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Norditropin (somatropin) injection, for subcutaneous use

Norditropin® is a clear and colorless solution administered as a subcutaneous injection, used in
growth hormone-related disorders.

Short description

Norditropin (somatropin) is a recombinant human growth hormone, used for the replacement of endogenous growth hormone in children and adults with growth hormone deficiency. Endogenous growth hormone or somatotropin is naturally produced by the pituitary gland and is necessary to stimulate growth in children. Norditropin, a man-made version of growth hormone may be used in adults or children who have certain conditions that prevent normal growth. These conditions include growth hormone deficiency (inability to produce enough growth hormone), chronic kidney disease, idiopathic short stature (unexplained shortness), Noonan syndrome, Turner syndrome, Prader-Willi syndrome (PWS), short stature homeobox-containing gene (SHOX) deficiency, and short stature born small for gestational age (SGA) with no catch-up growth by age 2 to 4 years of age. Norditropin injections are administered subcutaneously via Norditropin FlexPro pens.

Figure 1: Norditropin FlexPro pens, different doses. (Source: https://www.norditropin.com)

 

Summary about Norditropin

Growth hormone (GH) or somatotropin is a peptide produced by the somatotroph cells in the anterior pituitary gland. It binds to a transmembrane receptor and leads to the production of insulin-like growth factor I (IGF-I), IGF binding protein 3 (IGFBP-3), and the acid-labile subunit (ALS). This 3-peptide compound is brought to target cells, binds to IGF-I receptor, and stimulates metabolic functions. In infancy, childhood and adolescence GH is essential for normal linear growth.
Norditropin (somatropin) is a man-made version of GH, used for the replacement of endogenous GH in children and adults with growth hormone deficiency. The goal of GH therapy in pediatric patients is to sustain normal linear growth and achieve a normal adult height. In addition to promoting linear growth, GH has favorable effects on muscle accretion and bone mineral density. GH stimulates osteoblast and osteoclast differentiation and promotes the accretion of bone mass. GH stimulates the proliferation of adipose precursor cells, restricts their differentiation into mature adipocytes, and limits deposition of fat in the abdominal visceral area. Consequently, children with growth hormone deficiency (GHD) demonstrate reduced linear growth, reduced lean body mass, increased body fat with disproportionate deposition of visceral and truncal fat, subnormal bone mineral density and lipid abnormalities. Untreated patients with adult onset GHD demonstrate all the pediatric consequences with the exception of a linear growth effect. Untreated adults with GHD have also decreased muscle strength, impaired cardiac function, and decreased quality of life.
Norditropin is approved by the FDA for the treatment of:

  • Children with growth failure due to growth hormone deficiency (GHD),
  • Short stature associated with Noonan syndrome,
  • Short stature associated with Turner syndrome,
  • Short stature born small for gestational age (SGA) with no catch-up growth by age 2 to 4 years and
  • Treatment of adults with either adult onset or childhood onset GHD.

Norditropin is administered subcutaneously and is available preloaded in the Norditropin FlexPro pens in following doses:

  • 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 FlexPro pen

The safety of GH treatment, and the safety profile of Norditropin, have been established in many clinical studies. In one of them, pediatric patients were followed for up to 13 years and the safety profile was evaluated. Norditropin should not be used in following cases:

  • Critical illness caused by certain types of heart or stomach surgery, trauma or breathing (respiratory) problems
  • In children with Prader-Willi syndrome who are severely obese or have breathing problems including sleep apnea
  • Cancer or other tumors
  • Allergy to somatropin or any of the ingredients in Norditropin
  • Diabetic retinopathy
  • In children with closed bone growth plates (epiphyses)

The most common side effects of Norditropin include injection site reactions, rashes, and headaches.

 

 

Norditropin (somatropin)

Active Ingredient

Somatotropin

Administration Route

Subcutaneous

Alcohol Warning

No data about interaction

Available Strength

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

Breastfeeding Warning

Caution is recommended.
Excreted into human milk: UnknownFollowing subcutaneous administration of radiolabelled medication in animal studies, radioactivity was transferred to milk reaching four  times the concentration found in maternal plasma. However, absorption of the intact protein in the gastrointestinal tract of the infant is considered extremely unlikely.

Clinical Pharmacology

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
Absorption
Somatropin has been studied following subcutaneous and intravenous administration in adult healthy subjects and GHD patients. A single dose administration of 4 mg NORDITROPIN in healthy subjects (n=26) with suppressed endogenous growth hormone resulted in a mean (SD) Cmax of 34.9 (10.4) ng/mL after approximately 3.0 hours. After a 180-min IV infusion of NORDITROPIN (33 ng/kg/min) administered to GHD patients (n=9), a mean (SD) hGH steady state serum level of approximately 23.1 (15.0) ng/mL was reached at 150 min.
After a SC dose of 0.024 mg/kg or 3 IU/m2 given in the thigh to adult GHD patients (n=18), mean (SD) Cmax values of 13.8 (5.8) and 17.1 (10.0) ng/mL were observed for the 4 and 8 mg NORDITROPINvials, respectively, at approximately 4 to 5 hr. post dose. The absolute bioavailability for NORDITROPINafter the SC route of administration is currently not known.
Distribution
The mean (SD) apparent volume of distribution of somatropin after single dose subcutaneous administration of 4 mg NORDITROPINin healthy subjects is 43.9 (14.9) L.
Elimination
Metabolism. Extensive metabolism studies have not been conducted. The metabolic fate of somatropin involves classical protein catabolism in both the liver and kidneys.
Excretion. The mean apparent terminal T1/2 values in healthy adult subjects (n=26) was 2.0 (0.5) hours. In GHD patients receiving 180-min IV infusion of NORDITROPIN(33 ng/kg/min), a mean clearance rate of approximately 2.3 (1.8) mL/min/kg or 139 (105) mL/min for hGH was observed. Following infusion, serum hGH levels had a biexponential decay with a terminal elimination half-life (T1/2) of approximately 21.1 (5.1) min. The mean apparent terminal T1/2 values in GHD patients receiving a SC dose of 0.024 mg/kg or 3 IU/m2 was estimated to be approximately 7 to 10 hr. The longer half-life observed after subcutaneous administration is due to slow absorption from the injection site. Urinary excretion of intact somatropin has not been measured.
Geriatric patients. The pharmacokinetics of somatropin have not been studied in patients greater than 65 years of age.
Pediatric patients. The pharmacokinetics of somatropin in pediatric patients are similar to those of adults.
Male and Female Patients. No gender-specific pharmacokinetic studies have been performed with somatropin. The available literature indicates that the pharmacokinetics of somatropin are similar in men and women.
Patients with Renal or Hepatic Impairment. No studies have been performed with somatropin.

Cost

Approximate Retail Price
from  http://www.goodrx.com/Norditropin
solution for injection:
  • 5 mg/1.5 mL (1 flexpro, 1.5 mL): $1,766.70
  • 10 mg/1.5 mL (1 flexpro, 1.5 mL): $2,478.38
  • 15 mg/1.5 mL (1 flexpro, 1.5 mL): $2,978.06

solution for injection:

  • 30 mg/3 mL (1 flexpro, 3 mL): $4,250.08

Dosage Form

Injection

Dose Schedule

Pediatric GHD: 0.024 to 0.034 mg/kg/day, 6 to 7 times a week
Noonan Syndrome: Up to 0.066 mg/kg/day
Turner Syndrome: Up to 0.067 mg/kg/day
SGA: Up to 0.067 mg/kg/day
Adult GHD: 0.004 mg/kg/day to be increased as tolerated to not more than 0.016 mg/kg/day after approximately 6 weeks, or a starting dose of approximately 0.2 mg/day (range, 0.15 to 0.30 mg/day) increased gradually every 1 to 2 months by increments of approximately 0.1 to 0.2 mg/day.

Drug Class

H01AC – Somatropin and somatropin agonists

Drug Unit

mg/ml

Food Warning

No known interactions

Included In
Health Insurance Plan

Norditropin sometimes is covered by health insurance if considered medically necessary, but some patients have had coverage denied. The Magic Foundation offers help making the case for coverage or appealing a denial, and outlines patients’ experiences getting approval.

Interacting Drug

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

Is Available Generically

No. There is currently no therapeutically equivalent version of Norditropin FlexPro available.

Is Proprietary

Yes

Label Details

https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021148s049lbl.pdf

Legal Status

Legal.
Is not subject to the Controlled Substances Act.

Manufacturer

Novo Nordisk

Maximum Intake

0.016 mg/kg daily

Mechanism of Action

Somatropin binds to the human growth hormone receptor (GHR). Upon binding, soatropin causes dimerization of GHR, activation of the GHR-associated JAK2 tyrosine kinase, and tyrosyl phosphorylation of both JAK2 and GHR. These events recruit and/or activate a variety of signaling molecules, including MAP kinases, insulin receptor substrates, phosphatidylinositol 3′ phosphate kinase, diacylglycerol, protein kinase C, intracellular calcium, and Stat transcription factors. These signaling molecules contribute to the GH-induced changes in enzymatic activity, transport function, and gene expression that ultimately culminate in changes in growth and metabolism.

Non Proprietary Name

Somatropin

Overdosage

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

Pregnancy Category

 
AU TGA pregnancy category B2: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage.
US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Pregnancy Warning

Use is not recommended unless clearly needed.
Animal studies did not show any teratogenicity or adverse effects on gestation, morphogenesis, parturition, lactation, postnatal development, or reproductive capacity of the offspring; a slight increase in fetal death and increased body weight of pups, and reduced pregnancy rate, increased litter size, irregular estrus cycles, and decreased sperm motility in the parents were seen. There are no controlled data in human pregnancy.

Prescribing Info

https://www.novo-pi.com/norditropin.pdf

Prescription Status

Prescription drug

Proprietary Name

Norditropin FlexPro

Related Drugs

Tesamorelin, Mecasermin rinfabate, Sermorelin, Mecasermin, Somatrem

Rxcui

849851
847247

Warning

 
Acute Critical Illness: Potential benefit of treatment continuation should be weighed against the potential risk.
Prader-Willi Syndrome in Children: Evaluate for signs of upper airway obstruction and sleep apnea before initiation of treatment for GHD. Discontinue treatment if these signs occur.
Neoplasm: Monitor patients with preexisting tumors for progression or recurrence. Increased risk of a second neoplasm in childhood cancer survivors treated with somatropin – in particular meningiomas in patients treated with radiation to the head for their first neoplasm.
Impaired Glucose Tolerance and Diabetes Mellitus: May be unmasked. Periodically monitor glucose levels in all patients. Doses of concurrent antihyperglycemic drugs in diabetics may require adjustment.
Intracranial Hypertension: Exclude preexisting papilledema. May develop and is usually reversible after discontinuation or dose reduction.
Hypersensitivity: Serious hypersensitivity reactions may occur. In the event of an allergic reaction, seek prompt medical attention.
Fluid Retention (i.e., edema, arthralgia, carpal tunnel syndrome – especially in adults): May occur frequently. Reduce dose as necessary.
Hypoadrenalism: Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism.
Hypothyroidism: May first become evident or worsen.
Slipped Capital Femoral Epiphysis: May develop. Evaluate children with the
onset of a limp or hip/knee pain.
Progression of Preexisting Scoliosis: May develop.
Pancreatitis: Consider pancreatitis in patients with persistent severe abdominal pain.

Links:
https://www.norditropin.com/
https://www.drugs.com/mtm/norditropin-flexpro-pen.html
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1058e17c-9261-459c-a3e6-fae38d196c14
https://www.drugbank.ca/drugs/DB00052

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