Nutropin Depot

As with all protein pharmaceuticals, 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. In clinical studies of pediatric patients who were treated with Nutropin Depot (somatropin (rdna origin) for inj) , 0/138 patients with GHD screened for antibody production developed antibodies with binding capacities ≥ 2 mg/L at any time during a treatment period of up to 17.4 months.

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.

In studies involving 138 pediatric patients treated with Nutropin Depot (somatropin (rdna origin) for inj) , the most frequent adverse reactions were injection-site reactions, which occurred in nearly all patients. On average, 2 to 3 injection-site adverse reactions were reported per injection. These reactions included nodules (61% of injections), erythema (53%), pain post-injection (47%), pain during injection (43%), bruising (20%), itching (13%), lipoatrophy (13%), and swelling or puffiness (8%). The intensity of these reactions was generally rated mild to moderate, with pain during injection occasionally rated as severe (7%).

Adverse reactions observed less frequently in the Nutropin Depot (somatropin (rdna origin) for inj) studies which were considered possibly, probably, or definitely related to the drug by the treating physician (usually occurring 1–3 days postdose) included: headache (13% of subjects), nausea (8%), lower extremity pain (7%), fever (7%), and vomiting (5%). These symptoms were generally self-limited and well-tolerated. One patient experienced a generalized body rash that was most likely an allergic reaction to Nutropin Depot (somatropin (rdna origin) for inj) .

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.

Other adverse drug reactions that have been reported in GH-treated patients include the following: 1) Metabolic: mild, transient peripheral edema; 2) Musculoskeletal: arthralgia, carpal tunnel syndrome; 3) Skin: rare increased growth of pre-existing nevi; patients should be monitored for malignant transformation; 4) Endocrine: gynecomastia; and 5) Rare pancreatitis. Of these reactions, only edema ( < 1% of patients) and arthralgia (4%) were reported as related to drug in the Nutropin Depot (somatropin (rdna origin) for inj) studies.

General

In vivo preclinical and clinical testing has demonstrated that growth hormone (GH) stimulates longitudinal bone growth and elevates insulin-like growth factor-I (IGF-I) levels.

Actions that have been demonstrated for hGH include:

1. Tissue Growth - 1) Skeletal Growth: GH stimulates skeletal growth in pediatric patients with growth failure due to a lack of adequate secretion of endogenous GH. Skeletal growth is accomplished at the epiphyseal plates at the ends of a growing bone. Growth and metabolism of epiphyseal plate cells are directly stimulated by GH and one of its mediators, IGF-I. Serum levels of IGF-I are low in children and adolescents who are growth hormone deficient (GHD), but increase during treatment with GH. In pediatric patients, new bone is formed at the epiphyses in response to GH and IGF-I. This results in linear growth until these growth plates fuse at the end of puberty. 2) Cell Growth: Treatment with hGH results in an increase in both the number and the size of skeletal muscle cells. 3) Organ Growth: GH increases the size of internal organs, including kidneys, and increases red cell mass. Treatment of hypophysectomized or genetic dwarf rats with GH results in increases in organ and overall body growth. In normal rats subjected to nephrectomy-induced uremia, GH promoted skeletal and body growth.
2. Protein Metabolism - Linear growth is facilitated in part by GH-stimulated protein synthesis. This is reflected by nitrogen retention as demonstrated by a decline in urinary nitrogen excretion and blood urea nitrogen during GH therapy.
3. Carbohydrate Metabolism - GH is a modulator of carbohydrate metabolism. Patients with inadequate endogenous secretion of GH sometimes experience fasting hypoglycemia that is improved by treatment with GH. GH therapy may decrease insulin sensitivity. Administration of hGH formulated for daily dosing resulted in increased mean fasting and postprandial insulin levels, more commonly in overweight or obese individuals. Mean trough levels for fasting and postprandial insulin were unchanged after 3 or 6 months of Nutropin Depot (somatropin (rdna origin) for inj) therapy in GHD children. As with daily GH, mean trough levels for fasting glucose, postprandial glucose, and hemoglobin A1c remained unchanged after 3 or 6 months of Nutropin Depot (somatropin (rdna origin) for inj) therapy.
4. Lipid Metabolism - In GHD patients, administration of GH formulated for daily dosing resulted in lipid mobilization, reduction in body fat stores, increased plasma fatty acids, and decreased plasma cholesterol levels.
5. Mineral Metabolism - The retention of total body potassium in response to GH administration apparently results from cellular growth. Serum levels of inorganic phosphorus may increase slightly in patients with inadequate secretion of endogenous GH due to metabolic activity associated with bone growth as well as increased tubular reabsorption of phosphate by the kidney. Serum calcium is not significantly altered in these patients. Sodium retention also occurs. (See PRECAUTIONS: Laboratory Tests.) GH therapy results in increases in serum alkaline phosphatase.
6. Connective Tissue Metabolism - GH stimulates the synthesis of chondroitin sulfate and collagen as well as the urinary excretion of hydroxyproline.

Pharmacokinetics

Nutropin Depot (somatropin (rdna origin) for inj) is a long-acting dosage form of somatropin designed to be administered by subcutaneous (SC) injection once or twice monthly. Following the injection, bioactive rhGH is released from the microspheres into the SC environment initially by diffusion, followed by both polymer degradation and diffusion. Although no studies have been performed that address the distribution, elimination, or metabolism of Nutropin Depot (somatropin (rdna origin) for inj) , once released and absorbed the rhGH is believed to be distributed and eliminated in a manner similar to somatropin formulated for daily administration.

The serum hGH concentration-time profiles of single doses of 0.75 mg/kg and 1.5 mg/kg of Nutropin Depot (somatropin (rdna origin) for inj) have been characterized in pediatric GHD patients (refer to Figure 1). The in vivo profiles are characterized by an initial rapid release followed by a slow decline in GH concentration. Both the maximum concentrations achieved (Cmax) and total exposure (AUC0-28 days) appear to be proportional to dose. Serum hGH levels greater than 1 µg/L persist for approximately 11-14 days postdose for the two doses. Repeated dosing of Nutropin Depot (somatropin (rdna origin) for inj) over 6 months showed no progressive accumulation of GH.

Absorption - In a study of Nutropin Depot (somatropin (rdna origin) for inj) in pediatric patients with GHD, an SC dose of 0.75 mg/kg (n = 12) or 1.5 mg/kg (n = 8) was administered. The mean ± SD hGH Cmax values were 48±26 µg/L and 90±23 µg/L, respectively, at 12-13 hours postdose. The corresponding AUC0-28 days values were 83±49 µg • day/L and 140±34 µg•day/L, respectively, for the two doses. For the 0.75 mg/kg and 1.5 mg/kg doses, the AUC0-2days accounted for approximately 52±16 percent and 61±10 percent of the total AUC0-28 days, respectively. Estimates of relative bioavailability in GHD children for a single dose of Nutropin Depot (somatropin (rdna origin) for inj) ranged from 33% to 38% when compared to a single dose of Nutropin AQ® [somatropin (rDNA origin) injection] in healthy adults, and from 48% to 55% when compared to chronically dosed Protropin® (somatrem for injection) in GHD children.

Distribution - Animal studies with rhGH formulated for daily administration showed that GH localizes to highly perfused organs, particularly the liver and kidney. The volume of distribution at steady state for rhGH formulated for daily administration in healthy adult males is about 50 mL/kg body weight, approximating the serum volume.

Metabolism - Both the liver and kidney have been shown to be important metabolizing organs for GH. Animal studies using rhGH formulated for daily administration suggest that the kidney is the dominant organ of clearance. GH is filtered at the glomerulus and reabsorbed in the proximal tubules. It is then cleaved within renal cells into its constituent amino acids, which return to the systemic circulation.

Elimination - The mean terminal t1/2 after intravenous (IV) administration of rhGH formulated for daily administration in healthy adult males is estimated to be 19.5+3.1 minutes. Clearance of rhGH after IV administration in healthy adults and children is reported to be in the range of 116-174 mL/hr/kg.

Figure 1: Single-Dose Mean (SD) GH Concentrations in Pediatric GHD Patients

Special Populations

Pediatric - Available literature data suggest that rhGH clearances are similar in adults and children.

Gender - Following administration of either 0.75 mg/kg or 1.5 mg/kg Nutropin Depot (somatropin (rdna origin) for inj) , Day 1 GH levels were higher in females compared to males. No relationship was observed between gender and pharmacodynamic marker (IGF-I and IGFBP-3) levels.

Race - The effect of race on Nutropin Depot (somatropin (rdna origin) for inj) disposition is unknown due to the limited number of non-Caucasian patients in the Nutropin Depot (somatropin (rdna origin) for inj) studies.

Growth Hormone Deficiency - Nutropin Depot (somatropin (rdna origin) for inj) has not been studied in healthy adults or children. However, reported values for clearance of rhGH formulated for daily administration in adults and children with GHD range from 138-245 mL/hr/kg and are similar to those observed in healthy adults and children. Mean terminal t1/2 values following IV and SC administration in adult and pediatric patients with GHD are also similar to those observed in healthy adult males.

Renal Insufficiency - Nutropin Depot (somatropin (rdna origin) for inj) has not been studied in patients with renal insufficiency. Children and adults with chronic renal failure (CRF) and end-stage renal disease (ESRD) tend to have decreased clearance of rhGH formulated for daily administration compared with normals. Endogenous GH production may also increase in some individuals with ESRD. However, no GH accumulation has been reported in children with CRF or ESRD dosed with daily regimens.

Hepatic Insufficiency - Nutropin Depot (somatropin (rdna origin) for inj) has not been studied in patients with hepatic insufficiency. A reduction in clearance of rhGH formulated for daily administration has been noted in patients with severe liver dysfunction. The clinical significance of this decrease is unknown.

Pharmacodynamics

IGF-I levels peaked between 1.5 and 3.5 days postdose and remained above baseline for approximately 16 to 20 days, confirming GH activity for an extended period. Repeated dosing of Nutropin Depot (somatropin (rdna origin) for inj) over 6 months showed no progressive accumulation of IGF-I (as shown in Figure 2) or IGF-binding protein 3 (IGFBP-3).

Figure 2: Repeated-Dose Mean (SD) IGF-I Concentrations in Pediatric GHD Patients

Efficacy Studies

In two multicenter, open-label clinical studies in prepubertal children (mean age (± SD) 7.4+2.8) with idiopathic or organic GHD previously untreated with rhGH, 91 patients were treated with Nutropin Depot (somatropin (rdna origin) for inj) at 1.5 mg/kg once monthly or 0.75 mg/kg twice monthly by subcutaneous injection for up to six months. (See DOSAGE AND ADMINISTRATION for the number of injections required per dose.) The mean prestudy growth rate was 4.8±2.4 cm/yr (n=89). The dose-pooled, mean 6-month annualized growth rate on Nutropin Depot therapy was 8.4±2.2 cm/yr (n=89).

Seventy-six patients continued treatment in an extension study. For patients who completed 12 months the mean growth rate was 7.8±1.9 cm/yr for the two dose groups combined (n=69). Mean height SD score changed from -3.0±1.0 prestudy to -2.5±0.9 at Month 12 (n=69). The mean 0 to 12 month change in bone age was 1.0±0.4 years (n=63). During the long-term extension study, fourteen of seventy-five (19%) patients discontinued due to dissatisfaction with growth response. Historical studies of GHD children treated with daily Protropin® (somatrem for injection) or Nutropin® [somatropin (rDNA origin) for injection] injections for 12 months at 0.3 mg/kg weekly had the following mean values: baseline growth rate 3.6 to 4.8 cm/yr; first year growth rate 10.1 to 11.3 cm/yr; first year change in bone age 1.1 to 1.5 years.

In a dose-ranging study, 24 patients previously treated with daily GH (mean age 9.6±2.2 years; mean duration of prior GH therapy 2.8±1.6 yr, range 0.9 to 6.1 yr) were switched to Nutropin Depot (somatropin (rdna origin) for inj) therapy at the above doses. The mean growth rate on previous treatment was 8.2±3.0 cm/yr (range 3.2 to 13.1 cm/yr) and on Nutropin Depot (somatropin (rdna origin) for inj) was 5.1±2.0 cm/yr (range 2.4 to 9.6 cm/yr). During a long-term extension study, four of ten previously treated patients discontinued due to dissatisfaction with growth response. Historical studies of GHD children (n=181) treated with daily Protropin or Nutropin at a dose of 0.3 mg/kg weekly had the following mean growth rates: first year growth rate 9.7 to 11.4 cm/yr; second year growth rate 8.1 to 8.9 cm/yr; third year growth rate 7.5 to 7.8 cm/yr; fourth year growth rate 6.6 to 7.1 cm/yr.

• Genentech, Inc.

Nutropin Depot is part of the drug class:

• Somatropin and somatropin agonists

Nutropin Depot® [somatropin (rDNA origin) for injectable suspension] is indicated for the long‑term treatment of growth failure due to a lack of adequate endogenous GH secretion.

Considerations for use:As with any GH treatment, patients should be monitored closely throughout therapy for growth response to Nutropin Depot. Failure to respond adequately requires careful assessment, as described under DOSAGE AND ADMINISTRATION. Patients for whom no discernible cause is found should be considered for a course of treatment with a daily form of rhGH. Experience in patients who were treated with daily GH and switched to Nutropin Depot is limited.

Growth hormone 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. Two placebo‑controlled clinical trials in non‑growth hormone‑deficient adult patients (n = 522) with these conditions revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin‑treated patients (doses 5.3–8 mg/day) compared to those receiving placebo (see WARNINGS).

Nutropin Depot should not be used for growth promotion in pediatric patients with closed epiphyses.

Nutropin Depot should not be used in patients with active neoplasia. GH therapy should be discontinued if evidence of neoplasia develops.

Growth hormone is contraindicated in patients with Prader‑Willi syndrome who are severely obese or have severe respiratory impairment
(see WARNINGS). Nutropin Depot is not indicated for the treatment of short stature in genetically confirmed Prader‑Willi syndrome.

As with all protein pharmaceuticals, 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. In clinical studies of pediatric patients who were treated with Nutropin Depot, 0/138 patients with GHD screened for antibody production developed antibodies with binding capacities ≥ 2 mg/L at any time during a treatment period of up to 17.4 months.

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.

In studies involving 138 pediatric patients treated with Nutropin Depot, the most frequent adverse reactions were injection‑site reactions, which occurred in nearly all patients. On average, 2 to 3 injection‑site adverse reactions were reported per injection. These reactions included nodules (61% of injections), erythema (53%), pain post‑injection (47%), pain during injection (43%), bruising (20%), itching (13%), lipoatrophy (13%), and swelling or puffiness (8%). The intensity of these reactions was generally rated mild to moderate, with pain during injection occasionally rated as severe (7%).

Adverse reactions observed less frequently in the Nutropin Depot studies which were considered possibly, probably, or definitely related to the drug by the treating physician (usually occurring 1–3 days postdose) included: headache (13% of subjects), nausea (8%), lower extremity pain (7%), fever (7%), and vomiting (5%). These symptoms were generally self‑limited and well‑tolerated. One patient experienced a generalized body rash that was most likely an allergic reaction to Nutropin Depot.

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.

Other adverse drug reactions that have been reported in GH‑treated patients include the following: 1) Metabolic: mild, transient peripheral edema; 2) Musculoskeletal: arthralgia, carpal tunnel syndrome; 3) Skin: rare increased growth of pre‑existing nevi; patients should be monitored for malignant transformation; 4) Endocrine: gynecomastia; and 5) Rare pancreatitis. Of these reactions, only edema (< 1% of patients) and arthralgia (4%) were reported as related to drug in the Nutropin Depot studies.