Peginterferon Alfa-2a

Peginterferon alfa-2a is recombinant interferon alfa-2a, produced in Escherichia coli, covalently conjugated with bis-[monomethoxy polyethylene glycol] at one mole of polymer per mole of protein. Its average molecular mass is about 60,000, of which the protein makes up about 20,000. It has the antiviral and antiproliferative activities in vitro that are characteristic of interferon alfa-2a. The strength refers to the interferon alfa-2a part only, and its potency should not be compared with that of another pegylated or non-pegylated protein of the same therapeutic class.

Mechanism of Action

• Receptor signalling: peginterferon alfa-2a binds to and activates human type I interferon receptors, which dimerise and activate the JAK/STAT pathway. This raises the expression of many genes involved in the innate antiviral response.
• Antiviral and antiproliferative activity: pegylation does not remove the in vitro activities of interferon alfa-2a, but it greatly slows clearance (see Pharmacokinetics).
• Hepatitis C virus: in responding patients given 180 micrograms, HCV RNA falls in two phases. The first starts 24 to 36 hours after the first dose; the second continues over the next 4 to 16 weeks in patients who reach a sustained response. Ribavirin had no significant effect on the initial viral kinetics over the first 4 to 6 weeks.
• Polycythaemia vera and essential thrombocythaemia: the efficacy data are mainly bibliographical, from two prospective, investigator-initiated, open-label studies (MPD-RC 112 and MPD-RC 111). MPD-RC 112 compared hydroxycarbamide with peginterferon alfa-2a in treatment-naive, high-risk patients with essential thrombocythaemia (81 patients) or polycythaemia vera (87 patients).

Pharmacokinetics

• Absorption: after a single subcutaneous injection of 180 micrograms, serum concentrations are measurable within 3 to 6 hours, about 80% of the peak is reached within 24 hours, and peak concentrations occur 72 to 96 hours after the dose. Absolute bioavailability is 84%, similar to interferon alfa-2a. Exposure was lower when the injection was given in the arm.
• Distribution: found mainly in the bloodstream and extracellular fluid, with a steady-state volume of distribution of 6 to 14 litres after intravenous dosing. In rats it is distributed to the liver, kidney and bone marrow.
• Metabolism: not fully characterised; studies in rats indicate that the kidney is a major route of excretion of radiolabelled material.
• Elimination: systemic clearance is about 100-fold lower than that of native interferon alfa-2a. The terminal half-life after intravenous dosing in healthy subjects is about 60 to 80 hours, against 3 to 4 hours for standard interferon; after subcutaneous dosing in patients the mean is about 160 hours (range 84 to 353), which may partly reflect sustained absorption.
• Linearity and accumulation: exposure rises in proportion to dose with once-weekly dosing. In chronic hepatitis B or C, serum concentrations accumulate 2 to 3 fold after 6 to 8 weeks of weekly dosing and then stop accumulating; the peak-to-trough ratio after 48 weeks is about 1.5 to 2, and concentrations are sustained across the full week (168 hours).
• Special populations: a lower dose is used in adults with severe renal impairment or end-stage renal disease (see Administration and Dosage).

Pegasys is indicated for the following uses. Polycythaemia vera and essential thrombocythaemia are listed in the SmPC covering the pre-filled syringes; the SmPC for the 180 microgram vial lists chronic hepatitis B and C only.

• Polycythaemia vera: as monotherapy in adults.
• Essential thrombocythaemia: as monotherapy in adults.
• Chronic hepatitis B, adults: HBeAg-positive or HBeAg-negative chronic hepatitis B (CHB) in adult patients with compensated liver disease and evidence of viral replication, increased alanine aminotransferase (ALT) and histologically verified liver inflammation and/or fibrosis.
• Chronic hepatitis B, children and adolescents 3 years of age and older: HBeAg-positive CHB in non-cirrhotic children and adolescents with evidence of viral replication and persistently elevated serum ALT. The SmPC points to its sections 4.2, 4.4 and 5.1 for the decision to start treatment in paediatric patients.
• Chronic hepatitis C, adults: in combination with other medicinal products, for chronic hepatitis C (CHC) in patients with compensated liver disease. Genotype-specific activity is described in sections 4.2 and 5.1 of the SmPC.
• Chronic hepatitis C, children and adolescents 5 years of age and older: in combination with ribavirin, for treatment-naive children and adolescents who are positive for serum HCV-RNA. When deciding to start treatment in childhood, the growth inhibition induced by combination therapy must be considered; its reversibility is uncertain, and the decision is made case by case.

• Hypersensitivity to the active substance, to alfa interferons or to any of the excipients.
• History or presence of autoimmune diseases (the SmPC for the 180 microgram vial names autoimmune hepatitis instead).
• Pre-existing thyroid disease, unless it can be controlled with conventional treatment (pre-filled syringe SmPC).
• Severe hepatic dysfunction or decompensated cirrhosis of the liver.
• A history of severe pre-existing cardiac disease, including unstable or uncontrolled cardiac disease in the previous six months.
• HIV-HCV patients with cirrhosis and a Child-Pugh score of 6 or more, except if only due to indirect hyperbilirubinaemia caused by medicinal products such as atazanavir and indinavir.
• Combination with telbivudine.
• Neonates and young children up to 3 years old, because of the excipient benzyl alcohol.
• In paediatric patients, the presence or history of a severe psychiatric condition, particularly severe depression, suicidal ideation or suicide attempt.

The SmPC summarises reactions seen with monotherapy in chronic hepatitis B or C and with ribavirin in chronic hepatitis C, together with post-marketing reports. In polycythaemia vera and essential thrombocythaemia, studies and retrospective analyses showed no side effects beyond those of the hepatitis studies. The most frequent there were flu-like symptoms, injection site reactions, peripheral sensory neuropathies, visual disturbances, grade 1/2 depression, leukopenia, increased aspartate aminotransferase, hypertension, fatigue, lymphopenia, anaemia, diarrhoea, nausea, headache, musculoskeletal pain, skin toxicity, asthenia and gastrointestinal symptoms. In chronic hepatitis B (48 weeks of treatment, 24 weeks of follow-up) adverse events occurred in 88% of Pegasys patients against 53% on lamivudine, serious ones in 6% against 4%, and 5% stopped Pegasys because of adverse events or laboratory abnormalities.

Very common (≥1/10): anorexia; depression, anxiety, insomnia; headache, dizziness, impaired concentration; dyspnoea, cough; diarrhoea, nausea, abdominal pain; alopecia, dermatitis, pruritus, dry skin; myalgia, arthralgia; pyrexia, rigors, pain, asthenia, fatigue, injection site reaction, irritability. In chronic hepatitis B patients on monotherapy, depression, insomnia, dizziness, diarrhoea, nausea, abdominal pain, rigors, pain, injection site reaction and irritability were common rather than very common.

Common (≥1/100 to <1/10): infections (bronchitis, upper respiratory tract infection, oral candidiasis, herpes simplex, fungal, viral and bacterial infections); thrombocytopenia, anaemia, lymphadenopathy; hypothyroidism, hyperthyroidism; aggression, mood alteration, emotional disorders, nervousness, decreased libido; syncope, migraine, memory impairment, weakness, hypoaesthesia, hyperaesthesia, paraesthesia, tremor, taste disturbance, nightmares, somnolence; blurred vision, eye pain, eye inflammation, dry eye; vertigo, earache; tachycardia, peripheral oedema, palpitations; flushing; exertional dyspnoea, epistaxis, nasopharyngitis, sinus and nasal congestion, rhinitis, sore throat; vomiting, dyspepsia, dysphagia, mouth ulceration, gingival bleeding, glossitis, stomatitis, flatulence, dry mouth; psoriasis, urticaria, eczema, rash, increased sweating, skin disorder, photosensitivity reaction, night sweats; back pain, arthritis, muscle weakness, bone pain, neck pain, musculoskeletal pain, muscle cramps; impotence; chest pain, influenza-like illness, malaise, lethargy, hot flushes, thirst; weight decreased.

Uncommon (≥1/1,000 to <1/100): pneumonia, skin infection; hepatic neoplasm; sarcoidosis, thyroiditis; diabetes; dehydration; suicidal ideation, hallucinations; peripheral neuropathy; retinal haemorrhage; hearing loss; hypertension; wheezing; gastrointestinal bleeding; hepatic dysfunction.

Rare (≥1/10,000 to <1/1,000): endocarditis, otitis externa; pancytopenia; anaphylaxis, systemic lupus erythematosus, rheumatoid arthritis; diabetic ketoacidosis; suicide, psychotic disorder; coma, convulsions, facial palsy; optic neuropathy, papilloedema, retinal vascular disorder, retinopathy, corneal ulcer; myocardial infarction, congestive heart failure, cardiomyopathy, angina, arrhythmia, atrial fibrillation, pericarditis, supraventricular tachycardia; cerebral haemorrhage, vasculitis; interstitial pneumonitis (including fatal outcome), pulmonary embolism; peptic ulcer, pancreatitis; hepatic failure, cholangitis, fatty liver; myositis; renal insufficiency; substance overdose.

Very rare (<1/10,000): aplastic anaemia; idiopathic or thrombotic thrombocytopenic purpura; vision loss; Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, erythema multiforme.

Not known: sepsis; pure red cell aplasia; liver and renal graft rejection, Vogt-Koyanagi-Harada disease; mania, bipolar disorders, homicidal ideation; cerebral ischaemia; serous retinal detachment, optic neuritis; peripheral ischaemia; pulmonary arterial hypertension; ischaemic colitis, tongue pigmentation; rhabdomyolysis.

Selected reactions:

• Laboratory values: increased ALT and bilirubin, electrolyte disturbance (low potassium, calcium and phosphate), hyperglycaemia, hypoglycaemia and raised triglycerides. Blood counts fall (leucopenia, neutropenia, lymphopenia, thrombocytopenia, haemoglobin); this generally improves with dose modification and returns to pre-treatment levels within 4–8 weeks of stopping. With 180 micrograms plus ribavirin 1,000/1,200 mg for 48 weeks, moderate neutropenia (0.5 to 0.749 ×10⁹/L) occurred in 24% of patients and severe neutropenia (below 0.5 ×10⁹/L) in 5%.
• Pulmonary arterial hypertension: reported with interferon alfa products, notably in patients with risk factors (portal hypertension, HIV infection, cirrhosis), typically several months after starting.
• Antibodies and thyroid: neutralising anti-interferon antibodies developed in 1–5% of patients (more often in hepatitis B) without a link to lack of response. Thyroid laboratory abnormalities requiring intervention occurred in 4.9% of patients given Pegasys with ribavirin.
• HIV–HCV co-infection: the profile was similar to that in HCV mono-infection. CD4+ counts fell during the first 4 weeks without a fall in CD4+ percentage, reversibly on dose reduction or stopping, and HIV viraemia control was not appreciably affected.
• Children and adolescents: in studies of hepatitis B (111 patients aged 3 to 17) and hepatitis C (114 patients aged 5 to 17), the safety profile was similar to that in adults. In the hepatitis C study, influenza-like illness (91%), headache (64%), gastrointestinal disorder (56%) and injection-site reaction (45%) were most prevalent with Pegasys plus ribavirin. After 48 weeks of combination therapy, 43% had a fall of 15 percentiles or more in weight and 25% in height; two years after treatment, 16% and 11% respectively remained that far below their baseline curves. The SmPC states that the data are not sufficient to conclude that growth inhibition is always reversible.

Interaction studies have been done only in adults. The SmPC section on interactions covers further medicines used alongside Pegasys, including in HIV–HCV co-infection; it should be read before combining treatments.

• Theophylline: Pegasys inhibits CYP1A2. After 180 micrograms weekly for 4 weeks the AUC of theophylline rose by 25%. Serum theophylline is monitored and its dose adjusted; the effect is likely greatest after more than 4 weeks. The same study showed no effect on CYP3A4, 2C9, 2C19 or 2D6 activity.
• Methadone: in 24 HCV patients on methadone maintenance (median 95 mg, range 30 to 150 mg), 180 micrograms weekly for 4 weeks raised mean methadone levels by 10–15%. The clinical significance is unknown, but patients should be monitored for signs and symptoms of methadone toxicity, and in patients on high doses the risk of QTc prolongation should be considered.
• Azathioprine: ribavirin may interfere with azathioprine metabolism and cause accumulation of a metabolite linked to myelotoxicity. Peginterferon alfa-2a with ribavirin and azathioprine should be avoided; pancytopenia and bone marrow suppression have been reported 3 to 7 weeks after starting this combination, and reversed within 4 to 6 weeks of withdrawal.
• Telbivudine: combination is contraindicated.
• HIV treatments: ribavirin with zidovudine is not recommended because of an increased risk of anaemia. With stavudine plus interferon, with or without ribavirin, pancreatitis and/or lactic acidosis occurred in 3% (12 of 398) of patients. Patients on highly active antiretroviral therapy may be at higher risk of lactic acidosis, and co-infected patients with advanced cirrhosis on such therapy, including didanosine, may be at higher risk of hepatic decompensation when ribavirin is combined with interferons.
• Other myelosuppressive agents: use Pegasys with caution.
• Food: DrugBank advises drinking plenty of fluids during treatment.

Treatment should be started only by a physician experienced in the treatment of polycythaemia vera, essential thrombocythaemia, or hepatitis B or C (the 180 microgram vial SmPC refers to hepatitis B or C only). The SmPCs of medicines used in combination, such as ribavirin, should also be consulted. Monotherapy for hepatitis C should be considered only when other medicines are contraindicated.

Method of Administration and Self-Injection

• Pegasys is injected subcutaneously into the abdomen or thigh. Exposure was lower in studies when it was injected into the arm.
• Pegasys is designed for administration by the patient or a carer. Each syringe (or vial) is for one person only and for single use.
• Appropriate training is recommended for non-healthcare professionals who give the injection. The Instructions for the User supplied in the carton must be followed carefully by the patient.
• The vial presentation needs a sterile needle and syringe to prepare the dose. The 90 microgram syringe is marked for doses of 90, 65, 45, 30, 20 and 10 micrograms, and the 135 microgram syringe for 135, 90 and 45 micrograms.

Polycythaemia Vera and Essential Thrombocythaemia (Adults)

• The dose is titrated individually. The recommended starting dose is 45 micrograms once weekly subcutaneously, raised by 45 micrograms each month until the blood values are stabilised. The dose may be adapted and/or the interval prolonged as appropriate for the patient.
• Stabilisation in polycythaemia vera means haematocrit below 45% without phlebotomy, platelets of 400 ×10⁹/L or less and leukocytes below 10 ×10⁹/L. In essential thrombocythaemia it means platelets of 400 ×10⁹/L or less and leukocytes below 10 ×10⁹/L.
• The maximum recommended single dose is 180 micrograms once weekly.
• If adverse reactions develop, the dose is reduced or treatment is paused until they settle, and then restarted at a lower dose than the one that caused them. If haematocrit, platelets or leukocytes rise, the dose and/or interval is adapted individually.

Chronic Hepatitis B (Adults)

• 180 micrograms once weekly for 48 weeks, for both HBeAg-positive and HBeAg-negative disease.

Chronic Hepatitis C (Adults)

• 180 micrograms once weekly in combination with oral ribavirin, or as monotherapy. The ribavirin dose is given in Table 1 of the SmPC and is taken with food.
• Duration with ribavirin depends on genotype. Genotype 1 with detectable HCV RNA at week 4: 48 weeks. 24 weeks may be considered in genotype 1 with low baseline viral load (800,000 IU/mL or less) or in genotype 4 if HCV RNA is negative at week 4 and stays negative at week 24, but this may carry a higher risk of relapse than 48 weeks. Shortening treatment in genotype 1 with high baseline viral load (above 800,000 IU/mL) needs even more caution. Genotype 2 or 3 with detectable HCV RNA at week 4: 24 weeks. 16 weeks may be considered in selected genotype 2 or 3 patients with low baseline viral load who are HCV negative by week 4 and stay negative at week 16.
• Doses for other patient groups, for dose reduction when laboratory values change, and for children and adolescents are given in section 4.2 of the SmPC.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: none needed in mild or moderate impairment. In adults with severe renal impairment or end-stage renal disease, 135 micrograms once weekly is recommended; patients are monitored and the dose reduced further if adverse reactions occur.
• Hepatic impairment: Pegasys has been shown to be effective and safe in compensated cirrhosis (Child-Pugh A), and mild liver impairment needs no adjustment. It has not been evaluated in decompensated cirrhosis (Child-Pugh B or C, or bleeding oesophageal varices), where it is contraindicated.
• Children and adolescents: contraindicated in neonates and young children up to 3 years because of benzyl alcohol. According to the 180 microgram vial SmPC, experience is limited in hepatitis C at 3 to 5 years and in children not adequately treated before, and there are no data in children co-infected with HIV or with renal impairment. Paediatric dosing is given in the SmPC.

Psychiatric and Central Nervous System Effects

• Severe central nervous system effects, particularly depression, suicidal ideation and attempted suicide, have been seen in some patients during Pegasys therapy and even after it was stopped, mainly during the 6-month follow-up period.
• Other effects have been seen with alfa interferons: aggressive behaviour (sometimes directed against others, such as homicidal ideation), bipolar disorders, mania, confusion and altered mental status.
• All patients should be closely monitored for any signs or symptoms of psychiatric disorders. If they appear, the prescribing physician must bear in mind their potential seriousness and consider adequate treatment. If psychiatric symptoms persist or worsen, or suicidal ideation is identified, it is recommended to stop Pegasys and follow the patient, with psychiatric intervention as appropriate.
• Existing or past severe psychiatric conditions: if treatment is judged necessary, it should be started only after appropriate individualised diagnosis and management of the psychiatric condition. Use in children and adolescents with an existing or past severe psychiatric condition is contraindicated.
• Substance use: HCV-infected patients who also have a substance use disorder (alcohol, cannabis and others) are at higher risk of developing psychiatric disorders, or of worsening existing ones, when treated with alfa interferon. If treatment is judged necessary, psychiatric co-morbidities and the potential for other substance use should be carefully assessed and managed before starting, and an interdisciplinary approach with a mental health care provider or addiction specialist should be considered. Patients are closely monitored during therapy and even after stopping, with early intervention if psychiatric disorders or substance use re-emerge or develop.

Growth and Development in Children and Adolescents

During up to 48 weeks of Pegasys with or without ribavirin in patients aged 3 to 17 years, weight loss and growth inhibition were common, and their reversibility is uncertain. The expected benefit is weighed case by case against these findings and against the child’s disease (for example evidence of fibrosis progression), co-morbidities such as HIV co-infection, and response predictors (HBV genotype and ALT for hepatitis B; HCV genotype and HCV-RNA for hepatitis C). Whenever possible the child should be treated after the pubertal growth spurt. There are no data on long-term effects on sexual maturation.

Laboratory Tests and Blood Counts

• Standard haematological and biochemical tests are advised for all patients before treatment. Suggested baseline values are platelets of at least 90,000/mm³, neutrophils of at least 1,500/mm³ and adequately controlled thyroid function (TSH and T4).
• Haematological tests are repeated after 2 and 4 weeks and biochemical tests at 4 weeks, then periodically, including glucose.
• White cell and neutrophil counts usually fall within the first 2 weeks, and platelet counts fall; both recover after dose reduction or stopping. Anaemia (haemoglobin below 10 g/dL) occurred in up to 15% of hepatitis C patients on the combination with ribavirin, more often in women.
• Caution with other potentially myelosuppressive agents. Re-treatment of patients who stopped earlier therapy because of haematological reactions has not been adequately studied.

Endocrine, Cardiovascular and Liver Effects

• Thyroid and glucose: thyroid abnormalities or worsening of pre-existing disorders have been reported with alfa interferons. TSH and T4 are checked before treatment, which may start or continue if TSH can be kept normal with medicines. Hypoglycaemia, hyperglycaemia and diabetes mellitus have been observed; patients whose condition cannot be controlled should not start, or should stop, treatment.
• Cardiovascular: hypertension, supraventricular arrhythmias, congestive heart failure, chest pain and myocardial infarction have been linked to alfa interferons. An ECG is recommended before treatment in patients with cardiac abnormalities, and therapy is suspended or stopped if cardiovascular status worsens.
• Liver function: Pegasys is stopped in patients who develop hepatic decompensation. ALT can rise above baseline, so liver enzymes and function are checked regularly on long-term therapy, and treatment is stopped if the rise is progressive and clinically significant despite dose reduction or comes with increased direct bilirubin. In chronic hepatitis B, ALT flares during treatment are not uncommon; more frequent liver monitoring is recommended.

Immune, Eye, Lung, Skin and Other Warnings

• Hypersensitivity: serious acute reactions (urticaria, angioedema, bronchoconstriction, anaphylaxis) are rare; treatment is stopped and medical therapy given at once. Transient rashes do not need interruption.
• Autoimmune disease: auto-antibodies and autoimmune disorders have been reported, and predisposed patients may be at higher risk. Vogt-Koyanagi-Harada syndrome has been reported in hepatitis C patients; if suspected, antiviral treatment is withdrawn and corticosteroids discussed.
• Fever and infections: fever may be part of the flu-like syndrome, but other causes, particularly serious infections and neutropenia, must be ruled out. Serious bacterial, viral and fungal infections and sepsis have been reported.
• Eyes: retinopathy (retinal haemorrhages, cotton wool spots, papilloedema, optic neuropathy, retinal artery or vein obstruction) with possible loss of vision has been reported rarely. All patients should have a baseline eye examination, and patients with pre-existing eye disorders periodic examinations; treatment is stopped for new or worsening eye disorders.
• Lungs: dyspnoea, infiltrates, pneumonia and pneumonitis have been reported; treatment is stopped for persistent or unexplained infiltrates or impaired lung function.
• Skin and sarcoidosis: alfa interferons can worsen or provoke psoriasis and sarcoidosis; caution in psoriasis.
• Transplantation: safety and efficacy with ribavirin have not been established in liver or other transplant recipients; liver and renal graft rejection has been reported.
• Teeth: dental and periodontal disorders, and damage from dry mouth, have been reported with Pegasys plus ribavirin; patients should brush twice daily, have regular dental checks and rinse the mouth after vomiting.
• Traceability: the name and batch number of the product given must be clearly recorded.

HIV–HCV Co-infection

The SmPCs of the antiretroviral medicines used alongside should be read for overlapping toxicities. Caution applies when adding Pegasys and ribavirin to antiretroviral therapy because of lactic acidosis, and in advanced cirrhosis because of hepatic decompensation; patients are closely monitored and Pegasys is stopped at once in hepatic decompensation. Efficacy and safety data are limited at CD4 counts below 200 cells/µL.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: little or no human data. Animal studies with interferon alfa-2a showed reproductive toxicity. Pegasys is used in pregnancy only if the potential benefit justifies the potential risk to the foetus.
• Breastfeeding: it is unknown whether peginterferon alfa-2a passes into milk; breastfeeding should be stopped before treatment starts.
• Fertility: no data in women. A prolonged menstrual cycle was seen in female monkeys.
• With ribavirin: ribavirin is teratogenic and/or embryocidal in all animal species tested and is contraindicated in pregnancy. Extreme care is needed to avoid pregnancy in female patients or partners of male patients. Female patients of childbearing potential must use effective contraception during treatment and for 4 months afterwards; male patients or their female partners for 7 months afterwards.

Excipients

Pegasys contains benzyl alcohol, which may cause allergic reactions. Intravenous benzyl alcohol has been linked to serious adverse events and death in neonates (“gasping syndrome”); the product must not be given to premature babies or neonates and may cause toxic and anaphylactoid reactions in infants and children up to 3 years. High volumes should be used with caution, especially with liver or kidney impairment, because of accumulation and toxicity (metabolic acidosis). It also contains polysorbate 80, which may cause allergic reactions, and less than 1 mmol (23 mg) of sodium per dose.

Effect on Driving

Pegasys has a minor or moderate influence on the ability to drive and use machines. Patients who develop dizziness, confusion, somnolence or fatigue should avoid driving or operating machinery.

Store Pegasys in a refrigerator at 2–8 °C. Do not freeze. Keep the pre-filled syringe or vial in its outer carton to protect it from light. Because it must stay refrigerated, Pegasys is moved and held in a continuous cold chain (2–8 °C, never frozen) until it reaches the patient or the treating clinic. The pre-filled syringe holds 0.5 mL of solution in siliconised Type I glass, with a needle.

• Pre-filled syringe, 90 micrograms: 3 years.
• Pre-filled syringe, 135 micrograms: 4 years.
• Pre-filled syringe, 180 micrograms: 4 years.
• Vial, 180 micrograms: 4 years.

Prescription only (Rx), subject to restricted medical prescription (Annex II B of the marketing authorisation). Treatment must be started by a physician experienced in the treatment of the condition. Because Pegasys is designed to be injected by the patient or a carer after training, it is supplied to the patient or to the treating clinic on prescription, with cold-chain delivery at 2–8 °C.