Report summarizes 20-year safety data on recombinant human GH in childrenLeukemia has not been confirmed as a major safety issue, but other signals have been detected.
Twenty years after the FDA approved recombinant human growth hormone for use in children in the United States, a new report concluded that the overall safety profile continues to be favorable, but careful monitoring for the presence of certain conditions is important during and after therapy.
Twenty-year data from the National Cooperative Growth Study (NCGS) indicate that leukemia, considered to be a major safety issue associated with GH, has not been confirmed or substantiated in children taking GH. Data indicate three observed events vs. 5.6 expected events in an age-matched general population based on years at risk (standard incidence ratio=0.54; 95% CI, 0.11-1.58). Intracranial and extracranial de novo malignancies were not significantly increased in patients without risk factors (29 confirmed vs. 26 expected; SIR=1.12; 95% CI, 0.75-1.61).
“We continue to see no increase in new malignancies or recurrences of central nervous system tumors in rhGH-treated children without risk factors. The low number of cases of new-onset leukemia without risk factors also confirms previous reports that GH therapy does not increase the incidence of leukemia in children not at risk,” researchers wrote in the Journal of Clinical Endocrinology & Metabolism.
However, the data highlight specific populations at potential risk, according to the researchers.
Such at-risk populations include children with prior malignancies who showed an increased incidence of second tumors, especially if the primary malignancy was treated with radiation therapy, and children with bilateral retinoblastoma. Data revealed second neoplasms in 49 patients; 37 had irradiation of the initial tumor, including five patients with retinoblastoma and three with bilateral retinoblastoma.
“That our data are consistent with an increase in the occurrence of second malignant tumors in children treated with rhGH is of some concern,” the researchers wrote. “Although the risk of developing a new tumor in any patient with a past malignancy is elevated regardless of rhGH therapy, this risk in those with a prior malignancy appears to be further increased by rhGH.”
Twenty-year data
The open-label, multicenter, postmarketing NCGS was established by Genentech after rhGH was approved in 1985 to monitor the safety and efficacy in children with growth disorders.
Researchers presented 20-year data on 54,996 children (65% boys) between 1985 and 2006. Enrolled patients were followed until rhGH discontinuation. Data comprise 195,419 patient-years of treatment with Genentech rhGH products.
“The overall incidence of adverse events and serious adverse events from the NCGS continues to be stable, compared with prior NCGS safety analyses,” the researchers wrote.
As of Jan. 1, 2006, there were 4,084 submitted adverse event reports: 1,559 were deemed serious, including 174 deaths. Researchers who assessed the adverse events determined most were unrelated to rhGH or did not provide a causality assessment. The most common cause of death was recurrent or new-onset central nervous system tumor, particularly in patients with organic GH deficiency. Other causes of death included respiratory failure, pneumonia/pneumonitis, cerebral edema and cardiac arrest.
Nineteen (11%) of the 174 deaths were related to rhGH. Causes of death included neoplasms, craniopharyngioma, glioblastoma, medulloblastoma recurrence, astrocytoma, brain neoplasm, neuroblastoma, osteosarcoma recurrence and pineoblastoma.
Specific groups identified as being at risk for sudden death included patients with Turner syndrome, Prader-Willi syndrome, adrenocorticotropic hormone deficiency, and from aortic dissection and rupture or respiratory failure.
Patients who used rhGH for an idiopathic short stature indication had the lowest incidence of adverse events.
Reported targeted adverse events associated with or exacerbated by rhGH included type 1 diabetes, intracranial hypertension, slipped capital femoral epiphysis, scoliosis and pancreatitis. The overall incidences remained infrequent (<1%) and were comparable with previous NCGS safety reports.
New targeted association
“New safety signals of events potentially associated with rhGH treatment, including the risk of secondary malignancies after irradiation, deaths from adrenal insufficiency and deaths in Prader-Willi syndrome, have emerged,” the researchers wrote.
Eleven events of acute adrenal insufficiency occurred in patients with organic GH deficiency and idiopathic panhypopituitarism, including four deaths. These findings are “consistent with a reported increased risk for adrenal insufficiency in hypopituitary patients with or without rhGH treatment,” according to the researchers. The time of onset of initiation to event ranged from within 24 hours to seven years (mean, 2.5 years).
Among the 511 patients in the NCGS with Prader-Willi syndrome, two died (0.44%) within six months of rhGH initiation. “The temporal relationship to the onset of rhGH therapy implies that an enhanced drug-related risk at the start of therapy cannot be excluded,” the researchers said. They recommended pretreatment evaluation for evidence of airway obstruction and sleep apnea, as respiratory impairment and morbid obesity remain contraindications to rhGH therapy.
Other recommendations based on the 20-year NCGS data include:
* Evaluation and adjustment of baseline and stress doses of glucocorticoids when GH therapy is initiated.
* Appropriate monitoring for insulin resistance among rhGH users;
* Monitoring of intracranial hypertension among children with Turner syndrome, chronic renal insufficiency and Prader-Willi syndrome.
* Continued vigilance by the practitioner to ensure long-term safety.
“Careful monitoring in the post-marketing setting is essential to adequately characterize the safety profile of a drug because rare adverse events may not be detected in clinical trials in which a relatively small number of patients are exposed to the drug,” the researchers concluded.
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