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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 and WARNINGS AND PRECAUTIONS].
• ^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 and WARNINGS AND PRECAUTIONS]
• ^a,bGlucose intolerance including impaired glucose tolerance/impaired fasting glucose as well as overt diabetes mellitus [WARNINGS AND PRECAUTIONS]
• ^bIntracranial hypertension [see WARNINGS AND PRECAUTIONS]
• ^bSignificant diabetic-retinopathy [see CONTRAINDICATIONS]
• ^bSlipped capital femoral epiphysis in pediatric patients [see WARNINGS AND PRECAUTIONS]
• ^bProgression of preexisting scoliosis in pediatric patients [see WARNINGS AND PRECAUTIONS]
• ^bPancreatitis [see WARNINGS AND PRECAUTIONS]
• ^aFluid 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.

Clinical Trials in Pediatric GHD Patients

The following events were observed during clinical studies with Omnitrope® Cartridge conducted in children with GHD:

Table 1: Incidence of Adverse Reactions Reported in ≥ 5% Pediatric Patients with GHD During Treatment with Omnitrope® Cartridge (N=86)

The following events were observed during clinical studies with Omnitrope® for injection conducted in children with GHD:

Table 2: Incidence of Adverse Reactions Reported in ≥ 5% Pediatric Patients with GHD During Treatment with Omnitrope® for Injection (N=44)

Clinical Trials in PWS

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 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.

Table 3: Adverse Events Reported by ≥ 5% of 1,145 Adult GHD Patients During Clinical Trials of Another Somatropin Product and Placebo, Grouped by Duration of Treatment

Post-Trial Extension Studies in Adults

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 influences by several factors including assay methodology, sample handling, timing of sample col,ection, 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 and WARNINGS AND PRECAUTIONS].

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]).

Metabolic

New-onset type 2 diabetes mellitus in patients.

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].

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].

Last reviewed on RxList: 6/1/2011
This monograph has been modified to include the generic and brand name in many instances.