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:
- b Sudden 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]
- b Intracranial 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,b Glucose intolerance including impaired glucose
tolerance/impaired fasting glucose as well as overt diabetes mellitus [see Warnings and Precautions]
- b Intracranial hypertension [see Warnings and Precautions]
- b Significant diabetic retinopathy [see Contraindications]
- b Slipped capital femoral epiphysis in pediatric patients
[see Warnings and Precautions]
- b Progression of preexisting scoliosis in pediatric patients
[see Warnings and Precautions]
- a Fluid retention manifested by edema, arthralgia, myalgia,
nerve compression syndromes including carpal tunnel syndrome/paraesthesias [see Warnings
and Precautions]
- a Unmasking of latent central hypothyroidism [see Warnings
and Precautions]
- a Injection 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 children with GHD
In clinical studies with GENOTROPIN in pediatric GHD patients, the
following events were reported infrequently: injection site reactions,
including pain or burning associated with the injection, fibrosis,
nodules, rash, inflammation, pigmentation, or bleeding; lipoatrophy;
headache; hematuria; hypothyroidism; and mild hyperglycemia.
Clinical Trials in PWS
In two clinical studies with GENOTROPIN in pediatric patients with Prader-Willi syndrome,
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 GENOTROPIN, 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. Anti-hGH antibodies were not detected in any of the
patients treated with GENOTROPIN.
Clinical Trials in children with Turner Syndrome
In two clinical studies with GENOTROPIN 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 children with Idiopathic Short Stature
In two open-label clinical studies with GENOTROPIN in pediatric patients with ISS,
the most commonly encountered adverse events include upper respiratory tract infections,
influenza, tonsillitis, nasopharyngitis, gastroenteritis, headaches, increased appetite,
pyrexia, fracture, altered mood, and arthralgia. In one of the two studies, during
Genotropin treatment, 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 GENOTROPIN 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 1 displays the adverse events reported by 5% or more of adult GHD
patients in clinical trials after various durations of treatment with GENOTROPIN.
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 1
Adverse Events Reported by ≥ 5% of 1,145 Adult GHD Patients During Clinical
Trials of GENOTROPIN 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 GENOTROPIN. All 12 patients had predisposing
factors, e.g., elevated glycated hemoglobin levels and/or marked obesity, prior
to receiving GENOTROPIN. Of the 3,031 patients receiving GENOTROPIN, 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.
Anti-hGH Antibodies
As with all protein drugs, a small percentage of patients may develop
antibodies to the protein. GH antibodies with binding capacities lower
than 2 mg/L have not been associated with growth attenuation. In a very
small number of patients, when binding capacity was greater than 2 mg/L,
interference with the growth response was observed.
In 419 pediatric patients evaluated in clinical studies with GENOTROPIN
lyophilized powder, 244 had been treated previously with GENOTROPIN or
other growth hormone preparations and 175 had received no previous growth
hormone therapy. Antibodies to growth hormone (anti-hGH antibodies) were
present in six previously treated patients at baseline. Three of the six
became negative for anti-hGH antibodies during 6 to 12 months of treatment
with GENOTROPIN. Of the remaining 413 patients, eight (1.9%) developed
detectable anti-hGH antibodies during treatment with GENOTROPIN;
none had an antibody binding capacity > 2 mg/L. There was no evidence
that the growth response to GENOTROPIN was affected in these antibody-positive patients.
Periplasmic Escherichia coli Peptides
Preparations of GENOTROPIN contain a small amount of periplasmic Escherichia coli
peptides (PECP). Anti-PECP antibodies are found in a small number of patients treated
with GENOTROPIN, but these appear to be of no clinical significance.
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 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, if any, remains to be established [see Contraindications and Warnings and Precautions].
The following additional adverse reactions have been observed during the appropriate
use of somatropin: headaches (children and adults), gynecomastia
(children), and pancreatitis (children).