should not be used for growth promotion in pediatric patients with closed epiphyses.
should not be used in patients with severe generalized infections who are in acute shocks.
is contraindicated in patients with a known hypersensitivity to growth hormone or any of its excipients.
is contraindicated in patients with presence of active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with growth hormone. Should be discontinued if there is evidence of recurrent activity.
Since growth hormone deficiency may be an early sign of the presence of a pituitary tumor (or, rarely, other brain tumors), the presence of such tumors should be ruled out prior to initiation of treatment.
Should not be used in patients with any evidence of progression or
recurrence of an underlying intracranial tumor.
Is contraindicated in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma.
Is contraindicated in patients with acute respiratory failure.
Is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.
should not be used in patients with severe generalized infections who are in acute shocks.
is contraindicated in patients with a known hypersensitivity to growth hormone or any of its excipients.
is contraindicated in patients with presence of active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with growth hormone. Should be discontinued if there is evidence of recurrent activity.
Since growth hormone deficiency may be an early sign of the presence of a pituitary tumor (or, rarely, other brain tumors), the presence of such tumors should be ruled out prior to initiation of treatment.
Should not be used in patients with any evidence of progression or
recurrence of an underlying intracranial tumor.
Is contraindicated in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma.
Is contraindicated in patients with acute respiratory failure.
Is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.
Diagnosis and therapy with should be initiated and monitored by physicians who are appropriately qualified and experienced in the diagnosis and management of patients with the therapeutic indication of use.
Myositis is a very rare adverse event that may be related to the preservative metacresol. In the case of myalgia or disproportionate pain at injection site, myositis should be considered and if confirmed, a presentation without metacresol should be used.
The maximum recommended daily dose should not be exceeded.
The treatment of short bowel syndrome in adult patients should be instructed by physicians who are experienced in diagnosing and managing adult short bowel syndrome patients.
Insulin sensitivity
Glucose intolerance and diabetes mellitus: Glucose levels should be monitored periodically in all patients treated with growth hormone, especially in those with risk factors for diabetes mellitus, such as obesity, Turner syndrome (for pediatric patients with Turner syndrome, it is recommended that fasting insulin and glucose shall be measured before starting treatment and annually after starting treatment) or a family
history of diabetes mellitus, patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during growth hormone therapy. The doses of antihyperglycemic drugs (e.g., insulin or oral/injectable agents) may require adjustment in these patients.
Thyroid function
Hypothyroidism may develop during growth hormone therapy in very few patients, which should be corrected promptly to avoid the compromised curative effect of growth hormone. Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism. Therefore, thyroid function should be monitored periodically during growth hormone administration, and, thyroid
hormone replacement should be initiated if necessary or adjust the dosage of the growth hormone.
Hypoadrenalism
Patients receiving somatropin therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or starting doses following initiation of somatropin treatment.
Use with oral oestrogen therapy
If a woman taking somatropin begins oral oestrogen therapy, the dose of somatropin may need to be increased to maintain the serum IGF-1 levels within the normal age-appropriate range. Conversely, if a woman on somatropin discontinues oral oestrogen therapy, the dose of somatropin may need to be reduced to avoid excess of growth hormone and/or side effects.
Neoplasia
In childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent GH deficiency and were treated with growth hormone, an increased risk of a second neoplasm has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between growth hormone replacement therapy and CNS tumor recurrence. Monitor all patients receiving growth hormone therapy who have a history of GH deficiency secondary to an intracranial neoplasm for progression or recurrence of the tumor.
Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, phyisicans should thoroughly consider the risks and benefits of starting growth hormone in these patients. If treatment with growth hormone is initiated, these patients should be carefully monitored for development of neoplasms.
In patients with endocrine disorders, including growth hormone deficiency, slipped epiphyses of the hip may occur more frequently than in the general population. Children limping during treatment with somatropin, should be examined clinically.
In the treatment of somatropin in patients with achondroplasia and O-shaped legs, O-shaped legs may deteriorate. Such patients shall be closely monitored during medication. Discontinue treatment and take appropriate measures if abnormalities occur.
In the treatment of somatropin in patients with achondroplasia accompanied with foramen magnum stenosis or spinal stenosis, somatropin treatment should only be considered when it is assessed that the benefits of the drug for improving short stature is greater than the risk of the foramen magnum stenosis or deterioration of spinal stenosis, since somatropin products may deteriorate the symptoms. Regular monitoring such as MRI should be adequately performed. Discontinue somatropin when stenosis of the foramen magnum or deterioration of spinal canal stenosis is observed.
Benign intracranial hypertension
In case of severe or recurrent headache, visual problems, nausea and/or vomiting, a funduscopy for papilloedema is recommended. If papilloedema is confirmed, a diagnosis of benign intracranial hypertension should be considered and, if appropriate, the growth
hormone treatment should be discontinued. At present there is insufficient evidence to give specific advice on the continuation of growth hormone treatment in patients with resolved intracranial hypertension. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary. Patients with Turner syndrome may be at increased risk for the development of intracranial hypertension.
Leukaemia
Leukaemia has been reported in a small number of growth hormone deficiency patients, some of whom have been treated with somatropin. However, there is no evidence that leukaemia incidence is increased in growth hormone recipients without predisposition factors.
Antibodies
As the growth hormone is a protein pharmaceutical, a small percentage of patients treated with growth hormone may develop antibodies to the protein. Studies have shown that in patients who treated with growth hormone for the first time, a small number of patients receiving growth hormone for up to 6 months developed growth hormone specific antibodies, but the antibody concentration did not exceed 2mg/L.
Long-Term Treatment with growth hormone, there is no exact clinical significance when the antibody binding capacity is low even if the antibody is produced. However, it may affect the therapeutic effect when the antibody binding capacity was greater than 2 mg/L. In addition to an evaluation of compliance with the prescribed treatment program and thyroid status, testing for antibodies to growth hormone should be carried out in any patient who fails to respond to therapy.
Elderly patients
Experience in patients above 80 years is limited. Elderly patients may be more sensitive to the action, and therefore may be more prone to develop adverse reactions.
Acute critical illness
Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with growth hormone. Two
placebo-controlled clinical trials in non-GH deficient adult patients (n=522) with these conditions in intensive care units (ICU) revealed a significant increase in mortality (42% vs. 19%) among growth hormone-treated patients (doses 5.3-8mg/day) compared to those
receiving placebo. The safety of continuing growth hormone treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with growth hormone in patients experiencing acute critical illnesses
should be weighed against the potential risk.
Pancreatitis
Although rare, pancreatitis should be considered in somatropin-treated patients, especially children who develop abdominal pain.
Turner syndrome
It is recommended to monitor the growth of hands and feet in patients with Turner syndrome treated with growth hormone; if excessive growth of hands and feet is observed, it should be considered to reduce the dose to a lower level within the treatment range. Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear and hearing disorders. Growth hormone treatment may increase the occurrence of otitis media in patients with Turner syndrome. In addition, patients with Turner syndrome should be monitored closely for cardiovascular disorders (e.g., stroke, aortic aneurysm/dissection, hypertension) as these patients are also at risk for these conditions.
Noonan syndrome
Congenital heart disease is the main manifestation of Noonan syndrome. And there was no evidence of growth hormone-induced ventricular hypertrophy or exacerbation of preexisting ventricular hypertrophy. Children with Noonan syndrome and significant cardiac disease should be fully assessed whether the severity of cardiac disease has a significant effect on growth before treatment with growth hormone.
SHOX gene deficiency
Monitor the size or number of cutaneous nevi, gynecomastia, joint pain, especially in patients with SHOX deficiency. Be alert to these abnormalities, which may occur during growth hormone therapy.
Small for gestational age
In short children born SGA other medical reasons or treatments that could explain growth disturbance should be ruled out before starting treatment.
In SGA children it is recommended to measure fasting insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk for diabetes mellitus (e.g. familial history of diabetes, obesity, severe insulin resistance, acanthosis
nigricans) oral glucose tolerance testing (OGTT) should be performed.
If overt diabetes occurs, growth hormone should not be administered.
In SGA children it is recommended to measure the IGF-I level before start of treatment and twice a year thereafter. If on repeated measurements IGF-I levels exceed +2 SD compared to references for age and pubertal status, the IGF-I / IGFBP-3 ratio could be taken into account to consider dose adjustment.
Experience in initiating treatment in SGA patients near onset of puberty is limited. It is therefore not recommended to initiate treatment near onset of puberty. Experience in patients with Silver-Russell syndrome is limited.
Some of the height gain obtained with treating short children born SGA with growth hormone may be lost if treatment is stopped before final height is reached.
Severe Hypersensitivity
Patients and caregivers should be informed that allergic reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs.
Fluid Retention
Clinical manifestations of fluid retention (e.g. edema, postoperative myalgia syndrome, nerve compression syndromes including carpal tunnel syndrome/paraesthesias) are usually transient and dose dependent.
Increased fluid retention resulting in tissue turgor (swelling, particularly in the hands and feet) and arthralgia resulting in musculoskeletal discomfort (pain, swelling and/or stiffness) and carpal tunnel syndrome may occur during treatment with somatropin on short bowel syndrome, but may resolve spontaneously or with analgesic therapy or after reducing the dosage. If the symptoms of carpal tunnel syndrome do not resolve by decreasing the dosage, discontinue somatropin treatment.
Laboratory Tests
Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone and IGF-1 may increase during growth hormone therapy.
IGF-1
For pediatric patients with Turner syndrome, it is recommended that the IGF-1 level shall be measured before starting treatment and twice a year after starting treatment. The dose should be decreased if the repeated measurement results of IGF-1 level exceed +2 SD when compared with the age- and gender-specific normal range.
Athletes should administer with caution.
Patients with a history of tetracucline allergy should not use.
Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per dose. Patients on low sodium diets can be informed that this medicinal product is essentially 'sodium free'.
Myositis is a very rare adverse event that may be related to the preservative metacresol. In the case of myalgia or disproportionate pain at injection site, myositis should be considered and if confirmed, a presentation without metacresol should be used.
The maximum recommended daily dose should not be exceeded.
The treatment of short bowel syndrome in adult patients should be instructed by physicians who are experienced in diagnosing and managing adult short bowel syndrome patients.
Insulin sensitivity
Glucose intolerance and diabetes mellitus: Glucose levels should be monitored periodically in all patients treated with growth hormone, especially in those with risk factors for diabetes mellitus, such as obesity, Turner syndrome (for pediatric patients with Turner syndrome, it is recommended that fasting insulin and glucose shall be measured before starting treatment and annually after starting treatment) or a family
history of diabetes mellitus, patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during growth hormone therapy. The doses of antihyperglycemic drugs (e.g., insulin or oral/injectable agents) may require adjustment in these patients.
Thyroid function
Hypothyroidism may develop during growth hormone therapy in very few patients, which should be corrected promptly to avoid the compromised curative effect of growth hormone. Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism. Therefore, thyroid function should be monitored periodically during growth hormone administration, and, thyroid
hormone replacement should be initiated if necessary or adjust the dosage of the growth hormone.
Hypoadrenalism
Patients receiving somatropin therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or starting doses following initiation of somatropin treatment.
Use with oral oestrogen therapy
If a woman taking somatropin begins oral oestrogen therapy, the dose of somatropin may need to be increased to maintain the serum IGF-1 levels within the normal age-appropriate range. Conversely, if a woman on somatropin discontinues oral oestrogen therapy, the dose of somatropin may need to be reduced to avoid excess of growth hormone and/or side effects.
Neoplasia
In childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent GH deficiency and were treated with growth hormone, an increased risk of a second neoplasm has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between growth hormone replacement therapy and CNS tumor recurrence. Monitor all patients receiving growth hormone therapy who have a history of GH deficiency secondary to an intracranial neoplasm for progression or recurrence of the tumor.
Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, phyisicans should thoroughly consider the risks and benefits of starting growth hormone in these patients. If treatment with growth hormone is initiated, these patients should be carefully monitored for development of neoplasms.
In patients with endocrine disorders, including growth hormone deficiency, slipped epiphyses of the hip may occur more frequently than in the general population. Children limping during treatment with somatropin, should be examined clinically.
In the treatment of somatropin in patients with achondroplasia and O-shaped legs, O-shaped legs may deteriorate. Such patients shall be closely monitored during medication. Discontinue treatment and take appropriate measures if abnormalities occur.
In the treatment of somatropin in patients with achondroplasia accompanied with foramen magnum stenosis or spinal stenosis, somatropin treatment should only be considered when it is assessed that the benefits of the drug for improving short stature is greater than the risk of the foramen magnum stenosis or deterioration of spinal stenosis, since somatropin products may deteriorate the symptoms. Regular monitoring such as MRI should be adequately performed. Discontinue somatropin when stenosis of the foramen magnum or deterioration of spinal canal stenosis is observed.
Benign intracranial hypertension
In case of severe or recurrent headache, visual problems, nausea and/or vomiting, a funduscopy for papilloedema is recommended. If papilloedema is confirmed, a diagnosis of benign intracranial hypertension should be considered and, if appropriate, the growth
hormone treatment should be discontinued. At present there is insufficient evidence to give specific advice on the continuation of growth hormone treatment in patients with resolved intracranial hypertension. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary. Patients with Turner syndrome may be at increased risk for the development of intracranial hypertension.
Leukaemia
Leukaemia has been reported in a small number of growth hormone deficiency patients, some of whom have been treated with somatropin. However, there is no evidence that leukaemia incidence is increased in growth hormone recipients without predisposition factors.
Antibodies
As the growth hormone is a protein pharmaceutical, a small percentage of patients treated with growth hormone may develop antibodies to the protein. Studies have shown that in patients who treated with growth hormone for the first time, a small number of patients receiving growth hormone for up to 6 months developed growth hormone specific antibodies, but the antibody concentration did not exceed 2mg/L.
Long-Term Treatment with growth hormone, there is no exact clinical significance when the antibody binding capacity is low even if the antibody is produced. However, it may affect the therapeutic effect when the antibody binding capacity was greater than 2 mg/L. In addition to an evaluation of compliance with the prescribed treatment program and thyroid status, testing for antibodies to growth hormone should be carried out in any patient who fails to respond to therapy.
Elderly patients
Experience in patients above 80 years is limited. Elderly patients may be more sensitive to the action, and therefore may be more prone to develop adverse reactions.
Acute critical illness
Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with growth hormone. Two
placebo-controlled clinical trials in non-GH deficient adult patients (n=522) with these conditions in intensive care units (ICU) revealed a significant increase in mortality (42% vs. 19%) among growth hormone-treated patients (doses 5.3-8mg/day) compared to those
receiving placebo. The safety of continuing growth hormone treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with growth hormone in patients experiencing acute critical illnesses
should be weighed against the potential risk.
Pancreatitis
Although rare, pancreatitis should be considered in somatropin-treated patients, especially children who develop abdominal pain.
Turner syndrome
It is recommended to monitor the growth of hands and feet in patients with Turner syndrome treated with growth hormone; if excessive growth of hands and feet is observed, it should be considered to reduce the dose to a lower level within the treatment range. Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear and hearing disorders. Growth hormone treatment may increase the occurrence of otitis media in patients with Turner syndrome. In addition, patients with Turner syndrome should be monitored closely for cardiovascular disorders (e.g., stroke, aortic aneurysm/dissection, hypertension) as these patients are also at risk for these conditions.
Noonan syndrome
Congenital heart disease is the main manifestation of Noonan syndrome. And there was no evidence of growth hormone-induced ventricular hypertrophy or exacerbation of preexisting ventricular hypertrophy. Children with Noonan syndrome and significant cardiac disease should be fully assessed whether the severity of cardiac disease has a significant effect on growth before treatment with growth hormone.
SHOX gene deficiency
Monitor the size or number of cutaneous nevi, gynecomastia, joint pain, especially in patients with SHOX deficiency. Be alert to these abnormalities, which may occur during growth hormone therapy.
Small for gestational age
In short children born SGA other medical reasons or treatments that could explain growth disturbance should be ruled out before starting treatment.
In SGA children it is recommended to measure fasting insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk for diabetes mellitus (e.g. familial history of diabetes, obesity, severe insulin resistance, acanthosis
nigricans) oral glucose tolerance testing (OGTT) should be performed.
If overt diabetes occurs, growth hormone should not be administered.
In SGA children it is recommended to measure the IGF-I level before start of treatment and twice a year thereafter. If on repeated measurements IGF-I levels exceed +2 SD compared to references for age and pubertal status, the IGF-I / IGFBP-3 ratio could be taken into account to consider dose adjustment.
Experience in initiating treatment in SGA patients near onset of puberty is limited. It is therefore not recommended to initiate treatment near onset of puberty. Experience in patients with Silver-Russell syndrome is limited.
Some of the height gain obtained with treating short children born SGA with growth hormone may be lost if treatment is stopped before final height is reached.
Severe Hypersensitivity
Patients and caregivers should be informed that allergic reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs.
Fluid Retention
Clinical manifestations of fluid retention (e.g. edema, postoperative myalgia syndrome, nerve compression syndromes including carpal tunnel syndrome/paraesthesias) are usually transient and dose dependent.
Increased fluid retention resulting in tissue turgor (swelling, particularly in the hands and feet) and arthralgia resulting in musculoskeletal discomfort (pain, swelling and/or stiffness) and carpal tunnel syndrome may occur during treatment with somatropin on short bowel syndrome, but may resolve spontaneously or with analgesic therapy or after reducing the dosage. If the symptoms of carpal tunnel syndrome do not resolve by decreasing the dosage, discontinue somatropin treatment.
Laboratory Tests
Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone and IGF-1 may increase during growth hormone therapy.
IGF-1
For pediatric patients with Turner syndrome, it is recommended that the IGF-1 level shall be measured before starting treatment and twice a year after starting treatment. The dose should be decreased if the repeated measurement results of IGF-1 level exceed +2 SD when compared with the age- and gender-specific normal range.
Athletes should administer with caution.
Patients with a history of tetracucline allergy should not use.
Sodium content
This medicinal product contains less than 1 mmol sodium (23 mg) per dose. Patients on low sodium diets can be informed that this medicinal product is essentially 'sodium free'.
11 β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-1): The microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Endogenous and exogenous
somatropin inhibit 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. As a consequence, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with somatropin. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1.
Concomitant treatment with glucocorticoids inhibits the growth-promoting effects of somatropin containing products. Patients with Adrenocorticotropic hormone (ACTH) deficiency should have their glucocorticoid replacement therapy carefully adjusted to avoid any inhibitory effect on growth. Therefore, patients treated with glucocorticoids should have their growth monitored carefully to assess the potential impact of glucocorticoid treatment on growth.
Growth hormone decreases the conversion of cortisone to cortisol and may unmask previously undiscovered central hypoadrenalism or render low glucocorticoid replacement doses ineffective.
Data from an interaction study performed in growth hormone deficient adults, suggests that somatropin administration may increase the clearance of compounds known to be metabolised by cytochrome P450 isoenzymes. The clearance of compounds metabolised by cytochrome P 450 3A4 (e.g. sex steroids, corticosteroids, anticonvulsants and ciclosporin) may be especially increased resulting in lower plasma levels of these compounds. The clinical significance of this is unknown.
In women on oral oestrogen replacement, a higher dose of growth hormone may be required to achieve the treatment goal.
somatropin inhibit 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. As a consequence, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with somatropin. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1.
Concomitant treatment with glucocorticoids inhibits the growth-promoting effects of somatropin containing products. Patients with Adrenocorticotropic hormone (ACTH) deficiency should have their glucocorticoid replacement therapy carefully adjusted to avoid any inhibitory effect on growth. Therefore, patients treated with glucocorticoids should have their growth monitored carefully to assess the potential impact of glucocorticoid treatment on growth.
Growth hormone decreases the conversion of cortisone to cortisol and may unmask previously undiscovered central hypoadrenalism or render low glucocorticoid replacement doses ineffective.
Data from an interaction study performed in growth hormone deficient adults, suggests that somatropin administration may increase the clearance of compounds known to be metabolised by cytochrome P450 isoenzymes. The clearance of compounds metabolised by cytochrome P 450 3A4 (e.g. sex steroids, corticosteroids, anticonvulsants and ciclosporin) may be especially increased resulting in lower plasma levels of these compounds. The clinical significance of this is unknown.
In women on oral oestrogen replacement, a higher dose of growth hormone may be required to achieve the treatment goal.
Pregnancy
Animal studies are insufficient with regard to effects on pregnancy, embryofoetal development, parturition or postnatal development). No clinical studies on exposed pregnancies are available. Therefore, somatropin containing products are not recommended during pregnancy and in women of childbearing potential not using contraception.
Breast-feeding
There have been no clinical studies conducted with somatropin containing products in breast-feeding women. It is not known whether somatropin is excreted in human milk, but absorption of intact protein from the gastrointestinal tract of the infant is extremely unlikely. Therefore caution should be exercised when somatropin containing products are
administered to breast-feeding women.
Animal studies are insufficient with regard to effects on pregnancy, embryofoetal development, parturition or postnatal development). No clinical studies on exposed pregnancies are available. Therefore, somatropin containing products are not recommended during pregnancy and in women of childbearing potential not using contraception.
Breast-feeding
There have been no clinical studies conducted with somatropin containing products in breast-feeding women. It is not known whether somatropin is excreted in human milk, but absorption of intact protein from the gastrointestinal tract of the infant is extremely unlikely. Therefore caution should be exercised when somatropin containing products are
administered to breast-feeding women.
Has no influence on the ability to drive and use machines.
Patients with growth hormone deficiency are characterized by extracellular
volume deficit. When treatment with somatropin is started this
deficit is rapidly corrected. In adult patients adverse effects
related to fluid retention, such as oedema peripheral, face oedema,
musculoskeletal stiffness, arthralgia, myalgia and paraesthesia are
common. In general these adverse effects are mild to moderate, arise
within the first months of treatment and subside spontaneously or
with dose-reduction.
The incidence of these adverse effects is related to the administered
dose, the age of patients, and possibly inversely related to the age
of patients at the onset of growth hormone deficiency. In children
such adverse effects are uncommon.
Reduced serum cortisol levels
Somatropin has been reported to reduce serum cortisol levels, possibly by
affecting carrier proteins or by increased hepatic clearance. The
clinical relevance of these findings may be limited. Nevertheless,
corticosteroid replacement therapy should be optimised before
initiation of therapy.
Pediatric Patients
Pediatric Growth Hormone Deficiency (GHD)
In the studies of growth hormone deficiency in children, the following
adverse reactions are rare, such as injection site reactions,
including injection site pain, redness, fibrosis, nodules, rash,
inflammation, pigmentation or bleeding; lipoatrophy; headache;
hematuria; thyroid decreased function; transient mild hyperglycemia;
and mild and transient edema.
Noonan Syndrome
A two-year prospective, randomized, parallel dose group trial in 21
children, 3-14 years old, with Noonan syndrome. Doses were 0.033 and
0.066 mg/kg/day. After the initial two-year randomized trial,
children continued growth hormone treatment until final height, no
significant difference in the incidence of adverse events was seen
between the two groups. Congenital heart disease is an inherent
component of Noonan syndrome, and there was no evidence of
somatropin-induced ventricular hypertrophy or exacerbation of
preexisting ventricular hypertrophy (as judged by echocardiography)
during this study. Children who had severe cardiac disease were
excluded from the study; therefore, the safety of growth hormone in
children with Noonan syndrome and significant cardiac disease is not
known. Among children who received 0.033 mg/kg/day, there was one
adverse event of scoliosis; among children who received 0.066
mg/kg/day, there were four adverse events of scoliosis. Mean serum
IGF-1 standard deviation score (SDS) levels did not exceed +1 in
response to growth hormone treatment. The mean serum IGF-1 level was
low at baseline and normalized during treatment.
SHOX Deficiency
In a 2-year randomized, open-label study, the adverse events in
association with growth hormone treatment and clinically significant
are presented in Table 1. In treatment groups, the mean fasting
plasma glucose concentration was similar to the baseline value and
remained in the normal range after the first year treatment, no
patient developed diabetes mellitus or had an above normal value for
fasting plasma glucose. During the second year study period, the
proportion of patients who had at least one IGF-1 concentration
greater than 2 SD above the age-and gender-appropriate mean was 10 of
27 [37.0%] for the growth hormone-treated group vs. 0 of 24 patients
[0.0%] for the untreated group. The proportion of patients who had at
least one IGFBP-3 concentration greater than 2 SD above the age-and
gender appropriate mean was 16 of 27 [59.3%] for the growth hormone
treated group vs. 7 of 24 [29.2%] for the untreated group.
Short Stature due to Achondroplasia
Somatropin was studied in 46 patients in a clinical safety study, of which,
adverse reactions including laboratory tests abnormalities were
observed in 25 patients (54.3%). The most common adverse reactions
were: O-leg deterioration (2 patients, 4.3%), oral glucose tolerance
test (OGTT) abnormalities (10 patients, 21.7%), eosinophilia (6
patients, 13.0%), glycosylated hemoglobin (HbA1) increase (6
patients, 13.0%). In the safety evaluation of 103 patients in the
performance survey, 17 patients (6.5%) had been observed for adverse
reactions including laboratory tests abnormalities. The main adverse
reactions were atypical lymphocyte increase (3 patients, 2.9%),
spinal stenosis (3 patients, 2.9%), increased creatine kinase (CK) (2
patients, 1.9%).
Turner syndrome
Excessive growth of hands and feet had been reported in children with Turner
syndrome during growth hormone treatment.
In two randomized, open-label trials, a trend toward an increased
incidence of otitis media and otitis externa was observed in patients
with Turner syndrome treated with high doses of growth hormone.
However, compared with the low-dose group in this trial, the
increased incidence of ear infections did not lead to an increase in
ear surgery / catheter placement.
Small for gestational age (SGA)
In a foreign study, 53 pediatric patients were treated with 2 doses of
recombinant human growth hormone (0.033 or 0.067 mg/kg/day) to final
height for up to 13 years (mean duration of treatment 7.9 and 9.5
years for girls and boys, respectively). The most frequently reported
adverse reactions were influenza-like illness, upper respiratory
tract infection, bronchitis, gastroenteritis, abdominal pain, otitis
media, pharyngitis, arthralgia, headache, gynecomastia, and increased
sweating. One pediatric patient treated with 0.067 mg/kg/day for 4
years was reported with disproportionate growth of the lower jaw, and
another patient treated with 0.067 mg/kg/day developed a melanocytic
nevus. 4 pediatric patients treated with 0.067 mg/kg/day and 2
pediatric patients treated with 0.033 mg/kg/day had increased fasting
blood glucose levels after 1 year of treatment. In addition, small
increases in fasting blood glucose and insulin levels after 1-2 years
of recombinant human growth hormone treatment appeared to be
dose-dependent.
In another foreign study, 98 Japanese pediatric patients were treated
with 2 doses of recombinant human growth hormone (0.033 or 0.067
mg/kg/day) for 1 or 2 years. Adverse reactions were otitis media,
arthralgia and impaired glucose tolerance. Arthralgia and transiently
impaired glucose tolerance were reported in the 0.067 mg/kg/day
treatment group.
In a domestic clinical trial of recombinant human growth hormone
injection for the treatment of 120 pediatric patients (aged 2-7
years) with SGA, patients were randomized (1:1) to a low dose of
recombinant human growth hormone injection of 0.033 mg/kg/day (n=60)
or a high dose of 0.066 mg/kg/day (n=60) subcutaneously. In the 0.033
mg/kg/day group and 0.066 mg/kg/day group, 50 patients (84.75%) and
52 patients (88.14%) reported adverse events and 14 patients (23.73%)
and 20 patients (33.90%) reported adverse reactions, respectively,
the majority of which were mild. No serious adverse reaction
occurred. There was no statistically significant difference in the
incidence of adverse events and adverse reactions between the 2
groups (p>0.05). The very common(≥1/10) adverse reaction was
the increase in serum insulin level; common (≥1/100, <1/10)
adverse reactions were the increases in serum thyroid-stimulating
hormone and blood glucose levels, injection site reactions, and rash;
uncommon (≥1/1000, <1/100) adverse reactions were papular rash,
eyelid edema, peripheral swelling, limb pain, arthralgia, nipple
pain, allergic dermatitis, increases in alanine aminotransferase,
aspartate aminotransferase, and glycosylated hemoglobin levels.
Immunogenicity:
A total of 8 patients (6.7%) were positive for anti-drug antibodies
during the trial. No neutralizing antibodies were not tested. There
was no adverse event related to immunogenicity during the trial.
Leukaemia
Cases of leukaemia have been reported in children with a GH deficiency,
some of whom were treated with somatropin and included in the
post-marketing experience. However, there is no evidence of an
increased risk of leukaemia without predisposition factors, such as
radiation to the brain or head.
Slipped capital femoral epiphysis and Legg-Calve-Perthes disease
Slipped capital femoral epiphysis and Legg-Calve-Perthes disease have been
reported in children treated with GH. Slipped capital femoral
epiphysis occurs more frequently in case of endocrine disorders and
Legg-Calve-Perthes is more frequent in case of short stature. But, it
is unknown if these 2 pathologies are more frequent or not while
treated with somatropin. Their diagnosis should be considered in a
child with a discomfort or pain in the hip or knee.
Adult patients
Short Bowel Syndrome
In a double-blind, randomized, placebo-controlled clinical trial, 32
patients were exposed to somatropin for 4 weeks. Of the 41 patients
enrolled in the trial, 16 patients received subcutaneous somatropin
(0.1mg/kg /day) plus supportive oral diet, 16 patients received
subcutaneous somatropin (0.1mg/kg /day) plus supportive oral diet
plus oral glutamine (30 grams / day), and 9 patients received placebo
with specialized oral diet and oral glutamine (30 grams / day). The
most common adverse reactions occurring in greater than 20% of
patients treated with somatropin alone and at a higher frequency than
in the control group include peripheral edema, facial edema,
arthralgia, injection site pain, flatulence, and abdominal pain
(Table 2). After 4 weeks of treatment with somatropin, patients were
discharged for follow-up on a supportive oral diet supplemented
either with glutamine or glutamine placebo, and subjects were
re-evaluated as outpatients 12 weeks later. No new adverse drug
reactions were observed in the follow up period.
Adult Growth Hormone Deficiency (GHD)
Adult-onset GH deficiency, the main adverse reactions were systemic edema,
peripheral edema, joint pain, pain and stiffness in the limbs,
myalgia, hypoesthesia and feeling dull. These reactions were reported
early in therapy and tended to be transient or responsive to dosage
titration. When the patients maintain a therapeutic dose above
0.00625 mg/kg/day, carpal tunnel syndrome may develop, and symptoms
abated in these patients after dosage reduction.
Childhood-onset GH deficiency, the main adverse reactions were aspartate
aminotransferase increased, alanine aminotransferase increased,
headache, edema, pain, weakness, myalgia, and respiratory disorder.
In patients with childhood-onset GH deficiency, the incidence of
adverse reactions with growth hormone therapy is lower than those
with adult-onset GH deficiency.
Post-Marketing Experience from foreign growth hormone products: Because these
adverse reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.
Therefore, the occurrence of the following adverse reactions may be
different from the actual application of growth hormone therapy in
patients.
Severe Hypersensitivity Reactions: Very rare, serious systemic
hypersensitivity reactions including anaphylactic reactions and
angioedema have been reported in foreign literature.
Neurologicsystem: Headaches (common in children and occasional in adults).
Skin—Increase in size or number of cutaneous nevi, especially in patients
with SHOX deficiency.
Endocrine:Gynecomastia.
Gastrointestinal: Pancreatitis. Pancreatitis should be considered in any growth
hormone-treated patient, especially a child, who develops abdominal
pain.
Metabolic:New-onset type 2 diabetes mellitus in patients.
Neoplasia: Leukemia has been reported in a small number of pediatric patients
treated with growth hormone. It is uncertain whether these cases of
leukemia are related to GH therapy, the pathology of GH deficiency
itself, or other associated treatments such as radiation therapy.
Currently, it is not certain that the treatment of growth hormone is
associated with leukemia.
volume deficit. When treatment with somatropin is started this
deficit is rapidly corrected. In adult patients adverse effects
related to fluid retention, such as oedema peripheral, face oedema,
musculoskeletal stiffness, arthralgia, myalgia and paraesthesia are
common. In general these adverse effects are mild to moderate, arise
within the first months of treatment and subside spontaneously or
with dose-reduction.
The incidence of these adverse effects is related to the administered
dose, the age of patients, and possibly inversely related to the age
of patients at the onset of growth hormone deficiency. In children
such adverse effects are uncommon.
Reduced serum cortisol levels
Somatropin has been reported to reduce serum cortisol levels, possibly by
affecting carrier proteins or by increased hepatic clearance. The
clinical relevance of these findings may be limited. Nevertheless,
corticosteroid replacement therapy should be optimised before
initiation of therapy.
Pediatric Patients
Pediatric Growth Hormone Deficiency (GHD)
In the studies of growth hormone deficiency in children, the following
adverse reactions are rare, such as injection site reactions,
including injection site pain, redness, fibrosis, nodules, rash,
inflammation, pigmentation or bleeding; lipoatrophy; headache;
hematuria; thyroid decreased function; transient mild hyperglycemia;
and mild and transient edema.
Noonan Syndrome
A two-year prospective, randomized, parallel dose group trial in 21
children, 3-14 years old, with Noonan syndrome. Doses were 0.033 and
0.066 mg/kg/day. After the initial two-year randomized trial,
children continued growth hormone treatment until final height, no
significant difference in the incidence of adverse events was seen
between the two groups. Congenital heart disease is an inherent
component of Noonan syndrome, and there was no evidence of
somatropin-induced ventricular hypertrophy or exacerbation of
preexisting ventricular hypertrophy (as judged by echocardiography)
during this study. Children who had severe cardiac disease were
excluded from the study; therefore, the safety of growth hormone in
children with Noonan syndrome and significant cardiac disease is not
known. Among children who received 0.033 mg/kg/day, there was one
adverse event of scoliosis; among children who received 0.066
mg/kg/day, there were four adverse events of scoliosis. Mean serum
IGF-1 standard deviation score (SDS) levels did not exceed +1 in
response to growth hormone treatment. The mean serum IGF-1 level was
low at baseline and normalized during treatment.
SHOX Deficiency
In a 2-year randomized, open-label study, the adverse events in
association with growth hormone treatment and clinically significant
are presented in Table 1. In treatment groups, the mean fasting
plasma glucose concentration was similar to the baseline value and
remained in the normal range after the first year treatment, no
patient developed diabetes mellitus or had an above normal value for
fasting plasma glucose. During the second year study period, the
proportion of patients who had at least one IGF-1 concentration
greater than 2 SD above the age-and gender-appropriate mean was 10 of
27 [37.0%] for the growth hormone-treated group vs. 0 of 24 patients
[0.0%] for the untreated group. The proportion of patients who had at
least one IGFBP-3 concentration greater than 2 SD above the age-and
gender appropriate mean was 16 of 27 [59.3%] for the growth hormone
treated group vs. 7 of 24 [29.2%] for the untreated group.
Short Stature due to Achondroplasia
Somatropin was studied in 46 patients in a clinical safety study, of which,
adverse reactions including laboratory tests abnormalities were
observed in 25 patients (54.3%). The most common adverse reactions
were: O-leg deterioration (2 patients, 4.3%), oral glucose tolerance
test (OGTT) abnormalities (10 patients, 21.7%), eosinophilia (6
patients, 13.0%), glycosylated hemoglobin (HbA1) increase (6
patients, 13.0%). In the safety evaluation of 103 patients in the
performance survey, 17 patients (6.5%) had been observed for adverse
reactions including laboratory tests abnormalities. The main adverse
reactions were atypical lymphocyte increase (3 patients, 2.9%),
spinal stenosis (3 patients, 2.9%), increased creatine kinase (CK) (2
patients, 1.9%).
Turner syndrome
Excessive growth of hands and feet had been reported in children with Turner
syndrome during growth hormone treatment.
In two randomized, open-label trials, a trend toward an increased
incidence of otitis media and otitis externa was observed in patients
with Turner syndrome treated with high doses of growth hormone.
However, compared with the low-dose group in this trial, the
increased incidence of ear infections did not lead to an increase in
ear surgery / catheter placement.
Small for gestational age (SGA)
In a foreign study, 53 pediatric patients were treated with 2 doses of
recombinant human growth hormone (0.033 or 0.067 mg/kg/day) to final
height for up to 13 years (mean duration of treatment 7.9 and 9.5
years for girls and boys, respectively). The most frequently reported
adverse reactions were influenza-like illness, upper respiratory
tract infection, bronchitis, gastroenteritis, abdominal pain, otitis
media, pharyngitis, arthralgia, headache, gynecomastia, and increased
sweating. One pediatric patient treated with 0.067 mg/kg/day for 4
years was reported with disproportionate growth of the lower jaw, and
another patient treated with 0.067 mg/kg/day developed a melanocytic
nevus. 4 pediatric patients treated with 0.067 mg/kg/day and 2
pediatric patients treated with 0.033 mg/kg/day had increased fasting
blood glucose levels after 1 year of treatment. In addition, small
increases in fasting blood glucose and insulin levels after 1-2 years
of recombinant human growth hormone treatment appeared to be
dose-dependent.
In another foreign study, 98 Japanese pediatric patients were treated
with 2 doses of recombinant human growth hormone (0.033 or 0.067
mg/kg/day) for 1 or 2 years. Adverse reactions were otitis media,
arthralgia and impaired glucose tolerance. Arthralgia and transiently
impaired glucose tolerance were reported in the 0.067 mg/kg/day
treatment group.
In a domestic clinical trial of recombinant human growth hormone
injection for the treatment of 120 pediatric patients (aged 2-7
years) with SGA, patients were randomized (1:1) to a low dose of
recombinant human growth hormone injection of 0.033 mg/kg/day (n=60)
or a high dose of 0.066 mg/kg/day (n=60) subcutaneously. In the 0.033
mg/kg/day group and 0.066 mg/kg/day group, 50 patients (84.75%) and
52 patients (88.14%) reported adverse events and 14 patients (23.73%)
and 20 patients (33.90%) reported adverse reactions, respectively,
the majority of which were mild. No serious adverse reaction
occurred. There was no statistically significant difference in the
incidence of adverse events and adverse reactions between the 2
groups (p>0.05). The very common(≥1/10) adverse reaction was
the increase in serum insulin level; common (≥1/100, <1/10)
adverse reactions were the increases in serum thyroid-stimulating
hormone and blood glucose levels, injection site reactions, and rash;
uncommon (≥1/1000, <1/100) adverse reactions were papular rash,
eyelid edema, peripheral swelling, limb pain, arthralgia, nipple
pain, allergic dermatitis, increases in alanine aminotransferase,
aspartate aminotransferase, and glycosylated hemoglobin levels.
Immunogenicity:
A total of 8 patients (6.7%) were positive for anti-drug antibodies
during the trial. No neutralizing antibodies were not tested. There
was no adverse event related to immunogenicity during the trial.
Leukaemia
Cases of leukaemia have been reported in children with a GH deficiency,
some of whom were treated with somatropin and included in the
post-marketing experience. However, there is no evidence of an
increased risk of leukaemia without predisposition factors, such as
radiation to the brain or head.
Slipped capital femoral epiphysis and Legg-Calve-Perthes disease
Slipped capital femoral epiphysis and Legg-Calve-Perthes disease have been
reported in children treated with GH. Slipped capital femoral
epiphysis occurs more frequently in case of endocrine disorders and
Legg-Calve-Perthes is more frequent in case of short stature. But, it
is unknown if these 2 pathologies are more frequent or not while
treated with somatropin. Their diagnosis should be considered in a
child with a discomfort or pain in the hip or knee.
Adult patients
Short Bowel Syndrome
In a double-blind, randomized, placebo-controlled clinical trial, 32
patients were exposed to somatropin for 4 weeks. Of the 41 patients
enrolled in the trial, 16 patients received subcutaneous somatropin
(0.1mg/kg /day) plus supportive oral diet, 16 patients received
subcutaneous somatropin (0.1mg/kg /day) plus supportive oral diet
plus oral glutamine (30 grams / day), and 9 patients received placebo
with specialized oral diet and oral glutamine (30 grams / day). The
most common adverse reactions occurring in greater than 20% of
patients treated with somatropin alone and at a higher frequency than
in the control group include peripheral edema, facial edema,
arthralgia, injection site pain, flatulence, and abdominal pain
(Table 2). After 4 weeks of treatment with somatropin, patients were
discharged for follow-up on a supportive oral diet supplemented
either with glutamine or glutamine placebo, and subjects were
re-evaluated as outpatients 12 weeks later. No new adverse drug
reactions were observed in the follow up period.
Adult Growth Hormone Deficiency (GHD)
Adult-onset GH deficiency, the main adverse reactions were systemic edema,
peripheral edema, joint pain, pain and stiffness in the limbs,
myalgia, hypoesthesia and feeling dull. These reactions were reported
early in therapy and tended to be transient or responsive to dosage
titration. When the patients maintain a therapeutic dose above
0.00625 mg/kg/day, carpal tunnel syndrome may develop, and symptoms
abated in these patients after dosage reduction.
Childhood-onset GH deficiency, the main adverse reactions were aspartate
aminotransferase increased, alanine aminotransferase increased,
headache, edema, pain, weakness, myalgia, and respiratory disorder.
In patients with childhood-onset GH deficiency, the incidence of
adverse reactions with growth hormone therapy is lower than those
with adult-onset GH deficiency.
Post-Marketing Experience from foreign growth hormone products: Because these
adverse reactions are reported voluntarily from a population of
uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.
Therefore, the occurrence of the following adverse reactions may be
different from the actual application of growth hormone therapy in
patients.
Severe Hypersensitivity Reactions: Very rare, serious systemic
hypersensitivity reactions including anaphylactic reactions and
angioedema have been reported in foreign literature.
Neurologicsystem: Headaches (common in children and occasional in adults).
Skin—Increase in size or number of cutaneous nevi, especially in patients
with SHOX deficiency.
Endocrine:Gynecomastia.
Gastrointestinal: Pancreatitis. Pancreatitis should be considered in any growth
hormone-treated patient, especially a child, who develops abdominal
pain.
Metabolic:New-onset type 2 diabetes mellitus in patients.
Neoplasia: Leukemia has been reported in a small number of pediatric patients
treated with growth hormone. It is uncertain whether these cases of
leukemia are related to GH therapy, the pathology of GH deficiency
itself, or other associated treatments such as radiation therapy.
Currently, it is not certain that the treatment of growth hormone is
associated with leukemia.
Symptoms
Acute overdosage could lead initially to hypoglycaemia and subsequently to hyperglycaemia.
Long-term overdosage could result in signs and symptoms consistent with the known effects of human growth hormone excess.
Acute overdosage could lead initially to hypoglycaemia and subsequently to hyperglycaemia.
Long-term overdosage could result in signs and symptoms consistent with the known effects of human growth hormone excess.
Pharmacotherapeutic group: Anterior pituitary lobe hormones and analogues, ATC code: H01A C01
Somatropin is a potent metabolic hormone of importance for the metabolism of
lipids, carbohydrates and proteins. In children with inadequate
endogenous growth hormone, somatropin stimulates linear growth and
increases growth rate. In adults, as well as in children, somatropin
maintains a normal body composition by increasing nitrogen retention
and stimulation of skeletal muscle growth, and by mobilization of
body fat. Visceral adipose tissue is particularly responsive to
somatropin. In addition to enhanced lipolysis, somatropin decreases
the uptake of triglycerides into body fat stores. Serum
concentrations of IGF-I and IGFBP-3 (Insulin-like Growth Factor
Binding Protein 3) are increased by somatropin. In addition, the
following actions have been demonstrated:
Lipid metabolism: Somatropin induces hepatic LDL cholesterol
receptors, and affects the profile of serum lipids and lipoproteins.
In general, administration of somatropin to growth hormone deficient
patients results in reductions in serum LDL and apolipoprotein B. A
reduction in serum total cholesterol may also be observed.
Carbohydrate metabolism: Somatropin increases insulin but fasting
blood glucose is commonly unchanged. Children with hypopituitarism
may experience fasting hypoglycemia. This condition is reversed by
somatropin.
Water and mineral metabolism: Growth hormone deficiency is associated
with decreased plasma and extracellular volumes. Both are rapidly
increased after treatment with somatropin. Somatropin induces the
retention of sodium, potassium and phosphorus.
Bone metabolism: Somatropin stimulates the turnover of skeletal bone.
Long-term administration of somatropin to growth hormone deficient
patients with osteopenia results in an increase in bone mineral
content and density at weight-bearing sites.
Physical capacity: Muscle strength and physical exercise capacity are
improved after long-term treatment with somatropin. Somatropin also
increases cardiac output, but the mechanism has yet to be clarified.
A decrease in peripheral vascular resistance may contribute to this
effect.
In clinical trials in short children born SGA doses of 0.033 and 0.067
mg/kg body weight per day have been used for treatment until final
height. In 56 patients who were continuously treated and have reached
(near) final height, the mean change from height at start of
treatment was +1.90 SDS (0.033 mg/kg body weight per day) and +2.19
SDS (0.067 mg/kg body weight per day). Literature data from untreated
SGA children without early spontaneous catch-up suggest a late growth
of 0.5 SDS.
Somatropin is a potent metabolic hormone of importance for the metabolism of
lipids, carbohydrates and proteins. In children with inadequate
endogenous growth hormone, somatropin stimulates linear growth and
increases growth rate. In adults, as well as in children, somatropin
maintains a normal body composition by increasing nitrogen retention
and stimulation of skeletal muscle growth, and by mobilization of
body fat. Visceral adipose tissue is particularly responsive to
somatropin. In addition to enhanced lipolysis, somatropin decreases
the uptake of triglycerides into body fat stores. Serum
concentrations of IGF-I and IGFBP-3 (Insulin-like Growth Factor
Binding Protein 3) are increased by somatropin. In addition, the
following actions have been demonstrated:
Lipid metabolism: Somatropin induces hepatic LDL cholesterol
receptors, and affects the profile of serum lipids and lipoproteins.
In general, administration of somatropin to growth hormone deficient
patients results in reductions in serum LDL and apolipoprotein B. A
reduction in serum total cholesterol may also be observed.
Carbohydrate metabolism: Somatropin increases insulin but fasting
blood glucose is commonly unchanged. Children with hypopituitarism
may experience fasting hypoglycemia. This condition is reversed by
somatropin.
Water and mineral metabolism: Growth hormone deficiency is associated
with decreased plasma and extracellular volumes. Both are rapidly
increased after treatment with somatropin. Somatropin induces the
retention of sodium, potassium and phosphorus.
Bone metabolism: Somatropin stimulates the turnover of skeletal bone.
Long-term administration of somatropin to growth hormone deficient
patients with osteopenia results in an increase in bone mineral
content and density at weight-bearing sites.
Physical capacity: Muscle strength and physical exercise capacity are
improved after long-term treatment with somatropin. Somatropin also
increases cardiac output, but the mechanism has yet to be clarified.
A decrease in peripheral vascular resistance may contribute to this
effect.
In clinical trials in short children born SGA doses of 0.033 and 0.067
mg/kg body weight per day have been used for treatment until final
height. In 56 patients who were continuously treated and have reached
(near) final height, the mean change from height at start of
treatment was +1.90 SDS (0.033 mg/kg body weight per day) and +2.19
SDS (0.067 mg/kg body weight per day). Literature data from untreated
SGA children without early spontaneous catch-up suggest a late growth
of 0.5 SDS.
Absorption
The bioavailability of subcutaneously administered somatropin is
approximately 80% in both healthy subjects and growth hormone
deficient patients. A subcutaneous dose of 0.10IU/kg of JINTROPIN®
in healthy adults can reach required drug concentration, half time,
clearance rate, bioavailability and other indicators are basically
consistent with foreign products of the same kind.
Elimination
The mean terminal half-life of somatropin after intravenous
administration in growth hormone deficient adults is about 0.4 hours.
However, after subcutaneous administration, half-lives of 2-3 hours
are achieved. The observed difference is likely due to slow
absorption from the injection site following subcutaneous
administration.
Sub-populations
The absolute bioavailability of somatropin seems to be similar in males
and females following s.c. administration.
Information about the pharmacokinetics of somatropin in geriatric and paediatric
populations, in different races and in patients with renal, hepatic
or cardiac insufficiency is either lacking or incomplete.
The bioavailability of subcutaneously administered somatropin is
approximately 80% in both healthy subjects and growth hormone
deficient patients. A subcutaneous dose of 0.10IU/kg of JINTROPIN®
in healthy adults can reach required drug concentration, half time,
clearance rate, bioavailability and other indicators are basically
consistent with foreign products of the same kind.
Elimination
The mean terminal half-life of somatropin after intravenous
administration in growth hormone deficient adults is about 0.4 hours.
However, after subcutaneous administration, half-lives of 2-3 hours
are achieved. The observed difference is likely due to slow
absorption from the injection site following subcutaneous
administration.
Sub-populations
The absolute bioavailability of somatropin seems to be similar in males
and females following s.c. administration.
Information about the pharmacokinetics of somatropin in geriatric and paediatric
populations, in different races and in patients with renal, hepatic
or cardiac insufficiency is either lacking or incomplete.
In studies regarding general toxicity, local tolerance and reproduction
toxicity no clinically relevant effects have been observed.
In vitro and in vivo genotoxicity studies on gene mutations and
induction of chromosome aberrations have been negative.
An increased chromosome fragility has been observed in one in-vitro
study on lymphocytes taken from patients after long term treatment
with somatropin and following the addition of the radiomimetic drug
bleomycin.The clinical significance of this finding is unclear.
In another study, no increase in chromosomal abnormalities was found in
the lymphocytes of patients who had received long term somatropin
therapy.
toxicity no clinically relevant effects have been observed.
In vitro and in vivo genotoxicity studies on gene mutations and
induction of chromosome aberrations have been negative.
An increased chromosome fragility has been observed in one in-vitro
study on lymphocytes taken from patients after long term treatment
with somatropin and following the addition of the radiomimetic drug
bleomycin.The clinical significance of this finding is unclear.
In another study, no increase in chromosomal abnormalities was found in
the lymphocytes of patients who had received long term somatropin
therapy.
Glycine, Sucrose, Methionine, Tween-80, Phosphate buffer solution
In the absence of compatibility studies, this medicinal product must not
be mixed with other medicinal products.
be mixed with other medicinal products.
3 years
Shelf life after reconstitution
After reconstitution, from a microbiological point of view, an immediate
use is recommended. However, the in-use stability for reconstitution
with sterile water for injection has been demonstrated for up to 72
hours at 2℃ - 8℃, in the original package. Store and transport
refrigerated (2℃ - 8℃). Do not freeze.
Shelf life after reconstitution
After reconstitution, from a microbiological point of view, an immediate
use is recommended. However, the in-use stability for reconstitution
with sterile water for injection has been demonstrated for up to 72
hours at 2℃ - 8℃, in the original package. Store and transport
refrigerated (2℃ - 8℃). Do not freeze.
Before Reconstitution:
Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the
original package in order to protect from light.
After Reconstitution:
Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the
original package in order to protect from light. For storage
conditions of the reconstituted medicinal product, see section 6.3.
Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the
original package in order to protect from light.
After Reconstitution:
Store in a refrigerator (2°C – 8°C). Do not freeze. Store in the
original package in order to protect from light. For storage
conditions of the reconstituted medicinal product, see section 6.3.
