Nutropin Aq

Name: Nutropin Aq

Adverse Reactions

The following important adverse reactions are also described elsewhere in the labeling:

  • Increased mortality in patients with acute critical illness [see Warnings and Precautions (5.1)]
  • Fatalities in children with Prader-Willi syndrome [see Warnings and Precautions (5.2)]
  • Neoplasms in pediatric patients [see Warnings and Precautions (5.3)]
  • Glucose intolerance and diabetes mellitus [see Warnings and Precautions (5.4)]
  • Intracranial hypertension [see Warnings and Precautions (5.5)]
  • Severe hypersensitivity [see Warnings and Precautions (5.6)]
  • Fluid retention [see Warnings and Precautions (5.7)]
  • Hypoadrenalism [see Warnings and Precautions (5.8)]
  • Hypothyroidism [see Warnings and Precautions (5.9)]
  • Slipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.10)]
  • Progression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.11)]
  • Otitis media and cardiovascular disorders in patients with Turner syndrome [see Warnings and Precautions (5.12)]
  • Osteodystrophy in pediatric patients with chronic kidney disease [see Warnings and Precautions (5.13)]
  • Lipoatrophy [see Warnings and Precautions (5.14)]
  • Pancreatitis [see Warnings and Precautions (5.16)]

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.

Pediatric Patients

Growth Hormone Deficiency (GHD)

Injection site discomfort has been reported. This is more commonly observed in children switched from another somatropin product to Nutropin AQ.

Turner Syndrome

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 somatropin.

Idiopathic Short Stature (ISS)

In a post-marketing surveillance study, the National Cooperative Growth Study (NCGS), the pattern of adverse events in over 8,000 patients with ISS was consistent with the known safety profile of growth hormone (GH), and no new safety signals attributable to GH were identified. The frequency of protocol-defined targeted adverse events is described in the table, below.

Table 1 Protocol-Defined Targeted Adverse Events in the ISS NCGS Cohort
Reported Events NCGS
(N = 8018)
AVN = avascular necrosis; SCFE = slipped capital femoral epiphysis.
Data obtained with several rhGH products (Nutropin, Nutropin AQ, Nutropin Depot and Protropin).
Any Adverse Event
  Overall 103 (1.3%)
Targeted Adverse Event
  Overall 103 (1.3%)
  Injection-site reaction 28 (0.3%)
  New onset or progression of scoliosis 16 (0.2%)
  Gynecomastia 12 (0.1%)
  Any new onset or recurring tumor (benign) 12 (0.1%)
  Arthralgia or arthritis 10 (0.1%)
  Diabetes mellitus 5 (0.1%)
  Edema 5 (0.1%)
  Cancer, neoplasm (new onset or recurrence) 4 (0.0%)
  Fracture 4 (0.0%)
  Intracranial hypertension 4 (0.0%)
  Abnormal bone or other growth 3 (0.0%)
  Central nervous system tumor 2 (0.0%)
  New or recurrent SCFE or AVN 2 (0.0%)
  Carpal tunnel syndrome 1 (0.0%)

In subjects treated in a long-term study of Nutropin for ISS, mean fasting and postprandial insulin levels increased, while mean fasting and postprandial glucose levels remained unchanged. Mean hemoglobin A1c (A1C) levels rose slightly from baseline as expected during adolescence; sporadic values outside normal limits occurred transiently.

Adult Patients

Growth Hormone Deficiency

In clinical studies with Nutropin AQ in GHD adults, edema or peripheral edema was reported in 41% of GH-treated patients and 25% of placebo-treated patients. In GHD adults, arthralgias and other joint disorders were reported in 27% of GH-treated patients and 15% of placebo-treated patients.

Nutropin therapy in adults with GHD of adult-onset was associated with an increase of median fasting insulin level 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 level after a 3-week post-washout period of 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 period, the median level was 9.0 µU/mL. The between-treatment group difference on the change from baseline to Month 12 in median fasting insulin level was significant, p < 0.0001. In childhood-onset subjects, there was an increase of median fasting insulin level 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 group differences for these changes were significant, p = 0.0007.

In subjects with adult-onset GHD, there were no between-treatment group differences on change from baseline to Month 12 in mean A1C level, p = 0.08. In childhood-onset GHD, the mean A1C level 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 group differences were significant, p = 0.009.

Immunogenicity

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 Nutropin with the incidence of antibodies to other products may be misleading. In the case of GH, antibodies with binding capacities lower than 2 mg/L 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/L, interference with the growth response was observed.

In clinical studies of pediatric patients that were treated with Nutropin for the first time, 0/107 GHD patients, 0/125 CKD patients, 0/112 TS, and 0/117 ISS patients screened for antibody production developed antibodies with binding capacities ≥ 2 mg/L at six months. In a clinical study of patients that were treated with Nutropin AQ for the first time, 0/38 GHD patients screened for antibody production for up to 15 months developed antibodies with binding capacities ≥ 2 mg/L.

Additional short-term immunologic and renal function studies were carried out in a group of pediatric patients with CKD 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 blood urea nitrogen (BUN). No adverse effects of GH antibodies were noted.

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.

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products [see Warnings and Precautions (5.6)].

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, CKD, or TS, if any, remains to be established [see Contraindications (4) and Warnings and Precautions (5.3)].

The following additional adverse reactions have been reported in GH-treated patients: gynecomastia (children), and pancreatitis [(Children and adults, see Warnings and Precautions (5.16)].

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