- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Chronic hepatitis BPegasys is indicated for the treatment of hepatitis B envelope antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B (CHB) in adult patients with compensated liver disease and evidence of viral replication, increased ALT and histologically verified liver inflammation and/or fibrosis (see sections 4.4 and 5.1).
Chronic hepatitis C
Adult patientsPegasys is indicated in combination with other medicinal products, for the treatment of chronic hepatitis C (CHC) in patients with compensated liver disease (see sections 4.2, 4.4 and 5.1). For hepatitis C virus (HCV) genotype specific activity, see sections 4.2 and 5.1. Paediatric patients 5 years of age and older:Pegasys in combination with ribavirin is indicated for the treatment of chronic hepatitis C in treatment-naïve children and adolescents 5 years of age and older who are positive for serum HCV-RNA.When deciding to initiate treatment in childhood, it is important to consider growth inhibition induced by combination therapy. The reversibility of growth inhibition is uncertain. The decision to treat should be made on a case by case basis (see section 4.4).
Chronic hepatitis B adult patientsThe recommended dosage and duration of Pegasys for both HBeAg-positive and HBeAg-negative chronic hepatitis B is 180 micrograms once weekly for 48 weeks by subcutaneous administration in the abdomen or thigh.
Chronic hepatitis C treatment-naïve adult patientsThe recommended dose for Pegasys is 180 micrograms once weekly by subcutaneous administration in the abdomen or thigh given in combination with oral ribavirin or as monotherapy.The dose of ribavirin to be used in combination with Pegasys is given in Table 1.The ribavirin dose should be administered with food.
Duration of treatment-dual therapy with Pegasys and ribavirinThe duration of combination therapy with ribavirin for chronic hepatitis C depends on viral genotype. Patients infected with HCV genotype 1 who have detectable HCV RNA at week 4 regardless of pre-treatment viral load should receive 48 weeks of therapy. Treatment for 24 weeks may be considered in patients infected with- genotype 1 with low viral load (LVL) (≤ 800,000 IU/ml) at baseline or- genotype 4who become HCV RNA negative at week 4 and remain HCV RNA negative at week 24. However, an overall 24 weeks treatment duration may be associated with a higher risk of relapse than a 48 weeks treatment duration (see section 5.1). In these patients, tolerability to combination therapy and additional prognostic factors such as degree of fibrosis should be taken into account when deciding on treatment duration. Shortening the treatment duration in patients with genotype 1 and high viral load (HVL) (>800, 000 IU/ml) at baseline who become HCV RNA negative at week 4 and remain HCV RNA negative at week 24 should be considered with even more caution since the limited data available suggest that this may significantly negatively impact the sustained virologic response.Patients infected with HCV genotype 2 or 3 who have detectable HCV RNA at week 4, regardless of pre-treatment viral load should receive 24 weeks of therapy. Treatment for only 16 weeks may be considered in selected patients infected with genotype 2 or 3 with LVL (≤ 800,000 IU/ml) at baseline who become HCV negative by week 4 of treatment and remains HCV negative by week 16. Overall 16 weeks of treatment may be associated with a lower chance of response and is associated with a higher risk of relapse than a 24 week treatment duration (see section 5.1). In these patients, tolerability to combination therapy and the presence of additional clinical or prognostic factors such as degree of fibrosis should be taken into account when considering deviations from standard 24 weeks treatment duration. Shortening the treatment duration in patients infected with genotype 2 or 3 with HVL (> 800,000 IU/ml) at baseline who become HCV negative by week 4 should be considered with more caution as this may significantly negatively impact the sustained virological response (see Table 1).Available data for patients infected with genotype 5 or 6 are limited; therefore combination treatment with 1,000/1,200 mg of ribavirin for 48 weeks is recommended.
Table 1: Dosing recommendations for combination therapy for HCV patients
|Genotype||Pegasys dose||Ribavirin dose||Duration|
|Genotype 1 LVL with RVR*||180 micrograms||<75 kg = 1000 mg ≥75 kg = 1200 mg||24 weeks or 48 weeks|
|Genotype 1 HVL with RVR*||180 micrograms||<75 kg = 1000 mg ≥75 kg = 1200 mg||48 weeks|
|Genotype 4 with RVR*||180 micrograms||<75 kg = 1000 mg ≥75 kg = 1200 mg||24 weeks or 48 weeks|
|Genotype 1 or 4 without RVR*||180 micrograms||<75 kg = 1000 mg ≥75 kg = 1200 mg||48 weeks|
|Genotype 2 or 3 without RVR**||180 micrograms||800 mg||24 weeks|
|Genotype 2 or 3 LVL with RVR**||180 micrograms||800 mg(a)||16 weeks(a) or 24 weeks|
|Genotype 2 or 3 HVL with RVR**||180 micrograms||800 mg||24 weeks|
Chronic hepatitis C treatment-experienced adult patientsThe recommended dose of Pegasys in combination with ribavirin is 180 mcg once weekly by subcutaneous administration. For patients <75 kg and ≥75 kg, 1000 mg daily and 1200 mg daily of ribavirin, respectively, and regardless of genotype, should be administered.Patients who have detectable virus at week 12 should stop therapy. The recommended total duration of therapy is 48 weeks. If patients infected with virus genotype 1, not responding to prior treatment with peginterferon and ribavirin are considered for treatment, the recommended total duration of therapy is 72 weeks (see section 5.1).
HIV-HCV co-infected adult patientsThe recommended dosage for Pegasys, alone or in combination with ribavirin, is 180 micrograms once weekly subcutaneously for 48 weeks. For patients infected with HCV genotype 1 <75 kg and ≥75 kg, 1000 mg daily and 1200 mg daily of ribavirin, respectively, should be administered. Patients infected with HCV genotypes other than genotype 1 should receive 800 mg daily of ribavirin. A duration of therapy less than 48 weeks has not been adequately studied.Duration of therapy when Pegasys is used in combination with other medicinal productsRefer also to the Summary of Product Characteristics of the medicinal products that are used in combination with Pegasys.
Predictability of response and non-response with Pegasys and ribavirin dual therapy treatment-naïve patientsEarly virological response by week 12, defined as a 2 log viral load decrease or undetectable levels of HCV RNA has been shown to be predictive for sustained response (see Tables 2 and 12).
Table 2: Predictive value of week 12 virological response at the recommended dosing regimen while on Pegasys combination therapy
|No response by week 12||No sustained response||Predictive Value||Response by week 12||Sustained response||Predictive Value|
|Genotype 1 (N= 569)||102||97||95%(97/102)||467||271||58% (271/467)|
|Genotype 2 and 3 (N=96)||3||3||100%(3/3)||93||81||87%(81/93)|
Predictability of response and non-response with Pegasys and ribavirin dual therapy treatment-experienced patientsIn non-responder patients re-treated for 48 or 72 weeks, viral suppression at week 12 (undetectable HCV RNA defined as <50 IU/ml) has been shown to be predictive for sustained virological response. The probabilities of not achieving a sustained virological response with 48 or 72 weeks of treatment if viral suppression was not achieved at week 12 were 96% (363 of 380) and 96% (324 of 339), respectively. The probabilities of achieving a sustained virological response with 48 or 72 weeks of treatment if viral suppression was achieved at week 12 were 35% (20 of 57) and 57% (57 of 100), respectively.
Dose adjustment for adverse reactions in adult patients
GeneralWhere dose adjustment is required for moderate to severe adverse reactions (clinical and/or laboratory) initial dose reduction to 135 micrograms is generally adequate for adult patients. In some cases, dose reduction to 90 micrograms or 45 micrograms is necessary. Dose increases to or towards the original dose may be considered when the adverse reaction abates (see section 4.4 for use and section 4.8). Haematological (see also Table 3)For adults, dose reduction is recommended if the neutrophil count is < 750/mm3. For patients with Absolute Neutrophil Count (ANC) < 500/mm3 treatment should be suspended until ANC values return to > 1000/mm3. Therapy should initially be re-instituted at 90 micrograms Pegasys and the neutrophil count monitored. Guidance for dose reduction based on ANC levels for paediatric patients is provided in Table 7.Dose reduction to 90 micrograms is recommended if the platelet count is < 50,000/mm3. Cessation of therapy is recommended when platelet count decreases to levels < 25,000/mm3.Specific recommendations for management of treatment-emergent anaemia in adults are as follows: ribavirin should be reduced to 600 milligrams/day (200 milligrams in the morning and 400 milligrams in the evening) if either of the following apply: (1) a patient without significant cardiovascular disease experiences a fall in haemoglobin to < 10 g/dl and ≥ 8.5 g/dl, or (2) a patient with stable cardiovascular disease experiences a fall in haemoglobin by ≥ 2 g/dl during any 4 weeks of treatment. A return to original dosing is not recommended. Ribavirin should be discontinued if either of the following applies: (1) a patient without significant cardiovascular disease experiences a fall in haemoglobin confirmed to < 8.5 g/dl; (2) a patient with stable cardiovascular disease maintains a haemoglobin value < 12 g/dl despite 4 weeks on a reduced dose. If the abnormality is reversed, ribavirin may be restarted at 600 milligrams daily, and further increased to 800 milligrams daily at the discretion of the treating physician. A return to original dosing is not recommended. Table 3: Dose adjustment for adverse reaction (for further guidance see also text above)
|Reduce ribavirin to 600 mg||Withhold ribavirin||Reduce Pegasys to 135/90/45 micrograms||Withhold Pegasys||Discontinue combination|
|Absolute Neutrophil Count||< 750/mm3||< 500/mm3|
|Platelet Count||< 50,000/mm3 > 25,000/mm3||< 25,000/mm3|
|Haemoglobin - no cardiac disease||< 10 g/dl, and ≥ 8.5 g/dl||< 8.5 g/dl|
|Haemoglobin - stable cardiac disease||decrease ≥ 2 g/dl during any 4 weeks||< 12 g/dl despite 4 weeks at reduced dose|
Liver functionFluctuations in abnormalities of liver function tests are common in patients with chronic hepatitis C. Increases in ALT levels above baseline (BL) have been observed in patients treated with Pegasys, including patients with a virological response.In chronic hepatitis C clinical trials with adult patients, isolated increases in ALT (≥ 10x ULN, or ≥ 2x BL for patients with a BL ALT ≥ 10x ULN) which resolved without dose-modification were observed in 8 of 451 patients treated with combination therapy. If ALT increase is progressive or persistent, the dose should be reduced initially to 135 micrograms. When increases in ALT levels are progressive despite dose reduction, or are accompanied by increased bilirubin or evidence of hepatic decompensation, therapy should be discontinued (see section 4.4). Guidance for dose reduction based on ALT levels for paediatric patients is provided in Table 7.For chronic hepatitis B patients, transient flares of ALT levels sometimes exceeding 10 times the upper limit of normal are not uncommon, and may reflect immune clearance. Treatment should normally not be initiated if ALT is >10 times the upper limit of normal. Consideration should be given to continuing treatment with more frequent monitoring of liver function during ALT flares. If the Pegasys dose is reduced or withheld, therapy can be restored once the flare is subsiding (see section 4.4).
Older peopleAdjustments in the recommended dosage of 180 micrograms once weekly are not necessary when instituting Pegasys therapy in elderly patients (see section 5.2).
Renal impairmentIn patients with end stage renal disease, a starting dose of 135 micrograms should be used (see section 5.2). Regardless of the starting dose or degree of renal impairment, patients should be monitored and appropriate dose reductions of Pegasys during the course of therapy should be made in the event of adverse reactions.
Hepatic impairmentIn patients with compensated cirrhosis (e.g., Child-Pugh A), Pegasys has been shown to be effective and safe. Pegasys has not been evaluated in patients with decompensated cirrhosis (e.g., Child-Pugh B or C or bleeding oesophageal varices) (see section 4.3).The Child-Pugh classification divides patients into groups A, B, and C, or "Mild", "Moderate" and "Severe" corresponding to scores of 5-6, 7-9 and 10-15, respectively.
|Assessment||Degree of abnormality||Score|
|Encephalopathy||None Grade 1-2 Grade 3-4*||1 2 3|
|Ascites||Absent Slight Moderate||1 2 3|
|S-Bilirubin (mg/dl) SI unit = μmol/l)||<2 2.0-3 >3 <34 34-51 >51||1 2 3 1 2 3|
|S-Albumin (g/dl)||>3.5 3.5-2.8 <2.8||1 2 3|
|INR||<1.7 1.7-2.3 >2.3||1 2 3|
Duration of treatmentThe duration of treatment with Pegasys in combination with ribavirin in paediatric patients with chronic hepatitis C depends on viral genotype. Patients infected with viral genotypes 2 or 3 should receive 24 weeks of treatment, while patients infected with any other genotype should receive 48 weeks of therapy.Patients who still have detectable levels of HCV-RNA despite an initial 24 weeks of therapy, should discontinue therapy, as it is unlikely they will be able to achieve a sustained virological response with continued therapy.
Table 4: Pegasys dosing recommendations for paediatric patients aged 5 to 17 years
|Body Surface Area (BSA) range (m2)||Weekly dose (mcg)|
Table 5: Ribavirin dosing recommendations for paediatric patients aged 5 to 17 years
|Body weight kg (lbs)||Ribavirin daily dose (Approx. 15 mg/kg/day)||Ribavirin number of tablets|
|23 33 (51-73)||400 mg/day||1 x 200 mg tablets A.M. 1 x 200 mg tablets P.M.|
|34 46 (75-101)||600 mg/day||1 x 200 mg tablets A.M. 2 x 200 mg tablets P.M.|
|47 59 (103-131)||800 mg/day||2 x 200 mg tablets A.M. 2 x 200 mg tablets P.M.|
|60 74 (132-163)||1000 mg/day||2 x 200 mg tablets A.M. 3 x 200 mg tablets P.M.|
|≥75 (>165)||1200 mg/day||3 x 200 mg tablets A.M. 3 x 200 mg tablets P.M.|
Dose adjustment for adverse reactions in paediatric patientsFor paediatric patients, based on toxicities (see Table 6), up to three levels of dose modification can be made before dose interruption or discontinuation is considered.
Table 6: Pegasys dose modification recommendations in paediatric patients
|Starting dose(mcg)||1 level reduction(mcg)||2 level reduction(mcg)||3 level reduction(mcg)|
Table 7: Pegasys dose modification recommendations for toxicities in paediatric patients
|Toxicity||Pegasys dose modification|
|Neutropenia||750-999 cells/mm3: Week 1-2 - immediate 1 level adjustment; Week 3-48: no modification. 500-749 cells/mm3: Week 1-2 - interrupt dosing until >750 cells/mm3 then resume dose with a 1 level adjustment, assess weekly for the next 3 weeks to verify ANC >750 cells/mm3; Week 3-48 - immediate 1 level adjustment. 250-499 cells/mm3: Week 1-2 - interrupt dosing until >750 cells/mm3 then resume dose with a 2 level adjustment; Week 3-48 - interrupt dosing until >750 cells/mm3 then resume dose with a 1 level adjustment. < 250 cells/mm3 (or febrile neutropenia) discontinue treatment.|
|Increased alanine transaminase (ALT)||For persistent or increasing elevations ≥5 but <10 x ULN, reduce dose with a 1 level adjustment and monitor weekly ALT level to ensure it is stable or decreasing For persistent ALT values ≥10 x ULN discontinue treatment.|
Table 8: Ribavirin dose modification recommendations in paediatric patients
|Full dose(Approx. 15 mg/kg/day)||One step dose modification(Approx. 7.5 mg/kg/day)||Ribavirin number of tablets|
|400 mg/day||200 mg/day||1 x 200 mg tablets A.M.|
|600 mg/day||400 mg/day||1 x 200 mg tablets A.M. 1 x 200 mg tablets P.M.|
|800 mg/day||400 mg/day||1 x 200 mg tablets A.M. 1 x 200 mg tablets P.M.|
|1000 mg/day||600 mg/day||1 x 200 mg tablets A.M. 2 x 200 mg tablets P.M.|
|1200 mg/day||600 mg/day||1 x 200 mg tablets A.M. 2 x 200 mg tablets P.M.|
Method of administrationPegasys is administered subcutaneously in the abdomen or thigh. Exposure to Pegasys was decreased in studies following administration of Pegasys in the arm (see section 5.2).Pegasys is designed for administration by the patient or carer. Each syringe/pen should be used by one person only and is for single use.Appropriate training is recommended for non-healthcare professionals administering this medicinal product. The Instructions for the User, provided in the carton, must be followed carefully by the patient.
|Psychiatric and Central Nervous System (CNS): Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during Pegasys therapy, and even after treatment discontinuation mainly during the 6-month follow-up period. Other CNS effects including aggressive behaviour (sometimes directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of mental status have been observed with alfa interferons. All patients should be closely monitored for any signs or symptoms of psychiatric disorders. If symptoms of psychiatric disorders appear, the potential seriousness of these undesirable effects must be borne in mind by the prescribing physician and the need for adequate therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal ideation is identified, it is recommended that treatment with Pegasys be discontinued, and the patient followed, with psychiatric intervention as appropriate. Patients with existence of, or history of severe psychiatric conditions: If treatment with Pegasys is judged necessary in patients with existence or history of severe psychiatric conditions, this should only be initiated after having ensured appropriate individualised diagnostic and therapeutic management of the psychiatric condition. The use of Pegasys in children and adolescents with existence of or history of severe psychiatric conditions is contraindicated (see section 4.3). Patients with substance use/abuse: HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders when treated with alfa interferon. If treatment with alfa interferon is judged necessary in these patients, the presence of psychiatric co-morbidities and the potential for other substance use should be carefully assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach including a mental health care provider or addiction specialist should be considered to evaluate, treat and follow the patient. Patients should be closely monitored during therapy and even after treatment discontinuation. Early intervention for re-emergence or development of psychiatric disorders and substance use is recommended.|
|Growth and development (children and adolescents): During the course of Pegasys plus ribavirin therapy lasting up to 48 weeks in patients aged 5 to 17 years, weight loss and growth inhibition were common (see sections 4.8 and 5.1). The expected benefit of treatment should be carefully weighed against the safety findings observed for children and adolescents in the clinical trials on a case by case basis (see sections 4.8 and 5.1). - It is important to consider that the combination therapy induced a growth inhibition during treatment, the reversibility of which is uncertain. - This risk should be weighed against the disease characteristics of the child, such as evidence of disease progression (notably fibrosis), co-morbidities that may negatively influence the disease progression (such as HIV co-infection), as well as prognostic factors of response (HCV genotype and viral load). Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the risk of growth inhibition. There are no data on long term effects on sexual maturation.|
Laboratory tests prior to and during therapyPrior to beginning Pegasys therapy, standard haematological and biochemical laboratory tests are recommended for all patients.The following may be considered as baseline values for initiation of treatment:- Platelet count ≥ 90,000/mm3- Absolute neutrophil counts ≥ 1500/mm3- Adequately controlled thyroid function (TSH and T4)Haematological tests should be repeated after 2 and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy (including glucose monitoring).In clinical trials, Pegasys treatment was associated with decreases in both total white blood cell (WBC) count and absolute neutrophil count (ANC), usually starting within the first 2 weeks of treatment (see section 4.8). Progressive decreases after 8 weeks of therapy were infrequent. The decrease in ANC was reversible upon dose reduction or cessation of therapy (see section 4.2), reached normal values by 8 weeks in the majority of patients and returned to baseline in all patients after about 16 weeks.Pegasys treatment has been associated with decreases in platelet count, which returned to pre-treatment levels during the post-treatment observation period (see section 4.8). In some cases, dose modification may be necessary (see section 4.2).The occurrence of anaemia (haemoglobin <10 g/dl) has been observed in up to 15% of chronic hepatitis C patients in clinical trials on the combined treatment of Pegasys with ribavirin. The frequency depends on the treatment duration and the dose of ribavirin (see section 4.8). The risk of developing anaemia is higher in the female population.Caution should be exercised when administering Pegasys in combination with other potentially myelosuppressive agents.Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the administration of a peginterferon and ribavirin concomitantly with azathioprine. This myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy and concomitant azathioprine and did not recur upon re-introduction of either treatment alone (see section 4.5).The use of Pegasys and ribavirin combination therapy in chronic hepatitis C patients who failed prior treatment has not been adequately studied in patients who discontinued prior therapy for haematological adverse reactions. Physicians considering treatment in these patients should carefully weigh the risks versus the benefits of re-treatment.
Endocrine systemThyroid function abnormalities or worsening of pre-existing thyroid disorders have been reported with the use of alfa interferons, including Pegasys. Prior to initiation of Pegasys therapy, TSH and T4 levels should be evaluated. Pegasys treatment may be initiated or continued if TSH levels can be maintained in the normal range bypharmaceutical means. TSH levels should be determined during the course of therapy if a patient develops clinical symptoms consistent with possible thyroid dysfunction (see section 4.8). Hypoglycaemia, hyperglycaemia and diabetes mellitus have been observed with Pegasys (see section 4.8). Patients with these conditions who cannot be effectively controlled by medication should not begin Pegasys monotherapy or Pegasys/ribavirin combination therapy. Patients who develop these conditions during treatment and cannot be controlled with medication should discontinue Pegasys or Pegasys/ribavirin therapy.
Cardiovascular systemHypertension, supraventricular arrhythmias, congestive heart failure, chest pain and myocardial infarction have been associated with alfa interferon therapies, including Pegasys. It is recommended that patients who have pre-existing cardiac abnormalities have an electrocardiogram prior to initiation of Pegasys therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued. In patients with cardiovascular disease, anaemia may necessitate dose reduction or discontinuation of ribavirin (see section 4.2).
Liver functionIn patients who develop evidence of hepatic decompensation during treatment, Pegasys should be discontinued. Increases in ALT levels above baseline have been observed in patients treated with Pegasys, including patients with a viral response. When the increase in ALT levels is progressive and clinically significant, despite dose reduction, or is accompanied by increased direct bilirubin, therapy should be discontinued (see sections 4.2 and 4.8).In chronic hepatitis B, unlike chronic hepatitis C, disease exacerbations during therapy are not uncommon and are characterised by transient and potentially significant increases in serum ALT. In clinical trials with Pegasys in HBV, marked transaminase flares have been accompanied by mild changes in other measures of hepatic function and without evidence of hepatic decompensation. In approximately half the cases of flares exceeding 10 times the upper limit of normal, Pegasys dosing was reduced or withheld until the transaminase elevations subsided, while in the rest therapy was continued unchanged. More frequent monitoring of hepatic function was recommended in all instances.
HypersensitivitySerious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been rarely observed during alfa interferon therapy. If this occurs, therapy must be discontinued and appropriate medical therapy instituted immediately. Transient rashes do not necessitate interruption of treatment.
Autoimmune diseaseThe development of auto-antibodies and autoimmune disorders has been reported during treatment with alfa interferons. Patients predisposed to the development of autoimmune disorders may be at increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be evaluated carefully, and the benefit-risk of continued interferon therapy should be re-assessed (see also Endocrine system in sections 4.4 and 4.8).Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment should be withdrawn and corticosteroid therapy discussed (see section 4.8).
Fever/infectionsWhile fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent fever, particularly serious infections (bacterial, viral, fungal) must be ruled out, especially in patients with neutropenia. Serious infections (bacterial, viral, fungal) and sepsis have been reported during treatment with alfa interferons including Pegasys. Appropriate anti-infective therapy should be started immediately and discontinuation of therapy should be considered.
Ocular changesRetinopathy including retinal haemorrhages, cotton wool spots, papilloedema, optic neuropathy and retinal artery or vein obstruction which may result in loss of vision have been reported in rare instances with Pegasys. All patients should have a baseline eye examination. Any patient complaining of decrease or loss of vision must have a prompt and complete eye examination. Adult and paediatric patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during Pegasys therapy. Pegasys treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.
Pulmonary changesPulmonary symptoms, including dyspnoea, pulmonary infiltrates, pneumonia, and pneumonitis have been reported during therapy with Pegasys. In case of persistent or unexplained pulmonary infiltrates or pulmonary function impairment, treatment should be discontinued.
Skin disorderUse of alfa interferons has been associated with exacerbation or provocation of psoriasis and sarcoidosis. Pegasys must be used with caution in patients with psoriasis, and in cases of onset or worsening of psoriatic lesions, discontinuation of therapy should be considered.
TransplantationThe safety and efficacy of Pegasys and ribavirin treatment have not been established in patients with liver and other transplantations. Liver and renal graft rejections have been reported with Pegasys, alone or in combination with ribavirin.
HIV-HCV coinfectionPlease refer to the respective Summary of Product Characteristics of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with Pegasys with or without ribavirin. In study NR15961, patients concurrently treated with stavudine and interferon therapy with or without ribavirin, the incidence of pancreatitis and/or lactic acidosis was 3% (12/398).Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of developing lactic acidosis. Caution should therefore be exercised when adding Pegasys and ribavirin to HAART therapy (see ribavirin SmPC).Co-infected patients with advanced cirrhosis receiving HAART may also be at increased risk of hepatic decompensation and possibly death if treated with ribavirin in combination with interferons, including Pegasys. Baseline variables in co-infected cirrhotic patients that may be associated with hepatic decompensation include: increased serum bilirubin, decreased haemoglobin, increased alkaline phosphatase or decreased platelet count, and treatment with didanosine (ddI).The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.5).During treatment, co-infected patients should be closely monitored for signs and symptoms of hepatic decompensation (including ascites, encephalopathy, variceal bleeding, impaired hepatic synthetic function; e.g., Child-Pugh score of 7 or greater). The Child-Pugh scoring may be affected by factors related to treatment (i.e. indirect hyperbilirubinemia, decreased albumin) and not necessarily attributable to hepatic decompensation. Treatment with Pegasys should be discontinued immediately in patients with hepatic decompensation.In patients co-infected with HIV-HCV, limited efficacy and safety data are available in patients with CD4 counts less than 200 cells/µl. Caution is therefore warranted in the treatment of patients with low CD4 counts.
Dental and periodontal disordersDental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving Pegasys and ribavirin combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of Pegasys and ribavirin. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they should be advised to rinse out their mouth thoroughly afterwards.
Use of peginterferon as long term maintenance monotherapy (unapproved use)In a randomised, controlled US study (HALT-C) of HCV non-responder patients with varied degrees of fibrosis where 3.5 years of treatment with 90 micrograms/week of Pegasys monotherapy was studied, no significant reductions were observed in the rate of fibrosis progression or related clinical events.
ExcipientPegasys contains benzyl alcohol. Must not be given to premature babies or neonates. May cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.
HCV monoinfected patients and HBV monoinfected patientsIn a pharmacokinetic study of 24 HCV patients concomitantly receiving methadone maintenance therapy (median dose 95 mg; range 30 mg to 150 mg), treatment with Pegasys 180 micrograms sc once weekly for 4 weeks was associated with mean methadone levels that were 10% to 15% higher than at baseline. The clinical significance of this finding is unknown; nonetheless, patients should be monitored for the signs and symptoms of methadone toxicity. Especially in patients on a high dose of methadone, the risk for QTc prolongation should be considered.Ribavirin, by having an inhibitory effect on inosine monophosphate dehydrogenase, may interfere with azathioprine metabolism possibly leading to an accumulation of 6-methylthioinosine monophosphate (6-MTIMP), which has been associated with myelotoxicity in patients treated with azathioprine. The use of peginterferon alfa-2a and ribavirin concomitantly with azathioprin should be avoided. In individual cases where the benefit of administering ribavirin concomitantly with azathioprine warrants the potential risk, it is recommended that close haematologic monitoring be done during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatment with these medicinal products should be stopped (see section 4.4).Results from pharmacokinetic substudies of pivotal phase III trials demonstrated no pharmacokinetic interaction of lamivudine on Pegasys in HBV patients or between Pegasys and ribavirin in HCV patients.A clinical trial investigating the combination of telbivudine 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration for the treatment of HBV, indicates that the combination is associated with an increased risk for developing peripheral neuropathy. The mechanism behind these events is not known; thus, co-treatment with telbivudine and other interferons (pegylated or standard) may also entail an excess risk. Moreover, the benefit of the combination of telbivudine with interferon alfa (pegylated or standard) is not currently established.Therefore, the combination of Pegasys with telbivudine is contraindicated (see section 4.3).
HIV-HCV co-infected patientsNo apparent evidence of drug interaction was observed in 47 HIV-HCV co-infected patients who completed a 12 week pharmacokinetic substudy to examine the effect of ribavirin on the intracellular phosphorylation of some nucleoside reverse transcriptase inhibitors (lamivudine and zidovudine or stavudine). However, due to high variability, the confidence intervals were quite wide. Plasma exposure of ribavirin did not appear to be affected by concomitant administration of nucleoside reverse transcriptase inhibitors (NRTIs).Co-administration of ribavirin and didanosine is not recommended. Exposure to didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased in vitro when didanosine is co-administered with ribavirin. Reports of fatal hepatic failure as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactataemia/lactic acidosis have been reported with use of ribavirin.Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4). Consideration should be given to replacing zidovudine in a combination anti-retroviral therapy regimen if this is already established. This would be particularly important in patients with a known history of zidovudine induced anaemia.
PregnancyThere are no or limited amount of data from the use of peginterferon alfa-2a in pregnant women. Studies in animals with interferon alfa-2a have shown reproductive toxicity (see section 5.3) and the potential risk for humans is unknown. Pegasys is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
BreastfeedingIt is unknown whether peginterferon alfa-2a/metabolites are excreted in human milk. Because of the potential for adverse reactions in breastfed infants, breastfeeding should be discontinued prior to initiation of treatment.
FertilityThere are no data on the effects of peginterferon alfa-2a on fertility in women. A prolongation of the menstrual cycle has been seen with peginterferon alfa-2a in female monkeys (see section 5.3).
Use with ribavirinSignificant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Ribavirin therapy is contraindicated in women who are pregnant. Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking Pegasys in combination with ribavirin. Female patients of childbearing potential must use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients or their female partners must use an effective contraceptive during treatment and for 7 months after treatment has been concluded. Please refer to the ribavirin SmPC.
Summary of the safety profile
Chronic hepatitis CThe frequency and severity of the most commonly reported adverse reactions with Pegasys are similar to those reported with interferon alfa-2a (see Table 9).The most frequently reported adverse reactions with Pegasys 180 micrograms were mostly mild to moderate in severity and were manageable without the need for modification of doses or discontinuation of therapy.
Chronic hepatitis BIn clinical trials of 48 weeks treatment and 24 weeks follow-up, the safety profile for Pegasys in chronic hepatitis B was similar to that seen in chronic hepatitis C. With the exception of pyrexia the frequency of the majority of the reported adverse reactions was notably less in CHB patients treated with Pegasys monotherapy compared with HCV patients treated with Pegasys monotherapy (see Table 9). Adverse events were experienced by 88% of Pegasys-treated patients as compared with 53% of patients in the lamivudine comparator group, while 6% of the Pegasys-treated and 4% of the lamivudine-treated patients experienced serious adverse events during the studies. Adverse events or laboratory abnormalities led to 5% of patients withdrawing from Pegasys treatment, while less than 1% of patients withdrew from lamivudine treatment for these reasons. The percentage of patients with cirrhosis who withdrew from treatment was similar to that of the overall population in each treatment group.
Chronic hepatitis C in prior non-responder patientsOverall, the safety profile for Pegasys in combination with ribavirin in prior non-responder patients was similar to that in naïve patients. In a clinical trial of non-responder patients to prior pegylated interferon alfa-2b/ribavirin, which exposed patients to either 48 or 72 weeks of treatment, the frequency of withdrawal for adverse events or laboratory abnormalities from Pegasys treatment and ribavirin treatment was 6% and 7%, respectively, in the 48 week arms and 12% and 13% ,respectively, in the 72 week arms. Similarly for patients with cirrhosis or transition to cirrhosis, the frequencies of withdrawal from Pegasys treatment and ribavirin treatment were higher in the 72-week treatment arms (13% and 15%) than in the 48-week arms (6% and 6%). Patients who withdrew from previous therapy with pegylated interferon alfa-2b/ribavirin because of haematological toxicity were excluded from enrolling in this trial.In another clinical trial, non-responder patients with advanced fibrosis or cirrhosis (Ishak score of 3 to 6) and baseline platelet counts as low as 50,000/mm3 were treated for 48 weeks. Haematologic laboratory abnormalities observed during the first 20 weeks of the trial included anaemia (26% of patients experienced a haemoglobin level of <10 g/dl), neutropenia (30% experienced an ANC <750/mm3), and thrombocytopenia (13% experienced a platelet count <50,000/ mm3) (see section 4.4).
Chronic hepatitis C and HIV co-infectionIn HIV-HCV co-infected patients, the clinical adverse reaction profiles reported for Pegasys, alone or in combination with ribavirin, were similar to those observed in HCV mono-infected patients For HIV-HCV patients receiving Pegasys and ribavirin combination therapy other undesirable effects have been reported in ≥ 1% to ≤ 2% of patients: hyperlactacidaemia/lactic acidosis, influenza, pneumonia, affect lability, apathy, tinnitus, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and chromaturia. Pegasys treatment was associated with decreases in absolute CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. The decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. The use of Pegasys had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data are available in co-infected patients with CD4+ cell counts <200/µl.
Tabulated list of adverse reactionsTable 9 summarises the undesirable effects reported with Pegasys monotherapy in CHB or CHC patients and with Pegasys in combination with ribavirin in CHC patients. Undesirable effects reported in clinical studies are grouped according to frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000). For spontaneous reports of undesirable effects from post-marketing experience, the frequency is not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in decreasing order of seriousness.Table 9: Undesirable effects reported with Pegasys monotherapy for HBV or HCV or in combination with ribavirin for HCV patients in clinical trials and post marketing
|Body system||Very common||Common||Uncommon||Rare||Very rare||Frequency not known|
|Infections and infestations||Bronchitis, upper respiratory infection, oral candidiasis, herpes simplex, fungal, viral and bacterial infections||Pneumonia, skin infection||Endocarditis, otitis externa||Sepsis|
|Neoplasms benign and malignant||Hepatic neoplasm|
|Blood and lymphatic system disorders||Thrombocytopenia, anaemia, lymphadenopathy||Pancytopenia||Aplastic anaemia||Pure red cell aplasia|
|Immune system disorders||Sarcoidosis, thyroiditis||Anaphylaxis, systemic lupus erythematosus rheumatoid arthritis||Idiopathic or thrombotic thrombocytopenic purpura||Liver and renal graft rejection, Vogt-Koyanagi-Harada disease|
|Endocrine disorders||Hypothyroidism, hyperthyroidism||Diabetes||Diabetic ketoacidosis|
|Metabolism and nutrition disorders||Anorexia||Dehydration|
|Psychiatric disorders||Depression*, anxiety, insomnia*||Aggression, mood alteration, emotional disorders, nervousness, libido decreased||Suicidal ideation, hallucinations||Suicide, psychotic disorder||Mania, bipolar disorders, homicidal ideation|
|Nervous system disorders||Headache, dizziness*, concentration impaired||Syncope, migraine, memory impairment, weakness, hypoaesthesia, hyperaesthesia, paraesthesia, tremor, taste disturbance, nightmares, somnolence||Peripheral neuropathy||Coma, convulsions, facial palsy||Cerebral ischaemia|
|Eye disorders||Vision blurred, eye pain, eye inflammation, xerophthalmia||Retinal haemorrhage||Optic neuropathy, papilledema, retinal vascular disorder, retinopathy, corneal ulcer||Vision loss||Serous retinal detachment|
|Ear and labyrinth disorders||Vertigo, earache||Hearing loss|
|Cardiac disorders||Tachycardia, oedema peripheral, palpitations||Myocardial infarction, congestive heart failure, cardio-myopathy, angina, arrhythmia, atrial fibrillation, pericarditis, supraventricular tachycardia|
|Vascular disorders||Flushing||Hypertension||Cerebral haemorrhage, vasculitis||Peripheral ischaemia|
|Respiratory, thoracic and mediastinal disorders||Dyspnoea, cough||Dyspnoea exertional, epistaxis, nasopharyngitis, sinus congestion, nasal congestion, rhinitis, sore throat||Wheezing||Interstitial pneumonitis including fatal outcome, pulmonary embolism||Pulmonary arterial hypertension§|
|Gastrointestinal disorders||Diarrhoea*, nausea*, abdominal pain*||Vomiting, dyspepsia, dysphagia, mouth ulceration, gingival bleeding, glossitis, stomatitis, flatulence, dry mouth||Gastro-intestinal bleeding||Peptic ulcer, pancreatitis||Ischaemic colitis, tongue pigmentation|
|Hepato-biliary disorders||Hepatic dysfunction||Hepatic failure, cholangitis, fatty liver|
|Skin and subcutaneous tissue disorders||Alopecia, dermatitis, pruritis, dry skin||Psoriasis, urticaria, eczema, rash, sweating increased, skin disorder, photosensitivity reaction, night sweats||Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, erythema multiforme|
|Musculoskeletal and connective tissue disorders||Myalgia, arthralgia||Back pain, arthritis, muscle weakness, bone pain, neck pain, musculoskeletal pain, muscle cramps||Myositis||Rhabdo-myolysis|
|Renal and urinary disorders||Renal insufficiency|
|Reproductive system and breast disorders||Impotence|
|General disorders and administration site conditions||Pyrexia, rigors*, pain*, asthenia, fatigue, injection site reaction*, irritability*||Chest pain, influenza like illness, malaise, lethargy, hot flushes, thirst|
|Injury, poisoning and procedural complications||Substance overdose|
Description of selected adverse reactionsPulmonary arterial hypertensionCases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, 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.
Laboratory valuesPegasys treatment was associated with abnormal laboratory values: ALT increase, bilirubin increase, electrolyte disturbance (hypokalaemia, hypocalcaemia, hypophosphataemia), hyperglycaemia, hypoglycaemia and elevated triglycerides (see section 4.4.). With both Pegasys monotherapy, and also the combined treatment with ribavirin, up to 2% of patients experienced increased ALT levels that led to dose modification or discontinuation of the treatment.Treatment with Pegasys was associated with decreases in haematological values (leucopenia, neutropenia, lymphopenia, thrombocytopenia and haemoglobin), which generally improved with dose modification, and returned to pre-treatment levels within 4-8 weeks upon cessation of therapy (see sections 4.2 and 4.4).Moderate (ANC: 0.749 - 0.5 x 109/l) and severe (ANC: < 0.5 x 109/l) neutropenia was observed respectively in 24% (216/887) and 5% (41/887) of patients receiving Pegasys 180 micrograms and ribavirin 1000/1200 milligrams for 48 weeks.
Anti-interferon antibodies1-5% of patients treated with Pegasys developed neutralising anti-interferon antibodies. As with other interferons, a higher incidence of neutralising antibodies was seen in chronic hepatitis B. However in neither disease was this correlated with lack of therapeutic response.
Thyroid functionPegasys treatment was associated with clinically significant abnormalities in thyroid laboratory values requiring clinical intervention (see section 4.4). The frequencies observed (4.9%) in patients receiving Pegasys/ribavirin (NV15801) are similar to those observed with other interferons.
Laboratory values for HIV-HCV co-infected patientsAlthough haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HIV-HCV patients, the majority could be managed by dose modification and the use of growth factors and infrequently required premature discontinuation of treatment. Decrease in ANC levels below 500 cells/mm3 was observed in 13% and 11% of patients receiving Pegasys monotherapy and combination therapy, respectively. Decrease in platelets below 50,000/mm3 was observed in 10% and 8% of patients receiving Pegasys monotherapy and combination therapy, respectively. Anaemia (haemoglobin < 10 g/dl) was reported in 7% and 14% of patients treated with Pegasys monotherapy or in combination therapy, respectively.Paediatric population
Chronic hepatitis CIn a clinical trial with 114 paediatric patients (5 to 17 years of age) treated with Pegasys alone or in combination with ribavirin (see section 5.1), dose modifications were required in approximately one-third of patients, most commonly for neutropenia and anaemia. In general, the safety profile observed in paediatric patients was similar to that seen in adults. In the paediatric study, the most prevalent adverse reactions in patients treated with combination therapy for up to 48 weeks with Pegasys and ribavirin were influenza-like illness (91%), headache (64%), gastrointestinal disorder (56%), and injection-site reaction (45%). A full listing of adverse reactions reported in this treatment group (n=55) is provided in Table 10. Seven patients receiving combination Pegasys and ribavirin treatment for 48 weeks discontinued therapy for safety reasons (depression, psychiatric evaluation abnormal, transient blindness, retinal exudates, hyperglycaemia, type 1 diabetes mellitus, and anaemia). Most of the adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 2 patients in the Pegasys plus ribavirin combination therapy group (hyperglycaemia and cholecystectomy).
Table 10: Adverse reactions reported among paediatric patients infected with HCV and assigned to Pegasys plus ribavirin in study NV17424
|Body system||Very common||Common|
|Infections and infestations||Infectious mononucleosis, pharyngitis streptococcal, influenza, gastroenteritis viral, candidiasis, gastroenteritis, tooth abscess, hordeolum, urinary tract infection, nasopharyngitis|
|Blood and lymphatic system disorders||Anaemia|
|Metabolism and nutrition disorders||Decreased appetite||Hyperglycaemia, type 1 diabetes mellitus|
|Psychiatric disorders||Insomnia||Depression, anxiety, hallucination, abnormal behaviour, aggression, anger, attention deficit / hyperactivity disorder|
|Nervous system disorders||Headache||Dizziness, disturbance in attention, migraine|
|Eye disorders||Blindness transient, retinal exudates, visual impairment, eye irritation, eye pain, eye pruritis|
|Ear and labyrinth disorders||Ear pain|
|Respiratory, thoracic and mediastinal disorders||Dyspnoea, epistaxis|
|Gastrointestinal disorders||Gastrointestinal disorder||Abdominal pain upper, stomatitis, nausea, aphthous stomatitis, oral disorder|
|Skin and subcutaneous tissue disorders||Rash, pruritus, alopecia||Swollen face, drug eruption|
|Musculoskeletal and connective tissue disorders||Musculoskeletal pain||Back pain, pain in extremity|
|Renal and urinary disorders||Dysuria, incontinence, urinary tract disorder|
|Reproductive system and breast disorders||Vaginal discharge|
|General disorders and administration site conditions||Influenza-like illness, injection site reaction, irritability, fatigue||Pyrexia, vessel puncture site haematoma, pain|
|Investigations||Psychiatric evaluation abnormal|
|Surgical and medical procedures||Tooth extraction, cholecystectomy|
|Social circumstances||Educational problem|
Laboratory valuesDecreases in haemoglobin, neutrophils and platelets may require dose reduction or permanent discontinuation from treatment (see Table 3 and Table 7). Most laboratory abnormalities noted during the clinical trial returned to baseline levels shortly after discontinuation of treatment.Reporting of suspected adverse reactionsReporting 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 (see details below). IrelandHPRA Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.iee-mail: firstname.lastname@example.orgMaltaADR Reporting Website: www.medicinesauthority.gov.mt/adrportal United KingdomYellow Card Scheme Website: www.mhra.gov.uk/yellowcard
Mechanism of actionThe conjugation of PEG reagent (bis-monomethoxypolyethylene glycol) to interferon alfa-2a forms a pegylated interferon alfa-2a (Pegasys). Pegasys possesses the in vitro antiviral and antiproliferative activities that are characteristic of interferon alfa-2a.Interferon alfa-2a is conjugated with bis-[monomethoxy polyethylene glycol] at a degree of substitution of one mole of polymer/mole of protein. The average molecular mass is approximately 60,000 of which the protein moiety constitutes approximately 20,000.Pharmacodynamic effectsHCV RNA levels decline in a biphasic manner in responding patients with hepatitis C who have received treatment with 180 micrograms Pegasys. The first phase of decline occurs 24 to 36 hours after the first dose of Pegasys and is followed by the second phase of decline which continues over the next 4 to 16 weeks in patients who achieve a sustained response. Ribavirin had no significant effect on the initial viral kinetics over the first 4 to 6 weeks in patients treated with the combination of ribavirin and pegylated interferon alfa-2a or interferon alfa.
Clinical efficacy and safety
Chronic hepatitis BAll clinical trials recruited patients with chronic hepatitis B who had active viral replication measured by HBV DNA, elevated levels of ALT and a liver biopsy consistent with chronic hepatitis. Study WV16240 recruited patients who were positive for HBeAg, while study WV16241 recruited patients who were negative for HBeAg and positive for anti-HBe. In both studies the treatment duration was 48 weeks, with 24 weeks of treatment-free follow-up. Both studies compared Pegasys plus placebo vs Pegasys plus lamivudine vs lamivudine alone. No HBV-HIV co-infected patients were included in these clinical trials.Response rates at the end of follow-up for the two studies are presented in Table 11. In study WV16240, the primary efficacy endpoints were HBeAg seroconversion and HBV-DNA below 105 copies/ml. In study WV16241, the primary efficacy endpoints were ALT normalisation and HBV-DNA below 2 x 104 copies/ml. HBV-DNA was measured by the COBAS AMPLICOR™ HBV MONITOR Assay (limit of detection 200 copies/ml).A total of 283/1351 (21%) of patients had advanced fibrosis or cirrhosis, 85/1351 (6%) had cirrhosis. There was no difference in response rate between these patients and those without advanced fibrosis or cirrhosis.
Table 11: Serological, virological and biochemical responses in chronic hepatitis B
|HBeAg positive Study WV16240||HBeAg negative / anti-HBe positive Study WV16241|
|Response Parameter||Pegasys 180 mcg & Placebo (N=271)||Pegasys 180 mcg & Lamivudine 100 mg (N=271)||Lamivudine 100 mg (N=272)||Pegasys 180 mcg & Placebo (N=177)||Pegasys 180 mcg & Lamivudine 100 mg (N=179)||Lamivudine 100 mg (N=181)|
|HBeAg Seroconversion||32% #||27%||19%||N/A||N/A||N/A|
|HBV DNA response *||32% #||34%||22%||43% #||44%||29%|
|ALT Normalisation||41% #||39%||28%||59% #||60%||44%|
|HBsAg Seroconversion||3% #||3%||0%||3%||2%||0%|
Chronic hepatitis C
Predictability of responsePlease refer to section 4.2, in Table 2.
Dose-response in monotherapyIn a direct comparison with 90 micrograms, the 180 micrograms-dose was associated with superior sustained virological response in patients with cirrhosis, but in a study in non-cirrhotic patients very similar results were obtained with doses of 135 micrograms and 180 micrograms.
Confirmatory clinical trials in adult treatment-naïve patientsAll clinical trials recruited interferon-naïve patients with chronic hepatitis C confirmed by detectable levels of serum HCV RNA, elevated levels of ALT (with the exception of study NR16071) and a liver biopsy consistent with chronic hepatitis. Study NV15495 specifically recruited patients with a histological diagnosis of cirrhosis (about 80%) or transition to cirrhosis (about 20%). Only HIV-HCV co-infected patients were included in the study NR15961 (see Table 20). These patients had stable HIV disease and mean CD4 T-cell count was about 500 cells/µl.For HCV monoinfected patients and HIV-HCV co-infected patients, for treatment regimens, duration of therapy and study outcome see Tables 12, 13, 14 and Table 20, respectively. Virological response was defined as undetectable HCV RNA as measured by the COBAS AMPLICOR™ HCV Test, version 2.0 (limit of detection 100 copies/ml equivalent to 50 International Units/ml) and sustained response as one negative sample approximately 6 months after end of therapy.Table 12: Virological response in HCV patients
|Pegasys monotherapy||Pegasys combination therapy|
|non-cirrhotic and cirrhotic||cirrhotic||non-cirrhotic and cirrhotic|
|Study NV15496 + NV15497 + NV15801||Study NV15495||Study NV15942||Study NV15801|
|Pegasys180 mcg||Interferon alfa-2a6 MIU/3 MIU & 3 MIU||Pegasys180 mcg||Interferon alfa-2a3 MIU||Pegasys180 mcg & Ribavirin1000/1200 mg||Pegasys180 mcg & Ribavirin1000/1200 mg||Interferon Alfa-2b3 MIU & Ribavirin1000/1200 mg|
|(N=701) 48 weeks||(N=478) 48 weeks||(N=87) 48 weeks||(N=88) 48 weeks||(N=436) 48 weeks||(N=453) 48 weeks||(N=444) 48 weeks|
|Response at End of Treatment||55 - 69%||22 - 28%||44%||14%||68%||69%||52%|
|Overall Sustained Response||28 - 39%||11 - 19%||30%*||8%*||63%||54%**||45%**|
Table 13: Sustained virological response based on genotype and pre-treatment viral load after Pegasys combination therapy with ribavirin in HCV patients
|Study NV15942||Study NV15801|
|Pegasys180 mcg & Ribavirin800 mg 24 weeks||Pegasys180 mcg & Ribavirin1000/1200 mg 24 weeks||Pegasys180 mcg & Ribavirin800 mg 48 weeks||Pegasys180 mcg & Ribavirin1000/1200 mg 48 weeks||Pegasys180 mcg & Ribavirin1000/1200 mg 48 weeks||Interferon alfa-2b3 MIU & Ribavirin1000/1200 mg 48 weeks|
|Genotype 1Low viral load High viral load||29% (29/101)41% (21/51) 16% (8/50)||42% (49/118)* 52% (37/71) 26% (12/47)||41% (102/250)* 55% (33/60) 36% (69/190)||52% (142/271)* 65% (55/85) 47% (87/186)||45% (134/298) 53% (61/115) 40% (73/182)||36% (103/285) 44% (41/94) 33% (62/189)|
|Genotype 2/3Low viral load High viral load||84% (81/96) 85% (29/34) 84% (52/62)||81% (117/144) 83% (39/47) 80% (78/97)||79% (78/99) 88% (29/33) 74% (49/66)||80% (123/153) 77% (37/48) 82% (86/105)||71% (100/140) 76% (28/37) 70% (72/103)||61% (88/145) 65% (34/52) 58% (54/93)|
|Study NV15942||Study ML17131|
|Pegasys180 mcg & Ribavirin1000/1200 mg 24 weeks||Pegasys180 mcg & Ribavirin1000/1200 mg 48 weeks||Pegasys180 mcg & Ribavirin1000/1200 mg 24 weeks|
|Genotype 1 RVRLow viral load High viral load||90% (28/31) 93% (25/27) 75% (3/4)||92% (47/51) 96% (26/27) 88% (21/24)||77% (59/77) 80% (52/65) 58% (7/12)|
|Genotype 1 non RVR||24% (21/87)||43% (95/220)||-|
|Low viral load High viral load||27% (12/44) 21% (9/43)||50% (31/62) 41% (64/158)||--|
|Genotype 4 RVR||(5/6)||(5/5)||92% (22/24)|
|Genotype 4 non RVR||(3/6)||(4/6)||-|
Table 15: Relapse of virological response at the end of treatment for rapid virological response population
|Study NV15942||Study NV15801|
|Pegasys180 mcg & Ribavirin1000/1200 mg 24 weeks||Pegasys180 mcg & Ribavirin1000/1200 mg 48 weeks||Pegasys180 mcg & Ribavirin1000/1200 mg 48 weeks|
|Genotype 1 RVRLow viral load High viral load||6.7% (2/30) 3.8% (1/26) 25% (1/4)||4.3% (2/47) 0% (0/25) 9.1% (2/22)||0% (0/24) 0% (0/17) 0% (0/7)|
|Genotype 4 RVR||(0/5)||(0/5)||0% (0/4)|
|Pegasys 180 mcg &Ribavirin 800 mg 16 weeks||Pegasys 180 mcg & Ribavirin 800 mg 24 weeks||Treatment difference [95%CI]||p value|
|Genotype 2 or 3||65% (443/679)||76% (478/630)||-10.6% [-15.5% ; -0.06%]||P<0.0001|
|Genotype 2 or 3 RVRLow viral load High viral load||82% (378/461) 89% (147/166) 78% (231/295)||90% (370/410) 94% (141/150) 88% (229/260)||-8.2% [-12.8% ; -3.7%] -5.4% [-12% ; 0.9%] -9.7% [-15.9% ;-3.6%]||P=0.0006 P=0.11 P=0.002|
Table 17: Relapse of virological response after the end of treatment in genotype 2 or 3 patients with a rapid viral response
|Pegasys 180 mcg & Ribavirin 800 mg 16 weeks||Pegasys 180 mcg & Ribavirin 800 mg 24 weeks||Treatment difference [95%CI]||p value|
|Genotype 2 or 3 RVR||15% (67/439)||6% (23/386)||9.3% [5.2% ; 13.6%]||P<0.0001|
|Low viral load High viral load||6% (10/155) 20% (57/284)||1% (2/141) 9% (21/245)||5% [0.6% ; 10.3%] 11.5% [5.6% ; 17.4%]||P=0.04 P=0.0002|
Adult chronic hepatitis C prior treatment non-responder patientsIn study MV17150, patients who were non-responders to previous therapy with pegylated interferon alfa-2b plus ribavirin were randomised to four different treatments:• Pegasys 360 mcg/week for 12 weeks, followed by 180 mcg/week for a further 60 weeks• Pegasys 360 mcg/week for 12 weeks, followed by 180 mcg/week for a further 36 weeks• Pegasys 180 mcg/week for 72 weeks• Pegasys 180 mcg/week for 48 weeksAll patients received ribavirin (1000 or 1200 mg/day) in combination with Pegasys. All treatment arms had 24 week treatment-free follow-up.Multiple regression and pooled group analyses evaluating the influence of treatment duration and use of induction dosing clearly identified treatment duration for 72 weeks as the primary driver for achieving a sustained virological response. Differences in sustained virological response (SVR) based on treatment duration, demographics and best responses to previous treatment are displayed in Table 18.Table 18: Week 12 virological response (VR) and sustained virological response (SVR) in patients with virological response at week 12 after treatment with Pegasys and ribavirin combination therapy in nonresponders to peginterferon alfa-2b plus ribavirin
|Pegasys 360/180 or 180 mcg & Ribavirin 1000/1200 mg 72 or 48 Weeks (N = 942) Pts with VR at Wk 12 a(N = 876)||Pegasys 360/180 or 180 mcg & Ribavirin 1000/1200 mg 72 Weeks (N = 473) SVR in Pts with VR at Wk 12 b(N = 100)||Pegasys 360/180 or 180 mcg & Ribavirin 1000/1200 mg 48 Weeks (N = 469) SVR in Pts with VR at Wk 12 b(N = 57)|
|Overall Low viral load High viral load||18% (157/876) 35% (56/159) 14% (97/686)||57% (57/100) 63% (22/35) 54% (34/63)||35% (20/57) 38% (8/21) 32% (11/34)|
|Genotype 1/4 Low viral load High viral load||17% (140/846) 35% (54/154) 13% (84/663)||55% (52/94) 63% (22/35) 52% (30/58)||35% (16/46) 37% (7/19) 35% (9/26)|
|Genotype 2/3 Low viral load High viral load||58% (15/26) (2/5) (11/19)||(4/5) (3/4)||(3/10) (1/2) (1/7)|
|Cirrhosis StatusCirrhosis Noncirrhosis||8% (19/239) 22% (137/633)||(6/13) 59% (51/87)||(3/6) 34% (17/50)|
|Best Response during Previous Treatment≥2log10 decline in HCV RNA <2log10 decline in HCV RNA Missing best previous response||28% (34/121) 12% (39/323) 19% (84/432)||68% (15/22) 64% (16/25) 49% (26/53)||(6/12) (5/14) 29% (9/31)|
Table 19: Sustained virological response in HALT-C by previous treatment regimen in non-responder population
|Previous Treatment||Pegasys 180 mcg & Ribavirin 1000/1200 mg 48 weeks|
|Pegylated interferon||34% (13/38)|
|Interferon plus ribavirin||13% (90/692)|
|Pegylated interferon plus ribavirin||11% (7/61)|
HIV-HCV co-infected patientsThe virological responses of patients treated with Pegasys monotherapy and with Pegasys and ribavirin combination therapy in relation to genotype and pre-treatment viral load for HIV-HCV co-infected patients are summarised below in Table 20.Table 20: Sustained virological response based on genotype and pre-treatment viral load after Pegasys combination therapy with ribavirin in HIV-HCV co-infected patients
|Interferon alfa-2a 3 MIU & Ribavirin 800 mg48 weeks||Pegasys180 mcg & Placebo48 weeks||Pegasys180 mcg & Ribavirin 800 mg48 weeks|
|All patients||12% (33/285)*||20% (58/286)*||40% (116/289)*|
|Genotype 1||7% (12/171)||14% (24/175)||29% (51/176)|
|Low viral load||19% (8/42)||38% (17/45)||61% (28/46)|
|High viral load||3% (4/129)||5% (7/130)||18% (23/130)|
|Genotype 2-3||20% (18/89)||36% (32/90)||62% (59/95)|
|Low viral load||27% (8/30)||38% (9/24)||61% (17/28)|
|High viral load||17% (10/59)||35% (23/66)||63% (42/67)|
HCV patients with normal ALTIn study NR16071, HCV patients with normal ALT values were randomised to receive Pegasys 180 micrograms/week and ribavirin 800 milligrams/day for either 24 or 48 weeks followed by a 24 week treatment free follow-up period or no treatment for 72 weeks. The SVRs reported in the treatment arms of this study were similar to the corresponding treatment arms from study NV15942.
Paediatric populationIn the investigator sponsored CHIPS study (Chronic Hepatitis C International Paediatric Study), 65 children and adolescents (6-18 years) with chronic HCV infection were treated with Pegasys 100 mcg/m2 sc once weekly and ribavirin 15 mg/kg/day for 24 weeks (genotypes 2 and 3) or 48 weeks (all other genotypes). Preliminary and limited safety data demonstrated no obvious departure from the known safety profile of the combination in adults with chronic HCV infection, but, importantly, the potential impact on growth has not been reported. Efficacy results were similar to those reported in adults.In the NV17424 (PEDS-C) study, previously untreated paediatric patients 5 to 17 years of age (55% <12 years old) with compensated chronic hepatitis C and detectable HCV RNA were treated with Pegasys 180 mcg x BSA/1.73 m2 once weekly for 48 weeks with or without ribavirin 15 mg/kg/day. All patients were followed for 24 weeks post-treatment. A total of 55 patients received initial combination treatment of Pegasys plus ribavirin, of whom 51% were female, 82% were Caucasian, and 82% were infected with HCV genotype 1. The study efficacy results for these patients are summarised in Table 21.
Table 21: Sustained virological response in the NV17424 study
|Pegasys 180 mcg x BSA/1.73 m² + Ribavirin 15 mg/kg (N=55)*|
|All HCV genotypes**||29 (53%)|
|HCV genotype 1||21/45 (47%)|
|HCV genotype 2 and 3||8/10 (80%)|
AbsorptionFollowing a single subcutaneous injection of Pegasys 180 micrograms in healthy subjects, serum concentrations of peginterferon alfa-2a are measurable within 3 to 6 hours. Within 24 hours, about 80% of the peak serum concentration is reached. The absorption of Pegasys is sustained with peak serum concentrations reached 72 to 96 hours after dosing. The absolute bioavailability of Pegasys is 84% and is similar to that seen with interferon alfa-2a.
DistributionPeginterferon alfa-2a is found predominantly in the bloodstream and extracellular fluid as seen by the volume of distribution at steady-state (Vd) of 6 to 14 litres in humans after intravenous administration. From mass balance, tissue distribution and whole body autoradioluminography studies performed in rats, peginterferon alfa-2a is distributed to the liver, kidney and bone marrow in addition to being highly concentrated in the blood.
BiotransformationThe metabolism of Pegasys is not fully characterised; however studies in rats indicate that the kidney is a major organ for excretion of radiolabelled material.
EliminationIn humans, the systemic clearance of peginterferon alfa-2a is about 100-fold lower than that of the native interferon alfa-2a. After intravenous administration, the terminal half-life of peginterferon alfa-2a in healthy subjects is approximately 60 to 80 hours compared to values of 3-4 hours for standard interferon. The terminal half-life after subcutaneous administration in patients is longer with a mean value of 160 hours (84 to 353 hours). The terminal half-life may not only reflect the elimination phase of the compound, but may also reflect the sustained absorption of Pegasys.
Linearity/non-linearityDose-proportional increases in exposure of Pegasys are seen in healthy subjects and in patients with chronic hepatitis B or C after once-weekly dosing.In chronic hepatitis B or C patients, peginterferon alfa-2a serum concentrations accumulate 2 to 3 fold after 6 to 8 weeks of once weekly dosing compared to single dose values. There is no further accumulation after 8 weeks of once weekly dosing. The peak to trough ratio after 48 weeks of treatment is about 1.5 to 2. Peginterferon alfa-2a serum concentrations are sustained throughout one full week (168 hours).
Patients with renal impairmentRenal impairment is associated with slightly decreased CL/F and prolonged half-life. In patients (n=3) with CLcrea between 20 and 40 ml/min, the average CL/F is reduced by 25% compared with patients with normal renal function. In patients with end stage renal disease undergoing haemodialysis, there is a 25% to 45% reduction in the clearance, and doses of 135 micrograms result in similar exposure as 180 micrograms doses in patients with normal renal function (see section 4.2).
GenderThe pharmacokinetics of Pegasys after single subcutaneous injections was comparable between male and female healthy subjects.Paediatric populationIn a population pharmacokinetic study (NR16141), 14 children 2 to 8 years of age with CHC received Pegasys monotherapy at a dose of: 180 mcg x BSA of the child/1.73 m2. The PK model developed from this study shows a linear influence of BSA on the apparent clearance of the drug over the age range studied. Thus, the lower the BSA of the child, the lower the clearance of the drug and the higher the resultant exposure. The mean exposure (AUC) during the dosing interval is predicted to be 25% to 70% higher than that observed in adults receiving 180 mcg fixed dosing.
Older peopleIn subjects older than 62 years, the absorption of Pegasys after a single subcutaneous injection of 180 micrograms was delayed but still sustained compared to young healthy subjects (tmax of 115 hours vs. 82 hours, older than 62 years vs. younger, respectively). The AUC was slightly increased (1663 vs. 1295 ng·h/ml) but peak concentrations (9.1 vs. 10.3 ng/ml) were similar in subjects older than 62 years. Based on drug exposure, pharmacodynamic response and tolerability, a lower dose of Pegasys is not needed in the geriatric patient (see section 4.2).
Hepatic impairmentThe pharmacokinetics of Pegasys were similar between healthy subjects and patients with hepatitis B or C. Comparable exposure and pharmacokinetic profiles were seen in cirrhotic (Child-Pugh Grade A) and non-cirrhotic patients.
Site of administrationSubcutaneous administration of Pegasys should be limited to the abdomen and thigh, as the extent of absorption based on AUC was about 20% to 30% higher upon injection in the abdomen and thigh. Exposure to Pegasys was decreased in studies following administration of Pegasys in the arm compared to administration in the abdomen and thigh.
|Pre-filled syringe:||Prefilled pen:|
|EU/1/02/221/005 EU/1/02/221/006 EU/1/02/221/007 EU/1/02/221/008 EU/1/02/221/009 EU/1/02/221/010 EU/1/02/221/017||EU/1/02/221/011 EU/1/02/221/012 EU/1/02/221/013 EU/1/02/221/014 EU/1/02/221/015 EU/1/02/221/016|
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