Key Benefits:
Minister of Health and Solidarity,
Considering the social security code;
Considering the Public Health Code;
Having regard to the decree of 8 December 1994 taken for the application of article R. 163-2 of the Social Security Code and relating to repayable specialties;
Considering the decision of February 24, 2003, amending the list of repayable pharmaceutical specialties to social insured persons;
In the opinion of the Transparency Commission,
Stop it!
The list of repayable pharmaceutical specialties to social insured persons is amended in accordance with the provisions contained in annex I. The therapeutic information sheet provided for in Article R. 163-2 of the Social Security Code for SAIZEN is annexed to this Order.
The SAIZEN therapeutic information sheet, which was annexed to the above-mentioned decision of 24 February 2003, is repealed.
The Director General of Health and the Director of Social Security are responsible, each with respect to him, for the execution of this Order, which will be published and its annexes to the Official Journal of the French Republic.
A N N E X E I
For the specialties mentioned below, the only therapeutic indications that are entitled to care or reimbursement are:
In the child:
- the delay in growth associated with a deficit or absence of endogenous growth hormone secretion;
- the delay in growth in girls with gonadic dysgenesia (Turner syndrome) confirmed by chromosomal analysis;
- the retardation of growth due to chronic renal insufficiency (CRI), in the pre-pubber child;
- the retardation of growth (current size - 3 DS and adjusted parent size - - 1 DS) in children born small for gestational age with a birth size < - 2 DS, not having caught up in their growth delay (growth speed < 0 DS in the last year) at the age of 4 or more.
In the adult:
Alternative treatment in adults with severe somatotrope deficiency.
Patients with a severe somatotrope deficit acquired at adulthood are defined as those with known hypothalamo-hypophysary disease and at least another hypophysary hormone deficiency, except prolactin. A single dynamic test will be performed to diagnose or exclude a growth hormone deficiency.
In patients with a somatotrope deficiency acquired in childhood (without antecedent of hypothalamo-hypophysary pathology, or encephalic irradiation), two dynamic tests must be performed, except in case of low IGF-I ( ( - 2 DS), which can be considered as a test. The limit values of dynamic tests must be strictly defined.
You can see the table in the OJ
n° 184 of 10/08/2006 text number 19
These specialties are prescribed in accordance with the therapeutic information sheet in Appendix II.
A N N E X E I
THERAPEUTICAL INFORMATION
MÉDICAMENT D'EXCEPTION
SAIZEN
Growth hormones
SAIZEN 1.33 mg/ml, powder and solvent for injectable solution.
SAIZEN CLICKEASY 8 mg/1,37 ml, powder and solvent for multidose injectable solution.
SAIZEN (somatropine) is a biosynthetic growth hormone, produced by cloning of a linear mouse cell C127, which reproduces exactly the sequence of the natural somatotrope hormone.
Several specialties based on growth hormone are marketed. Each of these specialties has been assessed in indications and according to specific criteria. Not all have the same indications. When several of them have the same indication, for historical or administrative reasons (national MMA or mutual recognition), the wording of the indication is not always superposable. There are also slight variations in dosage ranges in MMAs, given clinical trials in record records.
SAIZEN, a biosynthetic human growth hormone, is a restricted prescription drug: an annual initial hospital prescription reserved for specialists in pediatrics and/or endocrinology and metabolic diseases in specialized services in pediatrics and/or endocrinology and metabolic diseases, whose conditions of care fall under the procedure of exceptional drugs
1. Reimbursable therapeutic indications
In the child:
- the delay in growth associated with a deficit or absence of endogenous growth hormone secretion;
- the delay in growth in girls with gonadic dysgenesia (Turner syndrome) confirmed by chromosomal analysis;
- the retardation of growth due to chronic renal insufficiency (CRI), in the pre-pubber child;
- the retardation of growth (current size - 3 DS and adjusted parent size - - 1 DS) in children born small for gestational age with a birth size < - 2 DS, not having caught up in their growth delay (growth speed < 0 DS in the last year) at the age of 4 or more.
In the adult:
Alternative treatment in adults with severe somatotrope deficiency.
Patients with a severe somatotrope deficit acquired at adulthood are defined as those with known hypothalamo-hypophysary disease and at least another hypophysary hormone deficiency, except prolactin. A single dynamic test will be performed to diagnose or exclude a growth hormone deficiency.
In patients with a somatotrope deficiency acquired in childhood (without antecedent of hypothalamo-hypophysary pathology, or encephalic irradiation), two dynamic tests must be performed, except in case of low IGF-I ( ( - 2 DS), which can be considered as a test. The limit values of dynamic tests must be strictly defined.
2. Dosage and mode of administration
SAIZEN 1.33 mg/ml is intended for single use.
SAIZEN CLICKEASY 8 mg/1,37 ml is intended for multidose use.
The dosage of SAIZEN must be adapted to each patient, depending on the body surface (m2) or body weight (kg).
It is recommended to administer SAIZEN at bedtime according to the following dosage:
2.1. Somatotrope deficit associated with inadequate secretion of endogenous growth hormone: 0.7 to 1.0 mg/m2 of body surface per day or 0.025 to 0.035 mg/kg of body weight per day, administered undercutaneous or intramuscular.
2.2. Growth rate for girls with gonadic dysgenesia (Turner syndrome): 1.4 mg/m2 of body surface per day or 0.045 to 0.050 mg/kg of body weight per day, undercutaneous.
Treatment concomitant with non-Androgenic anabolic steroids in patients with Turner syndrome can increase the response to treatment.
2.3. Growth rate associated with chronic kidney failure (CRI) in pre-pubilee children: 1.4 mg/m2 of body surface per day for approximately 0.045 to 0.050 mg/kg of body weight per day, undercutaneous.
Duration of treatment: treatment must be interrupted when the patient has reached a satisfactory adult size or when the epiphyses are welded.
2.4. Growth rate for children born small for gestational age: the recommended daily dose is 0.035 mg/kg bw per day (or 1 mg/m2/day corresponding to 0.1 IU/kg/day or 3 IU/m2/day) administered undercutaneous.
Duration of treatment: treatment is usually recommended until the final size is reached.
Treatment will be interrupted after the first year if growth speed is less than + 1 DS. It will have to be interrupted if the final size is reached (growth speed cm 2 cm/year) and, when a confirmation is necessary, if the bone age is 14 years (girls) or 16 years (boys), corresponding to the welding of the epiphyses.
2.5. Growth hormone deficit in adults:
At the beginning of somatropin treatment, it is recommended to administer low initial doses: 0.15-0.3 mg/day undercutaneous. The dose should then be adjusted progressively and controlled by the growth factor values (IGF-1). The recommended maintenance dose rarely exceeds 1.0 mg/day. In general, the lowest effective dose should be administered. In older or overweight patients, lower doses may be required.
3. Clinical interest
In the child, the growth hormone (growth hormone, GH) biosynthetic helps to correct the growth delay associated with a somatotrope deficit. It can also be useful to treat some children with a retardation of growth without a somatotrope deficit, in order to increase their growth rate (Turner syndrome, prepubère child with chronic kidney failure, child born small for gestational age).
In adults with a deep growth hormone deficiency, GH treatment may in some cases improve the quality of life and well-being of patients and lead to a change in body composition with an increase in lean mass.
3.1. In the child
3.1.1. Growth gap associated with a somatotrope deficit
Growth hormone deficiency may be secondary to an organic cause (pothalamo-hypophysary Smoking), irradiation (cranio-spinal or total body) or congenital. It is mostly idiopathic in current practice.
The formation of historical series shows that in the absence of substitute treatment by GH, the adult size of children with severe GH deficits would be between 130 and 150 cm in boys and between 130 and 140 cm in girls. These series are not representative of patients currently treated as the less profound deficits benefit from GH treatment.
In GH-treated children, clinical studies show a particularly net status catchup in the first year with a growth rate of 8 to 9 cm, reduced the following year. The follow-up of treated children confirms the continuation of a statusal gain in the third year, but catching up is generally no longer significant. For patients whose treatment began in the early 1990s, the average final size is 166 cm in the boy and 154 cm in the girl, bringing them closer to the average size observed in France. There are large inter-individual variations, so the assessment of the effect of treatment on the final size is delicate, especially in the moderate forms of deficit. However, patients with a deep and early deficit best respond to treatment.
Subcutaneous administration (SC) is preferable due to improved bioavailability and higher growth speed compared to intramuscular pathway (IM). In addition, the effect on growth is all the more marked as the frequency of injections is greater, which led to recommendations for the administration of SC 7 days a week.
Treatment is more effective in children with organic deficits than those with idiopathic deficits. Cranio-spinal irradiation is associated with the most unfavourable results.
The final size is higher when a gonadotrope deficit is associated with the somatotrope deficit and the two deficits are corrected, when the GH treatment was early and when the statusal delay was moderate.
3.1.2. Growth gap associated with Turner syndrome
Turner syndrome is characterized by an abnormal number and/or structure of X chromosome. Growth delay can be present from birth. It gradually increases to less than two standard deviations (- 2 DS) to 5-6 years and - 4 DS at the age of 12-13 years.
In the absence of any treatment, there is no peak of pubertal growth and growth extends beyond the usual age. The adult size is reached between 18 and 20 years; It is an average of 142 cm outside of any GH treatment.
The indication of exogenous GH treatment is based on the strengthening of the endogenous GH effect. In these children, a higher dose than in the treatment of GH deficit results in a significant increase in growth speed.
The increase in growth speed in the first year is between 2 and 5 cm for dosage 0.035 mg/kg/day but tends to decrease in the following years. The average final gain is from 4 to 9 cm compared to the projected size.
The GH is not alone involved in the statusrale growth; ovarian insufficiency of these patients also plays a role. Too early induction of puberty can cause GH to lose profit. However, the optimal age and therapeutic scheme of steroid replacement treatment remain controversial.
3.1.3. Growth gap associated with chronic kidney failure (CRI)
in the prepubious child
Chronic kidney failure (CRI) is defined by a reduced kidney function of at least 50% compared to normal. About half of the children with CRIs have an important statusal delay compared to children of the same age.
In GH-treated children a significant gain of status is observed in the first year, less net in the second year, as observed in other GH indications; there is little data on adult sizes after GH treatment.
The effect on growth seems less marked when children are dialysis. The therapeutic response is inversely correlated with the clearing of creatinine at the time of treatment. It was not evidence of significant acceleration of bone maturation.
3.1.4. Growth gap in children born small
for gestational age
Children born small for gestational age have a size below the reference numbers for a given gestation duration. The limit is less than 2 standard deviations (- 2 DS) of the reference curves.
Among these children, in most cases, post-natal growth is marked by an acceleration allowing them to control their delays from the end of the second year. However, 10-20% of them, according to the studies, maintain a statusal disability with a size below - 2DS compared to the average of the population.
In children who have not recovered their statusal delay at the age of 3, the constitution of a historical series has established that the adult sizes of untreated children whose size before puberty is < - 2.5 DS are very much below the normal area. The adult size is about 158 cm in the boy and 146 cm in the girl.
Uncertainties about the final size remain as there may be an acceleration of bone maturation during treatment and a slowdown of growth after its stop, leading to a loss of approximately 0.25 DS in the year following the stop, in a number of children.
It should be emphasized that in non-deficit children, the benefit of growth hormone treatment is not demonstrated in terms of improvement of the final size. In addition, there are uncertainties among these same children about the long-term tolerance of such treatment.
Given these uncertainties, the growth hormone is only refunded in this indication for children whose size at the time of treatment is less than or equal to - 3 DS. The Transparency Commission wishes to reassess growth hormones with a similar indication as soon as possible.
3.2. Somatotrope challenge in adults
Among the causes of somatotrope deficit in adults, tumoral pathologies occupy the first place. Hypophysary adenomas are the most common. Most Idiopathic Idiopathic deficits isolated in GH from childhood do not persist in adulthood. Normal growth hormone secretion is found in 70 to 80% of patients reassessed after puberty. In the event of antehypophysary insufficiency, even if it is correctly substituted on the thyreotrope, corticotrope and gonadotrope axes, symptoms attributed to the GH deficit not substituted persist.
The adult's somatotrope deficit leads to a change in body composition with an increase in fatty mass mainly at the abdominal level, a decrease in lean mass and muscular mass, increased fatigue and a decrease in bone density. Retrospective epidemiological studies show an increase in the incidence of cardiovascular disease mortality in patients with overall antehypophysal insufficiency despite the usual hormone replacement treatments. However, the real place of the somatotrop deficit in this decrease in life expectancy is not known.
Treatment by GH modifies the body composition with increase of lean mass and decrease of fat. This results in a reduction in the size/ hip ratio as well as the cutaneous fold. In addition, treated patients reported a subjective improvement in their physical capacity and strength to effort. The first days or weeks can be marked by a discreet weight gain and by the occurrence of malleolar edemas related to hydrosodized retention caused by GH treatment.
GH treatment seems to modestly improve the lipid profile. The evolution of blood glucose and insulinemia is very variable from one study to another. Currently available studies do not allow for an assessment of the effect of HG treatment with respect to atheronatal risk and the mortality of patients with HG deficits.
GH treatment for 12 months is moderately increasing bone mineral density. There are few studies assessing the effect of GH treatment on the incidence of fractures.
Long-term data on the efficacy and tolerance of growth hormone treatment are not available.
4. Terms of use
Treatment must be established in the hospital by specialists in paediatrics and/or endocrinology and metabolic diseases in specialized services in paediatrics and/or endocrinology and metabolic diseases.
Every year, the treatment interest must be reassessed to the hospital by these same specialists.
Renewal of the initial prescription to the same dosage is possible, in intermediate periods, by any doctor.
There are cases of non-responder patients, for which no predictive factors have been identified, both in children and adults.
To allow better patient follow-up, the change in GH is not recommended during the treatment, unless the hospital prescriptor who initiated the treatment the justified esteem.
The cessation of treatment is imperative in the event of the onset or evolution of a tumor process.
Specificity of the child:
GH treatment that does not improve the growth of patients whose epiphyses are welded, it is important to weigh well the decision to introduce treatment by sexual steroid hormones.
Compliance with updated legal records of the MMA is essential. Parents and/or families should be informed of the possible occurrence of certain adverse effects and patients subject to regular medical supervision.
4.1. Treatment
The authorized specialist must ensure that the patient meets the treatment criteria; the absence of contraindications must be verified; the prescribed specialty must possess the required indication.
4.1.1. In the child
4.1.1.1. Growth gap associated with a somatotrope deficit
Two conditions are necessary for the allocation of treatment:
- size - 2 DS according to French reference data;
- growth rate in the past year below normal for age (- 1 DS) or < 4 cm/year.
In addition, the diagnosis of the GH deficit must be duly proved by appropriate explorations. Since GH secretion is variable in the nycthemer, a single dose is insufficient to assert the GH deficit.
Two distinct stimulation tests shall be performed on different dates including at least one coupled: insulin/arginin, glucagon/propranolol, glucagon/betaxolol, clonidine/betaxolol. It is recommended to use, as a standard, a recombinant GH (1 mg = 3 IU). The results are expressed in mUI/l (or in μg/l). The whole data concludes that:
- a complete GH deficit: 2 tests < 10 mUI/l (3.3 μg/l);
- a possible partial deficit: peaks between 10 and 20 mUI/l (3.3 μg/l to 6.6 μg/l).
A single test having resulted in a response of GH ✱ 20 mUI/l (6.6 μg/l) must cause the diagnosis of somatotrope deficit to be removed.
In the case of a partial deficit associated with a 20 % overweight, the results of GH stimulation tests are falsely lowered and difficult to interpret. The diagnosis is based on the dose of IGF1: a normal result, even higher than normal, excludes the diagnosis of GH deficit associated with obesity and invites to practice a re-evaluation about 6 months after caloric restriction and weight loss.
In the case of a partial deficit associated with a small size of one or both parents, the GH treatment decision rests in addition to the size (- 2 DS) and the growth rate over the past year (< - 1 DS for age or < 4 cm/year), the bone age and the predicted size at adult age (lower to target size).
The search for a cause (MRI or hypophysal scanner) and associated hypophysal deficits is an important step in the process.
In case of leukemia or tumor history, it is strongly advised to wait for one year of remission before the start of treatment.
4.1.1.2. Growth gap associated with Turner syndrome
The diagnosis is based on the caryotype. This allows to define the number and/or structure anomalies of the X chromosome.
There is no lower age of treatment but the upper limit of treatment is a bone age of 12 years.
An estrogenic alternative treatment should be introduced lately to progressive dosage in order not to lose the profit induced by the GH.
4.1.1.3. Growth debt
associated with chronic kidney failure
When conservative treatment is not sufficient to maintain adequate growth speed for age, GH treatment can be indicated. The kidney function, determined by the measurement of creatinine clearance, shall be less than 60 ml/mn/1.73 m2 (normal 120 20 ml/mn/1.73 m2).
In order to confirm the growth delay, growth should have been followed for one year before starting the treatment.
The criteria for hormone treatment by the GH are:
- size - 2 DS according to French reference data;
- growth rate in the past year below normal for age (- 1 DS);
- chronological age 2 years;
- bone age < 11 years in the girl and < 13 years in the boy;
- lung signs absent or minimal.
Symptomatic treatment known as curative of chronic renal insufficiency (correction of dehydration and acidosis, prevention of kidney osteodystrophy and optimization of nutritional intakes) should have been introduced in advance (at least one year) and will be maintained throughout the duration of growth hormone treatment.
4.1.1.4. Growth gap in children born small
for gestational age
The decision to use growth hormone supplementation treatment should be taken with caution in children who are not carencil. The long-term effects of exposure to supraphysiological amounts of growth hormone are indeed very incompletely known. The pathological effects of excess growth hormone are well known in adults. The stimulation of IGF 1 production, cytokine capable of stimulating tumor growth, should not be neglected.
Other causes or treatments that may cause growth delays must be excluded before starting treatment.
The stimulation of growth in children can only be done before welding epiphyses.
The experience of a treatment start just before puberty in children born small for gestational age is limited. Therefore, it is not recommended to start treatment just before puberty.
The criteria for attribution of treatment by GH are:
- birth size below - 2 DS for gestational age;
- size at the time of processing - 3 DS for chronological age;
- children who have not recovered their growth retardation (growth rate < 0 DS in the last year) at the age of 4 years or older;
- adjusted parent size < - 1 DS.
4.1.2. In the adult
Growth hormone treatment should not be systematic in subjects with biological growth hormone deficit criteria.
There is no data to recommend initiation of GH treatment in adults over 60 years of age.
Explorations must be carried out only in patients with a disease that refers to a somatotrope deficit and which must be:
- a hypothalamo-hypophysary pathology operated or not;
- undergoes cerebrotic radiation therapy;
- had a somatotrope deficit in childhood.
It is not necessary to seek a somatotrope deficit in patients with a hypophysary microadenoma (size less than 1 cm in diameter) unless another antehypophysary deficiency (except the prolactin deficiency) is present.
Alternative treatment of other hormonal deficits has to be adapted and stable for three months. A plasma value of GH isolatedly low does not prove the somatotrope deficit.
The diagnosis of somatotrope deficit must be confirmed at adulthood. The necessary criterion is a GH peak less than 10 mUI/l (3.3 μg/l) during the growth hormone stimulation test by insulin hypoglycemia, apart from its contraindications.
The hypoglycemia test caused by intravenous injection of insulin with a blood glucose of 0.440 g/l (2.2 mmol/1) distinguishes the somatotrope deficit from the reduction of GH secretion that usually accompanies aging or obesity.
This test must be performed in endocrine services accustomed to its realization. It is contraindicated in patients with electrocardiographic signs or a history of ischemic and/or epilepsy heart disease. In these cases, another stimulation test will be used.
Further explorations may be required according to the patient's clinical characteristics.
4.1.2.1. Deficit somatotrope acquired during childhood
Somatotrope deficits isolated from childhood must be reassessed in a particular way. In these patients, the adult GH deficit is less likely. In these cases, two GH stimulation tests are necessary, namely the insulin hypoglycemia test and a second test (GHRH test, coupled test: GHRH-arginine, GHRH-ornithine, glucagon-betaxolol, glucagon-propranolol), except in the case of low IGF-1 levels (< - 2 DS).
4.1.2.2. Deficit somatotrope acquired at adulthood
Patients must have:
- a secondary somatotrope deficit to a hypothalamic or hypophysary pathology; and
- at least one other associated antehypophysary deficit (except the prolactin deficit) and correctly substituted (in this case only one GH stimulation test can suffice).
The treatment must be reserved for patients who have met the above criteria and have a marked deterioration in the quality of life as well as a modification of the body composition (absolute condition with an increase in the size/hanches ratio).
Before starting a GH alternative treatment, all hypophysal deficits must be properly substituted. This obvious attitude in case of thyreotrope deficiency (L-thyroxine) and corticotrope (hydrocortisone acetate) must also apply to the gonadotrope deficit (sexual steroids) in the absence of counter-indication.
The objective of the treatment is to obtain a maximum benefit by limiting the side effects. It is recommended to begin treatment with low dosages of the order from 0.15 to 0.30 mg/j in subcutaneous. The objective of the treatment is to obtain a normal insulin-like growth factor I (IGF1) concentration for sex and age.
At the beginning of the treatment, patients must be evaluated every 1 to 2 months, clinically and by an IGF1 dosage; the dose of GH should be adapted to the clinical tolerance and concentrations of IGF1. The effective minimum dose should be used. The introduction of treatment with low doses associated with gradual increase every 1 to 2 months reduces the occurrence of side effects. Depending on the results and tolerance, dosage can be increased within 3 to 6 months without exceeding the maximum doses of the MMA.
Patients should be informed of frequently occurring side effects: limb edema, arthralgia and myalgia, stiffness of ends, paresthesia. These symptoms are usually transient and dose-dependent. Posologies should be reduced in case of persistent symptoms.
In the event of a tumor process, in the absence of a precise diagnosis of tumor disease or if the tumor is clinically known to frequently recurrence, it is not advisable to introduce HG treatment. In other cases, before alternative treatment is introduced, the non-resumption of the evolutionary process should be ensured by a prior monitoring whose frequency is to be determined with oncologists and/or neurosurgeon through imaging (MRI).
4.2. Monitoring of treatment
4.2.1. In the child
4.2.1.1. General
Children treated by GH will be followed every 3 to 6 months in consultation with at least one clinical examination (size, weight, blood pressure, growth speed, pubertal signs...). The bone age will be determined every year, especially around the ages of puberty.
Due to the effect of growth hormone on the glucidic metabolism, patients must be monitored by dosage of the blood sugar to jeun every year.
A hypothyroidism can be revealed to the decoder of treatment; untreated, it can interfere with the response to GH treatment. An annual control of thyroid function (T4 free) must be carried out and, if necessary, substitute treatment will be introduced.
In case of corticotropic deficit, effective minimum doses of hydrocortisone must be used.
A concomitant treatment by glucocorticoids (prednisolone, high-dose inhaled corticosteroids, corticosteroid pommades) can inhibit the effect on the growth of GH treatment and is to be avoided to the extent possible.
In case of severe or repeated headaches, visual disorders, nausea and/or vomiting, it is recommended to make a background to look for a possible papillary edema and eliminate benign intracranial hypertension. This diagnosis can cause GH to stop the treatment.
The decision to continue the treatment must be taken on a case-by-case basis, depending on observance, tolerance to treatment and statusal catching.
In the child, transient skin reactions to the injection point are frequent.
Patients with endocrine disorders, including those related to a GH deficit, have an increased risk of epiphysiolysis. Any child with claudication or pain in the hip or knee, during growth hormone treatment, will be subject to appropriate clinical and radiological examination.
Dosage must be adapted every quarter depending on the child's weight or body surface.
4.2.1.2. Special cases according to indications
Growth gap associated with a somatotrop deficit:
When the somatotrope deficit is secondary to an intracranial lesion, radiological explorations (IRM) will be carried out regularly, in collaboration with oncologists and/or neurosurgeons, in order to detect a possible progression or relapse.
In patients with panhypopituitarism, the balance of associated substitute treatments should be monitored regularly.
The growth gain after the first year of treatment must have been at least 2 cm from the year before the treatment to conclude effectiveness. The following years, the growth rate must be at least equal to the mean for chronological age and/or for bone age and better than before treatment.
Growth gap associated with Turner syndrome:
Treatment is continued if the growth gain in the first year is at least 2 cm from the previous year. The following years, the growth speed must be:
4.5 cm/year up to 12 years;
3 cm/year when the bone age has reached or exceeded 12 years.
Growth gap associated with chronic kidney failure:
Although the decline in glomerular filtration does not appear to be altered by the GH, the kidney function must be monitored to detect excessive degradation. The growth gain after the first year of treatment must have been at least 2 cm from the year before the treatment. The following years, the growth rate must be at least equal to the average for age and better than before treatment. Initial dosage may be increased if necessary.
Growth rate among children born small for gestational age:
The administration scheme must be adapted to each patient;
The usual recommended dosage is 0.035 mg/kg body weight per day (1 mg/m2 of body surface per day) until the final size is reached.
The Transparency Commission will require a possible confirmation of its opinion favourable to the establishment of a study and its results: a systematic monitoring of the requirements will be carried out among patients treated by SAIZEN. The doctor will have to participate in the collection of data from the SERONO laboratory, in collaboration with the Transparency Commission, in the outpatient and hospital sectors.
4.2.2. In the adult
There is currently no validated criterion for assessing the effectiveness of adult treatment. Improvement is essentially subjective.
A follow-up of the requirements will be performed with patients newly treated by SAIZEN. The attending physician must participate in the collection of data set up by the SERONO laboratory, at the request of the Transparency Commission in the outpatient and hospital sectors.
Patients treated by the GH must have a clinical examination (weight, circumference-size/hanche, blood pressure) every 1 to 2 months until they get the best doses. When treatment is stabilized, 1 to 2 visits per year are sufficient.
An assessment of the quality of life and the parameters of body composition, comparing them to the data of the pre-treatment examination, makes it possible to determine the continuation of the treatment.
When the deficit is secondary to an intracranial injury, patients will need to be examined regularly (followed by MRI) in order to detect possible progression or recurrence. Any recurrence or progression of the tumor involves stopping the treatment.
Observance and results of the alternate treatment of associated antehypophysary deficits must be verified at least once a year.
The experience of long-term treatment by adult growth hormone is limited.
4.3. Termination of treatment
4.3.1. In the child
Growth gap associated with somatotrope deficit, associated with Turner syndrome:
Appearance or evolution of a tumoral process;
Growth speed under treatment less than 3 cm/year regardless of age;
Bone age:
15 years old or size 170 cm in the boy;
13 years old or size 160 cm in the girl.
These last two treatment cessation criteria can be discussed in case of severe growth hormone deficiency, if the genetic statusal potential is not reached.
Growth gap associated with chronic kidney failure:
Appearance or evolution of a tumoral process;
Growth speed under treatment less than 3 cm/year regardless of age;
Bone age:
15 years old or size 170 cm in the boy;
13 years old or size 160 cm in the girl.
These last two treatment cessation criteria can be discussed in case of severe growth hormone deficiency, if the genetic statusal potential is not reached.
Renal transplantation.
Growth rate among children born small for gestational age:
Appearance or evolution of a tumor process.
According to the RCP, the treatment should be interrupted:
- after the first year of treatment if the growth rate is less than + 1 DS;
- if growth speed is < 2 cm/year;
- and if the bone age is 14 (for girls) and 16 (for boys), corresponding to the welding of the epiphyses.
4.3.2. In the adult
There is no criterion for stopping GH treatment in adults. In studies, 12 to 35% of patients stop treatment after 12 months and 75% to 24 months. The need for daily subcutaneous injections is one of the main reasons for these treatment interruptions.
5. Conditions of use
These specialties are to be manipulated according to the strict conditions of asepsy.
SAIZEN must be reconstituted only with the solvent provided by the laboratory. The reconstituted solution should not be vigorously agitated because this can distort the active principle.
The 8 mg presentation offers a pharmaceutical advantage (conservation of lyophilisat at room temperature for transport).
Presentation 1.33 mg is administered using syringes; 8 mg CLICKEASY must be used with the ONE.CLICK or COOL-CLICK self-injector pen.
Conservation: maximum duration and special precautions:
You can see the table in the OJ
n° 184 of 10/08/2006 text number 19
6. Warning of prescriptors
Prescriptors should be cautioned that the benefit/risk ratio is only evaluated for the therapeutic indications retained by the MMA. The use of growth hormones in situations that have no justification in medical practice is not devoid of risks and raises ethical reserves.
The medical body must be aware of the risks associated with this misuse.
7. Economic and social specifications
7.1. Conditions of limitation and issuance
List I.
Annual initial hospital requirement for specialists in paediatrics and/or endocrinology and metabolic diseases in specialized services in paediatrics and/or endocrinology and metabolic diseases.
Renewal of the initial prescription to the same dosage (same dosage per kilogram or square metre for the child), in intermediate periods, possible by any doctor.
The pharmacist must ensure that the qualification of the prescriptor appearing on the initial hospital order is consistent; upon renewal of the prescription, it ensures that the hospital order is submitted for less than 1 year.
7.2. Care conditions
The prescription must be drafted on an exceptional drug order, in accordance with the therapeutic indications that are entitled to the refund mentioned in this form.
7.3. Cost of treatment
Growth hormones are very expensive medications that should only be used after individual estimates of the expected therapeutic benefit.
You can see the table in the OJ
n° 184 of 10/08/2006 text number 19
7.4. Similar drugs
You can see the table in the OJ
n° 184 of 10/08/2006 text number 19
AMM licensee and operator: SERONO France SA.
Any comments or requests for further information must be addressed to the High Health Authority, DEAPS, Drug Assessment Service, 2, Avenue du Stade-de-France, 93218 Saint-Denis-La Plaine Cedex.
Done in Paris, 11 July 2006.
For the Minister and by delegation:The Deputy Director
Financing
the care system,
J.-P. Vinquant
Deputy Director
Policy
health products,
H. Sainte Marie
