somatropin (Rx)

<10%

Norditropin

• Peripheral edema (42%)
• Edema (25%)
• Arthralgia (19%)
• Leg Edema (15%)
• Myalgia (15%)
• Infection (non-viral) (13%)
• Paraesthesia (11%)
• Skeletal Pain (11%)

Humatrope

• Edema (21.2%)
• Arthralgia (17.3%)
• Paresthesia (17.3%)
• Rhinitis (13.5%)
• Pain (13.5%)
• Myalgia (13.5%)
• Peripheral edema (11.5%)

1-10%

Norditropin

• Headache (9%)
• Bronchitis (9%)
• Flu-like symptoms (8%)
• Hypertension (8%)
• Gastroenteritis (8%)
• Other non-classifiable disorders (excludes accidental injury) (8%)
• Increased sweating (8%)
• Glucose tolerance abnormal (6%)
• Laryngitis (6%)
• Type 2 diabetes mellitus (5%)

Humatrope

• Back pain (9.6%)
• Headache (7.7%)
• Hypertension (7.7%)
• Acne (5.8%)
• Joint disorder (5.8%)
• Surgical procedure (5.8%)
• Flu syndrome (3.9%)

Postmarketing Reports

Immune system disorders: Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema

Skin: Increase in size or number of cutaneous nevi

Endocrine disorders: Hypothyroidism

Metabolism and nutrition disorders: Hyperglycemia

Musculoskeletal and connective tissue disorders: Slipped capital femoral epiphysis, Legg-Calvé-Perthes disease

Investigations: Increase in blood alkaline phosphatase level, decrease in serum thyroxin (T4) levels

Gastrointestinal: Pancreatitis

Neoplasm: Leukemia reported in a small number of GH deficient children treated with somatropin, somatrem (methionylated rhGH) and GH of pituitary origin

Frequency Not Defined

New onset type 2 diabetes mellitus reported in children and adults

Pediatric

• Slipped capital femoral epiphysis and Legg-Calve-Perthes disease (osteonecrosis/avascular necrosis; occasionally associated with slipped capital femoral epiphysis)
• Progression of preexisting scoliosis
• Hypothyroidism
• Hypoglycemia
• Seizures
• Pancreatitis
• Exacerbation of psoriasis
• Benign intracranial hypertension (uncommon)
• Hematuria
• Hematoma
• Leukemia
• Papilledema

Patients with Idiopathic Short Stature

• Otitis media
• Myalgia
• Scoliosis
• Arthralgia
• Hyperlipidemia
• Arthrosis
• Benign intracranial hypertension
• Type 2 diabetes mellitus
• Gyencomastia
• Arthralgia

Adults

• Headache
• Weakness
• Muscle pain
• Hyperglycemia
• Pancreatitis
• Glucosuria
• Edema
• Gastritis
• Diaphoresis
• Dizziness
• Joint disorder

Patients with Prader-Willi Syndrome

• Aggressiveness
• Arthralgia
• Edema
• Hair loss
• Headache
• Hypertension
• Benign intracranial hypertension
• Myalgia
• Increased mortality

Turner Syndrome

• Otitis media
• Ear disorders
• Joint pain
• Respiratory Illness
• Urinary tract infection
• Surgical procedures

HIV Patients with Wasting or Cachexia

• Arthralgia
• Arthrosis
• Myalgia
• Peripheral edema
• Headache
• Nausea
• Paresthesia
• Gynecomastia
• Edema

Short-bowel Syndrome

• Peripheral edeam
• Facial edema
• Arthralgia
• Nausea
• Flatulence
• Abdominal pain
• Vomiting

SHOX Deficiency

• Arthralgia
• Gynecomastia
• Excessive cutaneous nevi
• Scoliosis

Small for Gestational Age

• Mild, transient hyperglycemia
• Benign intracranial hypertension
• Precocious puberty
• Aggravation of pre-existing scoliosis
• Carpal tunnel syndrome
• Type 2 diabetes mellitus
• Otitis Media
• Headache

Postmarketing Reports

Acute critical illness

Sudden death

Intracranial tumors

Central hypothyroidism

Cardiovascular disorders

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema

Fluid retention

Hypoadrenalism

Contraindications

Hypersensitivity to metacresol or glycerin (diluent)

Hypersensitivity to benzyl alcohol

Acute critical illness after open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure due to the risk of increased mortality with use of pharmacologic doses of somatropin

Active malignancy

Pediatric patients with closed epiphyses

Active proliferative or severe non-proliferative diabetic retinopathy

Active malignancy, acute complications of open heart or abdominal surgery, multiple trauma, acute respiratory failure

Pediatric patients with Prader-Willi syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe respiratory impairment due to the risk of sudden death

Cautions

Increased mortality reported among patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure; benefit of treatment continuation should be weighed against potential risk (see Contraindications)

Reports of sudden death after initiating therapy with somatropin documented in pediatric patients with Prader-Willi syndrome who had ≥1 of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection; male patients with ≥1 factors may be at greater risk than females

Monitor blood glucose in patients with other risk factors (eg, obesity, Turner syndrome, family history of diabetes mellitus [DM]) for glucose intolerance during therapy and adjust antidiabetic treatment, as needed; new onset type 2 DM reported, monitor glucose levels periodically; doses of concurrent antihyperglycemic drugs in diabetics may require adjustment

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting reported; symptoms usually occurred within the first 8 weeks after initiation of therapy; all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose; perform funduscopic examination should be performed routinely before initiating treatment to exclude preexisting papilledema, and periodically thereafter

Serious systemic hypersensitivity reactions (eg, anaphylactic reactions, angioedema) reported with postmarketing use of somatropin products; inform patients and caregivers that such reactions are possible and prompt medical attention should be sought if allergic reaction occurs

Cases of pancreatitis reported; pediatric patients possibly at a greater risk compared to adults; published literature indicates that females who have Turner syndrome may be at greater risk than other pediatric patients receiving somatropin products; consider pancreatitis in patients who develop persistent severe abdominal pain

When somatropin is administered SC at same site over long period of time, tissue atrophy may result; may avoid by rotating injection site (see Administration)

Somatropin increases growth rate, and progression of existing scoliosis can occur in patients who experience rapid growth; monitor patients with a history of scoliosis for progression of scoliosis

Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including GH deficiency and Turner syndrome) or in patients undergoing rapid growth; evaluate pediatric patients with the onset of a limp or complaints of hip or knee pain

Not indicated for the treatment of non-GH deficient adults

Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol; “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations

When administering therapy to infants, reconstitute with normal saline, not the diluent provided; only one dose should be used per vial and the reconstituted product should be discarded after use

Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone and IGF-1 may increase after therapy

Somatropin-treated patients 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; patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of treatment; monitor for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism

Hypothyroidism

• Undiagnosed/untreated hypothyroidism may prevent an optimal response to therapy, in particular, the growth response in pediatric patients
• Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism
• In patients with GH deficiency, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment; consider periodic thyroid function tests and initiate or appropriately adjust thyroid hormone replacement therapy when indicated

Increased risk of neoplasms

• There is an increased risk of malignancy progression with somatropin treatment in patients with active malignancy; any preexisting malignancy should be inactive and its treatment complete prior to instituting somatotropin; discontinue somatotropin if there is evidence of recurrent activity (See Contraindications)
• An increased risk of a second neoplasm reported in patients treated with somatotropins after first neoplasm; intracranial tumors, in particular meningiomas, in patients treated with radiation to head for first neoplasm, were the most common of these second neoplasms; in adult cancer survivors, risk of occurrence unknown; given the limited data available, carefully monitor patients under growth hormone therapy for progression or recurrence of the tumor
• Owing to pediatric patients with certain rare genetic causes of short stature have an increased risk of developing malignancies, thoroughly consider the risks and benefits of starting treatment in these patients; monitor patients for increased growth, or potential malignant changes of preexisting nevi; any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin; discontinue somatotropin if there is evidence of recurrent activity

Zorbtive

• If moderate fluid retention, arthralgia, treat symptomatically or reduce dose by 50%
• Discontinue up to 5 days if severe toxicity, then restart at 50% dose; permanently discontinue if severe toxicity recurs or does not disappear within 5 days

Drug interactions overview

• Microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue; somatotropin inhibits 11βHSD-1; individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol; initiation of somatotropin may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations
• Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth promoting effects of somatotropin in pediatric patients
• Limited published data indicate that somatropin treatment increases CYP450 mediated antipyrine clearance; somatotropin may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes
• Oral estrogens may reduce the serum IGF-1 response to somatotropin
• Treatment with somatotropin may decrease insulin sensitivity, particularly at higher doses

Pregnancy

Limited available data with somatropin use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes

In animal reproduction studies, there was no evidence of fetal or neonatal harm when pregnant rats were administered SC somatotropin during organogenesis or during lactation at doses ~10-times higher than the maximal clinical dose of 0.016 mg/kg, based on body surface area

Diluent contains benzyl alcohol, which has been associated with gasping syndrome in neonates; the preservative benzyl alcohol can cause serious adverse events and death when administered intravenously to neonates and infants; if therapy needed during pregnancy, reconstitute with normal saline, use only one dose per vial, and discard reconstituted product after use, or use a benzyl alcohol-free formulation

Lactation

There are no data on presence of somatropin in human milk; limited published literature reports no adverse effects on breastfed infants with maternal administration of somatropin; no decrease in milk production or change in milk content during treatment with somatropin reported; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for somatotropin and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition

Diluent contains benzyl alcohol; if therapy needed during lactation, reconstitute with normal saline, use only one dose per vial, and discard after use or use a benzyl alcohol-free formulation

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Purified polypeptide of recombinant human growth hormone

Human growth hormone plays a role in the growth of linear bone, skeletal muscle, and organs by stimulating chondrocyte proliferation and differentiation. It also stimulates erythropoietin.

Absorption

Humatrope

• Peak plasma concentration: 415 ng/mL (0.02 mg/kg-dose); 53.2 ng/mL (0.1 mg/kg SC-dose); 63.3 ng/mL (0.1 mg/kg IM-dose)
• AUC: 156 ng•hr/mL (0.02 mg/kg-dose); 495 ng•hr/mL (0.1 mg/kg SC-dose); 585 ng•hr/mL (0.1 mg/kg IM-dose)

Norditropin

• IM/SC: Approximately 63% to 90% depending on formulation and route of administration
• Peak plasma concentration: 34.9 ng/mL (single 4 mg-dose); 13.8 ng/mL (0.024 mg/kg SC-dose)
• Peak plasma time: 3 hr (single 4 mg-dose)

Genotropin

• Bioavailability: ~80.5%
• Peak plasma time: 5.9 hr
• Peak plasma concentration, adults: 23 ng/mL (0.03 mg/kg SC-dose); 17.4 ng/mL (5.3 mg/mL)
• Peak plasma concentration, pediatric: 12.4 ng/mL (first injection) and 12.2 ng/mL (second injection), achieved at approximately 6 hr after dosing

Distribution

Vd (Genotropin): 1.3 L/kg

Vd (Humatrope): 0.0703 L/kg (0.02 mg/kg-dose); 1.55 L/kg (0.1 mg/kg SC-dose); 0.957 L/kg (0.1 mg/kg IM-dose)

Vd (Nutropin and Nutropin AQ): 50 mL/kg

Vd (Omniprobe): 1.4 L/kg

Vd (Saizen, Serostim, and Zorbtive): 12 L

Metabolism

Liver, kidneys

Elimination

Norditropin

• Half-life: 2hr; 7-10 hr (0.024 mg/kg SC-dose)
• Clearance: 2.3 mL/min/kg (infusion)
• Longer half-life observed after SC administration is due to slow absorption from the injection site
• Urinary excretion of intact somatropin has not been measured

Genotropin

• Half-life: 0.4 hr (IV); 3 hr (SC)
• Clearance: 0.3 L/hr/kg

Humatrope

• Half-life: 0.363 hr (0.02 mg/kg-dose); 4.hr (0.1 mg/kg SC-dose); 3.81 hr (0.1 mg/kg IM-dose)
• Clearance: 0.135 L/kg•hr (0.02 mg/kg-dose); 4.93 L/kg•hr (0.1 mg/kg SC-dose); 3.81 L/kg•hr (0.1 mg/kg IM-dose)

SC Administration

Do not administer IV

Administer by SC injection into back of upper arm, abdomen, buttock, or thigh with regular rotation of injection sites to avoid lipoatrophy

Visually inspect for particulate matter and discoloration; solution appear clear and colorless; do not use if solution is cloudy or contains particulate matter

Do not shake the drug

Storage

Humatrope

• Vials

  • Unused vials: Refrigerate at 2-8°C (36-46°F); do not freeze
  • Reconstituted vials: Refrigerate at 2-8°C (36-46°F) for up to 14 days

• Cartridges

  • Unused cartridges: Refrigerate at 2-8ºC (36-46ºF);do not freeze
  • Reconstituted cartridges: Refrigerate at 2-8ºC (36-46ºF) for up to 28 days after reconstitution; do not freeze; protect from heat

Genotropin

• Lyophilized powder

  • Unused drug: Refrigerate at 2-8ºC (36-46ºF); do not freeze; protect from light

• Cartridges

  • Unused cartridges: Refrigerate at 2-8ºC (36-46ºF) for up to 4 weeks; store in room temperature at <25ºC (77ºF) up to 3 months; do not freeze
  • Reconstituted cartridges: Refrigerate at 2-8ºC (36-46ºF) for up to 28 days after reconstitution; do not freeze; protect from heat

• Miniquick

  • After dispensing: Refrigerate at ≤25ºC (77ºF) for up to 3 months after dispensing
  • Reconstituted drug: Refrigerate at 2-8ºC (36-46ºF) for up to 24 hours after mixing it; do not freeze

Norditropin

• Unused vial: Refrigerate at 2-8ºC (36-46ºF) until expiration date; do not freeze; avoid direct light
• After first injection: Refrigerate at 2-8ºC (36-46ºF) for up to 4 weeks; store in room temperature at <25ºC (77ºF) up to 3 weeks

Nutropin AQ cartridge and NuSpin injection device content

• After initial use: Refrigerate at 2-8ºC (36-46ºF) for up to 28 days; do not freeze; protect from light