Merck Sharp & Dohme Limited

Children and adolescent population: Growth and development (chronic hepatitis C)

During the course of interferon (standard and pegylated)/ribavirin combination 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 title “Hypersensitivity Reactions” to following paragraph

Change of “medication” to “medicine”

Addition of title “adverse experiences including prolongation of coagulation markers and liver abnormalities” to next paragraph

Addition of “Discontinue treatment with IntronA in patients with chronic hepatitis who develop prolongation of coagulation markers which might indicate liver decomposition.” Before “Any patient developing liver function..” within same paragraph.

Addition of the following titles to the next 12 paragraphs

“hypotension”

“Need for adequate hydration”

“Pyrexia”

“Patients with debilitating medical conditions”

“Pulmonary conditions”

“Ocular adverse events”

Obtundations, coma and encephalopathy”

“Patients with pre-existing cardiac abnormalities”

“Hypertriglyceridemia”

“Patients with psoriasis and sarcoidosis”

“Kidney and liver graft rejections”

“Auto-antibodies and autoimmune disorders”

Addition of new paragraph below:

Concomitant chemotherapy

Administration of IntronA in combination with other chemotherapeutic agents (e.g., Ara-C, cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and duration), which may be life-threatening or fatal as a result of the concomitantly administered medicinal product. The most commonly reported potentially life-threatening or fatal adverse events include mucositis, diarrhoea, neutropaenia, renal impairment, and electrolyte disturbance. Because of the risk of increased toxicity, careful adjustments of doses are required for IntronA and for the concomitant chemotherapeutic agents (see section 4.5). When IntronA is used with hydroxyurea, the frequency and severity of cutaneous vasculitis may be increased.

Change from “H” to “h” in Chronic hepatitis C title.

Text after “Monotherapy” now moved down to new paragraph below.

Text after “Thyroid supplemental monitoring specific for children and adolescents” now moved down to new paragraph below.

Text after “HCV/HIV Coinfection” now moved down to new paragraph below.

“Concomitant chemotherapy” paragraph deleted

Text after “Dental and periodontal disorders” now moved down to new paragraph below.

Addition of “the following” after “During ALT flare” in second paragraph in Lab Tests section.

Addition of “must be monitored at two-weekly intervals” after “liver function tests” in this same sentence.

Deletion of “must be monitored at two-weekly intervals” at end of this sentence.

Addition of

“Important information about some of the ingredients of IntronA

This medicinal product contains less than 1 mmol sodium (23 mg) per 1 ml, i.e., essentially "sodium-free".” At end of  “Effect on fertility” section

4.5

Change from “dosage” to “dose” in third paragraph

4.6

Addition of “Fertility,” to “pregnancy and lactation” heading

Addition of sub heading “Women of childbearing potential/contraception in males and females”

Addition of “IntronA must be used with caution in fertile men” after first paragraph

Relocation of following paragraph at end of section to before “Pregnancy” paragraph:

Combination therapy with ribavirin

Ribavirin causes serious birth defects when administered during pregnancy. Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking IntronA in combination with ribavirin. Females of childbearing potential and their partners must each use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients and their female partners must each use an effective contraceptive during treatment and for 7 months after treatment has been concluded (see ribavirin SPC).

Addition of “Pregnancy” subheading

Addition of the following text:

Combination therapy with ribavirin

Ribavirin therapy is contraindicated in women who are pregnant.

Addition of “Breast-feeding” subheading

4.8

“Adults:” Addition of “to” in between frequency categories “common”, “uncommon” and “rarely” instead of commas.

Change from “Children and adolescents” to “Children and adolescent population”

“Chronic Hepatitis C - ” moved down to before “Combination therapy..”

5.1

Deletion of “Immunostimulants, cytokines and immunomodulators, interferons” in first sentence

Deletion of “adults” in “Long-Term efficacy data” sub heading

Text after “Long-Term efficacy data” sub heading moved down to new paragraph below

Change from “patients” to “population” in Chronic hepatitis C in children and adolescent ..” sub heading

Deletion of “Children and adolescents” from “Long-term efficacy” subheading

5.2

Relocation of following paragraph from end of section 5.2 to after “Urine levels..” paragraph:

Interferon neutralising factor assays were performed on serum samples of patients who received IntronA in Schering-Plough monitored clinical trials. Interferon neutralising factors are antibodies which neutralise the antiviral activity of interferon. The clinical incidence of neutralising factors developing in cancer patients treated systemically is 2.9 % and in chronic hepatitis patients is 6.2 %. The detectable titres are low in almost all cases and have not been regularly associated with loss of response or any other autoimmune phenomenon. In patients with hepatitis, no loss of response was observed apparently due to the low titres.

Addition of “population” to “Children and adolescent” subheading.

6.3

Addition of the following paragraph under 10MIU and 25MIU subsections:

“Within its shelf-life, for the purpose of transport, the solution can be kept at or below 25ºC for a period up to seven days before use. IntronA can be put back in the refrigerator at any time during this seven-day period. If the product is not used during the seven-day period, it cannot be put back in the refrigerator for a new storage period and must be discarded.”

6.4

Deletion of above added paragraph

Addition of “For storage conditions of the medicinal product, see section 6.3.” to end of section

6.5

Addition of “single dose” before “vial (type I glass) x 2 in 10MIU subsection

Removal of “with”, a full stop added after “(polypropylene) and addition of “The pack size also contains” to “1 injection syringe..”

Addition of “multidose” to vial (type 1 glass) x 2 in 25MIU subsection

Removal of “with”, a full stop added after “(polypropylene) and addition of “The pack size also contains” to “6 injection syringes..”

6.6

Change of “dosage” to “dose” twice in first paragraph

“introna” changed to “IntronA” in “No other medicinal product can be infused..” sentence

9.

Change from “Date of last renewal” to “Date of latest renewal”

Change from 23 May 2005 to 15 March 2010

10.

Date of revision of the text changed from 12 November 2009 to 15 March 2010

Growth and development (children and adolescents):

During the course of interferon (standard and pegylated)/ribavirin combination 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.

5^th Paragraph underneath box

                        “Fever” replaced by “pyrexia” twice

7^th Paragraph underneath box

                        “Fever” replaced by “pyrexia” once

Chronic Hepatitis C:

Supplemental monitoring specific for children and adolescents

Addition of “Thyroid” before “Supplemental monitoring…” in and now start of paragraph and instead of being a title in bold. 

Deletion of sub heading “Thyroid Monitoring:”

Addition of “thyroid stimulating hormone” before “TSH”

TSH now bracketed

4.8

Undesirable effects

2nd paragraph:

                        “Fever” replaced by “pyrexia” twice

                        Addition of Sub heading “Adults” above 3^rd paragraph

Table 1              General disorders Row: change from “fever” to “pyrexia”

Paragraph underneath table 1

                        “Fever” replaced by “pyrexia” once

Paediatric population

                        Deletion of Paediatric population sub title

Children and adolescents – Chronic Hepatitis C

                        Combination therapy with ribavirin added underneath title

“children or adolescents” changed to “children and adolescents”

“adverse events” changed to “adverse reactions”

“adverse event” changed to “adverse reaction”

“paediatric population” changed to “children and adolescent population”

“percentile” added to end of “decrease in height”

“percentile” replaced to “%” after 9

“percentile” added to end of “and weight”

“percentile” replaced to “%” after 13

The following added before (see section 4.4):

“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 IntronA and ribavirin, 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”

“Further more …” now new paragraph within which “fever” has been changed to “pyrexia”

Deletion of “Undesirable effects reported in paediatric clinical trials, and not previously reported at an incidence ³ 1 % in adults, are shown in Table 3. All effects reported at a ³ 10 % incidence in paediatric trials were previously reported in adults (Table 2) and are not repeated in the paediatric table.” Replaced with “The adverse reactions listed in Table 2 are based on experience from the two multicentre children and adolescent clinical trials.”

“Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (≥1/10); common (≥1/100, <1/10). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.”

Table 2

Change of title from:

“Adverse reactions very commonly and commonly reported in paediatric clinical trials Very common (≥1/10) - Common (≥1/100, <1/10)”

To:

“Adverse reactions very commonly and commonly reported during clinical trials in children and adolescent patients treated with IntronA in combination with ribavirin”

General disorders Tab: Change from “fever” to “pyrexia”

5.1

Chronic hepatits C

addition of “in adult patients” to title

Adult Patients: deleted from beginning of 12^th paragraph (“IntronA alone or in..”)

Clinical trials in paediatric patients with chronic hepatitis C:

                        Title changed to “Chronic hepatitis C in children and adolescent patients:”

Addition of “in the two multicentre trials” added before “sustained virological response..”

                        “these two multicentre trials for” added before “children with severe”

Table 5                        “Sustained” added to beginning of table title

                        Superscript 1 changed to superscript α in table and legend

                        Addition of the following paragraph underneath table 5:

                        “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 the 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 ribavirin 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).”

5.3

Last paragraph:  IntronA plus ribavirin: added before “No studies..”

“Preclinical juvenile toxicity results have demonstrated a minor, dose-related decrease in overall growth in neonatal rats dosed with ribavirin” added before “(see section…)”

“4.4 and” changed to “5.3 of”

10.0                  6 March 2009 changed to 12 November 2009