Ropeginterferon Alfa-2b

Ropeginterferon alfa-2b is a recombinant interferon alfa-2b conjugated with a two-arm methoxypolyethylene glycol (mPEG) chain, at one mole of polymer per mole of protein, and produced in Escherichia coli cells. Its average molecular mass is about 60 kDa, of which the PEG part accounts for about 40 kDa. Its potency should not be compared with that of any other pegylated or unpegylated interferon. Polycythaemia vera is a myeloproliferative neoplasm in which a V617F point mutation of the JAK2 kinase is present in about 95% of patients. The pivotal evidence is PROUD-PV, an open-label, randomised phase III study that compared ropeginterferon alfa-2b with hydroxycarbamide in 254 adults with polycythaemia vera.

Mechanism of Action

• Type I interferon: interferon alfa binds the transmembrane interferon alfa receptor (IFNAR). This starts a signalling cascade through kinases, particularly Janus kinase 1 (JAK1), and STAT proteins, which move into the nucleus and control distinct gene-expression programmes.
• Effect on blood-forming cells: interferon alfa inhibits the proliferation of haematopoietic and bone-marrow fibroblast progenitor cells and antagonises growth factors and other cytokines that have a role in the development of myelofibrosis. These actions may contribute to the benefit in polycythaemia vera.
• JAK2 allele burden: interferon alfa can decrease the mutated JAK2 V617F allele burden in patients with polycythaemia vera.
• Pegylation: attaching the large branched PEG chain is considered the main reason for the difference in elimination from unpegylated interferons.

Pharmacokinetics

• Absorption: absorption after subcutaneous injection is sustained, with peak serum concentrations after 3 to 6 days. Absolute bioavailability has not been investigated in humans; in monkeys it was about 80%, similar to pegylated interferon alfa-2a.
• Distribution: the drug stays mainly in the bloodstream and extracellular fluid, with a steady-state volume of distribution of 6.6 to 17 litres after doses of 50 to 450 micrograms. At steady state on 400 to 500 micrograms every 2 weeks, mean Cmax was 28.26 ng/mL, AUC over the dosing interval 7,504.0 ng·h/mL and trough 14.52 ng/mL. At 4-week intervals (100 to 500 micrograms, mean 350) these were 18.82 ng/mL, 6,021.3 ng·h/mL and 2.10 ng/mL.
• Metabolism: metabolism is not fully characterised. As for pegylated interferon alfa-2a in rats, elimination is considered to be mainly by hepatic metabolism, and DrugBank expects breakdown by proteolytic enzymes.
• Elimination: DrugBank gives a half-life of about seven days and a clearance of 1.7 to 2.5 L/h over doses of 100 to 500 micrograms.
• Special populations: the pharmacokinetics of other interferon alfa products were evaluated in renal impairment (see dosing below). They have not been determined in obese or underweight patients. No dose adjustment is needed for race.

• Polycythaemia vera: as monotherapy in adults, for the treatment of polycythaemia vera without symptomatic splenomegaly.

• Hypersensitivity to ropeginterferon alfa-2b or to any of the excipients.
• Pre-existing thyroid disease, unless it can be controlled with conventional treatment.
• Existing or past severe psychiatric disorder, particularly severe depression, suicidal ideation or suicide attempt.
• Severe pre-existing cardiovascular disease (for example uncontrolled hypertension or unstable angina), or a recent stroke or myocardial infarction.
• Present or past autoimmune disease.
• Immunosuppressed transplant recipients.
• Combination with telbivudine.
• Decompensated cirrhosis of the liver (Child-Pugh B or C).
• End-stage renal disease (GFR below 15 mL/min).

The reactions below come from clinical studies in 178 adults with polycythaemia vera. The most common were leukopenia (20.2%), thrombocytopenia (18.5%), arthralgia (13.5%), fatigue (12.4%), increased gamma-glutamyltransferase (11.2%), influenza-like illness (11.2%), myalgia (10.7%), anaemia (9.6%), increased alanine aminotransferase (8.4%), neutropenia (7.9%), pyrexia (7.9%), increased aspartate aminotransferase (7.3%), pruritus (6.8%), pain in extremity (6.7%), alopecia (6.7%), headache (6.2%), diarrhoea (5.7%), injection site reaction (5.6%), chills (5.1%) and dizziness (5.1%). The serious reactions were depression (1.1%), atrial fibrillation (1.1%) and acute stress disorder (0.6%).

Reactions marked † were reported during treatment with other interferon alfa medicines.

Very common (≥1/10): leukopenia, thrombocytopenia, increased gamma-glutamyltransferase, arthralgia, myalgia, influenza-like illness, fatigue.

Common (≥1/100 to <1/10): respiratory tract infection, influenza, rhinitis, fungal skin infection; pancytopenia, neutropenia, anaemia; hypothyroidism, hyperthyroidism, thyroiditis; hypertriglyceridaemia, decreased appetite; depression, aggression†, insomnia, anxiety, altered mood, mood swings, mood disorders; headache, dizziness, hypoaesthesia, somnolence, paraesthesia; dry eye; atrial fibrillation; microangiopathy; dyspnoea; diarrhoea, nausea, abdominal pain, constipation, abdominal distension, dry mouth; liver disorder, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood alkaline phosphatase; pruritus, alopecia, rash, erythema, psoriasis, xeroderma, acneiform dermatitis, hyperkeratosis, hyperhidrosis, dry skin; Sjögren’s syndrome, arthritis, pain in extremity, musculoskeletal pain, bone pain, muscle spasms; pyrexia, injection site reaction, asthenia, chills, general physical health deterioration, injection site erythema; positive antithyroid antibodies, increased thyroid-stimulating hormone, increased body temperature, positive antinuclear antibodies, increased lactate dehydrogenase, weight decreased.

Uncommon (≥1/1,000 to <1/100): oral herpes, herpes zoster, oral candidiasis, sinusitis, oesophageal candidiasis, vulvovaginal mycotic infection, hordeolum, onychomycosis; sarcoidosis; Basedow’s disease, diabetes mellitus†; suicide attempt†, suicidal ideation†, confusional state†, acute stress disorder, hallucination, emotional distress, nervousness, nightmare, irritability; polyneuropathy, peripheral motor neuropathy, radiculopathy, migraine, mental impairment, tremor, aura; retinal haemorrhage†, retinal exudates†, visual impairment, reduced visual acuity, blurred vision, ocular discomfort, eyelid eczema; deafness, tinnitus, vertigo; myocardial infarction†, atrioventricular block, intracardiac thrombus, aortic valve incompetence, cardiovascular disorder; Raynaud’s phenomenon, hypertension, haematoma, flushing; pneumonitis, cough, epistaxis, throat irritation; gastritis, abdominal wall disorder, flatulence, frequent bowel movements, odynophagia, gingival bleeding; hepatotoxicity, toxic hepatitis, hepatomegaly, non-acute porphyria; photosensitivity reaction, skin exfoliation, nail dystrophy; muscular weakness, neck pain, groin pain; haemorrhagic cystitis, dysuria, micturition urgency, urinary retention; erectile dysfunction, haematospermia; injection site pain, injection site pruritus, sensitivity to weather change; increased platelet count, increased blood uric acid, positive Coombs test.

Rare (≥1/10,000 to <1/1,000): bipolar disorder†, mania†; retinopathy†, optic neuropathy†, retinal artery occlusion†, retinal vein occlusion†; cardiomyopathy†, angina pectoris†; hepatic failure†.

Very rare (<1/10,000): idiopathic or thrombotic thrombocytopenic purpura†; blindness†; myocardial ischaemia†; lung infiltration†.

Not known: Vogt-Koyanagi-Harada disease†; acute hypersensitivity reactions† (for example urticaria, angioedema, bronchoconstriction, anaphylaxis); retinal detachment†; pulmonary fibrosis†, pneumonia†, pulmonary arterial hypertension† (a class label for interferon medicines); tooth disorder†, periodontal disease†; skin depigmentation†; tongue hyperpigmentation†.

Serious reactions in the studies: two patients had serious depression (1.1%) and recovered completely after permanent discontinuation; one had serious acute stress disorder (0.6%) and recovered after a dose reduction; three episodes of atrial fibrillation (1.1%, Grade 1 to 3) occurred in two patients, who were treated with appropriate medicines while ropeginterferon alfa-2b was continued. Gastrointestinal disorders occurred in 15.7% of patients, mostly diarrhoea (5.1%) and nausea (4.5%). Central nervous system effects including suicide attempt, suicidal ideation, aggression, bipolar disorder, mania and confusion have been reported with interferon alfa.

No interaction studies have been performed with ropeginterferon alfa-2b. Enzymes of protein catabolism are thought to be involved in its metabolism, and the role of transport proteins is not known.

• Telbivudine: with pegylated interferon alfa-2a in patients with hepatitis B, it increased the risk of peripheral neuropathy. The combination with ropeginterferon alfa-2b is contraindicated.
• Medicines handled by cytochrome enzymes: interferon alfa has been shown to influence the activity of cytochrome enzymes. Care should be taken when ropeginterferon alfa-2b is combined with their substrates, notably those with a narrow therapeutic margin such as theophylline or methadone. The SmPC also names vortioxetine and risperidone as examples whose blood concentrations may rise. See the SmPC for the full wording.
• Myelosuppressive or chemotherapeutic agents: caution is needed when ropeginterferon alfa-2b is given with other potentially myelosuppressive or chemotherapeutic agents.
• Narcotics, hypnotics and sedatives: they must be given with caution together with ropeginterferon alfa-2b.

Treatment should be started under the supervision of a physician experienced in the management of the disease. The medicine is for subcutaneous use and for long-term treatment. It can be given by a physician, a nurse, a family member or the patient, once trained in subcutaneous injection with the pre-filled pen. The instructions for use in the package leaflet should be followed.

Titration Phase

• The dose is titrated individually. The recommended starting dose is 100 micrograms, or 50 micrograms in patients on another cytoreductive therapy.
• The dose is raised gradually by 50 micrograms every two weeks (while any other cytoreductive therapy is reduced gradually, as appropriate) until the blood counts are stable: haematocrit below 45%, platelets below 400 × 10⁹/L and leukocytes below 10 × 10⁹/L.
• The maximum recommended single dose is 500 micrograms every two weeks. Phlebotomy as rescue treatment may be needed to normalise blood hyperviscosity.

Maintenance Phase

• The dose that stabilised the blood counts is kept at a two-week interval for at least 1.5 years. After that, the dose may be adapted and/or the interval extended to up to every four weeks, as appropriate for the patient.
• If adverse events develop, the dose is reduced or treatment is interrupted until they abate, and treatment restarts at a lower dose than the one that caused them.
• If haematocrit, platelets or leukocytes rise, the dose and/or the interval is adapted individually.

Method of Administration

• The injection goes under the skin of the abdomen, around but not within 5 cm of the navel, or of the thigh. Do not inject into skin that is irritated, reddened, bruised, infected or scarred.
• The 250 micrograms/0.5 mL pen delivers doses from 50 to 250 micrograms (each click represents 5 micrograms), and the 500 micrograms/0.5 mL pen from 50 to 500 micrograms.

Special Populations

• Hepatic impairment: no dose adjustment in mild impairment (Child-Pugh A); another pegylated interferon alfa product was safe in compensated cirrhosis. It is contraindicated in decompensated cirrhosis (Child-Pugh B or C). If liver enzyme increases are progressive and persistent, the dose is reduced; if they remain progressive and clinically significant despite dose reduction, or hepatic decompensation appears, treatment is stopped.
• Renal impairment: no adjustment in mild (GFR 60–89 mL/min) or moderate (GFR 30–59 mL/min) impairment. In severe impairment (GFR 15–29 mL/min) the recommended starting dose is 50 micrograms. It is contraindicated in end-stage renal disease (GFR below 15 mL/min).
• Elderly: no adjustment of the starting dose.
• Obese or underweight patients: the pharmacokinetics have not been determined, so no dose recommendation can be given.
• Children and adolescents: safety and efficacy have not been established; no data are available.

Titration Phase and Blood Monitoring

Reaching the individual optimal dose takes longer than with hydroxycarbamide (on average about 3.7 months against about 2.6 months), so other products such as hydroxycarbamide may be preferred where an early fall in raised blood counts is needed to prevent thrombosis and bleeding. During titration the effect on cardiovascular and thromboembolic risk may not be fully established. Patients are monitored closely, with regular complete blood counts (haematocrit, leukocytes, platelets) also after the optimal dose has been reached, and phlebotomy as rescue treatment may be needed.

Psychiatric and Central Nervous System Effects

CNS effects, particularly depression, were seen in some patients in the clinical development programme. Other CNS effects, including suicidal ideation, attempted suicide, aggression, bipolar disorder, mania and confusion, have been seen with other interferon alfa medicines. Patients should be closely monitored for symptoms of psychiatric disorders, and the treating physician should consider management if such symptoms emerge. If psychiatric symptoms worsen, stopping ropeginterferon alfa-2b is recommended. It must not be given to anyone with a current or past severe psychiatric disorder, particularly severe depression, suicidal ideation or suicide attempt.

Thyroid and Diabetes

Pre-existing thyroid disease must be treated and controlled with conventional therapy before treatment. Patients with symptoms of thyroid dysfunction during treatment should have thyroid-stimulating hormone levels checked; if they can be kept in the normal range, treatment can continue. Diabetes mellitus has been seen with other interferon alfa medicines. Patients whose diabetes cannot be controlled with medicines should not start treatment, and those who develop it during treatment and cannot be controlled should stop.

Cardiovascular System

Cardiac events including cardiomyopathy, myocardial infarction, atrial fibrillation and ischaemic coronary artery disorders have been associated with interferon alfa. Patients with a history of cardiovascular disorders are monitored closely. Severe pre-existing cardiovascular disease, or a recent stroke or myocardial infarction, is a contraindication.

Respiratory System

Lung infiltration, pneumonitis, pneumonia and pulmonary arterial hypertension have rarely been observed with interferon alfa. Patients with respiratory symptoms are monitored closely and treatment is stopped if necessary.

Eyes

Severe eye disorders such as retinopathy, retinal haemorrhage, retinal exudates, retinal detachment and retinal artery or vein occlusion, which may lead to blindness, have rarely been observed with interferon alfa. Eye examinations are advised before and during treatment, especially in patients with diabetes mellitus or hypertension. Anyone reporting reduced or lost vision or other eye symptoms needs an immediate eye examination, and stopping treatment should be considered if new or worsening eye disorders develop.

Acute Hypersensitivity

Serious acute hypersensitivity reactions (urticaria, angioedema, bronchoconstriction, anaphylaxis) have rarely been observed with other interferon alfa medicines. If one occurs, ropeginterferon alfa-2b must be stopped and appropriate medical therapy started immediately. Transient rashes do not require interruption.

Liver Function

Interferon alfa therapy has been associated with hepatotoxicity with significant rises in liver enzymes, and hepatic failure in patients infected with hepatitis C virus has been reported with other interferon alfa medicines. Raised liver enzymes and bilirubin have been seen with ropeginterferon alfa-2b, mostly transient and in the first year of treatment, and liver disorders have been reported after long-term use. Liver enzymes and hepatic function should be checked regularly during long-term treatment. Treatment is stopped if the rise stays progressive and clinically significant despite dose reduction, or if hepatic decompensation develops.

Renal Function

Patients should be monitored regardless of the starting dose or degree of renal impairment. If renal function falls during treatment, ropeginterferon alfa-2b is stopped.

Teeth and Mouth

Dental and periodontal disorders that may lead to tooth loss have been reported with other interferon alfa medicines, and dry mouth during long-term treatment could damage teeth and the lining of the mouth. Patients should brush their teeth thoroughly twice daily and have regular dental examinations.

Skin Disorders

Treatment is associated with pruritus, alopecia, rash, erythema, psoriasis, xeroderma, acneiform dermatitis, hyperkeratosis and hyperhidrosis. If these appear or worsen, stopping treatment must be considered.

Traceability

The name and batch number of the administered product must be clearly recorded.

Excipients

• Benzyl alcohol: high volumes should be used with caution and only if necessary, especially in people with liver or kidney impairment, because of the risk of accumulation and toxicity (metabolic acidosis).
• Polysorbate 80: each 0.5 mL contains 0.025 mg; polysorbates may cause allergic reactions.
• Sodium: less than 1 mmol (23 mg) per mL, that is, essentially sodium-free.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential must use effective contraception during treatment, unless otherwise discussed with the physician.
• Pregnancy: there are no or limited data on interferon alfa in pregnant women, and animal studies showed reproductive toxicity. Besremi is not recommended during pregnancy or in women of childbearing potential not using contraception.
• Breastfeeding: it is not known whether it passes into human milk and a risk to newborns and infants cannot be excluded. A decision must be made whether to stop breastfeeding or to stop or abstain from treatment, weighing the benefit of breastfeeding for the child against the benefit of therapy for the woman.
• Fertility: there are no data on fertility in women or men.

Effect on Driving

Besremi has a minor influence on the ability to drive and use machines. Patients who feel dizzy or sleepy, or who hallucinate, should not drive or use machines.

Store the pre-filled pens in a refrigerator at 2–8 °C. Do not freeze. Keep each pen in the outer carton to protect it from light. Because the product is refrigerated, the cold chain should be kept unbroken from dispatch until the patient stores it at home.

After first use, a pen may be kept for a maximum of 30 days in the refrigerator (2–8 °C), with the cap on and in the outer carton to protect it from light. It may be used up to two times within those 30 days. Any medicine left in the pen after the second use or after 30 days must be discarded.

3 years for both strengths. After first use, a pen may be kept for up to 30 days in the refrigerator (see Storage Conditions).

Prescription only (Rx), on restricted medical prescription (Annex II B of the marketing authorisation), with treatment started under the supervision of a physician experienced in the management of the disease. Besremi is a pre-filled pen that a physician, nurse, family member or the trained patient can inject, so it is supplied to the patient or to the treating clinic on prescription, delivered cold-chain at 2–8 °C.