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Somatropin, rh-GH
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General Information for use in GH deficiency:
0.1 to 0.2 mg subcutaneously once daily, initially. Increase the dose by 0.1 to 0.2 mg/dose every 1 to 2 months based on clinical response, serum IGF-1 concentrations, and tolerability. Smaller dose increments and longer time intervals may be necessary.[69452]
0.2 to 0.3 mg subcutaneously once daily, initially. Increase the dose by 0.1 to 0.2 mg/dose every 1 to 2 months based on clinical response, serum IGF-1 concentrations, and tolerability.[69452]
0.4 to 0.5 mg subcutaneously once daily, initially. The dose may be higher for persons transitioning from pediatric treatment; in persons transitioning from pediatric to adult care, resume treatment at 50% of the dose used in childhood. Increase the dose by 0.1 to 0.2 mg/dose every 1 to 2 months based on clinical response, serum IGF-1 concentrations, and tolerability.[69452]
0.15 to 0.3 mg (Usual dose: 0.2 mg) subcutaneously once daily, initially; increase the dose by 0.1 to 0.2 mg/dose every 1 to 2 months based on clinical response, serum IGF-1 concentrations, and tolerability. Alternatively, 0.04 mg/kg/week or less subcutaneously in 6 or 7 divided daily doses, initially; increase the dose every 4 to 8 weeks up to 0.08 mg/kg/week based on clinical response, serum IGF-1 concentrations, and tolerability. Persons with obesity are more likely to experience adverse effects when dosed by weight. Consider a lower starting dose and smaller dose increments for older persons.[45045]
0.15 to 0.3 mg (Usual dose: 0.2 mg) subcutaneously once daily, initially; increase the dose by 0.1 to 0.2 mg/dose every 1 to 2 months based on clinical response, serum IGF-1 concentrations, and tolerability. Alternatively, 0.006 mg/kg/dose subcutaneously once daily, initially; increase the dose up to 0.0125 mg/kg/day based on clinical response, serum IGF-1 concentrations, and tolerability. Weight-based dosing is not recommended for persons with obesity as they are more likely to experience adverse effects when dosed by weight. Consider a lower starting dose and smaller dose increments for older persons.[30059]
0.15 to 0.3 mg (Usual dose: 0.2 mg) subcutaneously once daily, initially; increase the dose by 0.1 to 0.2 mg/dose every 1 to 2 months based on clinical response, serum IGF-1 concentrations, and tolerability. Alternatively, 0.004 mg/kg/dose or less subcutaneously once daily, initially; increase the dose after approximately 6 weeks up to 0.016 mg/kg/day based on clinical response, serum IGF-1 concentrations, and tolerability. Persons with obesity are more likely to experience adverse effects when dosed by weight. Consider a lower starting dose and smaller dose increments for older persons.[58095]
0.15 to 0.3 mg (Usual dose: 0.2 mg) subcutaneously once daily, initially; increase the dose by 0.1 to 0.2 mg/dose every 1 to 2 months based on clinical response, serum IGF-1 concentrations, and tolerability. Alternatively, 0.006 mg/kg/dose or less subcutaneously once daily, initially; increase the dose up to 0.0125 mg/kg/day based on clinical response, serum IGF-1 concentrations, and tolerability. Persons with obesity are more likely to experience adverse effects when dosed by weight. Consider a lower starting dose and smaller dose increments for older persons.[49770] [56647]
0.15 to 0.3 mg (Usual dose: 0.2 mg) subcutaneously once daily, initially; increase the dose by 0.1 to 0.2 mg/dose every 1 to 2 months based on clinical response, serum IGF-1 concentrations, and tolerability. Alternatively, 0.006 mg/kg/dose or less subcutaneously once daily, initially; increase the dose up to 0.025 mg/kg/day based on clinical response, serum IGF-1 concentrations, and tolerability. Persons with obesity are more likely to experience adverse effects when dosed by weight. Consider a lower starting dose and smaller dose increments for older persons.[49770] [56647]
0.15 to 0.3 mg (Usual dose: 0.2 mg) subcutaneously once daily, initially; increase the dose by 0.1 to 0.2 mg/dose every 1 to 2 months based on clinical response, serum IGF-1 concentrations, and tolerability. Alternatively, 0.04 mg/kg/week or less subcutaneously in 7 divided daily doses, initially; increase the dose every 4 to 8 weeks up to 0.08 mg/kg/week based on clinical response, serum IGF-1 concentrations, and tolerability. Persons with obesity are more likely to experience adverse effects when dosed by weight. Consider a lower starting dose and smaller dose increments for older persons.[45044]
0.15 to 0.3 mg (Usual dose: 0.2 mg) subcutaneously once daily, initially; increase the dose by 0.1 to 0.2 mg/dose every 1 to 2 months based on clinical response, serum IGF-1 concentrations, and tolerability. Alternatively, 0.005 mg/kg/dose or less subcutaneously once daily, initially; increase the dose after 4 weeks up to 0.01 mg/kg/day based on clinical response, serum IGF-1 concentrations, and tolerability. Persons with obesity are more likely to experience adverse effects when dosed by weight. Consider a lower starting dose and smaller dose increments for older persons.[56649]
0.15 to 0.3 mg (Usual dose: 0.2 mg) subcutaneously once daily, initially; increase the dose by 0.1 to 0.2 mg/dose every 1 to 2 months based on clinical response, serum IGF-1 concentrations, and tolerability. Alternatively, 0.006 mg/kg/dose subcutaneously once daily, initially; increase the dose up to 0.0125 mg/kg/day based on clinical response, serum IGF-1 concentrations, and tolerability. Weight-based dosing is not recommended for persons with obesity as they are more likely to experience adverse effects when dosed by weight. Consider a lower starting dose and smaller dose increments for older persons.[59579]
0.16 to 0.24 mg/kg subcutaneously per week divided into 6 or 7 equal daily injections.
0.18 mg/kg/week (0.54 International Units/kg) subcutaneously or IM divided into equal doses given either on 3 alternate days, 6 times per week, or daily. The maximum replacement dosage is 0.1 mg/kg (0.3 International Units/kg) given 3 times per week. Dosage should be individualized for each patient.
0.024 to 0.034 mg/kg/dose subcutaneously given 6 to 7 times a week. Dosage should be individualized for each patient.[58095]
0.3 mg/kg/week (approximately 0.9 International Units/kg) subcutaneously divided into daily injections is recommended. In pubertal patients, a weekly dosage of up to 0.7 mg/kg divided daily may be used. Dosage should be individualized for each patient.
Initially, 1.5 mg/kg subcutaneously on the same day each month or 0.75 mg/kg twice each month on the same days of each month (e.g., days 1 and 15).
0.16 to 0.24 mg/kg subcutaneously per week divided into 6 or 7 equal daily injections, preferably administered in the evenings.[45044]
0.18 mg/kg/week subcutaneously or IM; the dose can be divided into equal injections administered daily, 3 times/week, or 6 times/week.
0.18 mg/kg to 0.3 mg/kg subcutaneously per week, divided into equal injections given 3, 6, or 7 times per week. Individualize dosage for each patient based on the growth response. If poor growth persists during the first year of treatment, assess compliance and evaluate other causes such as hypothyroidism, under-nutrition, advanced bone age, and antibodies to recombinant human GH.[59579]
Generally, 0.24 mg/kg subcutaneously per week divided into 6 or 7 equal daily injections.[45044] [45045] [58095] Genotropin or Omnitrope should only be used in Prader-Willi syndrome patients who have a diagnosis of growth hormone deficiency.
Generally, 0.48 mg/kg subcutaneously per week divided into 6 or 7 equal daily injections for children who have not manifested catch-up growth by age 2. For younger children with a baseline HSDS between -2 and -3, the initial dose is 0.24 mg/kg/week subcutaneously with upwards titration as needed. For children with a baseline HSDS less than -3 or for older/prepubertal children, the recommended initial dose is 0.48 mg/kg/week subcutaneously with a reduction in dosage towards 0.24 mg/kg/week subcutaneously if substantial catch-up growth is seen during the first few years of treatment.
Up to 0.067 mg/kg/day subcutaneously (0.47 mg/kg/week) is recommended. For younger children with a baseline HSDS between -2 and -3, the initial dose is 0.033 mg/kg/day subcutaneously with upwards titration as needed. For children with a baseline HSDS less than -3 or for older/prepubertal children, the recommended initial dose is 0.067 mg/kg/day subcutaneously with a reduction in dosage towards 0.033 mg/kg/day subcutaneously if substantial catch-up growth is seen during the first few years of treatment.
0.48 mg/kg subcutaneously per week divided into 6 or 7 equal daily injections for children who have not manifested catch-up growth by age 2.[45044]
Up to 0.47 mg/kg subcutaneously per week, divided into equal injections given 3, 6, or 7 times per week. For younger children with a baseline HSDS between -2 and -3, the initial dose is 0.033 mg/kg/day subcutaneously with upwards titration as needed. For children with a baseline HSDS less than -3 or for older/prepubertal children, the recommended initial dose is 0.067 mg/kg/day subcutaneously with a gradual reduction in dosage if substantial catch-up growth is seen during the first few years of treatment.[59579]
0.35 mg/kg (approximately 1.05 International Units/kg) subcutaneously per week divided into daily injections (0.05 mg/kg/day). Dosage should be individualized for each patient. Hemodialysis patients should receive their injection at night just prior to going to sleep or at least 3 to 4 hours after hemodialysis to prevent hematoma formation due to the heparin. Chronic cycling peritoneal dialysis patients should receive their injection in the morning after they have completed dialysis. Chronic ambulatory peritoneal dialysis patients should receive the injection in the evening at the time of the overnight exchange. Nutropin may be continued up to the time of renal transplantation. There are insufficient data regarding the benefit of treatment beyond 3 years. No studies have been completed in patients who have received renal transplants and the use of Nutropin in patients with functioning renal allografts is not indicated.
45 to 50 mcg/kg/dose subcutaneously once daily, initially. Adjust dose based on growth response and insulin-like growth factor 1 concentrations. Max: 68 mcg/kg/day.[62669] [71106]
0.33 mg/kg/week subcutaneously in 6 or 7 equally divided doses. Discontinue treatment when epiphyses are fused.[45044] [45045]
Up to 0.375 mg/kg/week subcutaneously in 6 or 7 equally divided doses. Max: 0.054 mg/kg/day. Discontinue treatment when epiphyses are fused.[30059]
Up to 0.47 mg/kg/week subcutaneously in 6 or 7 equally divided doses. Max: 0.067 mg/kg/day. Discontinue treatment when epiphyses are fused.[58095]
Up to 0.375 mg/kg/week subcutaneously in 3 to 7 equally divided doses. Discontinue treatment when epiphyses are fused.[49770] [56647]
Up to 0.375 mg/kg/week subcutaneously in 3, 6, or 7 equally divided doses. Max: 0.054 mg/kg/day. Discontinue treatment when epiphyses are fused.[59579]
0.35 mg/kg subcutaneously per week divided into daily injections.
0.35 mg/kg subcutaneously per week, divided into equal injections given 3, 6, or 7 times per week.[59579]
Up to 0.066 mg/kg/day subcutaneously is recommended. Prior to initiating somatropin, ensure that the patient has short stature. Not all children with Noonan syndrome have short stature. Twenty-four children aged 3 to 14 years of age received doses of 0.033 mg/kg/day subcutaneously or 0.066 mg/kg/day subcutaneously for 2 years; after 2 years, the dose was adjusted based on growth response and continued until final height was achieved. Using the national reference, height gain from baseline increased 1.5 SDS (mean height gain of 9.9 cm in males and 9.1 cm in females at 18 years of age). Using the Noonan reference, height gain from baseline increased 1.6 SDS (mean height gain of 11.5 cm in males and 11 cm in girls at 18 years of age) was noted. During the first 2 years of treatment, height velocity was greater in the group receiving 0.066 mg/kg/day subcutaneously.
Up to 0.47 mg/kg subcutaneously per week divided into equal doses given 6 to 7 times per week. Discontinue treatment with Genotropin, Omnitrope, or Norditropin when epiphyses are fused.[45044] [45045] [58095]
Up to 0.37 mg/kg subcutaneously per week divided into equal doses given 6 to 7 times per week.
Up to 0.3 mg/kg subcutaneously per week divided into equal doses given once daily every day (i.e., 7 times/week).
Up to 0.37 mg/kg subcutaneously per week, divided into equal injections given 3, 6, or 7 times per week.[59579]
Dosage is based on weight; 0.1 mg/kg subcutaneously once daily at bedtime, not to exceed 6 mg/day. For weight more than 55 kg: 6 mg subcutaneously once daily at bedtime. For 45 to 55 kg: 5 mg subcutaneously once daily at bedtime. For 35 to 45 kg: 4 mg subcutaneously once daily at bedtime. If less than 35 kg: 0.1 mg/kg subcutaneously once daily at bedtime.[33527]
The manufacturer reports use in pediatric patients in 2 small studies; a total of 11 children with HIV associated failure to thrive were treated. In one study, a dose of 0.04 mg/kg/day subcutaneously for 26 weeks was used in 5 children (6 to 17 years). A second study used a dose of 0.07 mg/kg/day subcutaneously for 4 weeks in 6 children (8 to 14 years). Treatment was reported to be well tolerated and consistent with safety observations in growth hormone treated adults with AIDS wasting.[33527]
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
† Off-label indication
Somatropin, rh-GH is a purified recombinant growth hormone prepared by using either Escherichia coli or mammalian-cells. Endogenous human growth hormone (hGH) is produced in the pituitary gland. Somatropin is approved for treating growth hormone deficiency (GHD), growth failure, or short stature. Several somatropin products are available for growth-related indications, all with varying dosage regimens. Care should be taken in product selection as products may not be considered interchangeable. One product (Serostim) is solely approved for treating cachexia and AIDS wasting in adults. Somatropin (Serostim) has been studied in the treatment of HIV-associated lipodystrophy; limited data indicate use may decrease visceral adipose tissue, but this is still not an FDA-approved use. One product (Zorbtive) was approved to treat adults with short bowel syndrome, but is no longer marketed. Somatropin was originally approved by the FDA in 1987.
For storage information, see the specific product information within the How Supplied section.
Genotropin:
Humatrope:
Norditropin:
Nutropin:
Nutropin AQ:
Omnitrope:
Saizen:
Serostim:
Zomacton:
Somatropin has been associated with an increased risk of a new primary malignancy. Leukemia has been reported in a small number of growth hormone deficient patients treated with somatropin. It is uncertain if this increased risk is related to the pathology of growth hormone deficiency itself, growth hormone therapy, or other associated treatments such as radiation therapy for intracranial tumors. Additionally, in childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent growth hormone deficiency and were treated with somatropin, an increased risk of a new primary malignancy has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. It is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor recurrence in adults. Increases in the size or number of cutaneous nevi were reported during postmarketing surveillance.[58095] Monitor all patients with a history of growth hormone deficiency secondary to an intracranial neoplasm routinely while on somatropin therapy for progression or recurrence of the tumor. Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, consider the risks and benefits of starting somatropin in these patients. If treatment with somatropin is initiated, these patients should be carefully monitored for development of neoplasms. Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes, of preexisting nevi. Somatropin therapy should be discontinued if evidence of neoplasia develops.[30059] [56647]
In trials of growth hormone deficient (GHD) adults, rates of edema or peripheral edema have varied according to the brand of somatropin used and ranged from approximately 5% to 45%. In children with GHD, the rates have been approximately 3%. The edema appears to occur early in therapy and may be transient and/or respond to a dose reduction. Both fluid retention and peripheral edema have been commonly reported in patients receiving somatropin. Peripheral edema is more common in adults than children.[33527] [45045] [56647] [56649] [58095] [30059]
Increased intracranial pressure (intracranial hypertension), with papilledema, visual changes, severe head pain, nausea, and vomiting, has been reported in a small number of patients treated with growth hormone products. Symptoms usually occur within the first 8 weeks of treatment initiation. In all reported cases, symptoms resolved after termination of therapy or a reduction in dose. Funduscopic examination of patients is recommended upon initiation of therapy and periodically throughout treatment. If papilledema is observed during treatment, somatropin should be stopped. If intracranial hypertension is diagnosed, the treatment can be restarted at a lower dose. Patients with Turner syndrome may also be at an increased risk for developing intracranial hypertension.[30059]
Joint swelling (5—6%), myalgia (3—30%), musculoskeletal pain (5—14%), pain and stiffness of the extremities (2—19%), and back pain (3—11%) have been commonly associated with somatropin therapy. Some events are related to fluid retention and appear to occur more frequently in adults than in children, particularly arthralgia (11—37%). In adults treated with somatropin, muscle and joint pain usually occurred early in therapy and tended to be transient or respond to dosage reduction. Pain, swelling and/or stiffness may resolve with analgesic use or a reduction in frequency of dosing with somatropin. In addition, carpal tunnel syndrome (nerve entrapment syndrome, 1—5%) and arthrosis (8—11%), have also been reported. More serious adverse reactions that have been reported include slipped capital femoral epiphysis and progression of scoliosis (4—19%) in pediatric patients.[30059] [33527] [45044] [45045] [56647] [56649] [58095]
Metabolic complications have been frequently reported with somatropin therapy. During postmarketing surveillance of various products, there have been cases of new onset glucose intolerance, hyperglycemia, diabetes mellitus, and exacerbation of pre-existing diabetes mellitus.[30059] Some patients developed diabetic ketoacidosis and diabetic coma.[33527] [60682] Discontinuing treatment led to improvement in some patients, while glucose intolerance persisted in others. Monitor glucose concentrations closely during therapy; initiate or adjust antidiabetic treatment as necessary. Short-term overdosage may result in hypoglycemia.[30059] A greater incidence of impaired fasting glucose has been observed with higher doses. During clinical trials, Type 2 diabetes mellitus (DM) was reported in 5% of adults receiving somatropin.[58095] Hypothyroidism has been reported in approximately 5% to 16% of patients receiving somatropin therapy.[45044] [56649] During a 6 month placebo-controlled trial in growth hormone deficient (GHD) adults using the Saizen brand, approximately 10% required small upward adjustments of thyroid hormone replacement therapy for preexisting hypothyroidism, and 1 patient was newly diagnosed with hypothyroidism. Additionally, during the trial, 2 patients required upward adjustments of hydrocortisone maintenance therapy (unrelated to intercurrent stress, surgery, or disease) for preexisting hypoadrenalism, and 1 patient was newly diagnosed with adrenal insufficiency. Monitor thyroid tests periodically and initiate or adjust thyroid replacement therapy as necessary.[56649] Hyperlipidemia (8%) has also been reported, most often as hypertriglyceridemia (1% to 5%).[30059] [33527]
The most common central nervous system (CNS) adverse reactions reported in somatropin clinical trials were in adults and include headache (6—18%), paresthesias (2—17%), and hypoesthesia (2—15%). Asthenia or weakness (3—6%), fatigue (4—9%), insomnia (5%), depression (5%) and dizziness were also reported in trials.[30059] [33527] [45045] [56649] [58095] [60682] Seizures have been reported rarely.[56649]
Upper respiratory tract infection (32%) and fever (16%) have been reported in pediatric patients receiving somatropin.[59579] Naso-pharyngitis (3% to 14%), bronchitis (9%), rhinitis (5% to 14%), and flu like symptoms (4% to 23%) have been reported in somatropin-treated patients during clinical trials.[30059] [45045] [58095] Children with Turner syndrome reported otitis media (16% to 43%) and ear disorders (18%).[30059] Otitis media was reported in 10% of pediatric patients treated with somatropin for short stature due to growth hormone deficiency.[59579] In studies with Norditropin, otitis media and otitis externa were reported more frequently in patients receiving the highest doses.[58095] Increased cough (6% to 9%) has also been reported.[30059] [59579]
Somatropin administration is associated with an injection site reaction (pain or burning associated with injection), lipoatrophy, or nodule formation; lipoatrophy can be avoided by frequent rotation of the injection site. Other injection site reactions include hematoma (9%), fibrosis, erythema, pruritus, rash, swelling, bleeding, and skin hyperpigmentation.[45044] [45045] [56649]
Antibody formation occurs in approximately 2% of patients receiving somatropin. Growth hormone antibody binding capacities below 2 mg/L have not been associated with growth attenuation; however, in some cases when binding capacity exceeds 2 mg/L growth attenuation has been observed. Testing for growth hormone antibodies should be performed in any patient who fails to respond to somatropin therapy.[30059] [45045]
During postmarketing experience with somatropin, dermatologic and serious systemic hypersensitivity reactions including anaphylactoid reactions and angioedema have been reported.[30059] [33527] [45044] [45045] [49770] [56646] [56647] [56649] [58095] [59579] Acne vulgaris (6%), diaphoresis (8%), maculopapular rash (6%), alopecia, and eczema have been reported in patients taking somatropin therapy.[30059] [45045] [58095] [59579] Allergic reactions are possible and include rash; exacerbation of pre-existing psoriasis has also been reported.[56649]
Pancreatitis has been rarely reported in adults and children receiving somatropin, with children, and especially girls with Turner syndrome, appearing to be at greater risk compared to adults. Evaluate any patient who develops abdominal pain for pancreatitis. Other gastrointestinal adverse reactions reported in clinical trials include elevated hepatic enzymes (6% to 13%), abdominal pain (7%), gastritis (6%), gastroenteritis (8%), and diarrhea (5%). An increase in blood alkaline phosphatase concentration and a decrease in serum thyroxin (T4) concentrations have been reported during postmarketing surveillance.[30059] [45045] [58095] [59579]
Gynecomastia has been observed in both adults (3—6%) and children (5—8%) treated with somatropin in clinical trials.[30059] [33527]
Hypertension (3% to 8%) and chest pain (unspecified) (5%) have been reported in patients treated with somatropin in clinical trials.[30059] [56649] [58095] Eosinophilia (12%), anemia (6%), and pain (5%) have been reported in pediatric patients receiving somatropin in clinical trials.[45044] [59579] Hematuria has been rarely observed.[45045]
In August 2011, the FDA notified healthcare professionals that it has reviewed data from the SAGhE (Sante Adulte GH Enfant) study (a long-term epidemiological study conducted in France). The SAGhe Study found that patients with idiopathic growth hormone deficiency and idiopathic or gestational short stature treated with somatropin during childhood had a 30% increased risk of death compared to the general population. The FDA determined this evidence regarding recombinant human growth hormone and increased risk of death to be inconclusive.[45269] A 2016 study devised an advanced mortality model using the the Swedish Medical Birth Registry to estimate standardized mortality rates in patients receiving growth hormone compared to the general population. The authors concluded that the increase in mortality found in the SAGhE study was most likely related to basic characteristics of the growth hormone deficiency population (i.e. birth weight, birth length, and congenital malformations) rather than due to the use of growth hormone treatment itself.[61679]
Somatropin therapy may cause changes in some laboratory values. Serum levels of inorganic phosphorus, alkaline phosphatase, and parathyroid hormone may increase with somatropin therapy.
Somatropin is contraindicated in pediatric patients with epiphyseal closure. Linear growth can no longer occur in these patients. In addition, slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders or in patients undergoing rapid growth. Pediatric patients with the onset of a limp or complaints of hip or knee pain should be evaluated for slipped capital femoral epiphysis.[59579]
Response to somatropin therapy in children tends to decrease over time. However, in children in whom growth rate is not increased, especially during the first year of treatment, compliance as well as other causes of growth failure including thyroid abnormalities, malnutrition, advanced bone age, and antibodies to somatropin should be assessed. Any child taking somatropin that complains of hip or knee pain or the development of a limp should be evaluated by a clinician. Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders or in children undergoing rapid growth. In addition, children with growth failure secondary to renal impairment should be evaluated for progression of renal osteodystrophy. Slipped capital femoral epiphysis or avascular necrosis of the femoral head may occur in children with advanced renal osteodystrophy; x-rays of the hip should occur prior to initiating therapy with somatropin. In August 2011, the FDA notified healthcare professionals that it has reviewed data from the SAGhE (Sante Adulte GH Enfant) study (a long-term epidemiological study conducted in France), which found that patients with idiopathic growth hormone deficiency and idiopathic or gestational short stature treated with somatropin during childhood had a 30% increased risk of death compared to the general population. The FDA has determined the evidence regarding recombinant human growth hormone and increased risk of death to be inconclusive; a number of study design weaknesses were found which limit the interpretability of the study results. Additionally, the FDA reviewed the medical literature, as well as reports from the Agency's Adverse Event Reporting System (AERS). The FDA will continue to review this safety issue and expects to receive additional data from the SAGhE study in Spring 2012. The FDA will update the public when new information is available. Healthcare professionals and patients should continue to prescribe and use recombinant human growth hormone according to the labeled recommendations.[45269]
Some of the multi-dose somatropin products contain benzyl alcohol and should be used cautiously in neonates and patients with benzyl alcohol hypersensitivity. Benzyl alcohol has been associated with toxicity in newborns. If somatropin is to be used in neonates or in patients with benzoyl alcohol hypersensitivity, sterile water for injection, USP should be used for reconstitution and only one dose should be used per vial.
Somatropin is contraindicated in patients with active neoplastic disease. Any pre-existing neoplastic disease, specifically intracranial lesions (including pituitary tumors) must be inactive, and chemotherapy and radiation therapy complete, prior to beginning somatropin therapy. In childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent growth hormone deficiency and were treated with somatropin, an increased risk of a new primary malignancy has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. It is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor recurrence in adults. Monitor all patients with a history of growth hormone deficiency secondary to an intracranial neoplasm routinely while on somatropin therapy for progression or recurrence of the tumor. Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, consider the risks and benefits of starting somatropin in these patients. If treatment with somatropin is initiated, these patients should be carefully monitored for development of neoplasms. Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes, of preexisting nevi. Somatropin therapy should be discontinued if evidence of neoplasia develops.[56647]
Somatropin is contraindicated in patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or to patients having acute respiratory insufficiency. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n = 522) with these conditions revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin-treated patients (5.3 to 8 mg/day) compared to those receiving placebo. The safety of continuing somatropin treatment in patients receiving replacement doses for approved indications who currently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with somatropin in patients having acute critical illnesses should be weighed against the potential risk.
The manufacturers of Genotropin and Norditropin indicate that adult patients with obesity receiving somatropin for growth hormone deficiency may be more likely to experience adverse events when dosed by weight. Using a daily dose that is not weight-based may be preferable.
Somatropin is contraindicated in patients with Prader-Willi syndrome who are severely obese or have severe respiratory impairment. Unless patients with Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, somatotropin is not indicated for long-term treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome. There have been reports of fatalities with the use of growth hormone in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of respiratory insufficiency or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at increased risk. Patients with Prader-Willi syndrome should be evaluated for upper airway obstruction before initiation of treatment with growth hormone. If during treatment with growth hormone patients show signs of upper airway obstruction (including onset of or increased snoring), treatment should be interrupted. All patients with Prader-Willi syndrome should be evaluated for sleep apnea and monitored if sleep apnea is suspected. All patients with Prader-Willi syndrome should also have effective weight control and be monitored for signs of respiratory infections, which should be diagnosed as early as possible and treated aggressively. Patients with Prader-Willi syndrome may also be at increased risk of intracranial hypertension.
Somatropin should be used cautiously in patients with diabetes mellitus. Patients with diabetes or glucose intolerance and those patients with risk factors for diabetes or glucose intolerance should be monitored closely during treatment with somatropin. Risk factors for glucose intolerance include obesity (including obese patients with Prader-Willi Syndrome), Turner syndrome, or a family history of type II diabetes. Because somatropin may reduce insulin sensitivity, especially at higher doses, patients should be monitored for evidence of glucose intolerance. Glucose intolerance or acromegaly may occur with chronic overdosage of somatropin. Dose adjustments of antidiabetic medications may be necessary when somatropin is initiated. Due to the effects of somatropin on insulin sensitivity and blood glucose concentrations, somatropin is contraindicated in patients with diabetic retinopathy.[30059]
Patients with a history of scoliosis should receive somatropin with caution. Because growth hormone increases growth rate, patients with scoliosis can experience progression of scoliosis. Patients should be monitored for progression of scoliosis. In addition, skeletal abnormalities including scoliosis are commonly seen in untreated Turner's syndrome, Noonan's syndrome, and Prader-Willi syndrome patients. Clinicians should be aware of these abnormalities, which may manifest during growth hormone therapy.
Patients who have or at risk for pituitary hormone deficiencies, and are receiving somatropin, may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) adrenal insufficiency. Patients treated with glucocorticoid replacement for previously diagnosed adrenal insufficiency may require an increase in their maintenance or stress doses following initiation of somatropin treatment. In addition, patients with untreated hypothyroidism will have an inadequate response to somatropin therapy. Changes in thyroid hormone plasma levels may develop during somatropin therapy because patients with Turner's syndrome have an inherent risk of developing autoimmune thyroid disease. Periodic thyroid function tests should be performed and treatment with thyroid hormone initiated when indicated.[45045]
Somatropin therapy has been reported to cause increased intracranial pressure with papilledema, visual changes, headache, and nausea and/or vomiting. Symptoms usually occurred within the first eight weeks of somatropin therapy. Resolution of intracranial hypertension-associated symptoms occurred after discontinuation of somatropin therapy or after a reduction in the hormone dose. Funduscopic examination is recommended at the initiation and periodically during the course of somatropin therapy. Patients with chronic renal insufficiency, Prader-Willi syndrome, and Turner's syndrome may be at increased risk for developing intracranial hypertension.
No adequate and well controlled studies have been conducted in pregnant humans, and the potential for somatropin to cause adverse effects on the fetus or reproductive system is unknown. In animal studies that have been performed, differing doses exceeding the regular human dose revealed no evidence of impaired fertility or harm to the fetus. Inform females of childbearing age that use of somatropin during pregnancy has not been studied in humans, therefore, the effects of the drug on the fetus are unknown.[30059] [33527] [45044] [45045] [60682]
No data are available regarding the presence of somatropin in human milk, the effects of somatropin on the breast-fed infant, or the effects of somatropin on milk production. Limited published literature reports no adverse effects on breast-feeding infants with maternal administration of somatropin and no decrease in milk production or change in milk content during treatment with somatropin. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.[30059] [33527] [45044] [45045] [60682]
During treatment with somatropin, Turner's syndrome patients should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear or hearing disorders. In addition, patients with Turner's syndrome should be monitored closely for cardiovascular disorders such as stroke, aortic aneurysm, and hypertension because these patients are also at risk for these conditions.
Clinical studies of somatropin did not include sufficient numbers of geriatric subjects. Reported clinical experience had not identified differences in responses between geriatric and younger adult patients. In general, dose selection for an older adult should be cautious, usually starting at the low end of the dosing range. Geriatric patients are more at risk for the adverse effects of therapy compared to pediatric and younger adult patients. According to practice guidelines, growth hormone/somatropin should only be prescribed to patients with clinical features suggestive of adult growth hormone deficiency (GHD) and biochemically proven evidence of adult GHD. There are no data available to suggest that somatropin has beneficial effects in treating aging and age-related conditions and the enhancement of sporting performance; therefore, the prescription of the drug to adult patients for any reason other than the well-defined approved uses of the drug is not recommended.[60946] According to the Beers Criteria, growth hormone is considered a potentially inappropriate medication (PIM) in geriatric patients. Avoid use in the older adult due to its small effect on body composition relative to a significant adverse effect profile (e.g., edema, arthralgia, carpal tunnel syndrome, gynecomastia, elevated fasting glucose). Use in patients rigorously diagnosed by evidence-based criteria with growth hormone deficiency due to an established etiology is acceptable.[63923]
Somatropin (Serostim) has been used in patients with HIV-associated adipose redistribution syndrome (HARS); somatropin therapy may be less effective in females with HARS as compared to men. During clinical trials, 47 women receiving somatropin showed no difference from placebo with respect to reduction in visceral adipose tissue (VAT). Reasons for the lack of effectiveness may be the concomitant use of estrogen (6 patients) or a lower baseline VAT level as compared to men. Lower VAT levels have been demonstrated in several clinical trials to be associated with a reduced response to somatropin.
Patients who develop persistent, severe abdominal pain during somatropin treatment should be evaluated for pancreatitis, especially pediatric patients. Use with caution in patients with a past history of pancreatitis or with risk factors for pancreatitis. Pancreatitis has been rarely reported in adults and children receiving somatropin, with pediatric patients appearing to be at greater risk compared to adults. Girls with Turner syndrome may have an even greater risk of developing pancreatitis compared to others undergoing somatropin treatment.[49770]
Endogenous growth hormone is responsible for stimulating normal skeletal, connective tissue, muscle, and organ growth in children and adolescents. It also plays an important role in adult metabolism. Recombinant products mimic all of these actions. Somatropin binds to growth hormone (GH) receptors and produces a variety of physiologic effects that can be classified as being direct or indirect. The direct effects include antagonism of the peripheral action of insulin and the subsequent stimulation of insulin secretion; stimulation of the production of somatomedins or insulin-like growth factors (IGFs) in the liver and other tissues; stimulation of triglyceride hydrolysis in adipose tissue; stimulation of hepatic glucose output; induction of a positive calcium balance; and retention of sodium and potassium. These effects oppose the action of insulin on fat and carbohydrate metabolism and are potentiated by glucocorticoids.[56647][57484]
Somatomedins or insulin-like growth factors (IGFs) indirectly mediate the anabolic and growth-promoting effects of somatropin. IGFs circulate throughout the body and bind to specific IGF receptors. Two IGFs have been identified, IGF-1 and IGF-2. IGF-1 appears to be the principal mediator of the action of growth hormone, whereas IGF-2 has more insulin-like activity. The principal anabolic actions of IGFs include stimulation of amino acid transport, stimulation of DNA, RNA, and protein synthesis, and induction of cell proliferation and growth. IGF-1 is directly responsible for chondrogenesis, skeletal growth, and the growth of soft tissue. Linear growth is stimulated by affecting cartilaginous growth areas of long bones. Growth is also stimulated by increasing the number and size of skeletal muscle cells, influencing the size of organs, and increasing red cell mass through erythropoietin stimulation. The actions of growth hormone on the gut may be direct or mediated via the local or systemic production of IGF. In-vivo studies have shown that growth hormone enhances transmucosal transport of water, electrolytes, and nutrients. These indirect effects are inhibited by glucocorticoids.[57484]
Revision Date: 09/09/2024, 01:15:08 PMSomatropin is administered by intramuscular or subcutaneous injection. Peak plasma concentrations of somatropin are reached in 2—6 hours following administration. About 20% of the circulating somatropin is bound to growth hormone-binding protein. Peak plasma concentrations of IGF-1 occur about 20 hours after administration of somatropin. Somatropin is metabolized by the liver, kidney, and other tissues. Somatropin undergoes glomerular filtration and the molecule is cleaved in the kidney. Once cleavages occurs in the renal cells, the peptides and amino acids are returned to the systemic circulation. Little excretion occurs via the urine. The plasma elimination half-life is approximately 20—30 minutes. Because of continued release of somatropin from the intramuscular or subcutaneous site, serum concentrations decline with a half-life of about 3—5 hours. Because of the slow induction and clearance of IGF-1, the effects of somatropin last much longer than its elimination half-life.
Following subcutaneous injection of the depot formulation, somatropin is released from the microspheres initially by diffusion, followed by both polymer degradation and diffusion. The estimated bioavailability following a single dose of Nutropin Depot ranges from 33—38% when compared to single dose Nutropin AQ and from 48—55% when compared to chronically dosed Protropin. Once released and absorbed, somatropin is believed to distributed and eliminated in a manner similar to somatropin formulated for daily administration. Both the Cmax and AUC are proportional to the dose. Serum growth hormone levels > 1 mcg/l persist for approximately 11—14 days following single doses of 0.75 or 1.5 mg/kg.
It appears that the clearance of somatropin in children and adults is similar; however, no pharmacokinetic studies have been conducted in children with short bowel syndrome.
Biomedical literature indicates males may clear somatropin more quickly than females, although no gender-based analysis is available.
No adequate and well controlled studies have been conducted in pregnant humans, and the potential for somatropin to cause adverse effects on the fetus or reproductive system is unknown. In animal studies that have been performed, differing doses exceeding the regular human dose revealed no evidence of impaired fertility or harm to the fetus. Inform females of childbearing age that use of somatropin during pregnancy has not been studied in humans, therefore, the effects of the drug on the fetus are unknown.[30059] [33527] [45044] [45045] [60682]
No data are available regarding the presence of somatropin in human milk, the effects of somatropin on the breast-fed infant, or the effects of somatropin on milk production. Limited published literature reports no adverse effects on breast-feeding infants with maternal administration of somatropin and no decrease in milk production or change in milk content during treatment with somatropin. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.[30059] [33527] [45044] [45045] [60682]
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