Contraindications
GH therapy should not be initiated to treat patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma, or to patients having acute respiratory failure.Nutropin AQ and Nutropin should not be used for growth promotion in pediatric patients with closed epiphyses.
Nutropin AQ and Nutropin should not be used in patients with active neoplasia. GH therapy should be discontinued if evidence of neoplasia develops.
GH is contraindicated in patients with Prader-Willi syndrome who are severely obese or have severe respiratory impairment (see WARNINGS in full prescribing information). Unless patients with Prader-Willi syndrome also have a diagnosis of GH deficiency, Nutropin AQ and Nutropin are not indicated for the long-term treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.
WARNING
Benzyl alcohol as a preservative in Bacteriostatic Water for
Injection, USP (benzyl alcohol preserved), should not be used in
patients with a known sensitivity to benzyl alcohol.
Precautions
GeneralNutropin AQ and Nutropin should be prescribed by physicians experienced in the diagnosis and management of patients with GH deficiency, Turner syndrome, or chronic renal insufficiency (CRI). Experience with prolonged rhGH treatment in adults is limited.
Geriatric Usage: Clinical studies of Nutropin AQ and Nutropin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Patients with epiphyseal closure who were treated with GHreplacement therapy in childhood should be re-evaluated according to the criteria in the INDICATIONS AND USAGE section before continuation of GH therapy at the reduced dose level recommended for GH-deficient adults.
Diabetes mellitus
For patients with diabetes mellitus, the insulin dose may require adjustment when GH therapy is instituted. Because GH may reduce insulin sensitivity, particularly in obese individuals, patients should be observed for evidence of glucose intolerance. Patients with diabetes or glucose intolerance should be monitored closely during GH therapy.Nutropin therapy in adults with GHD of adult onset was associated with an increase of median fasting insulin in the Nutropin 0.0125 mg/kg/day group from 9.0 µU/mL at baseline to 13.0 µU/mL at Month 12 with a return to the baseline median after a 3-week post-washout period off GH therapy. In the placebo group there was no change from 8.0 µU/mL at baseline to Month 12, and after the post-washout the median was 9.0 µU/mL. The between-treatment-groups difference in change from baseline to Month 12 was significant, p < 0.0001. In childhood-onset subjects, there was a change of median fasting insulin in the Nutropin 0.025 mg/kg/day group from 11.0 µU/mL at baseline to 20.0 µU/mL at Month 12, in the Nutropin 0.0125 mg/kg/day group from 8.5 µU/mL to 11.0 µU/mL, and in the placebo group from 7.0 µU/mL to 8.0 µU/mL. The between-treatment-groups difference for these changes was significant, p = 0.0007.
In subjects with adult-onset GH deficiency, there was no between-treatment group difference in changes from baseline to Month 12 in mean HbA1c, p = 0.08. In childhood-onset mean HbA1c increased in the Nutropin 0.025 mg/kg/day group from 5.2% at baseline to 5.5% at Month 12, and did not change in the Nutropin 0.0125 mg/kg/day group from 5.1% at baseline or in the placebo group from 5.3% at baseline. The between-treatment-groups difference was significant, p = 0.009. Patients with a history of an intracranial lesion should be examined frequently for progression or recurrence of the lesion. In pediatric patients, clinical literature has demonstrated no relationship between GH-replacement therapy and central nervous system (CNS) tumor recurrence or new extracranial tumors. In adults, it is unknown whether there is any relationship between GH-replacement therapy and CNS tumor recurrence.
Patients with growth failure secondary to CRI should be examined periodically for evidence of progression of renal osteodystrophy. Slipped capital femoral epiphysis or avascular necrosis of the femoral head may be seen in children with advanced renal osteodystrophy, and it is uncertain whether these problems are affected by GH therapy for CRI patients. Physicians and parents should be alert to the development of a limp or complaints of hip or knee pain in patients treated with Nutropin AQ or Nutropin.
Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders or in patients undergoing rapid growth. Progression of scoliosis can occur in patients who experience rapid growth. Because GH increases growth rate, patients with a history of scoliosis who are treated with GH should be monitored for progression of scoliosis. GH has not been shown to increase the incidence of scoliosis. Skeletal abnormalities including scoliosis are commonly seen in untreated Turner syndrome patients. Physicians should be alert to these abnormalities which may manifest during GH therapy.
Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear or hearing disorders. In a randomized, controlled trial, there was a statistically significant increase, as compared to untreated controls, in otitis media (43% vs 26%) and ear disorders (18% vs 5%) in patients receiving GH. In addition, patients with Turner syndrome should be monitored closely for cardiovascular disorders (e.g. stroke, aortic aneurysm, hypertension) as these patients are also at risk for these conditions.
Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a smaller number of patients treated with GH products. Symptoms usually occurred within the first 8 weeks of the initiation of GH therapy. In all reported cases, IH-associated signs and symptoms resolved after termination of therapy or a reduction of the GH dose. Fundoscopic examination of patients is recommended at the initiation and periodically during the course of GH therapy. Patients with CRI and Turner syndrome patients may be at increased risk for development of IH.
As with any protein, local or systemic allergic reactions may occur. Parents/patients should be informed that such reactions are possible and that prompt medical attention should be sought if allergic reactions occur.
Adverse reactions
As with all protein pharmaceuticals, a small percentage of patients may develop antibodies to the protein. GH antibody binding capacities below 2 mg/L have not been associated with growth attenuation. In some cases when binding capacity exceeds 2 mg/L, growth attenuation has been observed.
Additional short-term immunologic and renal function studies were carried out in a group of patients with chronic renal insufficiency after approximately one year of treatment to detect other potential adverse effects of antibodies to GH. Testing included measurements of C1q, C3, C4, rheumatoid factor, creatinine, creatinine clearance, and BUN. No adverse effects of GH antibodies were noted.
In addition to an evaluation of compliance with the prescribed treatment program and thyroid status, testing for antibodies to GH should be carried out in any patient who fails to respond to therapy.
Injection site discomfort has been reported. This is more commonly observed in children switched from another GH product to Nutropin AQ or Nutropin. In studies in patients treated with Nutropin, injection site pain was reported infrequently.
Leukemia has been reported in a small number of GHD patients treated with GH. It is uncertain whether this increased risk is related to the pathology of GH deficiency itself, GH therapy, or other associated treatments such as radiation therapy for intracranial tumors. On the basis of current evidence, experts cannot conclude that GH therapy is responsible for these occurrences. The risk to GHD, CRI, or Turner syndrome patients, if any, remains to be established.
Because Nutropin AQ and Nutropin may reduce insulin sensitivity, patients should be monitored for evidence of glucose intolerance.
Serum levels of inorganic phosphorus, alkaline phosphatase, and parathyroid hormone (PTH) may increase with Nutropin AQ and Nutropin therapy.
Untreated hypothyroidism prevents optimal response to Nutropin AQ and Nutropin. Changes in thyroid hormone laboratory measurements may develop during Nutropin AQ or Nutropin treatment. Therefore, patients should have periodic thyroid function tests and should be treated with thyroid hormone when indicated.
Other adverse drug reactions that have been reported in GH-treated patients include the following:- Metabolic: mild, transient peripheral edema. In GHD adults, edema or peripheral edema was reported in 41% of GH-treated patients and 25% of placebo-treated patients;
- Musculoskeletal: arthralgias; carpal tunnel syndrome. In GHD adults, arthralgias and other joint disorders were reported in 27% of GH-treated patients and 15% of placebo-treated patients;
- Skin: rare increased growth of pre-existing nevi; patients should be monitored for malignant transformation; and
- Endocrine: gynecomastia. Rare pancreatitis.
