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  • CLASSES

    Growth Hormones
    Pituitary Hormones

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant growth hormone; less immunogenic than somatrem
    Used for growth hormone deficiency (GHD), growth failure, or short stature; also used for treating cachexia and AIDS wasting; also used for adults with short bowel syndrome
    Several brands are available with varying indications and dosage regimens

    COMMON BRAND NAMES

    Genotropin, Genotropin MiniQuick, Humatrope, Norditropin FlexPro, Nutropin AQ, Nutropin AQ NuSpin, Omnitrope, Saizen, Serostim, ZOMACTON, Zorbtive

    HOW SUPPLIED

    Genotropin/Genotropin MiniQuick/Humatrope/Omnitrope/Saizen/Serostim/ZOMACTON/Zorbtive Subcutaneous Inj Pwd F/Sol: 0.2mg, 0.4mg, 0.6mg, 0.8mg, 1mg, 1.2mg, 1.4mg, 1.6mg, 1.8mg, 2mg, 4mg, 5mg, 5.8mg, 6mg, 8.8mg, 10mg, 13.8mg, 24mg
    Humatrope Oral Inj Pwd F/Sol: 12mg
    Humatrope/Saizen Intramuscular Inj Pwd F/Sol: 5mg, 6mg, 8.8mg, 24mg
    Norditropin FlexPro/Nutropin AQ NuSpin/Omnitrope Subcutaneous Inj Sol: 1mL, 1.5mL, 2.5mg, 3mL, 5mg, 10mg, 15mg, 30mg

    DOSAGE & INDICATIONS

    For the treatment of growth hormone deficiency, growth failure, or short stature.
    NOTE: The response to somatropin therapy in pediatric patients tends to decline with time. However, the failure to increase growth rate, especially during the first year of therapy, necessitates close assessment of compliance and evaluation for underlying causes of growth failure, such as hypothyroidism, undernutrition, advanced bone age, and antibodies to recombinant human growth hormone.
    For replacement therapy in adults with growth hormone deficiency (GHD) for either childhood onset (secondary to congenital, genetic, acquired, or idiopathic causes) or adult onset (endogenous or associated with multiple hormone deficiencies, i.e., hypopituitarism, as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma).
    NOTE: In general, the diagnosis of both adult or childhood onset growth hormone deficiency should be confirmed by an appropriate growth hormone stimulation test. Stimulation testing may not be necessary in patients with congenital/genetic growth hormone deficiency or multiple pituitary hormone deficiencies due to organic disease.
    NOTE: Clinical response, side effects, and age- and gender-adjusted serum IGF-I levels may be used to guide dose titration. This approach will tend to result in larger doses for women compared to men, smaller doses for adult-onset GHD patients compared with childhood-onset GHD patients, and smaller doses for older and obese patients.
    NOTE: Patients with childhood onset growth hormone deficiency whose epiphyses are closed should be reevaluated before continuation of somatropin therapy.
    Subcutaneous dosage (Genotropin)
    Adults

    Initially, not more than 0.04 mg/kg SC per week divided into 6 or 7 equal daily injections. Increase dose, as needed, at 4 to 8 week intervals to a maximum of 0.08 mg/kg per week as 6 or 7 equal daily injections. Alternatively, 0.2 mg/day SC (range 0.15 to 0.3 mg/day SC) can be administered without consideration of body weight. Gradually increase the dose by 0.1 to 0.2 mg/day every 1 to 2 months as needed. Obese patients are more likely to experience adverse effects when dosed by weight.

    Geriatric

    See adult dosage. Consider giving a lower starting dose and smaller dose increments to minimize adverse events.

    Subcutaneous dosage (Humatrope)
    Adults

    Initially, not more than 0.006 mg/kg (0.018 International Units/kg/day) SC once daily. The dose may be increased based on individual patient requirements up to a maximum of 0.0125 mg/kg/day (0.0375 International Units/kg/day).

    Subcutaneous dosage (Norditropin)
    Adults

    Initially, not more than 0.004 mg/kg SC per day. After 6 weeks, the dose may be increased, as tolerated, to a maximum of 0.016 mg/kg per day. Alternatively, the following non-weight based approach may be used: initially, 0.2 mg SC per day (0.15—0.30 mg SC per day); increase dose gradually by increments of approximately 0.1—0.2 mg/day every 1—2 months based on clinical response and serum insulin-like growth factor I (IGF-I) concentrations. Decrease the dose as necessary based on the adverse events and/or serum IGF-I concentrations above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to person and between male and female patients. NOTE: Obese patients are more likely to experience adverse effects when dosed by weight.

    Geriatric

    See adult dosage. Consider giving a lower initial dose and smaller dose increments to minimize adverse events.

    Subcutaneous dosage (Nutropin and Nutropin AQ)
    Adults

    Initially, not more than 0.006 mg/kg SC once daily. The dose may be increased according to individual patient requirements to a maximum of 0.025 mg/kg once daily in patients < 35 years or 0.0125 mg/kg once daily in patients >= 35 years.

    Subcutaneous dosage (Omnitrope)
    Adults

    Initially, not more than 0.04 mg/kg SC per week divided into 7 equal daily injections, preferably administered in the evening. Increase dose as needed at 4—8 week intervals to a maximum of 0.08 mg/kg per week as 7 equal daily injections. Alternatively, 0.2 mg/day SC (range 0.15 to 0.3 mg/day SC) can be administered without consideration of body weight. Gradually increase the dose by 0.1 to 0.2 mg/day every 1 to 2 months as needed. Obese patients are more likely to experience adverse effects when dosed by weight.

    Subcutaneous dosage (Saizen)
    Adults

    Initially, not more than 0.005 mg/kg SC per day. After 4 weeks, the dose may be increased to a maximum of 0.01 mg/kg per day.

    Subcutaneous dosage (Valtropin)
    Adults

    Initially, 0.33 mg/day SC (equivalent to 0.005 mg/kg/day in a 66 kg adult) administered 6 days/week. After 4 weeks and if indicated, the dose may be increased up to a maximum of 0.66 mg/day (equivalent to 0.01 mg/kg/day in a 66 kg adult) administered 6 days/week. Alternatively, a starting dose of 0.2 mg/day SC (range 0.15—0.3 mg/day) can be given; the dose can be increased by 0.1—0.2 mg/day every 1—2 months as clinically indicated.

    For the long-term treatment of growth failure in children who have growth hormone deficiency due to inadequate growth hormone secretion.
    Subcutaneous dosage (Accretropin)
    Children

    0.18—0.3 mg/kg SC per week divided into 6 or 7 equal daily injections.

    Subcutaneous dosage (Genotropin)
    Children

    0.16—0.24 mg/kg SC per week divided into 6 or 7 equal daily injections.

    Subcutaneous or Intramuscular dosage (Humatrope)
    Children

    0.18 mg/kg/week (0.54 International Units/kg) SC or IM divided into equal doses given either on 3 alternate days, 6 times per week, or daily. The maximum replacement dosage is 0.1 mg/kg (0.3 International Units/kg) given three times per week. Dosage should be individualized for each patient.

    Subcutaneous dosage (Norditropin)
    Children

    0.024—0.034 mg/kg/dose SC given 6 to 7 times a week. Dosage should be individualized for each patient.

    Subcutaneous dosage (Nutropin, Nutropin AQ)
    Children

    0.3 mg/kg/week (approximately 0.9 International Units/kg) SC divided into daily injections is recommended. In pubertal patients, a weekly dosage of up to 0.7 mg/kg divided daily may be used. Dosage should be individualized for each patient.

    Subcutaneous dosage (Nutropin Depot)
    Children

    Initially, 1.5 mg/kg SC on the same day each month or 0.75 mg/kg twice each month on the same days of each month (e.g., days 1 and 15).

    Subcutaneous dosage (Omnitrope)
    Children

    0.16—0.24 mg/kg SC per week divided into 6 or 7 equal daily injections, preferably administered in the evenings.

    Subcutaneous or Intramuscular dosage (Saizen)
    Children

    0.18 mg/kg/week SC or IM; the dose can be divided into equal injections administered daily, 3 times/week, or 6 times/week.

    Subcutaneous dosage (Tev-Tropin, Zomacton)
    Children

    A dosage of up to 0.1 mg/kg/dose subcutaneously administered 3 times per week. Dosage should be individualized for each patient.

    Subcutaneous dosage (Valtropin)
    Children

    Generally, 0.17—0.3 mg/kg SC per week divided into equal doses and administered daily or 6 times/week. Dosage should be individualized for each patient.

    For growth failure due to Prader-Willi syndrome.
    Subcutaneous dosage (Genotropin or Omnitrope)

    NOTE: Genotropin or Omnitrope should only be used in Prader-Willi syndrome patients who have a diagnosis of growth hormone deficiency; Genotropin and Omnitrope are contraindicated in Prader-Willi syndrome patients who are severely obese or who have severe respiratory impairment.

    Children

    Generally, 0.24 mg/kg SC per week divided into 6 or 7 equal daily injections.

    For the long-term treatment of growth failure in children born small for gestational age (SGA) who fail to manifest catch-up growth by age 2—4.
    Subcutaneous dosage (Genotropin)
    Children

    Generally, 0.48 mg/kg SC per week divided into 6 or 7 equal daily injections for children who have not manifested catch-up growth by age 2. Recent data suggest that for younger children with a baseline HSDS between -2 and -3, the initial dose is 0.24 mg/kg/week SC with upwards titration as needed. For children with a baseline HSDS < -3 or for older/prepubertal children, the recommended initial dose is 0.48 mg/kg/week SC with a reduction in dosage towards 0.24 mg/kg/week SC if substantial catch-up growth is seen during the first few years of treatment.

    Subcutaneous dosage (Humatrope and Norditropin)
    Children

    Up to 0.067 mg/kg/day SC (0.47 mg/kg/week) is recommended. Recent data suggest that for younger children with a baseline HSDS between -2 and -3, the initial dose is 0.033 mg/kg/day SC with upwards titration as needed. For children with a baseline HSDS < -3 or for older/prepubertal children, the recommended initial dose is 0.067 mg/kg/day SC with a reduction in dosage towards 0.033 mg/kg/day SC if substantial catch-up growth is seen during the first few years of treatment.

    Subcutaneous dosage (Omnitrope)
    Children

    0.48 mg/kg SC per week divided into 6 or 7 equal daily injections for children who have not manifested catch-up growth by age 2.

    For growth failure associated with chronic renal failure up to the time of transplantation.
    Subcutaneous dosage (Nutropin only)
    Children

    0.35 mg/kg (approximately 1.05 International Units/kg) SC per week divided into daily injections (0.05 mg/kg/day). Dosage should be individualized for each patient. Hemodialysis patients should receive their injection at night just prior to going to sleep or at least 3—4 hours after hemodialysis to prevent hematoma formation due to the heparin. Chronic cycling peritoneal dialysis patients should receive their injection in the morning after they have completed dialysis. Chronic ambulatory peritoneal dialysis patients should receive the injection in the evening at the time of the overnight exchange. Nutropin may be continued up to the time of renal transplantation. There are insufficient data regarding the benefit of treatment beyond three years. NOTE: No studies have been completed in patients who have received renal transplants and the use of Nutropin in patients with functioning renal allografts is not indicated.

    For short stature associated with Turner's syndrome.
    Subcutaneous dosage (Accretropin)
    Children

    0.36 mg/kg SC per week divided into equal doses given 6 or 7 times/week.

    Subcutaneous dosage (Genotropin or Omnitrope)

    NOTE: Discontinue treatment with Genotropin or Omnitrope when epiphyses are fused.

    Children

    0.33 mg/kg SC per week divided into equal doses given 6 or 7 times/week.

    Subcutaneous dosage (Humatrope)
    Children

    Up to 0.375 mg/kg (1.125 International Units/kg) SC per week divided into equal doses given either daily or on 3 alternate days.

    Subcutaneous dosage (Norditropin)
    Children

    Up to 0.067 mg/kg/day SC is recommended.

    Subcutaneous dosage (Nutropin)
    Children

    Up to 0.375 mg/kg SC per week divided into equal doses given 3 to 7 times per week.

    Subcutaneous dosage (Valtropin)
    Children

    Up to 0.375 mg/kg SC per week divided into equal doses given either daily or 6 times/week.

    For short stature in children with SHOX (short stature homeobox-containing gene) deficiency.
    Subcutaneous dosage (Humatrope)
    Children

    0.35 mg/kg SC per week divided into daily injections.

    For short stature in children with Noonan Syndrome.
    Subcutaneous dosage (Norditropin only)
    Children

    Up to 0.066 mg/kg/day SC is recommended. Prior to initiating somatropin, ensure that the patient has short stature. Not all children with Noonan syndrome have short stature. Twenty-four children aged 3—14 years of age received doses of 0.033 mg/kg/day SC or 0.066 mg/kg/day SC for 2 years; after 2 years, the dose was adjusted based on growth response and continued until final height was achieved. Using the national reference, height gain from baseline increased 1.5 SDS (mean height gain of 9.9 cm in males and 9.1 cm in females at 18 years of age). Using the Noonan reference, height gain from baseline increased 1.6 SDS (mean height gain of 11.5 cm in males and 11 cm in girls at 18 years of age) was noted. During the first 2 years of treatment, height velocity was greater in the group receiving 0.066 mg/kg/day SC.

    For idiopathic short stature.
    Subcutaneous dosage (Genotropin or Omnitrope)

    NOTE: Discontinue treatment with Genotropin or Omnitrope when epiphyses are fused.

    Children

    Up to 0.47 mg/kg SC per week divided into equal doses given 6 to 7 times per week.

    Subcutaneous dosage (Humatrope)
    Children

    0.37 mg/kg SC per week divided into equal doses given 6 to 7 times per week.

    Subcutaneous dosage (Nutropin)
    Children

    Up to 0.3 mg/kg SC per week divided into equal doses given once daily every day (i.e., 7 times/week).

    For the treatment of HIV-associated failure to thrive in children, AIDS-associated wasting syndrome, or cachexia.
    NOTE: Injection sites should be rotated.
    For the treatment of HIV-associated adipose redistribution syndrome (HARS)†.
    Subcutaneous dosage (Serostim only)
    Adults

    Various treatment regimens have been used; the clinical significance of changes in visceral adipose tissue (VAT) with respect to improved cardiovascular profile in patients with HARS is not known. In one study, patients were randomized to 4 mg SC once daily at bedtime, 4 mg SC once every other day, or placebo for 12 weeks; subsequently, patients randomized to 4 mg SC once daily were re-randomized to 4 mg every other day or placebo for 12 weeks. Patients that were originally randomized to every other day dosing for the first 12 weeks continued to receive every other day dosing for 12 additional weeks. Patients originally randomized to placebo for the first 12 weeks received 4 mg SC once daily for the second 12 weeks. In a second study, patients were randomized to either somatropin 4 mg SC or placebo once daily at bedtime for 12 weeks. Following completion of the first 12 weeks, patients were re-randomized to either somatropin 2 mg SC every other day or placebo for an additional 24 weeks. In both studies, patients receiving either dose of somatropin (i.e., 4 mg once daily at bedtime or 4 mg every other day) for the first 12 weeks experienced significant reductions in VAT as compared to placebo (-28 cm3 for somatropin once daily at bedtime, -27 cm3 for somatropin once every other day, and -9 cm3 for placebo, p=0.034 and P=0.031, respectively, compared to placebo). Based on results from these studies, it appears that continued use of somatropin 4 mg SC every other day for an additional 12 weeks results in less reaccumulation of VAT than placebo (5.7 cm3 for somatropin vs. 17.7 cm3 for placebo, no p-value given); continued therapy with 2 mg SC every other day was not as effective as it resulted in similar fat reaccumulation as compared to placebo. It should be noted that both females and patients with lower baseline VAT levels demonstrated a smaller response to somatropin therapy.

    Subcutaneous dosage (Serostim only)
    Adults > 55 kg

    6 mg SC once daily at bedtime.

    Adults 45—55 kg

    5 mg SC once daily at bedtime.

    Adults 35—45 kg

    4 mg SC once daily at bedtime.

    Adults < 35 kg

    0.1 mg/kg SC once daily at bedtime.

    Children

    The manufacturer reports that in two small studies, 11 children with HIV associated failure to thrive received human growth hormone. In one study, a dose of 0.04 mg/kg/day SC for 26 weeks was used in five children ranging in age from 6 to 17 years. A second study used a dose of 0.07 mg/kg/day SC for 4 weeks in six children ages 8 to 14 years. Treatment was reported to be well tolerated and consistent with safety observations in growth hormone treated adults with AIDS wasting.

    For the treatment of short bowel syndrome in patients receiving specialized nutrition support as directed by a health care professional.
    NOTE: Changes to concomitant medications should be avoided during Zorbtive therapy.
    Subcutaneous dosage (Zorbtive only)
    Adults

    0.1 mg/kg SC once daily for 4 weeks. Do not exceed a maximum of 8 mg/day. Discontinue Zorbtive for up to 5 days to reduce severe toxicities, if needed. Upon resolution of symptoms, resume Zorbtive at 50% of the original dose. Permanently discontinue treatment if severe toxicity recurs or does not disappear within 5 days. Moderate fluid retention and arthralgias may respond to symptomatic treatment initially. Dosage selection for the elderly should usually start at the lower end of the dosage range. In clinical trials, Zorbtive (plus a specialized oral diet without glutamine) vs. diet alone significantly decreased the total amount of intravenous parenteral nutrition (TPN) by 2.1L/week. The addition of glutamine to the diet/Zorbtive group resulted in a significant decrease in IPN of 3.9 L/week. Frequency of TPN (days/week) was reduced by 1 day in the Zorbtive/diet group and by 2.2 days in the Zorbtive/diet/glutamine group, although significance was not reported. Other clinical reports have also documented a reduction in TPN usage. Somatropin effects on body weight, lean body mass, essential fatty acid status, stool mass and macronutrient absorption have been positive when compared to baseline (but not placebo) in some studies; the effect of somatropin on these endpoints is controversial.

    Geriatric

    See adult dosage. Dosage selection for the elderly should usually start at the lower end of the dosage range.

    MAXIMUM DOSAGE

    Somatropin, rh-GH doses must be individualized and are highly variable depending on the nature and severity of the disease, the formulation being used, and on patient response.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Injectable Administration

    Administer somatropin by intramuscular or subcutaneous injection. Do NOT administer intravenously.
    Discontinue therapy if final height is achieved or epiphyseal fusion occurs.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
     
     
    Accretropin:
    This product does not require reconstitution. Prior to administration, swirl the contents of the vial with a gentle rotary motion; do not shake. The solution should be clear. Store unopened vials under refrigeration at 2—8 degrees C (36—46 degrees F). Do not freeze. Protect from light. Once opened, the vial may be stored under refrigeration for up to 14 days. After 14 days, discard unused portion.
     
    Genotropin:
    This product is supplied as a powder, filled in a two-chamber cartridge with the active substance in the front chamber and the diluent in the rear chamber. The product is available in a 5 mg cartridge (green tip) and a 12 mg cartridge (purple tip). The 5 and 12 mg cartridges can be used with the Genotropin Pen or the Genotropin Mixer. Genotropin is also available, in various doses ranging from 0.2 mg—2 mg, in single use, auto-mix devices called Genotropin Miniquicks.
    Cartridges: Store cartridges in the refrigerator at 2—8 degrees C (36—46 degrees F) prior to reconstitution. Do not freeze; protect from light. A reconstitution device supplied by the manufacturer is used to mix the powder and the diluent. After the powder and diluent are mixed, gently tip the cartridge upside down a few times until completely dissolved. DO NOT SHAKE; this may cause denaturation of the protein. If the solution is cloudy, do not use. Following reconstitution, the 5 mg cartridge will contain a 5 mg/mL solution and the 12 mg cartridge will contain a 12 mg/mL solution; both the 5 mg and 12 mg cartridges contain overfill. The cartridges contain diluent with preservative (m-cresol) and may be stored under refrigeration for up to 28 days after reconstitution. Do not use the 5 mg and 12 mg cartridges in patients with m-cresol hypersensitivity
    Genotropin Minquicks: After dispensing, but prior to reconstitution, store at or below 25 degrees C (77 degrees F) for up to 3 months. A reconstitution device supplied by the manufacturer is used to mix the powder and diluent. Ten different strengths are available that each deliver a fixed volume of 0.25 mL. This product contains a diluent with no preservative, therefore, refrigerate after reconstitution and use within 24 hours. Use the reconstituted solution only once and discard any remaining solution.
     
    Humatrope:
    Prior to reconstitution, store under refrigeration at 2—8 degrees C (36—46 degrees F).
    Vials: Reconstitute each 5-mg vial with 1.5—5 mL of the supplied diluent (contains m-cresol as a preservative) or Bacteriostatic Water for Injection (contains benzoyl alcohol as a preservative); sterile water for injection can be used for patients with a hypersensitivity to both m-cresol and benzoyl alcohol. Direct the liquid against the glass vial wall. Swirl vial with a gentle rotary motion until contents are dissolved completely. Do not shake. If the solution is cloudy, do not use. Small, colorless particles may be present after refrigeration; this is not unusual for solutions containing proteins. Vials reconstituted with the diluent or bacteriostatic water are stable for 14 days when stored under refrigeration at 2—8 degrees C (36—46 degrees F). For vials reconstituted with sterile water, use the vial only once and discard the unused portion; if not used immediately, refrigerate (2—8 degrees C) and use within 24 hours. Avoid freezing reconstituted solutions.
    Cartridges: Reconstitute cartridges using ONLY the supplied diluent syringe; the cartridges are designed for use only with the Humatrope injection device. Once reconstituted, the cartridges are stable for up to 28 days when stored under refrigeration at 2—8 degrees C (36—46 degrees F). Store the injection device without the needle attached. Avoid freezing reconstituted solutions.
     
    Norditropin:
    Do not use reconstituted solution if cloudy or contains particulate matter.
    Prior to use, store under refrigeration at 2—8 degrees C (36—46 degrees F).
    Once a Norditropin pen is in use, the pen should be stored in the refrigerator (2—8 degrees C; 36—46 degrees F), and used within 4 weeks. Alternatively, the Norditropin pens may be stored in the pen at room temperatures, no higher than 25 degrees C (77 degrees F), for up to 3 weeks. NovoFine needles are recommended for administration. Wipe the stopper on the needle thread with rubbing alcohol to prevent contamination.
     
    Nutropin:
    Prior to reconstitution, store under refrigeration, 2—8 degrees C (36—46 degrees F).
    Reconstitute each 5-mg vial with 1—5 mL Bacteriostatic Water for Injection, USP (benzyl alcohol preserved) and each 10-mg vial with 1—10 mL of Bacteriostatic Water for Injection, USP (benzyl alcohol preserved). If using for newborns, reconstitute with sterile water for injection. Direct the liquid against the glass vial wall. Swirl vial with a gentle rotary motion until contents are dissolved completely. Do not shake. If the solution is cloudy after reconstitution or refrigeration, do not use. Small, colorless particles may be present after refrigeration; this is not unusual for solutions containing proteins. The pH after reconstitution with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved) is approximately 7.4.
    Solutions reconstituted with Bacteriostatic Water for Injection are stable for 14 days under refrigeration, 2—8 degrees C (36—46 degrees F). Solutions reconstituted with sterile water for injection should be used immediately and only once; discard any unused portions. Avoid freezing reconstituted solutions.
     
    Nutropin AQ:
    Does not require reconstitution. Solution should be clear. Small, colorless particles may be present after refrigeration; this is not unusual for solutions containing proteins. Allow vial or pen cartridge to come to room temperature and gently swirl. If solution is cloudy, do not use.
    Vials: Before needle insertion, wipe the vial septum with rubbing alcohol or antiseptic solution to prevent contamination by microorganisms that may be introduced by repeated needle insertions. Administer using sterile, disposable syringes and needles. Use syringes with small enough volume that the prescribed dose can be drawn from the vial with reasonable accuracy.
    Pen cartridge: Two strengths are available, 10 mg and 20 mg; intended for use only with Nutropin AQ Pen. Each pen and cartridge are color coded to ensure accurate placement of the 10 mg or 20 mg cartridge into the appropriate pen. Do not use the 20 mg cartridge in the pen intended for the 10 mg cartridge, and vice versa. Wipe septum of pen cartridge with rubbing alcohol or antiseptic solution to prevent contamination by microorganisms that may be introduced by repeated needle insertions. Administered using sterile, disposable needles. Follow the directions provided in the Nutropin AQ Pen Instructions for Use. The Nutropin AQ 10 pen allows for administration of a minimum 0.1 mg dose to a maximum 4 mg dose, in 0.1 mg increments. The Nutropin AQ 20 pen allows for administration of a minimum 0.2 mg dose to a maximum 8 mg dose, in 0.2 mg increments.
    Prefilled device: A prefilled multi-dose, dial a dose device is available in 3 strengths. Administer using disposable needles. Follow the directions provided in the Nutropin AQ NuSpin Instruction for Use. The Nutropin AQ Nuspin 5 allows for administration of a minimum dose of 0.05 mg to a maximum dose of 1.75 mg, in increments of 0.05 mg. The Nutropin AQ Nuspin 10 allows for administration of a minimum dose of 0.1 mg to a maximum dose of 3.5 mg, in increments of 0.1 mg. The Nutropin AQ Nuspin 20 allows for administration of a minimum dose of 0.2 mg to a maximum dose of 7 mg, in increments of 0.2 mg.
    After initial use, vials, cartridges, and prefilled devices are stable for 28 days when stored under refrigeration, 2—8 degrees C (36—46 degrees F); avoid freezing. Vials, cartridges, and prefilled devices are light sensitive; protect from light.
     
    Omnitrope:
    Prior to reconstitution, store vials under refrigerations at 2—8 degrees C (36—46 degrees F). Do not freeze. Store in the carton; Omnitrope is sensitive to light.
    Vials: Reconstitute the vial with diluent provided using a sterile, disposable syringe. Swirl the vial gently, but do not shake. If the solution is cloudy after reconstitution, the contents must not be injected. After reconstitution, the 1.5 mg vial may be stored under refrigeration, 2—8 degrees C (36—46 degrees F), for up to 24 hours. The 1.5 mg vial does not contain a preservative and should only be used once; discard any remaining solution. The 5.8 mg vial diluent contains benzoyl alcohol as a preservative. After reconstitution, the contents must be used within 3 weeks. After the first injection, store the 5.8 mg vial in the carton, to protect from light, in the refrigerator at 2—8 degrees C (36—46 degrees F). Avoid freezing.
    Omnitrope Pen 5 cartridge: Each 5 mg cartridge must be inserted into the Omnitrope Pen 5 delivery system. Follow the directions provided in the Omnitrope Instructions for Use. The cartridge contains benzoyl alcohol as a preservative. Once initially used, store under refrigeration at 2—8 degrees C (36—46 degrees F) for up to 28 days. Protect from light. Avoid freezing.
    Omnitrope Pen 10 cartridge: Each 10 mg cartridge must be inserted into the Omnitrope Pen 10 delivery system. Follow the directions provided in the Omnitrope Instructions for Use. Once initially used, store under refrigeration at 2—8 degrees C (36—46 degrees F) for up to 28 days. Protect from light. Avoid freezing.
     
    Saizen:
    Prior to reconstitution, store at room temperature (15—30 degrees C; 59—86 degrees F).
    Vials: Reconstitute each 5 mg vial with 1—3 mL bacteriostatic water for injection; reconstitute each 8.8 mg vial with 2—3 mL bacteriostatic water for injection (benzoyl alcohol preserved). In patients with hypersensitivity to benzyl alcohol, the vials can be mixed with sterile water for injection. Direct the liquid against the glass vial wall. Swirl vial with a gentle rotary motion until contents are dissolved completely. Do not shake. The solution should be clear; if it is cloudy immediately after reconstitution or refrigeration, do not use. Small, colorless particles may be present after refrigeration; this is not unusual for solutions containing proteins. After reconstitution, store vials mixed with bacteriostatic water for injection under refrigeration at 2—8 degrees C (36—46 degrees F) and use within 14 days. For vials mixed with sterile water for injection, the solution should be used immediately, and any unused portion should be discarded. Avoid freezing.
    Cartridges: Available in 4 mg and 8.8 mg click.easy cartridges for use in a compatible injection device. A reconstitution device supplied by the manufacturer is used to mix the Saizen with accompanying diluent containing metacresol. Cartridges reconstituted with the diluent containing metascresol are stable under refrigeration for up to 21 days. Avoid freezing.
     
    Serostim:
    Prior to reconstitution, store vials and diluent at room temperature (15—30 degrees C; 59—86 degrees F).
    Vials: Reconstitute the 5 mg or 6 mg vials with 0.5—1 mL of supplied diluent (sterile water for injection). Reconstitute the 4 mg vial with 0.5—1 mL of bacteriostatic water for injection (benzoyl alcohol preserved) and the 8.8 mg vial with 1—2 mL of bacteriostatic water for injection (benzoyl alcohol preserved). Direct the liquid against the glass vial wall. Swirl vial with a gentle rotary motion until contents are dissolved completely. Do not shake. The solution should be clear; if it is cloudy immediately after reconstitution or refrigeration, do not use. Small, colorless particles may be present after refrigeration; this is not unusual for solutions containing proteins. If reconstituted with sterile water for injection, use within 24 hours. If reconstituted with bacteristatic water for injection (benzoyl alcohol preserved), the solution is stable for up to 14 days under refrigeration (2—8 degrees C or 36—46 degrees F). Avoid freezing.
    Cartridges: Available in 8.8 mg click.easy cartridges for use in a compatible injection device. A reconstitution device is supplied by the manufacturer and is used to mix the Serostim with accompanying diluent containing metacresol. After reconstitution, cartridges are stable under refrigeration for up to 21 days. Avoid freezing.
     
    Serostim LQ:
    Prior to use, store under refrigeration (2—8 degrees C; 36—46 degrees F).
    Available in 6 mg single-use cartridges that do not require reconstitution. Administer using sterile, disposable syringes and needles.
    Bring to room temperature prior to injecting the dose. Discard single-use cartridge after use, even if some drug remains. Discard cartridges after the expiration date stated on the product. Do not freeze. Protect from light.
     
    Valtropin:
    Prior to dispensing, store vials and diluent under refrigeration (2—8 degrees C or 36—46 degrees F). After dispensing to patients, may be stored at or below 25 degrees C (77 degrees F) for up to 3 months.
    Reconstitute each 5 mg vial with the entire contents of the accompanying diluent, which contains metacresol as a preservative. If patients are allergic to metacresol, sterile water for injection can be used. Direct the liquid against the glass vial wall. Swirl vial with a gentle rotary motion until contents are dissolved completely. Do not shake. The solution should be clear; if it is cloudy or contains particulate matter immediately after reconstitution or after refrigeration, do not inject. The final concentration of the reconstituted solution is 3.33 mg/mL.
    After reconstituted with the provided diluent, solutions can be stored under refrigeration (2—8 degrees C or 36—46 degrees F) for up to 14 days. After reconstituted with sterile water for injection, use only one dose of Valtropin® per vial and discard the unused portion if not used immediately.
     
    Zomacton (formerly Tev-Tropin):
    Reconstitute each 5-mg vial with 1—5 mL bacteriostatic 0.9% NaCl and each 10-mg vial with 1 mL bacteriostatic water for injection (containing 0.33% metacresol as a preservative). When reconstituting for newborns, use sterile NaCl (unpreserved). Direct the liquid against the glass vial wall to prevent foaming. Swirl vial gently until contents are dissolved completely. Do not shake. The solution should be clear; if it is cloudy immediately after reconstitution, do not inject. Small, colorless particles may be present after refrigeration; this is not unusual for solutions containing proteins.
    Zomacton may be administered using a standard sterile disposable syringe or a Zoma-Jet Needle-Free injection device; refer to the User's Manual provided with the administration device.
    After reconstitution with bacteriostatic 0.9% sodium chloride, the solution may be stored under refrigeration (2—8 degrees C or 36—46 degrees F) for up to 14 days. After reconstitution with bacteriostatic water for injection (containing 0.33% metacresol), the solution may be stored under refrigeration (2—8 degrees C or 36—46 degrees F) for up to 28 days. Solution reconstituted using sterile normal saline (containing no preservative) should be used only once, with any remaining solution discarded. Do not freeze reconstituted solutions.
     
    Zorbtive:
    Unreconstituted vials of drug and diluent may be stored at room temperature (15—30 degrees C; 59—86 degrees F) until expiration date.
    Reconstitute each vial of 4 mg, 5 mg, or 6 mg with 0.5—1 mL sterile water for injection, USP. Reconstitute each 8.8 mg with 1—2 mL bacteriostatic water for injection (0.9% benzyl alcohol preserved); in newborns or patients with a benzoyl alcohol hypersensitivity, sterile water for injection can be used. Review manufacturer's labeling for expected concentrations. Direct the liquid against the glass vial wall. Swirl vial with a gentle rotary motion until contents are dissolved completely. Do not shake. The solution should be clear; if it is cloudy after reconstitution or refrigeration, do not use. Small, colorless particles may be present after refrigeration; this is not unusual for solutions containing proteins.
    After reconstitution with sterile water for injection, use the solution immediately and discard any unused portion. When using bacteriostatic water for injection, reconstituted solutions are stable for up to 14 days under refrigeration (2—8 degrees C; 36—46 degrees F). Avoid freezing vials of drug or diluent, or reconstituted vials.

    Intramuscular Administration

    Inject somatropin deeply into a large muscle. Aspirate prior to injection to avoid injection into a blood vessel. Rotate injection sites daily.

    Subcutaneous Administration

    Subcutaneous injection of somatropin volumes greater than 1 ml of reconstituted solution is not recommended. Inject SC taking care not to inject intradermally.
    Allow refrigerated solutions to come to room temperature prior to injection.
    Subcutaneous injections may be given in the thigh, buttocks, or abdomen. Rotate injection sites daily.

    STORAGE

    Genotropin:
    - Prior to dispensing, store in refrigerator (36 to 46 degrees F)
    - Protect from freezing
    - Protect from light
    - Reconstituted product may be stored under refrigeration (36 to 46 degrees F) for up to 28 days
    Genotropin MiniQuick:
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Prior to dispensing, store in refrigerator (36 to 46 degrees F)
    - Protect from light
    - Reconstituted product may be stored refrigerated in its carton at 36 to 46 degrees F for up to 24 hours if not used immediately
    - Store below 77 degrees F
    - Upon dispensing, product may be stored refrigerated (36 to 46 degrees F), or at or below 77 degrees F for up to 3 months
    Humatrope:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Reconstituted product may be stored for up to 14 days if refrigerated (36 to 46 degrees F)
    - Store unreconstituted product in refrigerator (36 to 46 degrees F)
    Norditropin:
    - Do not freeze
    - Protect from light
    - Store opened container in refrigerator (between 36 to 46 degrees F) for up to 30 days
    - Store unopened containers in refrigerator (36 to 46 degrees F)
    Norditropin FlexPro:
    - Avoid direct heat and sunlight
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Store opened container in refrigerator (36 to 46 degrees F) and use within 4 weeks OR may store for up to 3 weeks at no more than 77 degrees F
    - Store unopened containers in refrigerator (36 to 46 degrees F)
    Norditropin Nordiflex:
    - Avoid direct heat and sunlight
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Store opened container in refrigerator (36 to 46 degrees F) and use within 4 weeks OR may store for up to 3 weeks at no more than 77 degrees F
    - Store unopened containers in refrigerator (36 to 46 degrees F)
    Nutropin:
    - Protect from freezing
    - Reconstituted product may be stored for up to 14 days if refrigerated (36 to 46 degrees F)
    - Store unreconstituted product in refrigerator (36 to 46 degrees F)
    Nutropin AQ:
    - Product is stable for 28 days after initial use when stored under refrigeration (36 to 46 degrees F)
    - Protect from freezing
    - Protect from light
    Nutropin AQ NuSpin :
    - Do not freeze
    - Product is stable for 28 days after initial use when stored under refrigeration (36 to 46 degrees F)
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    Omnitrope:
    - Discard cartridge 28 days after 1st injection
    - Protect from freezing
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in carton
    - The cartridge should remain in the pen
    Saizen:
    - Protect from freezing
    - Reconstituted product should be refrigerated (35 to 46 degrees F) for up to 21 days
    - Store unreconstituted product at 59 to 86 degrees F
    Serostim:
    - Reconstituted product may be stored for up to 14 days if refrigerated (36 to 46 degrees F)
    - Store unreconstituted product at 59 to 86 degrees F
    Tev-Tropin:
    - Do not freeze reconstituted product
    - Reconstituted product may be stored for up to 14 days if refrigerated (36 to 46 degrees F)
    - Store unreconstituted product in refrigerator (36 to 46 degrees F)
    ZOMACTON:
    - Do not freeze reconstituted product
    - Protect from light
    - Store reconstituted product in refrigerator (36 to 46 degrees F), discard after 14 days
    - Store unreconstituted product in refrigerator (36 to 46 degrees F)
    Zorbtive:
    - Protect from freezing
    - Reconstituted product may be stored for up to 14 days if refrigerated (36 to 46 degrees F)
    - Store unreconstituted product at 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    In August 2011, the FDA notified healthcare professionals that it has reviewed data from the SAGhE (Sante Adulte GH Enfant) study (a long-term epidemiological study conducted in France). The SAGhe Study found that patients with idiopathic growth hormone deficiency and idiopathic or gestational short stature treated with somatropin during childhood had a 30% increased risk of death compared to the general population. The FDA determined this evidence regarding recombinant human growth hormone and increased risk of death to be inconclusive. A 2016 study devised an advanced mortality model using the the Swedish Medical Birth Registry to estimate standardized mortality rates in patients receiving growth hormone compared to the general population. The authors concluded that the increase in mortality found in the SAGhE study was most likely related to basic characteristics of the growth hormone deficiency population (i.e. birth weight, birth length, and congenital malformations) rather than due to the use of growth hormone treatment itself.
     
    Somatropin therapy may cause changes in some laboratory values. Serum levels of inorganic phosphorus, alkaline phosphatase, and parathyroid hormone may increase with somatropin therapy.

    Angioedema, cresol hypersensitivity, glycerin hypersensitivity, risk of serious hypersensitivity reactions or anaphylaxis

    Somatropin products are contraindicated in patients with a known hypersensitivity to somatropin or any of the product excipients. Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with post-marketing use of somatropin products. Patients and caregivers should be informed that there is a risk of serious hypersensitivity reactions or anaphylaxis and that prompt medical attention should be sought if an allergic reaction occurs. As with any hormonal product, local or systemic allergic reaction may occur. Several of the products contain m-cresol as a preservative. Some of the formulations recommend using sterile water for injection as a diluent in patients with m-cresol hypersensitivity; other products recommend using other formulations. The package insert of the specific product should be consulted for further information when using somatropin in patients with m-cresol hypersensitivity. Similarly, some of the formulations also contain glycerin. Do not use formulations of somatropin that contain glycerin in patients with glycerin hypersensitivity.

    Epiphyseal closure

    Somatropin is contraindicated for growth promotion in pediatric patients with epiphyseal closure. Linear growth can no longer occur in these patients. In addition, slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders or in patients undergoing rapid growth.

    Children, renal impairment, renal osteodystrophy

    Response to somatropin therapy in children tends to decrease over time. However, in children in whom growth rate is not increased, especially during the first year of treatment, compliance as well as other causes of growth failure including thyroid abnormalities, malnutrition, advanced bone age, and antibodies to somatropin should be assessed. Any child taking somatropin that complains of hip or knee pain or the development of a limp should be evaluated by a clinician. Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders or in children undergoing rapid growth. In addition, children with growth failure secondary to renal impairment should be evaluated for progression of renal osteodystrophy. Slipped capital femoral epiphysis or avascular necrosis of the femoral head may occur in children with advanced renal osteodystrophy; x-rays of the hip should occur prior to initiating therapy with somatropin. In August 2011, the FDA notified healthcare professionals that it has reviewed data from the SAGhE (Sante Adulte GH Enfant) study (a long-term epidemiological study conducted in France), which found that patients with idiopathic growth hormone deficiency and idiopathic or gestational short stature treated with somatropin during childhood had a 30% increased risk of death compared to the general population. The FDA has determined the evidence regarding recombinant human growth hormone and increased risk of death to be inconclusive; a number of study design weaknesses were found which limit the interpretability of the study results. Additionally, the FDA reviewed the medical literature, as well as reports from the Agency's Adverse Event Reporting System (AERS). The FDA will continue to review this safety issue and expects to receive additional data from the SAGhE study in Spring 2012. The FDA will update the public when new information is available. Healthcare professionals and patients should continue to prescribe and use recombinant human growth hormone according to the labeled recommendations.

    Benzyl alcohol hypersensitivity, neonates

    Some of the multi-dose somatropin products contain benzyl alcohol and should be used cautiously in neonates and patients with benzyl alcohol hypersensitivity. Benzyl alcohol has been associated with toxicity in newborns. If somatropin is to be used in neonates or in patients with benzoyl alcohol hypersensitivity, sterile water for injection, USP should be used for reconstitution and only one dose should be used per vial.

    Chemotherapy, neoplastic disease, radiation therapy, secondary malignancy

    Somatropin is contraindicated in patients with active neoplastic disease. Any pre-existing neoplastic disease, specifically intracranial lesions (including pituitary tumors) must be inactive, and chemotherapy and radiation therapy complete, prior to beginning somatropin therapy. In childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent growth hormone deficiency and were treated with somatropin, an increased risk of a secondary malignancy has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. It is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor recurrence in adults. Monitor all patients with a history of growth hormone deficiency secondary to an intracranial neoplasm routinely while on somatropin therapy for progression or recurrence of the tumor. Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, consider the risks and benefits of starting somatropin in these patients. If treatment with somatropin is initiated, these patients should be carefully monitored for development of neoplasms. Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes, of preexisting nevi. Somatropin therapy should be discontinued if evidence of neoplasia develops.

    Respiratory insufficiency, surgery, trauma

    Somatropin is contraindicated in patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or to patients having acute respiratory insufficiency. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin-treated patients (5.3—8 mg/day) compared to those receiving placebo. The safety of continuing somatropin treatment in patients receiving replacement doses for approved indications who currently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with somatropin in patients having acute critical illnesses should be weighed against the potential risk. Additionally, somatropin is contraindicated for use in pediatric patients with Prader-Willi syndrome and respiratory insufficiency as there have been reports of fatalities (see Prader-Willi discussion).

    Obesity

    The manufacturers of Genotropin and Norditropin indicate that adult patients with obesity receiving somatropin for growth hormone deficiency may be more likely to experience adverse events when dosed by weight (see Dosage). Using a daily dose that is not weight-based may be preferable. Additionally, somatropin is contraindicated for use in pediatric patients with Prader-Willi syndrome and obesity as there have been reports of fatalities (see Prader-Willi discussion).

    Respiratory infection, sleep apnea

    Somatropin is contraindicated in patients with Prader-Willi syndrome who are severely obese or have severe respiratory impairment. Unless patients with Prader-Willi syndrome also have a diagnosis of growth hormone deficiency, somatotropin is not indicated for long-term treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome. There have been reports of fatalities with the use of growth hormone in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of respiratory insufficiency or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at increased risk. Patients with Prader-Willi syndrome should be evaluated for upper airway obstruction before initiation of treatment with growth hormone. If during treatment with growth hormone patients show signs of upper airway obstruction (including onset of or increased snoring), treatment should be interrupted. All patients with Prader-Willi syndrome should be evaluated for sleep apnea and monitored if sleep apnea is suspected. All patients with Prader-Willi syndrome should also have effective weight control and be monitored for signs of respiratory infections, which should be diagnosed as early as possible and treated aggressively. Patients with Prader-Willi syndrome may also be at increased risk of intracranial hypertension.

    Diabetes mellitus, diabetic retinopathy

    Somatropin should be used cautiously in patients with diabetes mellitus. Patients with diabetes or glucose intolerance and those patients with risk factors for diabetes or glucose intolerance should be monitored closely during treatment with somatropin. Risk factors for glucose intolerance include obesity (including obese patients with Prader-Willi Syndrome), Turner syndrome, or a family history of type II diabetes. Because somatropin may reduce insulin sensitivity, especially at higher doses, patients should be monitored for evidence of glucose intolerance. Glucose intolerance or acromegaly may occur with chronic overdosage of somatropin. Dose adjustments of antidiabetic medications may be necessary when somatropin is initiated. Due to the effects of somatropin on insulin sensitivity and blood glucose concentrations, somatropin is contraindicated in patients with diabetic retinopathy.

    Scoliosis

    Patients with a history of scoliosis should receive somatropin with caution. Because growth hormone increases growth rate, patients with scoliosis can experience progression of scoliosis. Patients should be monitored for progression of scoliosis. In addition, skeletal abnormalities including scoliosis are commonly seen in untreated Turner's syndrome, Noonan's syndrome, and Prader-Willi syndrome patients. Clinicians should be aware of these abnormalities, which may manifest during growth hormone therapy.

    Adrenal insufficiency, hypothyroidism

    Patients who have or at risk for pituitary hormone deficiencies, and are receiving somatropin, may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) adrenal insufficiency. Patients treated with glucocorticoid replacement for previously diagnosed adrenal insufficiency may require an increase in their maintenance or stress doses following initiation of somatropin treatment. In addition, patients with untreated hypothyroidism will have an inadequate response to somatropin therapy. Changes in thyroid hormone plasma levels may develop during somatropin therapy because patients with Turner's syndrome have an inherent risk of developing autoimmune thyroid disease. Periodic thyroid function tests should be performed and treatment with thyroid hormone initiated when indicated.

    Increased intracranial pressure

    Somatropin therapy has been reported to cause increased intracranial pressure with papilledema, visual changes, headache, and nausea and/or vomiting. Symptoms usually occurred within the first eight weeks of somatropin therapy. Resolution of intracranial hypertension-associated symptoms occurred after discontinuation of somatropin therapy or after a reduction in the hormone dose. Funduscopic examination is recommended at the initiation and periodically during the course of somatropin therapy. Patients with chronic renal insufficiency, Prader-Willi syndrome, and Turner's syndrome may be at increased risk for developing intracranial hypertension.

    Pregnancy

    No adequate and well controlled studies have been conducted in pregnant humans, and the potential for somatropin to cause adverse effects on the fetus or reproductive system is unknown. In animal studies that have been performed, differing doses exceeding the regular human dose revealed no evidence of impaired fertility or harm to the fetus. Inform females of childbearing age that use of somatropin during pregnancy has not been studied in humans, therefore, the effects of the drug on the fetus are unknown.

    Breast-feeding

    No data are available regarding the presence of somatropin in human milk, the effects of somatropin on the breast-fed infant, or the effects of somatropin on milk production. Limited published literature reports no adverse effects on breast-feeding infants with maternal administration of somatropin and no decrease in milk production or change in milk content during treatment with somatropin. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Otitis media

    During treatment with somatropin, Turner's syndrome patients should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear or hearing disorders. In addition, patients with Turner's syndrome should be monitored closely for cardiovascular disorders such as stroke, aortic aneurysm, and hypertension because these patients are also at risk for these conditions.

    Geriatric

    Clinical studies of somatropin did not include sufficient numbers of geriatric subjects; however, reported clinical experience has not identified differences in responses between geriatric and younger adult patients. In general, dose selection for an older adult should be cautious, usually starting at the low end of the dosing range. Geriatric patients are more at risk for the adverse effects of therapy compared to pediatric and younger adult patients. According to practice guidelines, growth hormone/somatropin should only be prescribed to patients with clinical features suggestive of adult growth hormone deficiency (GHD) and biochemically proven evidence of adult GHD. There are no data are available to suggest that somatropin has beneficial effects in treating aging and age-related conditions and the enhancement of sporting performance; therefore, the prescription of the drug to adult patients for any reason other than the well-defined approved uses of the drug is not recommended. According to the Beers Criteria, growth hormone is considered a potentially inappropriate medication (PIM) for use in geriatric patients and should be avoided due to its small effect on body composition relative to a significant adverse effect profile (e.g., edema, arthralgia, carpal tunnel syndrome, gynecomastia, elevated fasting glucose). However, the Beers expert panel considers hormone replacement after pituitary gland removal to be an acceptable use in the elderly.

    Females

    Somatropin (Serostim) has been used in patients with HIV-associated adipose redistribution syndrome (HARS); somatropin therapy may be less effective in females with HARS as compared to men. During clinical trials, 47 women receiving somatropin showed no difference from placebo with respect to reduction in visceral adipose tissue (VAT). Reasons for the lack of effectiveness may be the concomitant use of estrogen (6 patients) or a lower baseline VAT level as compared to men. Lower VAT levels have been demonstrated in several clinical trials to be associated with a reduced response to somatropin.

    Pancreatitis

    Patients who develop persistent, severe abdominal pain during somatropin treatment should be evaluated for pancreatitis, especially pediatric patients. Use with caution in patients with a past history of pancreatitis or with risk factors for pancreatitis. Pancreatitis has been rarely reported in adults and children receiving somatropin, with pediatric patients appearing to be at greater risk compared to adults. Girls with Turner syndrome may have an even greater risk of developing pancreatitis compared to others undergoing somatropin treatment.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / 0-1.0
    pancreatitis / Delayed / 0-1.0
    increased intracranial pressure / Early / Incidence not known
    papilledema / Delayed / Incidence not known
    diabetic ketoacidosis / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    peripheral edema / Delayed / 3.0-45.0
    edema / Delayed / 3.0-45.0
    hypothyroidism / Delayed / 5.0-16.0
    elevated hepatic enzymes / Delayed / 6.0-13.0
    eosinophilia / Delayed / 12.0-12.0
    hematoma / Early / 9.0-9.0
    hyperlipidemia / Delayed / 8.0-8.0
    hypertension / Early / 3.0-8.0
    gastritis / Delayed / 6.0-6.0
    hypertriglyceridemia / Delayed / 1.0-5.0
    depression / Delayed / 5.0-5.0
    chest pain (unspecified) / Early / 5.0-5.0
    antibody formation / Delayed / 2.0-2.0
    hematuria / Delayed / 0-1.0
    hyperglycemia / Delayed / 10.0
    secondary malignancy / Delayed / Incidence not known
    fluid retention / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    bleeding / Early / Incidence not known
    erythema / Early / Incidence not known
    psoriasis / Delayed / Incidence not known

    Mild

    arthralgia / Delayed / 11.0-37.0
    myalgia / Early / 3.0-30.0
    headache / Early / 6.0-18.0
    paresthesias / Delayed / 2.0-17.0
    hypoesthesia / Delayed / 2.0-15.0
    musculoskeletal pain / Early / 5.0-14.0
    rhinitis / Early / 6.0-14.0
    back pain / Delayed / 3.0-11.0
    fatigue / Early / 4.0-9.0
    diaphoresis / Early / 8.0-8.0
    gynecomastia / Delayed / 3.0-8.0
    weakness / Early / 3.0-6.0
    asthenia / Delayed / 3.0-6.0
    cough / Delayed / 6.0-6.0
    acne vulgaris / Delayed / 6.0-6.0
    carpal tunnel syndrome / Delayed / 1.0-5.0
    insomnia / Early / 5.0-5.0
    nausea / Early / Incidence not known
    vomiting / Early / Incidence not known
    dizziness / Early / Incidence not known
    infection / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    injection site reaction / Rapid / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    alopecia / Delayed / Incidence not known
    rash (unspecified) / Early / Incidence not known

    DRUG INTERACTIONS

    Acarbose: (Minor) Administration of somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin, rh-GH is instituted.
    Acetohexamide: (Minor) Somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents. Monitor for signs indicating loss of diabetic control when therapy with somatropin is instituted.
    Alogliptin: (Minor) Endogenous counter-regulatory hormones such as growth hormone are released in response to hypoglycemia. When released, blood glucose concentrations rise. When somatropin, rh-GH, growth hormone is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents, such as alogliptin. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted.
    Alogliptin; Metformin: (Minor) Coadministration of metformin and somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of metformin. Patients receiving metformin should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin is instituted. (Minor) Endogenous counter-regulatory hormones such as growth hormone are released in response to hypoglycemia. When released, blood glucose concentrations rise. When somatropin, rh-GH, growth hormone is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents, such as alogliptin. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted.
    Alogliptin; Pioglitazone: (Minor) Endogenous counter-regulatory hormones such as growth hormone are released in response to hypoglycemia. When released, blood glucose concentrations rise. When somatropin, rh-GH, growth hormone is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents, such as alogliptin. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted.
    Alpha-glucosidase Inhibitors: (Minor) Administration of somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin, rh-GH is instituted.
    Amprenavir: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral protease inhibitors, a CYP3A4 substrate, are coadministered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate that in HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), somatropin did not adversely affect antiretroviral effectiveness as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Atazanavir: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral protease inhibitors, a CYP3A4 substrate, are coadministered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate that in HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), somatropin did not adversely affect antiretroviral effectiveness as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Atazanavir; Cobicistat: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral protease inhibitors, a CYP3A4 substrate, are coadministered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate that in HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), somatropin did not adversely affect antiretroviral effectiveness as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Azelastine; Fluticasone: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Beclomethasone: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Betamethasone: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Budesonide: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Budesonide; Formoterol: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Canagliflozin: (Minor) Endogenous counter-regulatory hormones such as growth hormone are released in response to hypoglycemia. When released, blood glucose concentrations rise. When somatropin, rh-GH, growth hormone is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted.
    Canagliflozin; Metformin: (Minor) Coadministration of metformin and somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of metformin. Patients receiving metformin should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin is instituted. (Minor) Endogenous counter-regulatory hormones such as growth hormone are released in response to hypoglycemia. When released, blood glucose concentrations rise. When somatropin, rh-GH, growth hormone is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted.
    Chlorpropamide: (Minor) Somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents. Monitor for signs indicating loss of diabetic control when therapy with somatropin is instituted.
    Ciclesonide: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Corticosteroids: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Corticotropin, ACTH: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Cortisone: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Cyclosporine: (Moderate) Somatropin may increase the activity of cytochrome-mediated metabolism of cyclosporine clearance.
    Dapagliflozin: (Minor) Endogenous counter-regulatory hormones such as growth hormone are released in response to hypoglycemia. When released, blood glucose concentrations rise. When somatropin, rh-GH, growth hormone is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted.
    Dapagliflozin; Metformin: (Minor) Coadministration of metformin and somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of metformin. Patients receiving metformin should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin is instituted. (Minor) Endogenous counter-regulatory hormones such as growth hormone are released in response to hypoglycemia. When released, blood glucose concentrations rise. When somatropin, rh-GH, growth hormone is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted.
    Dapagliflozin; Saxagliptin: (Minor) Endogenous counter-regulatory hormones such as growth hormone are released in response to hypoglycemia. When released, blood glucose concentrations rise. When somatropin, rh-GH, growth hormone is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted. (Minor) Exogenously administered somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents.
    Darunavir: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral protease inhibitors, a CYP3A4 substrate, are coadministered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate that in HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), somatropin did not adversely affect antiretroviral effectiveness as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Darunavir; Cobicistat: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral protease inhibitors, a CYP3A4 substrate, are coadministered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate that in HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), somatropin did not adversely affect antiretroviral effectiveness as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral protease inhibitors, a CYP3A4 substrate, are coadministered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate that in HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), somatropin did not adversely affect antiretroviral effectiveness as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Deflazacort: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Delavirdine: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral non-nucleoside reverse transcriptase inhibitors, a CYP3A4 substrate, are coadminsitered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), did not have decreased antiretroviral effectiveness, as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Desiccated Thyroid: (Minor) Excessive use of thyroid hormones with growth hormone (somatropin, rh-GH) may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to somatropin. Patients receiving concomitant therapy should be monitored closely to ensure appropriate therapeutic response to somatropin.
    Dexamethasone: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Efavirenz: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral non-nucleoside reverse transcriptase inhibitors, a CYP3A4 substrate, are coadminsitered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), did not have decreased antiretroviral effectiveness, as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Efavirenz; Emtricitabine; Tenofovir: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral non-nucleoside reverse transcriptase inhibitors, a CYP3A4 substrate, are coadminsitered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), did not have decreased antiretroviral effectiveness, as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Empagliflozin: (Minor) Endogenous counter-regulatory hormones such as growth hormone are released in response to hypoglycemia. When released, blood glucose concentrations rise. When somatropin, rh-GH, growth hormone is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted.
    Empagliflozin; Linagliptin: (Minor) Endogenous counter-regulatory hormones such as growth hormone are released in response to hypoglycemia. When released, blood glucose concentrations rise. When somatropin, rh-GH, growth hormone is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted. (Minor) Endogenous counter-regulatory hormones such as growth hormone are released in response to hypoglycemia. When released, blood glucose concentrations rise. When somatropin, rh-GH, growth hormone is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted.
    Empagliflozin; Metformin: (Minor) Coadministration of metformin and somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of metformin. Patients receiving metformin should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin is instituted. (Minor) Endogenous counter-regulatory hormones such as growth hormone are released in response to hypoglycemia. When released, blood glucose concentrations rise. When somatropin, rh-GH, growth hormone is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted.
    Estrogens: (Moderate) Somatropin can induce the activity of cytochrome-mediated metabolism of antipyrine clearance. Because estrogens are also metabolized in this way, somatropin may alter the metabolism of estrogens. In addition, growth-hormone deficient women also treated with estrogen replacement therapy require substantially more somatropin therapy to obtain comparable effects when compared to women not taking estrogen. Patients should be monitored for changes in efficacy of either drug when somatropin and estrogens are coadministered.
    Etravirine: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral non-nucleoside reverse transcriptase inhibitors, a CYP3A4 substrate, are coadminsitered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), did not have decreased antiretroviral effectiveness, as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Fludrocortisone: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Flunisolide: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Fluticasone: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Fluticasone; Salmeterol: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Fluticasone; Vilanterol: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Formoterol; Mometasone: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Fosamprenavir: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral protease inhibitors, a CYP3A4 substrate, are coadministered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate that in HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), somatropin did not adversely affect antiretroviral effectiveness as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Glimepiride: (Minor) Somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents. Monitor for signs indicating loss of diabetic control when therapy with somatropin is instituted.
    Glimepiride; Pioglitazone: (Minor) Somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents. Monitor for signs indicating loss of diabetic control when therapy with somatropin is instituted.
    Glimepiride; Rosiglitazone: (Minor) Somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents. Monitor for signs indicating loss of diabetic control when therapy with somatropin is instituted.
    Glipizide: (Minor) Somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents. Monitor for signs indicating loss of diabetic control when therapy with somatropin is instituted.
    Glipizide; Metformin: (Minor) Coadministration of metformin and somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of metformin. Patients receiving metformin should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin is instituted. (Minor) Somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents. Monitor for signs indicating loss of diabetic control when therapy with somatropin is instituted.
    Glyburide: (Minor) Somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents. Monitor for signs indicating loss of diabetic control when therapy with somatropin is instituted.
    Glyburide; Metformin: (Minor) Coadministration of metformin and somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of metformin. Patients receiving metformin should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin is instituted. (Minor) Somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents. Monitor for signs indicating loss of diabetic control when therapy with somatropin is instituted.
    Hydrocortisone: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Incretin Mimetics: (Minor) Endogenous counter-regulatory hormones such as growth hormone are released in response to hypoglycemia. When released, blood glucose concentrations rise. When somatropin, rh-GH, growth hormone is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted.
    Indinavir: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral protease inhibitors, a CYP3A4 substrate, are coadministered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate that in HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), somatropin did not adversely affect antiretroviral effectiveness as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Insulins: (Minor) Monitor patients receiving insulin closely for worsening glycemic control when somatropin, rh-GH is instituted and for signs of hypoglycemia when somatropin, rh-GH is discontinued. Endogenous counter-regulatory hormones are released in response to hypoglycemia. When released, blood glucose concentrations rise. When these hormones or their derivatives (e.g., somatropin, rh-GH) are administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of insulin.
    Levothyroxine: (Minor) Excessive use of thyroid hormones with growth hormone (somatropin, rh-GH) may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to somatropin. Patients receiving concomitant therapy should be monitored closely to ensure appropriate therapeutic response to somatropin.
    Linagliptin: (Minor) Endogenous counter-regulatory hormones such as growth hormone are released in response to hypoglycemia. When released, blood glucose concentrations rise. When somatropin, rh-GH, growth hormone is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted.
    Linagliptin; Metformin: (Minor) Coadministration of metformin and somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of metformin. Patients receiving metformin should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin is instituted. (Minor) Endogenous counter-regulatory hormones such as growth hormone are released in response to hypoglycemia. When released, blood glucose concentrations rise. When somatropin, rh-GH, growth hormone is administered exogenously, increases in blood glucose concentrations would be expected thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents, such as linagliptin, should be closely monitored for signs indicating loss of diabetic control when growth hormone is instituted.
    Liothyronine: (Minor) Excessive use of thyroid hormones with growth hormone (somatropin, rh-GH) may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to somatropin. Patients receiving concomitant therapy should be monitored closely to ensure appropriate therapeutic response to somatropin.
    Liotrix: (Minor) Excessive use of thyroid hormones with growth hormone (somatropin, rh-GH) may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to somatropin. Patients receiving concomitant therapy should be monitored closely to ensure appropriate therapeutic response to somatropin.
    Lopinavir; Ritonavir: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral protease inhibitors, a CYP3A4 substrate, are coadministered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate that in HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), somatropin did not adversely affect antiretroviral effectiveness as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Mecasermin rinfabate: (Major) Use caution in concomitant use of mecasermin and somatropin. Both agents are used in the treatment of growth disorders and share feedback and pathway systems. Their additive use has not been studied.
    Mecasermin, Recombinant, rh-IGF-1: (Major) Use caution in concomitant use of mecasermin and somatropin. Both agents are used in the treatment of growth disorders and share feedback and pathway systems. Their additive use has not been studied.
    Meglitinides: (Minor) Administration of somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin, rh-GH is instituted.
    Metformin: (Minor) Coadministration of metformin and somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of metformin. Patients receiving metformin should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin is instituted.
    Metformin; Pioglitazone: (Minor) Coadministration of metformin and somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of metformin. Patients receiving metformin should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin is instituted.
    Metformin; Repaglinide: (Minor) Coadministration of metformin and somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of metformin. Patients receiving metformin should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin is instituted.
    Metformin; Rosiglitazone: (Minor) Coadministration of metformin and somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of metformin. Patients receiving metformin should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin is instituted.
    Metformin; Saxagliptin: (Minor) Coadministration of metformin and somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of metformin. Patients receiving metformin should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin is instituted. (Minor) Exogenously administered somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents.
    Metformin; Sitagliptin: (Minor) Coadministration of metformin and somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of metformin. Patients receiving metformin should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin is instituted. (Minor) Exogenously administered somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents.
    Methylprednisolone: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Miglitol: (Minor) Administration of somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin, rh-GH is instituted.
    Mometasone: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Nelfinavir: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral protease inhibitors, a CYP3A4 substrate, are coadministered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate that in HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), somatropin did not adversely affect antiretroviral effectiveness as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Nevirapine: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral non-nucleoside reverse transcriptase inhibitors, a CYP3A4 substrate, are coadminsitered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), did not have decreased antiretroviral effectiveness, as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Non-nucleoside reverse transcriptase inhibitors: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral non-nucleoside reverse transcriptase inhibitors, a CYP3A4 substrate, are coadminsitered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), did not have decreased antiretroviral effectiveness, as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Ombitasvir; Paritaprevir; Ritonavir: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral protease inhibitors, a CYP3A4 substrate, are coadministered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate that in HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), somatropin did not adversely affect antiretroviral effectiveness as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Pramlintide: (Minor) Administration of somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin, rh-GH is instituted.
    Prednisolone: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Prednisone: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.
    Protease inhibitors: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral protease inhibitors, a CYP3A4 substrate, are coadministered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate that in HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), somatropin did not adversely affect antiretroviral effectiveness as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Ritonavir: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral protease inhibitors, a CYP3A4 substrate, are coadministered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate that in HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), somatropin did not adversely affect antiretroviral effectiveness as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Saquinavir: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral protease inhibitors, a CYP3A4 substrate, are coadministered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate that in HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), somatropin did not adversely affect antiretroviral effectiveness as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Saxagliptin: (Minor) Exogenously administered somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents.
    Simvastatin; Sitagliptin: (Minor) Exogenously administered somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents.
    Sitagliptin: (Minor) Exogenously administered somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents.
    Sulfonylureas: (Minor) Somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents. Monitor for signs indicating loss of diabetic control when therapy with somatropin is instituted.
    Testosterone: (Moderate) Somatropin can induce (i.e., increase) the activity of cytochrome-mediated metabolism of antipyrine clearance in man. Thus, this predicts that somatropin may affect other drugs metabolized via this pathway, like testosterone.
    Thiazolidinediones: (Minor) Administration of somatropin may result in increases in blood glucose concentrations, thereby decreasing the hypoglycemic effect of antidiabetic agents. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with somatropin, rh-GH is instituted.
    Thyroid hormones: (Minor) Excessive use of thyroid hormones with growth hormone (somatropin, rh-GH) may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to somatropin. Patients receiving concomitant therapy should be monitored closely to ensure appropriate therapeutic response to somatropin.
    Tipranavir: (Minor) When somatropin, an inducer of CYP3A4, and anti-retroviral protease inhibitors, a CYP3A4 substrate, are coadministered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate that in HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), somatropin did not adversely affect antiretroviral effectiveness as indicated by no change in the concentration of circulating CD4 counts or viral load.
    Tolazamide: (Minor) Somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents. Monitor for signs indicating loss of diabetic control when therapy with somatropin is instituted.
    Tolbutamide: (Minor) Somatropin increases blood glucose concentrations thereby decreasing the hypoglycemic effect of antidiabetic agents. Monitor for signs indicating loss of diabetic control when therapy with somatropin is instituted.
    Triamcinolone: (Moderate) Corticosteroids can retard bone growth and therefore, can inhibit the growth-promoting effects of somatropin. If corticosteroid therapy is required, the corticosteroid dose should be carefully adjusted.

    PREGNANCY AND LACTATION

    Pregnancy

    No adequate and well controlled studies have been conducted in pregnant humans, and the potential for somatropin to cause adverse effects on the fetus or reproductive system is unknown. In animal studies that have been performed, differing doses exceeding the regular human dose revealed no evidence of impaired fertility or harm to the fetus. Inform females of childbearing age that use of somatropin during pregnancy has not been studied in humans, therefore, the effects of the drug on the fetus are unknown.

    No data are available regarding the presence of somatropin in human milk, the effects of somatropin on the breast-fed infant, or the effects of somatropin on milk production. Limited published literature reports no adverse effects on breast-feeding infants with maternal administration of somatropin and no decrease in milk production or change in milk content during treatment with somatropin. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Endogenous growth hormone is responsible for stimulating normal skeletal, connective tissue, muscle, and organ growth in children and adolescents. It also plays an important role in adult metabolism. Recombinant products mimic all of these actions. Somatropin binds to growth hormone (GH) receptors and produces a variety of physiologic effects that can be classified as being direct or indirect. The direct effects include antagonism of the peripheral action of insulin and the subsequent stimulation of insulin secretion; stimulation of the production of somatomedins or insulin-like growth factors (IGFs) in the liver and other tissues; stimulation of triglyceride hydrolysis in adipose tissue; stimulation of hepatic glucose output; induction of a positive calcium balance; and retention of sodium and potassium. These effects oppose the action of insulin on fat and carbohydrate metabolism and are potentiated by glucocorticoids.Somatomedins or insulin-like growth factors (IGFs) indirectly mediate the anabolic and growth-promoting effects of somatropin. IGFs circulate throughout the body and bind to specific IGF receptors. Two IGFs have been identified, IGF-1 and IGF-2. IGF-1 appears to be the principal mediator of the action of growth hormone, whereas IGF-2 has more insulin-like activity. The principal anabolic actions of IGFs include stimulation of amino acid transport, stimulation of DNA, RNA, and protein synthesis, and induction of cell proliferation and growth. IGF-1 is directly responsible for chondrogenesis, skeletal growth, and the growth of soft tissue. Linear growth is stimulated by affecting cartilaginous growth areas of long bones. Growth is also stimulated by increasing the number and size of skeletal muscle cells, influencing the size of organs, and increasing red cell mass through erythropoietin stimulation. The actions of growth hormone on the gut may be direct or mediated via the local or systemic production of IGF. In-vivo studies have shown that growth hormone enhances transmucosal transport of water, electrolytes, and nutrients. These indirect effects are inhibited by glucocorticoids.

    PHARMACOKINETICS

    Somatropin is administered by intramuscular or subcutaneous injection. Peak plasma concentrations of somatropin are reached in 2—6 hours following administration. About 20% of the circulating somatropin is bound to growth hormone-binding protein. Peak plasma concentrations of IGF-1 occur about 20 hours after administration of somatropin. Somatropin is metabolized by the liver, kidney, and other tissues. Somatropin undergoes glomerular filtration and the molecule is cleaved in the kidney. Once cleavages occurs in the renal cells, the peptides and amino acids are returned to the systemic circulation. Little excretion occurs via the urine. The plasma elimination half-life is approximately 20—30 minutes. Because of continued release of somatropin from the intramuscular or subcutaneous site, serum concentrations decline with a half-life of about 3—5 hours. Because of the slow induction and clearance of IGF-1, the effects of somatropin last much longer than its elimination half-life.

    Subcutaneous Route

    Following subcutaneous injection of the depot formulation, somatropin is released from the microspheres initially by diffusion, followed by both polymer degradation and diffusion. The estimated bioavailability following a single dose of Nutropin Depot ranges from 33—38% when compared to single dose Nutropin AQ and from 48—55% when compared to chronically dosed Protropin. Once released and absorbed, somatropin is believed to distributed and eliminated in a manner similar to somatropin formulated for daily administration. Both the Cmax and AUC are proportional to the dose. Serum growth hormone levels > 1 mcg/l persist for approximately 11—14 days following single doses of 0.75 or 1.5 mg/kg.