Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639, Grenzach-Wyhlen, Germany
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.
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).
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.
During therapy with Pegasys +/- ribavirin lasting up to 48 weeks in patients aged 3 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 the treatment with Pegasys +/- ribavirin induced a growth inhibition during treatment, the reversibility of which is uncertain.
The risk of growth inhibition 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 (for HBVinfection mainly HBV genotype and ALT levels; for HCV-infection mainly HCV genotype and HCV-RNA levels) (see section 5.1).
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.
In order to improve the traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.
Prior 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:
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 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 pretreatment 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 CHC 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 CHC 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.
Thyroid 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 by pharmaceutical 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.
Hypertension, 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).
In 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 CHB, unlike CHC, 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 10x ULN, 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.
Serious, 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.
The 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 CHC 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).
While 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 antiinfective therapy should be started immediately and discontinuation of therapy should be considered.
Retinopathy 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 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.
Use 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.
The 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.
Please 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 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.
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.
Pegasys 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.
Interaction studies have only been performed in adults.
Administration of Pegasys 180 micrograms once weekly for 4 weeks in healthy male subjects did not show any effect on mephenytoin, dapsone, debrisoquine and tolbutamide pharmacokinetics profiles, suggesting that Pegasys has no effect on in vivo metabolic activity of cytochrome P450 3A4, 2C9, 2C19 and 2D6 isozymes.
In the same study, a 25% increase in the AUC of theophylline (marker of cytochrome P450 1A2 activity) was observed, demonstrating that Pegasys is an inhibitor of cytochrome P450 1A2 activity. Serum concentrations of theophylline should be monitored and appropriate dose adjustments of theophylline made for patients taking theophylline and Pegasys concomitantly. The interaction between theophylline and Pegasys is likely to be maximal after more than 4 weeks of Pegasys therapy.
In 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).
No 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 coadministered 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.
There 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.
It 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.
There 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).
Significant 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.
Pegasys has minor or moderate influence on the ability to drive and use machines. Patients who develop dizziness, confusion, somnolence or fatigue should be cautioned to avoid driving or operating machinery.
In clinical trials of 48 weeks treatment and 24 weeks follow-up, the safety profile for Pegasys in CHB was similar to that seen in CHC. 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 CHC 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.
The 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.
Overall, 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 cells/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 cells/mm³), and thrombocytopenia (13% experienced a platelet count <50,000 cells/mm³) (see section 4.4).
In 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.
Table 9 summarises the undesirable effects reported with Pegasys monotherapy in CHB or CHC adult 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 CHB or CHC or in combination with ribavirin for CHC patients in clinical trials and post marketing:
Common: Bronchitis, upper respiratory infection, oral candidiasis, herpes simplex, fungal, viral and bacterial infections
Uncommon: Pneumonia, skin infection
Rare: Endocarditis, otitis externa
Frequency not known: Sepsis
Uncommon: Hepatic neoplasm
Common: Thrombocytopenia, anaemia, lymphadenop athy
Rare: Pancytopenia
Very rare: Aplastic anaemia
Frequency not known: Pure red cell aplasia
Uncommon: Sarcoidosis, thyroiditis
Rare: Anaphylaxis, systemic lupus erythematosus rheumatoid arthritis
Very rare: Idiopathic or thrombotic thrombocytop enic purpura
Frequency not known: Liver and renal graft rejection, Vogt-Koyanagi-Harada disease
Common: Hypothyroidism, hyperthyroidism
Uncommon: Diabetes
Rare: Diabetic ketoacidosis
Very common: Anorexia
Uncommon: Dehydration
Very common: Depression*, anxiety, insomnia*
Common: Aggression, mood alteration, emotional disorders, nervousness, libido decreased
Uncommon: Suicidal ideation, hallucinations
Rare: Suicide, psychotic disorder
Frequency not known: Mania, bipolar disorders, homicidal ideation
Very common: Headache, dizziness*, concentration impaired
Common: Syncope, migraine, memory impairment, weakness, hypoaesthesia, hyperaesthesia, paraesthesia, tremor, taste disturbance, nightmares, somnolence
Uncommon: Peripheral neuropathy
Rare: Coma, convulsions, facial palsy
Frequency not known: Cerebral ischaemia
Common: Vision blurred, eye pain, eye inflammation, xerophthalmia
Uncommon: Retinal haemorrhage
Rare: Optic neuropathy, papilloedema, retinal vascular disorder, retinopathy, corneal ulcer
Very rare: Vision loss
Frequency not known: Serous retinal detachment
Common: Vertigo, earache
Uncommon: Hearing loss
Common: Tachycardia, oedema peripheral, palpitations
Rare: Myocardial infarction, congestive heart failure, cardiomyopathy, angina, arrhythmia, atrial fibrillation, pericarditis, supraventricular tachycardia
Common: Flushing
Uncommon: Hypertension
Rare: Cerebral haemorrhage, vasculitis
Frequency not known: Peripheral ischaemia
Very common: Dyspnoea, cough
Common: Dyspnoea exertional, epistaxis, nasopharyngitis, sinus congestion, nasal congestion, rhinitis, sore throat
Uncommon: Wheezing
Rare: Interstitial pneumonitis including fatal outcome, pulmonary embolism
Frequency not known: Pulmonary arterial hypertension§
Very common: Diarrhoea*, nausea*, abdominal pain*
Common: Vomiting, dyspepsia, dysphagia, mouth ulceration, gingival bleeding, glossitis, stomatitis, flatulence, dry mouth
Uncommon: Gastrointestinal bleeding
Rare: Peptic ulcer, pancreatitis
Frequency not known: Ischaemic colitis, tongue pigmentation
Uncommon: Hepatic dysfunction
Rare: Hepatic failure, cholangitis, fatty liver
Very common: Alopecia, dermatitis, pruritis, dry skin
Common: Psoriasis, urticaria, eczema, rash, sweating increased, skin disorder, photosensitivi ty reaction, night sweats
Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, erythema multiforme
Very common: Myalgia, arthralgia
Common: Back pain, arthritis, muscle weakness, bone pain, neck pain, musculoskeletal pain, muscle cramps
Rare: Myositis
Frequency not known: Rhabdomyolysis
Rare: Renal insufficiency
Common: Impotence
Very common: Pyrexia, rigors*, pain*, asthenia, fatigue, injection site reaction*, irritability*
Common: Chest pain, influenza like illness, malaise, lethargy, hot flushes, thirst
Common: Weight decreased
Rare: Substance overdose
* These adverse reactions were common (≥1/100 to <1/10) in CHB patients treated with Pegasys monotherapy
§ Class label for interferon products, see below Pulmonary arterial hypertension
Cases 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.
Pegasys 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 × 109/l) and severe (ANC: <0.5 × 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.
1-5% of patients treated with Pegasys developed neutralising anti-interferon antibodies. As with other interferons, a higher incidence of neutralising antibodies was seen in CHB. However in neither disease was this correlated with lack of therapeutic response.
Pegasys 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.
Although 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 cells/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.
In a clinical trial (YV25718) with 111 paediatric patients (3 to 17 years of age) treated with Pegasys for 48 weeks, the safety profile was consistent with that seen in adults with CHB and in paediatric patients with CHC.
The mean changes from baseline in height and weight for age Z-scores at Week 48 of treatment in study YV25718 were -0.07 and -0.21(n=108 and n=106 respectively) for Pegasys-treated patients as compared to -0.01 and -0.08 (n=47 each) in untreated patients. At Week 48 of Pegasys treatment, a height or weight percentile decrease of more than 15 percentiles on the normative growth curves was observed in 6% of patients for height and 11% of patient for weight, whereas in the untreated group it was 2% of patients for height and 9% for weight. No data is available on long-term follow-up posttreatment in these patients (see section 4.4).
In 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 onethird 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).
Growth inhibition was observed in paediatric patients (see section 4.4). Paediatric patients treated with Pegasys plus ribavirin combination therapy showed a delay in weight and height increases after 48 weeks of therapy compared with baseline. Patient ‘weight for age’ and ‘height for age’ percentiles of the normative population decreased during treatment. At the end of 2 years follow-up after treatment, most patients had returned to baseline normative growth curve percentiles for weight and height (mean weight percentile was 64% at baseline and 60% at 2 years post-treatment; mean height percentile was 54% at baseline and 56% at 2 years post-treatment). At the end of treatment, 43% of patients experienced a weight percentile decrease of 15 percentiles or more, and 25% (13 of 53) experienced a height percentile decrease of 15 percentiles or more on the normative growth curves. At 2 years posttreatment, 16% (6 of 38) of patients remained 15 percentiles or more below their baseline weight curve and 11% (4 of 38) remained 15 percentiles or more below their baseline height curve.
55% (21 of 38) of subjects who completed the original study enrolled in the long-term follow up extending up to 6 years post-treatment. The study demonstrated that the post-treatment recovery in growth at 2 years post-treatment was maintained to 6 years post-treatment. For a few subjects who were more than 15 percentiles below their baseline height curve at 2 years post-treatment, they either returned to baseline comparable height percentiles at 6 years post-treatment or a non-treatment related causative factor has been identified. The extent of available data is not sufficient to conclude that growth inhibition due to Pegasys exposure is always reversible.
Table 10. Adverse reactions reported among paediatric patients infected with HCV and assigned to Pegasys plus ribavirin in study NV17424:
Common: Infectious mononucleosis, pharyngitis streptococcal, influenza, gastroenteritis viral, candidiasis, gastroenteritis, tooth abscess, hordeolum, urinary tract infection, nasopharyngitis
Common: Anaemia
Very common: Decreased appetite
Common: Hyperglycaemia, type 1 diabetes mellitus
Very common: Insomnia
Common: Depression, anxiety, hallucination, abnormal behaviour, aggression, anger, attention deficit/hyperactivity disorder
Very common: Headache
Common: Dizziness, disturbance in attention, migraine
Common: Blindness transient, retinal exudates, visual impairment eye irritation, eye pain, eye pruritis
Common: Ear pain
Common: Dyspnoea, epistaxis
Very common: Gastrointestinal disorder
Common: Abdominal pain upper, stomatitis, nausea, aphthous stomatitis, oral disorder
Very common: Rash, pruritus, alopecia
Common: Swollen face, drug eruption,
Very common: Musculoskeletal pain
Common: Back pain, pain in extremity
Common: Dysuria, incontinence, urinary tract disorder
Common: Vaginal discharge
Very common: Influenza-like illness, injection site reaction, irritability, fatigue
Common: Pyrexia, vessel puncture site haematoma, pain
Common: Psychiatric evaluation abnormal
Common: Tooth extraction, cholecystectomy
Common: Educational problem
Decreases in haemoglobin, neutrophils, platelets or increased ALT may require dose reduction or permanent discontinuation from treatment (see section 4.2). Most laboratory abnormalities noted during the clinical trial returned to baseline levels shortly after discontinuation of treatment.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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