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FDA Drug information

Norditropin

Read time: 3 mins
Marketing start date: 21 Feb 2024

Summary of product characteristics


Adverse Reactions

6 ADVERSE REACTIONS The following important adverse reactions are also described elsewhere in the labeling: • Increased mortality in patients with acute critical illness [see Warnings and Precautions (5.1) ] • Sudden death in children 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) ] • Lipoatrophy [see Warnings and Precautions (5.13) ] Common adverse reactions in adult and pediatric patients include: upper respiratory infection, fever, pharyngitis, headache, otitis media, edema, arthralgia, paresthesia, myalgia, peripheral edema, flu syndrome, and impaired glucose tolerance. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk at 1-888-NOVO-444 (1-888-668-6444) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials performed with one somatropin 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 NORDITROPIN was 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 NORDITROPIN treatment 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 NORDITROPIN are 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 Placebo (N=52) NORDITROPIN (N=53) Adverse Reactions % % Peripheral Edema 8 42 Edema 0 25 Arthralgia 15 19 Leg Edema 4 15 Myalgia 8 15 Infection (non-viral) 8 13 Paraesthesia 6 11 Skeletal Pain 2 11 Headache 6 9 Bronchitis 0 9 Flu-like symptoms 4 8 Hypertension 2 8 Gastroenteritis 8 8 Other Non-Classifiable Disorders (excludes accidental injury) 6 8 Increased sweating 2 8 Glucose tolerance abnormal 2 6 Laryngitis 6 6 Type 2 diabetes mellitus 0 5 6.2 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 NORDITROPIN with 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 NORDITROPIN for 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 NORDITROPIN for short stature born SGA developed anti-rhGH antibodies. 6.3 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

Contraindications

4 CONTRAINDICATIONS NORDITROPIN 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) ]. • Hypersensitivity to NORDITROPIN or any of its excipients. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropin products [see Warnings and Precautions (5.6) ]. • Active proliferative or severe non-proliferative diabetic retinopathy. • Pediatric patients with closed epiphyses. • Acute Critical Illness ( 4 ) • Pediatric patients with Prader-Willi syndrome who are severely obese, have history of severe upper airway obstruction, or have severe respiratory impairment due to risk of sudden death ( 4 ) • Active Malignancy ( 4 ) • Hypersensitivity to somatropin or excipients ( 4 ) • Active Proliferative or Severe Non-Proliferative Diabetic Retinopathy ( 4 ) • Pediatric patients with closed epiphyses ( 4 )

Description

11 DESCRIPTION NORDITROPIN (somatropin) for injection is a recombinant human growth hormone. It is a polypeptide of recombinant DNA origin and is synthesized by a special strain of E. coli bacteria that has been modified by the addition of a plasmid which carries the gene for human growth hormone. NORDITROPIN contains the identical sequence of 191 amino acids constituting the naturally occurring pituitary human growth hormone with a molecular weight of about 22,000 Daltons. NORDITROPIN is supplied as a sterile solution for subcutaneous use in ready-to-administer prefilled pens with a volume of 1.5 mL or 3 mL. Each NORDITROPIN contains the following (see Table 3): Table 3 Component 5 mg/1.5 mL 10 mg/1.5 mL 15 mg/1.5 mL 30 mg/3 mL Somatropin 5 mg 10 mg 15 mg 30 mg Histidine 1 mg 1 mg 1.7 mg 3.3 mg Poloxamer 188 4.5 mg 4.5 mg 4.5 mg 9 mg Phenol 4.5 mg 4.5 mg 4.5 mg 9 mg Mannitol 60 mg 60 mg 58 mg 117 mg HCl/NaOH as needed as needed as needed as needed Water for Injection up to 1.5 mL up to 1.5 mL up to 1.5 mL up to 3 mL

Dosage And Administration

2 DOSAGE AND ADMINISTRATION • Administer by subcutaneous injection to the back of upper arm, abdomen, buttock, or thigh with regular rotation of injection sites ( 2.1 ) • Pediatric Dosage - divide the calculated weekly dosage into equal doses given either 6, or 7 days per week o GHD: 0.17 mg/kg/week to 0.24 mg/kg/week ( 2.2 ) o Noonan Syndrome: Up to 0.46 mg/kg/week ( 2.2 ) o Turner Syndrome: Up to 0.47 mg/kg/week ( 2.2 ) o SGA: Up to 0.47 mg/kg/week ( 2.2 ) o ISS: Up to 0.47 mg/kg/week ( 2.2 ) o Prader-Willi Syndrome: 0.24 mg/kg/week ( 2.2 ) • Adult Dosage: Either of the following two dosing regimens may be used: o Non-weight based dosing: Initiate with a dose of approximately 0.2 mg/day (range, 0.15 mg/day-0.3 mg/day) and increase the dose every 1-2 months by increments of approximately 0.1 mg/day-0.2 mg/day, according to individual patient requirements ( 2.3 ) o Weight-based dosing (Not recommended for obese patients): Initiate at 0.004 mg/kg daily and increase the dose according to individual patient requirements to a maximum of 0.016 mg/kg daily ( 2.3 ) 2.1 Administration and Use Instructions • 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) ]. • Fundoscopic examination should be performed routinely before initiating treatment with NORDITROPIN to exclude preexisting papilledema, and periodically thereafter [see Warnings and Precautions (5.5) ]. • 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. • 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. • Instructions for delivering the dosage are provided in the PATIENT INFORMATION and INSTRUCTIONS FOR USE leaflets enclosed with the NORDITROPIN FlexPro prefilled pen. 2.2 Pediatric Dosage • Individualize dosage for each patient based on the growth response. • Divide the calculated weekly NORDITROPIN dosage into equal doses given either 6, or 7 days per week. • The recommended weekly dose in milligrams (mg) per kilogram (kg) of body weight for pediatric patients is: o Pediatric GH Deficiency: 0.17 mg/kg/week to 0.24 mg/kg/week (0.024 to 0.034 mg/kg/day) o Noonan Syndrome: Up to 0.46 mg/kg/week (up to 0.066 mg/kg/day) o Turner Syndrome: Up to 0.47 mg/kg/week (up to 0.067 mg/kg/day) o Small for Gestational Age (SGA): Up to 0.47 mg/kg/week (up to 0.067 mg/kg/day) ▪ 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. o Idiopathic Short Stature: Up to 0.47 mg/kg/week (up to 0.067 mg/kg/day) o Prader-Willi Syndrome: 0.24 mg/kg/week (0.034 mg/kg/day) • 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. • Discontinue NORDITROPIN for stimulation of linear growth once epiphyseal fusion has occurred [see Contraindications (4) ]. 2.3 Adult Dosage • 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. • 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) ]. • Estrogen-replete women and patients receiving oral estrogen may require higher doses [see Drug Interactions (7) ]. • Administer the prescribed dose daily. • Either of two NORDITROPIN dosing regimens may be used: o Non-weight based ▪ 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. ▪ 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. ▪ Maintenance dosages will vary considerably from person to person, and between male and female patients. o Weight-based ▪ 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. ▪ Use the patient’s clinical response, adverse reactions, and determination of age- and gender-adjusted serum IGF-1 concentrations as guidance in dose titration. ▪ Not recommended for obese patients as they are more likely to experience adverse reactions with this regimen

Indications And Usage

1 INDICATIONS AND USAGE NORDITROPIN is a recombinant human growth hormone indicated for: • Pediatric : Treatment of pediatric patients with growth failure due to inadequate secretion of endogenous growth hormone (GH), short stature associated with Noonan syndrome, short stature associated with Turner syndrome, short stature born small for gestational age (SGA) with no catch-up growth by age 2 to 4 years, Idiopathic Short Stature (ISS), and growth failure due to Prader-Willi Syndrome ( 1.1 ) • Adult : Replacement of endogenous GH in adults with growth hormone deficiency ( 1.2 ) 1.1 Pediatric Patients NORDITROPIN is indicated for the treatment of pediatric patients with: • growth failure due to inadequate secretion of endogenous growth hormone (GH), • short stature associated with Noonan syndrome, • short stature associated with Turner syndrome, • short stature born small for gestational age (SGA) with no catch-up growth by age 2 years to 4 years of age, • 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, • growth failure due to Prader-Willi syndrome (PWS). 1.2 Adult Patients NORDITROPIN is indicated for the replacement of endogenous GH in adults with growth hormone deficiency (GHD)

Abuse

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

Controlled Substance

9.1 Controlled Substance NORDITROPIN contains somatropin, which is not a controlled substance.

Dependence

9.3 Dependence Somatropin is not associated with drug related withdrawal adverse reactions.

Drug Abuse And Dependence

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance NORDITROPIN contains somatropin, which is not a controlled substance. 9.2 Abuse Inappropriate use of somatropin may result in significant negative health consequences. 9.3 Dependence Somatropin is not associated with drug related withdrawal adverse reactions.

Overdosage

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

Adverse Reactions Table

Placebo

(N=52)

NORDITROPIN

(N=53)

Adverse Reactions

%

%

Peripheral Edema

8

42

Edema

0

25

Arthralgia

15

19

Leg Edema

4

15

Myalgia

8

15

Infection (non-viral)

8

13

Paraesthesia

6

11

Skeletal Pain

2

11

Headache

6

9

Bronchitis

0

9

Flu-like symptoms

4

8

Hypertension

2

8

Gastroenteritis

8

8

Other Non-Classifiable Disorders (excludes accidental injury)

6

8

Increased sweating

2

8

Glucose tolerance abnormal

2

6

Laryngitis

6

6

Type 2 diabetes mellitus

0

5

Drug Interactions

7 DRUG INTERACTIONS Table 2 includes a list of drugs with clinically important drug interactions when administered concomitantly with NORDITROPIN and instructions for preventing or managing them. Table 2: Clinically Important Drug Interactions with NORDITROPIN 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. NORDITROPIN inhibits 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Initiation of NORDITROPIN 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 NORDITROPIN [see Warnings and Precautions (5.8) ]. Examples: Cortisone acetate and prednisone may be effected 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 NORDITROPIN 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. NORDITROPIN may alter the clearance of compounds known to be metabolized by CP450 liver enzymes. Intervention: Careful monitoring is advisable when NORDITROPIN 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 NORDITROPIN. Intervention: Patients receiving oral estrogen replacement may require greater NORDITROPIN dosages [see Dosage and Administration (2.3) ] . Insulin and/or Other Hypoglycemic Agents Clinical Impact: Treatment with NORDITROPIN 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) ]. • Glucocorticoids : Patients treated with glucocorticoid for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of NORDITROPIN ( 7 ) • Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment : Adjust glucocorticoid replacement dosing in pediatric patients receiving glucocorticoid treatment to avoid both hypoadrenalism and an inhibitory effect on growth. ( 7 ) • Cytochrome P450-Metabolized Drugs : NORDITROPIN may alter the clearance. Monitor carefully if used with NORDITROPIN ( 7 ) • Oral Estrogen : Larger doses of NORDITROPIN may be required ( 7 ) • Insulin and/or Other Hypoglycemic Agents : Dose adjustment of insulin or hypoglycemic agent may be required ( 5.4 , 7 )

Drug Interactions Table

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. NORDITROPINinhibits 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Initiation of NORDITROPINmay 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 NORDITROPIN [see Warnings and Precautions (5.8)].

Examples:

Cortisone acetate and prednisone may be effected 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 NORDITROPINin 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. NORDITROPINmay alter the clearance of compounds known to be metabolized by CP450 liver enzymes.

Intervention:

Careful monitoring is advisable when NORDITROPINis administered in combination with drugs metabolized by CP450 liver enzymes.

Oral Estrogen

Clinical Impact:

Oral estrogens may reduce the serum IGF-1 response to NORDITROPIN.

Intervention:

Patients receiving oral estrogen replacement may require greater NORDITROPINdosages [see Dosage and Administration (2.3)].

Insulin and/or Other Hypoglycemic Agents

Clinical Impact:

Treatment with NORDITROPINmay 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)].

Clinical Pharmacology

12 CLINICAL PHARMACOLOGY 12.1 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. 12.2 Pharmacodynamics Subcutaneous administration of a single dose of 4 mg NORDITROPIN in 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. 12.3 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 NORDITROPIN in healthy subjects (n=26) with suppressed endogenous growth hormone resulted in a mean (SD) C max 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/m 2 given in the thigh to adult GHD patients (n=18), mean (SD) C max values of 13.8 (5.8) and 17.1 (10.0) ng/mL were observed for the 4 and 8 mg NORDITROPIN vials, respectively, at approximately 4 to 5 hr. post dose. The absolute bioavailability for NORDITROPIN after 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 NORDITROPIN in 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 T 1/2 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 (T 1/2 ) of approximately 21.1 (5.1) min. The mean apparent terminal T 1/2 values in GHD patients receiving a SC dose of 0.024 mg/kg or 3 IU/m 2 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.

Mechanism Of Action

12.1 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

12.2 Pharmacodynamics Subcutaneous administration of a single dose of 4 mg NORDITROPIN in 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

12.3 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 NORDITROPIN in healthy subjects (n=26) with suppressed endogenous growth hormone resulted in a mean (SD) C max 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/m 2 given in the thigh to adult GHD patients (n=18), mean (SD) C max values of 13.8 (5.8) and 17.1 (10.0) ng/mL were observed for the 4 and 8 mg NORDITROPIN vials, respectively, at approximately 4 to 5 hr. post dose. The absolute bioavailability for NORDITROPIN after 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 NORDITROPIN in 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 T 1/2 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 (T 1/2 ) of approximately 21.1 (5.1) min. The mean apparent terminal T 1/2 values in GHD patients receiving a SC dose of 0.024 mg/kg or 3 IU/m 2 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.

Effective Time

20200309

Version

27

Description Table

Component

5 mg/1.5 mL

10 mg/1.5 mL

15 mg/1.5 mL

30 mg/3 mL

Somatropin

5 mg

10 mg

15 mg

30 mg

Histidine

1 mg

1 mg

1.7 mg

3.3 mg

Poloxamer 188

4.5 mg

4.5 mg

4.5 mg

9 mg

Phenol

4.5 mg

4.5 mg

4.5 mg

9 mg

Mannitol

60 mg

60 mg

58 mg

117 mg

HCl/NaOH

as needed

as needed

as needed

as needed

Water for Injection

up to 1.5 mL

up to 1.5 mL

up to 1.5 mL

up to 3 mL

Dosage Forms And Strengths

3 DOSAGE FORMS AND STRENGTHS NORDITROPIN injection is a clear and colorless solution available as follows: • 5 mg in 1.5 mL (orange): NORDITROPIN FlexPro single-patient-use pen • 10 mg in 1.5 mL (blue): NORDITROPIN FlexPro single-patient-use pen • 15 mg in 1.5 mL (green): NORDITROPIN FlexPro single-patient-use pen • 30 mg in 3 mL (purple): NORDITROPIN FlexPro single-patient-use pen NORDITROPIN injection is available as ( 3 ): • 5 mg/1.5 mL (orange): FlexPro single-patient-use pen • 10 mg/1.5 mL (blue): FlexPro single-patient-use pen • 15 mg/1.5 mL (green): FlexPro single-patient-use pen • 30 mg/3 mL (purple): FlexPro single-patient-use pen

Spl Product Data Elements

Norditropin somatropin SOMATROPIN SOMATROPIN HISTIDINE HYDROCHLORIC ACID MANNITOL PHENOL POLOXAMER 188 SODIUM HYDROXIDE WATER Norditropin somatropin SOMATROPIN SOMATROPIN HISTIDINE HYDROCHLORIC ACID MANNITOL PHENOL POLOXAMER 188 SODIUM HYDROXIDE WATER Norditropin somatropin SOMATROPIN SOMATROPIN HISTIDINE HYDROCHLORIC ACID MANNITOL PHENOL POLOXAMER 188 SODIUM HYDROXIDE WATER Norditropin somatropin SOMATROPIN SOMATROPIN HISTIDINE POLOXAMER 188 PHENOL MANNITOL WATER SODIUM HYDROXIDE HYDROCHLORIC ACID

Nonclinical Toxicology

13 NONCLINICAL TOXICOLOGY 13.1 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.

Application Number

BLA021148

Brand Name

Norditropin

Generic Name

somatropin

Product Ndc

0169-7705

Product Type

HUMAN PRESCRIPTION DRUG

Route

SUBCUTANEOUS

Package Label Principal Display Panel

PRINCIPAL DISPLAY PANEL - NORDITROPIN FLEXPRO 5 MG/1.5 ML Norditropin ® FlexPro ® (somatropin) injection 5 mg/1.5 mL Prefilled Pen 1 x 1.5 mL prefilled pen Each 1.5 mL contains 5 mg somatropin CONTAINS ONE NORDITROPIN ® FlexPro ® 5 mg/1.5 mL Single patient use only Rx only NDC 0169-7704-21 List: 770421 5 mg Trade Carton

Information For Patients

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling. Advise the patient to read the FDA-approved patient labeling (Patient Information and 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 NORDITROPIN replacement therapy in adults may frequently occur. Inform patients of the clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias) and to report to their healthcare provider any of these signs or symptoms occur during treatment with NORDITROPIN . • 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 NORDITROPIN. 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 NORDITROPIN may be needed. Novo Nordisk ® is a registered trademark of Novo Nordisk A/S. NORDITROPIN ® and FlexPro ® are registered trademarks of Novo Nordisk Health Care AG. © 2002-2020 Novo Nordisk Health Care AG For information contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, New Jersey 08536, USA 1-888-668-6444 Manufactured by: Novo Nordisk A/S DK-2880 Bagsvaerd, Denmark

Clinical Studies

14 CLINICAL STUDIES 14.1 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 NORDITROPIN 0.025 mg/kg/day 0.05 mg/kg/day 0.1 mg/kg/day N Mean SD N Mean SD N Mean SD Change in Standing Height (cm) Baseline to Month 12 37 9.5 2.1 37 13.2* 2.6 34 13.7* 2.7 Baseline to Month 24 34 17.6 3.4 37 22.2* 4.7 33 23.7* 4.0 Change in Sitting Height (cm) Baseline to Month 12 32 5.4 2.4 36 6.5* 1.6 32 7.4** 1.5 Baseline to Month 24 29 9.3 2.5 35 10.8** 2.6 31 12.2** 2.0 Change in Bone Age (yr) Baseline to Month 12 37 1.3 0.9 38 1.7 0.8 34 1.6 0.8 Month 12 to Month 24 37 0.6 2.5 38 1.4 2.7 34 1.6* 0.8 *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 14.2 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 NORDITROPIN subcutaneously which was adjusted based on growth response after the first 2 years. After the initial two-year study, NORDITROPIN treatment continued until 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. 14.3 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 NORDITROPIN treatment 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 NORDITROPIN treatment 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 Dose A 0.045 mg/kg/day (n = 19) Dose B up to 0.067 mg/kg/day (n = 15) Dose C up to 0.089 mg/kg/day (n = 12) Total (n = 46) Baseline height (cm) 1 105 (12) 108 (12.7) 107 (11.7) 106 (11.9) Final height (cm) 1 157 (6.7) 163 (6.0) 163 (4.9) 161 (6.5) Number (%) of patients reaching normal height (height SDS >-2 using National standard) 10 (53%) 12 (80%) 10 (83%) 32 (70%) Height SDS (Turner standard) 2 Final [95% CI] 1.7 [1.4, 2.0] 2.5 [2.1, 2.8] 3 2.5 [2.1, 2.9] 4 NA Change from baseline [95% CI] 1.5 [1.2, 1.8] 2.2 [1.9, 2.5] 3 2.2 [1.9, 2.6] 4 NA Height SDS (National standard) 2 Final [95% CI] -1.9 [-2.2, -1.6] -1.2 [-1.5, -0.9] 4 -1.2 [-1.6, -0.8] 5 NA Change from baseline [95% CI] 0.7 [0.4, 1.0] 1.4 [1.1, 1.7] 4 1.4 [1.1, 1.8] 5 NA Values are expressed as mean (SD) unless otherwise indicated. SDS: Standard deviation score. 1 Unadjusted (raw) means; 2 Adjusted (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; 3 p=0.005 vs. Dose A; 4 p=0.006 vs. Dose A; 5 p=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 NORDITROPIN as 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). 14.4 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 ≥ 3 rd percentile within the first 2 years of life or at a later stage. Inclusion criteria included: birth length < 3 rd percentile for gestational age, and height velocity (cm/year) for chronological age < 50 th 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. NORDITROPIN was 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 NORDITROPIN was 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 NORDITROPIN treatment 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 Raw Mean ± SD (N) Dose A 0.033 mg/kg/day Dose B 0.067 mg/kg/day Total Baseline Height SDS -3.2 ± 0.7 (26) -3.2 ± 0.7 (27) -3.2 ± 0.7 (53) Adjusted least-squares mean ± standard error (N), Treatment Difference [95% confidence intervals] Height SDS: Change from Baseline at Year 2 2 1.4 ± 0.1 (26) 1.8 ± 0.1 (26) Treatment Diff = 0.4 [0.2, 0.7] 3 Height SDS: Change from Baseline at Final Height 1 1.4 ± 0.2 (19) 1.8 ± 0.2 (19) Treatment Diff = 0.5 [0.0, 0.9] 3 Final Height SDS 1 -1.8 ± 0.2 (19) -1.3 ± 0.2 (19) Final Height SDS > -2 13/19 (68%) 11/19 (58%) 24/38 (63%) SDS: Standard deviation score. 1 Adjusted (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 < 10 th 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 Raw Mean ± SD (N) No Treatment 0.033 mg/kg/day 0.067 mg/kg/day Height SDS: Baseline -2.9 ± 0.5 (15) -3.0 ± 0.6 (35) -2.9 ± 0.7 (34) Height SDS: Year 1 -2.8 ± 0.5 (15) -2.4 ± 0.6 (33) -2.0 ± 0.8 (34) Height SDS: Year 2 NA -2.2 ± 0.7 (33) -1.4 ± 0.7 (32) Adjusted least-squares mean ± standard error (N), Treatment Diff [95% confidence intervals] Height SDS: Change from Baseline at Year 1 1 0.1 ± 0.1 (15) 0.6 ± 0.1 (33) 0.9 ± 0.1 (34) 0.033 vs. No Treatment: Treatment Diff = 0.5, [0.3, 0.7] 2 0.067 vs. No Treatment: Treatment Diff = 0.8, [0.6, 1.0] 2 0.067 vs. 0.033: Treatment Diff = 0.3, [0.2, 0.5] 2 Height SDS: Change from Baseline at Year 2 1 NA 0.8 ± 0.1 (33) 1.4 ± 0.1 (32) 0.067 vs. 0.033: Treatment Diff = 0.6, [0.5, 0.8], p-value < 0.0001 SDS: Standard deviation score. 1 Adjusted (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 14.5 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* Another Somatropin Product Untreated (n=30) 0.033 mg/kg/day (n=30) 0.067 mg/kg/day (n=42) 0.033 vs Untreated (95% CI) 0.067 vs Untreated (95% CI) Baseline height SDS Final height SDS minus baseline 0.41 (0.58) 0.95 (0.75) 1.36 (0.64) +0.53 (0.20, 0.87)** +0.94 (0.63, 1.26)** Baseline predicted ht Final height SDS minus baseline predicted final height SDS 0.23 (0.66) 0.73 (0.63) 1.05 (0.83) +0.60 (0.09, 1.11)** +0.90 (0.42, 1.39)** 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 14.6 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. Table 9 – Efficacy of Another Somatropin Product in Pediatric Patients with Prader-Willi Syndrome (Mean ± SD) Study 1 Study 2 Another Somatropin Product (0.24 mg/kg/week) (n=15) Untreated Control (n=12) Another Somatropin Product (0.36 mg/kg/week) (n=7) Untreated Control (n=9) Linear growth (cm) Baseline height 112.7 ± 14.9 109.5 ± 12.0 120.3 ± 17.5 120.5 ± 11.2 Growth from 0 to 12 months 11.6* ± 2.3 5.0 ± 1.2 10.7* ± 2.3 4.3 ± 1.5 Baseline SDS -1.6 ± 1.3 -1.8 ± 1.5 -2.6 ± 1.7 -2.1 ± 1.4 SDS at 12 months -0.5* ± 1.3 -1.9 ± 1.4 -1.4* ± 1.5 -2.2 ± 1.4 * p <0.05 14.7 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 NORDITROPIN 0.017 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 NORDITROPIN produced a significant increase from baseline in LBM compared to placebo (Table 10). Table 10 – Lean Body Mass (kg) by TBP NORDITROPIN (n=15) Placebo (n=16) Baseline (mean) 50.27 51.72 Change from baseline at 6 months (mean) 1.12 -0.63 Treatment difference (mean) 95% confidence interval p-value 1.74 (0.65, 2.83) p=0.0028* *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 NORDITROPIN (n=15) Placebo (n=16) Baseline (mean) 44.74 42.26 Change from baseline at 6 months (mean) -2.83 1.92 Treatment difference (mean) 95% confidence interval p-value -4.74 (-7.18, -2.30) p=0.0004* *Least square mean based on an ANOVA model including treatment and sex as factors NORDITROPIN also 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 NORDITROPIN and 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 NORDITROPIN produced a significant increase from baseline in LBM compared to placebo (pooled data) (Table 12). Table 12 – Lean Body Mass (kg) by TBP NORDITROPIN (n=36) Placebo (n=13) Baseline (mean) 48.18 48.90 Change from baseline at 6 months (mean) 2.06 0.70 Treatment difference (mean) 95% confidence interval p-value 1.40 (0.39, 2.41) p=0.0079* *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 NORDITROPIN (n=36) Placebo (n=13) Baseline (mean) 34.55 34.07 Change from baseline at 6 months (mean) -6.00 -1.78 Treatment difference (mean) 95% confidence interval p-value -4.24 (-7.11, -1.37) p=0.0048* *Least square mean based on an ANOVA model including treatment as a factor

Clinical Studies Table

NORDITROPIN

0.025 mg/kg/day

0.05 mg/kg/day

0.1 mg/kg/day

N

Mean

SD

N

Mean

SD

N

Mean

SD

Change in Standing Height (cm)

Baseline to Month 12

37

9.5

2.1

37

13.2*

2.6

34

13.7*

2.7

Baseline to Month 24

34

17.6

3.4

37

22.2*

4.7

33

23.7*

4.0

Change in Sitting Height (cm)

Baseline to Month 12

32

5.4

2.4

36

6.5*

1.6

32

7.4**

1.5

Baseline to Month 24

29

9.3

2.5

35

10.8**

2.6

31

12.2**

2.0

Change in Bone Age (yr)

Baseline to Month 12

37

1.3

0.9

38

1.7

0.8

34

1.6

0.8

Month 12 to Month 24

37

0.6

2.5

38

1.4

2.7

34

1.6*

0.8

Geriatric Use

8.5 Geriatric Use The safety and effectiveness of NORDITROPIN in 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) ].

Pediatric Use

8.4 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) ].

Pregnancy

8.1 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 NORDITROPIN during 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, NORDITROPIN was administered via subcutaneous injection to pregnant rats from gestation Day 6 to 17, corresponding with the period of organogenesis. NORDITROPIN did 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, NORDITROPIN was 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).

Use In Specific Populations

8 USE IN SPECIFIC POPULATIONS 8.1 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 NORDITROPIN during 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, NORDITROPIN was administered via subcutaneous injection to pregnant rats from gestation Day 6 to 17, corresponding with the period of organogenesis. NORDITROPIN did 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, NORDITROPIN was 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). 8.2 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 NORDITROPIN and any potential adverse effects on the breastfed infant from NORDITROPIN or from the underlying maternal condition. 8.4 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) ]. 8.5 Geriatric Use The safety and effectiveness of NORDITROPIN in 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) ].

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING NORDITROPIN injection is a clear and colorless solution available as FlexPro prefilled pens: • NORDITROPIN FlexPro 5 mg/1.5 mL (orange) NDC 0169-7704-21 • NORDITROPIN FlexPro 10 mg/1.5 mL (blue) NDC 0169-7705-21 • NORDITROPIN FlexPro 15 mg/1.5 mL (green) NDC 0169-7708-21 • NORDITROPIN FlexPro 30 mg/3 mL (purple) NDC 0169-7703-21 Each NORDITROPIN FlexPro pen is for use by a single patient. A NORDITROPIN FlexPro pen must never be shared between patients, even if the needle is changed. Unused NORDITROPIN FlexPro prefilled pens must be stored at 2°C to 8°C/36°F to 46°F (refrigerator). Do not freeze. Avoid direct light. Table 14 – Storage Conditions and Expiration Before Use In-use (After 1 st injection) Storage requirement Storage Option 1 (Refrigeration) Storage Option 2 (Room temperature) 2ºC to 8 ºC/ 36ºF to 46 ºF Until exp. date 2ºC to 8 ºC/36ºF to 46 ºF 4 weeks Up to 25ºC/77ºF 3 weeks

How Supplied Table

Before Use

In-use (After 1st injection)

Storage

requirement

Storage Option 1

(Refrigeration)

Storage Option 2

(Room temperature)

2ºC to 8 ºC/

36ºF to 46 ºF

Until exp. date

2ºC to 8 ºC/36ºF to 46 ºF

4 weeks

Up to 25ºC/77ºF

3 weeks

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