Zomacton

Description for Zomacton

ZOMACTON (somatropin) for injection, is a recombinant human growth hormone. It is a polypeptide of recombinant DNA origin, has 191 amino acid residues and a molecular weight of about 22,124 daltons. It has an amino acid sequence identical to that of human growth hormone of pituitary origin. ZOMACTON is produced in a strain of Escherichia coli modified by insertion of the human growth hormone gene.

ZOMACTON is a sterile, white, lyophilized powder, for subcutaneous use, after reconstitution with the accompanying diluent.

ZOMACTON 5 mg vial contains recombinant somatropin 5 mg and mannitol 30 mg. The 5 mg vial is supplied in a combination package with an accompanying 5 mL vial of diluting solution. The diluent contains bacteriostatic 0.9% sodium chloride injection, USP, (normal saline), 0.9% benzyl alcohol as a preservative, and water for injection.

ZOMACTON 10 mg vial contains recombinant somatropin 10 mg, mannitol 10 mg, disodium phosphate dodecahydrate 3.57 mg, and sodium dihydrogen phosphate dehydrate 0.79 mg. The 10 mg vial is supplied in a combination package with an accompanying 1 Ml syringe of diluting solution. The diluent contains bacteriostatic water for injection with 0.33% metacresol as a preservative. Reconstituted solutions have a pH in the range of 7 to 9.

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 pediatric patients with Prader-Willi syndrome [see Warnings and Precautions (5.2)]
• Neoplasms [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)]
• Pancreatitis [see Warnings and Precautions (5.12)]
• Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.13)]
• Lipoatrophy [see Warnings and Precautions (5.14)]

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 different approved somatropin formulation and may not reflect the adverse reaction rates observed in practice.

Pediatric Patients

Growth Failure due to Inadequate Secretion of Endogenous Growth Hormone

ZOMACTON was evaluated in 164 pediatric patients with short stature due to GHD in an open-label study for 24 weeks. The subjects ranged in age from 2.1 to 17.7 years with a mean of 10.8 years. One hundred twenty (73%) of the subjects were male and 44 (27%) were female. Two subjects were Asian, 12 were Black, 130 were Caucasian, and 20 were categorized as ‘other’.

Table 1: Adverse Reactions > 5% in Pediatric Patients with Growth Failure Due to GHD Treated with ZOMACTON through 24 Weeks

Adverse Reaction	24 Week Exposure to ZOMACTON (n=164)
Upper respiratory infection	32%
Fever	16%
Pharyngitis	12%
Headache	11%
Otitis Media	10%
Increased cough	9%
Abdominal pain	7%
Anemia	6%
Maculopapular rash	6%
Diarrhea	5%
Pain	5%
Rhinitis	5%

All pediatric patients were carefully observed for signs or laboratory abnormalities of hypothyroidism. Fifteen patients had T4 values which occasionally fell below the central laboratory’s lower limit of normal; T4 levels rose to normal when tested during the next visit for all patients except one who continued to be monitored. Six of the 15 patients received thyroxine therapy before and throughout the study period, and thyroxine dose adjustments were made during the study in 3/6 subjects.

In studies with GH deficient pediatric patients, injection site pain was reported in 1.6% of patients. A mild and transient edema, which appeared in 1.6% of patients, was observed early during the course of treatment.

Short Stature Associated with Turner Syndrome

In a randomized, concurrent-controlled, open-label study, there was an increase in the occurrence of otitis media, ear disorders and surgical procedures in patients receiving another somatropin product at a dose of 0.3 mg/kg/week, compared with untreated control patients (Table 2). A similar increase in otitis media was observed in an 18-month placebo-controlled study.

Table 2: Adverse Reactions Occurring in Patients with Turner Syndrome Treated with 0.3 mg/kg/week of Another Somatropin product During a 4.7 Year Randomized Open-Label Study

	Untreated (n=62)	Somatropin (n=74)
Surgical procedure	27%	45%
Otitis media	26%	43%
Ear disorders	5%	18%

Idiopathic Short Stature

Adverse reactions from a randomized, placebo-controlled study of another somatropin product dosed at 0.22 mg/kg/week are presented in Table 3. Mean fasting serum insulin concentration increased 10% in the group treated with another somatropin product at the end of treatment relative to baseline, but remained within the normal reference range.

Table 3: Adverse Reactions Occurring in Patients with Idiopathic Short Stature Treated with Another Somatropin product during a 4.4 Year Randomized Placebo-Controlled Study

Adverse Reactions	Placebo (n=31)	Another Somatropin product (n=37)
Scoliosis	13%	19%
Otitis media	7%	16%
Hyperlipidemia	3%	8%
Gynecomastia	3%	5%
Hip pain	0%	3%
Arthralgia	3%	11%
Arthrosis	7%	11%
Myalgia	13%	24%
Hypertension	0%	3%

In a dose-response study with 239 patients treated for 2 years, mean fasting blood glucose, mean glycosylated hemoglobin, and the incidence of elevated fasting blood glucose concentrations were similar among dose groups. One patient developed glucose intolerance and high serum HbA_1c.

Short Stature or Growth Failure in SHOX Deficiency

Adverse reactions from a 2-year open-label study with another somatropin product compared to no treatment are presented in Table 4. During the study, the proportion of patients who had at least one IGF-1 concentration greater than 2.0 SD above the age- and gender- appropriate mean was 37.0% for the somatropin-treated group vs. 0% patients for the untreated group. The proportion of patients who had at least one IGFBP-3 concentration greater than 2.0 SD above the age and gender appropriate mean was 59% for the somatropin treated group vs. 29% for the untreated group.

Table 4: Adverse Reactions Occurring in
Patients with SHOX Deficiency Treated with Another Somatropin product for 2 years

	Untreated (n=25)	Another Somatropin product (n=27)
Arthralgia	8%	11%
Gynecomastia	0%	8%
Excessive number of cutaneous nevi	0%	7%
Scoliosis	0%	4%

Small for Gestational Age (SGA) with No Catch-up Growth by 2 Years to 4 Years of Age

In a 2-year study, 193 pediatric patients were treated with another somatropin product using 2 different treatment regimens: a fixed dose of 0.067 mg/kg/day (FHD group) or an individually adjusted dose regimen (IAD group; starting dose 0.035 mg/kg/day which could be increased as early as Month 3 to 0.067 mg/kg/day based on a validated growth prediction model). Adverse reactions included common childhood infectious diseases, otitis media, headaches, and slipped capital femoral epiphysis (n=1). Six patients (4 in the FHD group and 2 in the IAD group whose dose was increased from 0.035 mg/kg/day to 0.067 mg/kg/day [one at Month 3 and one at Year 1])) had impaired fasting glucose at Year 2. Two of 6 had impaired fasting glucose during the study, and 1 discontinued treatment at month 15 as a consequence. At study completion, 20-25% of patients had serum IGF-1 SDS values > +2.

The following adverse reactions were reported from an observational study of 340 pediatric patients who received another somatropin product with an average dosage of 0.041 mg/kg/day for an average of 3 years: type 2 diabetes mellitus (n=1), carpal tunnel syndrome (n=1) and exacerbation of preexisting scoliosis (n=1).

Adult Patients

Adult-Onset GH Deficiency

In the first 6 months of controlled blinded trials during which patients received either another somatropin product or placebo, patients who received this other somatropin product experienced a statistically significant increase in edema (another somatropin product 17% vs. placebo 4%, p=0.043) and peripheral edema (12% vs. 0%, respectively, p=0.017). Edema, muscle pain, joint pain, and joint disorder were reported early in therapy and tended to be transient or responsive to dosage titration.

Two of 113 patients developed carpal tunnel syndrome after beginning maintenance therapy without a low dose (0.00625 mg/kg/day) lead-in phase. Symptoms abated in these patients after dosage reduction.

All adverse reactions with ≥5% overall occurrence rate during 12 or 18 months of replacement therapy with another somatropin product are shown in Table 5 (adult-onset patients) and in Table 6 (childhood-onset patients).

Adult patients treated with another somatropin product who had been diagnosed with GH deficiency in childhood reported adverse reactions less frequently than those with adult-onset GH deficiency.

Table 5: Adverse Reactions Occurring ≥5% in Adult-Onset
Growth Hormone-Deficient Patients Treated with Another Somatropin product for 18 Months as Compared with 6-Month Placebo and 12-Month Exposure to Another Somatropin product^a

Adverse Reaction	18 Months Exposure [Placebo (6 Months)/GH (12 Months)] (n=46)	18 Months GH Exposure (n=52)
Edemab	15%	21%
Arthralgia	15%	17%
Paresthesia	13%	17%
Myalgia	13%	14%
Pain	13%	14%
Rhinitis	11%	14%
Peripheral edemac	17%	12%
Back pain	11%	10%
Headache	11%	8%
Hypertension	4%	8%
Acne	0%	6%
Joint disorder	2%	6%
Surgical procedure	2%	6%
Flu syndrome	7%	4%
a Abbreviations: GH= another somatropin product; n=number of patients receiving treatment in the period stated b p=0.04 as compared to placebo (6 months). c p=0.02 as compared to placebo (6 months).

Childhood-Onset GH Deficiency

Two double-blind, placebo-controlled trials were conducted in 67 adult patients who had received previous somatropin treatment during childhood. Patients were randomized to receive either placebo injections or another somatropin product (0.00625 mg/kg/day for the first 4 weeks, then 0.0125 mg/kg/day thereafter) for the first 6 months, followed by open-label use of another somatropin product for the next 12 months for all patients. The patients in these studies reported side effects less frequently than those with adult- onset GH deficiency. During the placebo-controlled phase (first 6 months) of the study, elevations of serum glutamic oxaloacetic transferase were reported significantly more often for somatropin-treated (12.5%) than placebo-treated patients (0.0%, p=0.031). No other events were reported significantly more often for somatropin-treated patients during the placebo-controlled phase.

Table 6: Adverse Reactions Occurring ≥5% in Childhood-Onset
Growth Hormone-Deficient Patients Treated with Another Somatropin product for 18 Months as Compared with 6-Month Placebo and 12-Month Exposure to Another Somatropin product^a

Adverse Reaction	18 Months Exposure [Placebo (6 Months)/GH (12 Months)] (n=35)	18 Months GH Exposure (n=32)
Flu syndrome	23%	16%
AST increasedb	6%	13%
Headache	11%	9%
Asthenia	3%	6%
Cough increased	0%	6%
Edema	9%	6%
Hypesthesia	0%	6%
Myalgia	6%	6%
Pain	9%	6%
Rhinitis	6%	6%
ALT increased	6%	6%
Respiratory disorder	6%	3%
Gastritis	6%	0%
Pharyngitis	14%	3%
a Abbreviations: GH=another somatropin product; n=number of patients receiving treatment in the period stated; ALT=alanine aminotransferase, formerly SGPT; AST=aspartate aminotransferase, formerly SGOT. b p=0.03 as compared to placebo (6 months).

In an ongoing post-marketing observational study of treatment with another somatropin product in 3,102 GH-deficient adults, hypertension, dyspnea, and sleep apnea were reported by 1% to less than 10% of patients after various durations of treatment.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of somatropin or ZOMACTON. Because the following 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.

Gastrointestinal disorders— Pancreatitis

Immune system disorders — Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema

Metabolism and nutrition disorders — New-onset type 2 diabetes mellitus

Musculoskeletal and connective tissue disorders – osteonecrosis in pediatric patients

Neoplasms benign, malignant and unspecified — Leukemia has been reported in a small number of GH deficient pediatric patients treated with somatropin, somatrem (methionylated rhGH), and GH of pituitary origin

Nervous system disorders — Headaches (common in pediatric patients and occasional in adults)

Reproductive system and breast disorders — Gynecomastia

Skin and subcutaneous tissue disorders — Increase in size or number of cutaneous nevi

Drug Interactions for Zomacton

Table 7 includes a list of drugs with clinically important drug interactions when administered concomitantly with ZOMACTON and instructions for preventing or managing them.

Table 7: Clinically Important Drug Interactions with ZOMACTON

Glucocorticoids
Clinical Impact:	Microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. ZOMACTON inhibits 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Initiation of ZOMACTON may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations.
Intervention:	Patients treated with glucocorticoid replacement for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of ZOMACTON [see Warnings and Precautions (5.8)].
Examples:	Cortisone acetate and prednisone may be affected more than others since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1.
Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment
Clinical Impact:	Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth promoting effects of ZOMACTON in pediatric patients.
Intervention:	Carefully adjust glucocorticoid replacement dosing in pediatric patients receiving glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth.
Cytochrome P450-Metabolized Drugs
Clinical Impact:	Limited published data indicate that somatropin treatment increases cytochrome P450 (CP450)- mediated antipyrine clearance. ZOMACTON may alter the clearance of compounds known to be metabolized by CP450 liver enzymes.
Intervention:	Careful monitoring is advisable when ZOMACTON is administered in combination with drugs metabolized by CP450 liver enzymes.
Oral Estrogen
Clinical Impact:	Oral estrogens may reduce the serum IGF-1 response to ZOMACTON.
Intervention:	Patients receiving oral estrogen replacement may require greater ZOMACTON dosages [see Dosage and Administration (2.2)].
Insulin and/or Other Hypoglycemic Agents
Clinical Impact:	Treatment with ZOMACTON may decrease insulin sensitivity, particularly at higher doses.
Intervention:	Patients with diabetes mellitus may require adjustment of their doses of insulin and/or other hypoglycemic agents [see Warnings and Precautions (5.4)].

DRUG ABUSE AND DEPENDENCE

Controlled Substance

ZOMACTON contains somatropin, which is not a controlled substance.

Abuse

Inappropriate use of somatropin may result in significant negative health consequences.

Dependence

Somatropin is not associated with drug related withdrawal adverse reactions.

Warnings for Zomacton

Included as part of the PRECAUTIONS section.

Precautions for Zomacton

Increased Mortality in Patients with Acute Critical Illness

Increased mortality 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 has been reported after treatment with pharmacologic doses of somatropin [see Contraindications (4)]. Two placebo-controlled clinical trials in non-GH deficient adult patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (42% vs. 19%) among somatropin-treated patients (doses 5.3 mg/day-8 mg/day) compared to those receiving placebo. The safety of continuing ZOMACTON treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. ZOMACTON is not indicated for the treatment of non-GH deficient adults.

Sudden Death in Pediatric Patients with Prader-Willi Syndrome

There have been reports of sudden death after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin. If, during treatment with somatropin, patients show signs of upper airway obstruction (including onset of, or increased, snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with Prader-Willi syndrome treated with somatropin should also have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively [see Contraindications (4)]. ZOMACTON is not indicated for the treatment of pediatric patients who have growth failure due to Prader-Willi syndrome.

Increased Risk of Neoplasms

Active Malignancy

There is an increased risk of malignancy progression with somatropin treatment in patients with active malignancy [see Contraindications (4)]. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with ZOMACTON. Discontinue ZOMACTON if there is evidence of recurrent activity.

Risk of Second Neoplasm in Pediatric Patients

There is an increased risk of a second neoplasm in pediatric cancer survivors who were treated with radiation to the brain/head and who developed subsequent GH deficiency and were treated with somatropin. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor recurrence. Monitor all patients receiving ZOMACTON who have a history of GH deficiency secondary to an intracranial neoplasm for progression or recurrence of the tumor.

New Malignancy During Treatment

Because pediatric patients with certain rare genetic causes of short stature have an increased risk of developing malignancies, thoroughly consider the risks and benefits of starting ZOMACTON in these patients. If ZOMACTON is initiated, these patients should be carefully monitored for development of neoplasms.

Monitor all patients receiving ZOMACTON carefully for increased growth, or potential malignant changes, of preexisting nevi. Advise patients/caregivers to report marked changes in behavior, onset of headaches, vision disturbances and/or changes in skin pigmentation or changes in the appearance of pre-existing nevi.

Glucose Intolerance and Diabetes Mellitus

Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses. New onset type 2 diabetes mellitus has been reported in patients taking somatropin. Previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked. Monitor glucose levels periodically in all patients receiving ZOMACTON, especially in those with risk factors for diabetes mellitus, such as obesity, Turner syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely. The doses of antidiabetic agents may require adjustment when ZOMACTON is initiated.

Intracranial Hypertension

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with somatropin. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin. In all reported cases, IH-associated signs and symptoms resolved rapidly after cessation of therapy or a reduction of the somatropin dose. Fundoscopic examination should be performed routinely before initiating treatment with ZOMACTON to exclude preexisting papilledema, and periodically thereafter. If papilledema is observed by fundoscopy, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with ZOMACTON can be restarted at a lower dose after IH-associated signs and symptoms have resolved. Patients with Turner syndrome may be at increased risk for the development of IH.

Severe Hypersensitivity

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropins. Patients and caregivers should be informed that such reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs [see Contraindications (4)].

Fluid Retention

Fluid retention during somatropin replacement therapy in adults may frequently occur. Clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paresthesias) are usually transient and dose dependent.

Hypoadrenalism

Patients receiving somatropin therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of ZOMACTON. Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism [see Drug Interactions (7)].

Hypothyroidism

Undiagnosed or untreated hypothyroidism may prevent response to ZOMACTON, in particular, the growth response in pediatric patients. Patients with Turner syndrome have an increased risk of developing autoimmune thyroid disease and primary hypothyroidism. In patients with GH deficiency, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Therefore, patients should have periodic thyroid function tests performed, and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated.

Slipped Capital Femoral Epiphysis in Pediatric Patients

Slipped capital femoral epiphysis may occur more frequently in patients undergoing rapid growth. Slipped capital femoral epiphysis may lead to osteonecrosis. Cases of slipped capital femoral epiphysis with or without osteonecrosis have been reported in pediatric patients with short stature receiving somatropin. Evaluate pediatric patients receiving ZOMACTON with the onset of a limp or complaints of hip or knee pain for slipped capital femoral epiphysis and osteonecrosis and manage accordingly.

Progression of Preexisting Scoliosis in Pediatric Patients

Somatropin increases the growth rate and progression of existing scoliosis can occur in patients who experience rapid growth. Somatropin has not been shown to increase the occurrence of scoliosis. Monitor patients with a history of scoliosis for progression of scoliosis.

Pancreatitis

Cases of pancreatitis have been reported in pediatric patients and adults receiving somatropin. The risk may be greater in pediatric patients compared with adults. Published literature indicates that girls who have Turner syndrome may be at greater risk than other pediatric patients receiving somatropin. Pancreatitis should be considered in patients who develop abdominal pain.

Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preserved Solution

Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol- preserved drugs, including the bacteriostatic 0.9% sodium chloride diluent provided with ZOMACTON 5 mg. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations.

When administering ZOMACTON 5 mg to infants, reconstitute with 0.9% sodium chloride injection, not with the diluent provided. Use only one dose per vial and discard the unused portion [see Use in Specific Populations (8.4)].

Lipoatrophy

When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. Rotate injection sites when administering ZOMACTON to reduce this risk [see Dosage and Administration (2.2)].

Laboratory Tests

Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone and IGF-1 may increase after ZOMACTON treatment.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

ZOMACTON has shown no potential for mutagenicity in the Ames Test. Carcinogenesis and fertility studies have not been conducted with ZOMACTON.

OVERDOSAGE

Acute overdosage may lead initially to hypoglycemia and subsequently to hyperglycemia. Overdose with somatropin is likely to cause fluid retention. Long-term overdosage may result in signs and symptoms of gigantism or acromegaly consistent with the known effects of excess growth hormone.

Contraindications for Zomacton

ZOMACTON is contraindicated in patients with:

• Acute critical illness after open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure due to the risk of increased mortality with use of pharmacologic doses of somatropin [see Warnings and Precautions (5.1)].
• Pediatric patients with Prader-Willi syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe respiratory impairment due to the risk of sudden death [see Warnings and Precautions (5.2)].
• Active malignancy [see Warnings and Precautions (5.3)].
• Known hypersensitivity to somatropin or to any excipients of Systemic hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with postmarketing use of somatropins [see Dosage and Administrations (2.4), Warnings and Precautions (5.6)].
• Active proliferative or severe non-proliferative diabetic retinopathy.
• Pediatric patients with closed epiphyses.

Clinical Pharmacology for Zomacton

Mechanism of Action

Somatropin binds to dimeric GH receptors located within the cell membranes of target tissue cells. This interaction results in intracellular signal transduction and subsequent induction of transcription and translation of GH-dependent proteins including IGF-1, IGF BP-3 and acid-labile subunit. Somatropin has direct tissue and metabolic effects or effects mediated indirectly by IGF-1, including stimulation of chondrocyte differentiation, and proliferation, stimulation of hepatic glucose output, protein synthesis, and lipolysis.

Somatropin stimulates skeletal growth in pediatric patients with GHD as a result of effects on the growth plates (epiphyses) of long bones. The stimulation of skeletal growth increases linear growth rate (height velocity) in most somatropin-treated pediatric patients. Linear growth is facilitated in part by increased cellular protein synthesis.

Pharmacodynamics

Subcutaneous administration of a single dose of 4 mg ZOMACTON in healthy subjects (n=54) with suppressed endogenous growth hormone results in an increased mean (SD) IGF-1 level from 233 (95) ng/mL predose to maximal level of 414 (120) ng/mL after approx. 24 hours. After 96 hours, the subjects displayed a mean (SD) IGF-1 concentration of 228 (74) ng/mL, comparable to the predose value.

Pharmacokinetics

Absorption

— Somatropin has been studied following subcutaneous, and intravenous administration in adult healthy subjects. A single subcutaneous dose of 4 mg ZOMACTON in healthy subjects (n=54) with suppressed endogenous growth hormone resulted in a mean (SD) Cmax of 38.1 (19.3) ng/mL after approximately 4.5 hours. The absolute bioavailability of somatropin is approximately 70% after subcutaneous administration.

Distribution

— The mean (SD) apparent volume of distribution of somatropin after single dose subcutaneous administration of 4 mg ZOMACTON in healthy subjects is 53.3 (24.6) L.

Elimination

Metabolism — Extensive metabolism studies have not been conducted. The metabolic fate of somatropin involves classical protein catabolism in both the liver and kidneys.

Excretion - In healthy subjects, mean somatropin clearance is 0.133 L/min following intravenous administration. The mean elimination half-life of intravenous somatropin is 0.42 hours, whereas subcutaneously administered somatropin has a mean half-life of

2.3 hours. The longer half-life observed after subcutaneous administration is due to slow absorption from the injection site. Urinary excretion of intact somatropin has not been measured.

Specific Populations

Geriatric patients — The pharmacokinetics of somatropin have not been studied in patients greater than 65 years of age.

Pediatric patients — The pharmacokinetics of somatropin in pediatric patients are similar to those of adults.

Male and Female Patients — No gender-specific pharmacokinetic studies have been performed with somatropin. The available literature indicates that the pharmacokinetics of somatropin are similar in men and women.

Patients with Renal or Hepatic Impairment — No studies have been performed with somatropin.

Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ZOMACTON or other somatropins.

In a clinical trial with another recombinant growth hormone during the first 6 months of somatropin therapy in 314 naive patients, 1.6% developed specific antibodies to somatropin (binding capacity ≥0.02 mg/L). None had antibody concentrations which exceeded 2 mg/L. Throughout 8 years of this same study, two patients (0.6%) had binding capacity >2 mg/L. Neither patient demonstrated a decrease in growth velocity at or near the time of increased antibody production. It has been reported that growth attenuation from pituitary-derived GH may occur when antibody concentrations are >1.5 mg/L.

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Instructions for Use).

• Neoplasms – Advise childhood cancer survivors/caregivers that individuals treated with brain/head radiation are at increased risk of secondary neoplasms and as a precaution need to be monitored for recurrence. Advise patients/caregivers to report marked changes in behavior, onset of headaches, vision disturbances and/or changes in skin pigmentation or changes in the appearance of pre-existing nevi.
• Fluid Retention - Advise patients that fluid retention during ZOMACTON replacement therapy in adults may frequently Inform patients of the clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paresthesias) and to report to their healthcare provider any of these signs or symptoms occur during treatment with ZOMACTON.
• Pancreatitis - Advise patients/caregivers that pancreatitis may develop and to report to their healthcare provider any new onset abdominal pain.
• Hypoadrenalism - Advise patients/caregivers who have or who are at risk for pituitary hormone deficiency(s) that hypoadrenalism may develop and to report to their healthcare provider if they experience hyperpigmentation, extreme fatigue, dizziness, weakness, or weight loss.
• Hypothyroidism - Advise patients/caregivers that undiagnosed/untreated hypothyroidism may prevent an optimal response to ZOMACTON. Advise patients/caregivers they may require periodic thyroid function tests.
• Intracranial Hypertension - Advise patients/caregivers to report to their healthcare provider any visual changes, headache, and nausea and/or vomiting.
• Hypersensitivity Reactions – Advise patients/caregivers that serious systemic hypersensitivity reactions (anaphylaxis and angioedema) are possible and that prompt medical attention should be sought if an allergic reaction occurs.
• Glucose Intolerance/ Diabetes Mellitus – Advise patients/caregivers that new onset impaired glucose intolerance/diabetes mellitus or exacerbation of preexisting diabetes mellitus can occur and monitoring of blood glucose during treatment with ZOMACTON may be needed.
• Females of Reproductive Potential – Instruct patients to inform their healthcare provider if they are pregnant or planning to become pregnant as they may potentially require the use of a different formulation of ZOMACTON.