinal products. If this occurs, ropeginterferon alfa-2b therapy must be discontinued and appropriate medical therapy instituted immediately. Transient rashes do not necessitate interruption of treatment.
Interferon alfa therapy has been associated with hepatotoxicity characterized by potentially significant increases in liver enzymes. Hepatic failure in hepatitis C virus infected patients was reported with other interferon alfa medicinal products.
Increases in ALT (≥3 times the upper limit of normal), AST (≥3 times the upper limit of normal), GGT (≥3 times the upper limit of normal) and bilirubin (>2 times the upper limit of normal) levels have been observed in patients treated with ropeginterferon alfa-2b. These elevations were mostly transient and occurred during the first treatment year.
Liver disorders have been reported in patients after long-term ropeginterferon alfa-2b therapy. Liver enzymes and hepatic function should be regularly controlled in patients with long-term ropeginterferon alfa-2b therapy. Treatment with ropeginterferon alfa-2b should be discontinued when, despite dose reduction, the increase in liver enzyme levels is progressive and clinically significant. In patients who develop evidence of hepatic decompensation during treatment, ropeginterferon alfa-2b should be discontinued. Ropeginterferon alfa-2b is contraindicated in patients with decompensated cirrhosis of the liver. Renal function
Regardless of the starting dose or degree of renal impairment, patients should be monitored. If renal function decreases during treatment, ropeginterferon alfa-2b therapy should be discontinued. Ropeginterferon alfa-2b is contraindicated in patients with end stage renal disease.
Dental and periodontal disorders
Dental and periodontal disorders, which may lead to loss of teeth, have been reported with other interferon alfa medicinal products. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with ropeginterferon alfa-2b. Patients should brush their teeth thoroughly twice daily and have regular dental examinations.
The use of ropeginterferon alfa-2b is associated with skin disorders (pruritus, alopecia, rash, erythema, psoriasis, xeroderma, dermatitis acneiform, hyperkeratosis, hyperhydrosis). In case of appearance or worsening of this skin disorders, the stop of the treatment must be envisaged.
Contains benzyl alcohol.
High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis). Contains less than 1 mmol sodium (23 mg) per mL, that is to say essentially ‘sodium-free’.
Leucopenia (19.1%), thrombocytopenia (18.5%), arthralgia (12.9%), fatigue (12.4%), increased gamma-glutamyltransferase (11.2%), influenza-like illness (10.7%), myalgia (10.7%)
Enzymes of the protein catabolism are considered to be involved in the metabolism of ropeginterferon alfa-2b. The involvement of transport proteins in absorption, distribution and elimination of ropeginterferon alfa-2b is not known. Interferon alfa has shown to influence the activity of cytochrome P450 (CYP) isozymes CYP1A2 and CYP2D6.
No interaction studies have been performed with ropeginterferon alfa-2b.
Interaction studies of other pegylated interferon alfa medicinal products
Co-administration of pegylated interferon alfa-2a with telbivudine in patients with hepatitis B increased the risk of developing peripheral neuropathy. A combination therapy with telbivudine and ropeginterferon alfa-2b is contraindicated.
Administration of 180 micrograms of pegylated interferon alfa-2a once weekly for 4 weeks in healthy male subjects did not show any effect on mephenytoin, dapsone, debrisoquine and tolbutamide pharmacokinetics profiles, suggesting that pegylated interferon alfa-2a has no effect on in vivo metabolic activity of cytochrome P450 (CYP) 3A4, 2C9, 2C19 and 2D6 isozymes. In the same study, a 25% increase in the AUC of theophylline (CYP1A2 substrate) was observed, demonstrating that pegylated interferon alfa-2a is an inhibitor of CYP1A2 activity.
Co-administration of pegylated interferon alfa-2b showed no significant interaction with tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), dapsone (N-acetyltransferase substrate) and modestly increased the exposure of caffeine (CYP1A2 substrate) and desipramine (CYP2D6 substrate).
Therefore, care should be taken when ropeginterferon alfa-2b is co-administered with CYP1A2 substrates notably those having a narrow therapeutic margin such as theophylline or methadone. Likewise, caution is recommended with CYP2D6 substrates (e.g. vortioxetine, risperidone) combined with ropeginterferon alfa-2b. Ropeginterferon alfa-2b may inhibit the activity of CYP1A2 and CYP2D6 and thus may increase the blood concentrations of these medicinal products.
No dose adaptions for ropeginterferon alfa-2b should be necessary when concomitantly administered with medicinal products metabolised via CYP2C9/19, CYP3A4 or by N-acetyltransferase.
Caution must be exercised when administering ropeginterferon alfa-2b in combination with other potentially myelosuppressive/chemotherapeutic agents.
Narcotics, hypnotics or sedatives must be administered with caution when used concomitantly with ropeginterferon alfa-2b.
Pregnancy and Lactation
There are no or limited amount of data from the use of interferon alfa in pregnant women.
Studies in animals have shown reproductive toxicity.
An abortifacient effect was reported in primates receiving other interferon alfa medicinal products.
As ropeginterferon alfa-2b may have the same effect, this drug is not recommended during pregnancy.
It is not known whether ropeginterferon alfa-2b is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from this therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
During the clinical study program, one accidental case of overdose has been reported with ropeginterferon alfa-2b. The patient received a 10-time higher starting dose as recommended and developed flu-like symptoms for three days which were rated as non-serious. The patient recovered completely after paracetamol administration and temporary discontinuation of ropeginterferon alfa-2b therapy.
There is no antidote for the medicinal product available. In case of an overdose, close monitoring of the patient and symptomatic treatment, if necessary, are recommended.
Store in a refrigerator (2 °C – 8).
Do not freeze.
Keep the pre-filled pen in the outer carton in order to protect from light.