BESREMI 250mcg / 0.5ml injection for pre-filled pen medication leaflet

Besremi 250 micrograms/0.5 mL solution for injection in pre-filled pen

Besremi 500 micrograms/0.5 mL solution for injection in pre-filled pen

Besremi 250 micrograms/0.5 mL solution for injection in pre-filled pen

Each pre-filled pen of 0.5 mL solution contains 250 micrograms of ropeginterferon alfa-2b asmeasured on a protein basis, corresponding to 500 micrograms/mL.

Besremi 500 micrograms/0.5 mL solution for injection in pre-filled pen

Each pre-filled pen of 0.5 mL solution contains 500 micrograms of ropeginterferon alfa-2b asmeasured on a protein basis, corresponding to 1,000 micrograms/mL.

The strength indicates the quantity of the interferon alpha-2b moiety of ropeginterferon alfa-2bwithout consideration of the pegylation.

Ropeginterferon alfa-2b is a covalent conjugate of the protein interferon alpha-2b, produced in

Escherichia coli cells by recombinant DNA technology, with a methoxypolyethylene glycol (mPEG)moiety.

The potency of this medicinal product should not be compared to that of another pegylated or non-pegylated protein of the same therapeutic class (see section 5.1).

Each pre-filled pen contains 10 mg benzyl alcohol per mL.

For the full list of excipients, see section 6.1.

Solution for injection in pre-filled pen (injection).

Clear, colourless to pale yellow solution.

Besremi is indicated as monotherapy in adults for the treatment of polycythaemia vera withoutsymptomatic splenomegaly.

Treatment should be initiated under supervision of a physician experienced in the management of thedisease.

Titration phase

The dose is titrated individually with a recommended starting dose of 100 micrograms (or50 micrograms in patients under another cytoreductive therapy). The dose should be graduallyincreased by 50 micrograms every two weeks (in parallel, other cytoreductive therapy should bedecreased 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 recommendedsingle dose is 500 micrograms injected every two weeks. Phlebotomy as rescue treatment to normaliseblood hyperviscosity may be necessary.

Maintenance phase

The dose at which stabilisation of the haematological parameters is achieved should be maintained in atwo-week administration interval for at least 1.5 years. After that, the dose may be adapted and/or theadministration 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 treatmentdiscontinued temporarily until adverse events abate; further, treatment should be re-initiated with alower dose than the dose that caused adverse events.

If an increase of haematological parameters (haematocrit, platelets, leukocytes) is observed, the doseand/or dosing interval needs to be adapted individually.

In patients with compensated cirrhosis (i.e. Child-Pugh A), another pegylated interferon alfa medicinalproduct (pegylated interferon alfa-2a) has been shown to be safe. No ropeginterferon alfa-2b doseadjustment 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 (see section 4.3).

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. Ifthe increase in liver enzymes is progressive and clinically significant despite dose reduction, or if thereis evidence of hepatic decompensation, therapy should be discontinued (see section 4.4).

The pharmacokinetic profile of other interferon alfa medicinal products (pegylated interferon alfa-2aand pegylated interferon alfa-2b) was evaluated in renal impaired patients (see section 5.2).

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 forropeginterferon 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 stagerenal disease (GFR <15 mL/min) (see section 4.3).

Adjustments in the recommended dose for ropeginterferon alfa-2b are not necessary when startingtherapy in elderly patients (see section 5.2).

Obese or underweighted patients

The pharmacokinetic profile of ropeginterferon alfa-2b has not been determined in obese andunderweighted patients. No recommendation on dose adjustment for ropeginterferon alfa-2b can begiven for these patients.

The safety and efficacy of Besremi in children and adolescents has not been established. No data areavailable (see section 4.4).

For subcutaneous use. The medicinal product is intended for long-term treatment and can beadministered by a physician, nurse, family member or patient when trained in the administration ofsubcutaneous injections with the pre-filled pen. The instructions for use in the package leaflet shouldbe followed.

The recommended injection site is the abdominal skin around but not within 5 cm of the navel or thethigh. Do not inject into an area where the skin is irritated, reddened, bruised, infected or scarred. Thepen can be adjusted to administer doses in 50 microgram intervals in the range of 50 to250 micrograms or 50 to 500 micrograms.

* 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, suicidalideation or suicide attempt

* Severe pre-existing cardiovascular disease, (i.e. uncontrolled hypertension, congestive heartfailure (≥ 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 (see section 4.5)

* 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 and the batch numberof 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) resultsin a prolonged time to reach the individual optimal dose compared to hydroxycarbamide. In a clinicalstudy in polycythaemia vera, the end of the mean individual titration phase for ropeginterferon alfa-2bwas reached after approximately 3.7 months, for hydroxycarbamide after approximately 2.6 months oftreatment. Thus, other products (e.g. hydroxycarbamide) may be preferred in patients for whom anearly 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 theunderlying disease may not be fully established. Patients should be closely monitored, particularlyduring 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 hasbeen established. Phlebotomy as rescue treatment to normalise blood hyperviscosity may be necessary.

Endocrine system

Before ropeginterferon alfa-2b therapy, any pre-existing thyroid disease needs to be treated andcontrolled with conventional therapy (see section 4.3). Patients who develop symptoms indicative of athyroid dysfunction during ropeginterferon alfa-2b therapy, should evaluate their thyroid stimulatinghormone (TSH) levels. If TSH levels can be controlled within the normal range, the therapy can becontinued.

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 notbegin ropeginterferon alfa-2b therapy. Patients who develop this condition during treatment andcannot 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 ropeginterferonalfa-2b during the clinical development program (see section 4.8). Other CNS effects, includingsuicidal ideation, attempted suicide, aggression, bipolar disorder, mania and confusion have beenobserved with other interferon alfa medicinal products. Patients should be closely monitored for anysymptoms of psychiatric disorders and therapeutic management should be considered by the treatingphysician if such symptoms emerge. If psychiatric symptoms worsen, it is recommended todiscontinue ropeginterferon alfa-2b therapy. Ropeginterferon alfa-2b must not be administered inpatients with existence of or history of severe psychiatric disorders, particularly severe depression,suicidal ideation or suicide attempt (see section 4.3).

Cardiovascular system

Cardiac events including cardiomyopathy, myocardial infarction, atrial fibrillation and ischaemiccoronary artery disorders have been associated with interferon alfa treatment (see section 4.8). Patientswith pre-existing or a history of cardiovascular disorders should be closely monitored duringropeginterferon 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 myocardialinfarction (see section 4.3).

Respiratory disorders such as lung infiltration, pneumonitis, pneumonia or pulmonary arterialhypertension have been observed rarely in patients treated with interferon alfa (see section 4.8).

Patients who develop respiratory symptoms should be monitored closely and if necessary,ropeginterferon alfa-2b therapy should be discontinued.

Visual system

Severe eye disorders such as retinopathy, retinal haemorrhage, retinal exudates, retinal detachment andretinal artery or vein occlusion which may result in blindness have been observed rarely in patientstreated with interferon alfa (see section 4.8). Patients should have eye examinations before and duringropeginterferon alfa-2b therapy, specifically in those patients with retinopathy associated disease suchas diabetes mellitus or hypertension. Any patient reporting a decrease or loss of vision or reportingother eye symptoms should have an immediate eye examination. Discontinuation of ropeginterferonalfa-2b should be considered in patients who develop new or worsening eye disorders.

Acute hypersensitivity

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 institutedimmediately. Transient rashes do not necessitate interruption of treatment.

Interferon alfa therapy has been associated with hepatotoxicity characterized by potentially significantincreases in liver enzymes. Hepatic failure in hepatitis C virus infected patients was reported withother interferon alfa medicinal products (see section 4.8).

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) levelshave been observed in patients treated with ropeginterferon alfa-2b. These elevations were mostlytransient and occurred during the first treatment year.

Liver disorders have been reported in patients after long-term ropeginterferon alfa-2b therapy (seesection 4.8). 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 discontinuedwhen, despite dose reduction, the increase in liver enzyme levels is progressive and clinicallysignificant. In patients who develop evidence of hepatic decompensation during treatment,ropeginterferon alfa-2b should be discontinued. Ropeginterferon alfa-2b is contraindicated in patientswith decompensated cirrhosis of the liver (see section 4.3).

Regardless of the starting dose or degree of renal impairment, patients should be monitored. If renalfunction decreases during treatment, ropeginterferon alfa-2b therapy should be discontinued.

Ropeginterferon alfa-2b is contraindicated in patients with end stage renal disease (see section 4.3).

Dental and periodontal disorders

Dental and periodontal disorders, which may lead to loss of teeth, have been reported with otherinterferon alfa medicinal products (see section 4.8). In addition, dry mouth could have a damagingeffect on teeth and mucous membranes of the mouth during long-term treatment with ropeginterferonalfa-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 orworsening of this skin disorders, the stop of the treatment must be envisaged.

Besremi contains benzyl alcohol.

High volumes should be used with caution and only if necessary, especially in subjects with liver orkidney impairment because of the risk of accumulation and toxicity (metabolic acidosis).

Besremi contains less than 1 mmol sodium (23 mg) per mL, that is to say essentially ‘sodium-free’.

Enzymes of the protein catabolism are considered to be involved in the metabolism of ropeginterferonalfa-2b. The involvement of transport proteins in absorption, distribution and elimination ofropeginterferon 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 Bincreased the risk of developing peripheral neuropathy. A combination therapy with telbivudine andropeginterferon alfa-2b is contraindicated (see section 4.3).

Administration of 180 micrograms of pegylated interferon alfa-2a once weekly for 4 weeks in healthymale subjects did not show any effect on mephenytoin, dapsone, debrisoquine and tolbutamidepharmacokinetics profiles, suggesting that pegylated interferon alfa-2a has no effect on in vivometabolic 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 thatpegylated 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) andmodestly increased the exposure of caffeine (CYP1A2 substrate) and desipramine (CYP2D6substrate).

Therefore, care should be taken when ropeginterferon alfa-2b is co-administered with CYP1A2substrates notably those having a narrow therapeutic margin such as theophylline or methadone.

Likewise, caution is recommended with CYP2D6 substrates (e.g. vortioxetine, risperidone) combinedwith 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 administeredwith medicinal products metabolised via CYP2C9/19, CYP3A4 or by N-acetyltransferase.

Caution must be exercised when administering ropeginterferon alfa-2b in combination with otherpotentially myelosuppressive/chemotherapeutic agents.

Narcotics, hypnotics or sedatives must be administered with caution when used concomitantly withropeginterferon alfa-2b.

Women of childbearing potential must use effective contraception during the treatment withropeginterferon alfa-2b, unless otherwise discussed with the physician.

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 pregnancyand in women of childbearing potential not using contraception.

It is not known whether ropeginterferon alfa-2b is excreted in human milk. A risk to thenewborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feedingor to discontinue/abstain from Besremi therapy taking into account the benefit of breast feeding for thechild and the benefit of therapy for the woman.

There are no data on the effect of ropeginterferon alfa-2b therapy on the fertility of females or males.

Besremi has minor influence on the ability to drive and use machines. Patients who experiencedizziness, somnolence or hallucination (see section 4.8) during Besremi therapy should avoid drivingor using machines.

The most common adverse reactions are leukopenia (19.1%), thrombocytopenia (18.5%), arthralgia(12.9%), fatigue (12.4%), increased gamma-glutamyltransferase (11.2%), influenza-like illness(10.7%), myalgia (10.7%), pyrexia (8.4%), pruritus (8.4%), increased alanine aminotransferase(8.4%), anaemia (7.9%), pain in extremity (6.7%), alopecia (6.7%), neutropenia (6.7%), increasedaspartate aminotransferase (6.2%), headache (6.2%), diarrhoea (5.6%), chills (5.1%), dizziness (5.1%)and injection site reaction (5.1%).

Serious adverse reactions are depression (1.1%), atrial fibrillation (1.1%) and acute stress disorder(0.6%).

Following treatment-related adverse reactions were reported with ropeginterferon alfa-2b in clinicalstudies in 178 polycythaemia vera adult patients. Adverse reactions are listed by system organ classand 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 fromavailable data).

System organ class Frequency Adverse reaction

Infections and common respiratory tract infection, rhinitis, fungal skin infectioninfestations uncommon oral herpes, herpes zoster, oral candidiasis, sinusitis,oesophageal candidiasis, vulvovaginal mycotic infection,hordeolum, onychomycosis

Blood and lymphatic very common leukopenia, thrombocytopeniasystem disorders common pancytopenia, neutropenia, anaemia

Immune system uncommon Basedow's disease, sarcoidosisdisorders very rare idiopathic or thrombotic thrombocytopenic purpura#not known Vogt-Koyanagi-Harada disease#, acute hypersensitivityreactions#**

Endocrine disorders common hypothyroidism, hyperthyroidism, thyroiditisuncommon diabetes mellitus#

Metabolism and common hypertriglyceridaemia, decreased appetitenutrition disorders

Psychiatric disorders common depression, aggression#, insomnia, anxiety, mood altered,mood swings, listlessuncommon suicide attempt#, suicidal ideation#, confusional state#,acute stress disorder, hallucination, emotional distress,nervousness, apathy, nightmare, irritabilityrare bipolar disorder#, mania#

Nervous system common headache, dizziness, hypoesthesia, somnolence,disorders paraesthesiauncommon polyneuropathy, peripheral motor neuropathy,radiculopathy, migraine, mental impairment, tremor, aura

Eye disorders common dry eyeuncommon retinal haemorrhage#, retinal exudates#, visual impairment,visual acuity reduced, vision blurred, ocular discomfort,eczema eyelidsrare retinopathy#, optic neuropathy#, retinal artery occlusion#,retinal vein occlusion#,very rare blindness#not known retinal detachment#

Ear and labyrinth uncommon deafness, tinnitus, vertigodisorders

Cardiac disorders common atrial fibrillationuncommon myocardial infarction#, atrioventricular block, intracardiacthrombus, aortic valve incompetence, cardiovasculardisorderrare cardiomyopathy#, angina pectoris#very rare myocardial ischemia#

Vascular disorders common microangiopathyuncommon Raynaud's phenomenon, hypertension, haematoma,flushing

Respiratory, thoracic common dyspnoeaand mediastinal uncommon pneumonitis, cough, epistaxis, throat irritationdisorders very rare lung infiltration#not known pulmonary fibrosis#, pneumonia#, pulmonary arterialhypertension#*

Gastrointestinal common diarrhoea, nausea, abdominal pain, constipation,disorders abdominal distension, dry mouthuncommon gastritis, abdominal wall disorder, flatulence, frequentbowel movements, odynophagia, gingival bleedingnot known tooth disorder#, periodontal disease#

Hepatobiliary very common gamma-glutamyltransferase increaseddisorders common liver disorder, alanine aminotransferase increased,aspartate aminotransferase increased, blood alkalinephosphatase increaseduncommon hepatotoxicity, hepatitis toxic, hepatomegalyrare hepatic failure#

Skin and common pruritus, alopecia, rash, erythema, psoriasis, xeroderma,subcutaneous tissue dermatitis acneiform, hyperkeratosis, hyperhidrosis, drydisorders skinuncommon photosensitivity reaction, skin exfoliation, nail dystrophynot known skin depigmentation#

Musculoskeletal and very common arthralgia, myalgiaconnective tissue common Sjogren's syndrome, arthritis, pain in extremity,disorders musculoskeletal pain, bone pain, muscle spasmsuncommon muscular weakness, neck pain, groin pain

Renal and urinary uncommon cystitis haemorrhagic, dysuria, micturition urgency,disorders urinary retention

Reproductive system uncommon erectile dysfunction, haematospermiaand breast disorders

General disorders very common influenza like illness, fatigueand administrationsite conditions common pyrexia, injection site reaction, asthenia, chills, generalphysical health deterioration, injection site erythemauncommon injection site pain, injection site pruritus, sensitivity toweather changenot known: tongue hyperpigmentation#

Investigations common antithyroid antibody positive, blood thyroid stimulatinghormone increased, body temperature increased,antinuclear antibody positive, blood lactate dehydrogenaseincreaseduncommon platelet count increased, blood uric acid increased,

Coombs test positive, weight decreased#Reported as adverse reactions during treatment with other interferon alfa medicinal products.

*Class label for interferon medicinal products, see below pulmonary arterial hypertension.

**e.g. urticaria, angioedema, bronchoconstriction or anaphylaxis.

Most common adverse reactions

The most common adverse reactions (including number of patients, incidence rate, severity grade,necessity for dose adaptation and outcome) reported during the ropeginterferon alfa-2b clinicaldevelopment program are summarised in Table 1.

Table 1. Most common adverse reactions during ropeginterferon alfa-2b treatment.

Ropeginterferon alfa-2b clinical studies

ADR >10% CTCAE Dose Drug Drug Recovered

PT N (%) IR intensity reduced interrupted discontinuedgrade ≥3

N (%) N (%) N (%) N (%) N (%)(N=178)

Leukopenia 34 (19.1) 27.2 3 (8.8)* 23 (67.6) 7 (20.6) n.r. 33 (97.1)

Thrombo- 33 (18.5) 15.0 4 (12.1)* 13 (39.4) 3 (9.1) 1 (3.0) 31 (94.0)cytopenia

Arthralgia 23 (12.9) 8.5 1 (4.3)* 4 (17.4) 4 (17.4) 2 (8.7) 22 (95.7)

Fatigue 22 (12.4) 10.1 n.r. 3 (13.6) 1 (4.5) 1 (4.5) 21 (95.5)

Influenza 19 (10.7) 6.3 n.r. 3 (15.8) 3 (15.8) n.r. 18 (94.7)like illness

Myalgia 19 (10.7) 6.0 n.r. 6 (31.6) 1 (5.3) n.r. 18 (94.7)

*No CTCAE grade 4 (life-threating or disabling) or grade 5 (death) adverse reactions have been reported.

Abbreviations: CTCAE, common terminology criteria for adverse events; n.r., not reported; ADR, adverse drugreaction; PT, preferred term; IR, incidence rate of mean adverse events per 100 patients per year; N, number ofpatients.

Gastrointestinal disorders have been reported with other interferon alfa medicinal products and havebeen reported in 15.2% of patients with ropeginterferon alfa-2b treatment. The most commongastrointestinal disorders reported in these studies were diarrhoea (5.1%; incidence rate: 2.8[events/100 patients per year]) and nausea (4.5%; incidence rate: 1.6 events/100 patients per year]).

CNS

In the clinical development program of ropeginterferon alfa-2b, two cases of serious depression (1.1%;incidence rate: 0.4 events/100 patients per year) occurred. The patients recovered completely afterpermanent medicinal product discontinuation. One patient who experienced serious acute stressdisorder (0.6%; incidence rate: 0.2 events/100 patients per year) with moderate intensity recoveredcompletely after the dose of ropeginterferon alfa-2b was reduced. CNS effects including suicideattempt, suicidal ideation, aggression, bipolar disorder, mania and confusion have been reported withinterferon alfa (see section 4.4).

Cardiovascular system

During ropeginterferon alfa-2b therapy, three cases of atrial fibrillation (1.1%; incidence rate:0.5 events/100 patients per year) with intensity grade 1 to 3 occurred in two patients. Ropeginterferonalfa-2b treatment was continued and the patients received appropriate medicinal products to treat theseevents. Patients recovered from the two events; one event was ongoing at the time of assessment.

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa, notably inpatients with risk factors for PAH (such as portal hypertension, HIV infection, cirrhosis). Events werereported at various time points typically several months after starting treatment with interferon alfa.

Visual system

Serious eye disorders have been reported with interferon alfa such as retinopathy, retinal haemorrhage,retinal exudates, retinal detachment and retinal artery or vein occlusion (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

During the clinical study program, one accidental case of overdose has been reported withropeginterferon alfa-2b. The patient received a 10-time higher starting dose as recommended anddeveloped flu-like symptoms for three days which were rated as non-serious. The patient recoveredcompletely after paracetamol administration and temporary discontinuation of ropeginterferon alfa-2btherapy.

There is no antidote for the medicinal product available. In case of an overdose, close monitoring ofthe patient and symptomatic treatment, if necessary, are recommended.

Pharmacotherapeutic group: Immunostimulants, interferons, ATC code: L03AB15

Ropeginterferon alfa-2b is a recombinant interferon alfa-2b conjugated with a two-armmethoxypolyethylene glycol (mPEG) at a degree of substitution of 1 mole of polymer/mole of protein.

The average molecular mass is approximately 60 kDa, of which the PEG moiety constitutesapproximately 40 kDa .

Interferon alfa belongs to the class of type I interferons which exhibit their cellular effects by bindingto a transmembrane receptor termed interferon alfa receptor (IFNAR). Binding to IFNAR initiates adownstream signalling cascade through the activation of kinases, particularly Janus kinase 1 (JAK1)and tyrosine kinase 2 (TYK2) and signal transducer and activator of transcription (STAT) proteins.

Nuclear translocation of STAT proteins controls distinct gene-expression programs and exhibitsvarious cellular effects. Interferon alfa was shown to have an inhibitory effect on the proliferation ofhematopoietic and bone marrow fibroblast progenitor cells and antagonised the action of growthfactors and other cytokines that have a role in the development of myelofibrosis. These actions may beinvolved in the therapeutic effects of interferon alfa in polycythaemia vera.

Further, it was demonstrated that interferon alfa is able to decrease the mutated JAK2V617F alleleburden in patients with polycythaemia vera (a V617F point mutation in the JAK2 kinase is a hallmarkof polycythaemia vera and is present in approximately 95% of patients).

An open label, randomised phase III study (PROUD-PV) evaluated the efficacy and safety ofropeginterferon alfa-2b in comparison to hydroxycarbamide in 254 adult polycythaemia vera patients(randomisation 1:1). Patients were stratified by previous exposure to hydroxycarbamide, age atscreening (≤60 or >60 years) and presence of thromboembolic events in the past. Characteristics of thestudy population are presented in Table 2.

Table 2. Patient characteristics at screening in the PROUD-PV Study.

Ropeginterferon alfa-2b Controltreatment arm treatment arm(n=127) (n=127)

Years* 58.5 ±10.81 57.9±13.10

Female n (%) 68 (53.5) 67 (52.8)

Male n (%) 59 (46.5) 60 (47.2)

White n (%) 127 (100.0) 127 (100.0)

Duration of PV (months)* 12.6±24.70 15.7±25.65

JAK2V617F allele burden (%)* 41.9±23.49 42.8±24.14

Haematological parameters

Haematocrit (%)* 47.8±5.22 48.6±5.39

Platelets (109/L)* 537.7±273.08 516.8±254.43

Leukocytes (109/L)* 11.5±4.76 11.9±4.88

Presence of splenomegaly

No n (%) 115 (90.6) 112 (88.2)

Yes n (%) 12 (9.4) 15 (11.8)

*values are mean ±SD.

Hydroxycarbamide treatment-naïve (n=160) or hydroxycarbamide treated (n=94) patients wererandomised to receive ropeginterferon alfa-2b or hydroxycarbamide. The dose was gradually increaseddepending on disease response and tolerability (for ropeginterferon alfa-2b, from 50 to500 micrograms administered subcutaneously every two weeks). The mean dose after 12 months oftreatment was 382 (±141) micrograms for ropeginterferon alfa-2b.

The disease response (defined as haematocrit <45% without phlebotomy [at least 3 months since lastphlebotomy], platelets <400 x 109/L and leukocytes <10 x 109/L after 12 months of treatment) was43.1% [53/123 of patients] in the ropeginterferon alfa-2b arm after 12 months of treatment.

An open-label, phase IIIb extension study (CONTINUATION-PV) enrolled 171 adult polycythaemiavera patients who previously completed the PROUD-PV Study to evaluate the long-term efficacy andsafety of ropeginterferon alfa-2b. Ninety-five patients continued to receive ropeginterferon alfa-2b(from 50 to 500 micrograms administered subcutaneously every two, three or four weeks). The meandose after 36 months of treatment (12-month treatment duration in the PROUD-PV Study and 24-month treatment duration in the extension study) was 363 (±149) micrograms for ropeginterferon alfa-2b.

The response to ropeginterferon alfa-2b treatment is presented in Table 3 and Table 4. After 36months of treatment, the complete haematological response was 70.5% and 52.6% of patients showeda complete haematological response with an improvement in disease burden.. Patients showed astatistically significant difference in the JAK2V617F allele burden (19.7%) and JAK2V617F allelechange from baseline (-22.9%).

Table 3. Disease response after 24 and 36 months of ropeginterferon alfa-2b.

Ropeginterferon alfa-2btreatment arm

Responder % (n/N)

Patients with 24 months of ropeginterferon alfa-2b treatment1

Complete haematological responsea 70.5 (67/95)

Complete haematological responsea and improvement in diseaseburdenb 49.5 (47/95)

Patients with 36 months of ropeginterferon alfa-2b treatment2

Complete haematological responsea 70.5 (67/95)

Complete haematological responsea and improvement in diseaseburdenb 52.6 (50/95)a defined as haematocrit <45% without phlebotomy (at least 3 months since last phlebotomy), platelets<400 x 109/L and leukocytes <10 x 109/L.b defined as the improvement of disease-related signs (clinically significant splenomegaly) and disease-relatedsymptoms (microvascular disturbances, pruritus, headache).112-month treatment duration in the PROUD-PV Study and 12-month treatment duration in the extension study212-month treatment duration in the PROUD-PV Study and 24-month treatment duration in the extension study

Table 4. JAK2V617F allele burden and changes from baseline in the CONTINUATION-PVextension study.

Ropeginterferon alfa-2b treatment arm1(n=94)

Mean % (± SD)

JAK2V617F allele burden 19.7 (±21.29)

JAK2V617F changes from baseline -22.9 (±24.79)1 Patients with 36 months of ropeginterferon alfa-2b treatment (12-month treatment duration in the PROUD-PV

Study and 24-month treatment duration in the extension study).

The European Medicines Agency has waived the obligation to submit the results of studies with

Besremi in all subsets of the paediatric population in the treatment of polycythaemia vera (see section4.2 for information on paediatric use).

The absorption of ropeginterferon alfa-2b is sustained in patients with peak serum concentrationsreached after 3 to 6 days.

The absolute bioavailability of subcutaneous administered ropeginterferon alfa-2b was notinvestigated in humans. Thus, no valid estimation of the absolute bioavailability could be done. Basedon data in monkeys, it is approx. 80%, similar to that seen forpegylated interferon alfa-2a.

Ropeginterferon alfa-2b is found mainly in the bloodstream and extracellular fluid as seen by thevolume of distribution at steady-state (Vd) of 6.6 to 17 litres in patients after subcutaneousadministration (dose range 50 - 450 micrograms). Mean Cmax was 2.4 ng/mL (with a dose of 50 -80 micrograms) to 49 ng/mL (with a dose of 450 micrograms) and AUC0-t ranged from 28.5 ng.h/mL(with a dose of 50 - 80 micrograms) to 552.6 ng.h/mL (with a dose of 450 micrograms) in patientsafter subcutaneous multiple dose administration. Inter-subject variability was observed with 25% and35% for AUC and Cmax, respectively, in healthy volunteers.

From mass balance, tissue distribution and whole body autoradioluminography studies performed inrats, it was shown that a similar interferon alfa medicinal product (pegylated interferon alfa-2a) wasdistributed to the liver, kidney and bone marrow in addition to being highly concentrated in the blood.

The metabolism of ropeginterferon alfa-2b is not fully characterised. The attachment of interferonalfa-2b to a high molecular weight (40 kDa) branched polyethylene glycol moiety is considered as themain reason for the differences in the elimination compared to unpegylated interferons. Studies in ratswith a similar interferon alfa medicinal product (pegylated interferon alfa-2a) showed a primarilyelimination via hepatic metabolism. The same elimination route is considered for ropeginterferonalfa-2b.

Pharmacokinetic interaction studies in humans with pegylated interferon alfa-2a indicated a moderateinhibitory effect on substrates metabolised by CYP1A2 and CYP2D6 (see section 4.5).

The elimination of ropeginterferon alfa-2b is not fully characterised. Studies with a similar interferonalfa medicinal product (pegylated interferon alfa-2a) indicated that the kidney is a major organ forexcretion of radiolabelled metabolic products (study in rats) and that the systemic clearance ofpegylated interferon alfa-2a in humans is about 100-fold lower compared to the native, unpegylatedinterferon alfa-2a.

After subcutaneous multiple dose administration (dose range 50 - 450 micrograms), the terminal half-life of ropeginterferon alfa-2b in patients is approximately 6 to 10 days and the clearance ofropeginterferon alfa-2b is 0.023 to 0.061 L/h.

The involvement of transport proteins in absorption, distribution and elimination of ropeginterferonalfa-2b is not known.

Over a dose range of 24 to 270 micrograms, ropeginterferon alfa-2b Cmax increased proportionally withdose in a pharmacokinetic study with healthy subjects. A higher than proportional increase in exposurewas observed. Inter-subject variability for ropeginterferon alfa-2b was 35% (Cmax) and 25% (AUC).

Comparable exposure and pharmacokinetic profile were reported for another interferon alfa medicinalproduct (pegylated interferon alfa-2a) in cirrhotic (Child-Pugh A) and non-cirrhotic patients.

Pharmacokinetics were not evaluated in patients with increased severity of hepatic impairment.

The pharmacokinetic profile in patients with moderate or severe renal impairment and in patients withend stage renal disease (ESRD) has been evaluated only for other pegylated interferon alfa medicinalproducts.

Patients with moderate or severe renal impairment receiving 180 micrograms of pegylated interferonalfa-2a once weekly showed a comparable or 60% higher drug plasma exposure, respectively,compared to subjects with normal renal function.

In 13 patients with ESRD requiring chronic haemodialysis, administration of 135 microgramspegylated interferon alfa-2a once weekly resulted in a 34% lower drug exposure than in patients withnormal renal function.

Patients with renal impairment receiving a single dose of 1.0 micrograms/kg pegylated interferonalfa-2b showed an increased relation of Cmax, AUC, and half-life to the degree of renal impairment.

Following multiple dosing of pegylated interferon alfa-2b (1.0 micrograms/kg subcutaneouslyadministered every week for four weeks), the clearance of pegylated interferon alfa-2b was reduced bya mean of 17% and 44% in patients with moderate or severe renal impairment, respectively, comparedto subjects with normal renal function. Based on single dose data, clearance was similar in patientswith severe renal impairment not on haemodialysis and in patients who received haemodialysis.

Only limited pharmacokinetic data are available from the use of ropeginterferon alfa-2b in the elderly.

Based on the results from the PROUD-PV and CONTINUATION-PV Study on drug exposure,pharmacodynamic response and tolerability, a dose adjustment for ropeginterferon alfa-2b is notconsidered necessary in the elderly population.

Obese or underweight patients

The pharmacokinetic profile of ropeginterferon alfa-2b has not been determined in obese andunderweight patients.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity and genotoxicity.

Reproductive and developmental studies were not performed with ropeginterferon alfa-2b. Interferonalfa was shown to be abortifacient in primates and ropeginterferon alfa-2b is expected to have asimilar effect. Effects on fertility was not assessed.

It is unknown if the active substance of the medicinal product is excreted into experimental animal orhuman milk (see section 4.6).

Sodium chloride

Sodium acetate, anhydrous

Acetic acid, glacial

Benzyl alcohol

Polysorbate 80

Water for injections

Not applicable.

Besremi 250 micrograms/0.5 mL solution for injection in pre-filled pen3 years.

Besremi 500 micrograms/0.5 mL solution for injection in pre-filled pen1.5 years.

After first use

The pre-filled pen may be stored for a maximum of 30 days in the refrigerator (2 °C - 8 °C) whenstored with the pen cap on and kept in the outer carton in order to protect from light. The pre-filled penmay be used up to two times within these 30 days. Any medicine remaining in the pre-filled pen afterthe second use and/or after 30 days must be discarded.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

Keep the pre-filled pen in the outer carton in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

Besremi 250 micrograms/0.5 mL solution for injection in pre-filled pen

The pre-filled pen is made of white polypropylene, with a grey push button and the strength“250 mcg/0.5 mL” highlighted in grey on the label. It delivers doses of 50 μg, 100 μg, 150 μg, 200 μgand 250 μg.

Besremi 250 micrograms/0.5 mL solution for injection in pre-filled pen is available in 2 pack-sizes:

- Packs containing 1 pre-filled pen and 2 injection needles

- Packs containing 3 pre-filled pens and 6 injection needles

Besremi 500 micrograms/0.5 mL solution for injection in pre-filled pen

The pre-filled pen is made of white polypropylene, with a blue push button and the strength“500 mcg/0.5 mL” highlighted in blue on the label. It delivers doses of 50 μg, 100 μg, 150 μg, 200 μg,250 μg, 300 μg, 350 μg, 400 μg, 450 μg and 500 μg.

Each pack of Besremi 500 micrograms/0.5 mL solution for in pre-filled pen contains:

- 1 pre-filled pen and 2 injection needles.

Each pre-filled pen contains a cartridge (type 1 colourless glass) with a grey plunger (bromobutylrubber) and a flanged cap (aluminium) with a stopper (bromobutyl rubber). The cartridge is sealed in apen injector. Each cartridge contains 0.5 mL of solution.

Before use, the pre-filled pen should be brought to room temperature (15 °C - 25 °C) for up to 15minutes.

Since Besremi is a solution, it does not require resuspension before use. Inspect the solution beforeuse. It may only be used if the solution is clear, colourless to pale yellow, with no particles visible.

The pre-filled pen label must always be checked before each injection to avoid medication errorsbetween Besremi 250 micrograms/0.5 mL solution for injection and Besremi 500 micrograms/0.5 mLsolution for injection. The 250 micrograms/0.5 mL pre-filled pen has a grey push button. The500 micrograms/0.5 mL pre-filled pen has a blue push button.

A new, sterile needle as provided with the pre-filled pen must be carefully attached onto the pre-filledpen before each injection. Needles must be discarded immediately after use.

If the pre-filled pen is used for the first time, the pen is prepared for injection by turning the dose knobuntil the icon of a “drop” in the display window is seen. While holding the pre-filled pen with theneedle pointing upwards, tap the pre-filled pen gently with the fingers so that any air bubbles risetowards the needle. Then press the push button until the display window shows “0”. This may berepeated up to six times. Once a droplet of liquid appears at the needle tip, the pre-filled pen and theneedle are working properly.

The dose can be set in steps of 50 micrograms by rotating the dose knob. If a certain dose cannot beset, an insufficient quantity of medicinal product may be left in the pen and a new pen must be used.

The needle should be inserted into the skin. The push button should be pressed in completely and helddown for at least 10 seconds before removing the needle.

To prevent possible transmission of disease or any kind of contamination, the use of Besremi pre-filledpen should remain strictly for a single patient, even when the needle is changed. The pre-filled penmay not be used more than twice and must be discarded 30 days after the first use, regardless of anymedicinal product remaining in the pre-filled pen.

Empty pens must never be reused and must be properly discarded.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

AOP Orphan Pharmaceuticals GmbH

Leopold-Ungar-Platz 21190 Vienna

Austria

EU/1/18/1352/001

EU/1/18/1352/002

EU/1/18/1352/003

15 February 2019

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.