Rebetol Oral Solution
4.1:
First paragraph addition of “peginterferon alfa-2b or” before “interferon alfa-2b..”
Addition of the following after the first paragraph and before “the decision to treat…”
When deciding not to defer treatment until adulthood, it is important to consider that the combination therapy induced a growth inhibition. The reversibility of growth inhibition is uncertain
Addition of the following after “Rebetol monotherapy must not be used”
There is no safety or efficacy information in children or adolescents on the use of Rebetol with other forms of interferon (i.e., not alfa-2b).
4.2:
Addition of peginterferon alfa-2b or” before interferon alfa 2b
“Posology” changed to “Dose to be administered”
Children aged three years and older, and adolescents
Changed to “Children 3 years of age and older and adolescents”
Orally added before “in two divided doses”
Deletion of “In clinical studies performed in this population ribavirin was used in a dose of 15 mg/kg/day (Table 1).”
Addition of “Dosing for children and adolescent patients is determined by body weight for Rebetol and by body surface area for peginterferon alfa-2b and interferon alfa-2b.
Addition of “The recommended dose of peginterferon alfa-2b is 60 µg/m2/week subcutaneously in combination with Rebetol 15 mg/kg/day (Table 1).”
Deletion of “Rebetol must be used in combination with interferon alfa-2b solution for injection, administered at a dose of”
Addition of “In clinical studies performed in this population ribavirin was used in a dose of 15 mg/kg/day (Table 1).” Before “3 million international units..”
Table 1 Addition of Children and adolescents in between “solution” and “dosage”
Duration of treatment
Genotype 1: Addition of “By extrapolation from clinical data on combination therapy with standard interferon in paediatric patients (negative predictive value 96 % for interferon alfa-2b/Rebetol)“ after “…1 year”
Addition of “12 weeks” after “virological response at”
Deletion of “(negative predictive value 96 %). Virological response is defined as absence of detectable HCV-RNA at Week 12 of treatment. Treatment should be discontinued in these patients”
Addition of “Therefore, it is recommended that children and adolescent patients receiving interferon alfa-2b (pegylated or non-pegylated) /Rebetol combination be discontinued from therapy if their week 12 HCV-RNA dropped < 2 log10 compared to pretreatment, or if they have detectable HCV-RNA at treatment week 24”
Addition of Genotype 4 paragraph:
Genotype 4: Only 5 children and adolescents with Genotype 4 were treated in the peginterferon alfa-2b/Rebetol clinical trial. The recommended duration of treatment is 1 year. It is recommended that children and adolescent patients receiving peginterferon alfa-2b/Rebetol combination be discontinued from therapy if their week 12 HCV-RNA dropped < 2 log10 compared to pretreatment, or if they have detectable HCV-RNA at treatment week 24.
Deletion of “Virological responses after 1 year of treatment and 6 months of follow-up were 36 % for genotype 1 and 81 % for genotype 2/3/4.”
Dose modification:
Table 2:
Addition of “based on laboratory parameters” to title.
Deletion of “to 7.5 mg/kg* per day *, and replaced with “(see note 1)” in Reduce only Rebetol daily dose column heading
Deletion of to one-half dose and replaced with “peginterferon alfa-2b” and “(see note 2)” in Reduce only peginterferon column heading.
Removal of one * from Discontinue heading
Change from Adult to Adults in second haemoglobin row and “Paediatric” replaced with “Children and adolescents”
Platelet row: change from: 80 x 109/l to 70 x 109/l
Bilirubin –direct: removal of one asterix
Bilirubin – indirect row/discontinue column: addition of “treated with interferon alfa-2b), or > 4 mg/dl (for > 4 weeks treated with peginterferon alfa-2b)*
ALT/AST Row/Discontinue column:
Deletion of one asterix from each entry
Table legend: * and ** asterix only.
Addition of Notes 1 and 1 after table
Note 1: In children and adolescent patients treated with Rebetol plus peginterferon alfa-2b, 1st dose reduction of Rebetol is to 12 mg/kg/day, 2nd dose reduction of Rebetol is to 8 mg/kg/day.
In children and adolescent patients treated with Rebetol plus interferon alfa-2b, reduce Rebetol dose to 7.5 mg/kg/day.
Note 2: In children and adolescent patients treated with Rebetol plus peginterferon alfa-2b, 1st dose reduction of peginterferon alfa-2b is to 40 µg/m2/week, 2nd dose reduction of peginterferon alfa-2b is to 20 µg/m2/week.
In children and adolescent patients treated with Rebetol plus interferon alfa-2b, reduce the interferon alfa-2b dose by one-half dose.
Special populations: Addition of paragraph:
Use in patients under the age of 18 years: Rebetol may be used in combination with peginterferon alfa-2b or interferon alfa-2b in children 3 years of age and older and adolescents. The selection of formulation is based on individual characteristics of the patient. Safety and effectiveness of Rebetol with other forms of interferon (i.e. not alfa-2b) in these patients have not been evaluated.
4.3
Pregnant women: addition of 4.6 and 5.3 after 4.4
Last sentence: addition of “peginterferon alfa-2b or” before interferon alfa-2b
4.4
Psychiatric and Central Nervous System (CNS):
Addition of “peginterferon alfa-2b or” before interferon alfa-2b
Addition of “such as homicidal ideation), bipolar disorder, mania” before “confusion and alterations of mental status…”
“or peginterferon alfa-2b” added after “interferon alfa-2b” at end of paragraph and in second paragraph
Addition of second paragraph title:
Patients with existence of or history of severe psychiatric conditions
New box added: Growth and development (children and adolescents)
Growth and development (children and adolescents):
During the course of interferon (standard and pegylated)/ribavirin 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.
1st paragraph after growth and development box:
Addition of “peginterferon alfa-2b or with”
Addition of “solution for injection” at end of paragraph
Haemolysis: deletion of (adults only) after peginterferon alfa-2b
Deletion of (adults, children and adolescents) after interferon alfa-2b
“See section 4.2” added to end of paragraph
Ocular changes: Replacement of “cotton wool spots” with “retinal exudates” and “obstruction” with “occlusion” after vien.
Growth and development…
Whole section deleted
Thyroid supplemental monitoring…
Addition of “to 21” after 12%
Addition of “pegylated and non pegylated” after 1st “interferon alfa 2b”
Addition of “thyroid stimulation hormone” before TSH
Addition of “approximately” before 4%
Addition of “pegylated and non-pegylated” after 2nd Interferon alfa-2b
Addition of “and during treatment with Rebetol and peginterferon alfa-2b” after 3rd Interferon alfa-2b.
HCV/HIV Co-infection:
Addition of sub-title: Mitochondrial toxicity and lactic acidosis
Adaption of the following sentences into 2 co-administration of Rebetol bullets
In particular, co-administration of Rebetol and didanosine is not recommended due to the risk of mitochondrial toxicity (see section 4.5).
Moreover, co-administration of Rebetol and stavudine should be avoided to limit the risk of overlapping mitochondrial toxicity
Addition of sub-title: Hepatic decompensation in HCV/HIV co-infected patients with advanced cirrhosis before paragraph beginning “Co-infected patients with advanced..”
Dental: Addition of “peginterferon alfa-2b or with” twice in paragraph before “interferon”
Laboratory tests: Addition of “HCV-RNA should be measured periodically during treatment (see section 4.2)” after Lab evaluations sentence.
Addition of title above sucrose and sorbitol paragraph:
Use in patients with rare hereditary disorders
4.6
Pregnancy and lactation “breast fed” changed to “breast feeding”
4.8
Children and adolescents
Addition of the following text after title:
In combination with peginterferon alfa-2b
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 Rebetol, 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 pegylated interferon alfa-2b and Rebetol, 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 and in height percentiles 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 (3 %) 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.
In combination with interferon alfa-2b
Addition of the following title above “In a clinical trial of 118 children..”
In combination with interferon alfa-2b
Addition of text to first two sentences as follows:
In clinical trials of 118 children and adolescents 3 to 16 years of age treated with combination therapy of interferon alfa-2b and Rebetol, 6 % discontinued therapy due to adverse reactions. In general, the adverse reaction profile in the limited children and adolescent population studied was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition, as decrease in height percentile (mean percentile decrease of 9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of 44th percentile, which was below the median of the normative population and less than their mean baseline height (48th percentile). Twenty (21 %) of 97 children had a > 15 percentile decrease in height percentile, of whom 10 of the 20 children had a > 30 percentile decrease in their height percentile from the start of treatment to the end of long-term follow-up (up to 5 years). During combination therapy for up to 48 weeks with interferon alfa-2b and Rebetol, growth inhibition is observed, the reversibility of which is uncertain. In particular, decrease in mean height percentile from baseline to the end of the long-term follow-up was most prominent in prepubertal age children (see section 4.4).
Pyrexia added to “Further more ….” Paragraph after injection site disorders
“paediatric clinical trials” changed to “two multicentre children and adolescents clinical trials using Rebetol with interferon alfa-2b or peginterferon alfa-2b.”
And uncommon(>1/1,000 to <1/100) added after common.
Table 3
Title “Adverse reactions very commonly and commonly reported during clinical trials of Rebetol with interferon alfa-2b injection in paediatric patients” changed to
“Adverse reactions very commonly, commonly and uncommonly reported during clinical trials in children and adolescents with Rebetol in combination with interferon alfa-2b or peginterferon alfa-2b”
Infections and infestations
Common: addition of nasopharyngitis, pharyngitis streptococcal, sinusitis, influenza and oral herpes
Uncommon: addition of Uncommon Row: pneumonia, ascariasis, enterobiasis, herpes zoster and cellulitis
Metabolism and nutrition disorders:
Very common: addition of increased appetite and decreased appetite
Common: deletion of increased appetite
Psychiatric disorders:
Common aggressive reaction changed to aggression
Addition of affect liability, mood altered and restlessness
Uncommon addition of Uncommon Row: Abnormal behaviour, depressed mood, emotional disorder, fear, nightmare
Nervous system disorders
Common: addition of disturbance in attention and poor quality of sleep
Uncommon: addition of Uncommon Row: Neuralgia, lethargy, psychomotor hyperactivity
Eye Disorders:
Uncommon: addition of Uncommon Row: Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred, photophobia
Addition of Ear and labyrinth disorders section:
Common: Vertigo
Addition of Cardiac disorders section:
Common: Tachycardia and palpitations
Vascular disorders:
Common: addition of Pallor
Uncommon: deletion of Pallor and addition of hypotension
Respiratory , thoracic …
Common: addition of pharygolaryngeal pain
Uncommon: addition of Uncommon Row: Wheezing and nasal discomfort
Gastro-intestinal disorders
Very common: deletion of diarrhoea vomiting and nausea and addition of abdominal pain upper vomiting, diarrhoea and nausea
Common deletion of right upper quadrant pain
Addition of apthous stomatitis, chelosis, stomach discomfort and oral pain
Uncommon: addition of Uncommon Row: Gingivitis
Hepatobiliary disorders:
Uncommon: addition of Uncommon Row: Hepatomegaly
Skin and subcut…
Common addition hyper hydrosis
Deletion of sweating increased
Relocation of puritis
Uncommon: addition of Uncommon Row: Pigmentation disorder, dermatitis atopic, skin exfoliation
Musculoskeletal and connect….
Common addition of Common Row: Pain in extremity, back pain, muscle contracture
Renal and urinary disorders
Common addition of proteinuria
Reproductive system and breast disorders
Uncommon addition of Uncommon Row: Femail: dysmenorrhoea
General…
Very common: addition of injection site erythema, injection site pain, pyrexia and asthenia.
Deletion of fever
Change from influenza-like symptoms to influenza-like illness
Common deletion of asthenia and injection site pain
Addition of pain, injection site pruritis, injection site rash, injection site dryness and feeling cold
Uncommon addition of Uncommon Row: Chest discomfort, facial pain, injection site induration
Investigations:
Very common deletion of body height decrease and weight decrease
Common addition of Common Row: Blood thyroid stimulating hormone increased, thyroglobulin increased
Uncommon addition of Uncommon Row: Anti-thyroid antibody positive
Injury, poisoning …
Uncommon addition of Uncommon Row: Contusion
Addition of the following paragraph under table 5
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.
Table 4
Title row: deletion of “injection” at end of title
Infections and infestations:
Common Addition of Bacterial infection (including sepsis), influenza respiratory track infection, bronchitis, sinusitis, otitis media, and rhinitis to list of AEs.
Uncommon row added: Injection site infection, lower respiratory tract infection
Blood and lymphatic system disorders:
Common: Haemolitic anaemia and leukopenia added
Immune system disorders:
Uncommon row added: Drug hypersensitivity added
Rare: rheumatoid arthritis (new or aggravated)
Not known: Removal of “rheumatoid arthritis (new or aggravated)”
Endocrine disorders:
Rare: Deleted
Metabolism and nutrition disorders:
Common: Removal of “thirst”
Uncommon addition of Diabetes mellitus
Psychiatric disorders:
Very common: “insomnia” moved to end of list
Common: addition of anger, mood altered, abnormal behaviour and apathy to list.
“decreased libido” moved further up list
Removal of “abnormal” before “crying”
Uncommon: Addition of panic attack and hallucination to ist
Rare: “Hallucination” replaced with “bipolar disorder”
Not known: Addition of Homicidal ideation* and mania* to list
Nervous system disorders:
Common: Addition of amnesia, memory impairment, syncope, migraine, hypertonia, disturbance in attention and tremor to list.
Tremor, migrane and hypertonia deleted
Uncommon section added:
Neuropathy, peripheral neuropathy added
Rare: peripheral neuropathy deleted
Not known: “neuropathies including” deleted
Eye disorders:
Common: visual disturbance, eye irritation and dry eye all added to list.
Rare: obstruction replaced by occlusion
deletion of cotton wool spots
addition of retinal exudates
Ear and labyrinth disorder:
Impairment replaced by impaired
earache replaced by ear pain.
Cardiac disorders:
Uncommon: Addition of Uncommon row: myocardial infarction
Rare: Deletion of * against cardiomyopathy
Very Rare: Deletion of myocardial infarction
Not known: Addition of not known row: Pericardial effusion and pericarditis
Vascular disorders:
Common: Deletion of syncope
Rare: Addition of Rare row: vasculitis
Respiratory, thoracic and mediastinal disorders:
Common: deletion of sinusitis, bronchitis and rhinitis
Addition of respiratory tract congestion, sinus congestin, increased upper airway secretion and pharyngolaryngeal pain.
Gastrointestinal disorders:
Common: addition of mouth ulceration, chelitis, abdominal distension and tooth disorder.
Uncommon: addition of uncommon row: pancreatitis and oral pain.
Rare: Ischaemic colitus replaced pancreatitis
Very Rare: deletion of ischaemic colitus
Skin and cutaneous disorders:
Common: addition of night sweats, hyperhydrosis and urticaria
Deletion of osis from furungulosis
Rare: Addition of Rare row: Cutaneous sarcoidosis
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
Renal and urinary disorders:
Common: addition of urine abnormality
Rare: deletion of asterix after renal failure
Reproductive system and breast disorders:
Common: addition of erectile dysfunction
General disorders…
Very common deletion of fever and flu like symptoms
Addition of pyrexia and influenza-like illness
Common deletion of face oedema
Addition of chest discomfort, feeling abnormal and thirst.
Uncommon: addition of Uncommon Row: face oedema
Rare: Change from very rare to rare
Investigations:
Common: deletion of urine abnormal
Paragraph under table 4
Change from + to and
Deletion of (adults only) after peginterferon alfa-2b in last sentence
5.1
First paragraph: addition of “peginterferon alfa-2b or” before interferon
change from “six “ to “6”
Rebetol clinical trials in children and adolescents
Addition of the following text and table under the heading and before “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 Rebetol 15 mg/kg per day plus pegylated interferon alfa-2b 60 µg/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 Rebetol and pegylated interferon alfa-2b needs to be carefully considered in this population (see sections 4.1, 4.4 and 4.8). The study results are summarized in Table 5.
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Table 5 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 = 125 IU/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.
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Rebetol in combination with interferon alfa-2b
Rebetol in combination with interferon alfa-2b
New title
Addition of “in the two multicellular trials s…”
Ribavirin changed to Rebetol
“The study results are summarised in Table 6” added o end of paragraph
Table 4 now called Table 6
Addition of “Sustained v” to “irological response…”
Addition of the following text underneath table 6
Long-term efficacy data - Children and adolescents
A five-year long-term, observational, follow-up study enrolled 97 paediatric chronic hepatitis C patients after treatment in two previously mentioned multicentre trials. Seventy percent (68/97) of all enrolled subjects completed this study of which 75 % (42/56) were sustained responders. The purpose of the study was to annually evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes for patients who were sustained responders 24 weeks post-treatment of the 48-week interferon alfa-2b and ribavirin treatment. All but one of the paediatric subjects remained sustained virologic responders during long-term follow-up after completion of treatment with interferon alfa-2b plus ribavirin. The Kaplan-Meier estimate for continued sustained response over 5 years is 98 % [95 % CI: 95 %, 100 %] for paediatric patients treated with interferon alfa-2b and ribavirin. Additionally, 98 % (51/52) with normal ALT levels at follow-up week 24 maintained normal ALT levels at their last visit.
SVR after treatment of chronic HCV with non-pegylated interferon alfa-2b with Rebetol results in long-term clearance of the virus providing resolution of the hepatic infection and clinical 'cure' from chronic HCV. However, this does not preclude the occurrence of hepatic events in patients with cirrhosis (including hepatocarcinoma).
5.2
Deletion of the following:
Children and adolescents: Multiple-dose pharmacokinetic properties for Rebetol capsules and interferon alfa-2b in children and adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in Table 6. The pharmacokinetics of Rebetol and interferon alfa-2b (dose-normalized) are similar in adults and children or adolescents.
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Table 6 Mean (% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and Rebetol capsules when administered to children or adolescents with chronic hepatitis C
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PARAMETER
|
Rebetol
15 mg/kg/day as 2 divided doses
(n = 17)
|
Interferon alfa-2b
3 MIU/m2 3 times a week
(n = 54)
|
|
Tmax (hr)
|
1.9 (83)
|
5.9 (36)
|
|
Cmax (ng/ml)
|
3,275 (25)
|
51 (48)
|
|
AUC*
|
29,774 (26)
|
622 (48)
|
|
Apparent clearance l/hr/kg
|
0.27 (27)
|
Not done
|
*AUC12 (ng.hr/ml) for Rebetol; AUC0-24 (IU.hr/ml) for interferon alfa-2b
Children and adolescents:
Addition of the title and following text under Hepatic function:
Children and adolescents:
Rebetol in combination with peginterferon alfa-2b
Multiple-dose pharmacokinetic properties for Rebetol and peginterferon alfa-2b 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 peginterferon alfa-2b at 60 µg/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 µg/kg/week. The pharmacokinetics of Rebetol (dose-normalized) in this trial were similar to those reported in a prior study of Rebetol in combination with interferon alfa-2b in children and adolescent patients and in adult patients.
Rebetol in combination with interferon alfa-2b
Multiple-dose pharmacokinetic properties for Rebetol capsules and interferon alfa-2b in children and adolescents with chronic hepatitis C between 5 and 16 years of age are summarized in Table 7. The pharmacokinetics of Rebetol and interferon alfa-2b (dose-normalized) are similar in adults and children or adolescents.
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Table 7. Mean (% CV) multiple-dose pharmacokinetic parameters for interferon alfa-2b and Rebetol capsules when administered to children or adolescents with chronic hepatitis C
|
PARAMETER
|
Rebetol
15 mg/kg/day as 2 divided doses
(n = 17)
|
Interferon alfa-2b
3 MIU/m2 3 times a week
(n = 54)
|
|
Tmax (hr)
|
1.9 (83)
|
5.9 (36)
|
|
Cmax (ng/ml)
|
3,275 (25)
|
51 (48)
|
|
AUC*
|
29,774 (26)
|
622 (48)
|
|
Apparent clearance l/hr/kg
|
0.27 (27)
|
Not done
|
*AUC12 (ng.hr/ml) for Rebetol; AUC0-24 (IU.hr/ml) for interferon alfa-2b
5.3
Addition of (see section 4.6) at end of 4th paragraph.
Deletion of alfa-2b after Ribavirin plus interferon alfa-2b
Addition of “peginterferon alfa-2b or” before interferon
9.0
Date of last renewal
Addition of 08 May 2009
10.0 Change from 23 April 2009 to 11 November 2009
