Key Benefits:
Minister of Health, Family and Persons with Disabilities,
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 January 24, 1997 to amend the list of repayable pharmaceutical specialties to social insured persons;
In view of the decision of 24 April 2002 to amend the list of repayable pharmaceutical specialties to social insured persons with regard to the GENOTONORM specialty;
After advice from the Transparency Commission,
After the advice of the High Medical Committee on Social Security,
Stop it!
The list of repayable pharmaceutical specialties to social insured persons is amended in accordance with the provisions contained in annex I.
In Appendix II, the therapeutic information sheet provided for in Article R. 163-2 of the Social Security Code is included.
The only therapeutic indications of GENOTONORM that are entitled to care or reimbursement are:
- retardation of growth due to somatotrope deficit or retardation of growth associated with Turner syndrome or chronic kidney failure;
- Prader-Willi syndrome (SPW) to improve growth and body composition. The diagnosis of SPW must be confirmed by the appropriate genetic test.
The provisions on GENOTONORM contained in the April 24, 2002 Order are repealed.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
(10 inscriptions)
The following specialties are listed on the list of reimbursable medicines to social insured persons, for which participation of the insured is provided in the first paragraph of article R. 322-1 of the Social Security Code.
These specialties are prescribed in accordance with the therapeutic information sheet in Appendix II.
You can see the table in the OJ
n° 256 of 01/11/2002 page 18145 to 18150
A N N E X E I
THERAPEUTICAL INFORMATION
MÉDICAMENT D'EXCEPTION
GENOTONORM
Growth hormones
GENOTONORM
GENOTONORM KABIVIAL 5.3 mg/1 ml, with preservative, powder and solvent for injectable cartridge solution (B/1).
GENOTONORM 5.3 mg/1 ml, 12 mg/1 ml, with preservative, powder and solvent for injectable cartridge solution (B/1).
GENOTONORM MiniQuick 0.2 mg/0.25 ml, 0.4 mg/0.25 ml, 0.6 mg/0.25 ml, 0.8 mg/0.25 ml, 1 mg/0.25 ml, 1.2 mg/0.25 ml, 1.4 mg/0.25 ml, 1.6 mg/0.25 ml, 1.8 mg/0.25 ml, 2 mg/0.25 ml, powder and solvent
Opinion of the High Medical Committee on Social Security
(Art. R. 163-2, 3rd paragraph, of the Social Security Code)
GENOTONORM, a biosynthetic human growth hormone, is a restricted prescription drug whose treatment conditions fall under the exceptional medication procedure.
Reimbursable therapeutic indications
In the child:
- retardation of growth due to somatotrope deficit or retardation of growth associated with Turner syndrome or chronic kidney failure;
- Prader-Willi syndrome (SPW) to improve growth and body composition.
The diagnosis of SPW must be confirmed by the appropriate genetic test.
Terms of use
Treatment must be established in the hospital by specialists in paediatrics and/or endocrinology and metabolic diseases in specialized services in pediatrics and/or endrocrinology 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.
To allow better patient follow-up, the change of growth hormone is not recommended during 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.
Growth hormone treatment does not improve the growth of patients whose epiphyses are welded, hence the interest of weighing well the introduction of sexual steroid hormone treatment.
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.
The "exceptional drugs" procedure includes the drafting of the prescription, in all cases, on a special order certifying compliance with the indications of the therapeutic information form. Conditions that are entitled to the care of GENOTONORM are long-term illnesses within the meaning of Article L. 324-1 of the Social Security Code, i.e., requiring continuous care of more than six months and are subject to the joint examination procedure between the attending physician and the consulting physician.
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GENOTONORM (somatropine) is a biosynthetic growth hormone produced by a strain of Escherichia coli that 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.
1. Reimbursable therapeutic indications
Growth gap associated with somatotrope deficit or growth retardation associated with Turner syndrome or chronic kidney failure.
Prader-Willi syndrome (SPW) to improve growth and body composition. The diagnosis of SPW must be confirmed by an appropriate genetic test.
2. Dosage and mode of administration
The dosage and the administration pattern must be adapted to each patient.
In general, it is recommended to administer the medication undercutaneous at night. The injection point will have to vary to avoid the appearance of lipoatrophies.
2.1. Growth debt associated with a deficit
somatotrope in the child
The recommended dosage is 0.025 to 0.035 mg/kg body weight per day or 0.7 to 1.0 mg/m2 of body surface per day. Higher doses can be used.
2.2. Growth gap associated with Turner syndrome
The recommended dosage is 0.045 to 0.050 mg/kg per day, or 1.4 mg/m2 of body surface per day.
2.3. Growth debt
associated with chronic kidney failure
The recommended dosage is 0.045 to 0.050 mg/kg body weight per day or 1.4 mg/m2 of body surface per day. Higher doses can be used if growth speed is too low. Adjustment of dosage may be required after six months of treatment.
2.4. Growth gap associated with Prader-Willi syndrome
In general, recommended dosage is 0.035 mg/kg body weight per day, 1 mg/m2 of body surface per day. The daily dose should not exceed 2.7 mg.
You can see the table in the OJ
n° 256 of 01/11/2002 page 18145 to 18150
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, child with chronic kidney failure) or improve their body composition (Prader-Willi syndrome).
3.1. Growth gap associated with a somatotrope deficit
Growth hormone deficiency may be secondary to an organic cause (pothalamo-hypophysary Smoking), irradiation (craniospinal 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. Craniospinal 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.
3.2. 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 eighteen and twenty 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 a dosage of 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.
3.3. Deficit of growth
chronic kidney (CRI) in children
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, significant status gains are 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.
3.4. Growth gap associated with Prader-Willi syndrome
Prader-Willi syndrome is a rare genetic disease (1/10 000 to 1/25,000 births) characterized in infants by hypotony and food difficulties, quickly replaced in children and adults by a massive obesity with bulimia. Other manifestations include more or less characteristic dysmorphic elements and a mental retardation of variable severity. Most children are small. They have abnormalities of the body composition (increasing fat, decreasing lean mass) more marked than in the common obesity where the lean mass is relatively preserved.
The benefit of growth hormone treatment in these patients is moderate. It concerns the size gain, and a modification of the body composition by increasing the lean mass and decreasing the fat mass.
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.
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.
GH treatment does not improve the growth of patients whose epiphyses are welded, hence the interest of well weighing the introduction of treatment by sexual steroid hormone.
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 child meets the treatment criteria; the absence of contraindications must be verified; the prescribed specialty must possess the required indication.
4.1.1. 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 speed 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/arginine, glucagon/propranolol, glucagon/betaxolol, clonidine/betaxolol. It is recommended to use, as a standard, a recombinant GH (1 mg = 3UI). 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 from GH ✱ 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 IGF 1: a normal or higher result than normal excludes the diagnosis of GH deficit associated with obesity and invites to practice re-evaluation about six 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.
4.1.2. 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.
4.1.3. 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/1.73m2 (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;
Speed of growth in the past year below normal for age (- 1 DS);
Chronological age 2 years;
Bone age < 13 in the girl and < 14 in the boy ;
Prepubious child or early puberty (tipcular volume less than 10 ml or breast development stage S3).
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.
4.1.4. Growth gap associated with Prader-Willi syndrome
The diagnosis of Prader-Willi syndrome is difficult to clinically assert. That's why a genetic test must be performed. Several confirmation tests exist:
- either the methylation analysis of the PWS locus by PCR or Southern blot (currently recommended as a first-line test with excellent sensitivity and specificity);
- either the search for microdeletion of the region 15(q11-13) in molecular cytogenetics (in situ hybridization, sensitivity of the order of 70%);
- the demonstration of a maternal uniparental disomie in Region 15(q11-13) (sensitivity of the order of 30%).
The completion of one of these tests with an abnormality is sufficient to confirm the diagnosis.
In the absence of patient data over 12 years of age and long-term tolerance information, it is recommended that GENOTONORM be limited to children under 12 years of age with Prader-Willi syndrome confirmed by appropriate genetic testing.
4.2. Monitoring of treatment
4.2.1. General
Children treated by GH will be followed every three to six 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 glucocorticoid (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.
The dosage must be adapted according to the weight or body surface of the child.
4.2.2. Special cases according to indications
Growth gap associated with a somatotrope 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 gap associated with Prader-Willi syndrome
Special monitoring should include:
- glucidic tolerance, due to the risk of non-insulin-dependent diabetes in this condition;
- examination of the skeleton due to the possible appearance or aggravation of scoliosis in this indication.
In addition, the profit analysis will need to focus on both growth and body composition that is recommended to follow through appropriate reviews.
The clinical trial data focused on the need for comprehensive, dietary care, in particular, of affection. Insulated use of GH treatment is not effective. Indeed, the medical service rendered by the GH in this pathology is moderate with an average efficacy/adverse effect ratio.
4.3. Termination of treatment
In cases of a somatotrope deficit
or 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 GH deficit, if the genetic statusal potential is not reached.
Delays in growth due to lack of
Chronic kidney
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.
Renal transplantation.
In Prader-Willi syndrome
Appearance or evolution of a tumoral process;
After the age of 14 or a growth rate 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.
5. Conditions of use
These specialties are to be manipulated according to the strict conditions of asepsy.
GENOTONORM should be reconstituted only with the solvent supplied by the laboratory. The reconstituted solution should not be vigorously agitated because this can distort the active principle.
Conservation: maximum duration and special precautions.
You can see the table in the OJ
n° 256 of 01/11/2002 page 18145 to 18150
These presentations, with the exception of GENOTONORM MINIQUICK presentations, are added to a preservative, meta-resol, which could lead to rare allergic reactions and pain at the injection point.
GENOTONORM MINIQUICK and GENOTONORM KABIVIAL 5.3 mg/1 ml are administered using syringes; GENOTONORM 5.3mg/1 ml and 12 mg /1 ml shall be used with the replenishment and injection device provided for each dosage.
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 reserved 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 (even dosage per kg or m2 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 less than one year.
7.2. Care conditions
Refund rate: 100%.
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° 256 of 01/11/2002 page 18145 to 18150
7.4. Similar drugs
You can see the table in the OJ
n° 256 of 01/11/2002 page 18145 to 18150
AMM licensee and operator: PHARMACIA SA
Any comments or requests for further information must be addressed
at AFSSAPS-DEMEIS, 143-147, boulevard Anatole-France, 93285 Saint-Denis Cedex.
Done in Paris, October 21, 2002.
For the Minister and by delegation:
Social Security:
Deputy Director
Financing
the care system,
S. Seiller
By preventing
Director General of Health:
Deputy Director
Policy
health products,
H. Sainte Marie
