somatropin
Dosage Form: injection, solution
FULL PRESCRIBING INFORMATION
Indications and Usage for Omnitrope
Pediatric Patients
Omnitrope® (somatropin [rDNA origin] injection) is indicated for the treatment of children with growth failure due to inadequate secretion of endogenous growth hormone (GH).
Omnitrope® [somatropin (rDNA origin) injection] is indicated for the treatment of pediatric patients who have growth failure due to Prader-Willi Syndrome (PWS). The diagnosis of PWS should be confirmed by appropriate genetic testing [see Contraindications (.
Omnitrope® [somatropin (rDNA origin) injection] is indicated for the treatment of growth failure in children born small for gestational age (SGA) who fail to manifest catch-up growth by age 2 years.
Omnitrope® [somatropin (rDNA origin) injection] is indicated for the treatment of growth failure associated with Turner syndrome.
Omnitrope® (somatropin [rDNA origin] injection) is indicated for the treatment of idiopathic short stature (ISS), also called non-growth hormone-deficient short stature, defined by height standard deviation score (SDS) ≤ -2.25, and associated with growth rates unlikely to permit attainment of adult height in the normal range, in pediatric patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other causes associated with short stature that should be observed or treated by other means.
Adult Patients
Omnitrope® (somatropin [rDNA origin] injection) is indicated for the replacement of endogenous GH in adults with growth hormone deficiency (GHD) who meet either of the following two criteria:
- Adult Onset (AO): Patients who have GHD, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or
- Childhood Onset (CO): Patients who were GH deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes.
Patients who were treated with somatropin for growth hormone deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin therapy at the reduced dose level recommended for growth hormone deficient adults. Confirmation of the diagnosis of adult growth hormone deficiency in both groups involves an appropriate growth hormone provocative test with two exceptions: (1) patients with multiple other pituitary hormone deficiencies due to organic disease; and (2) patients with congenital/genetic growth hormone deficiency.
Omnitrope Dosage and Administration
The weekly dose should be divided over 6 or 7 days of subcutaneous injections.
Therapy with Omnitrope® should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with short stature associated with GHD, Prader-Willi Syndrome (PWS), Turner syndrome (TS), those who were born small for gestational age (SGA), Idiopathic Short Stature (ISS) and adult patients with either childhood onset or adult onset GHD.
Dosing of Pediatric Patients
General Pediatric Dosing Information
The Omnitrope® dosage and administration schedule should be individualized based on the growth response of each patient.
Response to somatropin therapy in pediatric patients tends to decrease with time. However, in pediatric patients, the failure to increase growth rate, particularly during the first year of therapy, indicates the need for close assessment of compliance and evaluation for other causes of growth failure, such as hypothyroidism, undernutrition, advanced bone age and antibodies to recombinant human GH (rhGH).
Treatment with Omnitrope® for short stature should be discontinued when the epiphyses are fused.
Pediatric Growth Hormone Deficiency (GHD)
Generally, a dosage of 0.16 to 0.24 mg/kg body weight /week is recommended. The weekly dose should be divided over 6 or 7 days of subcutaneous injections.
Prader-Willi Syndrome (PWS)
Generally, a dosage of 0.24 mg/kg body weight/week is recommended. The weekly dose should be divided over 6 or 7 days of subcutaneous injections.
Small for Gestational Age (SGA)
Generally, a dosage of up to 0.48 mg/kg body weight/week is recommended. The weekly dose should be divided over 6 or 7 days of subcutaneous injections.
Turner Syndrome (TS)
Generally, a dose of 0.33 mg/kg body weight/week is recommended. The weekly dose should be divided over 6 or 7 days of subcutaneous injections.
Idiopathic Short Stature (ISS)
Generally, a dose up to 0.47 mg/kg of body weight/week is recommended. The weekly dose should be divided over 6 or 7 days of subcutaneous injections.
Dosing of Adult Patients
Adult Growth Hormone Deficiency (GHD)
Based on the weight-based dosing utilized in clinical studies with another somatropin product, the recommended dosage at the start of therapy is not more than 0.04 mg/kg/week given as a daily subcutaneous injection. The dose may be increased at 4- to 8-week intervals according to individual patient requirements to not more than 0.08 mg/kg/week. Clinical response, side effects, and determination of age- and gender-adjusted serum IGF-I levels may be used as guidance in dose titration.
Alternatively, taking into account recent literature, a starting dose of approximately 0.2 mg/day (range, 0.15-0.30 mg/day) may be used without consideration of body weight. This dose can be increased gradually every 1-2 months by increments of approximately 0.1 to 0.2 mg/day, according to individual patient requirements based on the clinical response and serum IGF-I concentrations. During therapy, the dose should be decreased if required by the occurrence of adverse events and/or serum IGF-I levels above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to person.
A lower starting dose and smaller dose increments should be considered for older patients, who are more prone to the adverse effects of somatropin than younger individuals. In addition, obese individuals are more likely to manifest adverse effects when treated with a weight-based regimen. In order to reach the defined treatment goal, estrogen-replete women may need higher doses than men. Oral estrogen administration may increase the dose requirements in women.
Preparation and Administration
Omnitrope® Cartridge 5 mg/1.5 mL and Cartridge 10 mg/1.5 mL
Each cartridge of Omnitrope® must be inserted into its corresponding Omnitrope® Pen 5 or Omnitrope® Pen 10 delivery system. Instructions for delivering the dosage are provided in the Omnitrope® INSTRUCTIONS FOR USE booklet enclosed with the Omnitrope® drug and the Omnitrope® Pens.
Omnitrope® for injection 5.8 mg/vial
Instructions for delivering the dosage are provided in the INSTRUCTIONS FOR USE leaflets enclosed with the Omnitrope® drug.
Once the diluent is added to the lyophilized powder, swirl gently; do not shake. Shaking may cause denaturation of the active ingredient.
Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Omnitrope® MUST NOT BE INJECTED if the solution is cloudy or contains particulate matter. Use it only if it is clear and colorless. Omnitrope must be refrigerated at 2° to 8°C (36° to 46°F).
Patients and caregivers who will administer Omnitrope® in medically unsupervised situations should receive appropriate training and instruction on the proper use of Omnitrope® from the physician or other suitably qualified health professional.
The dosage of Omnitrope® must be adjusted for the individual patient. The dose should be given daily by subcutaneous injections (administered preferably in the evening). Omnitrope® may be given in the thigh, buttocks, or abdomen.
Injection sites should always be rotated to avoid lipoatrophy.
Dosage Forms and Strengths
Omnitrope® Cartridges and vials (for injection) are available:
- 5 mg/1.5 mL Cartridge is a prefilled sterile somatropin solution containing benzyl alcohol in a glass cartridge ready to be administered with the Omnitrope® Pen 5.
- 10 mg/1.5 mL Cartridge is a prefilled sterile somatropin solution in a glass cartridge ready to be administered with the Omnitrope® Pen 10.
- 5.8 mg/vial is supplied with two vials, one containing somatropin as a powder and the other vial containing diluent (Bacteriostatic Water for Injection containing benzyl alcohol as a preservative).
Contraindications
Acute Critical Illness
Treatment with pharmacologic amounts of somatropin is contraindicated 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. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo [see Warnings And Precautions (5.1)].
Prader-Willi Syndrome in Children
Somatropin is contraindicated in patients with Prader-Willi Syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe respiratory impairment. There have been reports of sudden death when somatropin was used in such patients [see Warnings And Precautions (5.2)].
Active Malignancy
In general, somatropin is contraindicated in the presence of active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of recurrent activity. Since GHD 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. Somatropin should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor.
Diabetic Retinopathy
Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.
Closed Epiphyses
Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses.
Hypersensitivity
Omnitrope® is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. Localized reactions are the most common hypersensitivity reactions.
Warnings and Precautions
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 pharmacologic amounts of somatropin [see Contraindications (4.1)]. The safety of continuing somatropin 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 somatropin in patients experiencing acute critical illnesses should be weighed against the potential risk.
Prader-Willi Syndrome in Children
There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with Prader-Willi Syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi Syndrome should be evaluated for signs of upper airway obstruction (including onset of or increased snoring) and sleep apnea before initiation of treatment with somatropin. If, during treatment with somatropin, patients show signs of upper airway obstruction (including onset of or increased snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with Prader-Willi Syndrome treated with somatropin should also have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively [see Contraindications (4.2)].
Neoplasms
Patients with preexisting tumors or GHD secondary to an intracranial lesion should be monitored routinely for progression or recurrence of the underlying disease process. In pediatric patients, clinical literature has revealed no relationship between somatropin replacement therapy and central nervous system (CNS) tumor recurrence or new extracranial tumors. However, in childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients treated with somatropin after their first neoplasm. Intracranial tumors, in particular meningiomas, in patients treated with radiation to the head for their first neoplasm, were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor recurrence [see Contraindications (4.3)].
Patients should be monitored carefully for potential malignant transformation of skin lesions, i.e. increased growth of preexisting nevi.
Impaired Glucose Tolerance and Diabetes Mellitus
Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a result, previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked, and new onset type 2 diabetes mellitus has been reported in patients taking somatropin. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus, such as obesity, Turner Syndrome, 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 somatropin therapy. The doses of antihyperglycemic drugs (i.e., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients. [See Drug Interactions (7.5)]
Intracranial Hypertension (IH)
Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with somatropin products. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose.
Funduscopic examination should be performed routinely before initiating treatment with somatropin to exclude preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed by funduscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin can be restarted at a lower dose after IH-associated signs and symptoms have resolved. Patients with Turner syndrome and Prader-Willi Syndrome may be at increased risk for the development of IH.
Fluid Retention
Fluid retention during somatropin replacement therapy in adults may frequently occur. Clinical manifestations of fluid retention are usually transient and dose dependent.
Hypopituitarism
Patients with hypopituitarism (multiple pituitary hormone deficiencies) should have their other hormonal replacement treatments closely monitored during somatropin treatment.
Hypothyroidism
Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response in children. Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism and should have their thyroid function checked prior to initiation of somatropin therapy. In patients with GHD, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Therefore, patients treated with somatropin should have periodic thyroid function tests and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated.
Slipped Capital Femoral Epiphysis in Pediatric Patients
Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including GHD and Turner syndrome) or in patients undergoing rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated.
Progression of Preexisting Scoliosis in Pediatric Patients
Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases growth rate, patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis. However, somatropin has not been shown to increase the occurrence of scoliosis. Skeletal abnormalities including scoliosis are commonly seen in untreated Turner syndrome patients. Scoliosis is also commonly seen in untreated patients with Prader-Willi Syndrome. Physicians should be alert to these abnormalities, which may manifest during somatropin therapy.
Confirmation of Childhood Onset Adult GHD
Patients with epiphyseal closure who were treated with somatropin replacement therapy in childhood should be reevaluated according to the criteria in Indications And Usage (1.2) before continuation of somatropin therapy at the reduced dose level recommended for GH deficient adults.
Otitis Media and Cardiovascular Disorders in Turner Syndrome
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. Somatropin 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.
Local and Systemic Reactions
When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. This can be avoided by rotating the injection site [see Dosage And Administration (2.3)].
As with any protein, local or systemic allergic reactions may occur. Parents/Patients should be informed that such reactions are possible and that prompt medical attention should be sought if allergic reactions occur.
Laboratory Tests
Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and IGF-I may increase after somatropin therapy.
5.15 Pancreatitis
Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment, with some evidence supporting a greater risk in children compared with adults. Published literature indicates that girls who have Turner syndrome may be at greater risk than other somatropin-treated children. Pancreatitis should be considered in any somatropin treated patient, especially a child, who develops persistent severe abdominal pain.
Benzyl Alcohol
Benzyl alcohol, a component of Omnitrope® Cartridge 5 mg/1.5 mL and the diluent for Omnitrope® for injection 5.8 mg/vial, has been associated with serious adverse events and death, particularly in pediatric patients. The “gasping syndrome,” (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.
Adverse Reactions
Most Serious and/or Most Frequently Observed Adverse Reactions
This list presents the most seriousb and/or most frequently observeda adverse reactions during treatment with somatropin:
- bSudden death in pediatric patients with Prader-Willi Syndrome with risk factors including severe obesity, history of upper airway obstruction or sleep apnea and unidentified respiratory infection [see Contraindications (4.2) and Warnings and Precautions (5.2)].
- bIntracranial tumors, in particular meningiomas, in teenagers/young adults treated with radiation to the head as children for a first neoplasm and somatropin [see Contraindications (4.3) and Warnings and Precautions (5.3)]
- a,bGlucose intolerance including impaired glucose tolerance/impaired fasting glucose as well as overt diabetes mellitus [Warnings and Precautions (5.4)]
- bIntracranial hypertension [see Warnings and Precautions (5.5)]
- bSignificant diabetic-retinopathy [see Contraindications (4.4)]
- bSlipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.9)]
- bProgression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.10)]
- bPancreatitis [see Warnings and Precautions (5.15)]
- aFluid retention manifested by edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias [see Warnings and Precautions (5.6)]
- aUnmasking of latent central hypothyroidism [see Warnings and Precautions (5.8)]
- aInjection site reactions/rashes and lipoatrophy (as well as rare generalized hypersensitivity reactions) [see Warnings and Precautions (5.12)]
Clinical Trials Experience
Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical trials performed with a second somatropin formulation, and may not reflect the adverse reaction rates observed in practice.
Clinical Trials in Pediatric GHD Patients
The following events were observed during clinical studies with Omnitrope® Cartridge conducted in children with GHD:
| N=number of patients receiving treatment n=number of patients who reported the event during study period %=percentage of patients who reported the event during study period | |
| Adverse Event | n (%) |
| Elevated HbA1c | 12 (14%) |
| Eosinophilia | 10 (12%) |
| Hematoma | 8 (9%) |
The following events were observed during clinical studies with Omnitrope® for injection conducted in children with GHD:
| N=number of patients receiving treatment n=number of patients who reported the event during study period %= percentage of patients who reported the event during study period | |
| Adverse Event | n (%) |
| Hypothyroidism | 7 (16%) |
| Eosinophilia | 5 (11%) |
| Elevated HbA1c | 4 (9%) |
| Hematoma | 4 (9%) |
| Headache | 3 (7%) |
| Hypertriglyceridemia | 2 (5%) |
| Leg Pain | 2 (5%) |
In two clinical studies in pediatric patients with Prader-Willi Syndrome carried out with another somatropin product, the following drug-related events were reported: edema, aggressiveness, arthralgia, benign intracranial hypertension, hair loss, headache, and myalgia.
Clinical Trials in Children with SGA
In clinical studies of 273 pediatric patients born small for gestational age treated with another somatropin product, the following clinically significant events were reported: mild transient hyperglycemia, one patient with benign intracranial hypertension, two patients with central precocious puberty, two patients with jaw prominence, and several patients with aggravation of preexisting scoliosis, injection site reactions, and self-limited progression of pigmented nevi.
Clinical Trials in Children with Idiopathic Short Stature
In two open-label clinical studies conducted with another somatropin product in pediatric patients with ISS, the most commonly encountered adverse events were upper respiratory tract infections, influenza, tonsillitis, nasopharyngitis, gastroenteritis, headaches, increased appetite, pyrexia, fracture, altered mood, and arthralgia. In one of the two studies during treatment with this other somatropin product, the mean IGF-1 standard deviation (SD) scores were maintained in the normal range. IGF-1 SD scores above +2 SD were observed as follows: 1 subject (3%), 10 subjects (30%) and 16 subjects (38%) in the untreated control, 0.23 and the 0.47 mg/kg/week groups respectively, had at least one measurement; while 0 subjects (0%), 2 subjects (7%) and 6 subjects (14%) had two or more consecutive IGF-1 measurements above +2 SD.
Clinical Trials in Children with Turner Syndrome
In two clinical studies with another somatropin product in pediatric patients with Turner syndrome, the most frequently reported adverse events were respiratory illnesses (influenza, tonsillitis, otitis, sinusitis), joint pain, and urinary tract infection. The only treatment-related adverse event that occurred in more than 1 patient was joint pain.
Clinical Trials in Adults with GHD
In clinical trials with another somatropin product in 1,145 GHD adults, the majority of the adverse events consisted of mild to moderate symptoms of fluid retention, including peripheral swelling, arthralgia, pain and stiffness of the extremities, peripheral edema, myalgia, paresthesia, and hypoesthesia. These events were reported early during therapy, and tended to be transient and/or responsive to dosage reduction.
Table 3 displays the adverse events reported by 5% or more of adult GHD patients in clinical trials after various durations of treatment with another somatropin product. Also presented are the corresponding incidence rates of these adverse events in placebo patients during the 6-month double-blind portion of the clinical trials.
| n=number of patients receiving treatment during the indicated period %=percentage of patients who reported the event during the indicated period | |||||
| |||||
| Double Blind Phase | Open Label Phase Another Somatropin Product | ||||
| Adverse Event | Placebo 0–6 mo. (n = 572) % Patients | Another Somatropin Product 0–6 mo. (n = 573) % Patients | 6–12 mo. (n = 504) % Patients | 12–18 mo. (n = 63) % Patients | 18–24 mo. (n = 60) % Patients |
| Swelling, peripheral | 5.1 | 17.5* | 5.6 | 0 | 1.7 |
| Arthralgia | 4.2 | 17.3* | 6.9 | 6.3 | 3.3 |
| Upper respiratory infection | 14.5 | 15.5 | 13.1 | 15.9 | 13.3 |
| Pain, extremities | 5.9 | 14.7* | 6.7 | 1.6 | 3.3 |
| Edema, peripheral | 2.6 | 10.8* | 3.0 | 0 | 0 |
| Paresthesia | 1.9 | 9.6* | 2.2 | 3.2 | 0 |
| Headache | 7.7 | 9.9 | 6.2 | 0 | 0 |
| Stiffness of extremities | 1.6 | 7.9* | 2.4 | 1.6 | 0 |
| Fatigue | 3.8 | 5.8 | 4.6 | 6.3 | 1.7 |
| Myalgia | 1.6 | 4.9* | 2.0 | 4.8 | 6.7 |
| Back pain | 4.4 | 2.8 | 3.4 | 4.8 | 5.0 |
In expanded post-trial extension studies, diabetes mellitus developed in 12 of 3,031 patients (0.4%) during treatment with another somatropin product. All 12 patients had predisposing factors, e.g., elevated glycated hemoglobin levels and/or marked obesity, prior to receiving this other somatropin product. Of the 3,031 patients receiving this other somatropin product, 61 (2%) developed symptoms of carpal tunnel syndrome, which lessened after dosage reduction or treatment interruption (52) or surgery (9). Other adverse events that have been reported include generalized edema and hypoesthesia.
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Omnitrope with the incidence of antibodies to other products may be misleading. In the case of growth hormone, antibodies with binding capacities lower than 2 mg/mL have not been associated with growth attenuation. In a very small number of patients treated with somatropin, when binding capacity was greater than 2 mg/mL, interference with the growth response was observed.
Post-Marketing Experience
Because these adverse events 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. The adverse events reported during post-marketing surveillance do not differ from those listed/discussed above in Sections 6.1 and 6.2 in children and adults.
Leukemia has been reported in a small number of GH deficient children treated with somatropin, somatrem (methionylated rhGH) and GH of pituitary origin. It is uncertain whether these cases of leukemia are related to GH therapy, the pathology of GHD itself, or other associated treatments such as radiation therapy. On the basis of current evidence, experts have not been able to conclude that GH therapy per se was responsible for these cases of leukemia. The risk for children with GHD, if any, remains to be established [see Contraindications (4.3) and Warnings And Precautions (5.3)].
The following additional adverse reactions have been observed during the use of somatropin: headaches (children and adults), gynecomastia (children), and pancreatitis (children and adults [see Warnings and Precautions (5.15)].
New-onset type 2 diabetes mellitus has been reported.
Drug Interactions
11β-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. GH and 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.
Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment
Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth promoting effects of somatropin in children. Therefore, glucocorticoid replacement dosing should be carefully adjusted in children receiving concomitant somatropin and glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth.
Cytochrome P450-Metabolized Drugs
Limited published data indicate that somatropin treatment increases cytochrome P450 (CYP450)-mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CYP450 liver enzymes. However, formal drug interaction studies have not been conducted.
Oral Estrogen
In adult women on oral estrogen replacement, a larger dose of somatropin may be required to achieve the defined treatment goal [see Dosage And Administration (2.2)].
Insulin and/or Oral Hypoglycemic Agents
In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral agent may require adjustment when somatropin therapy is initiated [see Warnings And Precautions (5.4)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B
Animal reproduction studies have not been conducted with Omnitrope®. It is not known whether Omnitrope® can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.
Reproduction studies carried out with another somatropin product at doses of 0.3, 1, and 3.3 mg/kg/day administered subcutaneously in the rat and 0.08, 0.3, and 1.3 mg/kg/day administered intramuscularly in the rabbit (highest doses approximately 24 times and 19 times the recommended human therapeutic levels, respectively, based on body surface area) resulted in decreased maternal body weight gains but were not teratogenic. In rats receiving subcutaneous doses during gametogenesis and up to 7 days of pregnancy, 3.3 mg/kg/day (approximately 24 times human dose) produced anestrus or extended estrus cycles in females and fewer and less motile sperm in males. When given to pregnant female rats (days 1 to 7 of gestation) at 3.3 mg/kg/day a very slight increase in fetal deaths was observed. At 1 mg/kg/day (approximately seven times human dose) rats showed slightly extended estrus cycles, whereas at 0.3 mg/kg/day no effects were noted.
In perinatal and postnatal studies in rats, doses of 0.3, 1, and 3.3 mg/kg/day of this other somatropin product produced growth-promoting effects in the dams but not in the fetuses. Young rats at the highest dose showed increased weight gain during suckling but the effect was not apparent by 10 weeks of age. No adverse effects were observed on gestation, morphogenesis, parturition, lactation, postnatal development, or reproductive capacity of the offspring due to this other somatropin product. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
It is not known whether Omnitrope® is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Omnitrope® is administered to a nursing woman.
Geriatric Use
The safety and effectiveness of Omnitrope® in patients aged 65 and over have not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of somatropin, and therefore may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for older patients [see Dosage And Administrati
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