Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
Chronic hepatitis C

The frequency and severity of the most commonly reported adverse reactions with Pegasys are similar to those reported with interferon alfa-2a (see Table 4). 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 B

In 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 4). 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 patients

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/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).



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PEGASYS                                                          MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                     December 2015 Chronic hepatitis C and HIV co-infection

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.

Tabulated list of adverse reactions

Table 4 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 4: 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           Uncommon        Rare             Very rare    Frequency common                                                                    not known Infections and              Bronchitis,     Pneumonia,       Endocarditis,                 Sepsis infestations                upper           skin infection   otitis externa respiratory infection, oral candidiasis,
herpes simplex,
fungal, viral and bacterial infections
Neoplasms                                   Hepatic benign and                                  neoplasm malignant
Blood and                   Thrombocytop                     Pancytopenia     Aplastic     Pure red cell lymphatic                   enia, anaemia,                                    anaemia      aplasia system                      lymphadenopat disorders                   hy
Immune system                                Sarcoidosis,    Anaphylaxis,     Idiopathic   Liver and disorders                                    thyroiditis     systemic lupus   or           renal graft erythematosus,   thrombotic   rejection,
rheumatoid       thrombocy    Vogt- arthritis        topenic      Koyanagi- purpura      Harada disease



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PEGASYS                                                            MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                       December 2015 Body system     Very         Common           Uncommon         Rare              Very rare   Frequency common                                                                       not known Endocrine                    Hypothyroidis    Diabetes         Diabetic disorders                    m,                                ketoacidosis hyperthyroidis m



Metabolism and Anorexia                       Dehydration nutrition disorders
Psychiatric    Depression* Aggression,        Suicidal         Suicide,                      Mania, disorders      anxiety,     mood              ideation,        psychotic                     bipolar insomnia*    alteration,       hallucinations   disorder                      disorders, emotional                                                        homicidal disorders,                                                       ideation nervousness,
libido decreased
Nervous system Headache,    Syncope,          Peripheral       Coma,                         Cerebral disorders      dizziness*, migraine,          neuropathy       convulsions,                  ischaemia concentratio memory                             facial palsy n impaired   impairment,
weakness,
hypoaesthesia,
hyperaesthesia,
paraesthesia,
tremor, taste disturbance,
nightmares,
somnolence
Eye disorders               Vision blurred,   Retinal          Optic            Vision loss Serous retinal eye pain, eye     haemorrhage      neuropathy,                  detachment inflammation,                      papilledema,
xerophthalmia                      retinal vascular disorder,
retinopathy,
corneal ulcer
Ear and                      Vertigo,         Hearing loss labyrinth                    earache disorders
Cardiac                      Tachycardia,                      Myocardial disorders                    oedema                            infarction, peripheral,                       congestive palpitations                      heart failure,
cardiomyopath y, angina,
arrhythmia,
atrial fibrillation,
pericarditis,
supraventricula r tachycardia
Vascular                     Flushing         Hypertension     Cerebral                      Peripheral disorders                                                      haemorrhage,                  ischaemia vasculitis


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PEGASYS                                                                    MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                               December 2015 Body system        Very            Common              Uncommon        Rare               Very rare     Frequency common                                                                               not known Respiratory,       Dyspnoea,       Dyspnoea        Wheezing            Interstitial                     Pulmonary thoracic and       cough           exertional,                         pneumonitis                      arterial mediastinal                        epistaxis,                          including fatal                  hypertension disorders                          nasopharyngitis                     outcome,                         ** , sinus                             pulmonary congestion,                         embolism nasal congestion,
rhinitis, sore throat
Gastrointestinal Diarrhoea*,       Vomiting,       Gastrointestinal    Peptic ulcer,                    Ischaemic disorders        nausea*,          dyspepsia,      bleeding            pancreatitis                     colitis, abdominal         dysphagia,                                                           tongue pain*             mouth                                                                pigmentation ulceration,
gingival bleeding,
glossitis,
stomatitis,
flatulence, dry mouth
Hepato-biliary                                     Hepatic             Hepatic failure, disorders                                          dysfunction         cholangitis, fatty liver
Skin and           Alopecia,       Psoriasis,                                             Stevens- subcutaneous       dermatitis,     urticaria,                                             Johnson tissue disorders   pruritis, dry   eczema, rash,                                          syndrome, skin            sweating                                               toxic increased, skin                                        epidermal disorder,                                              necrolysis,
photosensitivit                                        angioedem y reaction,                                            a,
night sweats                                           erythema multiforme
Musculoskeletal Myalgia,           Back pain,                          Myositis                         Rhabdomyoly and connective arthralgia          arthritis,                                                           sis tissue disorders                   muscle weakness, bone pain, neck pain,
musculoskeleta l pain, muscle cramps
Renal and                                                              Renal urinary                                                                insufficiency disorders
Reproductive                       Impotence system and breast disorders
General            Pyrexia,        Chest pain,
disorders and      rigors*,        influenza like administration     pain*,          illness, malaise,
site conditions    asthenia,       lethargy, hot fatigue,        flushes, thirst injection site reaction*,
irritability*


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PEGASYS                                                                    MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                               December 2015 Body system       Very            Common            Uncommon           Rare              Very rare     Frequency common                                                                               not known Investigations                    Weight decreased
Injury,                                                                Substance poisoning and                                                          overdose procedural complications
*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 
Description of selected adverse reactions

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.
Laboratory values
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 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 antibodies
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 chronic hepatitis B. However in neither disease was this correlated with lack of therapeutic response.

Thyroid function
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.

Laboratory values for HIV-HCV co-infected patients
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/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

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PEGASYS                                                     MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                December 2015 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 post-treatment, 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.

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form
(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic @moh.health.gov.il ).