Growth Hormone (Systemic)

This monograph includes information on the following:

1) Somatrem
2) Somatropin, Recombinant


JAN:
Somatropin—Human growth hormone
{10}5
VA CLASSIFICATION
Primary: HS701

Commonly used brand name(s): Genotropin2; Genotropin Miniquick2; Humatrope2; Norditropin2; Norditropin® cartridges2; Nutropin2; Nutropin AQ2; Protropin1; Saizen2; Serostim2.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Growth hormone—

Indications

Accepted

Growth failure
Growth hormone deficiency–associated (treatment)—Somatrem and recombinant somatropin are indicated in children for long-term treatment of growth failure caused by pituitary growth hormone (GH) deficiency (pituitary dwarfism), including GH deficiency caused by cranial irradiation. {10}4 {10}3 {10}2 {10}1 {10}0 {20}9 {20}8 {20}7 {20}6 {20}5 {20}4 {20}3 {20}2 {20}1 {20}0{22}9 Failure to grow must be documented by a subnormal growth rate, and GH deficiency is usually identified by a lack of response to two standard pharmacologic stimuli that would normally provoke the release of somatropin or evidence of impaired spontaneous secretion or bioactivity of endogenous GH. {22}8 {22}7 {22}6 {22}5
—Recombinant somatropin ( Genotropin, Humatrope, Nutropin, Nutropin AQ) is also indicated in adults for treatment of growth failure caused by GH deficiency1 when both of the following criteria are present: {22}4 {22}3 {22}2 {22}1    #149; GH deficiency of adult onset, alone or with multiple hormone deficiencies, such as hypopituitarism, as a result of hypothalamic or pituitary disease, radiation therapy, surgery, or trauma. Or GH deficiency of childhood onset that was not confirmed until adulthood; and
   #149; Negative response to a standard growth hormone stimulation test, i.e., maximum peak of less than 5 nanograms per mL when measured by polyclonal antibody (RIA) or less than 2.5 nanograms per mL when measured by monoclonal antibody (IRMA).


Chronic renal insufficiency–associated (treatment)—Recombinant somatropin ( Nutropin, Nutropin AQ) is indicated in children for treatment of growth failure caused by chronic renal insufficiency. It has been shown to improve growth rate and correct the acquired height deficit seen in these patients. Somatropin may be used until the time of renal transplantation. However, there are insufficient data to establish benefit of therapy beyond 3 years. {22}0 {23}9 {23}8

Prader-Willi syndrome (PWS)-associated (treatment)1—Somatropin is indicated for long-term treatment of pediatric patients who have growth failure due to PWS. The diagnosis of PWS should be confirmed by appropriate genetic testing
{23}7
Turner's syndrome–associated (treatment) 1—Recombinant somatropin ( Humatrope, Nutropin, Nutropin AQ) is indicated for long-term treatment of short stature associated with Turner"s syndrome. {23}6 {23}5 {23}4
Cachexia, acquired immunodeficiency syndrome (AIDS)–associated (treatment) or
Weight loss, AIDS-associated (treatment)—Recombinant somatropin ( Serostim), in conjunction with the appropriate antiretroviral therapy, is indicated for treatment of AIDS-associated cachexia or weight loss. {23}3 {23}2

Unaccepted
There are currently insufficient data to establish the efficacy and the long-term safety of the use of growth hormone in treating idiopathic short stature. {23}1 {23}0 {25}9

Growth hormone is not recommended for growth promotion in pediatric patients with closed epiphyses. {25}8 {25}7 {25}6 {25}5 {25}4 {25}3 {25}2 {25}1 {25}0 {27}9 {27}8{27}7

The use of human growth hormone in older males to change body composition (e.g., to decrease adiposity and to prevent decline in muscle mass) is not recommended. {27}6 {27}5 {27}4 {27}3 {27}2

Growth hormone is not indicated in patients with functioning renal allografts. {27}1 {27}0

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Somatrem: Biosynthetic. A single polypeptide chain of 192 amino acids, one more (methionine) than naturally occurring human growth hormone, produced by a recombinant DNA process in Escherichia coli . {28}9 {28}8 {28}7
    Somatropin, recombinant: Biosynthetic, produced by a recombinant DNA process in E. coli ; {28}6 {28}5 {28}4 {28}3 same amino acid sequence as naturally occurring human growth hormone. {28}2 {28}1 {28}0 {10}9 {10}8 {10}7 {10}6 {10}5 A single polypeptide chain of 191 amino acids. {10}4 {10}3 {10}2 {10}1 {10}0 {20}9 {20}8 {20}7 {20}6 {20}5 {20}4 {20}3 {20}2
Molecular weight—
    Somatrem: 22,256.39 {20}1
    Somatropin: 22,125.19 {20}0


pH
    Genotropin (reconstituted solution): 6.7. {22}9
    Humatrope (reconstituted solution): 7.5. {22}8
    Norditropin (reconstituted solution): 7.3. {22}7
    Nutropin (reconstituted solution): 7.4. {22}6 {22}5
    Nutropin AQ: 6. {22}4 {22}3
    Protropin (reconstituted solution): 7.8. {22}2
    Saizen (reconstituted solution): 6.5 to 8.5. {22}1
    Serostim (reconstituted solution): 7.4 to 8.5. {22}0

Mechanism of action/Effect:

Human growth hormone is an anterior pituitary hormone. Most anabolic actions are thought to be mediated by insulin-like growth factor-I (IGF-I, which has also been known as somatomedin C), synthesized in the liver and other tissues in response to growth hormone stimulation. {25}9 {25}8 {25}7 {25}6 {25}5 {25}4 IGF-I concentrations are low in children with growth hormone deficiency but normalize in response to administration of exogenous growth hormone. {25}3 {25}2 {25}1 {25}0 {27}9 {27}8 {27}7 {27}6 {27}5 {27}4 {27}3

Growth hormone stimulates linear growth by affecting cartilaginous growth areas of long bones. {27}2 {27}1 {27}0 {28}9 {28}8 {28}7 {28}6 {28}5 {28}4 {28}3 {28}2 It also stimulates growth by increasing the number and size of skeletal muscle cells, {28}1 {28}0 {21}9 {21}8 {21}7 {21}6 {21}5 {21}4 {21}3 {21}2 {21}1 influencing the size of organs, and increasing red cell mass {21}0 {21}9 {21}8 {21}7 {21}6 {21}5 {21}4 {21}3 through erythropoietin stimulation. {21}2

Growth hormone influences metabolism of carbohydrates by decreasing insulin sensitivity and possibly by affecting glucose transport; {21}1 {21}0 {10}9 {10}8 of fats by causing mobilization of fatty acids; {10}7 {10}6 {10}5 {10}4 {10}3 {10}2 of minerals by causing the retention of phosphorus, sodium, and potassium through promotion of cellular growth; {10}1 {10}0 {20}9 {20}8 {20}7 {20}6 {20}5 {20}4 {20}3 {20}2 {20}1 {20}0 {22}9 of proteins by increasing protein synthesis, which results in nitrogen retention; {22}8 {22}7 {22}6 {22}5 {22}4 {22}3 {22}2 {22}1 {22}0 {25}9 {25}8 {25}7 {25}6 {25}5 and of connective tissue by stimulating synthesis of chondroitin sulfate and collagen, and by increasing urinary excretion of hydroxyproline. {25}4 {25}3 {25}2 {25}1 {25}0 {28}9 {28}8 {28}7


Other actions/effects:

In adults, increases in lean body mass, total body water, and physical performance, and decreases in body fat and waist circumference, are seen with growth hormone therapy. {28}6 {28}5 {28}4 {28}3

Absorption:


Bioavailability:

Genotropin: Approximately 80% following subcutaneous administration of a 0.03-mg-per-kg of body weight dose in the thigh. {28}2

Humatrope: 63% and 75% following intramuscular and subcutaneous administration, respectively. {28}1

Nutropin, Nutropin AQ: 81 ± 20%. {28}0 {29}9

Saizen: 70 to 80%. {29}8


Distribution:

Localizes to highly perfused organs, especially the kidneys and liver. {29}7 {29}6 {29}5


Vol D:

Genotropin: 1.3 ± 0.81 L per kg following administration to adults with growth hormone deficiency. {29}4

Humatrope: 0.07 L per kg following intravenous injection. {29}3

Nutropin, Nutropin AQ: At steady-state, 50 mL per kg of body weight in healthy adult males. {29}2 {29}1

Saizen, Serostim: 12 ± 1.08 L following intravenous injection to healthy volunteers. {29}0 {10}9


Biotransformation:

Primarily renal, also hepatic. In renal cells, growth hormone is cleaved into its constituent amino acids, which are returned to the systemic circulation. {10}8 {10}7 {10}6 {10}5 {10}4 {10}3 {10}2

Half-life:

Intravenous injection—Approximately 20 to 30 minutes (elimination). {10}1 {10}0 {27}9 {27}8 {27}7 {27}6 {27}5 {27}4 {27}3 {27}2

Intramuscular or subcutaneous injection—Serum concentrations decline with a half-life of approximately 3 to 5 hours, {27}1 {27}0 {26}9 {26}8 {26}7 {26}6 {26}5 reflecting continued release of the hormone from the injection site. {26}4 {26}3

Duration of action:

Approximately 12 to 48 hours. {26}2 {26}1

Elimination:
    Biliary (approximately 0.1% of a dose as unchanged drug). {26}0 {75}9


Precautions to Consider

Carcinogenicity/Mutagenicity

Carcinogenicity and mutagenicity testing have not been performed in animals or humans. {75}8 {75}7 {75}6 {75}5 {75}4 {75}3 {75}2 {75}1 {75}0 {28} {29} {30} Mutagenicity testing in vitro with recombinant somatropin did not reveal any mutagenic effects. {21} {29}

Anecdotal cases of acute and chronic leukemia have been reported in patients treated with human growth hormone, at an incidence slightly higher than that expected in the overall population. {20} {21} {65} {66} However, the exact relationship to human growth hormone therapy is unknown. {01} {10} {20} {21} {22} {23} {25} {27} {28} {29} {30} {65} {66} Leukemia has also been reported in hypopituitary patients who have not been treated with growth hormone. {44} {45} {46} {47} {48} {57}

Pregnancy/Reproduction
Fertility—
Studies in rats and rabbits administered doses of up to 31 and 62 times, respectively, the recommended human pediatric dose on a body surface area basis have not shown that somatropin causes impaired fertility. {25}

Pregnancy—
Studies have not been done in humans. {10} {20} {21} {23} {25} {26} {27} {28} {29} {30} {75}

Studies in rats and rabbits administered doses of up to 31 and 62 times, respectively, the recommended human pediatric dose on a body surface area basis have not shown that somatropin causes adverse effects in the fetus. {25}

FDA Pregnancy Category B ( Genotropin, Saizen, Serostim). {21} {25} {26} {75}

FDA Pregnancy Category C ( Humatrope, Norditropin, Nutropin, Nutropin AQ, Protropin). {01} {10} {20} {22} {23}

Breast-feeding

It is not known whether growth hormone is distributed into breast milk. {01} {10} {20} {21} {22} {23} {25} {26} {27} {28} {29} {30} {75}

Pediatrics

Safety and efficacy in pediatric patients with acquired immunodeficiency syndrome (AIDS) have not been established. {26} {75}


Geriatrics


Appropriate studies on the relationship of age to the effects of growth hormone have not been performed in the geriatric population. However, geriatrics-specific problems that would limit the usefulness of this medication in the elderly are not expected.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anabolic steroids{59}{66} or
Androgens or
Estrogens or
Thyroid hormones    (concurrent use of excessive doses of these hormones may accelerate epiphyseal closure, although hormone supplement therapy may be necessary in patients with deficiencies of these hormones to maintain the growth response to human growth hormone {05} {16} {59} {66} {72} {73})


» Corticosteroids, glucocorticoid{01}{10}{20}{21}{22}{23}{25}{27}{28}{29}{30} or
» Corticotropin (ACTH),{20}{21}{22}{28} especially with chronic therapeutic use    (inhibition of the growth response to human growth hormone may occur {01} {10} {20} {21} {23} {25} {27} {28} {29} {30} with chronic therapeutic use of corticotropin or with daily oral corticosteroid doses [per square meter of body surface area] in excess of:

• Betamethasone: 300 to 450 mcg


• Cortisone: 12.5 to 18.8 mg


• Dexamethasone: {68} 250 to 500 mcg


• Hydrocortisone: 10 to 15 mg {29}


• Methylprednisolone: 2 to 3 mg


• Prednisolone: 2.5 to 3.75 mg


• Prednisone: 2.5 to 3.75 mg


• Triamcinolone: 2 to 3 mg



Maximum parenteral corticosteroid doses are approximately one half maximum oral doses. In general, it is recommended that these doses not be exceeded during human growth hormone therapy and if larger doses are required, administration of human growth hormone should be postponed, except for brief administration of stress dosages during acute febrile illness or other acute stress; {37} however, there is great interindividual variation. {37} Also, concurrent use with corticotropin is not recommended; of the others, hydrocortisone or cortisone is usually preferred, except in extenuating circumstances {37})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alkaline phosphatase{01}{10}{21}{22}{23}{25}{27}{28}{29}{30}    (values may be increased {01} {10} {21} {22} {23} {25} {27} {28} {29} {30})


Glucose tolerance{01}{10}{20}{21}{26}{27}{28}{30}{31}{35}{56}{59}{66}    (may be reduced by high doses {10} {11} {20} {21} {26} {27} {28} {30} {35} {56} {66})


Inorganic phosphate{01}{10}{21}{22}{23}{25}{27}{28}{29}{30}{56}    (serum concentrations may be increased to normal during treatment with growth hormone as a result of metabolic activity associated with bone growth as well as increased tubular reabsorption of phosphate by the kidneys {22} {23} {28} {30} {56})


Nonesterified fatty acids{01}{10}{21}{22}{23}{25}{27}{28}{29}{30}{56}    (plasma concentrations may be increased as a result of lipid mobilization from body fat stores {01} {10} {21} {22} {25} {27} {28} {30} {56})


Parathyroid hormone{01}{22}{23}{28}{30}    (concentrations may be increased {01} {22} {23} {28} {30})


Thyroid function{27}{28}{30}{59}    (serum thyroxine [T 4] concentration, radioactive iodine uptake [RAIU], and thyroxine-binding capacity may be slightly decreased; {11} {14} {15} {16} {59} asymptomatic hypothyroidism usually occurs in less than 5%, but possibly up to 10 to 20%, {37} of patients with hypopituitarism {06} {07} {09} {11} {12} {13} {14} {16} {17} {59})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Diabetes mellitus{10}{21}{25}{29}    (growth hormone may cause insulin resistance; adjustment of insulin dosage may be needed {10} {21})


» Hypothyroidism, untreated{01}{10}{20}{22}{23}{27}{28}{29}{30}    (interferes with growth response to human growth hormone; {01} {10} {20} {21} {22} {23} {25} {27} {28} {29} {30} prior and/or concurrent thyroid hormone replacement therapy is recommended {01} {08} {16} {20} {21} {22} {23} {27} {28} {29} {30})


Malignancy,{03} especially intracranial tumor, actively growing{01}{10}{20}{21}{22}{23}{25}{27}{28}{29}{30} within the previous 12 months    (human growth hormone should not be used if there is evidence of progression or recurrent growth of an underlying tumor; {01} {20} {21} {27} {28} {29} {30} antitumor therapy and a reasonable period of observation should be complete before initiating growth hormone therapy {10} {21} {27} {65})


Sensitivity to any component of the growth hormone product prescribed{20}{26}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Antibodies to growth hormone, serologic evaluation for{01}{10}{20}{22}{23}{25}{27}{28}{29}{30}{37}    (in some cases, where growth rate falls during therapy and all other causes of growth inhibition have been ruled out, serologic evaluation for the presence of antibodies to growth hormone may be performed, with emphasis on binding capacity; {01} {20} {22} {23} {25} {27} {28} {29} {30} {37} antibodies to somatrem may be formed in the first 3 to 6 months of treatment {11} {14} but only rarely cause failure to respond to therapy; {27} {30} antibodies to recombinant somatropin have been detected in patients treated for 6 months or more; relative incidence of antibody formation is difficult to compare because different assays have been used; {37} {51} however, growth inhibition appears to be correlated more with high antibody binding capacity [exceeding 2 mg per L] {01} {20} {21} {22} {23} {25} {28} {30} than with growth hormone titer, {37} {67} and differences in antibody formation have demonstrated minimal clinical significance to date {49} {51})


Bone age determinations{25}{29}    (recommended annually during therapy, especially in pubertal patients on concurrent androgen, estrogen, {03} or thyroid replacement {29} therapy since concurrent use may accelerate epiphyseal maturation {25} {29} {73})


Calcium concentrations, serum{24} and
Parathyroid hormone concentrations, serum{24} and
Phosphorus concentrations, serum{24} and
Renal function determinations{22}{24}    (recommended periodically in patients with growth failure secondary to chronic renal insufficiency to detect progression of renal osteodystrophy {22} {23} {28})


Examinations to monitor intracranial lesion{01}{10}{20}{21}{22}{23}{27}{28}{29}{30}    (recommended at frequent intervals in patients with growth hormone deficiency secondary to an intracranial lesion {01} {10} {20} {22} {27} {28} {29} {30})


Examinations to monitor progression of scoliosis{01}{10}{22}{23}{27}{28}{30}    (although growth hormone has not been shown to increase the incidence of scoliosis, rapid growth can lead to progression of scoliosis; close monitoring is recommended {01} {10} {22} {23} {27} {28} {30})


Funduscopic examinations{01}{10}{20}{21}{22}{23}{25}{26}{27}{28}{29}{30}{75}    (recommended upon initiation and periodically during the course of growth hormone therapy, to detect intracranial hypertension {01} {10} {20} {21} {22} {23} {25} {26} {27} {28} {29} {30} {75})


Glucose concentrations{01}{10}{20}{21}{22}{23}{26}{27}{28}{29}{30}{75}    (recommended periodically because growth hormone can cause insulin resistance {10} {20} {21} {27} {28} {29} {30} {75})


Growth rate determinations from stadiometer measurements    (recommended every 3 to 6 months during therapy; {37} if the growth rate does not exceed the pretreatment growth rate by at least 2 cm per year, the patient should be checked for noncompliance or the presence of antibodies or other medical problems such as hypothyroidism or malnutrition {03} {36} {39} {55} {72})


Radiograph, hip{22}{23}{28}    (recommended prior to growth hormone therapy in patients with chronic renal insufficiency because risk of slipped capital femoral epiphysis and avascular necrosis of the femoral head are increased in patients with advanced renal osteodystrophy {22} {28})


Thyroid function determinations{01}{10}{20}{21}{22}{23}{25}{27}{29}{30}{59}    (recommended at regular intervals during therapy to detect hypothyroidism that develops during treatment; {01} {21} {22} {23} {27} {29} {30} untreated hypothyroidism interferes with response to human growth hormone {01} {16} {22} {23} {27} {29} {30} {59})




Side/Adverse Effects

Note: Prolonged use of excessive doses of human growth hormone in patients who are not growth hormone deficient may theoretically cause acromegalic features (face, hands, feet) and other problems associated with acromegaly, including organ enlargement, diabetes mellitus, atherosclerosis, hypertension, and nerve entrapment syndrome (carpal tunnel syndrome). {04} {06} {08} {09} {11} {13} {19} {31} {35} {52} {56} {66}
Development of antibodies to growth hormone may occur in a small number of patients. Interference with growth response has been seen only when antibody binding capacity exceeded 2 mg per L. {01} {20} {21} {22} {23} {25} {28} {29} {30} For patients receiving somatrem who exhibit attenuation of growth response as a result of an increased production of antibodies, consideration should be given to transferring to somatropin. It has been suggested, although not proven, that methionine on the N-terminus of somatrem causes development of antibodies. {30}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Otitis media or other ear disorders —in patients with Turner's syndrome{10}{22}{23}

Incidence rare
    
Allergic reaction (skin rash or itching){01}{22}{23}{25}{26}{28}{30}{41}{75}
    
intracranial hypertension (changes in vision; headache; nausea and vomiting; papilledema)—in children{01}{10}{20}{21}{22}{23}{25}{27}{28}{29}{30}
    
lipodystrophy at site of injection (depression of the skin){21}{25}{26}{27}{29}
    
pain and swelling at site of injection {01}{03}{10}{11}{21}{22}{23}{25}{28}{29}{30}
    
pancreatitis (abdominal pain or distension; nausea; vomiting){01}{10}{22}{23}{26}{28}{30}{75}
    
slipped capital femoral epiphysis (limp; pain in hip or knee)—in children{01}{10}{20}{21}{22}{25}{28}{29}{30}{42}{43}{53}{54}

Note: Symptoms of intracranial hypertension usually occur within the first 8 weeks of therapy and resolve with a reduction in growth hormone dose or discontinuation of therapy. {01} {10} {20} {21} {22} {23} {25} {27} {28} {30}
The risk of lipodystrophy may be decreased by rotating injection sites. {25} {26} {27} {29}
Slipped capital femoral epiphyses may also occur in growth hormone–deficient children not treated with growth hormone. {42} {54}




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent or rare
    
Carpal tunnel syndrome —mild and transient{01}{10}{21}{22}{23}{26}{28}{30}{75}
    
gynecomastia (enlargement of breasts){01}{10}{22}{23}{28}{30}
    
headache {10}{20}{21}{27}{29}
    
increased growth of nevi {01}{10}{22}{23}{28}{30}
    
joint pain {10}{21}{22}{23}
    
muscle pain {10}{20}{21}{26}{27}{75}
    
peripheral edema (swelling of hands, feet, or lower legs){01}{10}{21}{22}{23}{26}{27}{28}{30}{75}
    
unusual tiredness or weakness {20}{21}{27}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Hypoglycemia (anxiety; behavior change similar to drunkenness; blurred vision; cold sweats; confusion; cool, pale skin; difficulty in concentrating; drowsiness; excessive hunger; fast heartbeat; headache; nausea; nervousness; nightmares; restless sleep; shakiness; slurred speech; unusual tiredness or weakness)—initially{10}{21}{27}{29}
    
hyperglycemia (blurred vision; drowsiness; dry mouth; flushed, dry skin; fruit-like breath odor; increased frequency and volume of urination; ketones in urine; loss of appetite; nausea or vomiting; stomachache; tiredness; troubled breathing [rapid and deep]; unconsciousness; unusual thirst)—subsequently{10}{21}{22}{23}{27}{29}

Chronic
    
Acromegaly (amenorrhea; backache; changes in vision; excessive sweating; extreme weakness; headache; increase in hat, glove, or shoe size; joint pain; pain in extremities; polydipsia; polyuria){10}{21}{22}{23}{25}{26}{27}{28}{29}{30}{75}



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Growth Hormone (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to any component of the growth hormone product prescribed
Other medications, especially corticosteroids or corticotropin (ACTH)
Other medical problems, especially untreated hypothyroidism

Proper use of this medication
» Proper preparation and administration of medication

» Carefully selecting and rotating injection sites {18} {21} {26} {27} {28} {29} {30} {75}

» Safe handling and disposal of needles and syringes; {01} {10} {22} {23} {25} {26} {28} {30} {75} not reusing needles and syringes {75}

» Proper dosing

» Proper storage

Precautions while using this medication
» Importance of regular visits to physician


Side/adverse effects
Signs of potential side effects, especially otitis media or other ear disorders (in patients with Turner's syndrome), allergic reaction, intracranial hypertension (in children), lipodystrophy at site of injection, pain and swelling at site of injection, pancreatitis, and slipped capital femoral epiphysis (in children)


General Dosing Information
Patients receiving human growth hormone should be under the supervision of a physician trained in the use of and familiar with growth hormone therapy {01}{10}{20}{21}{22}{23}{25}{26}{27}{28}{29}{30}{36}{39}{75}

The dosage and schedule of administration must be individualized for each patient.{01}{10}{20}{21}{22}{23}{25}{27}{28}{29}

For treatment of growth failure
The dosage of human growth hormone may be increased above the recommended dosage in older children with hypopituitarism, especially those who have open epiphyses. {04}

Generally, after 2 or more years of treatment, growth rate will decrease if therapy is continued. Attenuation of growth may be spontaneous. {37} However, if this occurs, the patient should be checked for poor compliance with therapy, other medical problems (such as malnutrition or hypothyroidism), or the presence of antibodies. {03} {27} {36} {55} An increased dose of human growth hormone may be effective. {08} {18} In some patients, low doses of androgens or estrogens may be given concomitantly to restore the response, {03} as long as epiphyseal maturation of 11 years or greater is present. {04} {37}

Human growth hormone therapy should be continued as long as the patient is responsive, {36} until the patient reaches a mature adult height, or until epiphyses close.

For treatment of acquired immunodeficiency syndrome (AIDS)–associated cachexia or wasting
In some in vitro studies, growth hormone at concentrations of 50 to 250 nanograms per mL has been shown to potentiate human immunodeficiency virus (HIV) replication. However, when antiretroviral agents didanosine, lamivudine, or zidovudine were added to the culture medium, no increase in virus production was seen. The antiretroviral activity of stavudine and zalcitabine also was not shown to be affected by growth hormone in in vitro studies. In clinical trials, no increase in virus production was seen in patients receiving growth hormone; however, all patients concomitantly received antiretroviral agents. {26} {75}

If weight loss continues after two weeks of growth hormone therapy, other causes such as opportunistic infection should be considered. {75}

SOMATREM


Parenteral Dosage Forms

SOMATREM FOR INJECTION

Note: The specific activity of growth hormone is defined as International Units (IU) per mg of protein. In October 1994, a new standard was developed that changed the conversion amount from 2.6 IU per mg of growth hormone to 3 IU per mg of growth hormone. This change did not affect the milligram-per-kg dosing or the quantity (mg) of growth hormone per vial. The only change was the increase in the number of IUs per mg. {40}


Usual pediatric dose
Growth hormone deficiency–associated growth failure
Intramuscular or subcutaneous, up to 0.3 mg (0.9 IU) per kg of body weight a week with dosing and dosing regimen individualized according to the patient's needs. {01} {30} {70} It is recommended that this dose be divided into the appropriate dose for daily injection (six or seven times per week). The subcutaneous route of administration is preferred to the intramuscular route. {70}


Note: If the growth rate does not exceed the pretreatment growth rate by at least 2 cm per year, the patient should be checked for noncompliance or the presence of antibodies or other medical problems such as hypothyroidism or malnutrition. {03} {36} {39} {55} {72} If increasing the dose is not effective, treatment should be discontinued and the patient re-evaluated. {74}


Size(s) usually available:
U.S.—


5 mg (approximately 15 IU) per vial (Rx) [Protropin (mannitol 40 mg) (sodium phosphate 1.7 mg) ( Bacteriostatic Water for Injection, USP [benzyl alcohol preserved]){78}{81}{01}]


10 mg (approximately 30 IU) per vial (Rx) [Protropin ( mannitol 40 mg) (sodium phosphate 1.7 mg) (Bacteriostatic Water for Injection, USP [benzyl alcohol preserved] ){78}{81}{01}{69}]

Canada—


5 mg (approximately 15 IU) per vial (Rx) [Protropin (diluent—Bacteriostatic Water for Injection, USP){30}]


10 mg (approximately 30 IU) per vial (Rx) [Protropin ( diluent—Bacteriostatic Water for Injection, USP){30}]

Packaging and storage:
Prior to and following reconstitution, store between 2 and 8 °C (36 and 46 °F). {01} {30} Protect the lyophilized powder, diluent, and reconstituted solution from freezing. {01} {30}

Preparation of dosage form:
Using standard aseptic technique, 1 to 5 mL of bacteriostatic water for injection (benzyl alcohol–preserved only) should be added to the 5-mg vial or 1 to 10 mL to the 10-mg vial and swirled gently to dissolve. {01} {30} The vial should not be shaken. {01} {30} Cloudy solution should not be used. {01} {30}

If somatrem is to be administered to a neonate or to a patient with a known sensitivity to any component of the diluent, Sterile Water for Injection, USP should be used for reconstitution. {01} {30} Benzyl alcohol used as a preservative has been associated with toxicity in neonates. Each vial should then be used only for one dose and any unused portion discarded. {01} {30}

Stability:
When prepared with the diluent provided by the manufacturer, reconstituted solutions should be stored in the refrigerator and used within 14 days. {01} {30} If sterile water for injection is used for reconstitution, each vial should be used only for one dose and any unused portion discarded. {01} {30} If these procedures are not followed, sterility of the solution cannot be assured.


SOMATROPIN, RECOMBINANT


Parenteral Dosage Forms

SOMATROPIN, RECOMBINANT, INJECTION

Usual adult dose
Growth hormone deficiency–associated growth failure1Nutropin AQ or Nutropin


Initial:
Subcutaneous, up to 0.006 mg (0.018 IU) per kg of body weight a day. {10} {21} {22} {23}



Maintenance {10} {21}:
Patients up to 35 years of age: Subcutaneous, up to 0.025 mg (0.075 IU) per kg of body weight a day. {22} {23}

Patients 35 years of age or older: Subcutaneous, up to 0.0125 mg (0.0375 IU) per kg of body weight a day. {10} {22} {23}

Note: The dose should be decreased if required by the occurrence of side effects or excessive insulin-like growth factor-I (IGF-I) levels.{78}{79}{80}




Usual pediatric dose
Growth hormone deficiency–associated growth failure
Norditropin cartridge: Subcutaneous, 0.024 to 0.034 mg (0.072 to 0.102 IU) per kg of body weight a day, administered 6 to 7 times a week. {76}
Nutropin AQ or Nutropin{78}Subcutaneous, up to 0.3 mg (0.9 IU) per kg of body weight a week divided into equal doses and administered daily. {23}

In pubertal patients, a weekly dose of up to 0.7 mg per kg of body weight divided daily may be used.{78}{79}{80}

Chronic renal insufficiency–associated growth failure —Nutropin AQ or Nutropin{78}
Subcutaneous, up to 0.35 mg (1.05 IU) per kg of body weight a week divided into equal doses and administered daily. {22} {23} {28}

Note: Recombinant somatropin therapy may be continued until the time of renal transplantation. {22} {23} {28}
For patients requiring dialysis, it is recommended that somatropin be administered at the following times:


• Hemodialysis—At night just before going to sleep or at least three to four hours after hemodialysis to prevent heparin-induced hematoma formation. {22} {23} {28}


• Chronic cycling peritoneal dialysis—In the morning after dialysis is completed. {22} {23} {28}


• Chronic ambulatory peritoneal dialysis—In the evening at the time of the overnight exchange. {22} {23} {28}



Turner's syndrome–associated growth failure1Nutropin AQ
Subcutaneous, up to 0.375 mg (1.125 IU) per kg of body weight a week divided into the appropriate dose for daily injection (seven times per week) or, as an alternative, divided and injected three times a week (every other day). {10} {22} {23}


Strength(s) usually available
U.S.—


10 mg (approximately 30 IU) per 2 mL (Rx) [Nutropin AQ ( sodium chloride 17.4 mg) (phenol 5 mg) (polysorbate 20 4 mg) (sodium citrate 10 mM){23}{79}]


5 mg (approximately 15 IU) per vial (Rx) [Nutropin (mannitol 45 mg) (sodium phosphate 1.7 mg) ( glycine 1.7 mg) (Bacteriostatic Water for Injection, USP (benzyl alcohol preserved)){80}]


10 mg (approximately 30 IU) per vial (Rx) [Nutropin ( mannitol 90 mg) (sodium phosphate 3.4 mg) (glycine 3.4 mg) (Bacteriostatic Water for Injection, USP (benzyl alcohol preserved)){80}]


5 mg per 1.5 mL cartridge (Rx) [Norditropin® cartridges ( histidine [1 mg]) (mannitol [60 mg]) (phenol [4.5 mg]) (poloxamer 188 [4.5 mg] )]


10 mg per 1.5 mL cartridge (Rx) [Norditropin® cartridges ( histidine [1 mg]) (mannitol [60 mg]) (phenol [4.5 mg]) (poloxamer 188 [4.5 mg] )]


15 mg per 1.5 mL cartridge (Rx) [Norditropin® cartridges ( histidine [1 mg]) (mannitol [60 mg]) (phenol [4.5 mg]) (poloxamer 188 [4.5 mg] )]

Note: Norditropin cartridgesare intended for use only in the Nordipendelivery system.{76}


Canada—


5 mg (approximately 15 IU) per mL (Rx) [Nutropin AQ{28}]

Packaging and storage:
Nutropin AQ and Nutropin{80}Store between 2 and 8 °C (36 and 46 °F). Protect from freezing. {23} {28}

Norditropin cartridges: Prior to dispensing, store the delivery device at a temperature between 2 and 8 °C (36 and 46 °F). Protect from freezing and direct light.{76}

Stability:
Nutropin AQStable for up to 28 days after initial use if stored in the refrigerator. {23}

Nutropin Stable for 14 days after reconstitution with Bacteriostatic Water for Injection, USP. {80}

Norditropin cartridges: Once a cartridge has been inserted into the injector, it must be stored in the refrigerator and used within 4 weeks.{76}


SOMATROPIN, RECOMBINANT, FOR INJECTION

Note: The specific activity of growth hormone is defined as International Units (IU) per mg of protein. In October 1994, a new standard was developed that changed the conversion amount from 2.6 IU per mg of growth hormone to 3 IU per mg of growth hormone. This change did not affect the milligram-per-kg dosing or the quantity (mg) of growth hormone per vial. The only change was the increase in the number of IUs per mg. {10} {27} {40}


Usual adult dose
Growth hormone deficiency–associated growth failure1
See Somatropin, Recombinant, Injection .

Acquired immunodeficiency syndrome (AIDS)–associated cachexia or
AIDS-associated weight loss
For patients weighing more than 55 kg: Subcutaneous, 6 mg a day at bedtime. {26} {75}

For patients weighing 45 to 55 kg: Subcutaneous, 5 mg a day at bedtime. {26} {75}

For patients weighing 35 to 44 kg: Subcutaneous, 4 mg a day at bedtime. {26} {75}

For patients weighing up to 35 kg: Subcutaneous, 0.1 mg per kg of body weight a day at bedtime. {26} {75}


Usual pediatric dose
Growth hormone deficiency–associated growth failure
Genotropin, Norditropin: Subcutaneous, 0.16 to 0.24 (0.48 to 0.72 IU) per kg of body weight a week divided into the appropriate dose for daily injection (six or seven times per week). {20} {21}

Humatrope, Nutropin, Saizen: Intramuscular or subcutaneous, 0.18 to 0.3 mg (0.54 to 0.9 IU) per kg of body weight a week with dosing and dosing regimen individualized according to the patient's needs. This can be divided into the appropriate dose for daily injection (six or seven times per week) or, as an alternative, divided and injected three times a week (every other day). {10} {22} {25} {27} {28} {29} {70} The subcutaneous route of administration is preferred to the intramuscular route. {10} {22} {70}


Note: If the growth rate does not exceed the pretreatment growth rate by at least 2 cm per year, the patient should be checked for noncompliance or the presence of antibodies or other medical problems such as hypothyroidism or malnutrition. {03} {36} {39} {55} {72} If increasing the dose is not effective, treatment should be discontinued and the patient re-evaluated. {74}

Chronic renal insufficiency–associated growth failure
See Somatropin, Recombinant, Injection .

Prader-Willi syndrome (PWS)-associated growth failure1
Subcutaneous, 0.24 mg per kg of body weight per week divided into the appropriate dose for daily injection (six or seven times per week).
{77}
Turner's syndrome–associated growth failure1
See Somatropin, Recombinant, Injection .

AIDS-associated cachexia or
AIDS-associated weight loss
Safety and efficacy have not been established. {26} {75}


Size(s) usually available:
U.S.—


0.2 mg (approximately 0.6 IU) per two-chamber cartridge (Rx) [Genotropin Miniquick{21}]


0.4 mg (approximately 1.2 IU) per two-chamber cartridge (Rx) [Genotropin Miniquick{21}]


0.6 mg (approximately 1.8 IU) per two-chamber cartridge (Rx) [Genotropin Miniquick{21}]


0.8 mg (approximately 2.4 IU) per two-chamber cartridge (Rx) [Genotropin Miniquick{21}]


1 mg (approximately 3 IU) per two-chamber cartridge (Rx) [Genotropin Miniquick{21}]


1.2 mg (approximately 3.6 IU) per two-chamber cartridge (Rx) [Genotropin Miniquick{21}]


1.4 mg (approximately 4.2 IU) per two-chamber cartridge (Rx) [Genotropin Miniquick{21}]


1.5 mg (approximately 4.5 IU) per two-chamber cartridge (Rx) [Genotropin{21}]


1.6 mg (approximately 4.8 IU) per two-chamber cartridge (Rx) [Genotropin Miniquick{21}]


1.8 mg (approximately 5.4 IU) per two-chamber cartridge (Rx) [Genotropin Miniquick{21}]


2 mg (approximately 6 IU) per two-chamber cartridge (Rx) [Genotropin Miniquick{21}]


4 mg (approximately 12 IU) per vial (Rx) [Norditropin ( diluent—benzyl alcohol 1.5% per mL){20}] [Serostim{26}]


5 mg (approximately 15 IU) per vial (Rx) [Humatrope (diluent— m-cresol 0.3%) (glycerin 1.7% ){10}] [Nutropin (diluent—benzyl alcohol 0.9% per mL){22}] [Saizen ( diluent—benzyl alcohol 0.9%){25}] [Serostim{26}]


5.8 mg (approximately 17.4 IU) per two-chamber cartridge (Rx) [Genotropin{21}]


6 mg (approximately 18 IU) per vial (Rx) [Serostim{26}]


8 mg (approximately 24 IU) per vial (Rx) [Norditropin ( diluent—benzyl alcohol 1.5% per mL){20}]


10 mg (approximately 30 IU) per vial (Rx) [Nutropin ( diluent—benzyl alcohol 0.9% per mL){22}]


13.8 mg (approximately 41.4 IU) per two-chamber cartridge (Rx) [Genotropin{21}]

Canada—


3.33 mg (approximately 10 IU) per vial (Rx) [Saizen (diluent—benzyl alcohol){29}]


5 mg (approximately 15 IU) per vial (Rx) [Humatrope (diluent— m-cresol) (glycerin){27}] [Nutropin (diluent—benzyl alcohol ){28}] [Serostim{75}]


6 mg (approximately 18 IU) per vial (Rx) [Serostim{75}]


6.7 mg (approximately 20 IU) per cartridge (Rx) [Humatrope{27}]


10 mg (approximately 30 IU) per vial (Rx) [Nutropin ( diluent—benzyl alcohol){28}]


13.3 mg (approximately 40 IU) per cartridge (Rx) [Humatrope{27}]


26.6 mg (approximately 80 IU) per cartridge (Rx) [Humatrope{27}]

Packaging and storage:
Prior to and following reconstitution, store Genotropin, Humatrope, Norditropin, Nutropin, and Saizen at a temperature between 2 and 8 °C (36 and 46 °F). {10} {20} {21} {22} {27} {28} {29} Protect the lyophilized powder, diluent, and reconstituted solution from freezing {10} {20} {22} {27} {28} and direct light. {20} {27}

Prior to dispensing, store the Genotropin Miniquick delivery device at a temperature between 2 and 8 °C (36 and 46 °F); it may be stored at or below 25 °C (77 °F) for up to 3 months after dispensing. {21}

Prior to reconstitution, store Serostim at a temperature between 15 and 30 °C (59 and 86 °F). Following reconstitution, store Serostim at a temperature between 2 and 8 °C (36 and 46 °F). Protect the lyophilized powder, diluent, and reconstituted solution from freezing. {26} {75}

Preparation of dosage form:
Genotropin is available as a two-chamber cartridge with the lyophilized powder in the front chamber and the diluent in the rear chamber. A reconstitution device to mix the powder and diluent is also provided. The manufacturers instructions for reconstitution should be followed. {21}

Humatrope may be available as cartridges for use with pen injection devices. {27} The manufacturer's instructions for reconstitution and administration should be followed. {27}

For products that package the diluent and somatropin in separate vials, using standard aseptic technique the following amount of diluent should be added:

• For Humatrope—1.5 to 5 mL of the diluent provided by the manufacturer should be added to the 5-mg vial. {10} {27}


• For Norditropin—2 mL of the diluent provided by the manufacturer should be added to the 4-mg or 8-mg vial. The resulting somatropin concentration is 2 mg or 4 mg per mL when using the 4-mg or 8-mg vial, respectively. {20}


• For Nutropin—1 to 5 mL of the diluent provided by the manufacturer or bacteriostatic water for injection (benzyl alcohol–preserved only) should be added to the 5-mg vial, or 1 to 10 mL of the diluent provided by the manufacturer or bacteriostatic water for injection (benzyl alcohol–preserved only) should be added to the 10-mg vial. {22}


• For Saizen—5 mL of the diluent provided by the manufacturer should be added to the 3.33-mg vial, {29} or 1 to 3 mL of the diluent provided by the manufacturer or bacteriostatic water for injection (benzyl alcohol–preserved only) should be added to the 5-mg vial. {25}


• For Serostim—1 mL of the diluent provided by the manufacturer should be added to the 4-mg, 5-mg, or 6-mg vial. {26} {75}


To mix the diluent with the somatropin, the diluent must be injected while aimed against the glass wall of the vial, then swirled gently to dissolve the contents of the vial. {10} {20} {22} {25} {26} {27} {28} {29} {75} The vial should not be shaken. {10} {20} {22} {25} {27} {28} {29} Cloudy solutions or those containing particulate matter should not be used. {10} {20} {25} {26} {27} {28} {29} {75}

If somatropin is to be administered to a neonate or to a patient with a known sensitivity to any component of the diluent, sterile water for injection should be used for reconstitution. {10} {20} {22} {23} {25} {27} {28} Benzyl alcohol used as a preservative has been associated with toxicity in neonates. Each vial should then be used only for one dose and any unused portion discarded. {10} {20} {22} {25} {27} {28}

Stability:


Genotropin:
1.5-mg cartridge and Genotropin Miniquick: Diluent contains no preservative. Stable for up to 24 hours if stored in the refrigerator following reconstitution. Both should be used only for one dose and any unused portion discarded. {21}

5.8-mg and 13.8-mg cartridges: Diluent contains a preservative. Stable for up to 21 days if stored in the refrigerator following reconstitution. {21}



Humatrope, Norditropin, Nutropin, Saizen:
Stable for up to 14 days if stored in the refrigerator following reconstitution with the diluent provided by the manufacturer. {10} {20} {22} {25} {28} {29} If sterile water for injection is used for reconstitution, each vial should be refrigerated and used within 24 hours. {10} {27}



Serostim:
Stable for up to 24 hours if stored in the refrigerator following reconstitution. {26} {75}




Revised: 05/08/2002



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