Somatropinside effects

Other common somatropin-related adverse reactions include injection site reactions/rashes and lipoatrophy and headaches. To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch The following important adverse reactions are also described elsewhere in labeling:

Increased mortality in patients with acute critical illness

Fatalities in children with Prader-Willi Syndrome

Neoplasms

Glucose intolerance and diabetes mellitus

Intracranial hypertension

Severe hypersensitivity

Fluid retention

Hypoadrenalism

Hypothyroidism

Slipped capital femoral epiphysis in pediatric patients

Progression of preexisting scoliosis in pediatric patients

Otitis media and cardiovascular disorders in patients with Turner Syndrome

Lipoatrophy

Pancreatitis

Benzyl Alcohol

6.1 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 Pediatric GHD Patients The following events were observed during clinical studies with OMNITROPE Cartridge conducted in children with GHD: Table 1. Incidence of Adverse Reactions Reported in ≥ 5% Pediatric Patients with GHD During Treatment with OMNITROPE Cartridge (N=86) Adverse Event n (%) N=number of patients receiving treatment n=number of patients who reported the event during study period %=percentage of patients who reported the event during study period Elevated HbA1c 12 (14%) Eosinophilia 10 (12%) Hematoma 8 (9%) The following events were observed during clinical studies with OMNITROPE for injection conducted in children with GHD: Table 2. Incidence of Adverse Reactions Reported in ≥ 5% Pediatric Patients with GHD During Treatment with OMNITROPE for Injection (N=44) Adverse Event n (%) N=number of patients receiving treatment n=number of patients who reported the event during study period %= percentage of patients who reported the event during study period Hypothyroidism 7 (16%) Eosinophilia 5 (11%) Elevated HbA1c 4 (9%) Hematoma 4 (9%) Headache 3 (7%) Hypertriglyceridemia 2 (5%) Leg Pain 2 (5%) Clinical Trials in PWS In two clinical studies in pediatric patients with Prader-Willi Syndrome carried out with another somatropin product, 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 another somatropin product, 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. Clinical Trials in Children with Idiopathic Short Stature In two open-label clinical studies conducted with another somatropin product in pediatric patients with ISS, the most commonly encountered adverse events were upper respiratory tract infections, influenza, tonsillitis, nasopharyngitis, gastroenteritis, headaches, increased appetite, pyrexia, fracture, altered mood, and arthralgia. In one of the two studies during treatment with this other somatropin product, 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 Children with Turner Syndrome In two clinical studies with another somatropin product 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 Adults with GHD In clinical trials with another somatropin product 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 3 displays the adverse events reported by 5% or more of adult GHD patients in clinical trials after various durations of treatment with another somatropin product. 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 3. Adverse Events Reported by ≥ 5% of 1,145 Adult GHD Patients During Clinical Trials of Another Somatropin Product and Placebo, Grouped by Duration of Treatment Double Blind Phase Open Label Phase Another Somatropin Product Adverse Event Placebo 0–6 mo. (n = 572) % Patients Another Somatropin Product 0–6 mo. (n = 573) % Patients 6–12 mo. (n = 504) % Patients 12–18 mo. (n = 63) % Patients 18–24 mo. (n = 60) % Patients n=number of patients receiving treatment during the indicated period %=percentage of patients who reported the event during the indicated period Swelling, peripheral 5.1 17.5 Increased significantly when compared to placebo, P ≤.025: Fisher’s Exact Test (one-sided) 5.6 0 1.7 Arthralgia 4.2 17.3 6.9 6.3 3.3 Upper respiratory infection 14.5 15.5 13.1 15.9 13.3 Pain, extremities 5.9 14.7 6.7 1.6 3.3 Edema, peripheral 2.6 10.8 3.0 0 0 Paresthesia 1.9 9.6 2.2 3.2 0 Headache 7.7 9.9 6.2 0 0 Stiffness of extremities 1.6 7.9 2.4 1.6 0 Fatigue 3.8 5.8 4.6 6.3 1.7 Myalgia 1.6 4.9 2.0 4.8 6.7 Back pain 4.4 2.8 3.4 4.8

5.0 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 another somatropin product. All 12 patients had predisposing factors, e.g., elevated glycated hemoglobin levels and/or marked obesity, prior to receiving this other somatropin product. Of the 3,031 patients receiving this other somatropin product, 61 (2%) developed symptoms of carpal tunnel syndrome, which lessened after dosage reduction or treatment interruption or surgery. Other adverse events that have been reported include generalized edema and hypoesthesia.

6.2 Postmarketing

Experience The following adverse reactions have been identified during post approval use of somatropin or OMNITROPE. 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 postmarketing 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 somatropins. Leukemia has been reported in a small number of GH deficient 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. The following additional adverse reactions have been observed during the use of somatropin: headaches (children and adults), gynecomastia (children), osteonecrosis (children), and pancreatitis (children and adults). New-onset type 2 diabetes mellitus has been reported.