Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Tritherapy
Refer to the SmPC for boceprevir.
Bitherapy
The safety of Rebetol capsules is evaluated from data from four clinical trials in patients with no previous exposure to interferon (interferon-naïve patients): two trials studied Rebetol in combination with interferon alfa-2b, two trial studied Rebetol in combination with peginterferon alfa- 2b.

Patients who are treated with interferon alfa-2b and ribavirin after previous relapse from interferon therapy or who are treated for a shorter period are likely to have an improved safety profile than that described below.


The adverse reactions listed in Table 4 are based on experience from clinical trials in adult naïve patients treated for 1 year and post-marketing use. A certain number of adverse reactions, generally attributed to interferon therapy but that have been reported in the context of hepatitis C therapy (in combination with ribavirin) are also listed for reference in Table 4. Also, refer to peginterferon alfa-2b and interferon alfa-2b SmPCs for adverse reactions that may be attributable to interferons monotherapy. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥ 1/10,000 to <1/1,000); very rare (<1/10,000); not known. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 4       Adverse reactions reported during clinical trials or following the marketing use of Rebetol with pegylated interferon alfa-2b or interferon alfa-2b

System Organ Class                         Adverse Reactions
Infections and infestations
Very common:                         Viral infection, pharyngitis
Common:                              Bacterial infection (including sepsis), fungal infection, influenza, respiratory tract infection, bronchitis, herpes simplex, sinusitis, otitis media, rhinitis, urinary tract infection
Uncommon                             Injection site infection, lower respiratory tract infection Rare:                                Pneumonia*
Neoplasms benign, malignant and unspecified (including cysts and polyps) Common:                              Neoplasm unspecified
Blood and lymphatic system disorders
Very common:                         Anaemia, neutropenia
Common:                              Haemolitic anaemia, leukopenia, thrombocytopenia, lymphadenopathy, lymphopenia
Very rare:                           Aplastic anaemia*
Not known:                           Pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura
Immune system disorders
Uncommon:                            Drug hypersensitivity
Rare:                                Sarcoidosis*, rheumatoid arthritis (new or aggravated) Not known:                           Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus, vasculitis, acute hypersensitivity reactions including urticaria, angioedema,
bronchoconstriction, anaphylaxis
Endocrine disorders
Common:                              Hypothyroidism, hyperthyroidism

Metabolism and nutrition disorders
Very common:                               Anorexia
Common:                                    Hyperglycaemia, hyperuricaemia, hypocalcaemia, dehydration, increased appetite
Uncommon:                                  Diabetes mellitus, hypertriglyceridemia* Psychiatric disorders
Very common:                               Depression, anxiety, emotional lability, insomnia Common:                                    Suicidal ideation, psychosis, aggressive behaviour, confusion, agitation, anger, mood altered, abnormal behaviour, nervousness, sleep disorder, decreased libido apathy, abnormal dreams, crying
Uncommon:                                  Suicide attempts, panic attack, hallucination Rare:                                      Bipolar disorder*
Very rare:                                 Suicide*
Not known:                                 Homicidal ideation*, mania*, mental status change 

Table 4       Adverse reactions reported during clinical trials or following the marketing use of Rebetol with pegylated interferon alfa-2b or interferon alfa-2b

System Organ Class                         Adverse Reactions
Nervous system disorders
Very common:                               Headache, dizziness, dry mouth, concentration impaired Common:                                    Amnesia, memory impairment, syncope, migraine, ataxia, paraesthaesia, dysphonia, taste loss,
hypoaesthesia, hyperaesthesia, hypertonia, somnolence,
disturbance in attention, tremor, dysgeusia
Uncommon:                                  Neuropathy, peripheral neuropathy Rare:                                      Seizure (convulsion)*
Very rare:                                 Cerebrovascular haemorrhage*, cerebrovascular ischaemia*, encephalopathy*, polyneuropathy*
Not known:                                 Facial palsy, mononeuropathies Eye disorders
Common:                                    Visual disturbance, blurred vision, conjunctivitis, eye irritation, eye pain, abnormal vision, lacrimal gland disorder, dry eye
Rare:                                      Retinal haemorrhages*, retinopathies (including macular oedema)*, retinal artery occlusion*, retinal vein occlusion*, optic neuritis*, papilloedema*, loss of visual acuity or visual field*, retinal exudates
Ear and labyrinth disorders
Common:                                Vertigo, hearing impaired/loss, tinnitus, ear pain Cardiac disorders
Common:                                Palpitation, tachycardia
Uncommon:                              Myocardial infarction
Rare:                                  Cardiomyopathy, arrhythmia*
Very rare:                             Cardiac ischaemia*
Not known:                             Pericardial effusion*, pericarditis* Vascular disorders
Common:                                Hypotension, hypertension, flushing Rare:                                  Vasculitis
Very rare:                             Peripheral ischaemia*
Respiratory, thoracic and mediastinal disorders
Very common:                           Dyspnoea, coughing
Common:                                Epistaxis, respiratory disorder, respiratory tract congestion, sinus congestion, nasal congestion,
rhinorrhea, increased upper airway secretion,
pharyngolaryngeal pain, nonproductive cough
Very rare:                             Pulmonary infiltrates*, pneumonitis*, interstitial pneumonitis*
Gastro-intestinal disorders
Very common:                           Diarrhoea, vomiting, nausea, abdominal pain Common:                                Ulcerative stomatitis, stomatitis, mouth ulceration, colitis, upper right quadrant pain, dyspepsia,
gastroesophoageal reflux*, glossitis, cheilitis, abdominal distension, gingival bleeding, gingivitis, loose stools,
tooth disorder, constipation, flatulence
Uncommon:                              Pancreatitis, oral pain
Rare:                                  Ischaemic colitis
Very rare:                             Ulcerative colitis*
Not known:                             Periodontal disorder, dental disorder, tongue pigmentation
Hepatobiliary disorders
Common:                                Hepatomegaly, jaundice, hyperbilirubinemia* Very rare:                             Hepatotoxicity (including fatalities)* 

Table 4       Adverse reactions reported during clinical trials or following the marketing use of Rebetol with pegylated interferon alfa-2b or interferon alfa-2b

System Organ Class                    Adverse Reactions
Skin and subcutaneous tissue disorders
Very common:                          Alopecia, pruritus, skin dry, rash Common:                               Psoriasis, aggravated psoriasis, eczema, photosensitivity reaction, maculopapular rash,
erythematous rash, night sweats, hyperhidrosis,
dermatitis, acne, furuncule, erythema, urticaria, skin disorder, bruise, sweating increased, abnormal hair texture, nail disorder*
Rare:                                 Cutaneous sarcoidosis
Very rare:                            Stevens Johnson syndrome*, toxic epidermal necrolysis*, erythema multiforme*
Musculoskeletal and connective tissue disorders
Very common:                          Arthralgia, myalgia, musculoskeletal pain Common:                               Arthritis, back pain, muscle spasms, pain in extremity Uncommon:                             Bone pain, muscle weakness
Rare:                                 Rhabdomyolysis*, myositis*
Renal and urinary disorders
Common:                               Micturition frequency, polyuria, urine abnormality Rare:                                 Renal failure, renal insufficiency* Very rare:                            Nephrotic syndrome*
Reproductive system and breast disorders
Common:                               Female: amenorrhea, menorrhagia, menstrual disorder, dysmenorrhea, breast pain, ovarian disorder, vaginal disorder. Male: impotence, prostatitis, erectile dysfunction.
Sexual dysfunction (not specified)*
General disorders and administration site conditions
Very common:                          Injection site inflammation, injection site reaction, fatigue, rigors, pyrexia, influenza like illness, asthenia, irritability
Common:                               Chest pain, chest discomfort, peripheral oedema, malaise, injection site pain, feeling abnormal, thirst
Uncommon:                             Face oedema
Rare:                                 Injection site necrosis
Investigations
Very common:                          Weight decrease
Common:                               Cardiac murmur
* Since ribavirin is always prescribed with an alpha interferon product, and the listed adverse drug reactions included reflecting post-marketing experience do not allow precise quantification of frequency, the frequency reported above is from clinical trials using ribavirin in combination with interferon alfa-2b (pegylated or non- pegylated).

A reduction in haemoglobin concentrations by > 4 g/dl was observed in 30 % of patients treated with Rebetol and peginterferon alfa-2b and 37 % of patients treated with Rebetol and interferon alfa-2b. Haemoglobin levels dropped below 10 g/dl in up to 14 % of adult patients treated with Rebetol in combination with either peginterferon alfa-2b or interferon alfa-2b.

Most cases of anaemia, neutropaenia, and thrombocytopaenia were mild (WHO grades 1 or 2).
There were some cases of more severe neutropenia in patients treated with Rebetol in combination with peginterferon alfa-2b (WHO grade 3: 39 of 186 [21 %]; and WHO grade 4: 13 of 186 [7 %]); WHO grade 3 leukopenia was also reported in 7 % of this treatment group.

An increase in uric acid and indirect bilirubin values associated with haemolysis was observed in some patients treated with Rebetol used in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials, but values returned to baseline levels by four weeks after the end of therapy. Among those patients with elevated uric acid levels, very few patients treated with the 

combination developed clinical gout, none of which required treatment modification or discontinuation from the clinical trials.

HCV/HIV co-infected patients:
For HCV/HIV co-infected patients receiving Rebetol in combination with peginterferon alfa-2b, other adverse reactions (that were not reported in mono-infected patients) which have been reported in the studies with a frequency > 5 % were: oral candidiasis (14 %), lipodystrophy acquired (13 %), CD4 lymphocytes decreased (8 %), appetite decreased (8 %), gamma-glutamyltransferase increased (9 %), back pain (5 %), blood amylase increased (6 %), blood lactic acid increased (5 %), cytolytic hepatitis (6 %), lipase increased (6 %) and pain in limb (6 %).

Mitochondrial toxicity:
Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI regimen and associated-ribavirin for co-HCV infection (see section 4.4).

Laboratory values for HCV/HIV co-infected patients:
Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HCV/HIV co-infected patients, the majority could be managed by dose modification and rarely required premature discontinuation of treatment (see section 4.4). Haematological abnormalities were more frequently reported in patients receiving Rebetol in combination with peginterferon alfa-2b when compared to patients receiving Rebetol in combination with interferon alfa-2b. In Study 1 (see section 5.1), decrease in absolute neutrophil count levels below 500 cells/mm3 was observed in 4 % (8/194) of patients and decrease in platelets below 50,000/mm3 was observed in 4 % (8/194) of patients receiving Rebetol in combination with peginterferon alfa-2b. Anaemia (haemoglobin < 9.4 g/dl) was reported in 12 % (23/194) of patients treated with Rebetol in combination with peginterferon alfa-2b.

CD4 lymphocytes decrease:
Treatment with Rebetol in combination with peginterferon alfa-2b 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 Rebetol in combination with peginterferon alfa-2b had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data (N = 25) are available in co- infected patients with CD4+ cell counts < 200/µl (see section 4.4).

Please refer to the respective SmPC 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 Rebetol in combination with peginterferon alfa-2b.

Most of the changes in laboratory values in the Rebetol/peginterferon alfa-2b clinical trial were mild or moderate. Decreases in haemoglobin, white blood cells, platelets, neutrophils and increase in bilirubin may require dose reduction or permanent discontinuation from therapy (see section 4.2).
While changes in laboratory values were observed in some patients treated with Rebetol used in combination with peginterferon alfa-2b in the clinical trial, values returned to baseline levels within a few weeks after the end of therapy.