NORDITROPIN® CARTRIDGES (somatropin [rDNA origin] injection) 5 MG/1.5 ML, 10 MG/1.5 ML, OR 15 MG/1.5 ML for subcutaneous injection

NORDITROPIN - somatropin injection, solution 
NORDITROPIN NORDIFLEX - somatropin injection, solution 
Novo Nordisk Inc.

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NORDITROPIN® CARTRIDGES (somatropin [rDNA origin] injection) 5 MG/1.5 ML, 10 MG/1.5 ML, OR 15 MG/1.5 ML for subcutaneous injection

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use NORDITROPIN safely and effectively. See full prescribing information for NORDITROPIN.
NORDITROPIN (somatropin) injection, solution for subcutaneous use
NORDITROPIN NORDIFLEX (somatropin) injection, solution for subcutaneous use
Initial U.S. Approval: 1987

RECENT MAJOR CHANGES

Indications and Usage (1.1)

 
Short Stature in Small for Gestational Age (SGA) with No Catch-up Growth by Age 2-4 years 10/2008

Dosage and Administration (2.1)

 
Short Stature in SGA with No Catch-up Growth by Age 2-4 years 10/2008

INDICATIONS AND USAGE

Norditropin is a recombinant human growth hormone indicated for:

  • Pediatric: Treatment of children with growth failure due to growth hormone deficiency (GHD), short stature associated with Noonan syndrome, short stature associated with Turner syndrome and short stature born SGA with no catch-up growth by age 2-4 years (1.1)
  • Adult: Treatment of adults with either adult onset or childhood onset GHD (1.2)

DOSAGE AND ADMINISTRATION

Norditropin should be administered subcutaneously (2).

  • Pediatric GHD: 0.024-0.034 mg/kg/day, 6-7 times a week (2.1)
  • Noonan Syndrome: Up to 0.066 mg/kg/day (2.1)
  • Turner Syndrome: Up to 0.067 mg/kg/day (2.1)
  • SGA: Up to 0.067 mg/kg/day (2.1)
  • Adult GHD: 0.004 mg/kg/day to be increased as tolerated to not more than 0.016 mg/kg/day after approximately 6 weeks, or a starting dose of approximately 0.2 mg/day (range, 0.15-0.30 mg/day) increased gradually every 1-2 months by increments of approximately 0.1-0.2 mg/day (2.2)
  • Norditropin cartridges must be used with their corresponding color-coded NordiPen® delivery systems (2.3)
  • Injection sites should always be rotated to avoid lipoatrophy (2.3)

DOSAGE FORMS AND STRENGTHS

Cartridges are available for use with the corresponding NordiPens or preloaded in the Norditropin NordiFlex pens (3):

  • 5 mg/1.5 mL (orange): cartridge and Norditropin NordiFlex pen
  • 10 mg/1.5 mL (blue): Norditropin NordiFlex pen only
  • 15 mg/1.5 mL (green): cartridge and Norditropin NordiFlex pen

CONTRAINDICATIONS

  • Acute Critical Illness (4.1, 5.1)
  • Children with Prader-Willi syndrome who are severely obese or have severe respiratory impairment - reports of sudden death (4.2, 5.2)
  • Active Malignancy (4.3)
  • Active Proliferative or Severe Non-Proliferative Diabetic Retinopathy (4.4)
  • Children with closed epiphyses (4.5)
  • Known hypersensitivity to somatropin or excipients (4.6)

WARNINGS AND PRECAUTIONS

  • Acute Critical Illness: Potential benefit of treatment continuation should be weighed against the potential risk (5.1).
  • Prader-Willi Syndrome in Children: Evaluate for signs of upper airway obstruction and sleep apnea before initiation of treatment for GHD. Discontinue treatment if these signs occur (5.2).
  • Neoplasm: Monitor patients with preexisting tumors for progression or recurrence. Increased risk of a second neoplasm in childhood cancer survivors treated with somatropin - in particular meningiomas in patients treated with radiation to the head for their first neoplasm (5.3).
  • Impaired Glucose Tolerance and Diabetes Mellitus: May be unmasked. Periodically monitor glucose levels in all patients. Doses of concurrent antihyperglycemic drugs in diabetics may require adjustment (5.4).
  • Intracranial Hypertension: Exclude preexisting papilledema. May develop and is usually reversible after discontinuation or dose reduction (5.5).
  • Fluid Retention (i.e., edema, arthralgia, carpal tunnel syndrome - especially in adults): May occur frequently. Reduce dose as necessary (5.6).
  • Hypothyroidism: May first become evident or worsen (5.7).
  • Slipped Capital Femoral Epiphysis: May develop. Evaluate children with the onset of a limp or hip/knee pain (5.8).
  • Progression of Preexisting Scoliosis: May develop (5.9).

ADVERSE REACTIONS

Other common somatropin-related adverse reactions include injection site reactions/rashes and lipoatrophy (6.1) and headaches (6.3).



To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk at 1-888-NOVO-444 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch


DRUG INTERACTIONS

  • Inhibition of 11ß-Hydroxysteroid Dehydrogenase Type 1: May require the initiation of glucocorticoid replacement therapy. Patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance doses (7.1)
  • Glucocorticoid Replacement: Should be carefully adjusted (7.2)
  • Cytochrome P450-Metabolized Drugs: Monitor carefully if used with somatropin (7.3)
  • Oral Estrogen: Larger doses of somatropin may be required in women (7.4)
  • Insulin and/or Oral Hypoglycemic Agents: May require adjustment (7.5)


See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling

Revised: 11/2008

FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed

1. INDICATIONS AND USAGE

1.1 Pediatric Patients

1.2 Adult Patients

2. DOSAGE AND ADMINISTRATION

2.1 Dosing of Pediatric Patients

2.2 Dosing of Adult Patients

2.3 Preparation and Administration

3. DOSAGE FORMS AND STRENGTHS

4. CONTRAINDICATIONS

4.1 Acute Critical Illness

4.2 Prader-Willi Syndrome in Children

4.3 Active Malignancy

4.4 Diabetic Retinopathy

4.5 Closed Epiphyses

4.6 Hypersensitivity

5. WARNINGS AND PRECAUTIONS

5.1 Acute Critical Illness

5.2 Prader-Willi Syndrome in Children

5.3 Neoplasms

5.4 Glucose Intolerance

5.5 Intracranial Hypertension

5.6 Fluid Retention

5.7 Hypothyroidism

5.8 Slipped Capital Femoral Epiphysis in Pediatric Patients

5.9 Progression of Preexisting Scoliosis in Pediatric Patients

5.10 Otitis Media and Cardiovascular Disorders in Turner Syndrome

5.11 Confirmation of Childhood Onset Adult GHD

5.12 Local and Systemic Reactions

5.13 Laboratory Tests

6. ADVERSE REACTIONS

6.1 Most Serious and/or Most Frequently Observed Adverse Reactions

6.2 Clinical Trials Experience

6.3 Post-Marketing Surveillance

7. DRUG INTERACTIONS

7.1 Inhibition of 11ß-Hydroxysteroid Dehydrogenase Type 1 (11ßHSD-1)

7.2 Glucocorticoid Replacement

7.3 Cytochrome P450-Metabolized Drugs

7.4 Oral Estrogen

7.5 Insulin and/or Oral Hypoglycemic Agents

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.5 Geriatric Use

10. OVERDOSAGE

11. DESCRIPTION

12. CLINICAL PHARMACOLOGY

12.1 Mechanism Of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

14. CLINICAL STUDIES

14.1 Short Stature in Children with Noonan Syndrome

14.2 Short Stature in Children with Turner Syndrome

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

14.4 Adult Growth Hormone Deficiency (GHD)

16. HOW SUPPLIED/STORAGE AND HANDLING

17. PATIENT COUNSELING INFORMATION

17.1 FDA-Approved Patient Labeling


FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE

1.1 Pediatric Patients

Norditropin [somatropin (rDNA origin) injection] is indicated for the treatment of children with growth failure due to inadequate secretion of endogenous growth hormone (GH).

Norditropin [somatropin (rDNA origin) injection] is indicated for the treatment of children with short stature associated with Noonan syndrome.

Norditropin [somatropin (rDNA origin) injection] is indicated for the treatment of children with short stature associated with Turner syndrome.

 Norditropin [somatropin (rDNA origin) injection] is indicated for the treatment of children with short stature born small for gestational age (SGA) with no catch-up growth by age 2-4 years.

1.2 Adult Patients

Norditropin [somatropin (rDNA origin) injection] is indicated for the replacement of endogenous GH in adults with growth hormone deficiency (GHD) who meet either of the following two criteria:

According to current standards, confirmation of the diagnosis of adult growth hormone deficiency in both groups involves an appropriate growth hormone provocative test with two exceptions: (1) patients with multiple other pituitary hormone deficiencies due to organic disease; and (2) patients with congenital/genetic growth hormone deficiency.

2. DOSAGE AND ADMINISTRATION

For subcutaneous injection.

Therapy with Norditropin should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with short stature associated with GHD, Noonan syndrome, Turner syndrome or SGA, and adult patients with either childhood onset or adult onset GHD.

2.1 Dosing of Pediatric Patients

General Pediatric Dosing Information

The Norditropin dosage and administration schedule should be individualized based on the growth response of each patient. Serum insulin-like growth factor I (IGF-I) levels may be useful during dose titration.

Response to somatropin therapy in pediatric patients tends to decrease with time. However, in pediatric patients, the failure to increase growth rate, particularly during the first year of therapy, indicates the need for close assessment of compliance and evaluation for other causes of growth failure, such as hypothyroidism, undernutrition, advanced bone age and antibodies to recombinant human GH (rhGH).

Treatment with Norditropin for short stature should be discontinued when the epiphyses are fused.

Pediatric Growth Hormone Deficiency (GHD)

A dosage of 0.024 - 0.034 mg/kg/day, 6-7 times a week, is recommended.

Pediatric Patients with Short Stature Associated with Noonan Syndrome

Not all patients with Noonan syndrome have short stature; some will achieve a normal adult height without treatment. Therefore, prior to initiating Norditropin for a patient with Noonan syndrome, establish that the patient does have short stature.

A dosage of up to 0.066 mg/kg/day is recommended.

Pediatric Patients with Short Stature Associated with Turner Syndrome

A dosage of up to 0.067 mg/kg/day is recommended.

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

 A dosage of up to 0.067 mg/kg/day is recommended.

 Recent literature has recommended initial treatment with larger doses of somatropin (e.g., 0.067 mg/kg/day), especially in very short children (i.e., HSDS < -3), and/or older/early pubertal children, and that a reduction in dosage (e.g., gradually towards 0.033 mg/kg/day) should be considered if substantial catch-up growth is observed during the first few years of therapy. On the other hand, in younger SGA children (e.g., approximately < 4 years) (who respond the best in general) with less severe short stature (i.e., baseline HSDS values between -2 and -3), consideration should be given to initiating treatment at a lower dose (e.g., 0.033 mg/kg/day), and titrating the dose as needed over time. In all children, clinicians should carefully monitor the growth response, and adjust the rhGH dose as necessary.

2.2 Dosing of Adult Patients

Adult Growth Hormone Deficiency (GHD)

Based on the weight-based dosing utilized in the clinical studies, the recommended dosage at the start of therapy is not more than 0.004 mg/kg/day. The dose may be increased to not more than 0.016 mg/kg/day after approximately 6 weeks according to individual patient requirements. Clinical response, side effects, and determination of age- and gender-adjusted serum IGF-I levels may be used as guidance in dose titration.

Alternatively, taking into account recent literature, a starting dose of approximately 0.2 mg/day (range, 0.15-0.30 mg/day) may be used without consideration of body weight. This dose can be increased gradually every 1-2 months by increments of approximately 0.1-0.2 mg/day, according to individual patient requirements based on the clinical response and serum IGF-I concentrations. During therapy, the dose should be decreased if required by the occurrence of adverse events and/or serum IGF-I levels above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to person.

A lower starting dose and smaller dose increments should be considered for older patients, who are more prone to the adverse effects of somatropin than younger individuals. In addition, obese individuals are more likely to manifest adverse effects when treated with a weight-based regimen. In order to reach the defined treatment goal, estrogen-replete women may need higher doses than men. Oral estrogen administration may increase the dose requirements in women.

2.3 Preparation and Administration

Norditropin Cartridges must be administered using the NordiPen delivery systems. Each cartridge size has a corresponding, color-coded pen which is graduated to deliver the appropriate dose based on the concentration of Norditropin in the cartridge.

Norditropin® Cartridges 5 mg/1.5 mL and 15 mg/1.5 mL:

Each cartridge of Norditropin must be inserted into its corresponding NordiPen delivery system. Instructions for delivering the dosage are provided in the NordiPen INSTRUCTION booklet.

Norditropin NordiFlex® 5 mg/1.5 mL, 10 mg/1.5 mL, and 15 mg/1.5 mL:

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

Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Norditropin MUST NOT BE INJECTED if the solution is cloudy or contains particulate matter. Use it only if it is clear and colorless.

Injection sites should always be rotated to avoid lipoatrophy.

3. DOSAGE FORMS AND STRENGTHS

Cartridges are available for use with the corresponding NordiPens or preloaded in the Norditropin NordiFlex pens:

4. CONTRAINDICATIONS

4.1 Acute Critical Illness

Treatment with pharmacologic amounts of somatropin is contraindicated 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. 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 (41.9% vs. 19.3%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo [see Warnings and Precautions (5.1)].

4.2 Prader-Willi Syndrome in Children

Somatropin is contraindicated in patients with Prader-Willi syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe respiratory impairment [see Warnings and Precautions (5.2)]. There have been reports of sudden death when somatropin was used in such patients [see Warnings and Precautions (5.2)]. Norditropin is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.

4.3 Active Malignancy

In general, somatropin is contraindicated in the presence of active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of recurrent activity. Since GHD may be an early sign of the presence of a pituitary tumor (or, rarely, other brain tumors), the presence of such tumors should be ruled out prior to initiation of treatment. Somatropin should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor.

4.4 Diabetic Retinopathy

Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.

4.5 Closed Epiphyses

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

4.6 Hypersensitivity

Norditropin is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. Localized reactions are the most common hypersensitivity reactions.

5. WARNINGS AND PRECAUTIONS

5.1 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 (4.1)]. The safety of continuing somatropin treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with somatropin in patients experiencing acute critical illnesses should be weighed against the potential risk.

5.2 Prader-Willi Syndrome in Children

There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin. If, during treatment with somatropin, patients show signs of upper airway obstruction (including onset of or increased snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with Prader-Willi syndrome treated with somatropin should also have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively [see Contraindications (4.2)]. Norditropin is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.

5.3 Neoplasms

Patients with preexisting tumors or GHD secondary to an intracranial lesion should be monitored routinely for progression or recurrence of the underlying disease process. In pediatric patients, clinical literature has revealed no relationship between somatropin replacement therapy and central nervous system (CNS) tumor recurrence or new extracranial tumors. However, in childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients treated with somatropin after their first neoplasm. Intracranial tumors, in particular meningiomas, in patients treated with radiation to the head for their first neoplasm, 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.

Patients should be monitored carefully for potential malignant transformation of skin lesions, i.e. increased growth of preexisting nevi.

5.4 Glucose Intolerance

Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a result, previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked during somatropin treatment. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, 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 during somatropin therapy. The doses of antihyperglycemic drugs (i.e., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients.

5.5 Intracranial Hypertension

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with somatropin products. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose.

Funduscopic examination should be performed routinely before initiating treatment with somatropin to exclude preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed by funduscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin 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 Fluid Retention

Fluid retention during somatropin replacement therapy in adults may frequently occur. Clinical manifestations of fluid retention are usually transient and dose dependent.

5.7 Hypothyroidism

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

In patients with hypopituitarism (multiple hormone deficiencies), standard hormonal replacement therapy should be monitored closely when somatropin therapy is administered.

5.8 Slipped Capital Femoral Epiphysis in Pediatric Patients

Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including GHD and Turner syndrome) or in patients undergoing rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated.

5.9 Progression of Preexisting Scoliosis in Pediatric Patients

Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases growth rate, patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis. However, somatropin has not been shown to increase the occurrence of scoliosis. Skeletal abnormalities including scoliosis are commonly seen in untreated patients with Turner syndrome and Noonan syndrome. Scoliosis is also commonly seen in untreated patients with Prader-Willi syndrome. Physicians should be alert to these abnormalities, which may manifest during somatropin therapy.

5.10 Otitis Media and Cardiovascular Disorders in Turner Syndrome

Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear and hearing disorders. Somatropin treatment may increase the occurrence of otitis media in patients with Turner syndrome. In addition, patients with Turner syndrome should be monitored closely for cardiovascular disorders (e.g., stroke, aortic aneurysm/dissection, hypertension) as these patients are also at risk for these conditions.

5.11 Confirmation of Childhood Onset Adult GHD

Patients with epiphyseal closure who were treated with somatropin replacement therapy in childhood should be reevaluated according to the criteria in Indications and Usage (1.2) before continuation of somatropin therapy at the reduced dose level recommended for GH deficient adults.

5.12 Local and Systemic Reactions

When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. This can be avoided by rotating the injection site [see Dosage and Administration (2.3)].

As with any protein, local or systemic allergic reactions may occur. Parents/Patients should be informed that such reactions are possible and that prompt medical attention should be sought if allergic reactions occur.

5.13 Laboratory Tests

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

6. ADVERSE REACTIONS

6.1 Most Serious and/or Most Frequently Observed Adverse Reactions

This list presents the most seriousb and/or most frequently observeda adverse reactions during treatment with somatropin:

6.2 Clinical Trials Experience

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

Clinical Trials in Pediatric GHD Patients

As with all protein drugs, a small percentage of patients may develop antibodies to the protein. GH antibodies with binding capacities lower than 2 mg/L have not been associated with growth attenuation. In a very small number of patients, when binding capacity was greater than 2 mg/L, interference with the growth response was observed. In clinical trials, 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.

Clinical Trials in Children with Noonan Syndrome

Norditropin was studied in a two-year prospective, randomized, parallel dose group trial in 21 children, 3-14 years old, with Noonan syndrome. Doses were 0.033 and 0.066 mg/kg/day. After the initial two-year randomized trial, children continued Norditropin treatment until final height was achieved; randomized dose groups were not maintained. Final height and adverse event data were later collected retrospectively from 18 children; total follow-up was 11 years. An additional 6 children were not randomized, but followed the protocol and are included in this assessment of adverse events.

Based on the mean dose per treatment group, no significant difference in the incidence of adverse events was seen between the two groups. The most frequent adverse events were the common infections of childhood, including upper respiratory infection, gastroenteritis, ear infection, and influenza. Cardiac disorders was the system organ class with the second most adverse events reported. However, congenital heart disease is an inherent component of Noonan syndrome, and there was no evidence of somatropin-induced ventricular hypertrophy or exacerbation of preexisting ventricular hypertrophy (as judged by echocardiography) during this study. Children who had baseline cardiac disease judged to be significant enough to potentially affect growth were excluded from the study; therefore the safety of Norditropin in children with Noonan syndrome and significant cardiac disease is not known. Among children who received 0.033 mg/kg/day, there was one adverse event of scoliosis; among children who received 0.066 mg/kg/day, there were four adverse events of scoliosis [see Warnings and Precautions (5.9)]. Mean serum IGF-I standard deviation score (SDS) levels did not exceed +1 in response to somatropin treatment. The mean serum IGF-I level was low at baseline and normalized during treatment.

Clinical Trials in Children with Turner Syndrome

In two clinical studies wherein children with Turner syndrome were treated until final height with various doses of Norditropin as described in Clinical Studies (14.2), the most frequently reported adverse events were common childhood diseases including influenza-like illness, otitis media, upper respiratory tract infection, otitis externa, gastroenteritis and eczema. Otitis media adverse events in Study 1 were most frequent in the highest dose groups (86.4% in the 0.045-0.067-0.089 mg/kg/day group vs. 78.3% in the 0.045-0.067 mg/kg/day group vs. 69.6% in the 0.045 mg/kg/day group) suggesting a possible dose-response relationship. Of note, approximately 40-50% of these otitis media adverse events were designated as “serious” [see Warnings and Precautions (5.10)]. No patients in either study developed clearcut overt diabetes mellitus; however, in Study 1, impaired fasting glucose at Month 48 was more frequent in patients in the 0.045-0.067 mg/kg/day group (n=4/18) compared with the 0.045 mg/kg/day group (n=1/20). Transient episodes of fasting blood sugars between 100 and 126 mg/dL, and, on occasion, exceeding 126 mg/dL also occurred more often with larger doses of Norditropin in both studies [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. Three patients withdrew from the 2 high dose groups in Study 1 because of concern about excessive growth of hands or feet. In addition, in Study 1, exacerbation of preexisting scoliosis was designated a serious adverse reaction in two patients in the 0.045 mg/kg/day group [see Warnings and Precautions (5.9)].

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

Study 1 (Long-Term)

In a multi-center, randomized, double-blind study, 53 non-GHD children with short stature born SGA with failure to catch-up 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 events were common childhood diseases including influenza-like illness, upper respiratory tract infection, bronchitis, gastroenteritis, abdominal pain, otitis media, pharyngitis, arthralgia, and headache. Adverse events possibly/probably related to Norditropin were otitis media, arthralgia, headaches (no confirmed diagnoses of benign intracranial hypertension), gynecomastia, and increased sweating. One child treated with 0.067 mg/kg/day for 4 years was reported with disproportionate growth of the lower jaw, and another child treated with 0.067 mg/kg/day developed a melanocytic nevus [see Warnings and Precautions (5.3)]. There were no clear cut reports of exacerbation of preexisting scoliosis or slipped capital femoral epiphysis. No apparent differences between the treatment groups were observed. In addition, the timing of puberty was age-appropriate in boys and girls in both treatment groups. Therefore, it can be concluded that no novel adverse events potentially related to treatment with Norditropin were reported in long-term Study 1.

Study 2 (Short-Term)

In a multi-center, randomized, double-blind, parallel-group study, 98 Japanese non-GHD children with short stature born SGA with failure to catch-up were treated with 2 doses of Norditropin (0.033 or 0.067 mg/kg/day) for 2 years or were untreated for 1 year. The most frequently reported adverse events were common childhood diseases almost identical to those reported above for Study 1. Adverse events possibly/probably related to Norditropin were otitis media, arthralgia and impaired glucose tolerance. No apparent differences between the treatment groups were observed. However, arthralgia and transiently impaired glucose tolerance were only reported in the 0.067 mg/kg/day treatment group. Therefore, it can also be concluded that no novel adverse events potentially related to treatment with rhGH were reported in short-term Study 2.

As with all protein drugs, some patients may develop antibodies to the protein. Eighteen of the 76 children (~24%) treated with Norditropin developed anti-rhGH antibodies. However, these antibodies did not appear to be neutralizing in that the change from baseline in height SDS at Year 2 was similar in antibody positive and antibody negative children by treatment group.

In both Study 1 and Study 2, there were no clear cut cases of new onset diabetes mellitus, no children treated for hyperglycemia, and no adverse event withdrawals due to abnormalities in glucose tolerance. In Study 2, after treatment with either dose of Norditropin for 2 years, there were no children with consecutive fasting blood glucose levels between 100 and 126 mg/dL, or with fasting blood glucose levels > 126 mg/dL. Furthermore, mean hemoglobin A1c levels tended to decrease during long-term treatment in Study 1, and remained normal in Study 2. However, in Study 1, 4 children treated with 0.067 mg/kg/day of Norditropin and 2 children treated with 0.033 mg/kg/day of Norditropin shifted from normal fasting blood glucose levels at baseline to increased levels after 1 year of treatment (100 to 126 mg/dL or > 126 mg/dL). In addition, small increases in mean fasting blood glucose and insulin levels (within the normal reference range) after 1 and 2 years of Norditropin treatment appeared to be dose-dependent  [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

In both Study 1 and Study 2, there was no acceleration of bone maturation. A dose-dependent increase in mean serum IGF-I SDS levels within the reference range (but including a substantial number of children with serum IGF-1 SDS > +2) was observed after both long-term (Study 1) and short-term (Study 2) Norditropin treatment.

Clinical Trials in Adult GHD Patients

Adverse events with an incidence of ≥5% occurring in patients with AO GHD during the 6 month placebo-controlled portion of the largest of the six adult GHD Norditropin trials are presented in Table 1. Peripheral edema, other types of edema, arthralgia, myalgia, and paraesthesia were common in the Norditropin-treated patients, and reported much more frequently than in the placebo group. These types of adverse events are thought to be related to the fluid accumulating effects of somatropin. In general, these adverse events were mild and transient in nature. During the placebo-controlled portion of this study, approximately 5% of patients without preexisting diabetes mellitus treated with Norditropin were diagnosed with overt type 2 diabetes mellitus compared with none in the placebo group [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. Anti-GH antibodies were not detected.

Of note, the doses of Norditropin employed during this study (completed in the mid 1990s) were substantially larger than those currently recommended by the Growth Hormone Research Society, and, more than likely, resulted in a greater than expected incidence of fluid retention- and glucose intolerance-related adverse events. A similar incidence and pattern of adverse events were observed during the other three placebo-controlled AO GHD trials and during the two placebo-controlled CO GHD trials.

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

Norditropin

(N=53)

Placebo

(N=52)
Adverse Reactionsn

%

n%
Peripheral Edema224248
Edema132500
Arthralgia1019815
Leg Edema81524
Myalgia81548
Infection (non-viral) 71348
Paraesthesia61136
Skeletal Pain61112
Headache5936
Bronchitis5900
Flu-like symptoms4824
Hypertension4812
Gastroenteritis4848
Other Non-Classifiable Disorders
(excludes accidental injury)
4836
Increased sweating4812
Glucose tolerance abnormal3612
Laryngitis3636

The adverse event pattern observed during the open label phase of the study was similar to the one presented above.

6.3 Post-Marketing Surveillance

Because these adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The adverse events reported during post-marketing surveillance do not differ from those listed/discussed above in Sections 6.1 and 6.2 in children and adults.

Leukemia has been reported in a small number of GH deficient children treated with somatropin, somatrem (methionylated rhGH) and GH of pituitary origin. It is uncertain whether these cases of leukemia are related to GH therapy, the pathology of GHD itself, or other associated treatments such as radiation therapy. On the basis of current evidence, experts have not been able to conclude that GH therapy per se was responsible for these cases of leukemia. The risk for children with GHD, if any, remains to be established [see Contraindications (4.3) and Warnings and Precautions (5.3)].

The following additional adverse reactions have been observed during the appropriate use of somatropin: headaches (children and adults), gynecomastia (children), and pancreatitis (children).

7. DRUG INTERACTIONS

7.1 Inhibition of 11ß-Hydroxysteroid Dehydrogenase Type 1 (11ßHSD-1)

Somatropin inhibits 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD-1) in adipose/hepatic tissue and may significantly impact the metabolism of cortisol and cortisone. As a consequence, in patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism may be unmasked requiring glucocorticoid replacement therapy. In addition, patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses; this may be especially true for patients treated with cortisone acetate and prednisone since conversion of these drugs to their biologically active metabolites is dependent on the activity of the 11ßHSD-1 enzyme.

7.2 Glucocorticoid Replacement

Excessive glucocorticoid therapy may attenuate the growth promoting effects of somatropin in children. Therefore, glucocorticoid replacement therapy should be carefully adjusted in children with concomitant GH and glucocorticoid deficiency to avoid both hypoadrenalism and an inhibitory effect on growth.

7.3 Cytochrome P450-Metabolized Drugs

Limited published data indicate that somatropin treatment increases cytochrome P450 (CYP450)- mediated antipyrine clearance in man. These data suggest that somatropin administration may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CYP450 liver enzymes. However, formal drug interaction studies have not been conducted.

7.4 Oral Estrogen

In adult women on oral estrogen replacement, a larger dose of somatropin may be required to achieve the defined treatment goal [see Dosage and Administration (2.2)].

7.5 Insulin and/or Oral Hypoglycemic Agents

In patients with diabetes mellitus requiring drug therapy, the dose of insulin and/or oral agent may require adjustment when somatropin therapy is initiated [see Warnings and Precautions (5.4)].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with Norditropin. It is not known whether Norditropin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Norditropin should be given to a pregnant woman only if clearly needed.

8.3 Nursing Mothers

It is not known whether Norditropin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Norditropin is administered to a nursing woman.

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 (2.2)].

10. OVERDOSAGE

Short-Term

Short-term overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Furthermore, overdose with somatropin is likely to cause fluid retention.

Long-Term

Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess growth hormone [see Dosage and Administration (2)].

11. DESCRIPTION

Norditropin is a registered trademark of Novo Nordisk Health Care AG for somatropin, a polypeptide hormone of recombinant DNA origin. The hormone 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 cartridges are supplied as sterile solutions for subcutaneous injection in ready-to-administer cartridges or prefilled pens with a volume of 1.5 mL.

Each Norditropin Cartridge contains the following (see Table 2):

Table 2
Component5 mg/1.5 mL10 mg/1.5 mL15 mg/1.5 mL
Somatropin5 mg10 mg15 mg
Histidine1 mg1 mg1.7 mg
Poloxamer 1884.5 mg4.5 mg4.5 mg
Phenol4.5 mg4.5 mg4.5 mg
Mannitol60 mg60 mg58 mg
HCl/NaOHas neededas neededas needed
Water for Injectionup to 1.5 mLup to 1.5 mLup to 1.5 mL

12. CLINICAL PHARMACOLOGY

12.1 Mechanism Of Action

Somatropin (as well as endogenous GH) binds to a dimeric GH receptor in the cell membrane of target cells resulting in intracellular signal transduction and a host of pharmacodynamic effects. Some of these pharmacodynamic effects are primarily mediated by IGF-I produced in the liver and also locally (e.g., skeletal growth, protein synthesis), while others are primarily a consequence of the direct effects of somatropin (e.g., lipolysis) [see Clinical Pharmacology (12.2)].

12.2 Pharmacodynamics

Tissue Growth

The primary and most intensively studied action of somatropin is the stimulation of linear growth. This effect is demonstrated in children with GHD.

Skeletal Growth

The measurable increase in bone length after administration of somatropin results from its effect on the cartilaginous growth areas of long bones. Studies in vitro have shown that the incorporation of sulfate into proteoglycans is not due to a direct effect of somatropin, but rather is mediated by the somatomedins or insulin-like growth factors (IGFs). The somatomedins, among them IGF-I, are polypeptide hormones which are  synthesized in the liver, kidney, and various other tissues. IGF-I levels are low in the serum of hypopituitary dwarfs and hypophysectomized humans or animals, and increase after treatment with somatropin.

Cell Growth

It has been shown that the total number of skeletal muscle cells is markedly decreased in children with short stature lacking endogenous GH compared with normal children, and that treatment with somatropin results in an increase in both the number and size of muscle cells.

Organ Growth

Somatropin influences the size of internal organs, and it also increases red cell mass.

Protein Metabolism

Linear growth is facilitated in part by increased cellular protein synthesis. This synthesis and growth are reflected by nitrogen retention which can be quantitated by observing the decline in urinary nitrogen excretion and blood urea nitrogen following the initiation of somatropin therapy.

Carbohydrate Metabolism

Hypopituitary children sometimes experience fasting hypoglycemia that may be improved by treatment with somatropin. In healthy subjects, large doses of somatropin may impair glucose tolerance. Although the precise mechanism of the diabetogenic effect of somatropin is not known, it is attributed to blocking the action of insulin rather than blocking insulin secretion. Insulin levels in serum actually increase as somatropin levels increase. Administration of human growth hormone to normal adults and patients with growth hormone deficiency results in increases in mean serum fasting and postprandial insulin levels, although mean values remain in the normal range. In addition, mean fasting and postprandial glucose and hemoglobin A1C levels remain in the normal range.

Lipid Metabolism

Somatropin stimulates intracellular lipolysis, and administration of somatropin leads to an increase in plasma free fatty acids and triglycerides. Untreated GHD is associated with increased body fat stores, including increased abdominal visceral and subcutaneous adipose tissue. Treatment of growth hormone deficient patients with somatropin results in a general reduction of fat stores, and decreased serum levels of low density lipoprotein (LDL) cholesterol.

Mineral Metabolism

Administration of somatropin results in an increase in total body potassium and phosphorus and to a lesser extent sodium. This retention is thought to be the result of cell growth. Serum levels of phosphate increase in children with GHD after somatropin therapy due to metabolic activity associated with bone growth. Serum calcium levels are not altered. Although calcium excretion in the urine is increased, there is a simultaneous increase in calcium absorption from the intestine. Negative calcium balance, however, may occasionally occur during somatropin treatment.

Connective Tissue Metabolism

Somatropin stimulates the synthesis of chondroitin sulfate and collagen, and increases the urinary excretion of hydroxyproline.

12.3 Pharmacokinetics

A 180-min IV infusion of Norditropin (33 ng/kg/min) was administered to 9 GHD patients. A mean (±SD) hGH steady state serum level of approximately 23.1 (±15.0) ng/mL was reached at 150 min and a mean clearance rate of approximately 2.3 (±1.8) mL/min/kg or 139 (±105) mL/min for hGH was observed. Following infusion, serum hGH levels had a biexponential decay with a terminal elimination half-life (T1/2) of approximately 21.1 (±5.1) min.

In a study conducted in 18 GHD adult patients, where a SC dose of 0.024 mg/kg or 3 IU/m2 was given in the thigh, mean (±SD) Cmax 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 mean apparent terminal T1/2 values were estimated to be approximately 7 to 10 hr. However, the absolute bioavailability for Norditropin after the SC route of administration is currently not known.

The aqueous Norditropin cartridge formulation is bioequivalent to the lyophilized Norditropin vial formulation.

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity, mutagenicity, and fertility studies have not been conducted with Norditropin.

14. CLINICAL STUDIES

14.1 Short Stature in Children with Noonan Syndrome

A prospective, open label, randomized, parallel group trial with 21 children was conducted for 2 years to evaluate the efficacy and safety of Norditropin treatment for short stature in children with Noonan syndrome. An additional 6 children were not randomized, but did follow the protocol. After the initial two-year trial, children continued on Norditropin until final height. Retrospective final height and adverse event data were collected from 18 of the 21 subjects who were originally enrolled in the trial 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.

The twenty-four (24) (12 female, 12 male) children 3 – 14 years of age received either 0.033 mg/kg/day or 0.066 mg/kg/day of Norditropin subcutaneously which, after the first 2 years, was adjusted based on growth response.

In addition to a diagnosis of Noonan syndrome, key 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).

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.

Age at start of treatment was a factor for change in height SDS (national reference). The younger the age at start of treatment, the larger the change in height SDS.

Examination of gender subgroups did not identify differences in response to Norditropin.

Not all patients with Noonan syndrome have short stature; some will achieve a normal adult height without treatment. Therefore, prior to initiating Norditropin for a patient with Noonan syndrome, establish that the patient does have short stature.

14.2 Short Stature in Children with Turner Syndrome

Two randomized, parallel group, open label, multicenter studies were conducted in the Netherlands to evaluate the efficacy and safety of Norditropin for the treatment of children with short stature associated with Turner syndrome. 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 (the primary study), 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). Overall, 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 3, 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 3 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 3 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 3 - Final Height-Related Results After Treatment of Patients with Turner Syndrome with Norditropin in a Randomized, Dose Escalating Study
*
Unadjusted (raw) means
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
p=0.005 vs. Dose A
§
p=0.006 vs. Dose A
p=0.008 vs. Dose A

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)*105 (12)108 (12.7)107 (11.7)106 (11.9)
Final height (cm)*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)
Final [95% CI]1.7 [1.4, 2.0]2.5 [2.1, 2.8]2.5 [2.1, 2.9]§NA
Change from baseline [95% CI]1.5 [1.2, 1.8]2.2 [1.9, 2.5]2.2 [1.9, 2.6]§NA
Height SDS (National standard)
Final [95% CI]-1.9 [-2.2, -1.6]-1.2 [-1.5, -0.9]§-1.2 [-1.6, -0.8]NA
Change from baseline [95% CI]0.7 [0.4, 1.0]1.4 [1.1, 1.7]§1.4 [1.1, 1.8]NA
Values are expressed as mean (SD) unless otherwise indicated. SDS: Standard deviation score.

In Study 2 (a supportive study), 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).

14.3 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 in children with short stature born SGA with no catch-up growth. Changes in height and height velocity were compared to a national reference population in both studies.

Study 1

The pivotal study included 53 (38 male, 15 female) non-GHD, Dutch children 3-11 years of age with short stature born SGA with no catch-up growth. Catch-up growth was defined as obtaining a height of ≥ 3rd percentile within the first 2 years of life or at a later stage. These prepubertal children needed to meet the following additional inclusion criteria: birth length < 3rd percentile for gestational age, and height velocity (cm/year) for chronological age < 50th percentile.  Exclusion criteria included chromosomal abnormalities, signs of a syndrome (except for Silver-Russell syndrome), serious/chronic co-morbid disease, malignancy, and previous rhGH therapy. 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 4, for boys and girls combined, both mean final height SDS (Dose A, -1.8 vs. Dose B, -1.3), and increase in height SDS from baseline to final height (Dose A, 1.4 vs. Dose B, 1.8), 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 4).

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 4 - 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
*
Adjusted (least-squares) means based on an ANCOVA model including terms for treatment, gender, age at baseline, height SDS at baseline, and pubertal status.
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
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) and [95% confidence intervals]
Height SDS: Change from Baseline at Year 2*

1.4 + 0.1 (26)

[1.1, 1.6]

1.8 + 0.1 (26)

[1.5, 2.0]

Treatment Diff = 0.4

[0.2, 0.7]

p-value = 0.002

Height SDS: Change from Baseline at Final Heigh

1.4 + 0.2 (19)

[0.9, 1.8]

1.8 + 0.2 (19)

[1.4, 2.2]

Treatment Diff = 0.5

[0.0, 0.9]

p-value = 0.045

Final Height SDS

-1.8 + 0.2 (19)

[-2.2, -1.4]

-1.3 + 0.2 (19)

[-1.7, -0.9]

Final Height SDS > -213/19 (68%)11/19 (58%)24/38 (63%)
SDS: Standard deviation score.

Study 2

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

As seen in Table 5, 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 5 - 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
*
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.
Raw Mean + SD (N)

No Treatment

0.033

mg/kg/day

0.067

mg/kg/day

Total

Height SDS: Baseline-2.9 + 0.5 (15)-3.0 + 0.6 (35)-2.9 + 0.7 (34)-2.9 + 0.6 (84)
Height SDS: Year 1-2.8 + 0.5 (15)-2.4 + 0.6 (33)-2.0 + 0.8 (34)-2.3 + 0.7 (82)
Height SDS: Year 2NA-2.2 + 0.7 (33)-1.4 + 0.7 (32)-1.8 + 0.8 (65)
Adjustment least-squares mean + standard error (N) and [95% confidence intervals]

Height SDS: Change from Baseline at Year 1*

0.1 + 0.1 (15)

[-0.1, 0.2]

0.6 + 0.1 (33)

[0.5, 0.7]

0.9 + 0.1 (34)

[0.8, 1.0]

0.033 vs. No Treatment: Treatment Diff = 0.5, [0.3, 0.7], p<0.0001

0.067 vs. No Treatment: Treatment Diff = 0.8, [0.6, 1.0], p<0.0001

0.067 vs. 0.033: Treatment Diff = 0.3, [0.2, 0.5] p-value ,0.0001

Height SDS: Change from Baseline at Year 2*

NA

0.8 + 0.1 (33)

[0.7, 0.9]

1.4 + 0.1 (32)

[1.3, 1.6]

0.067 vs. 0.033: Treatment Diff = 0.6, [0.5, 0.8], p-value , 0.0001

SDS: Standard deviation score.

14.4 Adult 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 (rDNA origin) for 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 (p=0.0028) increase from baseline in LBM compared to placebo (Table 6).

Table 6 - Lean Body Mass (kg) by TBP

Norditropin

(n=15)

Placebo

(n=16)
Baseline (mean)50.2751.72
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

Analysis of the treatment difference on the change from baseline in percent TBF revealed a significant decrease (p=0.0004) in the Norditropin-treated group compared to the placebo group (Table 7).

Table 7 - Total Body Fat (%) by TBP

Norditropin

(n=15)

Placebo

(n=16)
Baseline (mean)44.7442.26
Change from baseline at 6 months (mean)-2.831.92

Treatment difference (mean)
95% confidence interval
p-value

-4.74
(-7.18, -2.30)
p=0.0004

Fifteen (48.4%) of the 31 randomized patients were male. The adjusted mean treatment differences on the increase in LBM and decrease in percent TBF from baseline were larger in males compared to females.

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 (p=0.0079) increase from baseline in LBM compared to placebo (pooled data) (Table 8).

Table 8 - Lean Body Mass (kg) by TBP

Norditropin

(n=36)

Placebo

(n=13)
Baseline (mean)48.1848.90
Change from baseline at 6 months (mean)2.060.70

Treatment difference (mean)
95% confidence interval
p-value

1.40
(0.39, 2.41)
p=0.0079

Analysis of the treatment difference on the change from baseline in percent TBF revealed a significant decrease (p=0.0048) in the Norditropin-treated groups (pooled data) compared to the placebo group (Table 9).

Table 9 - Total Body Fat (%) by TBP

Norditropin

(n=36)

Placebo

(n=13)
Baseline (mean)34.5534.07
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

Norditropin also significantly reduced intraabdominal, extraperitoneal and total abdominal fat volume, waist/hip ratio and LDL cholesterol, and significantly increased serum osteocalcin.

Forty four men were enrolled in an open label follow up study and treated with Norditropin for as long as 30 additional months. During this period, the reduction in waist/hip ratio achieved during the initial six months of treatment was maintained.

16. HOW SUPPLIED/STORAGE AND HANDLING

Norditropin Cartridges [somatropin (rDNA origin) injection] 5 mg/1.5 mL and 15 mg/1.5 mL:

Norditropin is individually cartoned in 5 mg/1.5 mL or 15 mg/1.5 mL cartridges which must be administered using the corresponding color-coded NordiPen delivery system.

Unused Norditropin cartridges must be stored at 2-8oC/36-46oF (refrigerator). Do not freeze. Avoid direct light.

5 mg/1.5 mL (orange) cartridges:

After a Norditropin cartridge (5 mg/1.5 mL) has been inserted into its NordiPen delivery system (NordiPen 5), it may be EITHER stored in the pen in the refrigerator (2-8ºC/36-46ºF) and used within 4 weeks OR stored for up to 3 weeks at not more than 25ºC (77ºF). Discard unused portion.

15 mg/1.5 mL (green) cartridges:

After a Norditropin cartridge (15 mg/1.5 mL) has been inserted into its NordiPen delivery system (NordiPen 15), it must be stored in the pen in the refrigerator (2-8ºC/36-46ºF) and used within 4 weeks. Discard unused portion after 4 weeks.

Norditropin NordiFlex prefilled pens [somatropin (rDNA origin) injection] 5 mg/1.5 mL, 10 mg/1.5 mL, and 15 mg/1.5 mL:

Norditropin NordiFlex is individually cartoned in 5 mg/1.5 mL, 10 mg/1.5 mL, or 15 mg/1.5 mL prefilled pens.

Unused Norditropin NordiFlex prefilled pens  must be stored at 2-8oC/36-46oF (refrigerator). Do not freeze. Avoid direct light.

5 mg/1.5 mL (orange) and 10 mg/1.5 mL (blue) prefilled pens:

After the initial injection, a Norditropin NordiFlex (5 mg/1.5 mL or 10 mg/1.5 mL) prefilled pen may be EITHER stored in the refrigerator (2-8ºC/36-46ºF) and used within 4 weeks OR stored for up to 3 weeks at not more than 25ºC (77ºF). Discard unused portion.

15 mg/1.5 mL (green) prefilled pens:

After the initial injection, a Norditropin NordiFlex 15 mg/1.5 mL prefilled pen  must be stored in the refrigerator (2-8ºC/36-46ºF) and used within 4 weeks. Discard unused portion after 4 weeks.

Table 10 - Storage Options
Norditropin Product FormulationBefore UseIn-use (After 1st injection)
Storage requirement

Storage Option 1

(Refrigeration)

Storage Option 2

(Room temperature)
5 mg

2-8 ºC/

36-46 ºF

Until exp date

2-8 ºC/36-46 ºF

4 weeks

Up to 25ºC/77ºF

3 weeks
10 mg

2-8 ºC/36-46 ºF

4 weeks

Up to 25ºC/77ºF

3 weeks
15 mg

2-8 ºC/36-46 ºF

4 weeks
Does Not Apply

17. PATIENT COUNSELING INFORMATION

[See FDA-Approved Patient Labeling (17.1)]

Patients being treated with Norditropin Cartridges or Norditropin NordiFlex prefilled pens (and/or their parents) should be informed about the potential risks and benefits associated with somatropin treatment [in particular, see Adverse Reactions (6.1) for a listing of the most serious and/or most frequently observed adverse reactions associated with somatropin treatment in children and adults]. This information is intended to better educate patients (and caregivers); it is not a disclosure of all possible adverse or intended effects.

Patients and caregivers who will administer Norditropin Cartridges or Norditropin NordiFlex prefilled pens should receive appropriate training and instruction on proper use from the physician or other suitably qualified health care professional. A puncture-resistant container for the disposal of used needles should be strongly recommended. Patients and/or parents should be thoroughly instructed in the importance of proper disposal, and cautioned against any reuse of needles. This information is intended to aid in the safe and effective administration of the medication.

If patients are prescribed Norditropin Cartridges (to be inserted into color-coded NordiPen delivery systems), physicians should instruct patients to read the NordiPen INSTRUCTION booklet provided with the NordiPen delivery systems.

If patients are prescribed Norditropin NordiFlex, physicians should instruct patients to read the PATIENT INFORMATION and INSTRUCTIONS FOR USE leaflets provided with the Norditropin NordiFlex prefilled pens.

Version: 10

Novo Nordisk® is a registered trademark of Novo Nordisk A/S.

Norditropin®, NordiPen® and Norditropin NordiFlex® are registered trademarks of Novo Nordisk Health Care AG.

© 2002-2008 Novo Nordisk Inc.

For information contact:

Novo Nordisk Inc.

100 College Road West

Princeton, New Jersey 08540, USA

1-888-NOVO-444

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd, Denmark

17.1 FDA-Approved Patient Labeling

Norditropin NordiFlex®

Somatropin (rDNA origin) injection

5 mg/1.5 mL Prefilled Pen

Your doctor will discuss with you the benefits and risks of Norditropin NordiFlex® (pronounced Nor-dee-tro-pin Nor-dee-flex). Read all of the information in this patient guide because it contains important information for you. If you have further questions, please ask your doctor or your pharmacist.

Norditropin NordiFlex has been prescribed for you and you must not pass it on to others.

What is the most important information I should know about Norditropin NordiFlex?

Store Norditropin NordiFlex in a refrigerator before use. Do not freeze it or expose it to heat.

Do not use Norditropin NordiFlex  if the solution in the cartridge does not appear clear and colorless. Check this by turning the pen upside down once or twice.

Norditropin NordiFlex is for use by one person only.

Do not use Norditropin NordiFlex if you need to make more than 4 air shots before the first injection.

Your doctor may measure your height, weight and your ability to produce growth hormone before you are prescribed Norditropin NordiFlex.

What is Norditropin NordiFlex?

Norditropin® is a clear and colorless solution.

Norditropin is used to treat the following:

Norditropin is injected using Norditropin NordiFlex, a multi-dose disposable 1.5 mL prefilled pen. Norditropin NordiFlex contains several doses of growth hormone solution. A dose is injected under the skin in the evening 6-7 times a week.

Norditropin NordiFlex is available in three strengths: 5 mg/1.5 mL, 10 mg/1.5 mL and 15 mg/1.5 mL (i.e. with a concentration of 3.3 mg/mL, 6.7 mg/mL and 10.0 mg/mL respectively).

Throw away Norditropin NordiFlex when the cartridge is empty.

Medicines are sometimes prescribed for purposes other than those listed in a patient guide. You should ask your doctor about any concerns and refer to the professional labeling for additional information.

What does Norditropin NordiFlex contain?

The cartridge in Norditropin NordiFlex contains human growth hormone called somatropin (so-ma-tro-pin) made through biotechnology. It is identical to the growth hormone produced in the human body.

The cartridge contains other ingredients: Histidine, Poloxamer 188, Phenol, Mannitol and Water for Injection.

Who should not use Norditropin NordiFlex?

Do not use Norditropin NordiFlex if you have any of the following conditions:

What should you consider if you are pregnant or breast-feeding?

If you become pregnant while you are using Norditropin NordiFlex, you are recommended to stop the treatment and discuss this with your doctor.

You are recommended not to use Norditropin NordiFlex while you are breast-feeding because growth hormone might pass into your milk.

Be sure to tell your doctor if you:

If any of the above applies to you, Norditropin NordiFlex may not be suitable. Your doctor will give you advice.

How should I use Norditropin NordiFlex?

Carefully follow the "Instructions for Use" on the other side of this patient guide.

You should inject Norditropin NordiFlex under the skin in the evening just before bedtime. You should change the injection area so you do not harm your skin.

NovoFine® disposable needles are designed to be used with Norditropin NordiFlex.

How much Norditropin should you take?

Your doctor will tell you how much Norditropin you should take. In children it depends on the body weight.

General guidelines for dosages are shown below.

Children with low or no growth hormone: 0.024 to 0.034 mg/kg body weight, 6-7 times a week

Children with Noonan syndrome: Up to 0.066 mg/kg/day

Children with Turner syndrome: Up to 0.067 mg/kg/day

Children born small for gestational age (SGA) with no catch-up growth by age 2-4 years: Up to 0.067 mg/kg/day

Adults: Not more than 0.004 mg/kg/day at start of therapy. Dosage may be increased as tolerated to not more than 0.016 mg/kg/day after approximately 6 weeks, or

Alternative dose for adults:

 
Approximately 0.2 mg/day (range, 0.15-0.30 mg/day) at start of therapy. Dosage can be increased gradually every 1-2 months by steps of approximately 0.1-0.2 mg/day, based on your doctor's recommendations.

If you forget to take a dose, take the next dose as usual - do not double your dose.

What should you do if you inject too much growth hormone using Norditropin NordiFlex?

If you inject too much growth hormone, contact your doctor.

How long should you continue to take Norditropin?

Discuss with your doctor how long you should take Norditropin.

What should I avoid while using Norditropin NordiFlex?

Be sure to tell your doctor about all of the medications you are taking especially if you are taking:

Adult height can be influenced if you are on Norditropin NordiFlex for growth failure and using glucocorticoids or thyroid hormone at the same time.

If you are treated with insulin and/or oral diabetes medicine, your insulin/oral diabetes medicine dose may need to be adjusted.

What are the possible side effects of Norditropin NordiFlex?

The following side effects are usually mild and temporary:

If you experience any of these symptoms, discuss this with your doctor.

In rare cases you may develop antibodies to growth hormone.

If you have symptoms of headaches, eyesight problems, nausea and/or vomiting, these may be symptoms of raised pressure in the brain. Contact your doctor immediately.

Be sure to tell your doctor if you have any other side effects not mentioned here.

Special warnings

In very rare cases children treated with growth hormone have experienced pain in the hip or knee or a limp. These symptoms may be caused by a slippage of the growth plate in the hip (slipped capital femoral epiphysis).

Scoliosis (curvature of the spine) can occur in children who experience rapid growth. Because growth hormone increases growth rate, patients should be monitored for progression of scoliosis.

Thyroid function tests should be performed periodically.

Patients with Turner syndrome have an increased risk of ear or hearing disorders. They should be carefully evaluated for middle ear infection (otitis media) and other ear disorders.

Skin lesions should be checked carefully for any cancerous changes.

The following tumors have been reported in patients treated with growth hormone: Leukemia in children, relapse of brain tumors in children and adults. However, there is no evidence that growth hormone is responsible for causing these diseases.

Talk to your doctor if you think you have any of these conditions.

How to store Norditropin NordiFlex?

Store unused Norditropin NordiFlex in a refrigerator (2ºC-8ºC/36ºF-46ºF). Do not freeze or expose it to heat. Avoid direct light.

After the initial injection, Norditropin NordiFlex 5 mg/1.5 mL may be EITHER stored in the refrigerator (2-8ºC/36-46ºF) and used within 4 weeks OR may be stored for up to 3 weeks at not more than 25ºC (77ºF). Discard unused portion.

Do not use Norditropin NordiFlex which has been frozen or exposed to temperatures higher than 25ºC (77ºF).

Always use a new NovoFine needle for each injection. Do not keep the needle screwed onto Norditropin NordiFlex when you are not using it.

Always keep the pen cap closed on Norditropin NordiFlex when you are not using it.

Never use Norditropin NordiFlex after the expiration date printed on the pen and on the carton.

Date of issue: October 31, 2008

Version: 6

Norditropin® and Norditropin NordiFlex® are registered trademarks of Novo Nordisk Health Care AG.

Novo Nordisk® and NovoFine® are registered trademarks of Novo Nordisk A/S.

© 2004-2008 Novo Nordisk Inc.

US Patent Nos. 6,235,004; 6,004,297 and other patents pending.

For assistance or further information, write to:

Novo Nordisk Inc.

100 College Road West

Princeton, NJ 08540, USA

1-888-NOVO-444

www.norditropin-us.com

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd, Denmark

INSTRUCTIONS FOR USE

Norditropin NordiFlex®

Somatropin (rDNA origin) injection

5 mg/1.5 mL Prefilled Pen

 Using the disposable Norditropin NordiFlex® 5 mg/1.5 mL Prefilled Pen

Norditropin NordiFlex 5 mg/1.5 mL is a multi-dose, disposable, prefilled pen with liquid growth hormone able to deliver doses from 0.025 to 1.5 mg. The dose can be adjusted in increments of 0.025 mg. Your doctor will determine the correct dose for you. Norditropin NordiFlex prefilled pen is designed to be used with NovoFine® disposable needles (sold separately). Norditropin NordiFlex prefilled pen is not recommended for people who are blind or have trouble seeing unless they have the help of a sighted individual trained to use Norditropin NordiFlex.

Please read these instructions carefully before using this pen

Image from Drug Label Content

1 Preparing Norditropin NordiFlex 5 mg/1.5 mL for injection

A. Pull off the pen cap and check if the growth hormone solution is clear and colorless by turning Norditropin NordiFlex upside down once or twice and view the solution through the residual scale window. DO NOT use Norditropin NordiFlex if the growth hormone solution is cloudy or contains particles. Use it only if it is clear and colorless.

Wash hands well and dry completely.

Wipe the front rubber stopper on the threaded plastic cap with an alcohol swab.

Image from Drug Label Content

B. Place a new NovoFine disposable needle onto Norditropin NordiFlex immediately before use. Remove the protective tab from the disposable needle and screw the needle tightly onto Norditropin NordiFlex. Pull off the outer and inner needle caps. Never place a disposable needle on your Norditropin NordiFlex until you are ready to give an injection. Remove the needle immediately after use. If the needle is not removed, some growth hormone may be expelled from Norditropin NordiFlex.

Image from Drug Label Content

 2 Performing an air shot

 Do an air shot before starting a new Norditropin NordiFlex as follows:

Small amounts of air may collect in the needle and cartridge. To avoid injecting air and ensure proper dosing, set the dosage selector to 0.025 mg. Each line between labeled dosages is 0.025 mg.

C. Dial 0.025 mg

Image from Drug Label Content

D. Hold Norditropin NordiFlex with the needle pointing up, tap the cartridge gently with your finger a few times to raise any air bubbles to the top of the cartridge.

Image from Drug Label Content

E. Still holding Norditropin NordiFlex with the needle up, press the push button all the way in. A drop of growth hormone should appear at the needle tip. If not, repeat the procedure, no more than 4 times.

If a drop of growth hormone still does not appear, call 1-888-NOVO-444 for help.

Image from Drug Label Content

3 Setting the dose

F. Check that the dose selector is set at 0.0. Dial the number of mg (milligram) that you need to inject. The dose can be changed up or down by turning the dose selector in either direction. When dialing back, be careful not to press the push button as growth hormone liquid will come out.

DO NOT use the clicking sound as a guide for selecting dose.

The numbers on the residual scale can be used to estimate the mg left in the cartridge. DO NOT use these numbers to measure the growth hormone dose.

You cannot set a dose higher than the number of mg left in the cartridge. Use a new Norditropin NordiFlex pen to inject the remaining amount of your dose. Be sure to remember the dose already received with the first dose. For example, if your dose is 0.6 mg and you can only set the dose selector to 0.4 mg, you will need to inject an additional 0.2 mg with a new Norditropin NordiFlex pen.

Image from Drug Label Content

4 Giving the injection

Use the injection procedure recommended by your doctor or healthcare professional.

G. This product is for subcutaneous use only. Insert the needle under the skin and deliver the dose by pressing the push button all the way in. Press the push button only when injecting.

After the injection, the needle should remain under the skin for at least 6 seconds. Keep the push button fully depressed until the needle is removed from the skin. This will ensure that the full dose has been delivered. Vary the injection site using the injection procedure recommended by your doctor.

After the injection, check the dosage indicator window to make sure it shows zero (0.0).

If zero does not appear, you did not receive the full dose. Call 1-888-NOVO-444 for assistance.

Image from Drug Label Content

5 Removing the needle

H. After the injection, remove the needle without recapping and dispose of it in a puncture-resistant container. Used needles should be placed in sharps container (such as red biohazard containers), hard plastic containers (such as detergent bottles), or metal containers (such as an empty coffee can). Such containers should be sealed and disposed of properly.

It is important that you use a new needle for each injection. Healthcare professionals, relatives and other caregivers should follow general precautionary measures for removal and disposal of needles to eliminate the risk of unintended needle stick injuries.

When the cartridge is empty, throw away Norditropin NordiFlex without the needle attached.

6 Maintenance

Norditropin NordiFlex should be handled with care. Protect Norditropin NordiFlex from dust, dirt, and direct sunlight.

You can clean the outside of Norditropin NordiFlex by wiping it with a soft cloth moistened with water. Do not soak Norditropin NordiFlex in alcohol, wash, or lubricate it.

7 Important Notes

8 Warranty

If your Norditropin NordiFlex is defective in materials or workmanship, Novo Nordisk Inc. will replace it at no charge if you mail the defective unit, postage prepaid to:

Novo Nordisk Inc.

Product Safety

100 College Road West

Princeton, NJ 08540, USA

Norditropin NordiFlex®

Somatropin (rDNA origin) injection

10 mg/1.5 mL Prefilled Pen

Your doctor will discuss with you the benefits and risks of Norditropin NordiFlex® (pronounced Nor-dee-tro-pin Nor-dee-flex). Read all of the information in this patient guide because it contains important information for you. If you have further questions, please ask your doctor or your pharmacist.

Norditropin NordiFlex has been prescribed for you and you must not pass it on to others.

What is the most important information I should know about Norditropin NordiFlex?

Store Norditropin NordiFlex in a refrigerator before use. Do not freeze it or expose it to heat.

Do not use Norditropin NordiFlex if the solution in the cartridge does not appear clear and colorless. Check this by turning the pen upside down once or twice.

Norditropin NordiFlex is for use by one person only.

Do not use Norditropin NordiFlex if you need to make more than 4 air shots before the first injection.

Your doctor may measure your height, weight and your ability to produce growth hormone before you are prescribed Norditropin NordiFlex.

What is Norditropin NordiFlex?

Norditropin® is a clear and colorless solution.

Norditropin is used to treat the following:

Norditropin is injected using Norditropin NordiFlex, a multi-dose disposable 1.5 mL prefilled pen. Norditropin NordiFlex contains several doses of growth hormone solution. A dose is injected under the skin in the evening 6-7 times a week.

Norditropin NordiFlex is available in three strengths: 5 mg/1.5 mL, 10 mg/1.5 mL and 15 mg/1.5 mL (i.e. with a concentration of 3.3 mg/mL, 6.7 mg/mL and 10.0 mg/mL respectively).

Throw away Norditropin NordiFlex when the cartridge is empty.

Medicines are sometimes prescribed for purposes other than those listed in a patient guide. You should ask your doctor about any concerns and refer to the professional labeling for additional information.

What does Norditropin NordiFlex contain?

The cartridge in Norditropin NordiFlex contains human growth hormone called somatropin (so-ma-tro-pin) made through biotechnology. It is identical to the growth hormone produced in the human body.

The cartridge contains other ingredients: Histidine, Poloxamer 188, Phenol, Mannitol and Water for Injection.

Who should not use Norditropin NordiFlex?

Do not use Norditropin NordiFlex if you have any of the following conditions:

What should you consider if you are pregnant or breast-feeding?

If you become pregnant while you are using Norditropin NordiFlex, you are recommended to stop the treatment and discuss this with your doctor.

You are recommended not to use Norditropin NordiFlex while you are breast-feeding because growth hormone might pass into your milk.

 

Be sure to tell your doctor if you:

If any of the above applies to you, Norditropin NordiFlex may not be suitable. Your doctor will give you advice.

How should I use Norditropin NordiFlex?

Carefully follow the “Instructions for Use” on the other side of this patient guide.

You should inject Norditropin NordiFlex under the skin in the evening just before bedtime. You should change the injection area so you do not harm your skin.

NovoFine® disposable needles are designed to be used with Norditropin NordiFlex.

How much Norditropin should you take?

Your doctor will tell you how much Norditropin you should take. In children it depends on the body weight.

General guidelines for dosages are shown below.

Children with low or no growth hormone: 0.024 to 0.034 mg/kg body weight, 6-7 times a week

Children with Noonan syndrome: Up to 0.066 mg/kg/day

Children with Turner syndrome: Up to 0.067 mg/kg/day

Children born small for gestational age (SGA) with no catch-up growth by age 2-4 years: Up to 0.067 mg/kg/day

Adults: Not more than 0.004 mg/kg/day at start of therapy. Dosage may be increased as tolerated to not more than 0.016 mg/kg/day after approximately 6 weeks, or

Alternative dose for adults:

 
Approximately 0.2 mg/day (range, 0.15-0.30 mg/day) at start of therapy. Dosage can be increased gradually every 1-2 months by steps of approximately 0.1-0.2 mg/day, based on your doctor's recommendations.

If you forget to take a dose, take the next dose as usual - do not double your dose.

What should you do if you inject too much growth hormone using Norditropin NordiFlex?

If you inject too much growth hormone, contact your doctor.

How long should you continue to take Norditropin?

Discuss with your doctor how long you should take Norditropin.

What should I avoid while using Norditropin NordiFlex?

Be sure to tell your doctor about all of the medications you are taking especially if you are taking:

Adult height can be influenced if you are on Norditropin NordiFlex for growth failure and using glucocorticoids or thyroid hormone at the same time.

If you are treated with insulin and/or oral diabetes medicine, your insulin/oral diabetes medicine dose may need to be adjusted.

What are the possible side effects of Norditropin NordiFlex?

The following side effects are usually mild and temporary:

If you experience any of these symptoms, discuss this with your doctor.

In rare cases you may develop antibodies to growth hormone.

If you have symptoms of headaches, eyesight problems, nausea and/or vomiting, these may be symptoms of raised pressure in the brain. Contact your doctor immediately.

Be sure to tell your doctor if you have any other side effects not mentioned here.

Special warnings

In very rare cases children treated with growth hormone have experienced pain in the hip or knee or a limp. These symptoms may be caused by a slippage of the growth plate in the hip (slipped capital femoral epiphysis).

Scoliosis (curvature of the spine) can occur in children who experience rapid growth. Because growth hormone increases growth rate, patients should be monitored for progression of scoliosis.

Thyroid function tests should be performed periodically.

Patients with Turner syndrome have an increased risk of ear or hearing disorders. They should be carefully evaluated for middle ear infection (otitis media) and other ear disorders.

Skin lesions should be checked carefully for any cancerous changes.

The following tumors have been reported in patients treated with growth hormone: Leukemia in children, relapse of brain tumors in children and adults. However, there is no evidence that growth hormone is responsible for causing these diseases.

Talk to your doctor if you think you have any of these conditions.

How to store Norditropin NordiFlex?

Store unused Norditropin NordiFlex in a refrigerator (2ºC-8ºC/36ºF-46ºF). Do not freeze or expose it to heat. Avoid direct light.

After the initial injection, Norditropin NordiFlex 10 mg/1.5 mL may be EITHER stored in the refrigerator (2-8ºC/36ºF-46ºF) and used within 4 weeks OR may be stored for up to 3 weeks at not more than 25ºC (77ºF). Discard unused portion.

Do not use Norditropin NordiFlex which has been frozen or exposed to temperatures higher than 25ºC (77ºF).

Always use a new NovoFine needle for each injection. Do not keep the needle screwed onto Norditropin NordiFlex when you are not using it.

Always keep the pen cap closed on Norditropin NordiFlex when you are not using it.

Never use Norditropin NordiFlex after the expiration date printed on the pen and on the carton.

Date of issue: October 31, 2008

Version: 6

Norditropin® and Norditropin NordiFlex ®  are registered trademarks of Novo Nordisk Health Care AG.

Novo Nordisk® and NovoFine® are registered trademarks of Novo Nordisk A/S.

© 2004-2008 Novo Nordisk Inc.

US Patent Nos. 6,235,004; 6,004,297 and other patents pending.

For assistance or further information, write to:

Novo Nordisk Inc.

100 College Road West

Princeton, NJ 08540, USA

1-888-NOVO-444

www.norditropin-us.com

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd, Denmark

INSTRUCTIONS FOR USE

Norditropin NordiFlex®

Somatropin (rDNA origin) injection

10 mg/1.5 mL Prefilled Pen

 Using the disposable Norditropin NordiFlex® 10 mg/1.5 mL Prefilled Pen

Norditropin NordiFlex 10 mg/1.5 mL is a multi-dose, disposable, prefilled pen with liquid growth hormone able to deliver doses from 0.05 to 3.0 mg. The dose can be adjusted in increments of 0.05 mg. Your doctor will determine the correct dose for you. Norditropin NordiFlex prefilled pen is designed to be used with NovoFine® disposable needles (sold separately). Norditropin NordiFlex prefilled pen is not recommended for people who are blind or have trouble seeing unless they have the help of a sighted individual trained to use Norditropin NordiFlex.

Please read these instructions carefully before using this pen

Image from Drug Label Content

1 Preparing Norditropin NordiFlex 10 mg/1.5 mL for injection

A. Pull off the pen cap and check if the growth hormone solution is clear and colorless by turning Norditropin NordiFlex upside down once or twice and view the solution through the residual scale window. DO NOT use Norditropin NordiFlex if the growth hormone solution is cloudy or contains particles. Use it only if it is clear and colorless.

Wash hands well and dry completely.

Wipe the front rubber stopper on the threaded plastic cap with an alcohol swab.

Image from Drug Label Content

B. Place a new NovoFine disposable needle onto Norditropin NordiFlex immediately before use. Remove the protective tab from the disposable needle and screw the needle tightly onto Norditropin NordiFlex. Pull off the outer and inner needle caps. Never place a disposable needle on your Norditropin NordiFlex until you are ready to give an injection. Remove the needle immediately after use. If the needle is not removed, some growth hormone may be expelled from Norditropin NordiFlex.

Image from Drug Label Content

2 Performing an air shot

Do an air shot before starting a new Norditropin NordiFlex as follows:

Small amounts of air may collect in the needle and cartridge. To avoid injecting air and ensure proper dosing, set the dosage selector to 0.05 mg. Each line between labeled dosages is 0.05 mg.

C. Dial 0.05 mg

Image from Drug Label Content

D. Hold Norditropin NordiFlex with the needle pointing up, tap the cartridge gently with your finger a few times to raise any air bubbles to the top of the cartridge.

Image from Drug Label Content

E. Still holding Norditropin NordiFlex with the needle up, press the push button all the way in. A drop of growth hormone should appear at the needle tip. If not, repeat the procedure, no more than 4 times.

If a drop of growth hormone still does not appear, call 1-888-NOVO-444 for help.

Image from Drug Label Content

3 Setting the dose

F. Check that the dose selector is set at 0.0. Dial the number of mg (milligram) that you need to inject. The dose can be changed up or down by turning the dose selector in either direction. When dialing back, be careful not to press the push button as growth hormone liquid will come out.

DO NOT use the clicking sound as a guide for selecting dose.

The numbers on the residual scale can be used to estimate the mg left in the cartridge. DO NOT use these numbers to measure the growth hormone dose.

You cannot set a dose higher than the number of mg left in the cartridge. Use a new Norditropin NordiFlex pen to inject the remaining amount of your dose. Be sure to remember the dose already received with the first dose. For example, if your dose is 0.6 mg and you can only set the dose selector to 0.4 mg, you will need to inject an additional 0.2 mg with a new Norditropin NordiFlex pen.

Image from Drug Label Content

4 Giving the injection

Use the injection procedure recommended by your doctor or healthcare professional.

G. This product is for subcutaneous use only. Insert the needle under the skin and deliver the dose by pressing the push button all the way in. Press the push button only when injecting.

After the injection, the needle should remain under the skin for at least 6 seconds. Keep the push button fully depressed until the needle is removed from the skin. This will ensure that the full dose has been delivered. Vary the injection site using the injection procedure recommended by your doctor.

After the injection, check the dosage indicator window to make sure it shows zero (0.0).

If zero does not appear, you did not receive the full dose. Call 1-888-NOVO-444 for assistance.

Image from Drug Label Content

5 Removing the needle

H. After the injection, remove the needle without recapping and dispose of it in a puncture-resistant container. Used needles should be placed in sharps container (such as red biohazard containers), hard plastic containers (such as detergent bottles), or metal containers (such as an empty coffee can). Such containers should be sealed and disposed of properly.

It is important that you use a new needle for each injection. Healthcare professionals, relatives and other caregivers should follow general precautionary measures for removal and disposal of needles to eliminate the risk of unintended needle stick injuries.

When the cartridge is empty, throw away Norditropin NordiFlex without the needle attached.

6 Maintenance

Norditropin NordiFlex should be handled with care. Protect Norditropin NordiFlex from dust, dirt, and direct sunlight.

You can clean the outside of Norditropin NordiFlex by wiping it with a soft cloth moistened with water. Do not soak Norditropin NordiFlex in alcohol, wash, or lubricate it.

7 Important Notes

8 Warranty

If your Norditropin NordiFlex is defective in materials or workmanship, Novo Nordisk Inc. will replace it at no charge if you mail the defective unit, postage prepaid to:

Novo Nordisk Inc.

Product Safety

100 College Road West

Princeton, NJ 08540, USA

Norditropin NordiFlex®

Somatropin (rDNA origin) injection

15 mg/1.5 mL Prefilled Pen

Your doctor will discuss with you the benefits and risks of Norditropin NordiFlex® (pronounced Nor-dee-tro-pin Nor-dee-flex). Read all of the information in this patient guide because it contains important information for you. If you have further questions, please ask your doctor or your pharmacist.

Norditropin NordiFlex has been prescribed for you and you must not pass it on to others.

What is the most important information I should know about Norditropin NordiFlex?

Store Norditropin NordiFlex in a refrigerator before use. Do not freeze it or expose it to heat.

Do not use Norditropin NordiFlex if the solution in the cartridge does not appear clear and colorless. Check this by turning the pen upside down once or twice.

Norditropin NordiFlex is for use by one person only.

Do not use Norditropin NordiFlex if you need to make more than 4 air shots before the first injection.

Your doctor may measure your height, weight and your ability to produce growth hormone before you are prescribed Norditropin NordiFlex.

What is Norditropin NordiFlex?

Norditropin® is a clear and colorless solution.

Norditropin is used to treat the following:

Norditropin is injected using Norditropin NordiFlex, a multi-dose disposable 1.5 mL prefilled pen. Norditropin NordiFlex contains several doses of growth hormone solution. A dose is injected under the skin in the evening 6-7 times a week.

Norditropin NordiFlex is available in three strengths: 5 mg/1.5 mL, 10 mg/1.5 mL and 15 mg/1.5 mL (i.e. with a concentration of 3.3 mg/mL, 6.7 mg/mL and 10.0 mg/mL respectively).

Throw away Norditropin NordiFlex when the cartridge is empty.

Medicines are sometimes prescribed for purposes other than those listed in a patient guide. You should ask your doctor about any concerns and refer to the professional labeling for additional information.

What does Norditropin NordiFlex contain?

The cartridge in Norditropin NordiFlex contains human growth hormone called somatropin (so-ma-tro-pin) made through biotechnology. It is identical to the growth hormone produced in the human body.

The cartridge contains other ingredients: Histidine, Poloxamer 188, Phenol, Mannitol and Water for Injection.

Who should not use Norditropin NordiFlex?

Do not use Norditropin NordiFlex if you have any of the following conditions:

What should you consider if you are pregnant or breast-feeding?

If you become pregnant while you are using Norditropin NordiFlex, you are recommended to stop the treatment and discuss this with your doctor.

You are recommended not to use Norditropin NordiFlex while you are breast-feeding because growth hormone might pass into your milk.

Be sure to tell your doctor if you:

If any of the above applies to you, Norditropin NordiFlex may not be suitable. Your doctor will give you advice.

How should I use Norditropin NordiFlex?

Carefully follow the “Instructions for Use” on the other side of this patient guide.

You should inject Norditropin NordiFlex under the skin in the evening just before bedtime. You should change the injection area so you do not harm your skin.

NovoFine® disposable needles are designed to be used with Norditropin NordiFlex.

How much Norditropin should you take?

Your doctor will tell you how much Norditropin you should take. In children it depends on the body weight.

General guidelines for dosages are shown below.

Children with low or no growth hormone: 0.024 to 0.034 mg/kg body weight, 6-7 times a week

Children with Noonan syndrome: Up to 0.066 mg/kg/day

Children with Turner syndrome: Up to 0.067 mg/kg/day

Children born small for gestational age (SGA) with no catch-up growth by age 2-4 years: Up to 0.067 mg/kg/day

Adults: Not more than 0.004 mg/kg/day at start of therapy. Dosage may be increased as tolerated to not more than 0.016 mg/kg/day after approximately 6 weeks, or

Alternative dose for adults:

 
Approximately 0.2 mg/day (range, 0.15-0.30 mg/day) at start of therapy. Dosage can be increased gradually every 1-2 months by steps of approximately 0.1-0.2 mg/day, based on your doctor's recommendations.

If you forget to take a dose, take the next dose as usual - do not double your dose.

What should you do if you inject too much growth hormone using Norditropin NordiFlex?

If you inject too much growth hormone, contact your doctor.

How long should you continue to take Norditropin?

Discuss with your doctor how long you should take Norditropin.

What should I avoid while using Norditropin NordiFlex?

Be sure to tell your doctor about all of the medications you are taking especially if you are taking:

Adult height can be influenced if you are on Norditropin NordiFlex for growth failure and using glucocorticoids or thyroid hormone at the same time.

If you are treated with insulin and/or oral diabetes medicine, your insulin/oral diabetes medicine dose may need to be adjusted.

What are the possible side effects of Norditropin NordiFlex?

The following side effects are usually mild and temporary:

If you experience any of these symptoms, discuss this with your doctor.

In rare cases you may develop antibodies to growth hormone.

If you have symptoms of headaches, eyesight problems, nausea and/or vomiting, these may be symptoms of raised pressure in the brain. Contact your doctor immediately.

Be sure to tell your doctor if you have any other side effects not mentioned here.

Special warnings

In very rare cases children treated with growth hormone have experienced pain in the hip or knee or a limp. These symptoms may be caused by a slippage of the growth plate in the hip (slipped capital femoral epiphysis).

Scoliosis (curvature of the spine) can occur in children who experience rapid growth. Because growth hormone increases growth rate, patients should be monitored for progression of scoliosis.

Thyroid function tests should be performed periodically.

Patients with Turner syndrome have an increased risk of ear or hearing disorders. They should be carefully evaluated for middle ear infection (otitis media) and other ear disorders.

Skin lesions should be checked carefully for any cancerous changes.

The following tumors have been reported in patients treated with growth hormone: Leukemia in children, relapse of brain tumors in children and adults. However, there is no evidence that growth hormone is responsible for causing these diseases.

Talk to your doctor if you think you have any of these conditions.

How to store Norditropin NordiFlex?

Store unused Norditropin NordiFlex in a refrigerator (2ºC-8ºC/36ºF-46ºF). Do not freeze or expose it to heat. Avoid direct light.

After the initial injection, Norditropin NordiFlex 15 mg/1.5 mL must be kept in a refrigerator and used within 4 weeks. Discard unused portion after 4 weeks.

Do not use Norditropin NordiFlex which has been frozen or exposed to temperatures higher than 25ºC (77ºF).

Always use a new NovoFine needle for each injection. Do not keep the needle screwed onto Norditropin NordiFlex when you are not using it.

Always keep the pen cap closed on Norditropin NordiFlex when you are not using it.

Never use Norditropin NordiFlex after the expiration date printed on the pen and on the carton.

Date of issue: October 31, 2008

Version: 5

Norditropin® and Norditropin NordiFlex ®  are registered trademarks of Novo Nordisk Health Care AG.

Novo Nordisk® and NovoFine® are registered trademarks of Novo Nordisk A/S.

© 2004-2008 Novo Nordisk Inc.

US Patent Nos. 6,235,004; 6,004,297 and other patents pending.

For assistance or further information, write to:

Novo Nordisk Inc.

100 College Road West

Princeton, NJ 08540, USA

1-888-NOVO-444

www.norditropin-us.com

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd, Denmark

INSTRUCTIONS FOR USE

Norditropin NordiFlex®

Somatropin (rDNA origin) injection

15 mg/1.5 mL Prefilled Pen

Using the disposable Norditropin NordiFlex® 15 mg/1.5 mL Prefilled Pen

Norditropin NordiFlex 15 mg/1.5 mL is a multi-dose, disposable, prefilled pen with liquid growth hormone able to deliver doses from 0.075 to 4.5 mg. The dose can be adjusted in increments of 0.075 mg. Your doctor will determine the correct dose for you. Norditropin NordiFlex prefilled pen is designed to be used with NovoFine® disposable needles (sold separately). Norditropin NordiFlex prefilled pen is not recommended for people who are blind or have trouble seeing unless they have the help of a sighted individual trained to use Norditropin NordiFlex.

Please read these instructions carefully before using this pen

Image from Drug Label Content

1 Preparing Norditropin NordiFlex 15 mg/1.5 mL for injection

A. Pull off the pen cap and check if the growth hormone solution is clear and colorless by turning Norditropin NordiFlex upside down once or twice and view the solution through the residual scale window. DO NOT use Norditropin NordiFlex if the growth hormone solution is cloudy or contains particles. Use it only if it is clear and colorless.

Wash hands well and dry completely.

Wipe the front rubber stopper on the threaded plastic cap with an alcohol swab.

Image from Drug Label Content

B. Place a new NovoFine disposable needle onto Norditropin NordiFlex immediately before use. Remove the protective tab from the disposable needle and screw the needle tightly onto Norditropin NordiFlex. Pull off the outer and inner needle caps. Never place a disposable needle on your Norditropin NordiFlex until you are ready to give an injection. Remove the needle immediately after use. If the needle is not removed, some growth hormone may be expelled from Norditropin NordiFlex.

Image from Drug Label Content

  2 Performing an air shot

Do an air shot before starting a new Norditropin NordiFlex as follows:

Small amounts of air may collect in the needle and cartridge. To avoid injecting air and ensure proper dosing, set the dosage selector to 0.075 mg. Each line between labeled dosages is 0.075 mg.

C. Dial 0.075 mg

Image from Drug Label Content

D. Hold Norditropin NordiFlex with the needle pointing up, tap the cartridge gently with your finger a few times to raise any air bubbles to the top of the cartridge.

Image from Drug Label Content

E. Still holding Norditropin NordiFlex with the needle up, press the push button all the way in. A drop of growth hormone should appear at the needle tip. If not, repeat the procedure, no more than 4 times.

If a drop of growth hormone still does not appear, call 1-888-NOVO-444 for help.

Image from Drug Label Content

3 Setting the dose

F. Check that the dose selector is set at 0.0. Dial the number of mg (milligram) that you need to inject. The dose can be changed up or down by turning the dose selector in either direction. When dialing back, be careful not to press the push button as growth hormone liquid will come out.

DO NOT use the clicking sound as a guide for selecting dose.

The numbers on the residual scale can be used to estimate the mg left in the cartridge. DO NOT use these numbers to measure the growth hormone dose.

You cannot set a dose higher than the number of mg left in the cartridge. Use a new Norditropin NordiFlex pen to inject the remaining amount of your dose. Be sure to remember the dose already received with the first dose. For example, if your dose is 0.6 mg and you can only set the dose selector to 0.3 mg, you will need to inject an additional 0.3 mg with a new Norditropin NordiFlex pen.

Image from Drug Label Content

4 Giving the injection

Use the injection procedure recommended by your doctor or healthcare professional.

G. This product is for subcutaneous use only. Insert the needle under the skin and deliver the dose by pressing the push button all the way in. Press the push button only when injecting.

After the injection, the needle should remain under the skin for at least 6 seconds. Keep the push button fully depressed until the needle is removed from the skin. This will ensure that the full dose has been delivered. Vary the injection site using the injection procedure recommended by your doctor.

After the injection, check the dosage indicator window to make sure it shows zero (0.0).

If zero does not appear, you did not receive the full dose. Call 1-888-NOVO-444 for assistance.

Image from Drug Label Content

5 Removing the needle

H. After the injection, remove the needle without recapping and dispose of it in a puncture-resistant container. Used needles should be placed in sharps container (such as red biohazard containers), hard plastic containers (such as detergent bottles), or metal containers (such as an empty coffee can). Such containers should be sealed and disposed of properly.

It is important that you use a new needle for each injection. Healthcare professionals, relatives and other caregivers should follow general precautionary measures for removal and disposal of needles to eliminate the risk of unintended needle stick injuries.

When the cartridge is empty, throw away Norditropin NordiFlex without the needle attached.

6 Maintenance

Norditropin NordiFlex should be handled with care. Protect Norditropin NordiFlex from dust, dirt, and direct sunlight.

You can clean the outside of Norditropin NordiFlex by wiping it with a soft cloth moistened with water. Do not soak Norditropin NordiFlex in alcohol, wash, or lubricate it.

7 Important Notes

8 Warranty

If your Norditropin NordiFlex is defective in materials or workmanship, Novo Nordisk Inc. will replace it at no charge if you mail the defective unit, postage prepaid to:

Novo Nordisk Inc.

Product Safety

100 College Road West

Princeton, NJ 08540, USA


NORDITROPIN 
somatropin   injection, solution
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)0169-7768
Route of AdministrationSUBCUTANEOUSDEA Schedule    
INGREDIENTS
Name (Active Moiety)TypeStrength
SOMATROPIN (somatropin) Active5 MILLIGRAM  In 1.5 MILLILITER
histidineInactive1 MILLIGRAM  In 1.5 MILLILITER
hydrochloric acidInactive 
MANNITOLInactive60 MILLIGRAM  In 1.5 MILLILITER
phenolInactive4.5 MILLIGRAM  In 1.5 MILLILITER
poloxamer 188Inactive4.5 MILLIGRAM  In 1.5 MILLILITER
sodium hydroxideInactive 
WATERInactive 
Product Characteristics
Color    Score    
ShapeSize
FlavorImprint Code
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
10169-7768-111 CARTRIDGE In 1 CARTONcontains a CARTRIDGE
11.5 mL (MILLILITER) In 1 CARTRIDGEThis package is contained within the CARTON (0169-7768-11)

NORDITROPIN 
somatropin   injection, solution
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)0169-7770
Route of AdministrationSUBCUTANEOUSDEA Schedule    
INGREDIENTS
Name (Active Moiety)TypeStrength
SOMATROPIN (somatropin) Active15 MILLIGRAM  In 1.5 MILLILITER
histidineInactive1.7 MILLIGRAM  In 1.5 MILLILITER
hydrochloric acidInactive 
MANNITOLInactive58 MILLIGRAM  In 1.5 MILLILITER
phenolInactive4.5 MILLIGRAM  In 1.5 MILLILITER
poloxamer 188Inactive4.5 MILLIGRAM  In 1.5 MILLILITER
sodium hydroxideInactive 
WATERInactive 
Product Characteristics
Color    Score    
ShapeSize
FlavorImprint Code
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
10169-7770-111 CARTRIDGE In 1 CARTONcontains a CARTRIDGE
11.5 mL (MILLILITER) In 1 CARTRIDGEThis package is contained within the CARTON (0169-7770-11)

NORDITROPIN NORDIFLEX 
somatropin   injection, solution
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)0169-7704
Route of AdministrationSUBCUTANEOUSDEA Schedule    
INGREDIENTS
Name (Active Moiety)TypeStrength
SOMATROPIN (somatropin) Active5 MILLIGRAM  In 1.5 MILLILITER
histidineInactive1 MILLIGRAM  In 1.5 MILLILITER
hydrochloric acidInactive 
MANNITOLInactive60 MILLIGRAM  In 1.5 MILLILITER
phenolInactive4.5 MILLIGRAM  In 1.5 MILLILITER
poloxamer 188Inactive4.5 MILLIGRAM  In 1.5 MILLILITER
sodium hydroxideInactive 
WATERInactive 
Product Characteristics
Color    Score    
ShapeSize
FlavorImprint Code
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
10169-7704-111 SYRINGE In 1 CARTONcontains a SYRINGE, PLASTIC
11.5 mL (MILLILITER) In 1 SYRINGE, PLASTICThis package is contained within the CARTON (0169-7704-11)

NORDITROPIN NORDIFLEX 
somatropin   injection, solution
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)0169-7705
Route of AdministrationSUBCUTANEOUSDEA Schedule    
INGREDIENTS
Name (Active Moiety)TypeStrength
SOMATROPIN (somatropin) Active10 MILLIGRAM  In 1.5 MILLILITER
histidineInactive1 MILLIGRAM  In 1.5 MILLILITER
hydrochloric acidInactive 
MANNITOLInactive60 MILLIGRAM  In 1.5 MILLILITER
phenolInactive4.5 MILLIGRAM  In 1.5 MILLILITER
poloxamer 188Inactive4.5 MILLIGRAM  In 1.5 MILLILITER
sodium hydroxideInactive 
WATERInactive 
Product Characteristics
Color    Score    
ShapeSize
FlavorImprint Code
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
10169-7705-111 SYRINGE In 1 CARTONcontains a SYRINGE, PLASTIC
11.5 mL (MILLILITER) In 1 SYRINGE, PLASTICThis package is contained within the CARTON (0169-7705-11)

NORDITROPIN NORDIFLEX 
somatropin   injection, solution
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)0169-7708
Route of AdministrationSUBCUTANEOUSDEA Schedule    
INGREDIENTS
Name (Active Moiety)TypeStrength
SOMATROPIN (somatropin) Active15 MILLIGRAM  In 1.5 MILLILITER
histidineInactive1.7 MILLIGRAM  In 1.5 MILLILITER
hydrochloric acidInactive 
MANNITOLInactive58 MILLIGRAM  In 1.5 MILLILITER
phenolInactive4.5 MILLIGRAM  In 1.5 MILLILITER
poloxamer 188Inactive4.5 MILLIGRAM  In 1.5 MILLILITER
sodium hydroxideInactive 
WATERInactive 
Product Characteristics
Color    Score    
ShapeSize
FlavorImprint Code
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
10169-7708-111 SYRINGE In 1 CARTONcontains a SYRINGE, PLASTIC
11.5 mL (MILLILITER) In 1 SYRINGE, PLASTICThis package is contained within the CARTON (0169-7708-11)

Revised: 11/2008Novo Nordisk Inc.