Besremi

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
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 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
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 as 
measured 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 as 
measured on a protein basis, corresponding to 1,000 micrograms/mL. 
 
The strength indicates the quantity of the interferon alpha-2b moiety of ropeginterferon alfa-2b 
without 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). 
 
Excipient with known effect 
Each pre-filled pen contains 10 mg benzyl alcohol per mL. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Solution for injection in pre-filled pen (injection). 
 
Clear, colourless to pale yellow solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Besremi is indicated as monotherapy in adults for the treatment of polycythaemia vera without 
symptomatic splenomegaly. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated under supervision of a physician experienced in the management of the 
disease. 
 
Posology 



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Titration phase 
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.  
 
Maintenance phase 
The dose at which stabilisation of the haematological 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 haematological parameters (haematocrit, platelets, leukocytes) is observed, the dose 
and/or dosing interval needs to be adapted individually.  
 
Special populations 
 
Hepatic impairment 
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 (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. 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 (see section 4.4).  
 
Renal impairment 
The pharmacokinetic profile of other interferon alfa medicinal products (pegylated interferon alfa-2a 
and 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 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) (see section 4.3). 
 
Elderly 
Adjustments in the recommended dose for ropeginterferon alfa-2b are not necessary when starting 
therapy in elderly patients (see section 5.2). 
 
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.  
 
Paediatric population 
The safety and efficacy of Besremi in children and adolescents has not been established. No data are 
available (see section 4.4). 
 
Method of administration  



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For subcutaneous use. The medicinal product is intended for long-term treatment and can be 
administered by a physician, nurse, family member or patient when trained in the administration of 
subcutaneous injections with the pre-filled pen. The instructions for use in the package leaflet should 
be followed. 
 
The recommended injection site is the abdominal skin around but not within 5 cm of the navel or the 
thigh. Do not inject into an area where the skin is irritated, reddened, bruised, infected or scarred. The 
pen can be adjusted to administer doses in 50 microgram intervals in the range of 50 to 
250 micrograms or 50 to 500 micrograms.  
 
4.3 Contraindications 
 

• 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 

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 (see section 4.5) 
• Decompensated cirrhosis of the liver (Child-Pugh B or C) 
• End stage renal disease (GFR <15 mL/min) 

 
4.4 Special warnings and precautions for use 
 
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, in particular 
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.  
 
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, in particular depression, have been observed in some patients treated with 
ropeginterferon alfa-2b during the clinical development program (see section 4.8). Other CNS effects, 



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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 (see section 4.3). 
 
Cardiovascular system 
Cardiac events including cardiomyopathy, myocardial infarction, atrial fibrillation and ischaemic 
coronary artery disorders have been associated with interferon alfa treatment (see section 4.8). 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 (see section 4.3). 
 
Respiratory system 
Respiratory disorders such as lung infiltration, pneumonitis, pneumonia or pulmonary arterial 
hypertension 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 and 
retinal artery or vein occlusion which may result in blindness have been observed rarely in patients 
treated with interferon alfa (see section 4.8). 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. 
 
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 instituted 
immediately. Transient rashes do not necessitate interruption of treatment. 
 
Liver function 
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 (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) 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 (see 
section 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 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 (see section 4.3). 
 
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 (see section 4.3). 



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Dental and periodontal disorders 
Dental and periodontal disorders, which may lead to loss of teeth, have been reported with other 
interferon alfa medicinal products (see section 4.8). 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. 
 
Skin disorders 
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. 
 
Excipients 
Besremi 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).  
 
Besremi contains less than 1 mmol sodium (23 mg) per mL, that is to say essentially ‘sodium-free’. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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 (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 
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. 



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Narcotics, hypnotics or sedatives must be administered with caution when used concomitantly with 
ropeginterferon alfa-2b. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception in females 
Women of childbearing potential have to 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). An abortifacient effect was 
reported in primates receiving other interferon alfa medicinal products. 
As ropeginterferon alfa-2b may have the same effect, this medicinal product is not recommended 
during pregnancy. 
 
Breast-feeding 
It is unknown whether the active substance of the medicinal product is excreted in human milk. A risk 
to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-
feeding or to discontinue/abstain from ropeginterferon alfa-2b therapy taking into account the benefit 
of breast feeding for the child and the benefit of therapy for the woman. 
 
Fertility 
There are no data on the effect of ropeginterferon alfa-2b therapy on the fertility of females or males.  
 
4.7 Effects on ability to drive and use machines 
 
Besremi has minor influence on the ability to drive and use machines. Patients who experience 
dizziness, somnolence or hallucination (see section 4.8) during Besremi therapy should avoid driving 
or using machines.  
 
4.8 Undesirable effects 
 
Summary of the safety profile 
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%), increased 
aspartate 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%).  
 
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 
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 
available data). 
 
System organ class Frequency Adverse reaction 
Infections and 
infestations 

common respiratory tract infection, rhinitis, fungal skin infection 
uncommon oral herpes, herpes zoster, oral candidiasis, sinusitis, 

oesophageal candidiasis, vulvovaginal mycotic infection, 
hordeolum, onychomycosis 



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Blood and lymphatic 
system disorders 

very common leukopenia, thrombocytopenia 
common pancytopenia, neutropenia, anaemia 

Immune system 
disorders 

uncommon Basedow's disease, sarcoidosis 
very rare idiopathic or thrombotic thrombocytopenic purpura# 
not known Vogt-Koyanagi-Harada disease#, acute hypersensitivity 

reactions#** 
Endocrine disorders common hypothyroidism, hyperthyroidism, thyroiditis 

uncommon diabetes mellitus# 
Metabolism and 
nutrition disorders 

common 
 

hypertriglyceridaemia, decreased appetite 
 

Psychiatric disorders 
 

common depression, aggression#, insomnia, anxiety, mood altered, 
mood swings, listless  

uncommon suicide attempt#, suicidal ideation#, confusional state#, 
acute stress disorder, hallucination, emotional distress, 
nervousness, apathy, nightmare, irritability 

rare bipolar disorder#, mania# 
Nervous system 
disorders 
 

common headache, dizziness, hypoesthesia, somnolence, 
paraesthesia  

uncommon polyneuropathy, peripheral motor neuropathy, 
radiculopathy, migraine, mental impairment, tremor, aura 

Eye disorders 
 

common dry eye 
uncommon retinal haemorrhage#, retinal exudates#, visual impairment, 

visual acuity reduced, vision blurred, ocular discomfort, 
eczema eyelids 

rare retinopathy#, optic neuropathy#, retinal artery occlusion#, 
retinal vein occlusion#,  

very rare blindness# 
not known retinal detachment# 

Ear and labyrinth 
disorders 

uncommon deafness, tinnitus, vertigo 

Cardiac disorders 
 

common atrial fibrillation 
uncommon myocardial infarction#, atrioventricular block, intracardiac 

thrombus, aortic valve incompetence, cardiovascular 
disorder 

rare cardiomyopathy#, angina pectoris# 
very rare myocardial ischemia# 

Vascular disorders 
 

common microangiopathy  
uncommon Raynaud's phenomenon, hypertension, haematoma, 

flushing 
Respiratory, thoracic 
and mediastinal 
disorders 

common dyspnoea 

uncommon pneumonitis, cough, epistaxis, throat irritation 
very rare  lung infiltration# 
not known pulmonary fibrosis#, pneumonia#, pulmonary arterial 

hypertension#* 
Gastrointestinal 
disorders 
 

common diarrhoea, nausea, abdominal pain, constipation, 
abdominal distension, dry mouth 

uncommon gastritis, abdominal wall disorder, flatulence, frequent 
bowel movements, odynophagia, gingival bleeding 

not known tooth disorder#, periodontal disease# 
Hepatobiliary very common gamma-glutamyltransferase increased 



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disorders 
 

common liver disorder, alanine aminotransferase increased, 
aspartate aminotransferase increased, blood alkaline 
phosphatase increased  

uncommon hepatotoxicity, hepatitis toxic, hepatomegaly 
rare hepatic failure# 

Skin and 
subcutaneous tissue 
disorders 

common pruritus, alopecia, rash, erythema, psoriasis, xeroderma, 
dermatitis acneiform, hyperkeratosis, hyperhidrosis, dry 
skin 

uncommon photosensitivity reaction, skin exfoliation, nail dystrophy  
not known skin depigmentation# 

Musculoskeletal and 
connective tissue 
disorders 
 

very common arthralgia, myalgia 
common Sjogren's syndrome, arthritis, pain in extremity, 

musculoskeletal pain, bone pain, muscle spasms  
uncommon muscular weakness, neck pain, groin pain 

Renal and urinary 
disorders  

uncommon cystitis haemorrhagic, dysuria, micturition urgency, 
urinary retention 

Reproductive system 
and breast disorders 

uncommon erectile dysfunction, haematospermia 

General disorders 
and administration 
site conditions 

very common influenza like illness, fatigue 
 

common pyrexia, injection site reaction, asthenia, chills, general 
physical health deterioration, injection site erythema 

uncommon injection site pain, injection site pruritus, sensitivity to 
weather change 

not known: tongue hyperpigmentation# 
Investigations 
 

common antithyroid antibody positive, blood thyroid stimulating 
hormone increased, body temperature increased, 
antinuclear antibody positive, blood lactate dehydrogenase 
increased 

uncommon 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. 
 
Description of selected adverse reactions 
 
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 clinical 
development program are summarised in Table 1. 
 
Table 1. Most common adverse reactions during ropeginterferon alfa-2b treatment. 
Ropeginterferon alfa-2b clinical studies  
ADR >10% 
PT 

 
N (%) 
 

 
IR 
 

CTCAE 
intensity 
grade ≥3 

N (%) 

Dose 
reduced 

 
N (%) 

Drug 
interrupted 

 
N (%) 

Drug 
discontinued 

 
N (%) 

Recovered 
 
 

N (%) 
(N=178)      

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

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

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) 



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Influenza 
like illness  

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

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 drug 
reaction; PT, preferred term; IR, incidence rate of mean adverse events per 100 patients per year; N: number of 
patients.  
 
Gastrointestinal disorders 
Gastrointestinal disorders have been reported with other interferon alfa medicinal products and have 
been reported in 15.2% of patients with ropeginterferon alfa-2b treatment. The most common 
gastrointestinal 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 after 
permanent medicinal product discontinuation. One patient who experienced serious acute stress 
disorder (0.6%; incidence rate: 0.2 events/100 patients per year) with moderate intensity recovered 
completely after the dose of ropeginterferon alfa-2b was reduced. CNS effects including suicide 
attempt, suicidal ideation, aggression, bipolar disorder, mania and confusion have been reported with 
interferon 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. Ropeginterferon 
alfa-2b treatment was continued and the patients received appropriate medicinal products to treat these 
events. Patients recovered from the two events, one event was ongoing at the time of assessment.  
 
Respiratory system 
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa, 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. 
 
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 of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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.  
 
 
5. PHARMACOLOGICAL PROPERTIES 
 

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5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Immunostimulants, interferons, ATC code: L03AB15 
 
Ropeginterferon alfa-2b is a recombinant interferon alfa-2b conjugated with a two-arm 
methoxypolyethylene 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 constitutes 
approximately 40 kDa . 
 
Mechanism of action 
Interferon alfa belongs to the class of type I interferons which exhibit their cellular effects by binding 
to a transmembrane receptor termed interferon alfa receptor (IFNAR). Binding to IFNAR initiates a 
downstream signalling cascade through the activation of kinases, in particular Janus kinase 1 (JAK1) 
and tyrosine kinase 2 (TYK2) and activator of transcription (STAT) proteins. Nuclear translocation of 
STAT proteins controls distinct gene-expression programs and exhibit various cellular effects. 
Interferon alfa was shown to have an inhibitory effect on the proliferation of hematopoietic and bone 
marrow fibroblast progenitor cells and antagonised the action of growth factors and other cytokines 
that have a role in the development of myelofibrosis. These actions may be involved in the therapeutic 
effects of interferon alfa in polycythaemia vera. 
Further, it was demonstrated that interferon alfa is able to decrease the mutated JAK2V617F allele 
burden in patients with polycythaemia vera (a V617F point mutation in the JAK2 kinase is a hallmark 
of polycythaemia vera and is present in approximately 95% of patients).  
 
Clinical efficacy and safety 
An open label, randomised phase III study (PROUD-PV) evaluated the efficacy and safety of 
ropeginterferon alfa-2b in comparison to hydroxycarbamide in 254 adult polycythaemia vera patients 
(randomisation 1:1). Patients were stratified by previous exposure to hydroxycarbamide, age at 
screening (≤60 or >60 years) and presence of thromboembolic events in the past. Characteristics of the 
study population are presented in Table 2.  
 
Table 2. Patient characteristics at screening in the PROUD-PV Study. 
 Ropeginterferon alfa-2b 

treatment arm 
(n=127) 

Control 
treatment arm 
(n=127) 

Age  
 Years* 

 
58.5 ±10.81 

 
57.9±13.10 

Gender  
  Female n (%) 
  Male n (%) 

 
68 (53.5) 
59 (46.5) 

 
67 (52.8) 
60 (47.2) 

Race 
  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 (%)* 
  Platelets (109/L)* 
  Leukocytes (109/L)* 

 
47.8±5.22 
537.7±273.08 
11.5±4.76 

 
48.6±5.39 
516.8±254.43 
11.9±4.88 

Presence of splenomegaly 
  No n (%) 
  Yes n (%) 

 
115 (90.6) 
12 (9.4) 

 
112 (88.2) 
15 (11.8) 

*values are mean ±SD.  
 
Hydroxycarbamide treatment-naïve (n=160) or hydroxycarbamide treated (n=94) patients were 
randomised to receive ropeginterferon alfa-2b or hydroxycarbamide. The dose was gradually increased 
depending on disease response and tolerability (for ropeginterferon alfa-2b, from 50 to 



12 

500 micrograms administered subcutaneously every two weeks). The mean dose after 12 months of 
treatment was 382 (±141) micrograms for ropeginterferon alfa-2b.  
The disease response (defined as haematocrit <45% without phlebotomy [at least 3 months since last 
phlebotomy], platelets <400 x 109/L and leukocytes <10 x 109/L after 12 months of treatment) was 
43.1% [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 polycythaemia 
vera patients who previously completed the PROUD-PV Study to evaluate the long-term efficacy and 
safety 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 mean 
dose 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 36 
months of treatment, the complete haematological response was 70.5%. Almost 50% of patients 
showed a complete haematological response with an improvement in disease burden after 36 months 
of treatment. Patients showed a statistically significant difference in the JAK2V617F allele burden 
(19.7%) and JAK2V617F allele change from baseline (-22.9%).  
 
Table 3. Disease response after 24 and 36 months of ropeginterferon alfa-2b. 
 Ropeginterferon alfa-2b 

treatment 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 disease 
burdenb 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 disease 
burdenb 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-related 
symptoms (microvascular disturbances, pruritus, headache).  
112-month treatment duration in the PROUD-PV Study and 12-month treatment duration in the extension study 
212-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-PV 
extension 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). 
 
Paediatric population 
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 section 
4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 



13 

The absorption of ropeginterferon alfa-2b is sustained in patients with peak serum concentrations 
reached after 3 to 6 days. 
 
The absolute bioavailability of subcutaneous administered ropeginterferon alfa-2b was not 
investigated in humans. Thus, no valid estimation of the absolute bioavailability could be done. Based 
on data in monkeys, it is approx. 80%, similar to that seen for pegylated interferon alfa-2a. 
 
Distribution 
Ropeginterferon alfa-2b is found mainly in the bloodstream and extracellular fluid as seen by the 
volume of distribution at steady-state (Vd) of 6.6 to 17 litres in patients after subcutaneous 
administration (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 patients 
after subcutaneous multiple dose administration. Inter-subject variability was observed with 25% and 
35% for AUC and Cmax, respectively, in healthy volunteers. 
 
From mass balance, tissue distribution and whole body autoradioluminography studies performed in 
rats, it was shown that a similar interferon alfa medicinal product (pegylated interferon alfa-2a) was 
distributed to the liver, kidney and bone marrow in addition to being highly concentrated in the blood. 
 
Biotransformation 
The metabolism of ropeginterferon alfa-2b is not fully characterised. The attachment of interferon 
alfa-2b to a high molecular weight (40 kDa) branched polyethylene glycol moiety is considered as the 
main reason for the differences in the elimination compared to unpegylated interferons. Studies in rats 
with a similar interferon alfa medicinal product (pegylated interferon alfa-2a) showed a primarily 
elimination via hepatic metabolism. The same elimination route is considered for ropeginterferon 
alfa-2b. 
 
Pharmacokinetic interaction studies in humans with pegylated interferon alfa-2a indicated a moderate 
inhibitory effect on substrates metabolised by CYP1A2 and CYP2D6 (see section 4.5). 
 
Elimination 
The elimination of ropeginterferon alfa-2b is not fully characterised. Studies with a similar interferon 
alfa medicinal product (pegylated interferon alfa-2a) indicated that the kidney is a major organ for 
excretion of radiolabelled metabolic products (study in rats) and that the systemic clearance of 
pegylated interferon alfa-2a in humans is about 100-fold lower compared to the native, unpegylated 
interferon 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 of 
ropeginterferon alfa-2b is 0.023 to 0.061 L/h.  
 
The involvement of transport proteins in absorption, distribution and elimination of ropeginterferon 
alfa-2b is not known. 
 
Linearity/non-linearity 
Over a dose range of 24 to 270 micrograms, ropeginterferon alfa-2b Cmax increased proportionally with 
dose in a pharmacokinetic study with healthy subjects. A higher than proportional increase in exposure 
was observed. Inter-subject variability for ropeginterferon alfa-2b was 35% (Cmax) and 25% (AUC). 
 
Hepatic impairment 
Comparable exposure and pharmacokinetic profile was reported for another interferon alfa medicinal 
product (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. 
 
Renal impairment 



14 

The pharmacokinetic profile in patients with moderate or severe renal impairment and in patients with 
end stage renal disease (ESRD) has been evaluated only for other pegylated interferon alfa medicinal 
products.  
Patients with moderate or severe renal impairment receiving 180 micrograms of pegylated interferon 
alfa-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 micrograms 
pegylated interferon alfa-2a once weekly resulted in a 34% lower drug exposure than in patients with 
normal renal function.  
 
Patients with renal impairment receiving a single dose of 1.0 micrograms/kg pegylated interferon 
alfa-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 subcutaneously 
administered every week for four weeks), the clearance of pegylated interferon alfa-2b was reduced by 
a mean of 17% and 44% in patients with moderate or severe renal impairment, respectively, compared 
to subjects with normal renal function. Based on single dose data, clearance was similar in patients 
with severe renal impairment not on haemodialysis and in patients who received haemodialysis. 
 
Elderly 
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 not 
considered necessary in the elderly population. 
 
Obese or underweight patients 
The pharmacokinetic profile of ropeginterferon alfa-2b has not been determined in obese and 
underweight patients.  
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity and genotoxicity.  
 
Reproductive and developmental studies were not performed with ropeginterferon alfa-2b. Interferon 
alfa was shown to be abortifacient in primates and ropeginterferon alfa-2b is expected to have a 
similar effect. Effects on fertility was not assessed.  
 
It is unknown if the active substance of the medicinal product is excreted into experimental animal or 
human milk (see section 4.6).  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium chloride 
Sodium acetate, anhydrous 
Acetic acid, glacial 
Benzyl alcohol 
Polysorbate 80 
Water for injections 
 
6.2 Incompatibilities 
 
Not applicable.  
 
6.3 Shelf life 



15 

 
Besremi 250 micrograms/0.5 mL solution for injection in pre-filled pen 
3 years. 
 
Besremi 500 micrograms/0.5 mL solution for injection in pre-filled pen 
1.5 years. 
 
After first use 
The pre-filled pen may be stored for a maximum of 30 days in the refrigerator (2 °C - 8 °C) when 
stored with the pen cap on and kept in the outer carton in order to protect from light. The pre-filled pen 
may be used up to two times within these 30 days. Any medicine remaining in the pre-filled pen after 
the second use and/or after 30 days must be discarded. 
 
6.4 Special precautions for storage 
 
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. 
 
6.5 Nature and contents of container  
 
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 μg 
and 250 μg. 
 
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 pre-filled pen contains a cartridge (type 1 colourless glass) with a grey plunger (bromobutyl 
rubber) and a flanged cap (aluminium) with a stopper (bromobutyl rubber). The cartridge is sealed in a 
pen injector. Each cartridge contains 0.5 mL of solution. 
 
Each pack contains 1 pre-filled pen and 2 injection needles. 
 
6.6 Special precautions for disposal and other handling 
 
Before use, the pre-filled pen should be brought to room temperature (15 °C - 25 °C) for up to 15 
minutes. 
Since Besremi is a solution, it does not require resuspension before use. Inspect the solution before 
use. 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 errors 
between Besremi 250 micrograms/0.5 mL solution for injection and Besremi 500 micrograms/0.5 mL 
solution for injection. The 250 micrograms/0.5 mL pre-filled pen has a grey push button. The 
500 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-filled 
pen 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 knob 
until the symbol of a “drop” in the display window is seen. While holding the pre-filled pen with the 
needle pointing upwards, tap the pre-filled pen gently with the fingers so that any air bubbles rise up 



16 

towards the needle. Then press the push button until the display window shows “0”. This may be 
repeated up to six times. Once a droplet of liquid appears at the needle tip, the pre-filled pen and the 
needle are working properly.  
 
The dose can be set in steps of 50 micrograms by rotating the dose knob. If a certain dose cannot be 
set, 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 held 
down 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-filled 
pen should remain strictly for a single patient, even when the needle is changed. The pre-filled pen 
may not be used more than twice, and must be discarded 30 days after the first use, regardless of any 
medicinal 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 local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
AOP Orphan Pharmaceuticals AG 
Wilhelminenstrasse 91/II f 
1160 Vienna 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1352/001 
EU/1/18/1352/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
  

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


17 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE 
SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE 
FOR BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



18 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer(s) of the biological active substance(s)  
PharmaEssentia Corp. 
3F, No. 28, Keya West Road 
Daya District 
428 Taichung 
TAIWAN 
 
Name and address of the manufacturer(s) responsible for batch release 
AOP Orphan Pharmaceuticals AG 
Wilhelminenstrasse 91/IIf 
1160 Vienna 
Austria 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic safety update reports  
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder shall submit the first periodic safety update report for this product 
within 6 months following authorisation. 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required  pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 
updates of the RMP. 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.  

 
 
  



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



21 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Besremi 250 micrograms/0.5 mL solution for injection in pre-filled pen 
ropeginterferon alfa-2b 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each pre-filled pen of 0.5 mL solution contains 250 micrograms of ropeginterferon alfa-2b as 
measured on a protein basis, corresponding to 500 micrograms/mL. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains sodium chloride, polysorbate 80, anhydrous sodium acetate, glacial acetic acid, water 
for injections, and benzyl alcohol.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection in pre-filled pen 
1 pre-filled pen + 2 injection needles 
0.5 mL solution 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Subcutaneous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
Shelf life after first use: may be stored for a maximum of 30 days in the refrigerator (2 °C - 8 °C) 
when stored with the pen cap on and kept in the outer carton in order to protect from light. 
Opened date: 
 
 



22 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Keep the pre-filled pen in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AOP Orphan Pharmaceuticals AG 
Wilhelminenstrasse 91/II f 
1160 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1352/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Besremi 250 micrograms/0.5 mL 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  



23 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
PEN LABEL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Besremi 250 mcg/0.5 mL injection 
ropeginterferon alfa-2b 
SC 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.5 mL 
 
 
6. OTHER 
 
 



24 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Besremi 500 micrograms/0.5 mL solution for injection in pre-filled pen 
ropeginterferon alfa-2b 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each pre-filled pen of 0.5 mL solution contains 500 micrograms of ropeginterferon alfa-2b as 
measured on a protein basis, corresponding to 1,000 micrograms/mL. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains sodium chloride, polysorbate 80, anhydrous sodium acetate, glacial acetic acid, water 
for injections, and benzyl alcohol. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Solution for injection in pre-filled pen 
1 pre-filled pen + 2 injection needles 
0.5 mL solution 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Subcutaneous use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
Shelf life after first use: may be stored for a maximum of 30 days in the refrigerator (2 °C - 8 °C) 
when stored with the pen cap on and kept in the outer carton in order to protect from light. 
Opened date: 
 
 



25 

9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator. 
Do not freeze. 
Keep the pre-filled pen in the outer carton in order to protect from light. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
AOP Orphan Pharmaceuticals AG 
Wilhelminenstrasse 91/II f 
1160 Vienna 
Austria 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/18/1352/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Besremi 500 micrograms/0.5 mL 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  



26 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
PEN LABEL  
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Besremi 500 mcg/0.5 mL injection 
ropeginterferon alfa-2b 
SC 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
0.5 mL 
 
 
6. OTHER 
 
  



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



28 

Package leaflet: Information for the user 
 

Besremi 250 micrograms/0.5 mL solution for injection in pre-filled pen 
ropeginterferon alfa-2b 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Besremi is and what it is used for 
2. What you need to know before you use Besremi 
3. How to use Besremi 
4. Possible side effects 
5. How to store Besremi 
6. Contents of the pack and other information 
 
 
1. What Besremi is and what it is used for 
 
Besremi contains the active substance ropeginterferon alfa-2b, which belongs to the class of medicinal 
products called interferons. Interferons are produced by your immune system to block the growth of 
cancer cells. 
 
Besremi is used as monotherapy for the treatment of polycythaemia vera in adults. Polycythaemia vera 
is a type of cancer in which the bone marrow produces too many red blood cells, white blood cells and 
platelets (cells that help the blood to clot). 
 
 
2. What you need to know before you use Besremi 
 
Do not use Besremi: 

- if you are allergic to ropeginterferon alfa-2b or any of the other ingredients of this medicine 
(listed in section 6). 

- if you have thyroid disease that is not controlled with medicines. 
- if you have or had severe mental disorders (such as depression or suicidal thoughts or if you 

tried to kill yourself). 
- if you have or had severe heart problems (such as heart attack or stroke). 
- if you have or had an autoimmune disease (such as rheumatoid arthritis, psoriasis or 

inflammatory bowel disease). 
- if you had an organ transplantation and you take medicines which suppress your immune 

system. 
- if you take telbivudine (a medicine used to treat hepatitis B infection). 
- if you have advanced, uncontrolled liver disease. 
- if you have severe kidney disease (with your kidneys working at less than 15% of their normal 

ability). 



29 

 
Warnings and precautions 
Talk to your doctor before using Besremi: 

- if you have thyroid disease. 
- if you have diabetes or high blood pressure − your doctor may ask you to have an eye 

examination. 
- if you have liver problems − you will have blood tests regularly to check how your liver is 

working if you are on a long-term Besremi therapy. 
- if you have kidney problems. 
- if you have psoriasis or other skin problems because they may get worse during treatment with 

Besremi. 
 

Once you have started Besremi treatment, talk to your doctor: 
- if you develop symptoms of depression (such as feelings of sadness, dejection, and suicidal 

thoughts). 
- if you develop signs of a severe allergic reaction (such as difficulty in breathing, wheezing or 

hives) while using Besremi – if this is the case you will need to seek medical help immediately. 
- if you develop symptoms of a cold or other respiratory infection (such as difficulty in breathing, 

cough, fever and chest pain). 
- if you have changes in your vision − you must tell your doctor and have an immediate eye 

examination. Severe eye problems may occur during Besremi therapy. Your doctor will usually 
check your vision before starting your treatment. If you have health problems which may lead to 
eye problems such as diabetes or high blood pressure, you doctor should check your vision also 
during treatment. If your vision worsens, your doctor may decide to discontinue your treatment. 

 
Dental and gum disorders, which may lead to loss of teeth, can occur with interferon medicines. In 
addition, dry mouth could damage teeth and the lining of the mouth during long-term treatment with 
Besremi. You should brush your teeth thoroughly twice daily and have regular dental checks. 
 
It will need a certain time to reach your individual optimal dose of Besremi. Your doctor will decide if 
it is necessary to treat you with another medicine for an early reduction of your blood cell number to 
prevent blood clots and bleeding. 
 
Children and adolescents 
Do not give this medicine to children and adolescents because no information is available on the use of 
Besremi in this age group. 
 
Other medicines and Besremi 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
 
Do not use Besremi if you are taking telbivudine (for treating hepatitis B) since the combination of 
these medicines increases the risk of peripheral neuropathy (numbness, tingling, or burning sensations 
in the arms and legs). Tell your doctor if you are being treated with telbivudine. 
 
Tell your doctor especially if you are taking any of the following medicines: 

- theophylline (a medicine used to treat respiratory diseases such as asthma) 
- methadone (a medicine used to treat pain or opioid dependence) 
- vortioxetine or risperidone (medicines used to treat mental disorders) 
- anti-cancer medicines such as those stopping or slowing the growth of blood-forming cells in 

the bone marrow (e.g. hydroxycarbamide) 
- medicines that work on the central nervous system to relieve pain, help you sleep, or have a 

calming effect (e.g. morphine, midazolam) 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before using this medicine. 



30 

 
Pregnancy 
The effect of Besremi during pregnancy is not known. The use of Besremi is not recommended during 
pregnancy. If you are a woman of childbearing potential, your doctor will discuss with you if effective 
birth control should be used during your treatment with Besremi. 
 
Breast-feeding 
It is not known if Besremi is present in breast milk. Your doctor will help you decide if you have to 
stop breast-feeding when you are using this medicine. 
 
Driving and using machines 
Do not drive or use machines if you feel dizzy, sleepy or confused while using Besremi. 
 
Besremi contains benzyl alcohol 
This medicine contains 5 mg benzyl alcohol in each 0.5 mL. Benzyl alcohol may cause allergic 
reactions. 
Ask your doctor or pharmacist for advice: 

- if you are pregnant or breast-feeding. 
- if you have a liver or kidney disease. 

This is because large amounts of benzyl alcohol can build-up in your body and may cause side effects 
(called “metabolic acidosis”). 
 
Besremi contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially ‘sodium-
free’. 
 
 
3. How to use Besremi 
 
Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
The dose will be set individually for you by your doctor for your condition. The usual starting dose of 
Besremi is 100 microgram every 2 weeks. Your doctor will then increase your dose stepwise and may 
adjust your dose during treatment. 
Your doctor will reduce your starting dose to 50 microgram if you have severe kidney problems. 
 
This medicine is for subcutaneous use which means that it is injected in the tissue under your skin. It 
should not be injected into an area of the body where the skin is irritated, reddened, bruised, infected 
or scarred. 
If you are injecting this medicine yourself, you will get clear instructions on how to prepare and inject 
it. 
To prevent passing on infectious diseases, you should never share Besremi pre-filled pen with anyone 
else, even when the needle is changed. 
 
Details on how to prepare and inject Besremi are given in the Instructions for Use. Read them 
before you start using Besremi. 
 
If you use more Besremi than you should 
Tell your doctor as soon as possible. 
 
If you forget to use Besremi 
You should inject the dose as soon as you remember. However, if more than 2 days have passed since 
you missed the dose, leave out the dose and inject the next dose when it is due. Do not inject a double 
dose to make up for a forgotten dose. Check with your doctor or pharmacist if you are not sure. 
 
If you stop using Besremi 



31 

Do not stop using Besremi before you have talked to your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Contact your doctor immediately if you notice any of the following serious side effects during 
your treatment with Besremi: 
 
Common side effects (may affect up to 1 in 10 people): 

- changes in your heart beat (when the heart beats very fast and uneven) 
 
Uncommon side effects (may affect up to 1 in 100 people): 

- attempted suicide, thoughts about killing yourself 
- loss of vision which may be caused by bleeding in the retina (the retina is the light-sensitive 

layer in the eye), or by build-up of fat in or under the retina  
 
Rare side effects (may affect up to 1 in 1,000 people): 

- loss of vision which may be caused by damage to the retina (such as obstruction of the blood 
vessels in the eye) or the optic nerve 

 
Very rare side effects (may affect up to 1 in 10,000 people): 

- blindness 
- breathing problems including shortness of breath, cough and chest pain which may be caused by 

lung infiltration, pneumonia (lung infection), pulmonary arterial hypertension (high blood 
pressure in the blood vessels bringing blood from the heart to the lungs) and pulmonary fibrosis 
(a lung disease where scars are formed in the lung tissue) 

 
Side effects with frequency not known (cannot be estimated from the available data): 

- detachment of the retina (you may experience eye problems including changes in vision) 
 
Other side effects 
 
Very common side effects (may affect more than 1 in 10 people): 

- decrease in the number of a type of white blood cells (called leucocytes) and in blood clotting 
cells (called platelets) 

- joint or muscle pain 
- flu-like symptoms, feeling tired 
- in blood tests: increase of an enzyme called gamma-glutamyltransferase 

 
Common side effects (may affect up to 1 in 10 people): 

- infection of the respiratory tract, runny or stuffy nose, fungal infections 
- decrease in the number or size of red blood cells 
- increase or decrease in the thyroid gland activity, increase of thyroid stimulating hormone, 

inflammation of the thyroid gland 
- increase of triglycerides (a type of lipid) in the blood, decreased appetite 
- aggressive behaviour, feeling depressed, feeling anxious, problems with falling asleep or 

staying asleep, mood changes, lacking bodily energy or motivation 
- headache, feeling dizzy, reduced sense of touch or sensation, feeling sleepy, sensation of 

tingling and ‘pins and needles’ 
- dry eyes 
- damage of the capillaries (very small blood vessels) in the body 
- breathing problems 



32 

- diarrhoea, nausea, abdominal pain or stomach discomfort, constipation, dry mouth 
- liver disorder, increase in certain liver enzymes (shown in blood tests) 
- itching, hair loss, rash, redness of skin, psoriasis, dry and scaly skin, acne, thickening of the 

outer layer of the skin, increased sweating 
- a disorder called Sjogren's syndrome where the body’s immune system attacks glands that 

produce fluid (such as the tear and saliva glands), arthritis, pain in arms and legs, bone pain, 
painful sudden tightening of a muscle 

- fever, weakness, chills, general health problems, irritation or redness at the site of injection 
- in blood tests: antibodies which are produced by the body´s immune system, increase of an 

enzyme called lactate dehydrogenase 
 
Uncommon side effects (may affect up to 1 in 100 people): 

- infection and re-infection with herpes, bacterial infections 
- increase in the number of platelets 
- autoimmune disorder of the thyroid gland, sarcoidosis (areas of inflamed tissue in different parts 

of the body) 
- diabetes 
- panic attack, hallucination (seeing, hearing or feeling things that are not there), feeling stressed, 

feeling nervous, lack of interest in activities, nightmare, irritability, confusion 
- damage to the nervous system, migraine, mental disorder (health condition involving changes in 

thinking, emotion or behaviour), visual or sensory disturbances, shaky hands 
- eye discomfort, eyelid eczema 
- hearing loss, ringing in ears (tinnitus), spinning feeling (vertigo) 
- heart disorders such as heart block (a disorder in the heart´s electrical activity), blood clots in 

the blood vessels of the heart, leakage of the aortic valve 
- high blood pressure, reduced blood supply to certain parts of the body, haematoma (collection 

of blood under the skin), flushing 
- inflammation of lung tissue, coughing, nosebleed, sore throat 
- inflammation of the stomach, abdominal wall disorder, intestinal gas, indigestion, painful 

swallowing, bleeding gums 
- inflammation of the liver, damage to the liver, enlarged liver 
- sensitivity to sunlight, peeling of the skin, nail disorder 
- muscle weakness, neck pain, groin pain 
- inflammation of the bladder, painful urination, increased need to urinate, inability to urinate 
- sexual problems 
- pain or itching at the site of injection, sensitivity to weather change 
- loss of weight 
- in blood tests: increase of uric acid, antibodies produced by the body´s immune system against 

red blood cells 
 
Rare side effects (may affect up to 1 in 1,000 people): 

- bipolar disorders (mood disorders with episodes of sadness and excitement), mania (extreme 
excitement or unreasonable enthusiasm) 

- cardiomyopathy (diseases that affect the heart muscle), angina pectoris (a severe chest pain as a 
result of blockage of the heart vessels) 

- liver failure 
 
Very rare side effects (may affect up to 1 in 10,000 people): 

- idiopathic or thrombotic thrombocytopenic purpura (increased bruising, bleeding, decreased 
platelets, anaemia and extreme weakness) 

- myocardial ischemia (reduced blood flow to your heart muscle) 
 
Side effects with frequency not known (cannot be estimated from the available data): 

- Vogt-Koyanagi-Harada disease (a rare disease that can lead to loss of vision, hearing and skin 
pigmentation), severe allergic reaction 

- discolouration of the skin 



33 

- periodontal (affecting gums) and dental disorders, change in colour of the tongue 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Besremi 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label and the outer carton after 
“EXP”. The expiry date refers to the last day of that month. 
 
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. 
 
Once opened, the pre-filled pen may be stored for a maximum of 30 days in the refrigerator (2 °C - 
8 °C) when stored with the pen cap on and kept in the outer carton in order to protect from light. 
 
Do not use this medicine if you notice that the pre-filled pen appears damaged, the solution is cloudy, 
has particles or flakes, or has any colour other than colourless to slightly yellow. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Besremi contains 
- The active substance is ropeginterferon alfa-2b. 
 Each pre-filled pen of 0.5 mL solution contains 250 micrograms of ropeginterferon alfa-2b as 

measured on a protein basis, corresponding to 500 micrograms/mL. 
- The other ingredients are sodium chloride, polysorbate 80, benzyl alcohol, anhydrous sodium 

acetate, glacial acetic acid, and water for injections. For benzyl alcohol and sodium, see 
section 2 “Besremi contains benzyl alcohol” and “Besremi contains sodium”. 

 
What Besremi looks like and contents of the pack 
Besremi is presented as a solution for injection (injection) in a pre-filled pen. Each pre-filled pen 
contains 0.5 mL of solution. It is available in packs containing 1 pre-filled pen and 2 injection needles. 
 
Marketing Authorisation Holder and Manufacturer 
AOP Orphan Pharmaceuticals AG 
Wilhelminenstrasse 91/II f 
1160 Vienna 
Austria 
 
 
This leaflet was last revised in . 
 
 
Other sources of information 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


34 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
------------------------------------------------------------------------------------------------------------------------ 
 

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


35 

Instructions for Use 
 
Please read this leaflet carefully before using the Besremi 250 micrograms pre-filled pen. If you 
have any further questions, ask your doctor or pharmacist. 
 
Your doctor or pharmacist will show you how to use the pen. 
The Besremi 250 micrograms pre-filled pen can be used to inject doses of 50, 100, 150, 200 and 
250 micrograms. At doses up to 100 micrograms, the same pen can be used twice. Your doctor will 
tell you the dose you need. Please note down your injection dates and dose as instructed by your 
doctor. 
If you need a dose of more than 250 micrograms, you require two Besremi 250 microgram pre-filled 
pens. You have to use a different injection site for each of the two pens. Your doctor or pharmacist 
will explain to you how to use the two pens. 
 
Store the pen in the outer carton in the refrigerator. 
Remove the pen from the refrigerator 15 minutes before the injection to let it reach room temperature. 
Find a well-lit area without significant distraction for the injection. 
 
You will need the following supplies for your injection: 
• Besremi pre-filled pen 
• Needle 
• Alcohol wipe 
• Optional: adhesive plaster 
 
The Besremi pre-filled pen comes with two needles. Always use a new needle for each injection. 
 
Do not use the pen if it appears damaged. If at any time during the use of the pen, you feel you may 
have damaged it (e. g. by dropping it or using excessive force), do not use the pen further. Get a new 
pen and start afresh. 
 
 
 
 
 
 
Description Besremi 250 micrograms pre-filled pen 
 

 
  



36 

 

• Before you begin, check that the product has not 
expired. 

• Wash your hands before you begin. 
• Remove the cap from the pen. 

 

 

• Check the solution through the inspection windows 
along the sides of the cartridge holder. 

• Do not use the pen if the solution is cloudy, has 
particles or flakes, or is any colour other than 
colourless to slightly yellow. 

 

 

• Take a new needle and remove the protective foil. 
• Click the needle onto the pen and make sure that it is 

firmly attached. 
 

 

• Remove the outer needle cap from the needle. 
• Do not put the outer needle cap back on the needle 

until after you have injected the medicine. 
• Do not touch the needle tip at any time. 
• If you have used your Besremi 250 microgram pre-

filled pen once before, continue directly with step 7. 
• If you are using this pen for the first time, continue 

with preparation of the pen in step 5. 

 

• If you are using your pen for the first time, prepare the 
pen for injection by turning the dose knob until you see 
the symbol of a “drop”. 

 



37 

 

• Hold the pen with the needle pointing upwards. 
Do not point towards your face or anyone else’s face. 
Then, tap the pen (cartridge holder) gently with your 
fingers to allow any air bubbles to rise to the top of the 
cartridge holder. 

• Press the push button with your thumb until the “0” 
mark is aligned with the dot in the display window. 
You will see the figures in the window change, and 
you will hear clicks when the button moves. You 
should see a droplet of liquid appearing at the needle 
tip. 

• If you do not see a droplet at the needle tip, repeat 
steps 5 and 6 up to six times until a droplet emerges. 

• If you do not see the droplet after the seventh time, ask 
your doctor or pharmacist for advice. 

 

• Set the dose your doctor told you by turning the dose 
knob. The selected dose must align with the dot and 
dose display window. Correct the dose if necessary by 
turning the dose knob. 

• If you are unable to reach the required dose setting by 
turning the dose knob, your pen may not have 
sufficient medicine left. Do not apply further force. 
Instead, get a new pen. 
 

 

• You have to inject the medicine subcutaneously (under 
the skin). Your doctor will tell you where you have to 
inject it. Possible injection sites are the belly (more 
than five centimeters away from the belly button) or 
the thigh. 

• If you need two pens, use a different injection site for 
each pen (e. g., right and left side of belly or right and 
left thigh). Do not inject into skin that is irritated, 
reddened, bruised, infected or scarred in any way. 

• Disinfect your skin in the injection area using an 
alcohol swab before the injection. 
Let the area dry before you inject the medicine. 

 



38 

 

• Hold the pen so that the display window and the label 
are visible during the injection. 

• Raise a fold of skin between the thumb and forefinger. 
Insert the needle at a 90 degrees angle until the blue 
protective sleeve on the needle is no longer visible. 

 

 

• Press the push button all the way down until the “0” 
mark is aligned with the dot in the display window. 
The clicking sounds will stop when the injection is 
complete. 

• Hold the push button down and wait for at least 10 
seconds before removing the needle. 

• Do not lift or move the pen during injection. 
 

 

• Carefully remove the needle from the skin. 
• Note: The blue protective sleeve locks automatically 

and the now visible red locking indicator covers the 
needle for your protection. 

• Keep the injection site clean until the small injection 
wound has closed. Apply an adhesive plaster if needed. 

Note: You may see a small droplet of liquid sitting on your 
skin after you remove the needle. This droplet is normal 
and does not mean that you underdosed. 



39 

 
• Unscrew the needle and dispose of it appropriately. 
 

 

• Put the cap back on the pen securely. 
 

Reuse of the pen: 
• Your doctor will tell you if you may use the pen for a 

second injection. In this case, place the pen back into 
the outer carton and store it in the refrigerator for the 
next use. Do not use the pen later than 30 days. 

Disposal of the pen: 
• Discard the pen after use as instructed by your doctor 

or pharmacist. 
 

 



40 

Package leaflet: Information for the user 
 

Besremi 500 micrograms/0.5 mL solution for injection in pre-filled pen 
ropeginterferon alfa-2b 

 
This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Besremi is and what it is used for 
2. What you need to know before you use Besremi 
3. How to use Besremi 
4. Possible side effects 
5. How to store Besremi 
6. Contents of the pack and other information 
 
 
1. What Besremi is and what it is used for 
 
Besremi contains the active substance ropeginterferon alfa-2b, which belongs to the class of medicinal 
products called interferons. Interferons are produced by your immune system to block the growth of 
cancer cells. 
 
Besremi is used as monotherapy for the treatment of polycythaemia vera in adults. Polycythaemia vera 
is a type of cancer in which the bone marrow produces too many red blood cells, white blood cells and 
platelets (cells that help the blood to clot). 
 
 
2. What you need to know before you use Besremi 
 
Do not use Besremi: 

- if you are allergic to ropeginterferon alfa-2b or any of the other ingredients of this medicine 
(listed in section 6). 

- if you have thyroid disease that is not controlled with medicines. 
- if you have or had severe mental disorders (such as depression or suicidal thoughts or if you 

tried to kill yourself). 
- if you have or had severe heart problems (such as heart attack or stroke). 
- if you have or had an autoimmune disease (such as rheumatoid arthritis, psoriasis or 

inflammatory bowel disease). 
- if you had an organ transplantation and you take medicines which suppress your immune 

system. 
- if you take telbivudine (a medicine used to treat hepatitis B infection). 
- if you have advanced, uncontrolled liver disease. 
- if you have severe kidney disease (with your kidneys working at less than 15% of their normal 

ability). 



41 

 
Warnings and precautions 
Talk to your doctor before using Besremi: 

- if you have thyroid disease. 
- if you have diabetes or high blood pressure − your doctor may ask you to have an eye 

examination. 
- if you have liver problems − you will have blood tests regularly to check how your liver is 

working if you are on a long-term Besremi therapy. 
- if you have kidney problems. 
- if you have psoriasis or other skin problems because they may get worse during treatment with 

Besremi. 
 

Once you have started Besremi treatment, talk to your doctor: 
- if you develop symptoms of depression (such as feelings of sadness, dejection, and suicidal 

thoughts). 
- if you develop signs of a severe allergic reaction (such as difficulty in breathing, wheezing or 

hives) while using Besremi – if this is the case you will need to seek medical help immediately. 
- if you develop symptoms of a cold or other respiratory infection (such as difficulty in breathing, 

cough, fever and chest pain). 
- if you have changes in your vision − you must tell your doctor and have an immediate eye 

examination. Severe eye problems may occur during Besremi therapy. Your doctor will usually 
check your vision before starting your treatment. If you have health problems which may lead to 
eye problems such as diabetes or high blood pressure, you doctor should check your vision also 
during treatment. If your vision worsens, your doctor may decide to discontinue your treatment. 

 
Dental and gum disorders, which may lead to loss of teeth, can occur with interferon medicines. In 
addition, dry mouth could damage teeth and the lining of the mouth during long-term treatment with 
Besremi. You should brush your teeth thoroughly twice daily and have regular dental checks. 
 
It will need a certain time to reach your individual optimal dose of Besremi. Your doctor will decide if 
it is necessary to treat you with another medicine for an early reduction of your blood cell number to 
prevent blood clots and bleeding. 
 
Children and adolescents 
Do not give this medicine to children and adolescents because no information is available on the use of 
Besremi in this age group. 
 
Other medicines and Besremi 
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines. 
 
Do not use Besremi if you are taking telbivudine (for treating hepatitis B) since the combination of 
these medicines increases the risk of peripheral neuropathy (numbness, tingling, or burning sensations 
in the arms and legs). Tell your doctor if you are being treated with telbivudine. 
 
Tell your doctor especially if you are taking any of the following medicines: 

- theophylline (a medicine used to treat respiratory diseases such as asthma) 
- methadone (a medicine used to treat pain or opioid dependence) 
- vortioxetine or risperidone (medicines used to treat mental disorders) 
- anti-cancer medicines such as those stopping or slowing the growth of blood-forming cells in 

the bone marrow (e.g. hydroxycarbamide) 
- medicines that work on the central nervous system to relieve pain, help you sleep, or have a 

calming effect (e.g. morphine, midazolam) 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before using this medicine. 



42 

 
Pregnancy 
The effect of Besremi during pregnancy is not known. The use of Besremi is not recommended during 
pregnancy. If you are a woman of childbearing potential, your doctor will discuss with you if effective 
birth control should be used during your treatment with Besremi. 
 
Breast-feeding 
It is not known if Besremi is present in breast milk. Your doctor will help you decide if you have to 
stop breast-feeding when you are using this medicine. 
 
Driving and using machines 
Do not drive or use machines if you feel dizzy, sleepy or confused while using Besremi. 
 
Besremi contains benzyl alcohol 
This medicine contains 5 mg benzyl alcohol in each 0.5 mL. Benzyl alcohol may cause allergic 
reactions. 
Ask your doctor or pharmacist for advice: 

- if you are pregnant or breast-feeding. 
- if you have a liver or kidney disease. 

This is because large amounts of benzyl alcohol can build-up in your body and may cause side effects 
(called “metabolic acidosis”). 
 
Besremi contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially ‘sodium-
free’. 
 
 
3. How to use Besremi 
 
Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
The dose will be set individually for you by your doctor for your condition. The usual starting dose of 
Besremi is 100 microgram every 2 weeks. Your doctor will then increase your dose stepwise and may 
adjust your dose during treatment. 
Your doctor will reduce your starting dose to 50 microgram if you have severe kidney problems. 
 
This medicine is for subcutaneous use which means that it is injected in the tissue under your skin. It 
should not be injected into an area of the body where the skin is irritated, reddened, bruised, infected 
or scarred. 
If you are injecting this medicine yourself, you will get clear instructions on how to prepare and inject 
it. 
To prevent passing on infectious diseases, you should never share Besremi pre-filled pen with anyone 
else, even when the needle is changed. 
 
Details on how to prepare and inject Besremi are given in the Instructions for Use. Read them 
before you start using Besremi. 
 
If you use more Besremi than you should 
Tell your doctor as soon as possible. 
 
If you forget to use Besremi 
You should inject the dose as soon as you remember. However, if more than 2 days have passed since 
you missed the dose, leave out the dose and inject the next dose when it is due. Do not inject a double 
dose to make up for a forgotten dose. Check with your doctor or pharmacist if you are not sure. 
 
If you stop using Besremi 



43 

Do not stop using Besremi before you have talked to your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Contact your doctor immediately if you notice any of the following serious side effects during 
your treatment with Besremi: 
 
Common side effects (may affect up to 1 in 10 people): 

- changes in your heart beat (when the heart beats very fast and uneven) 
 
Uncommon side effects (may affect up to 1 in 100 people): 

- attempted suicide, thoughts about killing yourself 
- loss of vision which may be caused by bleeding in the retina (the retina is the light-sensitive 

layer in the eye), or by build-up of fat in or under the retina  
 
Rare side effects (may affect up to 1 in 1,000 people): 

- loss of vision which may be caused by damage to the retina (such as obstruction of the blood 
vessels in the eye) or the optic nerve 

 
Very rare side effects (may affect up to 1 in 10,000 people): 

- blindness 
- breathing problems including shortness of breath, cough and chest pain which may be caused by 

lung infiltration, pneumonia (lung infection), pulmonary arterial hypertension (high blood 
pressure in the blood vessels bringing blood from the heart to the lungs) and pulmonary fibrosis 
(a lung disease where scars are formed in the lung tissue) 

 
Side effects with frequency not known (cannot be estimated from the available data): 

- detachment of the retina (you may experience eye problems including changes in vision) 
 
Other side effects 
 
Very common side effects (may affect more than 1 in 10 people): 

- decrease in the number of a type of white blood cells (called leucocytes) and in blood clotting 
cells (called platelets) 

- joint or muscle pain 
- flu-like symptoms, feeling tired 
- in blood tests: increase of an enzyme called gamma-glutamyltransferase 

 
Common side effects (may affect up to 1 in 10 people): 

- infection of the respiratory tract, runny or stuffy nose, fungal infections 
- decrease in the number or size of red blood cells 
- increase or decrease in the thyroid gland activity, increase of thyroid stimulating hormone, 

inflammation of the thyroid gland 
- increase of triglycerides (a type of lipid) in the blood, decreased appetite 
- aggressive behaviour, feeling depressed, feeling anxious, problems with falling asleep or 

staying asleep, mood changes, lacking bodily energy or motivation 
- headache, feeling dizzy, reduced sense of touch or sensation, feeling sleepy, sensation of 

tingling and ‘pins and needles’ 
- dry eyes 
- damage of the capillaries (very small blood vessels) in the body 
- breathing problems 



44 

- diarrhoea, nausea, abdominal pain or stomach discomfort, constipation, dry mouth 
- liver disorder, increase in certain liver enzymes (shown in blood tests) 
- itching, hair loss, rash, redness of skin, psoriasis, dry and scaly skin, acne, thickening of the 

outer layer of the skin, increased sweating 
- a disorder called Sjogren's syndrome where the body’s immune system attacks glands that 

produce fluid (such as the tear and saliva glands), arthritis, pain in arms and legs, bone pain, 
painful sudden tightening of a muscle 

- fever, weakness, chills, general health problems, irritation or redness at the site of injection 
- in blood tests: antibodies which are produced by the body´s immune system, increase of an 

enzyme called lactate dehydrogenase 
 
Uncommon side effects (may affect up to 1 in 100 people): 

- infection and re-infection with herpes, bacterial infections 
- increase in the number of platelets 
- autoimmune disorder of the thyroid gland, sarcoidosis (areas of inflamed tissue in different parts 

of the body) 
- diabetes 
- panic attack, hallucination (seeing, hearing or feeling things that are not there), feeling stressed, 

feeling nervous, lack of interest in activities, nightmare, irritability, confusion 
- damage to the nervous system, migraine, mental disorder (health condition involving changes in 

thinking, emotion or behaviour), visual or sensory disturbances, shaky hands 
- eye discomfort, eyelid eczema 
- hearing loss, ringing in ears (tinnitus), spinning feeling (vertigo) 
- heart disorders such as heart block (a disorder in the heart´s electrical activity), blood clots in 

the blood vessels of the heart, leakage of the aortic valve 
- high blood pressure, reduced blood supply to certain parts of the body, haematoma (collection 

of blood under the skin), flushing 
- inflammation of lung tissue, coughing, nosebleed, sore throat 
- inflammation of the stomach, abdominal wall disorder, intestinal gas, indigestion, painful 

swallowing, bleeding gums 
- inflammation of the liver, damage to the liver, enlarged liver 
- sensitivity to sunlight, peeling of the skin, nail disorder 
- muscle weakness, neck pain, groin pain 
- inflammation of the bladder, painful urination, increased need to urinate, inability to urinate 
- sexual problems 
- pain or itching at the site of injection, sensitivity to weather change 
- loss of weight 
- in blood tests: increase of uric acid, antibodies produced by the body´s immune system against 

red blood cells 
 
Rare side effects (may affect up to 1 in 1,000 people): 

- bipolar disorders (mood disorders with episodes of sadness and excitement), mania (extreme 
excitement or unreasonable enthusiasm) 

- cardiomyopathy (diseases that affect the heart muscle), angina pectoris (a severe chest pain as a 
result of blockage of the heart vessels) 

- liver failure 
 
Very rare side effects (may affect up to 1 in 10,000 people): 

- idiopathic or thrombotic thrombocytopenic purpura (increased bruising, bleeding, decreased 
platelets, anaemia and extreme weakness) 

- myocardial ischemia (reduced blood flow to your heart muscle) 
 
Side effects with frequency not known (cannot be estimated from the available data): 

- Vogt-Koyanagi-Harada disease (a rare disease that can lead to loss of vision, hearing and skin 
pigmentation), severe allergic reaction 

- discolouration of the skin 



45 

- periodontal (affecting gums) and dental disorders, change in colour of the tongue 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Besremi 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label and the outer carton after 
“EXP”. The expiry date refers to the last day of that month. 
 
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. 
 
Once opened, the pre-filled pen may be stored for a maximum of 30 days in the refrigerator (2 °C - 
8 °C) when stored with the pen cap on and kept in the outer carton in order to protect from light. 
 
Do not use this medicine if you notice that the pre-filled pen appears damaged, the solution is cloudy, 
has particles or flakes, or has any colour other than colourless to slightly yellow. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Besremi contains 
- The active substance is ropeginterferon alfa-2b. 
 Each pre-filled pen of 0.5 mL solution contains 500 micrograms of ropeginterferon alfa-2b as 

measured on a protein basis, corresponding to 1,000 micrograms/mL. 
- The other ingredients are sodium chloride, polysorbate 80, benzyl alcohol, anhydrous sodium 

acetate, glacial acetic acid, and water for injections. For benzyl alcohol and sodium, see 
section 2 “Besremi contains benzyl alcohol” and “Besremi contains sodium”. 

 
What Besremi looks like and contents of the pack 
Besremi is presented as a solution for injection (injection) in a pre-filled pen. Each pre-filled pen 
contains 0.5 mL of solution. It is available in packs containing 1 pre-filled pen and 2 injection needles. 
 
Marketing Authorisation Holder and Manufacturer 
AOP Orphan Pharmaceuticals AG 
Wilhelminenstrasse 91/II f 
1160 Vienna 
Austria 
 
 
This leaflet was last revised in . 
 
 
Other sources of information 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


46 

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
------------------------------------------------------------------------------------------------------------------------ 

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


47 

Instructions for Use 
 
Please read this leaflet carefully before using the Besremi 500 micrograms pre-filled pen. If you 
have any further questions, ask your doctor or pharmacist. 
 
Your doctor or pharmacist will show you how to use the pen. 
The Besremi 500 micrograms pre-filled pen can be used to inject doses of 50, 100, 150, 200, 250, 300, 
350, 400, 450 and 500 micrograms. At doses up to 250 micrograms, the same pen can be used twice. 
Your doctor will tell you the dose you need. Please note down your injection dates and dose as 
instructed by your doctor. 
 
Store the pen in the outer carton in the refrigerator. 
Remove the pen from the refrigerator 15 minutes before the injection to let it reach room temperature. 
Find a well-lit area without significant distraction for the injection. 
 
You will need the following supplies for your injection: 
• Besremi pre-filled pen 
• Needle 
• Alcohol wipe 
• Optional: adhesive plaster 
 
The Besremi pre-filled pen comes with two needles. Always use a new needle for each injection. 
 
Do not use the pen if it appears damaged. If at any time during the use of the pen, you feel you may 
have damaged it (e. g. by dropping it or using excessive force), do not use the pen further. Get a new 
pen and start afresh. 
 
 
 
 
 
 
Description Besremi 500 micrograms pre-filled pen 
 

 
  



48 

 

• Before you begin, check that the product has not 
expired. 

• Wash your hands before you begin. 
• Remove the cap from the pen. 

 

 

• Check the solution through the inspection windows 
along the sides of the cartridge holder. 

• Do not use the pen if the solution is cloudy, has particles 
or flakes, or is any colour other than colourless to 
slightly yellow. 

 

 

• Take a new needle and remove the protective foil. 
• Click the needle onto the pen and make sure that it is 

firmly attached. 
 

 

• Remove the outer needle cap from the needle. 
• Do not put the outer needle cap back on the needle until 

after you have injected the medicine. 
• Do not touch the needle tip at any time. 
• If you have used your Besremi 500 microgram pre-filled 

pen once before, continue directly with step 7. 
• If you are using this pen for the first time, continue with 

preparation of the pen in step 5. 

 

• If you are using your pen for the first time, prepare the 
pen for injection by turning the dose knob until you see 
the symbol of a “drop”. 

 



49 

 

• Hold the pen with the needle pointing upwards. 
Do not point towards your face or anyone else’s face. 
Then, tap the pen (cartridge holder) gently with your 
fingers to allow any air bubbles to rise to the top of the 
cartridge holder. 

• Press the push button with your thumb until the “0” 
mark is aligned with the dot in the display window. 
You will see the figures in the window change, and you 
will hear clicks when the button moves. You should see 
a droplet of liquid appearing at the needle tip. 

• If you do not see a droplet at the needle tip, repeat steps 
5 and 6 up to six times until a droplet emerges. 

• If you do not see the droplet after the seventh time, ask 
your doctor or pharmacist for advice. 

 

• Set the dose your doctor told you by turning the dose 
knob. The selected dose must align with the dot and dose 
display window. Correct the dose if necessary by turning 
the dose knob. 

• If you are unable to reach the required dose setting by 
turning the dose knob, your pen may not have sufficient 
medicine left. Do not apply further force. 
Instead, get a new pen. 
 

 

• You have to inject the medicine subcutaneously (under 
the skin). Your doctor will tell you where you have to 
inject it. Possible injection sites are the belly (more than 
five centimeters away from the belly button) or the 
thigh. 

• Do not inject into skin that is irritated, reddened, 
bruised, infected or scarred in any way. 

• Disinfect your skin in the injection area using an alcohol 
swab before the injection. 
Let the area dry before you inject the medicine. 

 



50 

 

• Hold the pen so that the display window and the label 
are visible during the injection. 

• Raise a fold of skin between the thumb and forefinger. 
Insert the needle at a 90 degrees angle until the blue 
protective sleeve on the needle is no longer visible. 

 

 

• Press the push button all the way down until the “0” 
mark is aligned with the dot in the display window. 
The clicking sounds will stop when the injection is 
complete. 

• Hold the push button down and wait for at least 10 
seconds before removing the needle. 

• Do not lift or move the pen during injection. 
 

 

• Carefully remove the needle from the skin. 
• Note: The blue protective sleeve locks automatically and 

the now visible red locking indicator covers the needle 
for your protection. 

• Keep the injection site clean until the small injection 
wound has closed. Apply an adhesive plaster if needed. 

Note: You may see a small droplet of liquid sitting on your 
skin after you remove the needle. This droplet is normal 
and does not mean that you underdosed. 



51 

 
• Unscrew the needle and dispose of it appropriately. 

 

 

• Put the cap back on the pen securely. 
 

Reuse of the pen: 
• Your doctor will tell you if you may use the pen for a 

second injection. In this case, place the pen back into the 
outer carton and store it in the refrigerator for the next 
use. Do not use the pen later than 30 days. 

Disposal of the pen: 
• Discard the pen after use as instructed by your doctor or 

pharmacist. 
 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET