ADVERSE REACTIONS
As with all protein drugs, a small number of patients may develop antibodies to the protein. Growth hormone antibody with binding lower than 2 mg/L has not been associated with growth attenuation. In some cases when binding capacity is > 2 mg/L, interference with growth response has been 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.
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.
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.
Leukemia has been reported in a small number of pediatric patients who have been treated with growth hormone, including growth hormone of pituitary origin and recombinant somatropin. The relationship, if any, between leukemia and growth hormone therapy is uncertain.
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.
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 pre-existing 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.
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 5 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 5 Adverse Events Reported by >/= 5% of 1,145 Adult GHD Patients During Clinical Trials of GENOTROPIN and Placebo, Grouped by Duration of Treatment
| Adverse Event |
Double Blind Phase |
Open Label Phase GENOTROPIN |
Placebo
0-6 mo.
n = 572 % Patients |
GENOTROPIN
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 Arthralgia
Upper respiratory infection Pain, extremities Edema, peripheral Paresthesia Headache Stiffness of extremities Fatigue Myalgia Back pain |
5.1
4.2
14.5
5.9
2.6
1.9
7.7
1.6
3.8
1.6
4.4
|
17.5 *
17.3 *
15.5
14.7 *
10.8 *
9.6 *
9.9
7.9 *
5.8
4.9 *
2.8 |
5.6
6.9
13.1
6.7
3.0
2.2
6.2
2.4
4.6
2.0
3.4
|
0
6.3
15.9
1.6
0
3.2
0
1.6
6.3
4.8
4.8
|
1.7
3.3
13.3
3.3
0
0
0
0
1.7
6.7
5.0
|
* Increased significantly when compared to placebo, P </=.025: Fisher's Exact Test (one-sided)
n = number of patients receiving treatment during the indicated period.
% = percentage of patients who reported the event during the indicated period.
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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.
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