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Norditropin

Generic Name: somatropin (rDNA origin)
Dosage Form: injection, solution

Indications and Usage for Norditropin

Pediatric Patients

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

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

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

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

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:

Adult Onset (AO): Patients who have GHD, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or
Childhood Onset (CO): Patients who were GH deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes.

Patients who were treated with somatropin for GHD in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin therapy at the reduced dose level recommended for GHD adults. According to current standards, confirmation of the diagnosis of adult GHD 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.

Norditropin 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.

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 to 0.034 mg/kg/day, 6 to 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.

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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 to 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/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.

Dosing of Adult Patients

Adult Growth Hormone Deficiency (GHD)

Either of two approaches to Norditropin dosing may be followed: a non-weight-based regimen or a weight-based regimen.

Non-weight based — based on published consensus guidelines, 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 to 2 months by increments of approximately 0.1-0.2 mg/day, according to individual patient requirements based on the clinical response and serum insulin-like growth factor I (IGF-I) concentrations. The dose should be decreased as necessary on the basis of adverse events and/or serum IGF-I concentrations above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to person, and between male and female patients.

Weight-based — based on the dosing regimen used in the original adult GHD registration trials, the recommended dosage at the start of treatment 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 concentrations should be used as guidance in dose titration.

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.

Preparation and Administration

Norditropin® FlexPro® 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 FlexPro prefilled pen.

Norditropin NordiFlex® 30 mg/3 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.

Dosage Forms and Strengths

Norditropin is available preloaded in the Norditropin FlexPro or Norditropin NordiFlex pens:

5 mg/1.5 mL (orange): Norditropin FlexPro pen
10 mg/1.5 mL (blue): Norditropin FlexPro pen
15 mg/1.5 mL (green): Norditropin FlexPro pen
30 mg/3 mL (purple): Norditropin NordiFlex prefilled pen

Contraindications

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)].

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.

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.

Diabetic Retinopathy

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

Closed Epiphyses

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

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.

Warnings and Precautions

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.

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.

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.

Impaired Glucose Tolerance and Diabetes Mellitus

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. New onset type 2 Diabetes Mellitus has been reported in patients. 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/injectable agents) may require adjustment when somatropin therapy is instituted in these patients.

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.

Fluid Retention

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

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.

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.

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.

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.

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.

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.

Laboratory Tests

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

Pancreatitis

Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment, with some evidence supporting a greater risk in children compared with adults. Published literature indicates that girls who have Turner syndrome may be at greater risk than other somatropin-treated children. Pancreatitis should be considered in any somatropin-treated patient, especially a child, who develops persistent severe abdominal pain.

Adverse Reactions

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:

bSudden death in pediatric patients with Prader-Willi syndrome with risk factors including severe obesity, history of upper airway obstruction or sleep apnea and unidentified respiratory infection [see Contraindications (4.2) and Warnings and Precautions (5.2)]
bIntracranial tumors, in particular meningiomas, in teenagers/young adults treated with radiation to the head as children for a first neoplasm and somatropin [see Contraindications (4.3) and Warnings and Precautions (5.3)]
a,bGlucose intolerance including impaired glucose tolerance/impaired fasting glucose as well as overt diabetes mellitus [see Warnings and Precautions (5.4)]
bIntracranial hypertension [see Warnings and Precautions (5.5)]
bSignificant diabetic retinopathy [see Contraindications (4.4)]
bSlipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.8)]
bProgression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.9)]
aFluid retention manifested by edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias [see Warnings and Precautions (5.6)]
aUnmasking of latent central hypothyroidism [see Warnings and Precautions (5.7)]
aInjection site reactions/rashes and lipoatrophy (as well as rare generalized hypersensitivity reactions) [see Warnings and Precautions (5.12)]
Pancreatitis [see Warnings and Precautions (5.14)]

Clinical Trials Experience

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

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 Reactions

n

%

n

%

Peripheral Edema

22

42

4

8

Edema

13

25

0

0

Arthralgia

10

19

8

15

Leg Edema

8

15

2

4

Myalgia

8

15

4

8

Infection (non-viral)

7

13

4

8

Paraesthesia

6

11

3

6

Skeletal Pain

6

11

1

2

Headache

5

9

3

6

Bronchitis

5

9

0

0

Flu-like symptoms

4

8

2

4

Hypertension

4

8

1

2

Gastroenteritis

4

8

4

8

Other Non-Classifiable Disorders
(excludes accidental injury)

4

8

3

6

Increased sweating

4

8

1

2

Glucose tolerance abnormal

3

6

1

2

Laryngitis

3

6

3

6

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

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Norditropin with the incidence of antibodies to other products may be misleading. In the case of growth hormone, antibodies with binding capacities lower than 2 mg/mL have not been associated with growth attenuation. In a very small number of patients treated with somatropin, when binding capacity was greater than 2 mg/mL, interference with the growth response was observed.

In clinical trials, GHD pediatric patients receiving Norditropin for up to 12 months were tested for induction of antibodies, and 0/358 patients developed antibodies with binding capacities above 2 mg/L. Amongst these patients, 165 had previously been treated with other somatropin formulations, and 193 were previously untreated naive patients.

Post-Marketing Experience

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 and adults [see Warnings and Precautions (5.14)]).

New-onset type 2 diabetes mellitus has been reported.

Drug Interactions

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

The microsomal enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. GH and somatropin inhibit 11βHSD-1. Consequently, individuals with untreated GHD have relative increases in 11βHSD-1 and serum cortisol. Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. As a consequence, previously undiagnosed central (secondary) hypoadrenalism may be unmasked and glucocorticoid replacement may be required in patients treated with somatropin. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment; 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 11ßHSD-1.

Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment

Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth promoting effects of somatropin in children. Therefore, glucocorticoid replacement dosing should be carefully adjusted in children receiving concomitant somatropin and glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth.

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.

Oral Estrogen

Because oral estrogens may reduce the serum IGF-1 response to somatropin treatment, girls and women receiving oral estrogen replacement may require greater somatropin dosages [see Dosage and Administration (2.2)].

Insulin and/or Oral/Injectable Hypoglycemic Agents

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

USE IN SPECIFIC POPULATIONS

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.

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.

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)].

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)].

Norditropin Description

Norditropin is 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 is supplied as a sterile solution for subcutaneous injection in ready-to-administer prefilled pens with a volume of 1.5 mL or 3 mL.

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

Table 2

Component

5 mg/1.5 mL

10 mg/1.5 mL

15 mg/1.5 mL

30 mg/3 mL

Somatropin

5 mg

10 mg

15 mg

30 mg

Histidine

1 mg

1 mg

1.7 mg

3.3 mg

Poloxamer 188

4.5 mg

4.5 mg

4.5 mg

9.0 mg

Phenol

4.5 mg

4.5 mg

4.5 mg

9.0 mg

Mannitol

60 mg

60 mg

58 mg

117 mg

HCl/NaOH

as needed

as needed

as needed

as needed

Water for Injection

up to 1.5 mL

up to 1.5 mL

up to 1.5 mL

up to 3.0 mL

Norditropin - Clinical Pharmacology

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)].

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.

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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Clinical Studies

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.

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).

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 Height

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 > -2

13/19 (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 2

NA

-2.2 + 0.7 (33)

-1.4 + 0.7 (32)

-1.8 + 0.8 (65)

Adjusted 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.

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)

50.27

51.72

Change from baseline at 6 months (mean)

1.12

-0.63

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

1.74
(0.65, 2.83)
p=0.0028

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)

44.74

42.26

Change from baseline at 6 months (mean)

-2.83

1.92

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

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

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)

48.18

48.90

Change from baseline at 6 months (mean)

2.06

0.70

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

1.40
(0.39, 2.41)
p=0.0079

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)

34.55

34.07

Change from baseline at 6 months (mean)

-6.00

-1.78

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

-4.24
(-7.11, -1.37)
p=0.0048

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.

How Supplied/Storage and Handling

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

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

Norditropin FlexPro 5 mg/1.5 mL (orange) NDC 0169-7704-21
Norditropin FlexPro 10 mg/1.5 mL (blue) NDC 0169-7705-21
Norditropin FlexPro 15 mg/1.5 mL (green) NDC 0169-7708-21

 

Norditropin NordiFlex prefilled pen [somatropin (rDNA origin) injection] 30 mg/3 mL:

Norditropin NordiFlex is individually cartoned as a 30 mg/3 mL prefilled pen.

Norditropin NordiFlex 30 mg/3 mL (purple) NDC 0169-7703-11

Norditropin Flexpro 5 mg/1.5 mL (orange),10 mg/1.5 mL (blue), 15mg/1.5 mL (green) and NordiFlex 30 mg/3 mL (purple) prefilled pens:

Unused Norditropin FlexPro and NordiFlex prefilled pens must be stored at 2°C-8°C/36°F-46°F (refrigerator). Do not freeze. Avoid direct light.

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

Table 10 - Storage Options

Norditropin Product Formulation

Before Use

In-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

   

15 mg

   

30 mg

   

Patient Counseling Information

See FDA-approved patient labeling.

Patients being treated with Norditropin FlexPro 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 FlexPro 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 FlexPro or Norditropin NordiFlex, physicians should instruct patients to read the PATIENT INFORMATION and INSTRUCTIONS FOR USE leaflets provided with the Norditropin FlexPro and Norditropin NordiFlex prefilled pens.

Never Share a Norditropin Pen Between Patients

Counsel patients that they should never share a Norditropin pen with another person, even if the needle is changed. Sharing of the pen between patients may pose a risk of transmission of infection.

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

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

© 2002-2013 Novo Nordisk Health Care AG

For information contact:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, New Jersey 08536, USA

1-888-668-6444

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd, Denmark

PATIENT INFORMATION

 Norditropin® (Nor-dee-tro-pin) Cartridges

(somatropin [rDNA origin] injection)

for subcutaneous use

What is Norditropin?

Norditropin is a prescription medicine that contains human growth hormone, the same growth hormone made by the human body.

Norditropin is given by injection under the skin (subcutaneous) and is used to treat:

children who are not growing because of low or no growth hormone
children who are short (in stature) and who have Noonan syndrome or Turner syndrome
children who are short (in stature) because they were born small (small for gestational age-SGA) and have not caught-up in growth by age 2 to 4 years
adults who did not make enough growth hormone when they were children or when they became adults

Who should not use Norditropin?

Do not use Norditropin if:

you have a critical illness caused by certain types of heart or stomach surgery, trauma or breathing (respiratory) problems
you are a child with Prader-Willi syndrome who is severely obese or has breathing problems including sleep apnea  
you have cancer or other tumors
your healthcare provider tells you that you have certain types of eye problems caused by diabetes
you are a child with closed bone growth plates (epiphyses)
you are allergic to somatropin or any of the ingredients in Norditropin. See the end of this leaflet for a complete list of ingredients in Norditropin. 

What should I tell my healthcare provider before I start Norditropin?

Before you take  Norditropin, tell your healthcare provider if you:

have diabetes
had cancer or any tumor
have any other medical conditions
are pregnant or plan to become pregnant. It is not known if Norditropin will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
are breastfeeding or plan to breastfeed. It is not known if Norditropin passes into your breast milk. You and your healthcare provider should decide if you will take Norditropin while you breastfeed.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

Norditropin may affect how other medicines work, and other medicines may affect how Norditropin works.

How should I use Norditropin?

Read the detailed Instructions for Use that come with Norditropin.
Norditropin comes in 4 different dosage strengths. Your healthcare provider will prescribe the dose that is right for you.
Your healthcare provider will show you how to inject Norditropin.
Use Norditropin exactly as your healthcare provider tells you to.
Norditropin FlexPro pens and Norditropin NordiFlex pen are for use for 1 person only.
Do not share your Norditropin pen and needles with another person. You may give another person an infection or get an infection from them.

What are the possible side effects of Norditropin?

Norditropin can cause serious side effects, including:

high risk of death in people who have critical illnesses because of heart or stomach surgery, trauma or serious breathing (respiratory) problems
high risk of death in children with Prader-Willi syndrome who are severely obese or have breathing problems, including sleep apnea
return of tumor or cancerous growths
high blood sugar (hyperglycemia)
increase in pressure in the skull (intracranial hypertension). If you have headaches, eye problems, nausea or vomiting, swollen hands and feet due to fluid retention contact your healthcare provider right away.
decrease in thyroid hormone levels. Your healthcare provider will do blood tests to check your thyroid hormone levels.
hip and knee pain or a limp in children (slipped capital femoral epiphysis)
worsening of curvature of the spine (scoliosis)
middle ear infection, hearing problems or ear problems in people with Turner syndrome, redness, itching and tissue weakness in the area of skin you inject
increase in phosphorus, alkaline phosphatase and parathyroid hormone levels in your blood. Your healthcare provider will do blood tests to check this.

The most common side effects of Norditropin include:

headaches
muscle pain
joint stiffness
high blood sugar (hyperglycemia)
sugar in your urine (glucosuria)

These are not all the possible side effects of Norditropin. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How do I store Norditropin?

New or unused Norditropin FlexPro pens and Norditropin NordiFlex pen:

Keep Norditropin in a refrigerator between 36ºF to 46ºF (2ºC to 8ºC).
Do not freeze or expose Norditropin to heat.
Keep Norditropin away from direct light.
Do not use Norditropin that has been frozen or in temperatures warmer than 77ºF (25ºC).
Do not use Norditropin after the expiration date printed on the carton and the pen.

Used Norditropin FlexPro pens and Norditropin NordiFlex pen:

After the first injection of Norditropin,

either

store remaining Norditropin in the refrigerator between 36ºF to 46ºF (2ºC to 8ºC) and use within 4 weeks

or

store remaining Norditropin at room temperature no warmer than 77ºF (25ºC) and use within 3 weeks

Keep Norditropin and all medicines out of the reach of children.

General Information about the safe and effective use of Norditropin.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about Norditropin that is written for health professionals. Do not use Norditropin for a condition for which it was not prescribed. Do not give Norditropin to other people, even if they have the same symptoms that you have. It may harm them.

What are the ingredients in Norditropin?

Active ingredient: somatropin (rDNA origin)

Inactive ingredients: Histidine, Poloxamer 188, Phenol, Mannitol, HCl/NaOH (as needed) and Water for Injection

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd, Denmark

You may also report side effects to Novo Nordisk at 1-888-668-6444.

INSTRUCTIONS FOR USE

Norditropin® (Nor-dee-tro-pin) FlexPro®

(somatropin [rDNA origin] injection)

5 mg/1.5 mL Pen

Note:

Norditropin is for use under the skin only (subcutaneous).
Do not share your Norditropin Pen and needles with another person. You may give another person an infection or get an infection from them.

Norditropin® FlexPro®

Figure A

Supplies you will need for a Norditropin Injection. See Figure A.

Norditropin FlexPro Prefilled Pen
1 Novo Nordisk disposable needle. Needles are not included with the Pen.
2 alcohol swabs
flat surface like a table
a sharps disposal container. See Step 6 for information on how to dispose of used needles and syringes.

6 Steps you should follow for a Norditropin injection:

Step 1. Preparing the Norditropin FlexPro Pen

Step 2. Attaching the needle to the Norditropin FlexPro Pen

Step 3. Priming a new Pen

Step 4. Selecting the correct dose of Norditropin

Step 5. Selecting the injection site and injecting the dose of Norditropin

Step 6. What to do after the injection is completed.

Step 1. Preparing the Norditropin FlexPro Pen.

Pull off the Pen cap. See Figure B.

Figure B

Look in the growth hormone scale window. Check that the liquid medicine in the Pen is clear and colorless by tipping it upside down 1 or 2 times. If the liquid looks unclear or cloudy, do not use the Pen. See Figure C.

Figure C

Wash your hands well and dry them.
Wipe the front stopper on the needle thread with an alcohol swab. See Figure D.

Figure D

Step 2. Attaching the needle to the Norditropin FlexPro Pen.

Never place a needle on your Pen until you are ready to give an injection.
Take a new disposable needle and tear off the paper tab. See Figure E.

Figure E

Holding the Pen with one hand, firmly press the needle onto the needle thread of the Pen.
Screw the needle in a clockwise direction until the needle will not turn anymore. See Figure F.

Figure F

Pull off the outer needle cap. See Figure G.

Figure G

Pull off the inner needle cap and throw them both away. See Figure H. If you try to put the needle caps back on, you may accidentally hurt yourself with the needle.
A drop of liquid may appear at the needle tip. This is normal.

Figure H

Step 3. Priming a new Pen.

Checking the growth hormone flow in the pen (priming) is not needed for a Pen you have used before. If the Pen has already been primed, go to Step 4.
Before you use a new Pen you must first prepare it for use. Hold the Pen with one hand and turn the dose selector clockwise to select 0.025 mg. You will hear a faint click when you turn the dose selector. This is the smallest amount of medicine for a dose. See Figure I.

Figure I

Hold the Pen with the needle pointing up. Tap the top of the Pen gently a few times to let any air bubbles rise to the top. See Figure J.

Figure J

Press the dose button until the “0” in the display window lines up with the pointer and a drop of liquid appears at the needle tip. See Figure K.

Figure K

If no drop appears, repeat Step 3 again up to 6 times.
If you still do not see a drop of liquid, change the needle and repeat Step 3 again.
If a drop of liquid still does not appear after repeating Step 3 and changing the needle, call Novo Nordisk at 1-888-668-6444 for help.

Step 4. Selecting the correct dose of Norditropin.

Use the dose selector on your Norditropin FlexPro Pen to make sure you have the exact dose selected. You can select up to 2 mg per dose.
To start, check that the pointer on the Pen is set at “0”. See Figure L.

Figure L

Select the dose you need by turning the dose selector clockwise. If you go beyond your dose, turn the dose selector counterclockwise until the right number of mg lines up with the pointer.
To guide you, the dose selector click sound is different when turned clockwise (softer click) or counterclockwise (louder click). You will hear a click for every single unit dialed.
When dialing counterclockwise, be careful not to press the dose button as liquid will come out.
You can use the growth hormone scale on the side of the Pen to see approximately how much growth hormone is left in the Pen. You can also use the dose selector to see exactly how much growth hormone is left in the Pen.
If the Pen contains less than 2 mg, turn the dose selector until it stops. The number that lines up with the pointer shows how many mg is left in the Pen.
You cannot set a dose higher than the number of mg left in the Pen.
If there is not enough Norditropin left in the Pen to deliver your full dose, use a new Norditropin FlexPro Pen to inject the remaining amount of your dose or contact your healthcare provider.
Remember to subtract the dose already received. For example, if the dose is 0.7 mg and you can only set the dose selector to 0.35 mg, you should inject another 0.35 mg with a new Norditropin FlexPro Pen. See Figure L.

Important:

Never use the Pen clicks to count the number of mg you select. Only the display window and pointer will show the exact number.
Never use the growth hormone scale to measure how much liquid to inject. Only the display window and pointer will show the exact number.

Step 5. Selecting the injection site and injecting the dose of Norditropin.

Change the injection site every day.
Select the injection site and wipe the skin with an alcohol swab as your healthcare provider showed you.
Insert the needle under the skin as your healthcare provider showed you. See Figure M.

Figure M

After inserting the needle into the skin, push and hold the dose button in as far as it will go to give the dose. Inject until the “0” in the display window lines up with the pointer. As you do this, you may hear or feel a firm click. See Figure M.
If you remove your finger from the dose button before the “0” is in the display window the full dose has not been received. Leave the needle in the skin and press and hold the dose button again until the “0” lines up with the pointer.

If the injection button cannot be pushed in completely or “0” does not appear in the display window, you did not receive the full dose. Call Novo Nordisk at 1-888-668-6444 for assistance. You may need a new Pen.

After the “0” in the display window lines up with the pointer, leave the needle under the skin for at least 6 seconds to make sure that you get your full dose. Let go of the dose button while you wait.

Important:

Always press the dose button to inject the dose. Turning the dose selector will not inject the dose.
Never touch the display window when you inject, as this can block the injection.
Carefully lift the pen to remove the needle from the skin. After that, you may see a drop of liquid at the needle tip. This is normal and does not affect the dose you received. See Figure N.

Figure N

Step 6. What to do after the injection is completed.

Do not recap the needle. Recapping a needle can lead to a needle stick injury. Remove the needle from the Pen after each injection.
Carefully remove the needle from the Pen by turning the needle in a counterclockwise direction. See Figure O.

Figure O

Put the Pen cap back on.
If there is medicine left in the Pen, store the Pen as directed in the Patient Information that comes with this Pen.
If the Pen is empty, throw the Pen away as directed below. Put your used needles and Pen in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and Pens in your household trash.
If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
o
made of a heavy-duty plastic,
o
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
o
upright and stable during use,
o
leak-resistant, and
o
properly labeled to warn of hazardous waste inside the container.
When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and Pens. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.
Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

Care of your Norditropin FlexPro Pen:

You must take care of your Norditropin FlexPro Pen:

Do not drop your Pen or knock it against hard surfaces. If you drop it or think that something is wrong with it, always screw on a new disposable needle and check the growth hormone flow (priming) before you inject.
Do not try to refill your Pen. It is prefilled.
Do not try to repair your Pen or pull it apart.
Do not expose your Pen to dust, dirt or any kind of liquid.
Do not try to wash, soak or lubricate your Pen. Clean the Norditropin FlexPro Pen with a mild detergent on a moistened cloth.
Always keep your Pen and needles out of reach of others, especially children.

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

Norditropin NordiFlex 30 mg

US Patent Nos. 5,849,700; 5,849,704; 6,004,297; RE41956; RE43834 and other patents pending.

Norditropin FlexPro

US Patent Nos. 5,849,700; 5,849,704; 6,899,699; 7,686,786 and other patents pending.

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

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

© 2004-2013 Novo Nordisk Health Care AG

For further information contact:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, NJ 08536, USA

1-888-668-6444

Norditropin-us.com

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd

Denmark

Revised: 10/2013

INSTRUCTIONS FOR USE

Norditropin® (Nor-dee-tro-pin) FlexPro®

(somatropin [rDNA origin] injection)

10 mg/1.5 mL Pen

Note:

Norditropin is for use under the skin only (subcutaneous).
Do not share your Norditropin Pen and needles with another person. You may give another person an infection or get an infection from them.

Norditropin® FlexPro®

Figure A

Supplies you will need for a Norditropin Injection. See Figure A.

Norditropin FlexPro Prefilled Pen
1 Novo Nordisk disposable needle. Needles are not included with the Pen.
2 alcohol swabs
flat surface like a table
a sharps disposal container. See Step 6 for information on how to dispose of used needles and syringes.

6 Steps you should follow for a Norditropin injection:

Step 1. Preparing the Norditropin FlexPro Pen

Step 2. Attaching the needle to the Norditropin FlexPro Pen

Step 3. Priming a new Pen

Step 4. Selecting the correct dose of Norditropin

Step 5. Selecting the injection site and injecting the dose of Norditropin

Step 6. What to do after the injection is completed.

Step 1. Preparing the Norditropin FlexPro Pen.

Pull off the Pen cap. See Figure B.

Figure B

Look in the growth hormone scale window. Check that the liquid medicine in the Pen is clear and colorless by tipping it upside down 1 or 2 times. If the liquid looks unclear or cloudy, do not use the Pen. See Figure C.

Figure C

Wash your hands well and dry them.
Wipe the front stopper on the needle thread with an alcohol swab. See Figure D.

Figure D

Step 2. Attaching the needle to the Norditropin FlexPro Pen.

Never place a needle on your Pen until you are ready to give an injection.
Take a new disposable needle and tear off the paper tab. See Figure E.

Figure E

Holding the Pen with one hand, firmly press the needle onto the needle thread of the Pen.
Screw the needle in a clockwise direction until the needle will not turn anymore. See Figure F.

Figure F

Pull off the outer needle cap. See Figure G.

Figure G

Pull off the inner needle cap and throw them both away. See Figure H.

If you try to put the needle caps back on, you may accidentally hurt yourself with the needle.

A drop of liquid may appear at the needle tip. This is normal.

Figure H

Step 3. Priming a new Pen.

Checking the growth hormone flow in the pen (priming) is not needed for a Pen you have used before. If the Pen has already been primed, go to Step 4.
Before you use a new Pen you must first prepare it for use. Hold the Pen with one hand and turn the dose selector clockwise to select 0.05 mg. You will hear a faint click when you turn the dose selector. This is the smallest amount of medicine for a dose. See Figure I.

Figure I

Hold the Pen with the needle pointing up. Tap the top of the Pen gently a few times to let any air bubbles rise to the top. See Figure J.

Figure J

Press the dose button until the “0” in the display window lines up with the pointer and a drop of liquid appears at the needle tip. See Figure K.

Figure K

If no drop appears, repeat Step 3 again up to 6 times.
If you still do not see a drop of liquid, change the needle and repeat Step 3 again.
If a drop of liquid still does not appear after repeating Step 3 and changing the needle, call Novo Nordisk at 1-888-668-6444 for help.

Step 4. Selecting the correct dose of Norditropin.

Use the dose selector on your Norditropin FlexPro Pen to make sure you have the exact dose selected. You can select up to 4 mg per dose.
To start, check that the pointer on the Pen is set at “0”. See Figure L.

Figure L

Select the dose you need by turning the dose selector clockwise. If you go beyond your dose, turn the dose selector counterclockwise until the right number of mg lines up with the pointer.
To guide you, the dose selector click sound is different when turned clockwise (softer click) or counterclockwise (louder click). You will hear a click for every single unit dialed.
When dialing counterclockwise, be careful not to press the dose button as liquid will come out.
You can use the growth hormone scale on the side of the Pen to see approximately how much growth hormone is left in the Pen. You can also use the dose selector to see exactly how much growth hormone is left in the Pen.
If the Pen contains less than 4 mg, turn the dose selector until it stops. The number that lines up with the pointer shows how many mg is left in the Pen.
You cannot set a dose higher than the number of mg left in the Pen.
If there is not enough Norditropin left in the Pen to deliver your full dose, use a new Norditropin FlexPro Pen to inject the remaining amount of your dose or contact your healthcare provider.
Remember to subtract the dose already received. For example, if the dose is 1.4 mg and you can only set the dose selector to 0.7 mg, you should inject another 0.7 mg with a new Norditropin FlexPro Pen. See Figure L.

Important:

Never use the Pen clicks to count the number of mg you select. Only the display window and pointer will show the exact number.
Never use the growth hormone scale to measure how much liquid to inject. Only the display window and pointer will show the exact number.

Step 5. Selecting the injection site and injecting the dose of Norditropin.

Change the injection site every day.
Select the injection site and wipe the skin with an alcohol swab as your healthcare provider showed you.
Insert the needle under the skin as your healthcare provider showed you. See Figure M.

Figure M

After inserting the needle into the skin, push and hold the dose button in as far as it will go to give the dose. Inject until the “0” in the display window lines up with the pointer. As you do this, you may hear or feel a firm click. See Figure M.
If you remove your finger from the dose button before the “0” is in the display window the full dose has not been received. Leave the needle in the skin and press and hold the dose button again until the “0” lines up with the pointer.

If the injection button cannot be pushed in completely or “0” does not appear in the display window, you did not receive the full dose. Call Novo Nordisk at 1-888-668-6444 for assistance. You may need a new Pen.

After the “0” in the display window lines up with the pointer, leave the needle under the skin for at least 6 seconds to make sure that you get your full dose. Let go of the dose button while you wait.

Important:

Always press the dose button to inject the dose. Turning the dose selector will not inject the dose.
Never touch the display window when you inject, as this can block the injection.
Carefully lift the pen to remove the needle from the skin. After that, you may see a drop of liquid at the needle tip. This is normal and does not affect the dose you received. See Figure N.

Figure N

Step 6. What to do after the injection is completed.

Do not recap the needle. Recapping a needle can lead to a needle stick injury. Remove the needle from the Pen after each injection.
Carefully remove the needle from the Pen by turning the needle in a counterclockwise direction. See Figure O.

Figure O

Put the Pen cap back on.
If there is medicine left in the Pen, store the Pen as directed in the Patient Information that comes with this Pen.
If the Pen is empty, throw the Pen away as directed below. Put your used needles and Pen in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and Pens in your household trash.
If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
o
made of a heavy-duty plastic,
o
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
o
upright and stable during use,
o
leak-resistant, and
o
properly labeled to warn of hazardous waste inside the container.
When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and Pens. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.
Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

Care of your Norditropin FlexPro Pen:

You must take care of your Norditropin FlexPro Pen:

Do not drop your Pen or knock it against hard surfaces. If you drop it or think that something is wrong with it, always screw on a new disposable needle and check the growth hormone flow (priming) before you inject.
Do not try to refill your Pen. It is prefilled.
Do not try to repair your Pen or pull it apart.
Do not expose your Pen to dust, dirt or any kind of liquid.
Do not try to wash, soak or lubricate your Pen. Clean the Norditropin FlexPro Pen with a mild detergent on a moistened cloth.
Always keep your Pen and needles out of reach of others, especially children.

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

Norditropin NordiFlex 30 mg

US Patent Nos. 5,849,700; 5,849,704; 6,004,297; RE41956; RE43834 and other patents pending.

Norditropin FlexPro

US Patent Nos. 5,849,700; 5,849,704; 6,899,699; 7,686,786 and other patents pending.

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

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

© 2004-2013 Novo Nordisk Health Care AG

For further information contact:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, NJ 08536, USA

1-888-668-6444

Norditropin-us.com

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd

Denmark

Revised: 10/2013

INSTRUCTIONS FOR USE

Norditropin® (Nor-dee-tro-pin) FlexPro®

(somatropin [rDNA origin] injection)

15 mg/1.5 mL Pen

Note:

Norditropin is for use under the skin only (subcutaneous).
Do not share your Norditropin Pen and needles with another person. You may give another person an infection or get an infection from them.

Norditropin® FlexPro®

Figure A

Supplies you will need for a Norditropin Injection. See Figure A.

Norditropin FlexPro Prefilled Pen
1 Novo Nordisk disposable needle. Needles are not included with the Pen.
2 alcohol swabs
flat surface like a table
a sharps disposal container. See Step 6 for information on how to dispose of used needles and syringes.

6 Steps you should follow for a Norditropin injection:

Step 1. Preparing the Norditropin FlexPro Pen

Step 2. Attaching the needle to the Norditropin FlexPro Pen

Step 3. Priming a new Pen

Step 4. Selecting the correct dose of Norditropin

Step 5. Selecting the injection site and injecting the dose of Norditropin

Step 6. What to do after the injection is completed.

Step 1. Preparing the Norditropin FlexPro Pen.

Pull off the Pen cap. See Figure B.

Figure B

Look in the growth hormone scale window. Check that the liquid medicine in the Pen is clear and colorless by tipping it upside down 1 or 2 times. If the liquid looks unclear or cloudy, do not use the Pen. See Figure C.

Figure C

Wash your hands well and dry them.
Wipe the front stopper on the needle thread with an alcohol swab. See Figure D.

Figure D

Step 2. Attaching the needle to the Norditropin FlexPro Pen.

Never place a needle on your Pen until you are ready to give an injection.
Take a new disposable needle and tear off the paper tab. See Figure E.

Figure E

Holding the Pen with one hand, firmly press the needle onto the needle thread of the Pen.
Screw the needle in a clockwise direction until the needle will not turn anymore. See Figure F.

Figure F

Pull off the outer needle cap. See Figure G.

Figure G

Pull off the inner needle cap and throw them both away. See Figure H.
If you try to put the needle caps back on, you may accidentally hurt yourself with the needle.
A drop of liquid may appear at the needle tip. This is normal.

Figure H

Step 3. Priming a new Pen.

Checking the growth hormone flow in the pen (priming) is not needed for a Pen you have used before. If the Pen has already been primed, go to Step 4.
Before you use a new Pen you must first prepare it for use. Hold the Pen with one hand and turn the dose selector clockwise to select 0.1 mg. You will hear a faint click when you turn the dose selector. This is the smallest amount of medicine for a dose. See Figure I.

Figure I

Hold the Pen with the needle pointing up. Tap the top of the Pen gently a few times to let any air bubbles rise to the top. See Figure J.

Figure J

Press the dose button until the “0” in the display window lines up with the pointer and a drop of liquid appears at the needle tip. See Figure K.

Figure K

If no drop appears, repeat Step 3 again up to 6 times.
If you still do not see a drop of liquid, change the needle and repeat Step 3 again.
If a drop of liquid still does not appear after repeating Step 3 and changing the needle, call Novo Nordisk at 1-888-668-6444 for help.

Step 4. Selecting the correct dose of Norditropin.

Use the dose selector on your Norditropin FlexPro Pen to make sure you have the exact dose selected. You can select up to 8 mg per dose.
To start, check that the pointer on the Pen is set at “0”. See Figure L.

Figure L

Select the dose you need by turning the dose selector clockwise. If you go beyond your dose, turn the dose selector counterclockwise until the right number of mg lines up with the pointer.
To guide you, the dose selector click sound is different when turned clockwise (softer click) or counterclockwise (louder click). You will hear a click for every single unit dialed.
When dialing counterclockwise, be careful not to press the dose button as liquid will come out.
You can use the growth hormone scale on the side of the Pen to see approximately how much growth hormone is left in the Pen. You can also use the dose selector to see exactly how much growth hormone is left in the Pen.
If the Pen contains less than 8 mg, turn the dose selector until it stops. The number that lines up with the pointer shows how many mg is left in the Pen.
You cannot set a dose higher than the number of mg left in the Pen.
If there is not enough Norditropin left in the Pen to deliver your full dose, use a new Norditropin FlexPro Pen to inject the remaining amount of your dose or contact your healthcare provider.
Remember to subtract the dose already received. For example, if the dose is 0.6 mg and you can only set the dose selector to 0.3 mg, you should inject another 0.3 mg with a new Norditropin FlexPro Pen. See Figure L.

Important:

Never use the Pen clicks to count the number of mg you select. Only the display window and pointer will show the exact number.
Never use the growth hormone scale to measure how much liquid to inject. Only the display window and pointer will show the exact number.

Step 5. Selecting the injection site and injecting the dose of Norditropin.

Change the injection site every day.
Select the injection site and wipe the skin with an alcohol swab as your healthcare provider showed you.
Insert the needle under the skin as your healthcare provider showed you. See Figure M.

Figure M

After inserting the needle into the skin, push and hold the dose button in as far as it will go to give the dose. Inject until the “0” in the display window lines up with the pointer. As you do this, you may hear or feel a firm click. See Figure M.
If you remove your finger from the dose button before the “0” is in the display window the full dose has not been received. Leave the needle in the skin and press and hold the dose button again until the “0” lines up with the pointer.

If the injection button cannot be pushed in completely or “0” does not appear in the display window, you did not receive the full dose. Call Novo Nordisk at 1-888-668-6444 for assistance. You may need a new Pen.

After the “0” in the display window lines up with the pointer, leave the needle under the skin for at least 6 seconds to make sure that you get your full dose. Let go of the dose button while you wait.

Important:

Always press the dose button to inject the dose. Turning the dose selector will not inject the dose.
Never touch the display window when you inject, as this can block the injection.
Carefully lift the pen to remove the needle from the skin. After that, you may see a drop of liquid at the needle tip. This is normal and does not affect the dose you received. See Figure N.

Figure N

Step 6. What to do after the injection is completed.

Do not recap the needle. Recapping a needle can lead to a needle stick injury. Remove the needle from the Pen after each injection.
Carefully remove the needle from the Pen by turning the needle in a counterclockwise direction. See Figure O.

Figure O

Put the Pen cap back on.
If there is medicine left in the Pen, store the Pen as directed in the Patient Information that comes with this Pen.
If the Pen is empty, throw the Pen away as directed below. Put your used needles and Pen in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and Pens in your household trash.
If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
o
made of a heavy-duty plastic,
o
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
o
upright and stable during use,
o
leak-resistant, and
o
properly labeled to warn of hazardous waste inside the container.
When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and Pens. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.
Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

Care of your Norditropin FlexPro Pen:

You must take care of your Norditropin FlexPro Pen:

Do not drop your Pen or knock it against hard surfaces. If you drop it or think that something is wrong with it, always screw on a new disposable needle and check the growth hormone flow (priming) before you inject.
Do not try to refill your Pen. It is prefilled.
Do not try to repair your Pen or pull it apart.
Do not expose your Pen to dust, dirt or any kind of liquid.
Do not try to wash, soak or lubricate your Pen. Clean the Norditropin FlexPro Pen with a mild detergent on a moistened cloth.
Always keep your Pen and needles out of reach of others, especially children.

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

Norditropin NordiFlex 30 mg

US Patent Nos. 5,849,700; 5,849,704; 6,004,297; RE41956; RE43834 and other patents pending.

Norditropin FlexPro

US Patent Nos. 5,849,700; 5,849,704; 6,899,699; 7,686,786 and other patents pending.

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

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

© 2004-2013 Novo Nordisk Health Care AG

For further information contact:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, NJ 08536, USA

1-888-668-6444

Norditropin-us.com

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd

Denmark

Revised: 10/2013

INSTRUCTIONS FOR USE

Norditropin® (Nor-dee-tro-pin) NordiFlex®

(somatropin [rDNA origin] injection)

30 mg/3 mL Pen

Note:

Norditropin is for use under the skin only (subcutaneous).
Do not share your Norditropin Pen and needles with another person. You may give another person an infection or get an infection from them.

Norditropin® NordiFlex®

Figure A

Supplies you will need for a Norditropin Injection. See Figure A.

Norditropin NordiFlex Prefilled Pen
1 Novo Nordisk disposable needle. Needles are not included with the Pen.
2 alcohol swabs
flat surface like a table
a sharps disposal container. See Step 6 for information on how to dispose of used needles and syringes.

6 Steps you should follow for a Norditropin injection:

Step 1. Preparing the Norditropin NordiFlex Pen

Step 2. Attaching the needle to the Norditropin NordiFlex Pen

Step 3. Priming a new Pen

Step 4. Selecting the correct dose of Norditropin

Step 5. Selecting the injection site and injecting the dose of Norditropin

Step 6. What to do after the injection is completed

Step 1. Preparing the Norditropin NordiFlex Pen.

Pull off the Pen cap. See Figure B.

Figure B

Look in the residual scale window. Check that the liquid medicine in the Pen is clear and colorless by tipping it upside down 1 or 2 times. If the liquid looks unclear or cloudy, do not use the Pen. See Figure C.

Figure C

Wash your hands well and dry them.
Wipe the front stopper on the needle thread with an alcohol swab. See Figure D.

Figure D

Step 2. Attaching the needle to the Norditropin NordiFlex Pen.

Never place a needle on your Pen until you are ready to give an injection.
Take a new disposable needle and tear off the protective tab. See Figure E.

Figure E

Holding the Pen with one hand, firmly press the needle onto the needle thread of the Pen.
Screw the needle in a clockwise direction until the needle will not turn anymore. See Figure F.

Figure F

Pull off the outer needle cap. See Figure G.

Figure G

Pull off the inner needle cap and throw them both away. See Figure H.

If you try to put the needle caps back on, you may accidentally hurt yourself with the needle.

A drop of liquid may appear at the needle tip. This is normal.

Figure H

Step 3. Priming a new Pen.

Checking the growth hormone flow in the pen (priming) is not needed for a Pen you have used before. If the Pen has already been primed, go to Step 4.
Before you use a new Pen you must first prepare it for use. Hold the Pen with one hand and turn the dosage selector clockwise to select 0.1 mg. You will hear a faint click when you turn the dosage selector. This is the smallest amount of medicine for a dose. See Figure I.

Figure I

Hold the Pen with the needle pointing up. Tap the top of the Pen gently a few times to let any air bubbles rise to the top. See Figure J.

Figure J

Press the push button until the “0.0” in the residual scale window lines up with the pointer and a drop of liquid appears at the needle tip. See Figure K.

Figure K

If no drop appears, repeat Step 3 again up to 6 times.
If you still do not see a drop of liquid, change the needle and repeat Step 3 again.
If a drop of liquid still does not appear after repeating Step 3 and changing the needle, call Novo Nordisk at 1-888-668-6444 for help.

Step 4. Selecting the correct dose of Norditropin.

Use the dosage selector on your Norditropin NordiFlex Pen to make sure you have the exact dose selected. You can select up to 6 mg per dose.
To start, check that the pointer on the Pen is set at “0.0”. See Figure L.

Figure L

Select the dose you need by turning the dosage selector clockwise. If you go beyond your dose, turn the dosage selector counterclockwise until the right number of mg lines up with the pointer.
Use the dosage indicator, not the clicking sound, as a guide for selecting the dose.
When dialing counterclockwise, be careful not to press the push button as liquid will come out.
You can use the residual scale window on the side of the Pen to see approximately how much growth hormone is left in the Pen. You can also use the dosage selector to see exactly how much growth hormone is left in the Pen.
If the Pen contains less than 6 mg, turn the dosage selector until it stops. The number that lines up with the pointer shows how many mg is left in the Pen.
You cannot set a dose higher than the number of mg left in the Pen.
If there is not enough Norditropin left in the Pen to deliver your full dose, use a new Norditropin NordiFlex Pen to inject the remaining amount of your dose or contact your healthcare provider.
Remember to subtract the dose already received. For example, if the dose is 0.6 mg and you can only set the dosage selector to 0.3 mg, you should inject another 0.3 mg with a new Norditropin NordiFlex Pen. See Figure L.

Important:

Never use the Pen clicks to count the number of mg you select. Only the dosage indicator window and pointer will show the exact number.
Never use the residual scale window to measure how much liquid to inject. Only the dosage indicator window and pointer will show the exact number.

Step 5. Selecting the injection site and injecting the dose of Norditropin.

Change the injection site every day.
Select the injection site and wipe the skin with an alcohol swab as your healthcare provider showed you.
Insert the needle under the skin as your healthcare provider showed you. See Figure M.

Figure M

After inserting the needle into the skin, press the push button in as far as it will go to give the dose until the “0.0” in the dosage indicator window lines up with the pointer. As you do this, you may hear a click. See Figure M.
If you remove your finger from the push button before the “0.0” is in the dosage indicator window the full dose has not been received. Leave the needle in the skin and press the push button again until the “0.0” lines up with the pointer.

If the push button cannot be pushed in completely or “0.0” does not appear in the dosage indicator window, you did not receive the full dose. Call Novo Nordisk at 1-888-668-6444 for assistance. You may need a new Pen.

After the “0.0” in the dosage indicator window lines up with the pointer, leave the needle under the skin for at least 6 seconds with your thumb on the push button to make sure that you get your full dose. Keep the push button fully pushed in until the needle has been removed from the skin.

Important:

Always press the push button to inject the dose. Turning the dosage selector will not inject the dose.
Never touch the dosage indicator window when you inject, as this can block the injection.
Carefully lift the pen to remove the needle from the skin. After that, you may see a drop of liquid at the needle tip. This is normal and does not affect the dose you received. See Figure N.

Figure N

Step 6. What to do after the injection is completed.

Do not recap the needle. Recapping a needle can lead to a needle stick injury. Remove the needle from the Pen after each injection.
Carefully remove the needle from the Pen by turning the needle in a counterclockwise direction. See Figure O.

Figure O

Put the Pen cap back on.
If there is medicine left in the Pen, store the Pen as directed in the Patient Information that comes with this Pen.
If the Pen is empty, throw the Pen away as directed below. Put your used needles and Pen in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and Pens in your household trash.
If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
o
made of a heavy-duty plastic,
o
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,
o
upright and stable during use,
o
leak-resistant, and
o
properly labeled to warn of hazardous waste inside the container.
When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and Pens. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.
Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

Care of your Norditropin NordiFlex Pen:

You must take care of your Norditropin NordiFlex Pen:

Do not drop your Pen or knock it against hard surfaces. If you drop it or think that something is wrong with it, always screw on a new disposable needle and check the growth hormone flow (priming) before you inject.
Do not try to refill your Pen. It is prefilled.
Do not try to repair your Pen or pull it apart.
Do not expose your Pen to dust, dirt or any kind of liquid.
Do not try to wash, soak or lubricate your Pen. Clean the Norditropin NordiFlex Pen with a mild detergent on a moistened cloth.
Always keep your Pen and needles out of reach of others, especially children.

This Patient Information and Instructions for Use has been approved by the U.S. Food and Drug Administration.

Norditropin NordiFlex 30 mg

US Patent Nos. 5,849,700; 5,849,704; 6,004,297; RE41956; RE43834 and other patents pending.

Norditropin FlexPro

US Patent Nos. 5,849,700; 5,849,704; 6,899,699; 7,686,786 and other patents pending.

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

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

© 2004-2013 Novo Nordisk Health Care AG

For further information contact:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, NJ 08536, USA

1-888-668-6444

Norditropin-us.com

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd

Denmark

Revised: 10/2013

PRINCIPAL DISPLAY PANEL - Norditropin FLEXPRO 5 MG/1.5 ML

Norditropin®  FlexPro®

Somatropin (rDNA origin) injection

5 mg/1.5 mL Prefilled Pen

1 x 1.5 mL prefilled disposable pen

Each 1.5 mL contains 5 mg somatropin

CONTAINS ONE

Norditropin® FlexPro® 5 mg/1.5 mL

Single patient use only

Rx only

NDC 0169-7704-21

List: 770421

PRINCIPAL DISPLAY PANEL - Norditropin FLEXPRO 10 MG/1.5 ML

Norditropin®  FlexPro®

Somatropin (rDNA origin) injection

10 mg/1.5 mL Prefilled Pen

1 x 1.5 mL prefilled disposable pen

Each 1.5 mL contains 10 mg somatropin

CONTAINS ONE

Norditropin® FlexPro® 10 mg/1.5 mL

Single patient use only

Rx only

NDC 0169-7705-21

List: 770521

PRINCIPAL DISPLAY PANEL - Norditropin FLEXPRO 15 MG/1.5 ML

Norditropin®  FlexPro®

Somatropin (rDNA origin) injection

15 mg/1.5 mL Prefilled Pen

1 x 1.5 mL prefilled disposable pen

Each 1.5 mL contains 15 mg somatropin

CONTAINS ONE

Norditropin® FlexPro® 15 mg/1.5 mL

Single patient use only

Rx only

NDC 0169-7708-21

List: 770821

PRINCIPAL DISPLAY PANEL - Norditropin NORDIFLEX 30 MG/3 ML

Norditropin  NordiFlex®

Somatropin (rDNA origin) injection

30 mg/3 mL Prefilled Pen

1 x 3 mL prefilled disposable pen

Each 3 mL contains 30 mg somatropin

CONTAINS ONE

Norditropin NORDIFLEX® 30 mg/3 mL

Single patient use only

Rx only

NDC 0169-7703-11

List: 770311

Store non-injected/unused pen refrigerated (2ºC-8ºC/36ºF-46ºF). Do not store with needles. After initial injection, EITHER keep pen refrigerated for 4 weeks OR store not above 25ºC (77ºF) for 3 weeks. Do not freeze. Discard unused portion. Avoid direct light. Keep out of the reach and sight of children. For subcutaneous administration only. Please read the enclosed leaflet before use.

US Patent Nos. 5,849,704; 6,004,297; RE 41,956; RE 43,834 and other patents pending.

Norditropin 
somatropin injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0169-7704
Route of Administration SUBCUTANEOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
SOMATROPIN (SOMATROPIN) SOMATROPIN 5 mg  in 1.5 mL
Inactive Ingredients
Ingredient Name Strength
HISTIDINE 1 mg  in 1.5 mL
HYDROCHLORIC ACID  
MANNITOL 60 mg  in 1.5 mL
PHENOL 4.5 mg  in 1.5 mL
POLOXAMER 188 4.5 mg  in 1.5 mL
SODIUM HYDROXIDE  
WATER  
Packaging
# Item Code Package Description
1 NDC:0169-7704-21 1 SYRINGE, PLASTIC in 1 CARTON
1 1.5 mL in 1 SYRINGE, PLASTIC
2 NDC:0169-7704-92 1 SYRINGE, PLASTIC in 1 CARTON
2 1.5 mL in 1 SYRINGE, PLASTIC
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021148 01/03/2005
Norditropin 
somatropin injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0169-7705
Route of Administration SUBCUTANEOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
SOMATROPIN (SOMATROPIN) SOMATROPIN 10 mg  in 1.5 mL
Inactive Ingredients
Ingredient Name Strength
HISTIDINE 1 mg  in 1.5 mL
HYDROCHLORIC ACID  
MANNITOL 60 mg  in 1.5 mL
PHENOL 4.5 mg  in 1.5 mL
POLOXAMER 188 4.5 mg  in 1.5 mL
SODIUM HYDROXIDE  
WATER  
Packaging
# Item Code Package Description
1 NDC:0169-7705-21 1 SYRINGE, PLASTIC in 1 CARTON
1 1.5 mL in 1 SYRINGE, PLASTIC
2 NDC:0169-7705-92 1 SYRINGE, PLASTIC in 1 CARTON
2 1.5 mL in 1 SYRINGE, PLASTIC
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021148 01/02/2006
Norditropin 
somatropin injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0169-7708
Route of Administration SUBCUTANEOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
SOMATROPIN (SOMATROPIN) SOMATROPIN 15 mg  in 1.5 mL
Inactive Ingredients
Ingredient Name Strength
HISTIDINE 1.7 mg  in 1.5 mL
HYDROCHLORIC ACID  
MANNITOL 58 mg  in 1.5 mL
PHENOL 4.5 mg  in 1.5 mL
POLOXAMER 188 4.5 mg  in 1.5 mL
SODIUM HYDROXIDE  
WATER  
Packaging
# Item Code Package Description
1 NDC:0169-7708-21 1 SYRINGE, PLASTIC in 1 CARTON
1 1.5 mL in 1 SYRINGE, PLASTIC
2 NDC:0169-7708-92 1 SYRINGE, PLASTIC in 1 CARTON
2 1.5 mL in 1 SYRINGE, PLASTIC
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021148 01/03/2005
Norditropin 
somatropin injection, solution
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0169-7703
Route of Administration SUBCUTANEOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
SOMATROPIN (SOMATROPIN) SOMATROPIN 30 mg  in 3 mL
Inactive Ingredients
Ingredient Name Strength
HISTIDINE 3.3 mg  in 3 mL
POLOXAMER 188 9 mg  in 3 mL
PHENOL 9 mg  in 3 mL
MANNITOL 117 mg  in 3 mL
WATER  
SODIUM HYDROXIDE  
HYDROCHLORIC ACID  
Packaging
# Item Code Package Description
1 NDC:0169-7703-11 1 SYRINGE in 1 CARTON
1 3 mL in 1 SYRINGE
2 NDC:0169-7703-91 1 SYRINGE in 1 CARTON
2 3 mL in 1 SYRINGE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021148 03/30/2009
Labeler - Novo Nordisk (622920320)
Establishment
Name Address ID/FEI Operations
Novo Nordisk A/S 306711800 MANUFACTURE(0169-7704, 0169-7705, 0169-7708, 0169-7703)
Revised: 10/2013
 
Novo Nordisk
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