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Genotropin (somatropin) injection, for subcutaneous use

Summary about Genotropin

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.

Genotropin is a man-made copy of natural growth hormone. It has been used to treat more than 83,000 children around the world for more than 30 years.

 

Figure 1: Genotropin Pen  (Source: https://www.genotropin.com/ )

Genotropin is approved by the Food and Drug Administration (FDA) for the treatment of several growth disorders in children and adults, including:

  • Growth hormone deficiency (GHD) in children
  • Small for gestational age (SGA) in children
  • Idiopathic short stature (ISS) in children
  • Prader-Willi syndrome (PWS) in children
  • Turner syndrome (TS) in girls and
  • Growth hormone deficiency (GHD) in adults

Genotropin is administered by injection under the skin with one of two device options including:

  • GENOTROPIN Pen, a multi-dose pen with digital display, and
  • GENOTROPIN MiniQuick, a portable option for families on the go.

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 favourable 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.

Genotropin is contrainidicated in following cases:

  • Acute critical illness
  • Children with Prader-Willi Syndrome who are severely obese or have severe respiratory impairment – reports of sudden death
  • Active malignancy
  • Hypersensitivity to somatropin or its excipients
  • Active proliferative or severe non-proliferative diabetic retinopathy
  • Children with closed epiphyses
  • Known hypersensitivity to somatropin or excipients
  • Diabetic retinopathy.

Figure 2: Genotropin MiniQuick (Source: https://www.genotropin.com/ )

 

 

Genotropin (somatropin)

Active Ingredient

Somatropin

Administration Route

Subcutaneous

Alcohol Warning

No data about the interaction

Available Strength

GENOTROPIN lyophilized powder:
  • 5 mg two-chamber cartridge (green tip, with preservative)
    concentration of 5 mg/mL
  • 12 mg two-chamber cartridge (purple tip, with preservative)
    concentration of 12 mg/mL

GENOTROPIN MINIQUICK Growth Hormone Delivery Device containing a two-chamber cartridge of GENOTROPIN (without preservative)

  • 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, and 2.0 mg

Breastfeeding Warning

Caution is recommended. Excretion into human milk is unknown.

Following 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

Following a 0.03 mg/kg subcutaneous (SC) injection in the thigh of 1.3 mg/mL GENOTROPIN to adult GHD patients, approximately 80% of the dose was systemically available as compared with that available following intravenous dosing. Results were comparable in both male and female patients. Similar bioavailability has been observed in healthy adult male subjects.

In healthy adult males, following an SC injection in the thigh of 0.03 mg/kg, the extent of absorption (AUC) of a concentration of 5.3 mg/mL GENOTROPIN was 35% greater than that for 1.3 mg/mL GENOTROPIN. The mean (± standard deviation) peak (Cmax) serum levels were 23.0 (± 9.4) ng/mL and 17.4 (± 9.2) ng/mL, respectively.

In a similar study involving pediatric GHD patients, 5.3 mg/mL GENOTROPIN yielded a mean AUC that was 17% greater than that for 1.3 mg/mL GENOTROPIN. The mean Cmax levels were 21.0 ng/mL and 16.3 ng/mL, respectively.

Adult GHD patients received two single SC doses of 0.03 mg/kg of GENOTROPIN at a concentration of 1.3 mg/mL, with a one- to four-week washout period between injections. Mean Cmax levels were 12.4 ng/mL (first injection) and 12.2 ng/mL (second injection), achieved at approximately six hours after dosing.

There are no data on the bioequivalence between the 12 mg/mL formulation and either the 1.3 mg/mL or the 5.3 mg/mL formulations.

Distribution

The mean volume of distribution of GENOTROPIN following administration to GHD adults was estimated to be 1.3 (± 0.8) L/kg.

Metabolism

The metabolic fate of GENOTROPIN involves classical protein catabolism in both the liver and kidneys. In renal cells, at least a portion of the breakdown products are returned to the systemic circulation. The mean terminal half-life of intravenous GENOTROPIN in normal adults is 0.4 hours, whereas subcutaneously administered GENOTROPIN has a half-life of 3.0 hours in GHD adults. The observed difference is due to slow absorption from the subcutaneous injection site.

Excretion

The mean clearance of subcutaneously administered GENOTROPIN in 16 GHD adult patients was 0.3 (± 0.11) L/hrs/kg.

Special Populations

Pediatric: The pharmacokinetics of GENOTROPIN are similar in GHD pediatric and adult patients.

Gender: No gender studies have been performed in pediatric patients; however, in GHD adults, the absolute bioavailability of GENOTROPIN was similar in males and females.

Race: No studies have been conducted with GENOTROPIN to assess pharmacokinetic differences among races.

Renal or hepatic insufficiency: No studies have been conducted with GENOTROPIN in these patient populations.

Cost

Approximate Retail Price

from  http://www.goodrx.com/Genotropin

lyophilisate for solution for injection:

  • 1.4 mg (1 dual-chamber syringe, with needle, 1.4 mg): $1,784.72

lyophilisate for solution for injection:

  • 0.6 mg (1 dual-chamber syringe, with needle, 0.6 mg): $2,539.92

lyophilisate for solution for injection:

  • 1.8 mg (4 dual-chamber syringe, with needle, 1.8 mg): $7,845.08

lyophilisate for solution for injection:

  • 0.8 mg (2 dual-chamber syringe, with needle, 0.8 mg): $3,247.32

lyophilisate for solution for injection:

  • 1.6 mg (1 dual-chamber syringe, with needle, 1.6 mg): $6,103.51

lyophilisate for solution for injection:

  • 2 mg (4 dual-chamber syringe, with needle, 2 mg): $22,227.10

lyophilisate for solution for injection:

  • 0.4 mg (2 dual-chamber syringe, with needle, 0.4 mg): $893.41

lyophilisate for solution for injection:

  • 1.2 mg (1 dual-chamber syringe, with needle, 1.2 mg): $6,326.99

lyophilisate for solution for injection:

  • 0.2 mg (4 dual-chamber syringe, with needle, 0.2 mg): $2,222.50

lyophilisate for solution for injection:

  • 1 mg (1 dual-chamber syringe, with needle, 1 mg): $7,112.56

lyophilisate for solution for injection:

  • 5 mg (2 dual-chamber syringe, with needle, with preservative, 5 mg): $1,510.73

lyophilisate for solution for injection:

  • 12 mg (1 dual-chamber syringe, with needle, with preservative, 12 mg): $1,680.39

Dosage Form

Injection for subcutaneous use

Dose Schedule

Pediatric GHD: 0.16 to 0.24 mg/kg/week

Prader-Willi Syndrome: 0.24 mg/kg/week

Small for Gestational Age: Up to 0.48 mg/kg/week

Turner Syndrome: 0.33 mg/kg/week

Idiopathic Short Stature: up to 0.47 mg/kg/week

Adult GHD: Either a non-weight based or a weight based dosing regimen may be followed, with doses adjusted based on treatment response and IGF-I concentrations

Non-weight based dosing: A starting dose of approximately 0.2mg/day (range, 0.15-0.30 mg/day) may be used without consideration of body weight, and increased gradually every 1-2 months by increments of approximately 0.1-0.2 mg/day.

Weight based dosing: The recommended initial dose is not more than 0.04 mg/kg/week; the dose may be increased as tolerated to not more than 0.08 mg/kg/week at 4–8 week intervals.

Drug Class

H01AC – Somatropin and somatropin agonists

Drug Unit

mg/ml

Food Warning

No known interactions

Included In
Health Insurance Plan

Genotropin 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 adjustedCytochrome P450-Metabolized Drugs:
Monitor carefully if used with somatropinOral Estrogen:
Larger doses of somatropin may be required in womenInsulin and/or Oral/Injectable Hypoglycemic Agents:
May require adjustment

Is Available Generically

No. There is currently no therapeutically equivalent version of Genotropin available.

Is Proprietary

Yes

Label Details

https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020280s088lbl.pdf

Legal Status

Legal.

Is not subject to the Controlled Substances Act.

Manufacturer

Pfizer Inc.

Maximum Intake

0.0125 mg/kg/day

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.accessdata.fda.gov/drugsatfda_docs/label/2016/020280s088lbl.pdf

Prescription Status

Prescription drug

Proprietary Name

Genotropin

Related Drugs

Tesamorelin, Mecasermin rinfabate, Sermorelin, Mecasermin, Somatrem

RxCUI

202828

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.genotropin.com/
https://www.drugs.com/pro/genotropin.html
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ffebf88b-d257-4542-9808-74d9b7167765
https://www.drugbank.ca/drugs/DB00052

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