Besremi · 4.3 Contraindications · 1

HOS-097729 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The most common adverse reactions are leukopenia (20.2%), thrombocytopenia (18.5%), arthralgia (13.5%), fatigue (12.4%), increased gamma-glutamyltransferase (11.2%), influenza-like illness (11.2%), myalgia (10.7%), anaemia (9.6%), increased alanine aminotransferase (8.4%), neutropenia (7.9%), pyrexia (7.9%), increased aspartate aminotransferase (7.3%), pruritus (6.8%), pain in extremity (6.7%), alopecia (6.7%), headache (6.2%), diarrhoea (5.7%), injection site reaction (5.6%), chills (5.1%), and dizziness (5.1%). Serious adverse reactions are depression (1.1%), atrial fibrillation (1.1%) and acute stress disorder (0.6%). Tabulated list of adverse reactions Following treatment-related adverse reactions were reported with ropeginterferon alfa-2b in clinical studies in 178 polycythaemia vera adult patients. Adverse reactions are listed by system organ class 1/100 to < 1/1 000 to < 1/10 000 to < 1/1 000), very rare (< 1/10 000) or not known (cannot be estimated from available data). System organ class Frequency Adverse reaction Infections and common respiratory tract infection, influenza, rhinitis, fungal skin infestations infection uncommon oral herpes, herpes zoster, oral candidiasis, sinusitis, oesophageal candidiasis, vulvovaginal mycotic infection, hordeolum, onychomycosis Blood and lymphatic very common leukopenia, thrombocytopenia system disorders common pancytopenia, neutropenia, anaemia Immune system uncommon sarcoidosis disorders very rare idiopathic or thrombotic thrombocytopenic purpura# not known Vogt-Koyanagi-Harada disease#, acute hypersensitivity reactions#** Endocrine disorders common hypothyroidism, hyperthyroidism, thyroiditis uncommon Basedow's disease, diabetes mellitus# Metabolism and common hypertriglyceridaemia, decreased appetite nutrition disorders Psychiatric disorders common depression, aggression#, insomnia, anxiety, mood altered,

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HOS-097725 · has-contraindication-information · PDF-Seite 4

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 • 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 unstable angina) or recent stroke or myocardial infarction • History or presence of autoimmune disease • Immunosuppressed transplant recipients • Combination with telbivudine (see section 4.5) • Decompensated cirrhosis of the liver (Child-Pugh B or C) • End stage renal disease (GFR < 15 mL/min)

HOS-097724 · has-indication-information · PDF-Seite 2

Besremi is indicated as monotherapy in adults for the treatment of polycythaemia vera without symptomatic splenomegaly.

HOS-097727 · has-interaction-information · PDF-Seite 6

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 6 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 (see section 4.3). 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 pegylated interferon alfa-2a is a Co-administration of pegylated interferon alfa-2b showed no significant interaction with tolbutamide 9 -acetyltransferase substrate) and substrate). Therefore, care should be taken when ropeginterferon alfa-2b is co- substrates notably those having a narrow therapeutic margin such as theophylline or methadone. e.g., vortioxetine, risperidone) combined with ropeginterferon alfa-2b. Ropeginterferon alfa-2b may 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 9/19 -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.

HOS-097728 · has-pregnancy-information · PDF-Seite 7

Women of childbearing potential/Contraception in females Women of childbearing potential must use effective contraception during the treatment with ropeginterferon alfa-2b, unless otherwise discussed with the physician. Pregnancy There are no or limited amount of data from the use of interferon alfa in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). As ropeginterferon alfa-2b may have the same effect, Besremi is not recommended during pregnancy and in women of childbearing potential not using contraception. Breast-feeding 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 Besremi therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. 7 Fertility There are no data on the effect of ropeginterferon alfa-2b therapy on the fertility of females or males.

HOS-097726 · has-warning-information · PDF-Seite 4

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Dose titration phase The recommended posology for the titration phase of ropeginterferon alfa-2b (see section 4.2) 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 haematocrit level, leukocyte and platelet counts should be performed regularly also after the individual optimal dose has been established. Phlebotomy as rescue treatment to normalise blood hyperviscosity may be necessary. 4 Endocrine system Before ropeginterferon alfa-2b therapy, any pre-existing thyroid disease needs to be treated and controlled with conventional therapy (see section 4.3). 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 (see section 4.8). 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 (see section 4.8). Other CNS effects, including suicidal ideation, attempted suicide, aggression, bipolar disorder, mania and confusion have been obser

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