Norditropin

Pediatric Patients

NORDITROPIN is indicated for the treatment of pediatric patients with:

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growth failure due to inadequate secretion of endogenous growth hormone (GH),

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short stature associated with Noonan syndrome,

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short stature associated with Turner syndrome,

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short stature born small for gestational age (SGA) with no catch-up growth by age 2 years to 4 years of age,

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Idiopathic Short Stature (ISS), height standard deviation score (SDS) <-2.25, and associated with growth rates unlikely to permit attainment of adult height in the normal range,

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growth failure due to Prader-Willi syndrome (PWS).

Adult Patients

NORDITROPINis indicated for the replacement of endogenous GH in adults with growth hormone deficiency (GHD)

Administration and Use Instructions

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Therapy with NORDITROPIN should be supervised by a physician who is experienced in the diagnosis and management of patients with the conditions for which NORDITROPIN is indicated [see Indications and Usage (1)].

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Fundoscopic examination should be performed routinely before initiating treatment with NORDITROPIN to exclude preexisting papilledema, and periodically thereafter [see Warnings and Precautions (5.5)].

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Administer NORDITROPIN by subcutaneous injection to the back of the upper arm, abdomen, buttocks, or thigh with regular rotation of injection sites to avoid lipoatrophy.

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Inspect visually for particulate matter and discoloration. NORDITROPIN should be clear and colorless. If the solution is cloudy or contains particulate matter do not use.

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Instructions for delivering the dosage are provided in the PATIENT INFORMATION and INSTRUCTIONS FOR USE leaflets enclosed with the NORDITROPIN FlexPro prefilled pen.

Pediatric Dosage

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Individualize dosage for each patient based on the growth response.

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Divide the calculated weekly NORDITROPIN dosage into equal doses given either 6, or 7 days per week.

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The recommended weekly dose in milligrams (mg) per kilogram (kg) of body weight for pediatric patients is:

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Pediatric GH Deficiency: 0.17 mg/kg/week to 0.24 mg/kg/week (0.024 to 0.034 mg/kg/day)

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Noonan Syndrome: Up to 0.46 mg/kg/week (up to 0.066 mg/kg/day)

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Turner Syndrome: Up to 0.47 mg/kg/week (up to 0.067 mg/kg/day)

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Small for Gestational Age (SGA): Up to 0.47 mg/kg/week (up to 0.067 mg/kg/day)

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In very short pediatric patients, HSDS less than -3, and older pubertal pediatric patients consider initiating treatment with a larger dose of NORDITROPIN (up to 0.067 mg/kg/day). Consider a gradual reduction in dosage if substantial catch-up growth is observed during the first few years of therapy. In pediatric patients less than 4 years of age with less severe short stature, baseline HSDS values between -2 and -3, consider initiating treatment at 0.033 mg/kg/day and titrate the dose as needed.

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Idiopathic Short Stature: Up to 0.47 mg/kg/week (up to 0.067 mg/kg/day)

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Prader-Willi Syndrome: 0.24 mg/kg/week (0.034 mg/kg/day)

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Assess compliance and evaluate other causes of poor growth such as hypothyroidism, under-nutrition, advanced bone age and antibodies to recombinant human growth hormone if patients experience failure to increase height velocity, particularly during the first year of treatment.

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Discontinue NORDITROPIN for stimulation of linear growth once epiphyseal fusion has occurred [see Contraindications (4)].

Adult Dosage

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Patients who were treated with somatropin for GH deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin for GH deficient adults.

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Consider using a lower starting dose and smaller dose increment increases for geriatric patients as they may be at increased risk for adverse reactions with NORDITROPIN than younger individuals [see Use in Specific Populations (8.5)].

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Estrogen-replete women and patients receiving oral estrogen may require higher doses [see Drug Interactions (7)].

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Administer the prescribed dose daily.

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Either of two NORDITROPIN dosing regimens may be used:

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Non-weight based

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Initiate NORDITROPIN with a dose of approximately 0.2 mg/day (range, 0.15 mg/day to 0.3 mg/day) and increase the dose every 1-2 months by increments of approximately 0.1 mg/day to 0.2 mg/day, according to individual patient requirements based on the clinical response and serum insulin-like growth factor 1 (IGF-1) concentrations.

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Decrease the dose as necessary on the basis of adverse reactions and/or serum IGF-1 concentrations above the age- and gender-specific normal range.

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Maintenance dosages will vary considerably from person to person, and between male and female patients.

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Weight-based

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Initiate NORDITROPIN at 0.004 mg/kg daily and increase the dose according to individual patient requirements to a maximum of 0.016 mg/kg daily.

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Use the patient’s clinical response, adverse reactions, and determination of age- and gender-adjusted serum IGF-1 concentrations as guidance in dose titration.

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Not recommended for obese patients as they are more likely to experience adverse reactions with this regimen

Pregnancy

Risk Summary

Limited available data with somatropin use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, there was no evidence of fetal or neonatal harm when pregnant rats were administered subcutaneous NORDITROPINduring organogenesis or during lactation at doses approximately 10-times higher than the maximal clinical dose of 0.016 mg/kg, based on body surface area (see Data).

The estimated background risk of birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

In an embryo-fetal development study, NORDITROPINwas administered via subcutaneous injection to pregnant rats from gestation Day 6 to 17, corresponding with the period of organogenesis. NORDITROPINdid not adversely affect fetal viability or developmental outcomes at maternal doses that were approximately 10-times the clinical dose of 0.016 mg/kg, based on body surface area.

In a pre- and post-natal development study in pregnant rats, NORDITROPINwas administered from gestation Day 17 through lactation Day 21 (weaning). No adverse developmental effects were observed in the offspring at doses up to 1.1 mg/kg (approximately 10 times the clinical dose of 0.016 mg/kg, based on body surface area).

Lactation

Risk Summary

There is no information regarding the presence of somatropin in human milk. Limited published data indicate that exogenous somatropin does not increase normal breastmilk concentrations of growth hormone. No adverse effects on the breastfed infant have been reported with somatropin. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NORDITROPINand any potential adverse effects on the breastfed infant from NORDITROPINor from the underlying maternal condition.

Pediatric Use

Safety and effectiveness of NORDITROPIN in pediatric patients have been established in growth failure due to inadequate secretion of endogenous growth hormone, short stature associated with Noonan syndrome, short stature associated with Turner syndrome, short stature in children born small for gestational age (SGA) with no catch-up growth by age 2 years to 4 years of age, idiopathic short stature (ISS), and growth failure due to Prader-Willi syndrome (PWS).

Growth Failure due to Inadequate Secretion of Endogenous Growth Hormone

Safety and effectiveness of NORDITROPIN have been established in pediatric patients with growth failure due to growth hormone deficiency in a multi-center, prospective, randomized, open-label, dose-response study in 111 pediatric patients conducted for a two-year period [see Clinical Studies (14.1)].

Short Stature Associated with Noonan Syndrome

Safety and effectiveness of NORDITROPIN have been established in pediatric patients with Noonan syndrome in a prospective, open-label, randomized, parallel group study in 21 pediatric patients conducted for 2 years [see Clinical Studies (14.2)].

Short Stature Associated with Turner Syndrome

Safety and effectiveness of NORDITROPIN have been established in pediatric patients with short stature associated with Turner syndrome in two randomized, parallel group, open-label, multicenter studies in 87 pediatric patients [see Clinical Studies (14.3)].

Short Stature in Children Born Small for Gestational Age (SGA) with No Catch-up Growth by Age 2 Years to 4 Years of Age

Safety and effectiveness of NORDITROPIN have been established in pediatric patients with short stature born SGA with no catch-up growth in a multi-center, randomized, double-blind, two-arm study to final height in 53 pediatric patients and in a randomized study of 84 prepubertal, non-GHD, Japanese pediatric patients [see Clinical Studies (14.4)].

Idiopathic Short Stature (ISS)

Safety and effectiveness of NORDITROPIN have been established in pediatric patients with ISS based on data from a randomized, open-label clinical study with another somatropin product in 105 pediatric patients [see Clinical Studies (14.5)].

Growth Failure Due to Prader-Willi Syndrome (PWS)

Safety and effectiveness of NORDITROPIN have been established in pediatric patients with growth failure due to Prader-Willi Syndrome based on data from two randomized, open label, controlled clinical trials with another somatropin product in pediatric patients. 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. [see Contraindications (4), Warnings and Precautions (5.2), Clinical Studies (14.6)].

Geriatric Use

The safety and effectiveness of NORDITROPINin patients aged 65 and over has not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of somatropin, and therefore may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for older patients [see Dosage and Administration (2.3)].

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 amounts of somatropin [see Contraindications (4)]. Two placebo-controlled clinical trials in non-growth hormone 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 5.3-8 mg/day) compared to those receiving placebo. The safety of continuing NORDITROPINtreatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. NORDITROPIN 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 NORDITROPIN, 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 NORDITROPINshould 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)].

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 NORDITROPIN. Discontinue NORDITROPIN 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 NORDITROPIN 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 NORDITROPIN in these patients. If NORDITROPIN is initiated, carefully monitor patients for development of neoplasms.

Monitor all patients receiving NORDITROPIN 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 NORDITROPIN, 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 NORDITROPIN 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 products. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating treatment with NORDITROPIN to exclude preexisting papilledema, and periodically thereafter. If papilledema is observed by funduscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with NORDITROPIN 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.

5.6 Severe Hypersensitivity

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products. 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/paraesthesias) 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 NORDITROPINtreatment. 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/untreated hypothyroidism may prevent an optimal response to NORDITROPIN, in particular, the growth response in pediatric patients. Patients with Turner syndrome have an inherently 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 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 with endocrine disorders (including GH deficiency and Turner syndrome) or in patients undergoing rapid growth. Evaluate pediatric patients with the onset of a limp or complaints of hip or knee pain.

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 products. There may be a greater risk in pediatric patients compared with adults. Published literature indicates that females who have Turner syndrome may be at greater risk than other pediatric patients receiving somatropin products. Pancreatitis should be considered in patients who develop persistent severe abdominal pain.

Lipoatrophy

When somatropin products are administered subcutaneously at the same site over a long period of time, tissue atrophy may result. Rotate injection sites when administering NORDITROPIN to reduce this risk [see Administration and Use Instructions (2.1)].

Laboratory Tests

Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and IGF-I may increase after NORDITROPIN treatment.

Clinical Trials Experience

Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials performed with one somatropin product cannot always be directly compared to the rates observed during the clinical trials performed with another somatropin product, and may not reflect the adverse reaction rates observed in practice.

Pediatric Patients

Growth Failure due to Inadequate Secretion of Endogenous Growth Hormone

In one randomized, open label, clinical study the most frequent adverse reactions were headache, pharyngitis, otitis media and fever. There were no clinically significant differences between the three doses assessed in the study (0.025, 0.05 and 0.1 mg/kg/day).

Short Stature Associated with Noonan Syndrome

NORDITROPINwas studied in 21 pediatric patients, 3 years to 14 years of age at doses of 0.033 mg/kg/day and 0.066 mg/kg/day. After the two-year study, patients continued NORDITROPINtreatment until final height was achieved; randomized dose groups were not maintained. Adverse reactions were later collected retrospectively from 18 pediatric patients; total follow-up was 11 years. An additional 6 pediatric patients were not randomized, but followed the protocol and are included in this assessment of adverse reactions.

The most frequent adverse reactions were upper respiratory infection, gastroenteritis, ear infection, and influenza. Cardiac disorders was the system organ class with the second most adverse reactions reported. Scoliosis was reported in 1 and 4 pediatric patients receiving doses of 0.033 mg/kg/day and 0.066 mg/kg/day respectively. The following additional adverse reactions also occurred once: insulin resistance and panic reaction for the 0.033 mg/kg/day dose group; injection site pruritus, bone development abnormal, depression, and self-injurious ideation in the 0.066 mg/kg/day dose group. Headache occurred in 2 cases in the 0.066 mg/kg/day dose group.

Short Stature Associated with Turner Syndrome

In two clinical studies in pediatric patients that were treated until final height with various doses of NORDITROPIN, the most frequently reported adverse reactions were influenza-like illness, otitis media, upper respiratory tract infection, otitis externa, gastroenteritis, eczema and, impaired fasting glucose. Adverse reactions in study 1 were most frequent in the highest dose groups. Three patients in study 1 had excessive growth of hands and/or feet in the high dose groups. Two patients in study 1 had a serious adverse reaction of exacerbation of preexisting scoliosis in the 0.045 mg/kg/day group.

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

In a study, 53 pediatric patients were treated with 2 doses of NORDITROPIN(0.033 or 0.067 mg/kg/day) to final height for up to 13 years (mean duration of treatment 7.9 and 9.5 years for girls and boys, respectively). The most frequently reported adverse reactions were influenza-like illness, upper respiratory tract infection, bronchitis, gastroenteritis, abdominal pain, otitis media, pharyngitis, arthralgia, headache, gynecomastia, and increased sweating. One pediatric patient treated with 0.067 mg/kg/day for 4 years was reported with disproportionate growth of the lower jaw, and another patient treated with 0.067 mg/kg/day developed a melanocytic nevus. 4 pediatric patients treated with 0.067 mg/kg/day and 2 pediatric patients treated with 0.033 mg/kg/day of NORDITROPIN had increased fasting blood glucose levels after 1 year of treatment. In addition, small increases in mean fasting blood glucose and insulin levels after 1 and 2 years of NORDITROPIN treatment appeared to be dose-dependent.

In a second study, 98 Japanese pediatric patients were treated with 2 doses of NORDITROPIN(0.033 or 0.067 mg/kg/day) for 2 years or were untreated for 1 year. Adverse reactions were otitis media, arthralgia and impaired glucose tolerance. Arthralgia and transiently impaired glucose tolerance were reported in the 0.067 mg/kg/day treatment group.

Idiopathic Short Stature

In two open-label clinical studies with another somatropin product in pediatric patients, the most common adverse reactions were upper respiratory tract infections, influenza, tonsillitis, nasopharyngitis, gastroenteritis, headaches, increased appetite, pyrexia, fracture, altered mood, and arthralgia.

Growth Failure Due to Prader-Willi Syndrome

In two clinical studies in pediatric patients with PWS carried out with another somatropin product, the following adverse reactions were reported: edema, aggressiveness, arthralgia, benign intracranial hypertension, hair loss, headache, and myalgia.

Adult Patients

Adults with Growth Hormone Deficiency

Adverse reactions with an incidence of ≥5% occurring in patients with AO GHD during the 6 month placebo-controlled portion of a clinical trial for NORDITROPINare presented in Table 1.

Table 1 – Adverse Reactions with ≥5% Overall Incidence in Adult Onset Growth Hormone

Deficient Patients Treated with NORDITROPIN During a Six Month Placebo-Controlled Clinical Trial

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

In clinical trials, GH deficient pediatric patients receiving NORDITROPINfor up to 12 months were tested for induction of antibodies, and 0/358 patients developed antibodies with binding capacities above 2 mg/L. Amongst these patients, 165 had previously been treated with other somatropin formulations, and 193 were previously untreated naive patients. Eighteen of 76 children (~24%) treated with NORDITROPINfor short stature born SGA developed anti-rhGH antibodies.

Post-Marketing Experience

Because these adverse reactions 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.

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

Skin — Increase in size or number of cutaneous nevi

Endocrine disorders — Hypothyroidism

Metabolism and nutrition disorders — Hyperglycemia

Musculoskeletal and connective tissue disorders —Slipped capital femoral epiphysis— Legg-Calvé-Perthes disease

Investigations — Increase in blood alkaline phosphatase level — Decrease in serum thyroxin (T4) levels

Gastrointestinal — Pancreatitis

Neoplasm — Leukemia has been reported in a small number of GH deficient children treated with somatropin, somatrem (methionylated rhGH) and GH of pituitary origin

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 mediated indirectly by IGF-1, including stimulation of chondrocyte differentiation, and proliferation, stimulation 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 NORDITROPINin healthy subjects (n=26) with suppressed endogenous growth hormone results in an increased mean (SD) IGF-1 level from 190 (46) ng/mL predose to maximal level of 276 (49) ng/mL after approx. 24 hours. After 96 hours, the subjects displayed a mean (SD) IGF-1 concentration of 196 (41) ng/mL, comparable to the predose value.

Pharmacokinetics

Absorption - Somatropin has been studied following subcutaneous and intravenous administration in adult healthy subjects and GHD patients. A single dose administration of 4 mg NORDITROPINin healthy subjects (n=26) with suppressed endogenous growth hormone resulted in a mean (SD) Cmax of 34.9 (10.4) ng/mL after approximately 3.0 hours. After a 180-min IV infusion of NORDITROPIN(33 ng/kg/min) administered to GHD patients (n=9), a mean (SD) hGH steady state serum level of approximately 23.1 (15.0) ng/mL was reached at 150 min.

After a SC dose of 0.024 mg/kg or 3 IU/m2 given in the thigh to adult GHD patients (n=18), mean (SD) Cmax values of 13.8 (5.8) and 17.1 (10.0) ng/mL were observed for the 4 and 8 mg NORDITROPINvials, respectively, at approximately 4 to 5 hr. post dose. The absolute bioavailability for NORDITROPINafter the SC route of administration is currently not known.

Distribution— The mean (SD) apparent volume of distribution of somatropin after single dose subcutaneous administration of 4 mg NORDITROPINin healthy subjects is 43.9 (14.9) 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 – The mean apparent terminal T1/2 values in healthy adult subjects (n=26) was 2.0 (0.5) hours. In GHD patients receiving 180-min IV infusion of NORDITROPIN(33 ng/kg/min), a mean clearance rate of approximately 2.3 (1.8) mL/min/kg or 139 (105) mL/min for hGH was observed. Following infusion, serum hGH levels had a biexponential decay with a terminal elimination half-life (T1/2) of approximately 21.1 (5.1) min. The mean apparent terminal T1/2 values in GHD patients receiving a SC dose of 0.024 mg/kg or 3 IU/m2 was estimated to be approximately 7 to 10 hr. 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.

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.

Carcinogenesis and Mutagenesis, Impairment of Fertility

Carcinogenicity and mutagenicity studies have not been conducted with NORDITROPIN.

Impairment of Fertility

In a rat study evaluating female fertility, animals were administered once daily subcutaneous doses of 0.1, 0.3, and 1.1 mg/kg NORDITROPIN beginning two weeks prior to mating, throughout mating and during the first 7 days of pregnancy. Delays in the time to mating were observed at doses greater than or equal to 0.3 mg/kg (approximately 3 times the maximum adult clinical dose of 0.016 mg/kg, based on body surface area), but these doses were also associated with increases in the number of corpora lutea and implantations. A decrease in the pregnancy rate was observed at the dose of 1.1 mg/kg (approximately 10 times the clinical dose of 0.016 mg/kg, based on body surface area). Male fertility parameters have not been evaluated with administration of NORDITROPIN.

Growth Failure due to Inadequate Secretion of Endogenous Growth Hormone

The efficacy and safety of NORDITROPIN was assessed in a multicenter, prospective randomized, open label, dose response study with three doses (0.025, 0.05 and 0.1 mg/kg/day). A total of 111 pediatric patients with GH deficiency were randomized to each dose; 37(0.025 mg/kg/day):38(0.05 mg/kg/day):36(0.1 mg/kg/day). Patients met the following entry criteria: chronological age ≥ 3 years with a skeletal age < 10 years if male and < 8 years if female; pubertal stage = stage 1; previously untreated GH deficiency; peak plasma hormone concentration < 7 ng/ml or < 10 ng/ml (depending on assay used) in two tests.

The results are displayed in Table 4. The adjusted mean increases in HSDS over the 2-year period were 0.81, 1.57 and 1.73 in the 0.025, 0.05 and 0.1 mg/kg/day dose groups, respectively. There was no significant difference in ΔHSDS between the 0.05 and 0.1 mg/kg/day treatment groups. Height velocity (HV, cm/year) and HVSDS increased considerably after initiation of treatment, with the greatest response observed during the first year of treatment.

Table 4 – Efficacy of NORDITROPIN in Pediatric GH Deficiency

 

*Significant (p <0.05) change from baseline compared to the 0.025 mg/kg/group

**Significant (p <0.05) change from baseline compared to both other groups

Short Stature Associated with Noonan Syndrome

A prospective, open label, randomized, parallel group study with 21 pediatric patients was conducted for 2 years to evaluate the efficacy and safety of NORDITROPIN. Additional 6 children were not randomized, but did follow the protocol. Inclusion criteria included bone age determination showing no significant acceleration, prepubertal status, height SDS <-2, and HV SDS <1 during the 12 months pre-treatment. Exclusion criteria were previous or ongoing treatment with growth hormone, anabolic steroids or corticosteroids, congenital heart disease or other serious disease perceived to possibly have major impact on growth, FPG >6.7 mmol/L (>120 mg/dL), or growth hormone deficiency (peak GH levels <10 ng/mL). The twenty-four, 12 female and 12 male, patients 3 – 14 years of age received either 0.033 mg/kg/day or 0.066 mg/kg/day of NORDITROPINsubcutaneously which was adjusted based on growth response after the first 2 years.

After the initial two-year study, NORDITROPIN treatment continueduntil final height. Retrospective final height was collected from 18 patients in the study and the 6 who had followed the protocol without randomization. Historical reference materials of height velocity and adult height analyses of Noonan patients served as the controls.

Patients obtained a final height (FH) gain from baseline of 1.5 and 1.6 SDS estimated according to the national and the Noonan reference, respectively. A height gain of 1.5 SDS (national) corresponds to a mean height gain of 9.9 cm in boys and 9.1 cm in girls at 18 years of age, while a height gain of 1.6 SDS (Noonan) corresponds to a mean height gain of 11.5 cm in boys and 11.0 cm in girls at 18 years of age.

A comparison of HV between the two treatment groups during the first two years of treatment for the randomized subjects was 10.1 and 7.6 cm/year with 0.066 mg/kg/day versus 8.55 and 6.7 cm/year with 0.033 mg/kg/day, for Year 1 and Year 2, respectively.

Short Stature Associated with Turner Syndrome

Two randomized, parallel group, open label, multicenter studies were conducted in the Netherlands to evaluate the efficacy and safety of NORDITROPIN. Patients were treated to final height in both studies [height velocity (HV) < 2 cm/year]. Changes in height were expressed as standard deviation scores (SDS) utilizing reference data for untreated Turner syndrome patients as well as the national Dutch population.

In Study 1, 68 euthyroid Caucasian patients stratified based on age and baseline height SDS were randomized in a 1:1:1 ratio to three different NORDITROPINtreatment regimens: 0.045 mg/kg/day (Dose A) for the entire study; 0.045 mg/kg/day for the first year and 0.067 mg/kg/day thereafter (Dose B); or 0.045 mg/kg/day for the first year, 0.067 for the second year, and 0.089 mg/kg/day thereafter (Dose C). At baseline, mean age was 6.5 years, mean height SDS (National standard) was -2.7, and mean HV during the previous year was 6.5 cm/year. Patients also received estrogen therapy after age 12 and following four years of NORDITROPINtreatment if they did not have spontaneous puberty.

Patients were treated for a mean of 8.4 years. As seen in Table 5, overall mean final height was 161 cm in the 46 children who attained final height. Seventy percent of these children reached a final height within the normal range (height SDS > -2 using the National standard). A greater percentage of children in the two escalated dose groups reached normal final height. The mean changes from baseline to final height in height SDS after treatment with Dose B and Dose C were significantly greater than the mean changes observed after treatment with Dose A (utilizing both the National and Turner standards). The mean changes from baseline to final height in height SDS (Turner standard) in Table 5 correspond to mean height gains of 9.4, 14.1 and 14.4 cm after treatment with Doses A, B and C, respectively. The mean changes from baseline to final height in height SDS (National standard) in Table 5 correspond to mean height gains of 4.5, 9.1 and 9.4 cm after treatment with Doses A, B and C, respectively. In each treatment group, peak HV was observed during treatment Year 1, and then gradually decreased each year; during Year 4, HV was less than the pre-treatment HV. However, between Year 2 and Year 6, a greater HV was observed in the two dose escalation groups compared to the 0.045 mg/kg/day group.

Table 5 – Final Height-Related Results After Treatment of Patients with Turner Syndrome with NORDITROPIN in a Randomized, Dose Escalating Study

Values are expressed as mean (SD) unless otherwise indicated. SDS: Standard deviation score.

1Unadjusted (raw) means; 2Adjusted (least squares) means based on an ANCOVA model including terms for treatment,

duration of treatment, age at baseline, bone age at baseline, height SDS at baseline, age at onset of puberty and mid-parental target height SDS;

3p=0.005 vs. Dose A; 4p=0.006 vs. Dose A; 5p=0.008 vs. Dose A

In Study 2, 19 euthyroid Caucasian patients (with bone age ≤13.9 years) were randomized to treatment with 0.067 mg/kg/day of NORDITROPINas a single subcutaneous dose in the evening, or divided into two doses (1/3 morning and 2/3 evening). All subjects were treated with concomitant ethinyl estradiol. Overall, at baseline, mean age was 13.6 years, mean height SDS (National standard) was -3.5 and mean HV during the previous year was 4.3 cm/year. Patients were treated for a mean of 3.6 years. In that there were no significant differences between the two treatment groups for any linear growth variables, the data from all patients were pooled. Overall mean final height was 155 cm in the 17 children who attained final height. Height SDS changed significantly from -3.5 at baseline to -2.4 at final height (National standard), and from 0.7 to 1.3 at final height (Turner standard).

Short Stature in Children Born Small for Gestational Age (SGA) with No Catch-up Growth by Age 2-4 Years

A multi-center, randomized, double-blind, two-arm study to final height (Study 1) and a 2-year, multi-center, randomized, double-blind, parallel-group study (Study 2) were conducted to assess the efficacy and safety of NORDITROPIN. Changes in height and height velocity were compared to a national reference population in both studies.

Study 1 included 53, 38 male, 15 female, non-GHD, Dutch prepubertal pediatric patients 3-11 years of age with short stature born SGA with no catch-up growth. Catch-up growth was defined as obtaining a height of ≥ 3rd percentile within the first 2 years of life or at a later stage. Inclusion criteria included: birth length < 3rd percentile for gestational age, and height velocity (cm/year) for chronological age < 50th percentile.Exclusion criteria included chromosomal abnormalities, signs of a syndrome (except for Silver-Russell syndrome), serious/chronic co-morbid disease, malignancy, and previous rhGH therapy. NORDITROPINwas administered subcutaneously daily at bedtime at a dose of approximately 0.033 (Dose A) or 0.067 mg/kg/day (Dose B) for the entire treatment period. Final height was defined as a height velocity below 2 cm/year. Treatment with NORDITROPINwas continued to final height for up to 13 years. Mean duration of treatment was 9.5 years (boys) and 7.9 years (girls).

38 out of 53 children (72%) reached final height. Sixty-three percent (24 out of 38) of the children who reached final height were within the normal range of their healthy peers (Dutch national reference). For both doses combined, actual mean final height was 171 (SD 6.1) cm in boys and 159 (SD 4.3) cm in girls.

As seen in Table 6, for boys and girls combined, both mean final height SDS, and increase in height SDS from baseline to final height, were significantly greater after treatment with Dose B (0.067 mg/kg/day). A similar dose response was observed for the increase in height SDS from baseline to Year 2 (Table 6).

Overall mean height velocity at baseline was 5.4 cm/y (SD 1.2; n=29). Height velocity was greatest during the first year of NORDITROPINtreatment and was significantly greater after treatment with Dose B (mean 11.1 cm/y [SD 1.9; n=19]) compared with Dose A (mean 9.7 cm/y [SD 1.3; n=10]).

Table 6 – Study 1: Results for Final Height SDS and Change from Baseline to Final Height in Height SDS Using National Standard After Long-Term Treatment of SGA Children with NORDITROPIN

SDS: Standard deviation score.

1Adjusted (least-squares) means based on an ANCOVA model including terms for treatment, gender, age at baseline, bone age at baseline, height SDS at baseline, duration of treatment, peak GH after stimulation and baseline IGF-1.

2 Adjusted (least-squares) means based on an ANCOVA model including terms for treatment, gender, age at baseline, height SDS at baseline, and pubertal status.

3 p<0.05

In study 2, 84 randomized, prepubertal, non-GHD, Japanese children (age 3-8) were treated for 2 years with 0.033 or 0.067 mg/kg/day of NORDITROPIN subcutaneously daily at bedtime or received no treatment for 1 year. Additional inclusion criteria included birth length or weight SDS ≤ -2 or < 10th percentile for gestational age, height SDS for chronological age ≤ -2, and height velocity SDS for chronological age < 0 within one year prior to Visit 1. Exclusion criteria included diabetes mellitus, history or presence of active malignancy, and serious co-morbid conditions.

As seen in Table 7, for boys and girls combined, there was a dose-dependent increase in height SDS at Year 1 and Year 2. The increase in height SDS from baseline to Year 2 (0.033 mg/kg/day, 0.8 vs. 0.067 mg/kg/day, 1.4) was significantly greater after treatment with 0.067 mg/kg/day. In addition, the increase in height SDS at Year 1 was significantly greater in both active treatment groups compared to the untreated control group.

Table 7 – Study 2: Results for Change from Baseline in Height SDS At Year 1 and Year 2 Using National Standard After Short-Term Treatment of SGA Children with NORDITROPIN

SDS: Standard deviation score.

1Adjusted (least-squares) means based on an ANCOVA model including terms for treatment, gender, age at baseline, and height SDS at baseline. All children remained prepubertal during the study.

2 p< 0.0001

Idiopathic Short Stature (ISS)

The efficacy and safety of another somatropin product was evaluated in 105 patients who were retrospectively identified as having ISS in a randomized, open-label, clinical study. Patients were enrolled on the basis of short stature, stimulated GH secretion > 10 ng/mL, and prepubertal status. All patients were observed for height progression for 12 months and were subsequently randomized to this other somatropin product or observation only and followed to final height. Two doses of this other somatropin product were evaluated in this trial: 0.23 mg/kg/week (0.033 mg/kg/day) and 0.47 mg/kg/week (0.067 mg/kg/day). Baseline patient characteristics for the ISS patients who remained prepubertal at randomization (n= 105) were: mean (± SD): chronological age 11.4 (1.3) years, height SDS -2.4 (0.4), height velocity SDS -1.1 (0.8), and height velocity 4.4 (0.9) cm/yr, IGF-1 SDS -0.8 (1.4). Patients were treated for a median duration of 5.7 years. Results for final height SDS are displayed by treatment arm in Table 8. The observed mean gain in final height was 9.8 cm for females and 5.0 cm for males for both doses combined compared to untreated control subjects. A height gain of 1 SDS was observed in 10% of untreated subjects, 50% of subjects receiving 0.23 mg/kg/week and 69% of subjects receiving 0.47 mg/kg/week.

Table 8 – Final height SDS results for pre-pubertal patients with ISS*

Least square means based on ANCOVA (final height SDS and final height SDS minus baseline predicted height SDS were adjusted for baseline height SDS)

* Mean (SD) are observed values

**p<0.05

Growth Failure Due to Prader-Willi Syndrome (PWS)

The safety and efficacy of another somatropin product were evaluated in two randomized, open-label, controlled clinical studies. Patients received either this other somatropin product or no treatment for the first year of the studies, while all patients received this other somatropin product during the second year. This other somatropin product was administered as a daily SC injection, and the dose was calculated for each patient every 3 months. In Study 1, the treatment group received this other somatropin product at a dose of 0.24 mg/kg/week during the entire study. During the second year, the control group received this other somatropin product at a dose of 0.48 mg/kg/week. In Study 2, the treatment group received this other somatropin product at a dose of 0.36 mg/kg/week during the entire study. During the second year, the control group received this other somatropin product at a dose of 0.36 mg/kg/week.

The results are presented in Table 9. Linear growth continued to increase in the second year, when both groups received treatment with this other somatropin product.

* p <0.05

Adults with Growth Hormone Deficiency (GHD)

A total of six randomized, double-blind, placebo-controlled studies were performed. Two representative studies, one in adult onset (AO) GHD patients and a second in childhood onset (CO) GHD patients, are described below.

Study 1

A single center, randomized, double-blind, placebo-controlled, parallel-group, six month clinical trial was conducted in 31 adults with AO GHD comparing the effects of NORDITROPIN(somatropin) injection and placebo on body composition. Patients in the active treatment arm were treated with NORDITROPIN0.017 mg/kg/day (not to exceed 1.33 mg/day). The changes from baseline in lean body mass (LBM) and percent total body fat (TBF) were measured by total body potassium (TBP) after 6 months.

Treatment with NORDITROPINproduced a significant increase from baseline in LBM compared to placebo (Table 10).

Table 10 – Lean Body Mass (kg) by TBP

*Least square mean based on an ANOVA model including treatment and sex as factors

Analysis of the treatment difference on the change from baseline in percent TBF revealed a significant decrease in the NORDITROPIN-treated group compared to the placebo group (Table 11).

Table 11 – Total Body Fat (%) by TBP

*Least square mean based on an ANOVA model including treatment and sex as factors

NORDITROPINalso significantly increased serum osteocalcin (a marker of osteoblastic activity).

Study 2

A single center, randomized, double-blind, placebo-controlled, parallel-group, dose-finding, six month clinical trial was conducted in 49 men with CO GHD comparing the effects of NORDITROPINand placebo on body composition. Patients were randomized to placebo or one of three active treatment groups (0.008, 0.016, and 0.024 mg/kg/day). Thirty three percent of the total dose to which each patient was randomized was administered during weeks 1-4, 67% during weeks 5-8, and 100% for the remainder of the study. The changes from baseline in LBM and percent TBF were measured by TBP after 6 months.

Treatment with NORDITROPINproduced a significant increase from baseline in LBM compared to placebo (pooled data) (Table 12).

Table 12 – Lean Body Mass (kg) by TBP

*Least square mean based on an ANOVA model including treatment as a factor

Analysis of the treatment difference on the change from baseline in percent TBF revealed a significant decrease in the NORDITROPIN-treated groups (pooled data) compared to the placebo group (Table 13).

Table 13 – Total Body Fat (%) by TBP

*Least square mean based on an ANOVA model including treatment as a factor