Somatropin

Description

11 DESCRIPTION Nutropin AQ (somatropin) injection, for subcutaneous use is a human growth hormone (hGH) produced by recombinant DNA technology. Nutropin AQ has 191 amino acid residues and a molecular weight of 22,125 daltons. The amino acid sequence of the product is identical to that of pituitary-derived hGH. Nutropin AQ may contain not more than fifteen percent deamidated GH at expiration. The deamidated form of GH has been extensively characterized and has been shown to be safe and fully active. Nutropin AQ is a sterile liquid intended for subcutaneous administration. The product is nearly isotonic at a concentration of 5 mg of GH per mL and has a pH of approximately 6.0. Each pen cartridge or NuSpin contain either 5 mg, 10 mg or 20 mg of somatropin formulated in 17.4 mg sodium chloride, 5 mg phenol, 4 mg polysorbate 20, and 10 mM sodium citrate [see How Supplied/Storage and Handling (16) ] .

What Is Somatropin Used For?

1 INDICATIONS AND USAGE Nutropin AQ is a recombinant human growth hormone indicated for: Pediatric Patients : Treatment of children with growth failure due to growth hormone deficiency (GHD), idiopathic short stature (ISS), Turner syndrome (TS), and chronic kidney disease (CKD) up to the time of renal transplantation ( 1.1 ). Adult Patients: Treatment of adults with either childhood-onset or adult-onset GHD ( 1.2 ). 1.1 Pediatric Patients Growth Hormone Deficiency (GHD) - Nutropin AQ ® is indicated for the treatment of pediatric patients who have growth failure due to inadequate secretion of endogenous growth hormone (GH). Growth Failure Secondary to Chronic Kidney Disease (CKD) - Nutropin AQ is indicated for the treatment of growth failure associated with CKD up to the time of renal transplantation. Nutropin AQ therapy should be used in conjunction with optimal management of CKD. Idiopathic Short Stature (ISS) - Nutropin AQ is indicated for the treatment of ISS, also called non-GHD short stature, defined by height SDS ≤ –2.25, and associated with growth rates unlikely to permit attainment of adult height in the normal range, in pediatric patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other causes associated with short stature that should be observed or treated by other means. Short Stature Associated with Turner Syndrome (TS) - Nutropin AQ is indicated for the treatment of short stature associated with TS. 1.2 Adult Patients Nutropin AQ is indicated for the replacement of endogenous GH in adults with GHD who meet either of the following two criteria: Adult Onset : Patients who have GHD, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or Childhood Onset : Patients who were GH deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes. Patients who were treated with somatropin for GHD in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin therapy at the reduced dose level recommended for GH deficient adults. According to current standards, confirmation of the diagnosis of adult GHD in both groups involves an appropriate GH provocative test with two exceptions: (1) patients with multiple pituitary hormone deficiencies due to organic disease; and (2) patients with congenital/genetic GHD.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION For subcutaneous injection . Therapy with Nutropin AQ should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with short stature associated with growth hormone deficiency (GHD), chronic kidney disease, Turner syndrome, idiopathic short stature, or adult patients with either childhood-onset or adult-onset GHD. Nutropin AQ should be administered subcutaneously ( 2 ). Injection sites should always be rotated to avoid lipoatrophy ( 2.3 ). Pediatric GHD: Up to 0.3 mg/kg/week ( 2.1 ) Pubertal Patients: Up to 0.7 mg/kg/week ( 2.1 ) Idiopathic Short Stature: Up to 0.3 mg/kg/week ( 2.1 ) Chronic Kidney Disease: Up to 0.35 mg/kg/week ( 2.1 ) Turner Syndrome: Up to 0.375 mg/kg/week ( 2.1 ) Adult GHD: Either a non-weight based or weight-based dosing regimen may be followed, with doses adjusted based on treatment response and IGF-I concentrations ( 2.2 ). Non-weight-based: A starting dose of approximately 0.2 mg/day (range 0.15–0.3 mg/day) increased gradually every 1–2 months by increments of approximately 0.1–0.2 mg/day. Weight-based : Initiate from not more than 0.006 mg/kg/day; the dose may be increased up to a maximum of 0.025 mg/kg/day in patients ≤ 35 years old or 0.0125 mg/kg/day in patients > 35 years old. 2.1 Dosing for Pediatric Patients Nutropin AQ dosage and administration schedule should be individualized for each patient. Response to growth hormone (GH) therapy in pediatric patients tends to decrease with time. However, in pediatric patients failure to increase growth rate, particularly during the first year of therapy, suggests the need for close assessment of compliance and evaluation of other causes of growth failure, such as hypothyroidism, under-nutrition, advanced bone age and antibodies to recombinant human GH (rhGH). Treatment with Nutropin AQ for short stature should be discontinued when the epiphyses are fused. Pediatric Growth Hormone Deficiency (GHD ) A weekly dosage of up to 0.3 mg/kg of body weight divided into daily subcutaneous injection is recommended. In pubertal patients, a weekly dosage of up to 0.7 mg/kg divided daily may be used. Growth Failure Secondary to Chronic Kidney Disease (CKD) A weekly dosage of up to 0.35 mg/kg of body weight divided into daily subcutaneous injection is recommended. Nutropin AQ therapy may be continued up to the time of renal transplantation. In order to optimize therapy for patients who require dialysis, the following guidelines for injection schedule are recommended: Hemodialysis patients should receive their injection at night just prior to going to sleep or at least 3 to 4 hours after their hemodialysis to prevent hematoma formation due to the heparin. Chronic Cycling Peritoneal Dialysis (CCPD) patients should receive their injection in the morning after they have completed dialysis. Chronic Ambulatory Peritoneal Dialysis (CAPD) patients should receive their injection in the evening at the time of the overnight...

Side Effects (Adverse Reactions)

6 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) ] Common somatropin-related adverse reactions include injection site reactions. Additional common adverse reactions in adults include edema, arthralgias, and carpal tunnel syndrome ( 6.1 , 6.2 ). To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. 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 Even t 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 A 1c (A1C) levels rose slightly from baseline as expected during adolescence; sporadic values outside normal limits occurred transiently. Adult Patients Growth Hormone...

Drug Interactions

7 DRUG INTERACTIONS Inhibition of 11 β-Hydroxysteroid Dehydrogenase Type 1: May require the initiation of glucocorticoid replacement therapy. Patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance doses ( 7.1 , 7.2 ). Glucocorticoid replacement: Should be carefully adjusted ( 7.2 ). Cytochrome P450- Metabolized Drugs: Monitor carefully if used with somatropin ( 7.3 ). Oral estrogen: Larger doses of somatropin may be required in women ( 7.4 ). Insulin and/or other hypoglycemic agents: May require adjustment ( 7.5 ). 7.1 11 β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-1) The microsomal enzyme 11βHSD-1 is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Growth hormone (GH) and somatropin inhibit 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. As a consequence, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with somatropin. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1. 7.2 Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth-promoting effects of somatropin in children. Therefore, glucocorticoid replacement therapy should be carefully adjusted in children with concomitant GH and glucocorticoid deficiency to avoid both hypoadrenalism and an inhibitory effect on growth. The use of Nutropin AQ in patients with Chronic Kidney Disease (CKD) requiring glucocorticoid therapy has not been evaluated. Concomitant glucocorticoid therapy may inhibit the growth promoting effect of Nutropin AQ. Therefore, if glucocorticoid replacement is required for CKD, the glucocorticoid dose should be carefully adjusted to avoid an inhibitory effect on growth. In the clinical trials there was no evidence of drug interactions with Nutropin and commonly used drugs used in the management of CKD. 7.3 Cytochrome P450 (CYP450)-Metabolized Drugs Limited published data indicate that somatropin treatment increases CYP450-mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Careful monitoring is...

Contraindications

4 CONTRAINDICATIONS Acute critical illness ( 4 ). Children with Prader-Willi syndrome (PWS) who are severely obese or have severe respiratory impairment – reports of sudden death ( 4 ). Active malignancy ( 4 ). Hypersensitivity to somatropin or excipients ( 4 ). Active proliferative or severe non-proliferative diabetic retinopathy ( 4 ). Children with closed epiphysis ( 4 ). Acute Critical Illness Treatment with pharmacologic amounts of somatropin is contraindicated in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure [see Warnings and Precautions (5.1) ]. Prader-Willi Syndrome (PWS) in Children Somatropin is contraindicated in patients with PWS who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe respiratory impairment. There have been reports of sudden death when somatropin was used in such patients. Nutropin AQ is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed PWS [see Warnings and Precautions (5.2) ] . Active Malignancy In general, somatropin is contraindicated in the presence of active malignancy. Any pre-existing malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of recurrent activity. Since growth hormone deficiency (GHD) may be an early sign of the presence of a pituitary tumor (or, rarely, other brain tumors), the presence of such tumors should be ruled out prior to initiation of treatment. Somatropin should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor [see Warnings and Precautions (5.3) ]. Hypersensitivity Nutropin AQ is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. Systemic hypersensitivity reactions have been...

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Nutropin AQ. It is also not known whether Nutropin AQ can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Nutropin AQ should be given to a pregnant woman only if clearly needed.

8.3 Nursing Mothers There have been no studies conducted with Nutropin AQ in nursing mothers. It is not known whether Nutropin AQ is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Nutropin AQ is administered to a nursing mother.

Overdosage

10 OVERDOSAGE Short Term Short-term overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Furthermore, overdose with somatropin is likely to cause fluid retention. Long Term Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess growth hormone (GH) [see Dosage and Administration (2.2) ] .

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Pen Cartridge (2 mL): 10 mg 20 mg NDC 50242-043-14 NDC 50242-073-01 Nutropin AQ NuSpin (2 mL): 5 mg 10 mg 20 mg NDC 50242-075-01 NDC 50242-074-01 NDC 50242-076-01 Storage and Handling Nutropin AQ cartridge and NuSpin injection device contents are stable for 28 days after initial use when stored at 2–8°C/36–46°F (under refrigeration). Avoid freezing Nutropin AQ in the cartridge or NuSpin injection device. Nutropin AQ is light sensitive and the cartridges and Nutropin AQ NuSpin should be protected from light. Store the cartridge and Nutropin AQ NuSpin injection device refrigerated in a dark place when they are not in use.