Adverse reactions : תופעות לוואי

4.8   Undesirable effects

The salient safety issue of ribavirin is hemolytic anemia occurring within the first weeks of therapy. The hemolytic anemia associated with ribavirin therapy may result in deterioration of cardiac function and/or worsening of preexisting cardiac disease. An increase in uric acid and indirect bilirubin values associated with haemolysis were also observed in some patients (see below and section 4.4).

See peginterferon alfa-2a or interferon alfa-2a prescribing information for additional undesirable effects for either of these products.

The adverse events listed in this section are reported in clinical trials and/or as adverse drug reactions from spontaneous reports primarily when Copegus was used in combination with interferon alfa-2a or peginterferon alfa-2a.

Adverse events reported in patients receiving Copegus in combination with interferon alfa-2a are essentially the same as for those reported for Copegus in combination with peginterferon alfa-2a.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Chronic hepatitis C
The most frequently reported adverse events with Copegus in combination with peginterferon alfa-2a 180 µg were mostly mild to moderate in severity. Most of them were manageable without the need for discontinuation of therapy.

Chronic hepatitis C in prior non-responder patients
Overall, the safety profile for Copegus in combination with peginterferon alfa-2a in prior non-responder patients was similar to that in naive 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 peginterferon alfa-2a treatment and Copegus 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 peginterferon alfa-2a treatment and Copegus 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 fibrosisis 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 Human Immunodeficiency Virus Co-infection
In HIV-HCV co-infected patients, the clinical adverse event profiles reported for peginterferon alfa-2a, alone or in combination with ribavirin, were similar to those observed in HCV mono-infected patients.
For HIV-HCV patients receiving Copegus and peginterferon alfa-2a combination therapy other undesirable effects have been reported in ≥1% to ≤ 2% of patients: hyperlactacidaemia/lactic acidosis, influenza, pneumonia, affect lability, apathy, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and chromaturia. Peginterferon alfa-2a 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 peginterferon alfa-2a had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited 
COPEGUS                                                        MoH Approved Prescribing Information Tablets 200 mg                                                                        October 2015 safety data are available in co-infected patients with CD4+ cell counts <200/µl (see peginterferon alfa- 2a prescribing information).

Table 6 shows the undesirable effects reported in patients who have received Copegus primarily in combination with peginterferon alfa-2a or interferon alfa-2a.
Table 4     Undesirable Effects Reported with Copegus primarily in combination with Peginterferon alfa-2a or Interferon alfa-2a for HCV Patients
Body system            Very      Common         Uncommon            Rare         Very rare       Frequency common       ≥1/100 to      ≥1/1000 to     ≥1/10,000 to     <1/10,000       not known* ≥1/10         <1/10          <1/100         <1/1000
Infections and                 Upper           Lower           Endocarditis, infestations                   respiratory     respiratory     Otitis externa infection,      tract bronchitis,     infection,
oral            pneumonia,
candidiasis,    urinary tract herpes          infection, skin simplex         infection
Blood and        Anaemia,      Thrombo-                        Pancytopenia     Aplastic        Pure red cell lymphatic        neutropenia   cytopenia,                                       anaemia         aplasia system disorders               lymphadeno- pathy
Immune system                                  Sarcoidosis,    Anaphylaxis,     idiopathic or   Liver and disorders                                      thyroiditis     systemic         thrombotic      renal graft lupus            thrombocyto-    rejection,
erythemato-      penic purpura   Vogt- sus,                             Koyanagi- rheumatoid                       Harada arthritis                        disease
Endocrine                      Hypo-           Diabetes disorders                      thyroidism,
hyper- thyroidism
Metabolism and Anorexia                        Dehydration
Nutrition
Disorders
Psychiatric    Depression,     Mood            Suicidal        Suicide,                         Mania, disorders      insomnia        alteration,     ideation,       psychotic                        bipolar emotional       hallucina-      disorder                         disorders, disorders,      tions, anger                                     homicidal anxiety,                                                         ideation aggression,
nervousness,
libido decreased
Nervous system Headache,       Memory          Peripheral      Coma,            Cerebral disorders      dizziness,      impairment,     neuropathy      convulsions,     ischaemia concentration   syncope,                        facial palsy impaired        weakness,
migraine,
hypoaesthe- sia,
hyperaesthe- sia,
paraesthesia,
tremor, taste disturbance,
nightmares,
somnolence


COPEGUS                                                             MoH Approved Prescribing Information Tablets 200 mg                                                                             October 2015 Body system              Very       Common       Uncommon               Rare      Very rare    Frequency common        ≥1/100 to   ≥1/1000 to         ≥1/10,000 to  <1/10,000    not known* ≥1/10          <1/10       <1/100              <1/1000
Eye disorders                     Vision        Retinal            Optic         Vision loss   Serous retinal blurred, eye  haemorrhage        neuropathy,                 detachment pain, eye                        papilloedema,
inflammation,                    retinal xerophthalmia                    vascular disorder,
retinopathy,
corneal ulcer
Ear and                           Vertigo,         Hearing loss labyrinth                         earache,
disorders                         tinnitus
Cardiac                           Tachycardia,                     Myocardial disorders                         palpitations,                    infarction, oedema                           congestive peripheral                       heart failure,
angina,
supraventri- cular tachycardia arrhythmia,
atrial fibrillation,
pericarditis
Vascular                          Flushing,        Hypertension    Cerebral disorders                         hypotension                      haemorrhage, vasculitis
Respiratory,         Dyspnoea,    Dyspnoea         Wheezing        Interstitial thoracic and         cough        exertional,                      pneumonitis mediastinal                       epistaxis,                       with fatal disorders                         nasopharyn-                      outcome, gitis, sinus                     pulmonary congestion,                      embolism nasal congestion,
rhinitis, sore throat
Gastrointestinal     Diarrhoea,   Vomiting,        Gastrointes-    Peptic ulcer,               Colitis disorders            nausea,      dyspepsia,       tinal bleeding, pancreatitis                ischaemic, abdominal    dysphagia,       cheilitis,                                  colitis pain         mouth            gingivitis                                  ulcerative, ulceration,                                                  tongue gingival                                                     pigmentation bleeding,
glossitis,
stomatitis,
flatulence,
constipation,
dry mouth
Hepato-biliary                                     Hepatic         Hepatic disorders                                          dysfunction     failure, cholangitis,
fatty liver


COPEGUS                                                             MoH Approved Prescribing Information Tablets 200 mg                                                                             October 2015 Body system               Very          Common         Uncommon        Rare         Very rare    Frequency common          ≥1/100 to      ≥1/1000 to   ≥1/10,000 to    <1/10,000    not known* ≥1/10           <1/10          <1/100       <1/1000
Skin and             Alopecia,       Rash,                                         Toxic subcutaneous         dermatitis,     sweating                                      epidermal tissue disorders     pruritus, dry   increased,                                    necrolysis, skin            psoriasis,                                    Stevens- urticaria,                                    Johnson eczema, skin                                  syndrome,
disorder,                                     angioedema,
photosensiti-                                 erythema vity reaction,                                multiforme night sweats
Musculoskeletal Myalgia,             Back pain,                     Myositis                     Rhabdomyo- and connective arthralgia            arthritis,                                                  lysis tissue disorders                     muscle weakness,
bone pain,
neck pain,
musculoskelet al pain,
muscle cramps
Renal and                                                                                        Renal failure, Urinary                                                                                          nephrotic Disorders                                                                                        syndrome Reproductive                         Impotence system and breast disorders
General              Pyrexia,        Chest pain,
disorders and        rigors, pain,   influenza like administration       asthenia,       illness,
site conditions      fatigue,        malaise,
irritability    lethargy, hot flushes, thirst
Investigations                       Weight decreased
Injury and                                                          Substance poisoning                                                           overdose * Identified in postmarketing experience

Laboratory values: In clinical trials of Copegus in combination with peginterferon alfa-2a or interferon alfa-2a, the majority of cases of abnormal laboratory values were managed with dose modifications (see section 4.2). With peginterferon alfa-2a and Copegus combination treatment, up to 2% of patients experienced increased ALT levels that led to dose modification or discontinuation of treatment.

Haemolysis is the dose limiting toxicity of ribavirin therapy. A decrease in haemoglobin levels to <10 g/dl was observed in up to 15% of patients treated for 48 weeks with Copegus 1000/1200 mg in combination with peginterferon alfa-2a and up to 19% of patients in combination with interferon alfa- 2a. When Copegus 800 mg was combined with peginterferon alfa-2a for 24 weeks, 3% of patients had a decrease in haemoglobin levels to <10 g/dl. In most cases the decrease in haemoglobin occurred early in the treatment period and stabilised concurrently with a compensatory increase in reticulocytes.

Most cases of anaemia, leucopenia and thrombocytopenia were mild (WHO grade 1). WHO grade 2 laboratory changes were reported for haemoglobin (4% of patients), leucocytes (24% of patients) and thrombocytes (2% of patients). Moderate (absolute neutrophil count (ANC): 0.749-0.5x109/l) and severe (ANC: 0.5x109/l) neutropenia was observed in 24% (216/887) and 5% (41/887) of patients receiving 48 weeks of Copegus 1000/1200 mg in combination with peginterferon alfa-2a.

An increase in uric acid and indirect bilirubin values associated with haemolysis were observed in some patients treated with Copegus used in combination with peginterferon alfa-2a or interferon alfa-2a and 

COPEGUS                                                        MoH Approved Prescribing Information Tablets 200 mg                                                                        October 2015 values returned to baseline levels within 4 weeks after the end of therapy. In rare cases (2/755) this was associated with clinical manifestation (acute gout).

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 peginterferon alfa-2a monotherapy and combination therapy, respectively. Decrease in platelets below 50,000/mm3 was observed in 10% and 8% of patients receiving peginterferon alfa-2a monotherapy and combination therapy, respectively. Anaemia (haemoglobin <10 g/dl) was reported in 7% and 14% of patients treated with peginterferon alfa-2a monotherapy or in combination therapy, respectively.

Reporting of suspected adverse reactions
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 following links: http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic%40moh.he alth.gov.il or mail to: ADR@MOH.health.gov.il.