Omnitrope Injection

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.

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.

The FDA informed medical experts that it had evaluated SAGhE (Sante Adulte GH Enfant) trial data in August 2011 (a long-term epidemiological study conducted in France). In comparison to the general population, individuals treated with somatropin as children who had idiopathic growth hormone insufficiency and idiopathic or gestational low stature had a 30% higher risk of death, according to the SAGhe Study. Recombinant human growth hormone with an elevated risk of death: The FDA found this evidence to be inconclusive.^[3] An advanced mortality model was developed in 2016 utilizing the Swedish Medical Birth Registry to calculate the standard mortality rates for growth hormone-treated patients in comparison to the general population. The authors came to the conclusion that, rather than being caused by the administration of growth hormone therapy itself, the rise in mortality observed in the SAGhE study was likely related to fundamental traits of the population affected by growth hormone deficiency (such as birth weight, birth length, and congenital malformations). ^[4]

Some laboratory results may vary as a result of somatropin medication. With somatropin medication, serum levels of inorganic phosphorus, alkaline phosphatase, and parathyroid hormone may rise.

Somatropin products are contraindicated in patients with a known hypersensitivity to somatropin or any of the product excipients. Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with post-marketing use of somatropin products. Patients and caregivers should be informed that there is a risk of serious hypersensitivity reactions or anaphylaxis and that prompt medical attention should be sought if an allergic reaction occurs.^[5]^[6]^[1]^[2]^[7]^[8]^[9]^[10]^[11]^[12] As with any hormonal product, local or systemic allergic reaction may occur. Several of the products contain m-cresol as a preservative. Some of the formulations recommend using sterile water for injection as a diluent in patients with m-cresol hypersensitivity; other products recommend using other formulations. The package insert of the specific product should be consulted for further information when using somatropin in patients with m-cresol hypersensitivity. Similarly, some of the formulations also contain glycerin. Do not use formulations of somatropin that contain glycerin in patients with glycerin hypersensitivity.

When used to promote growth in pediatric patients with epiphyseal closure, somatropin is not recommended. These patients are no longer capable of linear growth. In addition, people with endocrine abnormalities or those going through rapid growth may experience slipping capital femoral epiphysis more frequently.

Children’s response to somatropin medication tends to decline over time. However, compliance as well as other causes of growth failure such as thyroid problems, malnutrition, advanced bone age, and antibodies to somatropin should be evaluated in children whose growth rate is not enhanced, particularly during the first year of treatment. A clinician should examine any child using somatropin who complains of hip or knee pain or who develops a limp. Patients with endocrine disorders or growing children may experience slipped capital femoral epiphysis more commonly. Children who experience growth failure due to renal impairment should also be examined for the development of renal osteodystrophy. Children with advanced renal osteodystrophy may develop slipped capital femoral epiphysis or avascular necrosis of the femoral head; x-rays of the hip should be taken prior to starting somatropin medication.

Idiopathic growth hormone deficiency and idiopathic or gestational short stature patients treated with somatropin during childhood had a 30% increased risk of death compared to the general population, according to data from the SAGhE (Sante Adulte GH Enfant) study, which the FDA reviewed in August 2011. Recombinant human growth hormone and an elevated risk of death have been linked, but the data isn’t definitive, according to the FDA; a number of flaws in the study’s design have been identified that restrict how well the findings can be understood. The FDA also examined information from the Agency’s Adverse Event Reporting System and the medical literature (AERS). The FDA will continue to investigate this safety concern and anticipates more information from the SAGhE study in the spring of 2012. When fresh information becomes available, the FDA will tell the public. Recombinant human growth hormone should continue to be prescribed and used by medical professionals and patients in accordance with labeling instructions.^[3]

In neonates and patients who have benzyl alcohol hypersensitivity, several multi-dose somatropin preparations that contain benzyl alcohol should be used with caution. In newborns, benzyl alcohol has been linked to toxicity. Sterile water for injection, USP should be used for reconstitution and only one dose should be administered per vial if somatropin is to be administered to newborns or patients who have benzoyl alcohol hypersensitivity.

Patients with neoplastic disease that is active should not take somatropin. Prior to starting somatropin medication, any pre-existing neoplastic disease, specifically intracranial lesions (including pituitary tumors), must be dormant and chemotherapy and radiation therapy must be finished. An elevated risk of a secondary malignancy has been noted in pediatric cancer survivors who underwent radiation therapy to the brain or head for their initial tumor and who later developed growth hormone insufficiency and were treated with somatropin.

Meningiomas, in particular, were the most prevalent of these second neoplasms, which included intracranial tumors. It is unclear if adult CNS tumor recurrence and somatropin replacement therapy are related in any way. While receiving somatropin therapy, all patients who have a history of growth hormone deficiency as a result of an intracranial neoplasm should be routinely checked for tumor development or recurrence. Consider the hazards and advantages of initiating somatropin in patients who have certain rare genetic causes of low stature since they have an elevated chance of developing cancer.

These patients should be closely watched for the emergence of neoplasms if somatropin medication is started. Patients receiving somatropin medication should be closely watched for any signs of accelerated nevi growth or potential malignant alterations. If signs of neoplasia appear, somatropin medication should be stopped.^[9]

Somatropin should not be used in individuals with severe critical illnesses brought on by complications from open heart surgery or abdominal surgery, multiple accidental injuries, or acute respiratory failure. Two placebo-controlled clinical trials in adult patients (n=522) with these conditions found that somatropin treatment (5.3–8 mg/day) resulted in a statistically significant increase in mortality (41.9% vs. 19.3%).

It has not been determined if it is safe to continue somatropin therapy in individuals getting replacement dosages for medical conditions for which the drug has been licensed. Therefore, the possible benefit of continuing somatropin medication should be balanced against the potential risk in patients with acute critical diseases. Additionally, because there have been instances of fatalities, somatropin is not advised for usage in children with Prader-Willi syndrome and respiratory insufficiency (see Prader-Willi discussion).

The safety of continuing somatropin therapy in patients receiving replacement doses for situations for which the medication has been approved has not been established. Therefore, in patients with acute critical conditions, the potential benefit of continued somatropin therapy should be weighed against the potential risk. Somatropin is also not recommended for use in children with Prader-Willi syndrome and respiratory insufficiency due to cases of mortality (see Prader-Willi discussion).

Patients with Prader-Willi syndrome who are extremely obese or have severe respiratory impairment should not take somatropin. Somatotropin is not recommended for the long-term therapy of pediatric patients with genetically proven Prader-Willi syndrome who have growth failure unless they also have a diagnosis of growth hormone insufficiency. Growth hormone use has been linked to mortality in pediatric Prader-Willi syndrome children who had one or more of the risk factors listed below: severe obesity, a history of respiratory failure or sleep apnea, or an unexplained respiratory infection.

Patients who are male and have one or more of these risk factors may be at higher risk. Before starting growth hormone therapy, patients with Prader-Willi syndrome should have their upper airways inspected for obstruction. Treatment with growth hormone should be stopped if patients exhibit symptoms of upper airway blockage (including the beginning or worsening of snoring).

If sleep apnea is suspected in any Prader-Willi syndrome patient, that patient should also be watched. All Prader-Willi syndrome patients should also maintain healthy weights and be closely watched for any indications of respiratory infections, which should be identified as soon as possible and quickly treated. Additionally, cerebral hypertension may be more common in Prader-Willi syndrome patients.

Patients with diabetes should utilize somatropin with caution. During somatropin therapy, patients with diabetes or glucose intolerance, as well as those who have risk factors for developing these conditions, should be continuously watched. Obesity (including obesity in Prader-Willi syndrome individuals), Turner syndrome, or a family history of type II diabetes are risk factors for glucose intolerance.

Patients should be watched for signs of glucose intolerance since somatropin may decrease insulin sensitivity, especially at larger dosages. Chronic somatropin overdose may result in glucose intolerance or acromegaly. When somatropin is started, it may be required to modify the dosage of antidiabetic drugs. Somatropin is not recommended for use in people with diabetic retinopathy because of how it affects blood glucose levels and insulin sensitivity.^[5]

Somatropin administration should be cautious for patients with a history of scoliosis. Growth hormone accelerates growth, which might cause scoliosis sufferers to undergo scoliosis progression. Scoliosis progression should be tracked in patients. In addition, people with untreated Turner’s syndrome, Noonan’s syndrome, and Prader-Willi syndrome may exhibit skeletal deformities, such as scoliosis. These anomalies, which could appear with growth hormone therapy, should be known to clinicians.

Patients using somatropin may experience decreased blood cortisol levels and/or the masking of central (secondary) adrenal insufficiency if they have or are at risk for pituitary hormone shortages. Following the start of somatropin therapy, patients receiving glucocorticoid replacement therapy for previously identified adrenal insufficiency might need to increase their maintenance or stress dosages.

Patients who have untreated hypothyroidism will also not respond well to somatropin medication. Due to the increased risk of autoimmune thyroid disease in Turner’s syndrome patients, changes in thyroid hormone plasma levels may occur with somatropin therapy. Periodic thyroid function testing should be carried out, and when necessary, thyroid hormone therapy should be started.^[2]

It has been shown that somatropin medication can result in elevated intracranial pressure, papilledema, visual abnormalities, headaches, nausea, and/or vomiting. Within the first eight weeks of somatropin medication, symptoms often started to appear. The symptoms of intracranial hypertension went away either when somatropin medication was stopped or after the hormone’s dosage was decreased. When starting somatropin therapy and at intervals thereafter, funduscopic examination is advised. Patients with Prader-Willi syndrome, Turner’s syndrome, and chronic renal insufficiency may be more likely to develop intracranial hypertension.

Somatropin has not been the subject of adequate and controlled research in pregnant women, and it is unclear whether it could have harmful effects on the developing fetus or the reproductive system. Different levels above the typical human dose used in animal research have not been associated with any fetal damage or reduced fertility. Remind women of reproductive age that because somatropin usage during pregnancy has not been researched in humans, it is uncertain how the medicine may affect the fetus.^[5]^[6]^[1]^[2]^[13]

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.^[5]^[6]^[1]^[2]^[13]

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; however, reported clinical experience has 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 are 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.^[14] According to the Beers Criteria, growth hormone is considered a potentially inappropriate medication (PIM) for use in geriatric patients and should be avoided 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). However, the Beers expert panel considers hormone replacement after pituitary gland removal to be an acceptable use in the elderly.^[15]

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.^[7]

The effects of somatropin (Humatrope) on bone mineral density (BMD) and bone mineral content (BMC) have been evaluated in patients with adult-onset growth hormone deficiency and adults with childhood-onset GH deficiency still requiring somatropin therapy as adults (transition patients). Men, but not women, in the adult-onset study had an increase of 4% in lumbar spine BMD relative to placebo. No significant change in hip BMD was seen in women or men. In transition patients, patients randomized to 12.5 mcg/kg/day of somatropin, versus 25 mcg/kg/day or placebo, experienced an increase of 2.9% in total BMC; patients in the other two groups did not experience any changes. Increases in lumbar spine BMD and BMC were also statistically significant in the 12.5 mcg/kg/day treatment group. The occurrence of osteoporotic fracture was not studied.^[5]

The effect of somatropin (Nutropin AQ) on visceral adipose tissue has been evaluated in an open-label trial of adult patients with both childhood-onset and adult-onset GH deficiency. Doses of somatropin of up to 0.012 mg/kg per day in women (all of whom received estrogen replacement therapy) and men under age 35 years, and up to 0.006 mg/kg per day in men over age 35 years were administered for 32 weeks. Compared with untreated patients, after 32 weeks visceral adipose tissue (VAT) in patients treated with somatropin decreased by 14.2% (p = 0.012). The effect of reducing VAT in adult GHD patients with somatropin on long-term cardiovascular morbidity and mortality has not been determined.^[9]

Somatropin has been associated with an increased risk of a secondary 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 secondary 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.^[5]^[9]

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.^[6]^[2]^[9]^[10]^[11]^[5]

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.^[5]

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.^[5]^[6]^[1]^[2]^[9]^[10]^[11]

Metabolic complications have been frequently reported with somatropin therapy. During post-marketing surveillance of various products, there have been cases of new onset glucose intolerance, hyperglycemia, diabetes mellitus, and exacerbation of pre-existing diabetes mellitus.^[5] Some patients developed diabetic ketoacidosis and diabetic coma.^[6]^[13] 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.^[5] A greater incidence of impaired glucose tolerance has been observed with higher doses. In patients with Turner syndrome treated with Norditropin, impaired fasting glucose after 4 years of treatment occurred in 22% of patients receiving 0.045 mg/kg/day for 1 year followed by 0.067 mg/kg/day thereafter compared with 5% of patients receiving 0.045 mg/kg/day.^[11] Hypothyroidism has been reported in approximately 5—16% of patients receiving somatropin therapy.^[1]^[10] 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.^[10] Hyperlipidemia (8%) has also been reported, most often as hypertriglyceridemia (1—5%).^[5]^[6]

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.^[5]^[6]^[2]^[10]^[11]^[13] Seizures have been reported rarely.^[10]

Flu like symptoms have been reported in approximately 4—23% of somatropin-treated patients in clinical trials. Upper respiratory tract infection (e.g., naso-pharyngitis 3—14%, bronchitis 9%, and rhinitis 6—14%) has been reported at a similar frequency.^[5]^[2]^[11] Children with Turner syndrome reported otitis media (16—43%) and ear disorders (18%).^[5] In a study with Norditropin, patients in group 1 (0.045 mg/kg/day for year 1, 0.067 mg/kg/day for year 2, and 0.089 mg/kg/day thereafter) experienced a higher rate of otitis media of 86.4% compared to 78.3% of patients in group 2 (0.045 mg/kg/day for 1 year followed by 0.067 mg/kg/day thereafter) and 69.6% of patients in group 3 (0.045 mg/kg/day). These findings suggest higher doses may increase the risk of otitis media, and it should be noted that 40—50% of the cases were considered to be serious.^[11] Increased cough (6%) has also been reported.^[5]

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.^[1]^[2]^[10]

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.^[5]^[2]

During post-marketing experience with somatropin, dermatologic and serious systemic hypersensitivity reactions including anaphylactoid reactions and angioedema have been reported.^[5]^[6]^[1]^[2]^[7]^[8]^[9]^[10]^[11]^[12] Acne vulgaris (6%), diaphoresis (8%), alopecia, and eczema have been reported in patients taking somatropin therapy.^[5]^[2]^[11] Allergic reactions are possible and include rash (unspecified), and exacerbation of pre-existing psoriasis has been reported.^[10]

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—13%), gastritis (6%), and gastroenteritis (8%).^[5]^[2]^[11]

Gynecomastia has been observed in both adults (3—6%) and children (5—8%) treated with somatropin in clinical trials.^[5]^[6]

Hypertension (3—8%) and chest pain (unspecified) (5%) have been reported in patients treated with somatropin in clinical trials.^[5]^[10]^[11] Eosinophilia was reported in approximately 12% of pediatric patients receiving somatropin in clinical trials.^[1] Hematuria has been rarely observed.^[2]