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Most Serious And/Or Most Frequently Observed Adverse Reactions
This list presents the most seriousa and/or most frequently observedb adverse reactions during treatment with somatropin:
- aSudden death in pediatric patients with Prader-Willi syndrome (PWS) with risk factors including severe obesity, history of upper airway obstruction or sleep apnea and unidentified respiratory infection [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
- aIntracranial tumors, in particular meningiomas, in teenagers/young adults treated with radiation to the head as children for a first neoplasm and somatropin [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
- aPancreatitis [see WARNINGS AND PRECAUTIONS]
- a,bGlucose intolerance including impaired glucose tolerance/impaired fasting glucose as well as overt diabetes mellitus [see WARNINGS AND PRECAUTIONS].
- aIntracranial hypertension [see WARNINGS AND PRECAUTIONS].
- aSignificant diabetic retinopathy [see CONTRAINDICATIONS].
- aSlipped capital femoral epiphysis in pediatric patients [see WARNINGS AND PRECAUTIONS].
- aProgression of preexisting scoliosis in pediatric patients [see WARNINGS AND PRECAUTIONS].
- bFluid retention manifested by edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias [see WARNINGS AND PRECAUTIONS].
- aUnmasking of latent central hypothyroidism [see WARNINGS AND PRECAUTIONS].
- aInjection site reactions/rashes and lipoatrophy (as well as rare generalized hypersensitivity reactions) [see WARNINGS AND PRECAUTIONS].
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.
Growth Hormone Deficiency (GHD)
Injection site discomfort has been reported. This is more commonly observed in children switched from another somatropin product to Nutropin AQ.
In a randomized, controlled trial, there was a statistically significant increase, as compared to untreated controls, in otitis media (43% vs. 26%) and ear disorders (18% vs. 5%) in patients receiving somatropin.
Idiopathic Short Stature (ISS)
In a post-marketing surveillance study, the National Cooperative Growth Study (NCGS), the pattern of adverse events in over 8,000 patients with ISS was consistent with the known safety profile of growth hormone (GH), and no new safety signals attributable to GH were identified. The frequency of protocol-defined targeted adverse events is described in the table, below.
Table 1 : Protocol-Defined Targeted Adverse
Events in the ISS NCGS Cohort
(N = 8018)
|Any Adverse Event|
|Targeted Adverse Event|
|Injection-site reaction||28 (0.3%)|
|New onset or progression of scoliosis||16 (0.2%)|
|Any new onset or recurring tumor (benign)||12 (0.1%)|
|Arthralgia or arthritis||10 (0.1%)|
|Diabetes mellitus||5 (0.1%)|
|Cancer, neoplasm (new onset or recurrence)||4 (0.0%)|
|Intracranial hypertension||4 (0.0%)|
|Abnormal bone or other growth||3 (0.0%)|
|Central nervous system tumor||2 (0.0%)|
|New or recurrent SCFE or AVN||2 (0.0%)|
|Carpal tunnel syndrome||1 (0.0%)|
|AVN= avascular necrosis; SCFE
= slipped capital femoral epiphysis.
Data obtained with several rhGH products (Nutropin, Nutropin AQ, Nutropin Depot and Protropin).
In subjects treated in a long-term study of Nutropin for ISS, mean fasting and postprandial insulin levels increased, while mean fasting and postprandial glucose levels remained unchanged. Mean hemoglobin A1c (A1C) levels rose slightly from baseline as expected during adolescence; sporadic values outside normal limits occurred transiently.
Growth Hormone Deficiency
In clinical studies with Nutropin AQ in GHD adults, edema or peripheral edema was reported in 41% of GH-treated patients and 25% of placebo-treated patients. In GHD adults, arthralgias and other joint disorders were reported in 27% of GH-treated patients and 15% of placebo-treated patients.
Nutropin therapy in adults with GHD of adult-onset was associated with an increase of median fasting insulin level in the Nutropin 0.0125 mg/kg/day group from 9.0 μU/mL at baseline to 13.0 μU/mL at Month 12 with a return to the baseline median level after a 3-week post-washout period of GH therapy. In the placebo group there was no change from 8.0 μU/mL at baseline to Month 12, and after the post-washout period, the median level was 9.0 μU/mL. The between-treatment group difference on the change from baseline to Month 12 in median fasting insulin level was significant, p < 0.0001. In childhood-onset subjects, there was an increase of median fasting insulin level in the Nutropin 0.025 mg/kg/day group from 11.0 μU/mL at baseline to 20.0 μU/mL at Month 12, in the Nutropin 0.0125 mg/kg/day group from 8.5 μU/mL to 11.0 μU/mL, and in the placebo group from 7.0 μU/mL to 8.0 μU/mL. The between-treatment group differences for these changes were significant, p = 0.0007.
In subjects with adult-onset GHD, there were no between-treatment group differences on change from baseline to Month 12 in mean A1C level, p = 0.08. In childhood-onset GHD, the mean A1C level increased in the Nutropin 0.025 mg/kg/day group from 5.2% at baseline to 5.5% at Month 12, and did not change in the Nutropin 0.0125 mg/kg/day group from 5.1% at baseline or in the placebo group from 5.3% at baseline. The between-treatment group differences were significant, p = 0.009.
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 GHD 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, CKD, or TS, if any, remains to be established [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
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 Nutropin with the incidence of antibodies to other products may be misleading. In the case of GH, antibodies with binding capacities lower than 2 mg/L 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/L, interference with the growth response was observed.
In clinical studies of pediatric patients that were treated with Nutropin for the first time, 0/107 GHD patients, 0/125 CKD patients, 0/112 TS, and 0/117 ISS patients screened for antibody production developed antibodies with binding capacities ≥ 2 mg/L at six months. In a clinical study of patients that were treated with Nutropin AQ for the first time, 0/38 GHD patients screened for antibody production for up to 15 months developed antibodies with binding capacities ≥ 2 mg/L.
Additional short-term immunologic and renal function studies were carried out in a group of pediatric patients with CKD after approximately one year of treatment to detect other potential adverse effects of antibodies to GH. Testing included measurements of C1q, C3, C4, rheumatoid factor, creatinine, creatinine clearance, and blood urea nitrogen (BUN). No adverse effects of GH antibodies were noted.
Read the Nutropin AQ (somatropin (rdna origin)) Side Effects Center for a complete guide to possible side effects
11 β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-1)
The microsomal enzyme 11βHSD-1 is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Growth hormone (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 therapy should be carefully adjusted in children with concomitant GH and glucocorticoid deficiency to avoid both hypoadrenalism and an inhibitory effect on growth.
The use of Nutropin AQ in patients with Chronic Kidney Disease (CKD) requiring glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth promoting effect of Nutropin AQ. Therefore, if glucocorticoid replacement is required for CKD, the glucocorticoid dose should be carefully adjusted to avoid an inhibitory effect on growth. In the clinical trials there was no evidence of drug interactions with Nutropin and commonly used drugs used in the management of CKD.
Cytochrome P450 (CYP450)-Metabolized Drugs
Limited published data indicate that somatropin treatment increases 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.
Because oral estrogens may reduce insulin-like growth factor (IGF-1) response to somatropin treatment, girls and women receiving oral estrogen replacement may require greater somatropin dosages [see DOSAGE AND ADMINISTRATION].
Insulin And/Or Oral/Injectable Hypoglycemic Agents
In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral/injectable hypoglycemic agents may require adjustment when somatropin therapy is initiated [see WARNINGS AND PRECAUTIONS].
Read the Nutropin AQ Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 6/8/2015
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