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:
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•
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].
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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]
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a,bGlucose intolerance including impaired glucose tolerance/impaired fasting glucose as well as overt diabetes mellitus [Warnings and Precautions (5.4)]
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bIntracranial hypertension [see Warnings and Precautions ]
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bSignificant diabetic-retinopathy [see Contraindications]
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bSlipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions ]
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bProgression of preexisting scoliosis in pediatric patients [see Warnings and Precautions]
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bPancreatitis [see Warnings and Precautions ]
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aFluid retention manifested by edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias [see Warnings and Precautions]
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aUnmasking of latent central hypothyroidism [see Warnings and Precautions ]
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aInjection site reactions/rashes and lipoatrophy (as well as rare generalized hypersensitivity reactions) [see Warnings and Precautions (
5.13
)]
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)
|
Adverse Event
|
n
(%)
|
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 |
|
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:
Table 2. Incidence of Adverse Reactions Reported in ≥ 5% Pediatric Patients with GHD During Treatment with Omnitrope® for Injection (N=44)
|
Adverse Event
|
n
(%)
|
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 |
|
Hypothyroidism
|
7 (16%)
|
|
Eosinophilia
|
5 (11%)
|
|
Elevated HbA1c
|
4 (9%)
|
|
Hematoma
|
4 (9%)
|
|
Headache
|
3 (7%)
|
|
Hypertriglyceridemia
|
2 (5%)
|
|
Leg Pain
|
2 (5%)
|
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 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.
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
|
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
|
n=number of patients receiving treatment during the indicated period
%=percentage of patients who reported the event during the indicated period |
|
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
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|
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
|
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Myalgia
|
1.6
|
4.9
|
2.0
|
4.8
|
6.7
|
|
Back pain
|
4.4
|
2.8
|
3.4
|
4.8
|
5.0
|
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 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 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].
New-onset type 2 diabetes mellitus has been reported.
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