Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Tritherapy
Refer to the Physician's Insert for boceprevir.
Bitherapy and monotherapy
Summary of the safety profile
The most common treatment-related adverse reactions reported during clinical trials with PegIntron in combination with ribavirin, seen in more than half of the study subjects, were fatigue, headache, and injection site reaction. Additional adverse reactions reported in more than 25 % of subjects included nausea, chills, insomnia, anaemia, pyrexia, myalgia, asthenia, pain, alopecia, anorexia, weight decreased, depression, rash and irritability. The most frequently reported adverse reactions were mostly mild to moderate in severity and were manageable without the need for modification of doses or discontinuation of therapy. Fatigue, alopecia, pruritus, nausea, anorexia, weight decrease, irritability and insomnia occur at a notably lower rate in patients treated with PegIntron monotherapy compared to those treated with combination therapy (see Table 6).

Tabulated summary of adverse reactions
The following treatment-related adverse reactions were reported in clinical trials or through post-marketing surveillance in patients treated with peginterferon alfa-2b, including PegIntron monotherapy or PegIntron/ribavirin . These reactions are listed in table 6 by system organ class and frequency (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) or not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 6         Adverse reactions reported in clinical trials or through post-marketing surveillance in patients treated with interferon alfa-2b, including PegIntron monotherapy or PegIntron + ribavirin.

Infections and infestations
Very common:                Viral infection *, pharyngitis*

Common:                          Bacterial infection (including sepsis), fungal infection, influenza, upper respiratory tract infection, bronchitis,
herpes simplex, sinusitis, otitis media, rhinitis
Uncommon:                 Injection site infection, lower respiratory tract infection Blood and lymphatic system disorders
Very common:                  Anaemia, neutropenia

Common:                       Heamolytic anemia , leukopaenia, thrombocytopaenia, lymphadenopathy

Very rare:                    Aplastic anaemia

Not known:                    Aplasia pure red cell
Immune system disorders
Uncommon:                     Drug hypersensitivity
Rare:                         Sarcoidosis

Not known:                    Acute hypersensitivity reactions including angioedema, anaphylaxis and anaphylactic reactions including anaphylactic shock, idiopathic thrombocytopenic purpura,
thrombotic thrombocytopenic purpura, systemic lupus erythematosus
Endocrine disorders
Common:                       Hypothyroidism, hyperthyroidism


Metabolism and nutrition disorders
Very common:                Anorexia
Common:                       Hypocalcemia, hyperuricemia, dehydration, increased appetite

Uncommon:                     Diabetes mellitus, hypertriglyceridaemia 
Rare:                         Diabetic ketoacidosis
Psychiatric disorders
Very common:                  Depression, anxiety*, emotional lability*, concentration impaired, insomnia

Common:                       Aggression, agitation, anger, mood altered, abnormal behaviour, nervousness, sleep disorder, libido decreased,
apathy, abnormal dreams, crying


Uncommon:                     Suicide, suicide attempted , suicidal ideation, psychosis, hallucination, panic attack

Rare:                          Bipolar disorders

Not known:               Homicidal ideation, mania,
Nervous system disorders
Very common:             Headache, dizziness
Common:                       Amnesia, memory impairment, syncope, migraine, ataxia, confusion, neuralgia, paraesthesia, hypoaesthesia,
hyperaesthesia, hypertonia, somnolence, disturbance in attention, tremor, dysgeusia


Uncommon:                    Neuropathy, peripheral neuropathy
Rare:                        Convulsion

Very rare:                   Cerebrovascular haemorrhage, cerebrovascular ischaemia, encephalopathy

Not known:                   Facial palsy, mononeuropathies
Eye disorders
Common:                      Visual disturbance, vision blurred, photophobia, conjunctivitis, eye irritation, lacrimal disorder, eye pain,
dry eye

Uncommon:                    Retinal exudates

Rare:                        Loss of visual acuity or visual fields, retinal haemorrhage, retinopathy, retinal artery obstruction, retinal vein occlusion, optic neuritis, papilloedema, macular oedema cotton wool spots

Not known:                  Serous retinal detachment
Ear and labyrinth disorders
Common:                     Hearing impairment/loss, tinnitus, vertigo 
Uncommon:                    Ear pain
Cardiac disorders
Common:                      Palpitation, tachycardia

Uncommon:                    Myocardial infarction
Rare:                        Congestive heart failure, cardiomyopathy, arrhythmia, pericarditis

Very rare:                   Cardiac ischaemia

Not known:                   Pericardial effusion
Vascular disorders
Common:                      Hypotension, hypertension, flushing
Rare:                      Vasculitis
Respiratory, thoracic and mediastinal disorders
Very common:               Dyspnoea*, cough*

Common:                      Dysphonia, epistaxis, respiratory disorder, respiratory tract congestion, sinus congestion, nasal congestion,
rhinorrhea, nonproductive cough increased upper airway secretion, pharyngolaryngeal pain


Very rare:                   Interstitial lung disease,
Not Known:                  pulmonary fibrosis, pulmonary arterial hypertension# Gastrointestinal disorders
Very common:               Vomiting*, nausea, abdominal pain, diarrhoea, dry mouth* 
Common:                      Dyspepsia, gastroesophageal reflux disease, stomatitis, mouth ulceration, glossodynia, gingival bleeding,
constipation, flatulence, hemorrhoids, cheilitis, abdominal
distension, gingivitis, glossitis, tooth disorder

Uncommon:                            Pancreatitis, oral pain

Rare:                                Colitis ischaemic
Very rare:                           Colitis ulcerative

Not known:                           Tongue pigmentation

Hepatobiliary disorders
Common:                   Hyperbilirubinemia, hepatomegaly
Skin and subcutaneous tissue disorders
Very common:              Alopecia, pruritus*, dry skin*, rash*
Common:                              Psoriasis, photosensitivity reaction, rash maculo-papular, dermatitis, erythematous rash, eczema, night sweats,
hyperhidrosis, acne, furuncle, erythema, urticaria,
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:              Myalgia, arthralgia, musculoskeletal pain

Common:                              Arthritis, back pain, muscle spasms, pain in extremity 
Uncommon:                            Bone pain, muscle weakness

Rare:                       Rhabdomyolysis, myositis, rheumatoid arthritis Renal and urinary disorders
Common:                     Micturition frequency, polyuria, urine abnormality 
Rare:                     Renal failure, renal insufficiency
Reproductive system and breast disorders
Common:                   Amenorrhoea, impotence, breast pain, menorrhagia, menstrual disorder, ovarian disorder, vaginal disorder,
sexual dysfunction, prostatitis, erectile dysfunction
General disorders and administration site conditions
Very common:              Injection site reaction*, Injection site inflammation, fatigue, asthenia, irritability, chills, pyrexia, influenza like illness,
pain

Common:                              Chest pain, chest discomfort, injection site pain, malaise, face oedema, oedema peripheral, feeling abnormal thirst

Rare:                                Injection site necrosis
Investigations
Very common:                         Weight decreased
*
These adverse reactions were common (≥1/100 to < 1/10) in clinical trials in patients treated with PegIntron monotherapy.
#
Class label for interferon products, see below Pulmonary arterial hypertension.

Description of selected adverse reactions
Most cases of neutropaenia and thrombocytopaenia were mild (WHO grades 1 or 2). There were some cases of more severe neutropenia in patients treated with the recommended doses of PegIntron in combination with ribavirin (WHO grade 3: 39 of 186 [21 %]; and WHO grade 4: 13 of 186 [7 %]).
In a clinical trial, approximately 1.2 % of patients treated with PegIntron or interferon alfa-2b in combination with ribavirin reported life-threatening psychiatric events during treatment. These events included suicidal ideation and attempted suicide (see section 4.4).

Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with pre- existing CVS disease and prior therapy with cardiotoxic agents (see section 4.4). Cardiomyopathy, that may be reversible upon discontinuation of interferon alpha, has been reported rarely in patients without prior evidence of cardiac disease.

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.

Ophthalmological disorders that have been reported rarely with alpha interferons include retinopathies (including macular oedema), retinal haemorrhages, retinal artery or vein obstruction, cotton wool spots, loss of visual acuity or visual field, optic neuritis, and papilloedema (see section 4.4).

A wide variety of autoimmune and immune-mediated disorders have been reported with alpha interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including mononeuropathies and Vogt-Koyanagi-Harada syndrome (see also section 4.4).

HCV/HIV co-infected patients
Summary of the safety profile
For HCV/HIV co-infected patients receiving PegIntron in combination with ribavirin, other undesirable effects (that were not reported in mono-infected patients) which have been reported in the larger 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 %).

Description of selected adverse reactions
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 PegIntron in combination with ribavirin when compared to patients receiving interferon alfa-2b in combination with ribavirin. 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 PegIntron in combination with ribavirin. Anaemia (hemoglobin < 9.4g/dl) was reported in 12% (23/194) of patients treated with PegIntron in combination with ribavirin.

CD4 lymphocytes decrease
Treatment with PegIntron in combination with ribavirin 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 PegIntron in combination with ribavirin 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 Physician's Insert 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 PegIntron in combination with ribavirin.

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.
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.gov.il