Merck Sharp & Dohme Limited

boceprevir, peginterferon alfa-2b or interferon alfa-2b Summary of Product Characteristics (SmPC) for prescribing information particular to that product.

Transfer into seminal fluid: Seminal transfer of ribavirin has been studied. Ribavirin concentration in seminal fluid is approximately two-fold higher compared to serum. However, ribavirin systemic exposure of a female partner after sexual intercourse with a treated patient has been estimated and remains extremely limited compared to therapeutic plasma concentration of ribavirin.

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.

·      Section 4.5 - (statement on co-administration of abacavir and rivavirin),

·      Section 4.4 & 4.5 (statement on the potential drug interaction with azathiorprine)

·      Section 4.8 - (deletion of Raynauds disease as an AE)

Also minor spelling corrections.

Rebetol Hard Capsules

4.1:
First paragraph:                        

Change from “(adults, children (3-years of age or older), and adolescents)” to “adults, children 3 years of age and older and adolescents”

Naïve patients: Adult patients:    

Removal of “serum”

                        Addition of “compensated cirrohosis and/or”
Children and adolescents:          

Addition of “3 years of age and older” after “children and before “and adolescents”

Addition of “peginterferon alfa-2b” before “interferon alfa-2b”

Deletion of “taking into account any evidence of disease progression such as hepatic inflammation and fibrosis, as well as prognostic factors for response, HCV genotype and viral load. The expected benefit of treatment should be weighed against the safety findings observed for paediatric subjects in the clinical trials”

After HCV-RNA addition of “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.”

            Change from (see sections 4.4, 4.8 and 5.1) to (see section 4.4).

4.2:

Addition of “Rebetol must be used in combination with either peginterferon alfa-2b or interferon alfa-2b.” in between first and second paragraphs.

Deletion of “There is no safety or efficacy information on the use of Rebetol with peginterferon alfa-2b in children or adolescents.

“Posology” changed to “Dose to be administered”

Adult patients:   Addition of “The dose of Rebetol is based on patient body weight (Table 1) under title heading.

Table 1             Change of weight range:

65-85 changed to 65-80

86-105 change to 81-105

Rebetol capsules in combi…     

Addition of “undetectable HCV-RNA or demonstrate adequate” before “virological response..”

Addition of “4 or” before “12 are highly likely…”

Addition of “and should be evaluated for discontinuation” after “sustained virological responders”

Genotype 1 section now bulleted

                        First bullet starts “Patients who have undedectable HCV-RNA at treatment week 12, treatment …” and includes rest of sentence.

Second bullet added: “Patients with detectable but ≥ 2 log decrease in HCV-RNA level from baseline at treatment week 12 should be reassessed at treatment week 24 and, if HCV-RNA is undetectable, they should continue with full course of therapy (i.e., a total of 48 weeks). However, if HCV-RNA is still detectable at treatment week 24, discontinuation of therapy should be considered.”

Third bullet includes rest of text “In the subset of patients with genotype 1..”

HCV/HIV Co-infection:   

Change of title to Duration of treatment – HCV/HIV co-infected patients

Duration of treatment – Retreatment:

Addition of “(i.e. HCV-RNA below the limits of detection) after “..fail to achieve virological response”

Children aged three years and older, and adolescents      

Changed to “Children 3 years of age and older and adolescents”

Addition of “Note: F” before “For patients who weigh <47kg..” instead of being in brackets after the title.

Addition of the following new paragraphs and title before “In clinical studies…”

“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.

Dose to be administered for the combination therapy with peginterferon alfa-2b:

The recommended dose of peginterferon alfa-2b is 60 µg/m²/week subcutaneously in combination with Rebetol 15 mg/kg/day (Table 2).

Dose to be administered for the combination therapy with interferon alfa-2b:”

Dose to be administered for the combination therapy with interferon alfa-2b:

First paragraph:

                        Addition of “million international units” inbetween 3 and (MIU)

Table 2:            Addition of “when used in combination with interferon alfa-2b or peginterferon alfa-2b in children and adolescents” in table title.

Duration of treatment in children and adolescents:

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”

                        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 for all patients:

Table 3:           

                        Addition of “based on laboratory parameters” to title.

Deletion of “adult to 600 mg/day^*, paediatric to 7.5 mg/kg” and replaced with “(see note 1)” in Reduce only Rebetol daily dose column heading

Deletion of “(adult) or interferon alfa-2b dose (adult and paediatric)

to one-half dose and replaced with “or interferon alfa-2b dose (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:

To:

Bilirubin –direct: removal of one asterix

Bilirubin – indirect row/discontinue column: change from:

Adult > 4 mg/dl

Paediatric > 5 mg/dl

(for > 4 weeks)

                        To:

> 4 mg/dl (adults)

> 5 mg/dl

(for > 4 weeks) (children and adolescents treated with interferon alfa-2b),

or

> 4 mg/dl (for > 4 weeks) (children and adolescents 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 adult patients, 1^st dose reduction of Rebetol is by 200 mg/day (except in patients receiving the 1,400 mg, dose reduction should be by 400 mg/day). If needed, 2^nd dose reduction of Rebetol is by an additional 200 mg/day.Patients whose dose of Rebetol is reduced to 600 mg daily receive one 200 mg capsule in the morning and two 200 mg capsules in the evening.

In children and adolescent patients treated with Rebetol plus peginterferon alfa-2b, 1^st dose reduction of Rebetol is to 12 mg/kg/day, 2^nd 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 adult patients treated with Rebetol plus peginterferon alfa-2b, 1^st dose reduction of peginterferon alfa-2b is to 1 µg/kg/week. If needed, 2^nd dose reduction of peginterferon alfa-2b is to 0.5 µg/kg/week.

In children and adolescent patients treated with Rebetol plus peginterferon alfa-2b, 1^st dose reduction of peginterferon alfa-2b is to 40 µg/m²/week, 2^nd dose reduction of peginterferon alfa-2b is to 20 µg/m²/week.

In adult patients and children and adolescent patients treated with Rebetol plus interferon alfa-2b, reduce the interferon alfa-2b dose by one-half dose.

Special populations:

Use in patients under the age of 18 years:                                   

Addition of “peginterferon alfa-2b or” before “interferon alfa-2b…”

(see section 4.1) deleted

4.4

Psychiatric and Central Nervous System (CNS):

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” in second paragraph

New box added: Growth and development (children and adolescents)

2^nd paragraph after growth and development box:

Addition of “selected” before chronic hepatitis C, in replacement of “the”.

Haemolysis:                  deletion of (adults only) after peginterferon alfa-2b

 
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 1^st “interferon alfa 2b”

Addition of “thyroid stimulation hormone” before TSH

Addition of “approximately” before 4%

Addition of “pegylated and non-pegylated” after 2^nd Interferon alfa-2b

Addition of “and during treatment with Rebetol and peginterferon alfa-2b” after 3^rd Interferon alfa-2b.

Laboratory tests:

Deletion of “Paediatric” and replacement with “Children and adolescents”

Addition of “HCV-RNA should be measured periodically during treatment (see section 4.2)” after Lab evaluations sentence.

4.6                   

Pregnancy and lactation “breast fed” changed to “breast feeding”

4.8

Adult patients:               Change from ”three” to “four” clinical trials

                                    Change from “one” to “two” trials studied

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

Children and adolescents:

Addition of the following paragraphs directly under the heading

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 (< 3^rd 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 3 percentiles and 7 percentiles, respectively, and 20% of the children continued to have inhibited growth (growth velocity < 3^rd 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.

Addition of title: “incombination with interferon alfa-2b” above “in clinical trials of 118 children…”

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 44^th percentile, which was below the median of the normative population and less than their mean baseline height (48^th 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 5

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”

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.

5.1

Pharmaceutical Group:   Parentheses around “excl. reverse transcriptase inhibitors”

Second paragraph:         change from “six “ to “6”

Table 7

Title:                             Moved to inside the table itself

Sub title                        P, O and W changed to small case from “Rebetol 800-1,400 mg/day Plus peginterferon alfa-2b 1.5 mg/kg Once Weekly”

Legend:                         All capitals changed to small case.

New section added after “in a non comparative trial” paragraph, which includes revision of tables 8 and addition of a new table 9:

A large randomized trial compared the safety and efficacy of treatment for 48 weeks with two peginterferon alfa-2b/Rebetol regimens [peginterferon alfa-2b 1.5 µg/kg and 1 µg/kg subcutaneously once weekly both in combination with Rebetol 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 8).

Table 8  Virologic response at treatment week 12, end of treatment response, relapse rate* and Sustained Virologic Response (SVR)

             *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 peginterferon alfa-2b (1.5 µg/kg)/Rebetol combination therapy resulted in a higher sustained virologic response rate compared to peginterferon alfa-2b 1 µg/kg dose. At the peginterferon alfa-2b 1.5 µg/kg plus Rebetol 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 in 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 9).

*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 < 2 log₁₀ decrease from baseline, patients to stop therapy.  If week 12 HCV-RNA is positive and decreased ≥ 2 log₁₀ from baseline, then retest HCV-RNA at week 24 and if positive, patients to stop therapy.

                                   
HCV/HIV Co-infected patients:    Change of “Table 9” to “Table 10”

Table 9;                                    Now called Table 10

                                                Change of some capitals to lower case

Legend:                                     Some spacing removed

“Patients who were HCV-RNA negative” paragraph

                                                Capital W’s changed to lower case

                                                Table 10 changed to Table 11

Table 10                                   now called Table 11

                                                Capital W’s changed to lower case

2 paragraphs under table 11:       change from W to w on all “week”

Long term efficacy data:             addition of “- Adults” to this title

                                                12 changed to twelve

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 12.

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” added before “results are summarised in …”

Table 11 changed to table 13

Table 11                       now called Table 13

                                    Addition of “Sustained v” to “irological response…”

Addition of the following text underneath table 13

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

Children and adolescents:          

                                    Addition of the following text underneath title:

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

Rebetol in combination with interferon alfa-2b

                                    Change from Table 12 to table 14

Table 12                       Now called table 14

                                    Title alignment changed

5.3

Ribavirin plus interferon             

Deletion of alfa-2b after Ribavirin plus interferon alfa-2b

9.0

Date of first authorisation           

addition of 0 to 7 May 1999

Date of last renewal                   

change from 02 September 2004 to 08 May 2009

10.0                              Change from 23 April 2009 to 11 November 2009

Section 2:        "Rebetol” deleted and replaced with “hard”

                        “Excipient: each hard capsule contains 40 mg of lactose monohydrate.” “Rebetol contains 40 mg of lactose monohydrate” deleted

Section 4.1:       "virus (HCV) infection" added after "chronic hepatitis C"
“(adults, children 3 years of age or older, and adolescents) replaced with “(adults, children (3 years of age and older) and adolescents)”

                        “or on the use of Rebetol with peginterferon alfa 2b in children or adolescents” deleted

                        “Please refer also to the peginterferon alfa-2b or interferon alfa-2b Summary of Product Characteristics (SPC) for prescribing information particular to that product.” Deleted

                        “or peginterferon alfa-2b,” added after “interferon alfa-2b”

 "hepatitis C viral ribonucleic acid ( )" added before and bracketing "HCV-RNA"

“(see section 4.4). Additionally, Rebetol is indicated,” deleted

“i” changed to “I”

“for the treatment of adult patients with chronic hepatitis C, not previously treated, without liver decompensation, with elevated alanine aminotransferase (ALT), who are positive for serum HCV-RNA, including” deleted

“also” added before “patients with clinically stable..”

“are included” added before (see section 4.4)

“Intended for use” replaced with “indicated”

“and adolescents” moved from before “3 years of age” to after “older”

“Previous treatment failure patients” changed to “Previously treated patients”

“alpha” changed to alfa”

“Additionally” deleted

“and ribavirin combination therapy or interferon alpha monotherapy” changed to “alone or in combination with ribavirin”

Section 4.2       “Please refer also to the peginterferon alfa-2b or interferon alfa-2b Summary of Product Characteristics (SPC) for prescribing information particular to that product.” added.

“There is no safety or efficacy information on the use of Rebetol with peginterferon alfa-2b in children or adolescents.” added.

"Dose to be administered" changed to "posology"
“for HCV monoinfected or HCV/HIV co-infected patients and whatever the genotype” inserted in table 1 heading

“C” changed to “c” in capsules

“Rebetol weight-based” added before “dosing” in HCV/HIV section and “(see Table 1)” added after “dosing”

“C” changed to “c” in capsules

“ribavirin” changed to Rebetol in section “Children aged…”

Changes to Table 3

-                          "if" changed to "when the below test value is reported ***" after "Discontinue combination therapy"

-                          "white blood cells" changed to "leukocytes"

-                          "serum" added before "creatinine”

-                          "Creatinine Clearance" row added, including "Discontinue Rebetol if CrCl <50ml/minute" entry under discontinue combi therapy column

-                          "(ALT)/ or A" added after "Alanine aminotransferase" and change from "(ALT)" to "(AST)" after "Aspartamine aminotransferase"

-                          "*** Refer to the SPC for interferon alfa-2b for dose modification and discontinuation." added to legend

Special Populations

o        "creatinine" added before "clearance" in use in renal impairment paragraph

o        ".0" added after 2 in mg/dl

o        "The use of ribavirin is contraindicated in patients with severe hepatic impairment or decompensated cirrhosis (see section 4.3)." added to Use in hepatic impairment paragraph

o        () around “3 years of age and older”

o        "nucleoside reverse transcriptase inhibitor ()" added around "NTRI" in Coinfection paragraph

Section 4.3:      “women who are breast feeding” changed to “lactation”

                        “S” deleted on Severe and replaced with “Patients with s”

                        “, including patients” deleted and replaced with “Patients”

“impairment (Child-Pugh Classification B or C)” inserted after “Severe hepatic” and “dysfunction” deleted.

 
Section 4.4:                  “event” deleted and replaced with “reaction” after “psychiatric adverse” in CNS box

Deleted - “Teratogenic risk: female patients: Rebetol must not be used by women who are pregnant (see section 4.3).  Extreme care must be taken to avoid pregnancy in female patients (see sections 4.6 and 5.3).  Male patients and their female partners: Extreme care must be taken to avoid pregnancy in partners of male patients taken Rebetol (see sections 4.6 and 5.3)

Deleted – “supplemental monitoring specific for children and adolescents”

                                    “D” deleted and replaced with “d” in development

“supplemental monitoring for children and adolescents” inserted after “Growth and development”

                                    “supplemental” inserted after “Thyroid”

                                    “M” changed to m in monitoring

                                    “for children and adolescents” inserted after “monitoring”

                                    “highly active anti-retroviral therapy ()” inserted around “HAART”

Section 4.6:                  “4.4” inserted after 4.3 in female patients section and male patients and their female partners section

                                    “(See section 4.4)” deleted

                                    “counseled” replaced with “advised” in male patients section

                                    “Lactation” replaced with “Breast-feeding”

“nursing” replaced with “breast-fed”

“nursing” replaced with “breast-feeding”

 
Section 4.8:                  “undesirable effects changed to “adverse reactions” in HCV/HIV section

“events” changed to “reactions” x 2

                                    “event” changed to “reaction”

Deleted – “Adverse reactions reported at a >10% incidence in paediatric trials were previously reported in adults (Table 4) and are not repeated in the paediatric table”

Section 4.9:                  “event” changed to reaction

Section 5.1:                  “previous treatment failures” changed to “Previously treated patients” changed to

Section 9:                    date of last renewal: “8 May 2004” changed to 23 April 2009”

Section 10:                   “2 December 2008” changed to “23 April 2009”

Section 11:                   Section added:              11. Legal Category

Prescription Only Medicine

                                    “1-09/22” changed to “05-09/23”

"Retreatment duration greater than 48 weeks in non-responder patients with genotype 1 has not been studied with pegylated interferon alfa-2b and ribavirin combination therapy."

Section 5.1, subsection headed ViraferonPeg/ribavirin retreatment of prior treatment failures updated included additions to Table 10

Section 10 - updated date of revision of text

Section 4.4

Sub section entitled:

HCV/HIV Co-infection - “Mitochondrial toxicity and lactic acidosis:”

The following sentence has been removed:

Moreover, patients treated with Rebetol and interferon alfa-2b or peginterferon alfa-2b combination therapy and zidovudine are at increased risk of developing anaemia.

And the following sentence has been added under “Haematological abnormalities in HCV/HIV co-infected patients:”

Patients treated with ribavirin and zidovudine are at increased risk of developing anaemia; therefore, the concomitant use of ribavirin with zidovudine is not recommended (see section 4.5).

Section 4.5

Under “Nucleoside analogs” the following has been added:

The exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV although the exact mechanism remains to be elucidated. The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4). Consideration should be given to replacing zidovudine in a combination anti-retroviral treatment (ART) regimen if this is already established. This would be particularly important in patients with a known history of zidovudine induced anaemia.

Section 5.1

Under the section entitled “Long-term efficacy data”, the following has been removed:

In a large study, 1,071 patients were enrolled after treatment in a prior non pegylated interferon alfa-2b or non pegylated interferon alfa-2b/Rebetol study to evaluate the durability of sustained virologic response and assess the impact of continued viral negativity on clinical outcomes. 462 patients completed at least 5 years of long-term follow-up and only 12 sustained responders' out of 492 relapsed during this study.

The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 97 % with a 95 % Confidence Interval of [95 %, 99 %].

And replaced with:

Two large long-term follow-up studies enrolled 1,071 patients and 567 patients after treatment in prior studies with nonpegylated interferon alfa-2b (with or without Rebetol) and pegylated interferon alfa-2b (with or without Rebetol), respectively. The purpose of the studies was to evaluate the durability of sustained virologic response (SVR) and assess the impact of continued viral negativity on clinical outcomes. At least 5 years of long-term follow-up was completed after treatment in 462 patients and 327 patients, respectively. 12 out of 492 sustained responders and only 3 out of 366 sustained responders relapsed, respectively, in the studies.

The Kaplan-Meier estimate for continued sustained response over 5 years is 97 % (95 % CI: 95-99 %) for patients receiving nonpegylated interferon alfa-2b (with or without Rebetol), and is 99 % (95 % CI: 98-100 %) for patients receiving pegylated interferon alfa-2b (with or without Rebetol).

And the following sentence has been changed from:

SVR after treatment of chronic HCV with non pegylated interferon alfa-2b (with or without 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).

To:

SVR after treatment of chronic HCV with interferon alfa-2b (pegylated and nonpegylated,with or without 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).

Section 10

Date of revision of test has been updated

Section 4.1

Changed from:

Relapse patients

Adult patients: Rebetol is indicated, in combination with interferon alfa-2b, for the treatment of adult patients with chronic hepatitis C who have previously responded (with normalisation of ALT at the end of treatment) to interferon alpha monotherapy but who have subsequently relapsed. Additionally, Rebetol is indicated, in combination with peginterferon alfa-2b, for the treatment of adult patients with chronic hepatitis C who have previously responded (with normalisation of ALT at the end of treatment) to interferon alpha monotherapy but who have subsequently relapsed (see section 4.4).

To:

Previous treatment failure patients

Adult patients: Rebetol is indicated, in combination with interferon alfa-2b, for the treatment of adult patients with chronic hepatitis C who have previously responded (with normalisation of ALT at the end of treatment) to interferon alpha monotherapy but who have subsequently relapsed. Additionally, Rebetol is indicated, in combination with peginterferon alfa-2b, for the treatment of adult patients with chronic hepatitis C who have failed previous treatment with interferon alpha (pegylated or nonpegylated) and ribavirin combination therapy or interferon alpha monotherapy (see section 5.1).

Section 4.2

Table 1 changed from:

a: 2 morning, 2 evening

b: 2 morning, 3 evening

c: 3 morning, 3 evening

to:

a: 2 morning, 2 evening

b: 2 morning, 3 evening

c: 3 morning, 3 evening

d: 3 morning, 4 evening

Next paragraph headed Duration of treatment now read Duration of treatment – Naïve patients

The following paragraph has been added to section 4.2:

Duration of treatment - Retreatment

Predictability of sustained virological response: All patients, irrespective of genotype, who have demonstrated serum HCV-RNA below the limits of detection at Week 12 should receive 48 weeks of therapy. Retreated patients who fail to achieve virological response at Week 12 are unlikely to become sustained virological responders after 48 weeks of therapy (see also section 5.1).

Section 4.4

The following paragraph has been removed from this section:

There is no experience with Rebetol in combination with peginterferon alfa-2b in patients who have relapsed after Rebetol + interferon alfa-2b therapy.

Section 4.5

In the section entitled Nucleoside analogs, the following paragraph has been removed:

Ribavirin was shown in vitro to inhibit phosphorylation of zidovudine and stavudine. The clinical significance of these findings is unknown. However, these in vitro findings raise the possibility that concurrent use of Rebetol with either zidovudine or stavudine might lead to increased HIV plasma viraemia (for co-administration with stavudine see also section 4.4). Therefore, it is recommended that plasma HIV RNA levels be closely monitored in patients treated with Rebetol concurrently with either of these two agents. If HIV RNA levels increase, the use of Rebetol concomitantly with reverse transcriptase inhibitors must be reviewed.

Section 5.1

The section entitled Relapse patients has been renamed Naïve patients has been removed.

In the paragraph located between Tables 6 and 7, the phrase which has not yet been validated has been removed at the end of the first sentence.

The section entitled Predictability of sustained viralogical response has been changed to Predictability of sustained viralogical response in naïve patients.

A new section regarding Previous treatment failure patients has been added to section 5.1 including a new Table 10, this has resulted in all following tables and references to these tables being renumbered.

Section 10

Date of revision of text changed from 09 July 2007 to 30 October 2007

Supplemental monitoring specific for children and adolescents

Changed from:

Dose modification for all patients

If severe adverse reactions or laboratory abnormalities develop during therapy with Rebetol and peginterferon alfa-2b or interferon alfa-2b, modify the dosages of each product if appropriate, until the adverse reactions abate. Guidelines were developed in clinical trials for dose modification (see Dosage modification guidelines, Table 3). 

Changed to:

Dose modification for all patients

Section 4.4.

In a large study, 1,071 patients were enrolled after treatment in a prior non pegylated interferon alfa-2b or non pegylated interferon alfa-2b/ribavirin study to evaluate the durability of sustained virologic response and assess the impact of continued viral negativity on clinical outcomes. 446 patients completed at least 5 years of long-term follow-up and only 12 sustained responders' out of 492 relapsed during this study.

The Kaplan-Meier estimate for continued sustained response over 5 years for all patients is 97 % with a 95 % Confidence Interval of [95 %, 99 %].