UMATROPE - UMATROPE - CT 4613 - English version

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Introduction UMATROPE 6 mg powder for solution and solvent for injection in multidose cartridge Box of 1 cartridge and 1 solvent solution pre-filled syringe (CIP: 342 158-7) UMATROPE 12 mg powder for solution and solvent for injection in multidose cartridge Box of 1 cartridge and 1 solvent solution pre-filled syringe (CIP: 342 159-3) UMATROPE 24 mg powder for solution and solvent for injection in multidose cartridge Box of 1 cartridge and 1 solvent solution pre-filled syringe (CIP: 342 160-1) Posted on Nov 10 2009 Active substance (DCI) somatropin ATC Code H01AC01 Laboratory / Manufacturer LILLY UMATROPE 6 mg powder for solution and solvent for injection in multidose cartridge Box of 1 cartridge and 1 solvent solution pre-filled syringe (CIP: 342 158-7) UMATROPE 12 mg powder for solution and solvent for injection in multidose cartridge Box of 1 cartridge and 1 solvent solution pre-filled syringe (CIP: 342 159-3) UMATROPE 24 mg powder for solution and solvent for injection in multidose cartridge Box of 1 cartridge and 1 solvent solution pre-filled syringe (CIP: 342 160-1) Posted on Nov 10 2009

Sujets

• Pédiatrie
• Maladie génétique
• RARE

Informations

• Publié par: haute-autorite-sante-maladies-urologiques
• Publié le: 04 juillet 2007
• Nombre de lectures: 13
• Licence : En savoir +
  Paternité, pas d'utilisation commerciale, partage des conditions initiales à l'identique
• Langue: English

Extrait

   

  The legally binding text is the original French version     TRANSPARENCY COMMITTEE

  OPINION   4 July 2007     UMATROPE 6 mg powder for solution and solvent for injection in multidose cartridge Box of 1 cartridge and 1 solvent solution pre-filled syringe (CIP: 342 158-7)   UMATROPE 12 mg powder for solution and solvent for injection in multidose cartridge Box of 1 cartridge and 1 solvent solution pre-filled syringe (CIP: 342 159-3)   UMATROPE 24 mg powder for solution and solvent for injection in multidose cartridge Box of 1 cartridge and 1 solvent solution pre-filled syringe (CIP: 342 160-1)     Applicant : LILLY   Somatropin   ATC Code: H01AC01   List I Initial annual hospital prescription for the use of specialists in paediatrics and/or endocrinology and metabolic diseases practising in facilities specialising in paediatrics and/or endocrinology and metabolic diseases.   Date of Marketing Authorisations:   Initial Marketing Authorisation: 21 November 1995 Extension of Indication: 22 March 2007   Reason for request: Inclusion on the list of medicines reimbursed by National Insurance and approved for use by hospitals in the new indication “ -growth delay (current height < 2.5 SDS and parental adjusted height -1 SDS) in children born small for gestational < age and with a birth weight and/or length < -2 SDS, who failed to show catch-up growth (height velocity < 0 SDS during the last year) by 4 years of age or later.”               Medical, Economic and Public Health Assessment Division

 

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1 CHARACTERISTICS OF THE MEDICINAL PRODUCT     1.1. Active ingredient   Somatropin   1.2. Indications   In children: Long-term treatment of children who have growth failure due to an inadequate secretion of normal endogenous growth hormone.   Treatment of short stature in children with Turner syndrome, confirmed by chromosome analysis.   Treatment of growth delay in prepubertal children with chronic renal insufficiency.   Humatrope is also indicated in the treatment of growth delay (current height < - 2,5 standard deviation score (SDS) and parental adjusted height < -1 SDS) in children born small for gestational age, with a birth weight and/or height < -2 SDS, who failed to show catch-up growth (height velocity < 0 SDS during the last year) by 4 years of age or later.   In adults: Humatrope is indicated for replacement therapy in adults with pronounced growth hormone deficiency.   Patients with severe growth hormone deficiency in adulthood are defined as patients with known hypothalamic-pituitary pathology and at least one known deficiency of a pituitary hormone (other than prolactin). These patients should undergo a single dynamic test in order to diagnose or exclude a growth deficiency.In patients with childhood onset isolated growth hormone deficiency (no evidence of hypothalamic- pituitary disease or cranial irradiation), two dynamic tests are recommended, except in case of low IGF-I concentrations (<-2 SDS), which may be considered for one test. The cut-off point of the dynamic test should be strict.   1.3. Dosage   Humatrope in cartridge formulation should only be administered by subcutaneous injection after reconstitution. The dosing and administration regimen should be personalised for each individual. For children born small for gestational age: The recommended dosage is 0.035 mg/kg of body weight per day by subcutaneous injection (1.0 mg/m2 body surface area per day) until final height is reached. Treatment should be discontinued after the first year of treatment, if the height velocity SDS is under –1.0 SDS. Treatment must be discontinued if height velocity is < 2 cm/year, and, if confirmation is required, bone age is > 14 years (girls) or > 16 years (boys), corresponding to closure of the epiphyseal growth plates.   The subcutaneous injection sites should be varied in order to avoid lipo-atrophy.  

 

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No

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No

3

 

   

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No

  2 SIMILAR MEDICINAL PRODUCTS     2.1. ATC Classification (2007)   H: SYSTEMIC HORMONAL PREPARATIONS, EXCLUDING SEX HORMONES H01: PITUITARY AND HYPOTHALAMIC HORMONES AND ANALOGUES H01A: ANTERIOR PITUITARY LOBE HORMONES AND ANALOGUES H01AC: SOMATROPIN AND ANALOGUES H01AC01: Somatropin   2.2. Medicines in the same therapeutic category   Table 1: Comparative table of indications for growth hormone   Growth delay in children Related to Associated Related to Related to Associated Growth Intrauterine growth to Turner kidney kidney to Prader- delay in growth hormone syndrome insufficiency insufficiency Willi children delay d deficiency in in pubertal Syndrome born small prepubertal children for children gestational age Yes Yes  No

Yes

No

No

No

No

Yes

Adult Growth hormone eficiency

No

Yes

Yes

Yes

Maxomat®

Genotonorm®

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

No

No

Yes

No

Zomacton®

  HUMATROPE is the 6th growth hormone for which inclusion in a comparable indication is requested, after MAXOMAT, GENOTONORM, NORDITROPIN, SAIZEN and OMNITROP.   2.3. Medicines with a similar therapeutic aim   None

Norditropin®

NutropinAq® 

Saizen®

Omnitrop®

  3 ANALYSIS OF AVAILABLE DATA     The laboratory added a phase III, open-label, non-comparative 1 , study to the file, conducted over two consecutive periods:

   Period I: 4 years  Period II: follow-up until adult height*  (N = 35) (N = 24)          of the treatment (N = 7) Reinstatement                 (0,067 mg/kg/j)     2 years of treatment 2 years of follow-up  (0,067 mg/kg/j) without treatment         Follow-up without treatment (N = 17)   Period I: 35 children (mean chronological age 9.3 ± 0.9 years) were treated with Humatrope for 2 years (daily dosage of 0.067 mg/kg) with a medical visit every 3 months, then every 6 months for the two following years.   Period II: 7 of 35 children were treated again with Humatrope at a dosage of 0.067 mg/kg/day: these were children who, at the end of the follow-up period for period 1, had lost more than 0.5 SDS with a bone age < 12 years (girls) and < 14 years (boys). All the children were followed until their adult height was reached *(N total  24, as 11 children were = unavailable at the end of period I). *adult height is defined as a height velocity≤1 cm/year, and/or bone age≥16 years for girls and≥18 years for boys.   Two primary endpoints were defined in the study protocol: change in height (expressed in SDS) and height velocity (also expressed in SDS).   In light of the fact that the dosage used (0.067 mg/kg/day) did not correspond to the one recommended by the SPC (0.035 mg/kg/day), the efficacy results for this study will not be detailed in this opinion.   In terms of safety, 215 adverse events were observed in 30 children (86% of patients). The most frequently observed events were respiratory disorders (31%), flu syndrome (20%), bronchitis (17%) and pharyngitis (17%). The most frequently affected systems were the respiratory system (51%), skin and related systems (40%) and the digestive system (34%).   18 adverse events were observed in 13 patients (37.1%), the most frequent of which were as follows: - serious body accidents reported in 2 patients; 3 - 5 digestive disorders reported in 4 patients; During the study, one fatality was reported due to suicide.   The quantity of effect of Humatrope in the indication and dosages recommended by the Marketing Authorisation could not be concluded based on this study. However, there is doubt as to the long-term safety of growth hormones in non-deficient children.                                                   1 Rosilio et al. Adult height of prepubertal short children born small for gestational age treated with GH. European Journal of Endocrinology 2005 (152): 835-43 .

 

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4 TRANSPARENCY COMMITTEE CONCLUSIONS     4.1. Actual benefit   Growth delay in children born small who failed to show catch-up growth by 4 years of age or later may affect quality of life.   The efficacy/adverse effects ratio is medium.   This is a symptomatic treatment.   This is a first-line therapy.   There are other growth hormones with this indication.   The psychosocial repercussions and the effect on quality of life related to growth delay in children born small for gestational age are poorly defined and vary greatly from one patient to another. Therefore, the disease’s burden cannot be quantified and therapeutic need cannot be established.   In light of the insufficient data regarding HUMATROPE’s effect on height and final body composition, improvement of the psychosocial or quality of life parameters for treated children, this medicinal product’s impact on public health cannot be determined.   Furthermore, there is uncertainty as to the long-term safety of growth hormones in non- deficient children and therefore a negative impact in terms of public health cannot be excluded. As a result, the medicinal product HUMATROPE is not expected to have a public health benefit .   The actual benefit of HUMATROPE in this indication is moderate. This opinion must be considered as provisional. The Transparency Committee would like to re-assess the growth hormones with a similar indication.   4.2. Improvement in actual benefit   HUMATROPE does not provide an improvement in actual benefit (IAB V) in the treatment of growth delay in children born small for gestational age compared to other growth hormones with a similar indication.   4.3. Therapeutic use   Small stature in itself does not constitute a disease. The decision to have recourse to growth hormone supplements must be undertaken with caution in non-deficient children. In fact, the long-term consequences of exposure to supraphysiological quantities of growth hormone are completely unknown. In adults, the pathological effects of excessive growth hormones are well known. Stimulation of IGF 1 production, a cytokine capable of inducing tumour proliferation, should not be ignored.            

 

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The 2007 Consensus Conference of the International Society of Paediatric Endocrinology and the Growth Hormone Research society 2 emphasised the absence of sufficient hindsight to reach conclusions with regards to the long-term benefit/risk ratio of a growth hormone treatment in children born small for gestation age. It recommends a long-term follow-up of all patients treated with growth hormones in childhood and/or adolescence.   Other causes or treatments possibly justifying growth delay should be excluded prior to initiating treatment. Growth stimulation in children should be only undertaken before closure of the epiphyseal growth plates. On the other hand, experience in treatment initiation near onset of puberty in children born small for gestational age is limited. Therefore, initiating treatment near onset of puberty is not recommended. A portion of the height gained may be lost if treatment is discontinued before final height is attained. Insulin and glycaemic levels should be measured prior to starting treatment, then yearly thereafter. In patients with increased risk of diabetes mellitus   (e.g.: family history of diabetes, obesity, severe insulin resistance, acanthosis   nigricans) an oral glucose tolerance test should be performed. If diabetes is diagnosed, growth hormone should not be administered as long as the diabetes is uncontrolled. Growth hormone therapy may be initiated thereafter under strict monitoring of the glycaemic levels. An increased dose of insulin may be necessary. Measuring the plasma concentration of IGF-1 is also recommended, prior to initiating the treatment, and should be undertaken twice yearly thereafter. If, at repeated measures, the IGF-1 levels are greater than + 2 SDS compared to standard values for gender, age, and pubertal status, the IGF-I/IGFBP-3 ratio must be taken into account to consider dose adjustment.  HUMATROPE treatment should be initiated in a hospital setting by physicians specialised in paediatrics and/or endocrinology and metabolic diseases practising in facilities specialised in paediatrics and/or endocrinology and metabolic diseases.   The treatment benefit must be revaluated each year by the same specialists.   4.4. Target population   Two stages are necessary to determine the target population for this indication:   1/ Estimate of the number of children born small for gestational age (height at birth < -2 SDS) - to the INSEE [French National Institute for Statistics and Economic Studies], According there were 774,355   births in France in 2005. - Approximately3% of newborns were of a height under – 2 SDS (corresponding to the 3  rd   percentile). A Swedish study (Albertsson-Wikland et al, 1994) confirms this result.   2/ Estimates of the number of children who failed to show catch-up growth by 4 years of age or later: - The majority of children born small for gestational age spontaneously attain their height within the first two years of life, only 10% maintain a height less than 2 SDS (specialist’s opinion). -cohort study (Hagenau), approximately 3% of children born small to a French  According for gestational age will maintain a height < - 2.5 SDS. - the hypothesis is that less than 3% of children will maintain a height less than Therefore, or equal to 3 SDS. -

                                             2  et al. Management of the child born small for gestational age child (SGA) through to adulthood: a consensus Clayton statement of the international societies of pediatric endocrinology and the growth hormone research society. J Clin Endocrin Metab. 2007

 

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Based on this information, the number of new cases for this indication would include a maximum of 700 children each year.   4.5. Transparency Committee recommendations   The Transparency Committee temporarily recommends inclusion on the list of medicines reimbursed by National Insurance and on the list of medicines approved for use by hospitals and various public services in the indication of growth delay in children born small for gestational age, pending a revaluation of the actual benefit of growth hormones with this indication or a similar indication.   4.5.1. Reimbursement perimeter   The Transparency Committee recommends reimbursement of the growth hormone in this indication only for children with a growth delay (current height less than or equal to 3 SDS - and parental adjusted height < -1 SDS) in children born small for gestational age with a birth height < -2 SDS, who failed to show catch-up growth (height velocity < 0 SDS during the last year) by 4 years of age or later.   For children, in the indication “Growth delay in children born small for gestational age”, the Transparency Committee subordinates any future confirmation of its favourable opinion to the performance of a follow-up study and its results. Such a study must include the following:  - Characteristics of patients receiving this treatment, -Observance, duration of treatment and reasons for discontinuation,   -  Effecton growth and final height of children, - of undesirable effects. Onset   4.5.2. Packaging: Appropriate for the prescription conditions   4.5.3. Reimbursement rate in this extension of indication: 100%   4.5.4. Exception Medicinal Product:   The Transparency Committee requests that these medicinal products be given the status of medicinal product for exceptional use in this indication.  

 

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