Growth and development (children and adolescents):
During the course of therapy lasting up to 48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common (see sections 4.8 and 5.1). The longer term data available in children treated with the combination therapy with standard interferon/ribavirin are also indicative of substantial growth retardation (> 15 percentile decrease in height percentile as compared to baseline) in 21 % of children despite being off treatment for more than 5 years.
Case by case benefit/risk assessment in children:
The expected benefit of treatment should be carefully weighed against the safety findings observed for children and adolescents in the clinical trials (see sections 4.8 and 5.1).
- It is important to consider that the combination therapy induced a growth inhibition, the reversibility of which is uncertain.
- This risk should be weighed against the disease characteristics of the child, such as evidence
of disease progression (notably fibrosis), co-morbidities that may negatively influence the
disease progression (such as HIV co-infection), as well as prognostic factors of response (HCV
genotype and viral load).
Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the risk of growth inhibition. There are no data on long term effects on sexual maturation.
Addition of “selected” to “All patients in the .. chronic hepatitis C studies..”
Cardiovascular system:
Addition of “adult” to first sentence after interferon alfa-2b
Addition of “There are no data in children or adolescents with a history of cardiac disease.” to end of paragraph
Pyrexia:
Change from Fever to Pyrexia throughout paragraph and title.
Pulmonary: Change from fever to pyrexia
Ocular changes:
Replacement of “cotton wool spots” with “retinal exudates” and “obstruction” with “occlusion” after vein.
Thyroid changes:
“adult” added before patients in first sentence
Deletion of “thyroid stimulation hormone (“
Addition of “Approximately 21 % of children treated with ViraferonPeg/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 ViraferonPeg therapy, TSH levels must be evaluated and any thyroid abnormality detected at that time must be treated with conventional therapy”
Addition of “Children and adolescents should be monitored every 3 months for evidence of thyroid dysfunction (e.g. TSH).” To end of paragraph
Laboratory Tests:
Addition of “HCV-RNA should be measured periodically during treatment (see section 4.2).”
4.8
Addition of “Adults” as a title
Adults
Addition of “in adults” after ribavirin in first sentence
Text regarding common AEs changed from:
“..were headache, fatigue, and injection site reaction. Additional important adverse reactions reported in more than 25 % of subjects included myalgia, fever, asthenia, alopecia, nausea, anorexia, weight decrease, depression, irritability and insomnia.”
To: “,,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
“d” added to “weight decrease”
Change of sentence from:
The following treatment-related adverse reactions were reported during therapy with ViraferonPeg
To: The following treatment-related adverse reactions were reported in clinical trials or through post-marketing surveillance in patients treated with peginterferon alfa-2b, including ViraferonPeg monotherapy or ViraferonPeg/ribavirin
Table 4 Addition of “peg” to interferon in title
Infections and infestations:
Very Common: Addition of viral to infection
Addition of pharyngitis*
Common Addition of influenza, upper respiratory track infection, bronchitis, sinusitis, and rhinitis to list of AEs.
Uncommon row added: Injection site infection, lower respiratory tract infection
Blood and lymphatic system disorders:
Very common: new row added including Anaemia and neutropenia
Common: Haemolytic anaemia and leukopenia added
Frequency not known: Pure red cell aplasia changed to aplasia pure red cell
Immune system disorders:
Uncommon row added: Drug hypersensitivity
Rare row added: Sarcoidosis
Frequency not known: Removal of “vasculitis” and “rheumatoid arthritis (new or aggravated)”
Endocrine disorders:
Rare: Deleted
Metabolism and nutrition disorders:
Very common Deletion of Weight Decrease
Common: Removal of “thirst”
Addition of dehydration and increased appetitie
Uncommon new row added including diabetes mellitus and hypertriglyceridaemia
Psychiatric disorders:
Very common: deletion of irritability and “insomnia” moved to end of list
Common: deletion of disorder after behaviour
Deletion of somnolence
Deletion of ing abnormal after dream
Deletion of appetite increased
aggressive behaviour changed to aggression, addition of anger, mood altered, abnormal (behaviour) abnormal (dreams) and crying to list.
Uncommon: Change from attempted suicide to suicide attempt
Addition of psychosis hallucination and panic attack to list
Rare: “psychosis” replaced with “bipolar disorder”
Not known: Addition of Homicidal ideation* to list
Nervous system disorders:
Very common: mouth dry deleted and dizziness added
Common: Addition of amnesia, memory impairment, syncope, somnlence, disturbance in attention and dysguesia to list.
Vertigo and increased sweating deleted
Uncommon: addition of row including neuropathy and neuropathy peripheral
Rare: Deletion of seizure and peripheral neuropathy and addition of convulsion
Frequency not known: deletion of neuropathies
Eye disorders:
Common: visual disturbance, photophobia, eye irritation and dry eye all added to list.
Change from blurred vision to vision blurred
Gland deleted from lacrimal
Uncommon: new row added including retinal exudates
Rare: obstruction replaced by occlusion
deletion of cotton wool spots
Ear and labyrinth disorder:
Common Impairment replaced by impaired
Addition of vertigo
Uncommon earache replaced by ear pain.
Cardiac disorders:
Common removal of s from palpitations
Uncommon: Addition of Uncommon row: myocardial infarction
Rare: cardiomyopathy moved further down list and pericarditis added
Very Rare: Deletion of myocardial infarction
Frequency not known: Deletion of pericarditis
Vascular disorders:
Common: Deletion of syncope
Rare: Addition of Rare row: vasculitis
Respiratory, thoracic and mediastinal disorders:
Very Common: addition of 0 in dyspnoea
deletion of pharyngitis and ing from coughing
Common:: Deletion of sinusitis, rhinitis, non productive cough and bronchitis
Addition of respiratory tract congestion, sinus congestion, increased upper airway secretion and pharyngolaryngeal pain.
Gastrointestinal disorders:
Very Common: deletion of anorexia
addition of dry mouth*
Common. Deletion of ulcerative, loose stools, taste perversion and dehydration
Disease added after reflux
Addition of mouth ulceration, glossodynia, cheilitis, abdominal distension and tooth disorder
Uncommon: addition of uncommon row: pancreatitis and oral pain.
Rare: colitus ischaemic replaced pancreatitis
Very Rare: deletion of ischaemic colitus
Addition of colitis ulcerative
Skin and cutaneous disorders:
Very common: Skin dry changed to dry skin
Common: Rash moved to before maculo
Deletion of “face or peripheral oedema”
addition of night sweats, hyperhydrosis
Deletion of osis from furungulosis
Rare: Addition of Rare row: Cutaneous sarcoidosis
Very Rare: Deletion of injection site necrosis
Musculoskeletal and connective tissue disorders:
Common: addition of back pain, muscle spasms and pain in extremity
Uncommon: addition of Uncommon Row: bone pain and muscle weakness
Rare: addition of rheumatoid arthritis
Renal and urinary disorders:
Common: addition of polyuria
“ity” added to abnormal
Reproductive system and breast disorders:
Common: deletion of impotence
addition of erectile dysfunction
General disorders…
Very common deletion of dizziness, rigors, fever and flu like symptoms
Asthenia moved in list
Addition of irritability, chills, pyrexia, influenza like illness, pain
Common deletion of RUQ pain
Addition of chest discomfort, injection site pain, face oedema, oedema peripheral, feeling abnormal and thirst.
Rare: addition of Uncommon Row: injection site necrosis
Investigations: Addition of new section
Very common: weight decreased
1st Paragraph below table:
removal of “a” from neutropaenia and thrombocytopaenia
4th paragraph below table:
Deletion of obstruction and cotton wool spots
Addition of occlusion and retinal exudates
HIV Coinfected patients
CD4 lymphocytes decrease
Addition of the following text before overdose section
Children and adolescents
In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated with
combination therapy of ViraferonPeg 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 ViraferonPeg and ribavirin, growth inhibition is observed, the reversibility of which is uncertain (see section 4.4). Weight loss and growth inhibition were very common during the treatment (at the end of treatment, mean decrease from baseline in weight andheight 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). Based on interim data from the long-term follow-up portion of this study, 22 % (16/74) of children had a >15 percentile decrease in height percentile, of whom 3 (4 %) children had a >30 percentile decrease despite being off treatment for more than 1 year. In particular, decrease in mean height percentile at year 1 of long-term follow-up was most prominent in prepubertal age children (see section 4.4).
In 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 ViraferonPeg in combination with ribavirin. These reactions are listed in Table 5 by system organ class and frequency (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 5 Adverse reactions very commonly, commonly and uncommonly reported in the clinical trial in children and adolescent patients treated with ViraferonPeg in combination with ribavirin.
|
Infections and infestations
Common:
Uncommon:
|
Fungal infection, influenza, oral herpes, otitis media, pharyngitis streptococcal, nasopharyngitis, sinusitis
Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis, urinary tract infection, gastroenteritis
|
|
Blood and lymphatic system
disorders
Very common:
Common:
|
Anaemia, leucopenia, neutropenia
Thrombocytopenia, lymphadenopathy
|
|
Endocrine disorders
Common:
|
Hypothyroidism
|
|
Metabolism and nutrition disorders
Very common:
|
Anorexia, decreased appetite
|
|
Psychiatric disorders
Common:
Uncommon:
|
Depression, aggression, affect lability, anger, agitation, anxiety, mood altered, restlessness, nervousness, insomnia
Abnormal behaviour, depressed mood, emotional disorder, fear, nightmare
|
|
Nervous system disorders
Very common:
Common:
Uncommon:
|
Headache, dizziness
Dysgeusia, syncope, disturbance in attention, somnolence, poor quality sleep
Neuralgia, lethargy, paraesthesia, hypoaesthesia, psychomotor hyperactivity, tremor
|
|
Eye disorders
Common:
Uncommon:
|
Eye pain
Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred, photophobia
|
|
Ear and labyrinth disorders
Common:
|
Vertigo
|
|
Cardiac disorders
Common:
|
Palpitations, tachycardia
|
|
Vascular disorders
Common:
Uncommon:
|
Flushing
Hypotension, pallor
|
|
Respiratory, thoracic and mediastinal disorders
Common:
Uncommon:
|
Cough, epistaxis, pharyngolaryngeal pain
Wheezing, nasal discomfort, rhinorrhoea
|
|
Gastrointestinal disorders
Very common:
Common:
Uncommon:
|
Abdominal pain, abdominal pain upper, vomiting, nausea
Diarrhoea, aphthous stomatitis, cheilosis, mouth ulceration, stomach discomfort, oral pain
Dyspepsia, gingivitis
|
|
Hepatobiliary disorders
Uncommon:
|
Hepatomegaly
|
|
Skin and subcutaneous tissue disorders
Very common:
Common:
Uncommon:
|
Alopecia, dry skin
Pruritus, rash, rash erythematous, eczema, acne, erythema
Photosensitivity reaction, rash maculo-papular, skin exfoliation, pigmentation disorder, dermatitis atopic, skin discolouration
|
|
Musculoskeletal and connective tissue disorders
Very common:
Common:
Uncommon:
|
Myalgia, arthralgia
Musculoskeletal pain, pain in extremity, back pain
Muscle contracture, muscle twitching
|
|
Renal and urinary disorders
Uncommon:
|
Proteinuria
|
|
Reproductive system and breast disorders
Uncommon:
|
Female: Dysmenorrhoea
|
|
General disorders and administration site conditions
Very common:
Common:
Uncommon:
|
Injection site erythema, fatigue, pyrexia, rigors, influenza-like illness, asthenia, pain, malaise, irritability
Injection site reaction, injection site pruritus, injection site rash injection site dryness, injection site pain, feeling cold
Chest pain, chest discomfort, facial pain
|
|
Investigations
Very common:
Common:
Uncommon:
|
Weight decreased
Blood thyroid stimulating hormone increased, thyroglobulin increased
Anti-thyroid antibody positive
|
|
Injury and poisoning
Uncommon:
|
Contusion
|
Most of the changes in laboratory values in the ViraferonPeg/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 (see section 4.2). While changes in laboratory values were observed in some patients treated with ViraferonPeg used in combination with ribavirin in the clinical trial, values returned to baseline levels within a few weeks after the end of therapy.
5.1
ViraferonPeg Clinical trials
“in Adults” added to title
Naïve patients Al references to
Table 5 changed to Table 6
Table 6 changed to Table 7
Table 7 changed to Table 8
Table 8 changed to Table 9
The following text added under “Limited historical data…” paragraph and before “predictability of virological response section:
A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two ViraferonPeg/ribavirin regimens [ViraferonPeg 1.5 µg/kg and 1 µg/kg subcutaneously once weekly both in combination with ribavirin 800 to 1,400 mg p.o. daily (in two divided doses)] and peginterferon alfa-2a 180 µg subcutaneously once weekly with ribavirin 1,000 to 1,200 mg p.o. daily (in two divided doses) in 3,070 treatment-naïve adults with chronic hepatitis C genotype 1. Response to the treatment was measured by Sustained Virologic Response (SVR) which is defined as undetectable HCV-RNA at 24 weeks post-treatment (see Table 9).
Table 9 Virologic response at treatment Week 12, end of treatment response, relapse rate *and Sustained Virologic Response (SVR)
|
Treatment group
|
% (number) of patients
|
|
|
|
|
ViraferonPeg 1.5 µg/kg + ribavirin
|
ViraferonPeg 1 µg/kg + ribavirin
|
peginterferon alfa-2a 180 µg + ribavirin
|
|
Undetectable HCV-RNA at treatment Week 12
|
40 (407/1,019)
|
36 (366/1,016)
|
45 (466/1,035)
|
|
|
End of treatment response
|
53 (542/1,019)
|
49 (500/1,016)
|
64 (667/1,035)
|
|
|
Relapse
|
24 (123/523)
|
20 (95/475)
|
32 (193/612)
|
|
|
SVR
|
40 (406/1,019)
|
38 (386/1,016)
|
41 (423/1,035)
|
|
|
SVR in patients with undetectable HCV-RNA at treatment Week 12
|
81 (328/407)
|
83 (303/366)
|
74 (344/466)
|
|
|
|
|
|
|
|
|
|
|
* (HCV-RNA PCR assay, with a lower limit of quantitation of 27 IU/ml)
Lack of early virologic response by Treatment Week 12 (detectable HCV-RNA
with a < 2 log10 reduction from baseline) was a criterion for discontinuation of treatment.
In all three treatment groups, sustained virologic response rates were similar. In patients of African American origin (which is known to be a poor prognostic factor for HCV eradication), treatment with ViraferonPeg (1.5 µg/kg)/ribavirin combination therapy resulted in a higher sustained virologic response rate compared to ViraferonPeg 1 µg/kg dose. At the ViraferonPeg 1.5 µg/kg plus ribavirin dose, sustained virologic response rates were lower in patients with cirrhosis, in patients with normal ALT levels, in patients with a baseline viral load > 600,000 IU/ml, and in patients > 40 years old. Caucasian patients had a higher sustained virologic response rate compared to the African Americans. Among patients with undetectable HCV-RNA at the end of treatment, the relapse rate was 24 %.
Predictability of sustained virological response– Naïve patients:
Change of first section including table to the following text
Predictability of sustained virological response – Naïve patients
Virological response by week 12 is defined as at least 2-log viral load decrease or undetectable levels of HCV-RNA.Virological response by week 4 is defined as at least 1-log viral load decrease or undetectable levels of HCV-RNA. These time points (Treatment Week 4 and Treatment Week 12) have been shown to be predictive for sustained response (Table 10).
|
Table 10 Predictive Value of In-Treatment Virologic Response while on ViraferonPeg 1.5 µg/kg/ribavirin 800-1,400 mg Combination Therapy
|
|
|
Negative
|
Positive
|
|
No response at Treatment Week
|
No sustained Response
|
Negative Predictive Value
|
Response at Treatment Week
|
Sustained Response
|
Positive Predictive Value
|
|
Genotype 1*
|
|
By Week 4***
(n=950)
|
|
|
|
|
|
|
|
HCV-RNA negative
|
834
|
539
|
65 %
(539/834)
|
116
|
107
|
92 %
(107/116)
|
|
HCV-RNA negative
or
≥ 1 log decrease in viral load
|
220
|
210
|
95 %
(210/220)
|
730
|
392
|
54 %
(392/730)
|
|
By Week 12***
(n=915)
|
|
|
|
|
|
|
|
HCV-RNA negative
|
508
|
433
|
85 %
(433/508)
|
407
|
328
|
81 %
(328/407)
|
|
HCV-RNA negative
or
≥ 2 log decrease in viral load
|
206
|
205
|
N/A†
|
709
|
402
|
57 %
(402/709)
|
|
Genotype 2, 3**
|
|
By Week 12
(n= 215)
|
|
|
|
|
|
|
|
HCV-RNA negative
or
≥ 2 log decrease in viral load
|
2
|
1
|
50 %
(1/2)
|
213
|
177
|
83 %
(177/213)
|
|
|
|
|
|
|
|
|
*Genotype 1 receive 48 weeks treatment
**Genotype 2, 3 receive 24 weeks treatment
***The presented results are from a single point of time. A patient may be missing or have had a different result for Week 4 or Week 12.
† These criteria were used in the protocol: If Week 12 HCV-RNA is positive and < 2log10 decrease from baseline, patients to stop therapy. If Week 12 HCV-RNA is positive and decreased ≥ 2log10 from baseline, then retest HCV-RNA at Week 24 and if positive, patients to stop therapy.
HCV/HIV Co-infected patients:
Change from Table 9 to Table 11 in text and on table
Change from Table 10 to Table 12 in text and on table
Addition of following text above section 5.2
ViraferonPeg clinical trials –in children and adolescents
Children and adolescents 3 to 17 years of age with compensated chronic hepatitis C and detectable HCV-RNA were enrolled in a multicentre trial and treated with ribavirin 15 mg/kg per day plus ViraferonPeg 60 mg/m2 once weekly for 24 or 48 weeks, based on HCV genotype and baseline viral load. All patients were to be followed for 24 weeks post-treatment. A total of 107 patients received treatment of whom 52 % were female, 89 % Caucasian, 67 % with HCV Genotype 1 and 63 % < 12 years of age. The population enrolled mainly consisted of children with mild to moderate hepatitis C. Due to the lack of data in children with severe progression of the disease, and the potential for undesirable effects, the benefit/risk of the combination of ViraferonPeg with ribavirin needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8). The study results are summarized in Table 13.
|
Table 13. Sustained virological response rates (na,b (%)) in previously untreated children and adolescents by genotype and treatment duration – All subjects
n = 107
|
|
|
24 weeks
|
48 weeks
|
|
All Genotypes
|
26/27 (96 %)
|
44/80 (55 %)
|
|
Genotype 1
|
-
|
38/72 (53 %)
|
|
Genotype 2
|
14/15 (93 %)
|
-
|
|
Genotype 3c
|
12/12 (100 %)
|
2/3 (67 %)
|
|
Genotype 4
|
-
|
4/5 (80 %)
|
|
a: Response to treatment was defined as undetectable HCV-RNA at 24 weeks post-treatment lower limit of detection=125IU/ml
b: n = number of responders/number of subjects with given genotype, and assigned treatment duration.
c: Patients with genotype 3 low viral load (< 600,000 IU/ml) were to receive 24 weeks of treatment while those with genotype 3 and high viral load (≥ 600,000 IU/ml) were to receive 48 weeks of treatment.
|
5.2
Children and adolescents:
New section added after elderly paragraph
Children and adolescents: Multiple-dose pharmacokinetic properties for ViraferonPeg and ribavirin (capsules and oral solution) in children and adolescent patients with chronic hepatitis C have been evaluated during a clinical study. In children and adolescent patients receiving body surface area-adjusted dosing of ViraferonPeg at 60 mg/m2/week, the log transformed ratio estimate of exposure during the dosing interval is predicted to be 58 % (90 % CI: 141-177 %) higher than observed in adults receiving 1.5 mg/kg/week
5.3 Addition of paragraph above section 6
No studies have been conducted in juvenile animals to examine the effects of treatment with ViraferonPeg on growth, development, sexual maturation, and behaviour . Preclicinal juvenile toxicity results have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with ribavirin (see section 5.3 of Rebetol SPC if ViraferonPeg is to be administered in combination with ribavirin).
10.0
Date of revision of the text
27 July 2009 to 12 November 2009
