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

NORDITROPIN is 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 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).

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.

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 Pediatric Patients 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 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)].

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 NORDITROPIN treatment 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 NORDITROPIN should also have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively [see Contraindications (4)].

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 somatropins. 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 somatropins. Patients and caregivers should be informed that such reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs [see Contraindications (4)].

Fluid Retention

Fluid retention during somatropin replacement therapy in adults may frequently occur. Clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/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 NORDITROPIN treatment. 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.