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SOMATROPIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Somatropin is a biosynthetic polypeptide hormone with an amino acid sequence identical to that of human growth hormone.
    B) Somatropin products may contain benzyl alcohol as an antimicrobial preservative. Benzyl alcohol has been associated with toxicity in newborns.
    1) Refer to "BENZYL ALCOHOL" management for further information.

Specific Substances

    1) Human growth hormone
    2) Recombinant growth hormone
    3) Somatotrophine
    4) Somatropin
    5) CB-311
    6) HGH
    7) LY-137998
    8) Molecular Formula: C990-H1528-N262-O300-S7
    9) CAS 12629-01-5

Available Forms Sources

    A) USES
    1) Somatropin is indicated for the treatment of children who have growth failure due to an inadequate secretion of normal endogenous growth hormone (Prod Info TEV-TROPIN(R) IV injection, 2011).
    2) Norditropin is a recombinant human growth hormone indicated for the following: treatment of children with growth failure due to growth hormone deficiency (GHD), short stature associated with Noonan syndrome, and short stature associated with Turner syndrome; and treatment of adults with either adult onset or childhood onset GHD (Prod Info NORDITROPIN(R) subcutaneous injection, 2007).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Peripheral edema, pancreatitis, hypo- and hyperglycemia, hypothyroidism, intracranial hypertension, tachycardia, hypertension, headache, agitation, fatigue, seizures, nausea and vomiting, hematuria, carpal tunnel syndrome, muscle and joint pain, gynecomastia and increased alkaline phosphatase have been reported following the therapeutic use of growth hormones.
    2) Somatropin products may contain benzyl alcohol as an antimicrobial preservative. Benzyl alcohol has been associated with toxicity in newborns.
    a) Refer to "BENZYL ALCOHOL" management for further information.
    B) WITH POISONING/EXPOSURE
    1) Somatropin is a biosynthetic polypeptide hormone with an amino acid sequence identical to that of human growth hormone. Overdose data are limited. Hyperglycemia may occur with an acute overdose. Symptoms of gigantism and/or acromegaly may be observed following long-term overdosage.
    0.2.20) REPRODUCTIVE
    A) Somatropin carries either a pregnancy category of FDA pregnancy category B or C, depending on the formulation. It is not known if somatropin is excreted into human breast milk.

Laboratory Monitoring

    A) Monitor vital signs following an overdose.
    B) Obtain baseline blood glucose level and monitor as indicated. Hyper- and hypoglycemia have been reported with clinical use.
    C) Monitor thyroid function following an overdose.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) Somatropin overdose information is limited. Treatment is symptomatic and supportive.
    B) Obtain baseline blood glucose level and monitor as indicated. Hyper- and hypoglycemia have been reported with therapeutic use.
    C) Monitor thyroid function following an overdose.

Range Of Toxicity

    A) A minimum toxic dose has not been established.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Peripheral edema, pancreatitis, hypo- and hyperglycemia, hypothyroidism, intracranial hypertension, tachycardia, hypertension, headache, agitation, fatigue, seizures, nausea and vomiting, hematuria, carpal tunnel syndrome, muscle and joint pain, gynecomastia and increased alkaline phosphatase have been reported following the therapeutic use of growth hormones.
    2) Somatropin products may contain benzyl alcohol as an antimicrobial preservative. Benzyl alcohol has been associated with toxicity in newborns.
    a) Refer to "BENZYL ALCOHOL" management for further information.
    B) WITH POISONING/EXPOSURE
    1) Somatropin is a biosynthetic polypeptide hormone with an amino acid sequence identical to that of human growth hormone. Overdose data are limited. Hyperglycemia may occur with an acute overdose. Symptoms of gigantism and/or acromegaly may be observed following long-term overdosage.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) EDEMA
    1) WITH THERAPEUTIC USE
    a) Peripheral edema has been reported in patients treated with growth hormone (Prod Info Nutropin(R), somatropin (rDNA origin) for injection, 2000; Prod Info Nutropin AQ(R), somatropin (rDNA origin) injection, 2000).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypertension has been reported following the use of growth hormone (Prod Info Humatrope(R), somatropin (rDNA origin) for injection, 2001; Prod Info Norditropin(R) cartridges, somatropin (rDNA origin) injection, 2000; Prod Info Serostim(R), somatropin (rDNA origin) for injection, 2000).
    C) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia has been reported with the use of growth hormone (Prod Info Humatrope(R), somatropin (rDNA origin) for injection, 2001; Prod Info Norditropin(R) cartridges, somatropin (rDNA origin) injection, 2000; Prod Info Serostim(R), somatropin (rDNA origin) for injection, 2000).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache has been reported (Prod Info Humatrope(R), somatropin (rDNA origin) for injection, 2001; Prod Info Genotropin(R), somatropin (rDNA origin) for injection, 2004; Prod Info Norditropin(R) cartridges, somatropin (rDNA origin) injection, 2000; Prod Info Serostim(R), somatropin (rDNA origin) for injection, 2000; Prod Info Nutropin Depot(TM), somatropin (rDNA origin) for injection, 1999).
    B) PSYCHOMOTOR AGITATION
    1) WITH THERAPEUTIC USE
    a) Of 151 patients treated with somatropin (2 or 5 units three times weekly) for complete growth hormone deficiency, one patient developed transient agitation and antisocial behavior (Guyda et al, 1975).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have been infrequently reported following the use of somatropin (Prod Info Saizen(R), somatropin (rDNA origin) for injection, 1999).
    D) FATIGUE
    1) Fatigue has been reported following the use of growth hormone (Prod Info Genotropin(R), somatropin (rDNA origin) for injection, 2004; Prod Info Serostim(R), somatropin (rDNA origin) for injection, 2000).
    E) BENIGN INTRACRANIAL HYPERTENSION
    1) WITH THERAPEUTIC USE
    a) Benign intracranial hypertension with papilledema (visual changes, headache, nausea and vomiting) has been reported in several patients treated with growth hormone products. Symptoms usually occurred within the first 8 weeks of therapy and resolved upon discontinuation of the therapy or a reduction of the growth hormone dose (Sweetman, 2002; USPDI , 2002; Prod Info Genotropin(R), somatropin (rDNA origin) for injection, 2004; Malozowski et al, 1995b).
    F) SECONDARY PERIPHERAL NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) Carpal tunnel syndrome is rare with somatropin therapy (Prod Info Humatrope(R), somatropin (rDNA origin) for injection, 2001; Prod Info Nutropin(R), somatropin (rDNA origin) for injection, 2000; Prod Info Nutropin AQ(R), somatropin (rDNA origin) injection, 2000; Prod Info Nutropin Depot(TM), somatropin (rDNA origin) for injection, 1999).
    2) WITH POISONING/EXPOSURE
    a) Bilateral median neuropathy, confirmed by nerve conduction velocities, developed in a male body builder during a self administered course of growth hormone (Dickerman et al, 2000).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea (up to 26%) and vomiting (up to 12%) have been reported with somatropin (Prod Info Serostim(R), somatropin (rDNA origin) for injection, 2000; Prod Info Nutropin Depot(TM), somatropin (rDNA origin) for injection, 1999).
    B) PANCREATITIS
    1) WITH THERAPEUTIC USE
    a) Rare cases of pancreatitis have been associated with the use of somatropin (Prod Info Humatrope(R), somatropin (rDNA origin) for injection, 2001; Prod Info Nutropin(R), somatropin (rDNA origin) for injection, 2000; Prod Info Nutropin AQ(R), somatropin (rDNA origin) injection, 2000; Prod Info Nutropin Depot(TM), somatropin (rDNA origin) for injection, 1999).
    b) CASE REPORT - A 12-year-old boy with pseudohypoparathyroidism and growth hormone deficiency, developed acute pancreatitis (serum amylase 798 U/L; lipase 320 U/L) after receiving 6 doses of growth hormone (0.05 mg/kg/day). Symptoms resolved upon discontinuation of the growth hormone therapy. Upon rechallenge, the patient developed similar symptoms (Malozowski et al, 1995a).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ALKALINE PHOSPHATASE RAISED
    1) WITH THERAPEUTIC USE
    a) Increased alkaline phosphatase may occur with somatropin use (USPDI , 2002; Prod Info Genotropin(R), somatropin (rDNA origin) for injection, 2004).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) BLOOD IN URINE
    1) WITH THERAPEUTIC USE
    a) Hematuria has been reported (Prod Info Genotropin(R), somatropin (rDNA origin) for injection, 2004; Prod Info Norditropin(R) cartridges, somatropin (rDNA origin) injection, 2000).
    B) GLYCOSURIA
    1) WITH THERAPEUTIC USE
    a) Glucosuria has been reported (Prod Info Genotropin(R), somatropin (rDNA origin) for injection, 2004; Prod Info Norditropin(R) cartridges, somatropin (rDNA origin) injection, 2000).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKEMIA
    1) WITH THERAPEUTIC USE
    a) Growth hormone use has been implicated with the induction of leukemia, however, the association is not clear (Prod Info Genotropin(R), somatropin (rDNA origin) for injection, 2004; Stahnke & Zeisel, 1989; Sartorio et al, 1989; Anon, 1988; Watanabe et al, 1988).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DISORDER OF SKIN
    1) WITH THERAPEUTIC USE
    a) Local reactions at injection site including pain, numbness, redness, and swelling have occurred with somatropin (Prod Info Humatrope(R), somatropin (rDNA origin) for injection, 2001; Prod Info Nutropin(R), somatropin (rDNA origin) for injection, 2000; Prod Info Nutropin AQ(R), somatropin (rDNA origin) injection, 2000; Prod Info Saizen(R), somatropin (rDNA origin) for injection, 1999). There have also been reports of fibrosis, nodules, rash, pigmentation, and bleeding at injection site with somatropin (Prod Info Genotropin(R), somatropin (rDNA origin) for injection, 2004).
    b) Rarely, increased in growth of preexisting nevi has been reported with somatropin (Prod Info Humatrope(R), somatropin (rDNA origin) for injection, 2001; Prod Info Nutropin(R), somatropin (rDNA origin) for injection, 2000; Prod Info Nutropin AQ(R), somatropin (rDNA origin) injection, 2000; Prod Info Nutropin Depot(TM), somatropin (rDNA origin) for injection, 1999).
    c) Exacerbation of existing psoriasis was infrequently seen with somatropin use (Prod Info Saizen(R), somatropin (rDNA origin) for injection, 1999).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCULOSKELETAL FINDING
    1) WITH THERAPEUTIC USE
    a) In adult patients, muscle pain, joint pain, joint disorder, and weakness have been reported (Prod Info Humatrope(R), somatropin (rDNA origin) for injection, 2001; Prod Info Norditropin(R) cartridges, somatropin (rDNA origin) injection, 2000).
    b) Increased tissue turgor has occurred with somatropin use (Prod Info Serostim(R), somatropin (rDNA origin) for injection, 2000).
    c) CASE SERIES- Mild inflammatory myositis, with myalgia and muscle weakness has been reported in 2 patients following growth hormone therapy. The authors suggested that myositis might be due to m-cresol used as a preservative in the preparation (Yordam, 1994).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) GYNECOMASTIA
    1) WITH THERAPEUTIC USE
    a) Rare cases of gynecomastia have been reported with somatropin (Prod Info Humatrope(R), somatropin (rDNA origin) for injection, 2001; Prod Info Nutropin(R), somatropin (rDNA origin) for injection, 2000; Prod Info Nutropin AQ(R), somatropin (rDNA origin) injection, 2000; Prod Info Nutropin Depot(TM), somatropin (rDNA origin) for injection, 1999).
    b) CASE SERIES - Prepubertal gynecomastia was reported in 22 patients during growth hormone therapy (Malozowski & Stadel, 2001).
    B) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Mild hyperglycemia has been reported (Prod Info Genotropin(R), somatropin (rDNA origin) for injection, 2004; Prod Info Norditropin(R) cartridges, somatropin (rDNA origin) injection, 2000).
    b) CASE REPORT - Nonketotic hyperglycemia developed in a 22-month-old child within weeks of beginning growth hormone therapy. In addition, she developed convulsions and metabolic acidosis; the patient died despite symptomatic treatment (Garg, 1994).
    2) WITH POISONING/EXPOSURE
    a) Hyperglycemia may occur with an acute overdose (Prod Info Nutropin AQ(R), somatropin (rDNA origin) injection, 2000).
    C) HYPOGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hypoglycemia has been observed following high acute dosage of growth hormones (Sweetman, 2002).
    b) Three cases of symptomatic hypoglycemia occurring 36 to 60 hours after injections of somatropin have been reported. In each case, patients were receiving somatropin injections three times a week. After modifying the dosage schedules so that growth hormone injections were given daily, hypoglycemic symptoms no longer occurred. The authors suggested that the problems with hypoglycemia were probably due to persistent insulin-like activity from somatomedins after the insulin antagonisms of growth hormone waned (Press et al, 1987).
    D) HYPOTHYROIDISM
    1) WITH THERAPEUTIC USE
    a) Reversible hypothyroidism developing in growth hormone deficient children treated with human growth hormone has been reported (USPDI , 2002; Lippe et al, 1975; Ranke et al, 1979).
    E) ACROMEGALY
    1) WITH POISONING/EXPOSURE
    a) Symptoms of gigantism and/or acromegaly may be observed following long-term overdosage (Prod Info Nutropin AQ(R), somatropin (rDNA origin) injection, 2000).
    F) EMPTY SELLA SYNDROME
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT - Pituitary atrophy (partial empty sella syndrome) has been reported in an athlete with a long history of abuse of exogenous growth hormone, testosterone and thyroid hormone (Dickerman & Jaikumar, 2001).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - A 12-year-old girl experienced an acute hypersensitivity reaction manifesting as generalized pruritic urticaria on two occasions immediately after being injected with 2 mg IM dose of somatropin (Walker et al, 1992). Skin testing confirmed the reaction to be due to the growth hormone itself rather than drug diluent. An acute desensitization protocol was then followed, and subsequently the child tolerated normal somatropin doses without difficulty.

Reproductive

    3.20.1) SUMMARY
    A) Somatropin carries either a pregnancy category of FDA pregnancy category B or C, depending on the formulation. It is not known if somatropin is excreted into human breast milk.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Somatropin carries either a pregnancy category of B or C, depending on the formulation.
    2) Somatropin is classified as US FDA Pregnancy Category C (Prod Info ZOMACTON(TM) subcutaneous injection, 2015; Prod Info Humatrope(R), somatropin (rDNA origin) for injection, 2001; Prod Info Nutropin(R), somatropin (rDNA origin) for injection, 2000; Prod Info Nutropin AQ(R), somatropin (rDNA origin) injection, 2000; Prod Info Nutropin Depot(TM), somatropin (rDNA origin) for injection, 1999). U.S. Food and Drug Administration's Pregnancy Category B (Prod Info Genotropin(R), somatropin (rDNA origin) for injection, 2004; Prod Info Serostim(R), somatropin (rDNA origin) for injection, 2000; Prod Info Saizen(R), somatropin (rDNA origin) for injection, 1999).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) It is not known if somatropin is excreted into human breast milk (Prod Info ZOMACTON(TM) subcutaneous injection, 2015; Prod Info Nutropin(R), somatropin (rDNA origin) for injection, 2000).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs following an overdose.
    B) Obtain baseline blood glucose level and monitor as indicated. Hyper- and hypoglycemia have been reported with clinical use.
    C) Monitor thyroid function following an overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor vital signs following an overdose.
    B) Obtain baseline blood glucose level and monitor as indicated. Hyper- and hypoglycemia have been reported with clinical use.
    C) Monitor thyroid function following an overdose.

Range Of Toxicity

Summary

    A) A minimum toxic dose has not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) GROWTH HORMONE DEFICIENCY
    1) Non-weight based: 0.2 mg/day (range, 0.15 to 0.3 mg/day) (Prod Info HUMATROPE(R) subcutaneous injection lyophilized powder, 2013; Prod Info GENOTROPIN(R) subcutaneous injection, 2014).
    2) Weight based: 0.006 mg/kg (6 mcg/kg). MAX dose: 0.0125 mg/kg (12.5 mcg/kg) daily (Prod Info HUMATROPE(R) subcutaneous injection lyophilized powder, 2013).
    7.2.2) PEDIATRIC
    A) DISEASE STATE
    1) GROWTH HORMONE DEFICIENCY-ASSOCIATED GROWTH FAILURE
    a) Humatrope(R): 0.026 mg/kg body weight to 0.043 mg/kg per day (0.18 to 0.3 mg/kg/week) subQ (Prod Info HUMATROPE(R) subcutaneous injection lyophilized powder, 2013).
    b) Norditropin(R) cartridge: 0.024 to 0.034 mg/kg/day subQ, 6 to 7 times per week (Prod Info Norditropin(R) Cartridges subcutaneous injection, 2013).
    c) Nutropin AQ(R): Up to 0.3 mg/kg/week subQ, divided into equal doses and administered daily (Prod Info Nutropin AQ(R) subcutaneous injection, 2014).
    d) Saizen(R): 0.18 mg/kg/week subQ; can be divided into equal doses given either on 3 alternate days, 6 times per week or daily (Prod Info SAIZEN(R) subcutaneous injection, 2014).
    e) Zomacton(TM): Up to 0.1 mg/kg subQ 3 times per week; MAX: Up to 0.3 mg/kg/week (Prod Info ZOMACTON(TM) subcutaneous injection, 2015).
    2) CHRONIC RENAL INSUFFICIENCY-ASSOCIATED GROWTH FAILURE
    a) Nutropin AQ(R): Up to 0.35 mg/kg/week subQ, divided into equal doses and administered daily; continued until renal transplantation (Prod Info Nutropin AQ(R) subcutaneous injection, 2014).
    3) TURNER'S SYNDROME-ASSOCIATED GROWTH FAILURE
    a) Nutropin AQ(R): Up to 0.375 mg/kkg/week subQ, divided into the appropriate dose for daily injection (7 times per week) or, divided and injected 3 times a week (every other day) (Prod Info Nutropin AQ(R) subcutaneous injection, 2014).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAMUSCULAR)MOUSE:
    a) 40 International Units/kg (RTECS, 2002)
    2) LD50- (ORAL)MOUSE:
    a) 160 International Units/kg (RTECS, 2002)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 80 International Units/kg (RTECS, 2002)
    4) LD50- (INTRAMUSCULAR)RAT:
    a) 40 International Units/kg (RTECS, 2002)
    5) LD50- (ORAL)RAT:
    a) 160 International Units/kg (RTECS, 2002)
    6) LD50- (SUBCUTANEOUS)RAT:
    a) 80 International Units/kg (RTECS, 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Somatropin, a polypeptide hormone, is derived from recombinant DNA technology. It has an amino acid sequence (191 amino acids) identical to that of pituitary-derived human growth hormone. Somatropin is synthesized by the addition of the human growth hormone gene to a modified strain of E. coli (Prod Info Genotropin(R), somatropin (rDNA origin) for injection, 2004).
    B) In studies, somatropin was therapeutically equivalent to pituitary-derived human growth hormone. In children who have growth hormone deficiency, treatment with somatropin resulted in an increase in growth rate and an increase in insulin-like growth factor-I levels similar to that seen with pituitary-derived human growth hormone. Somatropin has been shown to stimulate skeletal growth by increasing both the number and the size of the skeletal muscle cells, resulting in linear growth. It also influences the size of internal organs (Prod Info Nutropin AQ(R), somatropin (rDNA origin) injection, 2000).
    C) In studies, somatropin increased red cell mass, stimulated protein synthesis, influenced carbohydrate metabolism, induced lipid mobilization, stimulated chondroitin sulfate and collagen synthesis, stimulated urinary excretion of hydroxyproline (Prod Info Nutropin AQ(R), somatropin (rDNA origin) injection, 2000).

Physicochemical

Molecular Weight

    A) 191 amino acid residues and a molecular weight of 22,125 daltons (Prod Info Nutropin AQ(R), somatropin (rDNA origin) injection, 2000).

References

General Bibliography

    1) Anon: Growth hormone treatment and leukemia. Can Med Assoc J 1988; 139:877.
    2) Dickerman RD & Jaikumar S: Secondary partial empty sella syndrome in an elite bodybuilder. Neurol Res 2001; 23:336-338.
    3) Dickerman RD, Douglas JA, & East JW: Bilateral medial neuropathy and growth hormone use: a case report. Arch Phys Med Rehabil 2000; 81:1594-1595.
    4) Garg AK: Hyperglycemia during replacement growth hormone therapy. J Pediatr 1994; 125(2):329.
    5) Guyda H, Friesen H, & Bailey JD: Medical Research Council of Canada therapeutic trial of human growth hormone: first 5 years of therapy. Canad Med Assoc 1975; 112:1301-1309.
    6) Lippe BM, Van Herle AJ, & La Franchi SH: Reversible hypothyroidism in growth hormone-deficient children treated with human growth hormone. J Clin Endocrinol Metab 1975; 40(4):612-618.
    7) Malozowski S, Hung W, & Scott DC: Acute pancreatitis associated with growth hormone therapy for short stature. N Engl J Med 1995a; 332:401-402.
    8) Malozowski S, Tanner LA, & Wysowski DK: Benign intracranial hypertension in children with growth hormone deficiency treated with growth hormone. J Pediatr 1995b; 126(6):996-999.
    9) Press M, Notafrancesco A, & Genel M: Risk of hypoglycemia with alternate-day growth hormone injections. Lancet 1987; 1:1002-1004.
    10) Product Information: GENOTROPIN(R) subcutaneous injection, somatropin rDNA origin subcutaneous injection. Pharmacia & Upjohn Company (per FDA), New York, NY, 2014.
    11) Product Information: Genotropin(R), somatropin (rDNA origin) for injection. Pharmacia & Upjohn, Kalamazoo, MI, 2004.
    12) Product Information: HUMATROPE(R) subcutaneous injection lyophilized powder, somatropin rDNA origin subcutaneous injection lyophilized powder. Lilly USA, LLC (per DailyMed), Indianapolis, IN, 2013.
    13) Product Information: Humatrope(R), somatropin (rDNA origin) for injection. Eli Lilly & Company, Indianapolis, IN, 2001.
    14) Product Information: NORDITROPIN(R) subcutaneous injection, somatropin (rDNA) subcutaneous injection. Novo Nordisk,Inc, Princeton, NJ, 2007.
    15) Product Information: Norditropin(R) Cartridges subcutaneous injection, somatropin rDNA origin subcutaneous injection. Novo Nordisk Inc. (per FDA), Plainsboro, NJ, 2013.
    16) Product Information: Norditropin(R) cartridges, somatropin (rDNA origin) injection. Novo Nordisk, Princeton, NJ, 2000.
    17) Product Information: Nutropin AQ(R) subcutaneous injection, somatropin rDNA origin subcutaneous injection. Genentech, Inc. (per FDA), South San Francisco, CA, 2014.
    18) Product Information: Nutropin AQ(R), somatropin (rDNA origin) injection. Genentech, Inc, South San Francisco, CA, 2000.
    19) Product Information: Nutropin Depot(TM), somatropin (rDNA origin) for injection. Genentech, Inc, South San Francisco, CA, 1999.
    20) Product Information: Nutropin(R), somatropin (rDNA origin) for injection. Genentech, Inc, South San Francisco, CA, 2000.
    21) Product Information: SAIZEN(R) subcutaneous injection, somatropin rDNA origin subcutaneous injection. EMD Serono (per FDA), Rockland, MA, 2014.
    22) Product Information: Saizen(R), somatropin (rDNA origin) for injection. Serono Laboratories, Norwell, MA, 1999.
    23) Product Information: Serostim(R), somatropin (rDNA origin) for injection. Serono Laboratories, Norwell, MA, 2000.
    24) Product Information: TEV-TROPIN(R) IV injection, somatropin (rDNA origin) IV injection. Gate Pharmaceuticals (per FDA), Sellersville, PA, 2011.
    25) Product Information: ZOMACTON(TM) subcutaneous injection, somatropin rDNA origin subcutaneous injection. Ferring Pharmaceuticals Inc. (per DailyMed), Parsippany, NJ, 2015.
    26) Ranke M, Weber B, & Bierich JR: Long-term response to human growth hormone in 36 children with idiopathic growth hormone deficiency. Eur J Clin Invest 1979; 9:257-260.
    27) S Sweetman : Martindale: The Complete Drug Reference. London: Pharmaceutical Press (internet version). The Pharmaceutical Press. London, UK (Internet Version). Edition expires 2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    28) Sartorio A, Conti A, & Faglia G: Previous human GH treatment and leukemia (letter). J Endocrinol Invest 1989; 12:131-132.
    29) Stahnke N & Zeisel HJ: Growth hormone therapy and leukaemia. Eur J Pediatr 1989; 148:591-596.
    30) USPDI : Drug Information for the Health Care Professional, (internet version). US Pharmacopeial Convention, Inc. Rockville, MD (Internet Version). Edition expires 2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    31) Walker SB, Weiss ME, & Tattoni DS: Systemic reaction to human growth hormone treated with acute desensitization. Pediatrics 1992; 90:108-109.
    32) Watanabe S, Tsunematsu Y, & Fujimoto J: Leukaemia in patients treated with growth hormone (letter). Lancet 1988; 1:1159.