Norditropin

Name: Norditropin

Norditropin Overview

Norditropin is a brand name medication included in a group of medications called Somatropin and somatropin agonists. For more information about Norditropin see its generic Somatropin

Manufacturer

  • DispenseXpress, Inc.

  • Novo Nordisk, Inc.

Precautions While Using Norditropin

If you will be taking this medicine for a long time, it is very important that your doctor check you at regular visits for any problems or unwanted effects that may be caused by this medicine.

This medicine may cause a serious allergic reaction that requires immediate medical attention. Tell your doctor right away if you have a rash, itching, swelling of the face, tongue, or throat, trouble breathing, or chest pain after you receive the medicine.

This medicine may cause a dislocation in the hip bone, especially in patients with growth hormone deficiency or Turner syndrome. Check with your doctor right away if you or your child has a limp or pain in the hip or knee.

This medicine may affect blood sugar levels. Check with your doctor if you notice a change in the results of your blood or urine sugar tests or if you have any questions.

This medicine may cause an increased pressure in the head. Check with your doctor immediately if headache, nausea, vomiting, blurred vision, or any other change in vision occurs during treatment. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

This medicine may cause fluid retention (extra water in the body). Tell your doctor if you have burning, numbness, pain, or tingling in all fingers except the smallest finger, swelling of the hands and feet, or pain, swelling, or stiffness of the muscles. Your doctor may adjust your dose to reduce these side effects.

Pancreatitis has occurred rarely in some patients receiving somatropin. Tell your doctor right away if you have sudden and severe stomach pain, chills, constipation, nausea, vomiting, fever, or lightheadedness.

Using this medicine may increase your risk of getting cancer. Talk to your doctor if you have concerns about this risk.

Before you have any medical tests, tell the medical doctor in charge that you are using this certain brand of somatropin (Humatrope®). The results of some tests may be affected by this medicine.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

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. [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 [see Warnings and Precautions (5.3)].

• Hypersensitivity

Norditropin is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropin products [see Warnings and Precautions (5.6)].

• 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.

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)]. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (42% vs. 19%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo. The safety of continuing 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)]. Norditropin is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.

Neoplasms

In childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent GHD and were treated with somatropin, an increased risk of a second neoplasm has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor recurrence [see Contraindications (4)]. Monitor all patients with a history of GHD secondary to an intracranial neoplasm routinely while on somatropin therapy for progression or recurrence of the tumor.

Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, practitioners should thoroughly consider the risks and benefits of starting somatropin in these patients. If treatment with somatropin is initiated, these patients should be carefully monitored for development of neoplasms.

Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes, 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.

Hypersensitivity

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products. Patients and caregivers should be informed that such reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs [see Contraindications (4)].

Fluid Retention

Fluid retention during somatropin replacement therapy in adults may frequently occur. Clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias) are usually transient and dose dependent.

Hypoadrenalism

Patients receiving somatropin therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of somatropin treatment [see Section 7.1, 11-β Hydroxysteroid Dehydrogenase Type 1].

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.

Lipoatrophy

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)].

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.

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)].

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.

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) 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.

PRINCIPAL DISPLAY PANEL - Norditropin FLEXPRO 5 MG/1.5 ML

Norditropin®  FlexPro®

(somatropin) injection

5 mg/1.5 mL Prefilled Pen

1 x 1.5 mL prefilled 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

For the Consumer

Applies to somatropin: powder for solution

Other dosage forms:

  • powder for solution, solution

Along with its needed effects, somatropin (the active ingredient contained in Norditropin) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking somatropin:

More common
  • Abnormal or decreased touch sensation
  • bleeding after defecation
  • bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site
  • bloating or swelling of the face, arms, hands, lower legs, or feet
  • blood in the urine
  • burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
  • changes in skin color
  • cold flu-like symptoms
  • cold hands and feet
  • confusion
  • constipation
  • cough or hoarseness
  • darkened urine
  • decreased urination
  • diarrhea
  • difficult urination
  • dizziness
  • dry mouth
  • fainting or loss of consciousness
  • fast heartbeat
  • fast or irregular breathing
  • feeling unusually cold
  • fever or chills
  • full or bloated feeling
  • general feeling of discomfort or illness
  • headache
  • increase in heart rate
  • itching or skin rash
  • joint pain
  • light-colored stools
  • lightheadedness
  • loss of appetite
  • lower back or side pain
  • muscle aching or cramping
  • muscle pain or stiffness
  • nausea
  • pain
  • pain, redness, or swelling in the arm or leg
  • pains in the stomach, side, or abdomen, possibly radiating to the back
  • pressure in the stomach
  • rapid, shallow breathing
  • rapid weight gain
  • rectal bleeding
  • runny nose
  • shivering
  • sneezing
  • sore mouth or tongue
  • sore throat
  • stomach bloating, burning, cramping, or pain
  • sudden decrease in the amount of urine
  • sweating
  • swelling of the abdominal or stomach area
  • swelling of the eyes or eyelids
  • swelling or puffiness of the face
  • swollen joints
  • thirst
  • tightness in the chest
  • tingling of the hands or feet
  • trouble breathing
  • trouble sleeping
  • uncomfortable swelling around the anus
  • unpleasant breath odor
  • unusual tiredness or weakness
  • unusual weight gain or loss
  • vomiting
  • vomiting of blood
  • white patches in the mouth, tongue, or throat
  • wrinkled skin
  • yellow eyes or skin
Less common
  • Bone or skeletal pain
  • burning, numbness, pain, or tingling in all fingers except smallest finger
  • chest pain
  • depressed mood
  • dry skin and hair
  • feeling cold
  • hair loss
  • hoarseness or husky voice
  • slowed heartbeat
  • swelling of the ankles

Get emergency help immediately if any of the following symptoms of overdose occur while taking somatropin:

Symptoms of overdose
  • Anxiety
  • blurred vision
  • changes in vision
  • cold sweats
  • coma
  • cool, pale skin
  • decrease in the amount of urine
  • depression
  • excessive sweating
  • extreme weakness
  • flushed, dry skin
  • frequent urination
  • fruit-like breath odor
  • increase in hands and feet size
  • increased hunger
  • increased thirst
  • increased urination
  • increased volume of pale, diluted urine
  • nightmares
  • noisy, rattling breathing
  • pain in the arms or legs
  • seizures
  • shakiness
  • slurred speech
  • stop in menstruation
  • swelling of the fingers or hands
  • troubled breathing at rest

Some side effects of somatropin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Body aches or pain
  • breast pain
  • change in the color, amount, or odor of vaginal discharge
  • congestion
  • discoloration of the fingernails or toenails
  • dryness or soreness of the throat
  • excess air or gas in the stomach or intestines
  • frequent urge to defecate
  • increased sweating
  • passing gas
  • sneezing
  • straining while passing stool
  • stuffy nose
  • tender, swollen glands in neck
  • trouble with swallowing
  • voice changes
Less common
  • Discouragement
  • feeling sad or empty
  • irritability
  • lack of appetite
  • loss of interest or pleasure
  • tiredness
  • trouble concentrating

(web3)