Rastan®
Treatment with somatropin should be carried out by physicians experienced in the diagnosis and treatment of patients with GH deficiency or Shereshevsky-Turner syndrome.
The maximum recommended daily dose should not be exceeded (see section "Dosage and Administration").
Stimulation of longitudinal growth can be carried out in children before the closure of the epiphyseal growth plates.
Growth hormone deficiency in adults persists throughout life and requires appropriate treatment, but there are currently no results from long-term therapy in adults.
Shereshevsky-Turner syndrome
In patients with Shereshevsky-Turner syndrome, during treatment with somatropin, it is recommended to monitor the proportional growth of the upper and lower extremities, and if increased growth is detected, the dose of the drug should be reduced to the lower limit of the dose range.
Girls with Shereshevsky-Turner syndrome usually have an increased risk of developing otitis media, and therefore should be monitored by an otolaryngologist.
Chronic renal failure Growth impairment in children with chronic renal failure should be accurately established before starting treatment with somatropin by monitoring growth against the background of optimal treatment for chronic renal failure for one year. During somatropin therapy, conservative treatment of chronic renal failure with traditional medications and, if necessary, dialysis should be continued. Somatropin therapy should be discontinued during kidney transplantation.
Pouder-Willi syndrome There have been reports of deaths in children with PWS with GH deficiency who were treated with somatropin and had at least one of the following risk factors: severe obesity, a history of respiratory failure, sleep apnea, or an unidentified respiratory tract infection.
A possible risk factor may be the male gender of the patient.
Patients with PWS with one or more of these factors are at high risk when using somatropin.
Before prescribing somatropin to patients with GH deficiency in combination with PWV, the potential risk-benefit ratio should be considered.
In patients with PWS, treatment with somatropin must necessarily be associated with a calorie-restricted diet. Patients with PWS should actively monitor their body weight both before and during somatropin use.
Tumors
Patients with a history of malignant neoplasms should be carefully examined for recurrence. If malignancy occurs or recurs, somatropin therapy should be discontinued.
Patients with GH deficiency secondary to the presence of brain tumors should undergo more frequent examinations to exclude progression and relapse of the underlying disease.
Somatropin should not be prescribed if any signs of active tumor growth are detected. Before prescribing somatropin, the tumor process must be in an inactive phase and antitumor therapy must be completed. If signs of tumor regrowth appear, administration of the drug should be stopped.
The development of secondary benign and malignant neoplasms has been reported in patients with childhood cancer and receiving somatropin therapy. The most common complication was the development of intracranial tumors, in particular meningioma, in patients who had previously received radiotherapy to the head for primary tumors. However, recurrence of primary tumors has not been reported in this category of patients.
Leukemia
Leukemia has been reported in children treated with somatropin. The relationship between the occurrence of leukemia and somatropin therapy has not been established.
Benign intracranial hypertension
If severe or recurrent headaches, blurred vision, nausea and/or vomiting occur, fundoscopy is recommended to identify possible papilledema. When the diagnosis is confirmed, the presence of benign intracranial hypertension should be assessed and, if the diagnosis is confirmed, somatropin therapy should be discontinued.
To date, there are no clear guidelines for the use of growth hormone in patients with corrected intracranial hypertension. However, clinical experience suggests that resumption of somatropin treatment in many cases does not lead to relapse of intracranial hypertension. If the use of somatropin is resumed, careful monitoring is necessary for the possible appearance of symptoms of intracranial hypertension.
Epiphysiolysis
In patients with endocrine disorders, including GH deficiency, epiphysiolysis of the heads of long bones may be more common. A thorough examination is necessary if the child develops lameness during treatment.
Hypopituitarism
Patients with hypopituitarism (deficiency of several pituitary hormones) in the case of standard hormone replacement therapy with the introduction of somatropin should be under strict supervision.
Thyroid function
When treated with somatropin, increased conversion of thyroxine (T4) to triiodothyronine (T3) was detected, which may cause a decrease in the concentration of T4 and an increase in the concentration of T3 in the blood plasma.
In healthy volunteers, as a rule, the concentrations of thyroid hormones in the blood plasma remained within normal limits. The effect of somatropin on thyroid hormone concentrations may be of clinical significance in patients with central subclinical hypothyroidism who may potentially develop hypothyroidism. On the other hand, patients receiving thyroxine as hormone replacement therapy may develop hyperthyroidism. Based on this, it is recommended to monitor thyroid function after starting somatropin therapy, as well as whenever its dose is changed. Lack of adequate treatment for hypothyroidism may prevent optimal results from somatropin treatment.
Formation of antibodies to somatropin
The formation of antibodies to somatropin is possible. A study of the titer of antibodies to somatropin should be carried out in cases where the patient does not respond to therapy.
Insulin sensitivity
Somatropin reduces insulin sensitivity, especially in large doses in patients with high sensitivity, which can cause the development of hyperglycemia in patients with inadequate insulin secretion.
Thus, previously undiagnosed impaired glucose tolerance and diabetes mellitus may be detected.
In all patients receiving somatropin, periodic monitoring of glucose concentrations is necessary, especially in patients at high risk of developing diabetes mellitus: in patients with obesity, Turner syndrome, a family history of diabetes mellitus, when taking corticosteroids or a pre-existing impairment of glucose tolerance. During treatment with somatropin, more careful monitoring is required in patients diagnosed with type 1 or 2 diabetes mellitus or with impaired glucose tolerance (see section "Interaction with other drugs"). In such patients, the need for dose adjustment of hypoglycemic drugs should be assessed when prescribing somatropin.
Scoliosis
Some children during periods of excessively rapid growth (especially children with PWS) may experience progression of scoliosis. During the entire period of treatment with somatropin, monitoring should be carried out to identify signs of scoliosis. However, available evidence suggests that somatropin therapy does not affect the incidence or severity of scoliosis.
Pancreatitis
Compared with adults, pediatric patients receiving somatropin therapy may have an increased risk of developing pancreatitis. Despite the rarity of this complication, increased attention should be paid to pediatric patients with abdominal pain.
Obesity
Obese patients are more likely to experience adverse events when administered doses based on body weight.
Hyperestrogenism in women
Women with hyperestrogenism or women taking oral estrogens may need higher doses of somatropin than men.
Elderly age
Elderly patients may be more sensitive to the effects of somatropin and, therefore, the likelihood of developing side effects increases. Therefore, it is advisable to use a lower initial dose and a slower increase in the dose of the drug.
There is no experience in treating patients over 60 years of age with somatropin.
Urgent conditions
Safety of continued somatropin therapy in patients with severe illness associated with complications from open cardiac or abdominal surgery, multiple accident-related injuries, and patients with acute respiratory failure receiving replacement therapy for registered indications who are in the process of therapy the above-mentioned diseases appeared, not established. Therefore, the balance of potential risks and benefits of continuing somatropin therapy in patients in an urgent state must be carefully assessed.
Rastan
IM, with short stature due to inadequate endogenous secretion of growth hormone - 12 IU/sq.m/week or 0.6 IU/kg/week; if ineffective, the dose is increased to 20 IU/sq.m/week or to 0.8 IU/kg/week. The weekly dose should be divided into 3-6 injections (4 IU/sq.m or 0.2 IU/kg). Injections should be given in the evenings.
For insufficient growth in patients with gonadal dysgenesis (Turner syndrome) - 18 IU/sq.m/week or 0.6-0.7 IU/kg/week. In the second year of treatment, doses can be increased to 24 IU/sq.m/week or 0.8-1 IU/kg/week. The weekly dose of the drug should be divided into 7 single subcutaneous injections of 2.6 IU/sq.m or 0.09-0.1 IU/kg.
In some cases, when treating patients with Turner syndrome, it may be necessary to increase doses already in the first year of treatment. Treatment is stopped when the patient reaches a height sufficient for an adult, or when the epiphyses of the tubular bones close.
To prepare the solution, use the supplied NaCl solution; For injection, the strictly required amount of the drug is taken, the remaining solution is thrown away. After adding the solvent, you must carefully rotate the vial without shaking until the contents are completely dissolved. The resulting solution should be transparent. If the solution is cloudy or contains particles of undissolved drug, it should not be used for injection.
Norditropin penset: for growth hormone deficiency - subcutaneously, 0.07-0.1 IU/kg or 2-3 IU/sq.m 6-7 times a week. For Shereshevsky-Turner syndrome - subcutaneous, 0.14 IU/kg or 4.3 IU/sq.m 6-7 times a week. For chronic renal failure in children accompanied by growth retardation - subcutaneously, 0.14 IU/kg or 4.3 IU/sq.m 7 times a week. The dry substance is dissolved with the supplied solvent.
Genotropin: recommended dose - subcutaneous injection, 0.5-0.7 IU/kg or 12-16 IU/sq.m per week. For Shereshevsky-Turner syndrome - 1 IU/kg or 30 IU/sq.m/week. For chronic renal failure in children accompanied by growth retardation - 1 IU/kg or 30 IU/sq.m/week. After 6 months of therapy, it is necessary to adjust the dose. Adults with severe growth hormone deficiency - 0.125-0.25 IU/kg per week. The dose is selected depending on the effectiveness, adverse reactions, and the concentration of insulin-like growth factor in the blood serum. Elderly patients are prescribed lower doses.
Biosome: for growth hormone deficiency in children - 0.6-0.7 IU/kg or 18 IU/sq.m of body surface per week. For patients receiving the drug for a long time, as well as for children during puberty - 1 IU/kg per week. For Shereshevsky-Turner syndrome - up to 1 IU/kg or 30 IU/sq.m per week. The recommended dose is divided into 6-7 injections and administered subcutaneously in the evening. Better results are observed when treatment is prescribed at an earlier age. Treatment is continued until puberty or until the bone growth zones close. It is possible to stop treatment when the desired height is achieved. The drug is dissolved in the supplied solvent containing 0.9% benzyl alcohol: 4 IU in 1.1 ml, 8 IU in 2.1 ml. The volume of solvent drawn into the syringe is injected into the bottle, directing a stream of liquid to the wall of the vessel and without affecting the drug. Shake the bottle with gentle circular movements (do not shake!) until the drug is completely dissolved. Do not use a solution that is cloudy or contains undissolved particles.
Humatrop: for growth hormone deficiency - 0.18 mg/kg or 0.54 IU/kg per week. The dose is divided into equal parts and administered for 3 or 6 days a week intramuscularly or subcutaneously. The maximum dose for replacement therapy is 0.1 mg/kg or 0.3 IU/kg 3 times a week. For Shereshevsky-Turner syndrome - subcutaneously, 0.3-0.34 mg/kg or 0.9-1 IU/kg (24-28 IU/sq.m) per week. The weekly dose is divided into 6-7 injections, preferably at night.
Zomacton: the dose is set individually. The recommended dose is 0.5-0.7 IU/kg or 14.8-20.7 IU/sq.m per week. The weekly dose is divided into 6-7 subcutaneous injections. The maximum dose is 0.81 IU/kg or 24 IU/sq.m per week. Treatment is continued for several years.
Treatment of cachexia due to AIDS: patients weighing more than 55 kg - subcutaneously, 18 IU (6 mg) at bedtime, 45-55 kg - 15 IU (5 mg), 35-44 kg - 12 IU (4 mg) , less than 35 kg - 0.1 mg/kg/day.
drug: SC slowly, 1 time per day (usually at night). With insufficient secretion of growth hormone in children - 25-35 mcg/kg/day (0.07-0.1 IU/kg/day), which corresponds to 0.7-1 mg/sq.m/day (2-3 IU/sq.m/day ). For Shereshevsky-Turner syndrome, for chronic renal failure in children, accompanied by growth retardation - 50 mcg/kg/day (0.14 IU/kg), which corresponds to 1.4 mg/sq.m/day (4.3 IU/sq.m/day). If growth dynamics are insufficient, the dose is adjusted. For growth hormone deficiency in adults, the initial dose is 0.15-0.3 mg/day (0.45-0.9 IU/day), followed by an increase depending on the effectiveness. When selecting a dose, insulin-like growth factor type 1 (IGF-1) in the blood serum can be used as a control indicator. The maintenance dose is selected individually, but should not exceed 1 mg/day (3 IU/day). In the elderly, lower doses are recommended.
Shereshevsky-Turner syndrome (STS) is a chromosomal disease based on complete or partial X-monosomy, present in all cells or in a mosaic version. The main clinical signs of STS include anomalies of physical development, short stature and sexual infantilism [1-3].
Growth impairment is observed in 95% of cases of STS and is manifested by reduced weight and height indicators at birth, low growth rates and the absence of a growth spurt in adolescence [4–6]. The average final height in STS varies in different populations from 140 to 147 cm [5, 7].
Short stature often becomes a serious psychological problem and a cause of social maladjustment [8]. The development of a genetic engineering method for producing recombinant growth hormone (r-GH) has made a real revolution in the treatment of children with various types of short stature. It became possible, in particular, to increase the growth rate in children with STS and thereby significantly improve the growth prognosis.
The purpose of this work was to evaluate the effectiveness and safety of a two-year treatment of girls with STS with the domestic genetically engineered growth hormone drug (somatotropin) Rastan.
Material and methods
29 girls with a karyotyping-confirmed diagnosis of TTS were under observation.
Chronological age at diagnosis was 7.9±1.2 years (0÷13.1 years), at the time of initiation of therapy - 9.8±1.6 years (5.0÷15.1 years). Bone age corresponded to 7.5±1.1 years (4÷11 years).
Patient height was measured using a mechanical Harpender stadiometer (Holstan Ltd, Crymych, Dyfed, UK) to the nearest 0.1 cm. Body weight was measured using an electronic floor scale. Growth indicators were assessed in SDS.
The SDS of height and growth velocity for children with STS was calculated twice: using percentile tables for healthy children [9] and for children with STS [10]. The stage of sexual development was determined according to the classification of J. Tanner [11]. The degree of differentiation of the bone skeleton was assessed according to the standards developed by W. Greulich, S. Pule [12].
All examined patients received r-GH Rastan (Pharmstandard-UfaVITA OJSC) as a growth-stimulating therapy in the form of a lyophilisate of 1.33 mg to prepare a solution for subcutaneous administration. The strain and technology for producing somatotropin were developed at the Institute of Bioorganic Chemistry of the Russian Academy of Sciences under the leadership of Academician of the Russian Academy of Sciences A.I. Miroshnikova. r-GH was prescribed at a dose of 0.05 mg/kg body weight daily subcutaneously in the evening (20.00-22.00 hours). The duration of treatment was 24 months.
Growth dynamics, SDS growth, annual growth rate and SDS growth rate during the therapy period were used as criteria for assessing the effectiveness of the drug.
Statistical processing of the obtained data was carried out on a personal computer using Statistica for Windows, version 5.5 and Microsoft Excel (2002). Data are presented as mean ± standard deviation (min÷max). Differences were considered statistically significant at p<0.05.
results
Impaired growth and physical development were identified in all patients with STS. The mean height SDS compared to the healthy population was –3.0±1.1, and the mean height SDS calculated for patients with STS was –0.99±0.8. The characteristics of patients with STS are presented in Table. 1.
The average SDS value of parental height was 0.3±0.1 and did not differ from that in the healthy population.
Among the concomitant diseases, 9 girls had scoliosis, 12 had pathology of the cardiovascular system, and 8 had kidney pathology. However, the severity of these conditions was unlikely to significantly influence growth.
The average level of fasting blood plasma glucose was 4.5±0.6 mmol/l, the average level of glycated hemoglobin HbA1c was 5.4%, which was not outside the normal range.
The first Tanner stage of puberty was registered in 27 girls, and the second stage in 2 patients. When assessing the condition and function of the thyroid gland, autoimmune thyroiditis with a decrease in thyroid function was detected in 2 girls, for which therapy with levothyroxine sodium was prescribed, the dose of which varied from 50 to 100 mcg and was adjusted depending on the concentration of TSH and free thyroxine in the blood serum. Before starting r-GH therapy, only one girl received replacement therapy with microfollin (at a dose of 1/8 tablet per day). Another girl showed spontaneous sexual development (Tanner stage of mammary gland development B2) at the age of 12 years after 6 months of treatment with r-GH. The results of treatment with r-GH in patients with STS are presented in Table. 2.
Before the start of r-GH treatment, the height of girls with STS increased by an average of 4.2±0.6 cm/year. The average growth rate in the first year of treatment was 8.7±0.6 cm/year, in the second year of treatment - 6.2±1.2 cm/year. Over 2 years of r-GH therapy, girls gained an average of 14.9 cm in height.
The increase in height SDS was significant after 12 months (p=0.002) and 24 months (p=0.003) of r-GH treatment. In just 2 years, girls' height increased on average by 0.84 SD.
SDS growth rates also significantly increased after 12 months (p=0.001) and 24 months (p=0.004) of r-GH treatment.
Over 2 years of therapy, glycemic levels did not go beyond the normal range; the average HbA1c level in patients with STS after 2 years of treatment with r-GH was 5.8%.
Discussion
Short stature is a characteristic feature of TTS and is formed as a result of reduced growth rates in childhood and adolescence [7]. The results of numerous studies [4, 6] conducted in many countries indicate that girls with TTS who did not receive any growth-promoting therapy have a final body height that is 20 cm lower than the population average for girls.
In recent decades, it has been proven that the leading role in the pathogenesis of short stature in STS is played by direct genetic disorders caused by deletion of the SHOX gene located on the X chromosome [13], leading to disruption of the spontaneous secretion of growth hormone (GH), insensitivity to GH and disturbances in the system GH/insulin-like growth factor type 1.
The growth retardation of the 29 girls with STS we examined was significant. However, when compared with the population of girls with STS, it turned out that the growth retardation in these girls is slightly greater than the average typical for the standards of this syndrome (SDS 0.99 ± 0.37).
Currently, the most effective treatment for short stature in patients with STS are r-GH drugs prescribed for a long period. In many countries, research programs are exploring the potential of r-GH (alone or in combination with sex hormones) for the treatment of patients with TS with the aim of accelerating growth in childhood and increasing final height [14–16].
Treatment with r-GH in childhood in girls with STS is not replacement, but may have a positive effect [17].
It is generally accepted to treat patients with STS with r-GH at a dose of 0.375 mg/kg/week or 0.05 mg/kg/day, which is 50% higher than the standard dose used in children with somatotropic insufficiency.
Our treatment of girls with STS with r-GH at a dose of 0.05 mg/kg/day undoubtedly gave positive results. If before treatment girls grew on average about 4 cm per year, then during therapy in the 1st year the patients gained an average of 8.7 cm (+0.5 SD), in the second year 6.0 cm (+0 .34 SD).
Other studies that examined the dependence of the growth effect on the dose of r-GH confirmed the greater effectiveness of high doses. There are reports of a significant increase in height (10.6 cm) in 12 girls with STS who were treated with r-GH using a stepwise dose-increasing regimen. This regimen involved the use of r-GH at an initial dose of 0.7 units/kg/week, increasing to 1.4 units/kg/week, and then to 2.1 units/kg/week every 6 months, which made it possible to constantly maintain growth rate, 2 times higher than that before the start of therapy. At the same time, the increase in height in 17 girls with TTS who received a fixed standard dose of 0.9 units/kg/week was only 5.2 cm.
According to the results of one of the long-term studies (Dutch study), in which r-GH in doses of 0.045, 0.067 and 0.089 mg/kg/day was administered daily for 7 years, it was shown that the highest doses and the longest treatment led to an increase in final height from 159.1, 161.8 and 167.2 cm, respectively, and the maximum doses of r-GH provided the most pronounced increase in height (16 cm versus 12.5 cm) [18].
The final height gain, defined as the difference between the final height and that predicted before the start of therapy, after treatment with doses of r-GH (0.05 mg/kg/day) varied among different authors from 3.1 to 21.4 cm [15, 19— 27]. It should be noted that an important characteristic feature of all these studies was significant individual fluctuations in the final growth achieved. In our study, girls gained an average of 14.7 cm in height over 2 years of r-GH therapy, which corresponds to 0.84 SD, but no one has yet achieved final height. In earlier studies conducted at the ERC (N.N. Volevodz, 2005), the final height of patients with STS who received r-GH treatment did not reach a socially acceptable level, and the height of 3 patients who completed treatment was only 139.1. 140.5 and 144.9 cm [1]. This circumstance was associated with late administration of r-GH (on average 12 years) and a short period of treatment (on average 12 months), which did not allow them to achieve socially acceptable height.
Similar data were obtained from the National Cooperative Growth Study (NCGS). It states that the peak age for r-GH prescription is between 10 and 12 years of age. Thus, treatment started belatedly does not allow, unfortunately, r-GH to fully demonstrate its therapeutic effect and help the majority of these children achieve a height of 150 cm [17].
Currently, there are results of the use of r-GH in young children with STS. M. Davenport et al. [28] observed 88 girls with STS aged from 9 months to 4 years, of whom 45 received r-GH treatment at a dose of 0.05 mg/kg/day for 2 years, and 43 were in the control group and did not receive therapy . The children's height at the start of treatment was –1.4 and –1.8 SDS, respectively. By the end of the 2nd year of observation, growth rates in the treatment group corresponded to –0.3 SDS (+1.1 SDS), and in the control group –2.2 SDS (–0.5 SDS). Consequently, girls who did not receive r-GH treatment had worse growth indicators after 2 years, while the height deficit in girls with treatment decreased.
Thus, the results of numerous studies [29, 30] and multiple regression analyzes have shown that growth rate in the 1st year of therapy is considered an important prognostic indicator of the effectiveness of treatment in girls with STS. In addition, factors that positively influence the results of r-GH therapy include the dose and frequency of injections, the time of pubertal induction and the dose of estrogens used. The dependence of the degree of increase in final height on the duration of treatment was revealed.
When assessing the safety of therapy with r-GH Rastan, we did not note a single case of serious adverse events that would lead to discontinuation of the drug, as well as unexpected ones not typical for somatotropin. Currently, many publications raise concerns that treatment with r-GH may increase the risk of developing a number of complications inherent in STS, such as impaired carbohydrate tolerance, osteoarticular changes, dyslipidemia and cardiovascular diseases. Data from the KIGS study confirm that STS has a higher incidence of side effects than idiopathic GH deficiency (148 per 1000 years of treatment compared with 89/1000 years of treatment). In STS, diabetes mellitus types 1 and 2, scoliosis and epiphysiolysis of the femur were more often detected, and in terms of the frequency of headaches and intracranial hypertension, patients with STS were second only to patients with craniopharyngioma. However, all these complications themselves are characteristic of STS, and can partly be considered as concomitant diseases.
conclusions
1. Treatment of girls with TTS with the genetically engineered somatotropin drug Rastan allows one to achieve an increase in growth rates. During the 1st year of treatment, the increase in height was 8.7 cm, in the 2nd year - 6.0 cm (the average increase over 2 years of treatment was 14.7 cm).
2. During the study period of use of the drug r-GH Rastan, no adverse events were registered, which indicates its safety in childhood.
