Peginterferon alpha-2b interacts in the following cases:
The potential interaction of peginterferon alfa-2b on substrates of metabolic enzymes was evaluated in 3 multiple-dose clinical pharmacology studies. In these studies, the effects of multiple-dose regimens of peginterferon alfa-2b were investigated in Hepatitis C subjects (1.5 mcg/week) or healthy subjects (1 mcg/week or 3 mcg/week) (Table). A clinically significant pharmacokinetic interaction was not observed between peginterferon alfa-2b and tolbutamide, midazolam or dapsone; therefore, no dosing adjustment is necessary when peginterferon alfa-2b is administered with medicines metabolized by CYP2C9, CYP3A4 and N-acetyltransferase. Concomitant administration of peginterferon alfa-2b with caffeine or desipramine modestly increased the exposure of caffeine and desipramine.
Effect of Peginterferon alfa-2b on Co-administered Medicines:
| Co-administered Medicine | Dose of peginterferon alfa-2b | Study Population | Geometric Mean Ratio (Ratio with/without peginterferon alfa-2b) | |
|---|---|---|---|---|
| AUC (90% CI) | Cmax (90% CI) | |||
| Caffeine (CYP1A2 substrate) | 1.5 μg/kg/week (4 weeks) | Chronic Hepatitis C Subjects (N=22) | 1.39 (1.27, 1.51) | 1.02 (0.95, 1.09) |
| 1 μg/kg/week (4 weeks) | Healthy Subjects (N=24) | 1.18 (1.07, 1.31) | 1.12 (1.05, 1.19) | |
| 3 μg/kg/week (2 weeks) | Healthy Subjects (N=13) | 1.36 (1.25, 1.49) | 1.16 (1.10, 1.24) | |
| Tolbutamide (CYP2C9 substrate) | 1.5 μg/kg/week (4 weeks) | Chronic Hepatitis C Subjects ( (N=22) | 1.1# (0.94, 1.28) | NA |
| 1 μg/kg/week (4 weeks) | Healthy Subjects (N=24) | 0.90# (0.81, 1.00) | NA | |
| 3 μg/kg/week (2 weeks) | Healthy Subjects (N=13) | 0.95 (0.89, 1.01) | 0.99 (0.92, 1.07) | |
| Dextromethorphan hydrobromide (CYP2D6 and CYP3A substrate) | 1.5 μg/kg/week (4 weeks) | Chronic Hepatitis C Subjects (N=22) | 0.96## (0.73, 1.26) | NA |
| 1 μg/kg/week (4 weeks) | Healthy Subjects (N=24) | 2.03# (1.55, 2.67) | NA | |
| Desipramine (CYP2D6 substrate) | 3 μg/kg/week (2 weeks) | Healthy Subjects (N=13) | 1.30 (1.18, 1.43) | 1.08 (1.00, 1.16) |
| Midazolam (CYP3A4 substrate) | 1.5 μg/kg/week (4 weeks) | Chronic Hepatitis C Subjects (N=24) | 1.07 (0.91, 1.25) | 1.12 (0.94, 1.33) |
| 1 μg/kg/week (4 weeks) | Healthy Subjects (N=24) | 1.07 (0.99, 1.16) | 1.33 (1.15, 1.53) | |
| 3 μg/kg/week (2 weeks) | Healthy Subjects (N=13) | 1.18 (1.06, 1.32) | 1.24 (1.07, 1.43) | |
| Dapsone (N-acetyltransferase substrate) | 1.5 μg/kg/week (4 weeks) | Chronic Hepatitis C Subjects (N=24) | 1.05 (1.02, 1.08) | 1.03 (1.00, 1.06) |
# Calculated from urine data collected over an interval of 48-hours
## Calculated from urine data collected over an interval of 24-hours
Peginterferon alpha-2b should be used with caution in patients with moderate to severe renal impairment. In patients with moderate renal dysfunction (creatinine clearance 30-50 ml/minute), the starting dose of peginterferon alpha-2b should be reduced by 25%. Patients with severe renal dysfunction (creatinine clearance 15-29 ml/minute) should have the starting dose of peginterferon alpha-2b reduced by 50%. Data are not available for the use of peginterferon alpha-2b in patients with creatinine clearance <15 ml/minute. Patients with severe renal impairment, including those on hemodialysis, should be closely monitored. If renal function decreases during treatment, peginterferon alpha-2b therapy should be discontinued.
Patients with creatinine clearance < 50 ml/minute must not be treated with peginterferon alpha-2b in combination with ribavirin (see ribavirin SmPC). When administered in combination therapy, patients with impaired renal function should be more carefully monitored with respect to the development of anaemia.
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 alpha interferon. If treatment with alpha 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.
When administered in combination with other interferon preparations, effect of immunosuppressive therapy may be weakened in transplant (kidney, bone marrow, etc.) patients. It is considered that graft rejection reactions may be induced.
In patients with chronic hepatitis C that were on stable methadone maintenance therapy and naïve to peginterferon alfa-2b, addition of 1.5 microgram/kg/week of peginterferon alfa-2b subcutaneously for 4 weeks increased R-methadone AUC by approximately 15% (95% Cl for AUC ratio estimate 103–128%). The clinical significance of this finding is unknown; however, patients should be monitored for signs and symptoms of increased sedative effect, as well as respiratory depression. Especially in patients on a high dose of methadone, the risk for QTc prolongation should be considered.
Elevation of blood concentrations of antipyrine, warfarin has been reported when administered in combination with other interferon preparations and therefore care should be taken.
Co-administration of theophylline with peginterferon alpha-2b may increase the blood concentrations of theophylline. Careful co-administration of theophylline with peginterferon alpha-2b is recommended. Package inserts of theophylline should be referred to when co-administering with peginterferon alpha-2b. Metabolism of theophylline is suppressed by inhibitory action of peginterferon alpha-2b on CYP1A2.
Co-administration of thioridazine with peginterferon alpha-2b may increase the blood concentrations of thioridazine. Careful co-administration of thioridazine with peginterferon alpha-2b is recommended. Package inserts of thioridazine should be referred to when co-administering with peginterferon alpha-2b. Metabolism of thioridazine is suppressed by inhibitory action of peginterferon alpha-2b on CYP2D6.
When administered in combination with other interferon preparations, suppressive effect on bone marrow function may be strengthened and aggravation of blood cell reduction such as white blood cells decreased may occur. Mechanism of action is unknown, but it is considered that both medicines have bone marrow depressive effects.
Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during peginterferon alpha-2b 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 alpha interferons.
Patients should be closely monitored for any signs or symptoms of psychiatric disorders. If such symptoms 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 or homicidal ideation is identified, it is recommended that treatment with peginterferon alpha-2b be discontinued, and the patient followed, with psychiatric intervention as appropriate.
Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving peginterferon alpha-2b 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 peginterferon alpha-2b 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.
Infrequently, adult patients treated for chronic hepatitis C with interferon alpha have developed thyroid abnormalities, either hypothyroidism or hyperthyroidism. Approximately 21% of children treated with peginterferon alpha-2b/ribavirin combination therapy developed increase in thyroid stimulating hormone (TSH). Another approximately 2% had a transient decrease below the lower limit of normal. Prior to initiation of peginterferon alpha-2b therapy, TSH levels must be evaluated and any thyroid abnormality detected at that time must be treated with conventional therapy. Determine TSH levels if, during the course of therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the presence of thyroid dysfunction, peginterferon alpha-2b treatment may be continued if TSH levels can be maintained in the normal range by medicine. Children and adolescents should be monitored every 3 months for evidence of thyroid dysfunction (e.g. TSH).
Ophthalmologic disorders, including retinal haemorrhages, retinal exudates, serous retinal detachment, and retinal artery or vein occlusion have been reported in rare instances after treatment with alpha interferons. All patients should have a baseline eye examination. Any patient complaining of ocular symptoms, including loss of visual acuity or visual field must have a prompt and complete eye examination. Periodic visual examinations are recommended during peginterferon alpha-2b therapy, particularly in patients with disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of peginterferon alpha-2b should be considered in patients who develop new or worsening ophthalmological disorders.
Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed. Monitoring of lipid levels is, therefore, recommended.
While pyrexia may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent pyrexia must be ruled out.
Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alpha treated patients. Any patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function impairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alpha. Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear to be associated with resolution of pulmonary adverse events.
As with interferon alfa-2b, adult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders, receiving peginterferon alpha-2b therapy require close monitoring.
It is recommended that patients who have pre-existing cardiac abnormalities have electrocardiograms taken prior to and during the course of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require discontinuation of peginterferon alpha-2b therapy. There are no data in children or adolescents with a history of cardiac disease.
Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been observed rarely during interferon alfa-2b therapy. If such a reaction develops during treatment with peginterferon alpha-2b, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment.
Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of peginterferon alpha-2b in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies the potential risk.
Population group: only children (1 year - 12 years old) , adolescents (12 years - 18 years old)
During the course of therapy lasting up to 48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common. Long-term data available in children treated with the combination therapy of pegylated interferon/ribavirin are indicative of substantial growth retardation. Thirty two percent (30/94) of subjects demonstrated >15 percentile decrease in height-for-age percentile 5 years after completion of therapy.
There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals have shown reproductive toxicity. Interferon alfa-2b has been shown to be abortifacient in primates. Peginterferon alpha-2b is likely to also cause this effect.
The potential risk in humans is unknown. Peginterferon alpha-2b is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Ribavirin causes serious birth defects when administered during pregnancy, therefore ribavirin therapy is contraindicated in women who are pregnant.
It is not known whether the components of this medicinal product are excreted in human milk. Because of the potential for adverse reactions in breast-fed infants, breast-feeding should be discontinued prior to initiation of treatment.
Peginterferon alpha-2b is recommended for use in fertile women only when they are using effective contraception during the treatment.
Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking peginterferon alpha-2b in combination with ribavirin. Females 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 (see ribavirin SmPC).
There are no data available regarding potential effects of peginterferon alpha-2b treatment on male or female fertility.
Patients who develop fatigue, somnolence or confusion during treatment with peginterferon alfa-2b are cautioned to avoid driving or operating machines.
Refer to the SmPC for boceprevir.
The most common treatment-related adverse reactions reported during clinical trials with peginterferon alfa-2b in combination with ribavirin in adults, 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 decreased, irritability and insomnia occur at a notably lower rate in patients treated with peginterferon alfa-2b monotherapy compared to those treated with combination therapy.
The following treatment-related adverse reactions were reported in adults in clinical trials or through post-marketing surveillance in patients treated with peginterferon alfa-2b, including peginterferon alfa-2b monotherapy or peginterferon alfa-2b/ribavirin. These reactions are listed below 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.
Adverse reactions reported in adults in clinical trials or through post-marketing surveillance in patients treated with peginterferon alfa-2b, including peginterferon alfa-2b monotherapy or peginterferon alfa-2b + ribavirin:
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
Not known: Hepatitis B reactivation in HCV/HBV co-infected patients
Very common: Anaemia, neutropenia
Common: Haemolytic anaemia, leukopenia, thrombocytopenia, lymphadenopathy
Very rare: Aplastic anaemia
Not known: Aplasia pure red cell
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
Common: Hypothyroidism, hyperthyroidism
Very common: Anorexia
Common: Hypocalcemia, hyperuricemia, dehydration, increased appetite
Uncommon: Diabetes mellitus, hypertriglyceridaemia
Rare: Diabetic ketoacidosis
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 attempt, suicidal ideation, psychosis, hallucination, panic attack
Rare: Bipolar disorders
Not known: Homicidal ideation, mania
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, neuropathy peripheral
Rare: Convulsion
Very rare: Cerebrovascular haemorrhage, cerebrovascular ischaemia, encephalopathy
Not known: Facial palsy, mononeuropathies
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 occlusion, retinal vein occlusion, optic neuritis, papilloedema, macular oedema
Not known: Serous retinal detachment
Common: Hearing impaired/loss, tinnitus, vertigo
Uncommon: Ear pain
Common: Palpitations, tachycardia
Uncommon: Myocardial infarction
Rare: Congestive heart failure, cardiomyopathy, arrhythmia, pericarditis
Very rare: Cardiac ischaemia
Not known: Pericardial effusion
Common: Hypotension, hypertension, flushing
Rare: Vasculitis
Very common: Dyspnoea*, cough*
Common: Dysphonia, epistaxis, respiratory disorder, respiratory tract congestion, sinus congestion, nasal congestion, rhinorrhea, increased upper airway secretion, pharyngolaryngeal pain
Very rare: Interstitial lung disease
Not known: Pulmonary fibrosis, pulmonary arterial hypertension#
Very common: Vomiting*, nausea, abdominal pain, diarrhoea, dry mouth*
Common: Dyspepsia, gastroesophageal reflux disease, stomatitis, mouth ulceration, glossodynia, gingival bleeding, constipation, flatulence, haemorrhoids, cheilitis, abdominal distension, gingivitis, glossitis, tooth disorder
Uncommon: Pancreatitis, oral pain
Rare: Colitis ischaemic
Very rare: Colitis ulcerative
Not known: Tongue pigmentation
Common: Hyperbilirubinemia, hepatomegaly
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
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
Common: Micturition frequency, polyuria, urine abnormality
Rare: Renal failure, renal insufficiency
Common: Amenorrhoea, breast pain, menorrhagia, menstrual disorder, ovarian disorder, vaginal disorder, sexual dysfunction, prostatitis, erectile dysfunction
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
Very common: Weight decreased
* These adverse reactions were common (≥1/100 to <1/10) in clinical trials in patients treated with peginterferon alfa-2b monotherapy.
# Class label for interferon products, see below Pulmonary arterial hypertension.
Most cases of neutropenia and thrombocytopenia were mild (WHO grades 1 or 2). There were some cases of more severe neutropenia in patients treated with the recommended doses of peginterferon alfa-2b 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 peginterferon alfa-2b or interferon alfa-2b in combination with ribavirin reported life-threatening psychiatric events during treatment. These events included suicidal ideation and attempted suicide.
Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with pre-existing CVS disease and prior therapy with cardiotoxic agents. 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 occlusion, retinal exudates, loss of visual acuity or visual field, optic neuritis, and papilloedema.
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.
For HCV/HIV co-infected patients receiving peginterferon alfa-2b 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%).
Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI regimen and associated ribavirin for co-HCV infection.
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. Haematological abnormalities were more frequently reported in patients receiving peginterferon alfa-2b in combination with ribavirin when compared to patients receiving interferon alfa-2b in combination with ribavirin. In Study 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 peginterferon alfa-2b in combination with ribavirin. Anaemia (hemoglobin <9.4 g/dl) was reported in 12% (23/194) of patients treated with peginterferon alfa-2b in combination with ribavirin.
Treatment with peginterferon alfa-2b 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 peginterferon alfa-2b 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.
Please refer to the respective SmPCs 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 peginterferon alfa-2b in combination with ribavirin.
In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated with combination therapy of peginterferon alfa-2b and ribavirin, dose modifications were required in 25% of patients, most commonly for anaemia, neutropenia and weight loss. In general, the adverse reactions profile in children and adolescents was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition. During combination therapy for up to 48 weeks with peginterferon alfa-2b and ribavirin, growth inhibition was observed that resulted in reduced height in some patients. Weight loss and growth inhibition were very common during the treatment (at the end of treatment, mean decrease from baseline in weight and height percentile were of 15 percentiles and 8 percentiles, respectively) and growth velocity was inhibited (<3rd percentile in 70% of the patients).
At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height percentiles were still of 3 percentiles and 7 percentiles respectively, and 20% of the children continued to have inhibited growth (growth velocity <3rd percentile). Ninety-four of 107 subjects enrolled in the 5 year long-term follow-up trial. The effects on growth were less in those subjects treated for 24 weeks than those treated for 48 weeks. From pre-treatment to end of long-term followup among subjects treated for 24 or 48 weeks, height-for-age percentiles decreased 1.3 and 9.0 percentiles, respectively. Twenty-four percent of subjects (11/46) treated for 24 weeks and 40 % of subjects (19/48) treated for 48 weeks had a >15 percentile height-for-age decrease from pre-treatment to the end of the 5 year long-term follow-up compared to pre-treatment baseline percentile. Eleven percent of subjects (5/46) treated for 24 weeks and 13 % of subjects (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline of >30 height-for-age percentiles to the end of the 5 year long-term follow-up. For weight, pre-treatment to end of long-term follow-up, weightfor-age percentiles decreased 1.3 and 5.5 percentiles among subjects treated for 24 weeks or 48 weeks, respectively. For BMI, pre-treatment to end of long-term follow-up, BMI-for-age percentiles decreased 1.8 and 7.5 percentiles among subjects treated for 24 weeks or 48 weeks, respectively. Decrease in mean height percentile at year 1 of long-term follow-up was most prominent in prepubertal age children. The decline of height, weight and BMI Z scores observed during the treatment phase in comparison to a normative population did not fully recover at the end of long-term follow-up period for children treated with 48 weeks of therapy.
In the treatment phase of this study, the most prevalent adverse reactions in all subjects were pyrexia (80%), headache (62%), neutropenia (33%), fatigue (30%), anorexia (29%) and injection-site erythema (29%). Only 1 subject discontinued therapy as the result of an adverse reaction (thrombocytopenia). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7% (8/107) of all subjects and included injection site pain (1%), pain in extremity (1%), headache (1%), neutropenia (1%), and pyrexia (4%). Important treatment-emergent adverse reactions that occurred in this patient population were nervousness (8%), aggression (3%), anger (2%), depression/depressed mood (4%) and hypothyroidism (3%) and 5 subjects received levothyroxine treatment for hypothyroidism/elevated TSH.
The following treatment-related adverse reactions were reported in the study in children and adolescent patients treated with peginterferon alfa-2b in combination with ribavirin. These reactions are listed below 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, adverse reactions are presented in order of decreasing seriousness.
Adverse reactions very commonly, commonly and uncommonly reported in the clinical trial in children and adolescent patients treated with peginterferon alfa-2b in combination with ribavirin:
Common: Fungal infection, influenza, oral herpes, otitis media, pharyngitis streptococcal, nasopharyngitis, sinusitis Uncommon: Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis, urinary tract infection, gastroenteritis
Very common: Anaemia, leucopenia, neutropenia
Common: Thrombocytopenia, lymphadenopathy
Common: Hypothyroidism
Very common: Anorexia, decreased appetite
Common: Suicidal ideation§, suicide attempt§, depression, aggression, affect lability, anger, agitation, anxiety, mood altered, restlessness, nervousness, insomnia
Uncommon: Abnormal behaviour, depressed mood, emotional disorder, fear, nightmare
Very common: Headache, dizziness
Common: Dysgeusia, syncope, disturbance in attention, somnolence, poor quality sleep
Uncommon: Neuralgia, lethargy, paraesthesia, hypoaesthesia, psychomotor hyperactivity, tremor
Common: Eye pain
Uncommon: Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred, photophobia
Common: Vertigo
Common: Palpitations, tachycardia
Common: Flushing
Uncommon: Hypotension, pallor
Common: Cough, epistaxis, pharyngolaryngeal pain
Uncommon: Wheezing, nasal discomfort, rhinorrhoea
Very common: Abdominal pain, abdominal pain upper, vomiting, nausea
Common: Diarrhoea, aphthous stomatitis, cheilosis, mouth ulceration, stomach discomfort, oral pain
Uncommon: Dyspepsia, gingivitis
Uncommon: Hepatomegaly
Very common: Alopecia, dry skin
Common: Pruritus, rash, rash erythematous, eczema, acne, erythema
Uncommon: Photosensitivity reaction, rash maculo-papular, skin exfoliation, pigmentation disorder, dermatitis atopic, skin discolouration
Very common: Myalgia, arthralgia
Common: Musculoskeletal pain, pain in extremity, back pain
Uncommon: Muscle contracture, muscle twitching
Uncommon: Proteinuria
Uncommon: Female: Dysmenorrhoea
Very common: Injection site erythema, fatigue, pyrexia, rigors, influenza-like illness, asthenia, pain, malaise, irritability
Common: Injection site reaction, injection site pruritus, injection site rash injection site dryness, injection site pain, feeling cold
Uncommon: Chest pain, chest discomfort, facial pain
Very common: Growth rate decrease (height and/or weight decrease for age)
Common: Blood thyroid stimulating hormone increased, thyroglobulin increased
Uncommon: Anti-thyroid antibody positive
Uncommon: Contusion
§ class effect of interferon-alfa containing products – reported with standard interferon therapy in adult and paediatric patients; with peginterferon alfa-2b reported in adult patients.
Most of the changes in laboratory values in the peginterferon alfa-2b/ribavirin 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. While changes in laboratory values were observed in some patients treated with peginterferon alfa-2b used in combination with ribavirin in the clinical trial, values returned to baseline levels within a few weeks after the end of therapy.
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