Besremi - summary of medicine characteristics

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 PARTICULARS4.1 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

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 × 109/L and leukocytes <10 × 109/L). The maximum recommended single dose is 500 micrograms injected every two weeks. Phlebotomy as rescue treatment to normalise blood hyperviscosity may be necessary.

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 6089 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 1529 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

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

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Dose titration phase

The recommended posology for the titration phase of ropeginterferon alfa-2b (see section 4.2) results in a prolonged time to reach the individual optimal dose compared to hydroxycarbamide. In a clinical study in polycythaemia vera, the end of the mean individual titration phase for ropeginterferon alfa-2b was reached after approximately 3.7 months, for hydroxycarbamide after approximately 2.6 months of treatment. Thus, other products (e.g. hydroxycarbamide) may be preferred in patients for whom an early reduction in elevated blood counts is necessary to prevent thrombosis and bleeding.

During the titration phase the efficacy to reduce the cardiovascular and thromboembolic risk of the underlying disease may not be fully established. Patients should be closely monitored, particularly during the titration phase; complete blood counts including determination of haematocrit level, leukocyte and platelet counts should be performed regularly also after the individual optimal dose has been established. Phlebotomy as rescue treatment to normalise blood hyperviscosity may be necessary.

Endocrine system

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

Diabetes mellitus have been observed with other interferon alfa medicinal products (see section 4.8). Patients with this condition who cannot be effectively controlled by medicinal products should not begin ropeginterferon alfa-2b therapy. Patients who develop this condition during treatment and cannot be controlled by medicinal products should discontinue ropeginterferon alfa-2b therapy.

Central nervous system (CNS)

CNS effects, particularly depression, have been observed in some patients treated with ropeginterferon alfa-2b during the clinical development program (see section 4.8). Other CNS effects, including suicidal ideation, attempted suicide, aggression, bipolar disorder, mania and confusion have been 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 preexisting 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 longterm 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).

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.

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 must use effective contraception during the treatment with ropeginterferon alfa-2b, unless otherwise discussed with the physician.

Pregnancy

There are no or limited amount of data from the use of interferon alfa in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

As ropeginterferon alfa-2b may have the same effect, Besremi is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

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

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
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 disorders	very common	gamma-glutamyltransferase increased
	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)
Thrombocytopenia	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)
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

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 PROPERTIES5.1 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, particularly Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2) and signal transducer and activator of transcription (STAT) proteins. Nuclear translocation of STAT proteins controls distinct gene-expression programs and exhibits 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 JAK2 V617F 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
JAK2 V617F 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-naive (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

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 × 109/L and leukocytes <10 × 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% and 52.6% of patients showed a complete haematological response with an improvement in disease burden.. Patients showed a statistically significant difference in the JAK2 V617F allele burden (19.7%) and JAK2 V617F 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 response3	70.5 (67/95)
Complete haematological response3 and improvement in disease burden b	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 burden b	52.6 (50/95)

a defined as haematocrit <45% without phlebotomy (at least 3 months since last phlebotomy), platelets

<400 × 109/L and leukocytes <10 × 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. JAK2 V617F allele burden and changes from baseline in the CONTINUATION-PV extension study.

	Ropeginterferon alfa-2b treatment arm1 (n=94)
	Mean % (± SD)
JAK2 V617F allele burden	19.7 (±21.29)
JAK2 V617F 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

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 forpegylated 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 halflife 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 were 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

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 PARTICULARS6.1 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

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 gg, 100 gg, 150 gg, 200 gg and 250 gg.

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

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

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

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

The pre-filled pen is made of white polypropylene, with a blue push button and the strength

“500 mcg/0.5 mL” highlighted in blue on the label. It delivers doses of 50 gg, 100 gg, 150 gg, 200 gg, 250 gg, 300 gg, 350 gg, 400 gg, 450 gg and 500 gg.

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

Leopold-Ungar-Platz 2

1190 Vienna

Austria

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/18/1352/001

EU/1/18/1352/002

EU/1/18/1352/003

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

15 February 2019