isone may be effected more than others since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βhsd-1. non-replacement glucocorticoid treatment in pediatric patients clinical impact: non-replacement glucocorticoid treatment, including supraphysiologic glucocorticoid treatment, may attenuate the growth promoting effects of humatrope in pediatric patients. intervention: carefully adjust glucocorticoid dosing in pediatric patients receiving glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth. cytochrome p450-metabolized drugs clinical impact: limited published data indicate that somatropin treatment increases cytochrome p450 (cp450)-mediated antipyrine clearance. humatrope may alter the clearance of compounds known to be metabolized by cp450 liver enzymes. intervention: careful monitoring is advisable when humatrope is administered in combination with drugs metabolized by cp450 liver enzymes. oral estrogen clinical impact: oral estrogens may reduce the serum igf-1 response to humatrope. intervention: patients receiving oral estrogen may require greater humatrope dosages [see dosage and administration ( 2.3 )] . insulin and/or other hypoglycemic agents clinical impact: treatment with humatrope may decrease insulin sensitivity, particularly at higher doses. intervention: patients with diabetes mellitus may require adjustment of their doses of insulin and/or other hypoglycemic agents [see warnings and precautions ( 5.4 )]. replacement glucocorticoid treatment: patients treated with glucocorticoids for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of humatrope. ( 7 ) non-replacement glucocorticoid treament in pediatric patients: adjust glucocorticoid dosing in pediatric patients receiving glucocorticoid treatment to avoid both hypoadrenalism and an inhibitory effect on growth. ( 7 ) cytochrome p450-metabolized drugs: humatrope may alter the clearance. monitor carefully if used with humatrope. ( 7 ) oral estrogen: patients may require larger doses of humatrope. ( 7 ) insulin and/or other hypoglycemic agents: dose adjustment of insulin or hypoglycemic agent may be required. ( 5.4 , 7 )

ociated with growth rates unlikely to permit attainment of adult height in the normal range, short stature or growth failure in short stature homeobox-containing gene (shox) deficiency, short stature born small for gestational age (sga) with no catch-up growth by 2 years to 4 years of age. 1.2 adult patients humatrope is indicated for the replacement of endogenous gh in adults with gh deficiency.

icoid dose increases in those with known hypoadrenalism. ( 5.8 ) hypothyroidism: monitor thyroid function periodically as hypothyroidism may occur or worsen after initiation of somatropin. ( 5.9 ) slipped capital femoral epiphysis in pediatric patients: may occur; evaluate patients with onset of a limp or hip/knee pain. ( 5.10 ) progression of preexisting scoliosis in pediatric patients: monitor patients with scoliosis for progression. ( 5.11 ) pancreatitis: has been reported; consider pancreatitis in patients with abdominal pain, especially pediatric patients. ( 5.12 ) 5.1 acute critical illness increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic doses of somatropin [see contraindications ( 4 )] . two placebo-controlled clinical studies in non-gh deficient adult patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (42% vs. 19%) among somatropin-treated patients (doses 5.3-8.0 mg/day) compared to those receiving placebo. the safety of continuing humatrope treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. humatrope is not indicated for the treatment of non-gh deficient adults. 5.2 sudden death in pediatric patients with prader-willi syndrome there have been reports of sudden death after initiating therapy with somatropin in pediatric patients with prader-willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. male patients with one or more of these factors may be at greater risk than females. patients with prader-willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin. if, during treatment with somatropin, patients show signs of upper airway obstruction (including onset of, or increased, snoring) and/or new onset sleep apnea, treatment should be interrupted. all patients with prader-willi syndrome treated with somatropin should also have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively [see contraindications ( 4 )] . humatrope is not indicated for the treatment of pediatric patients who have growth failure due to prader-willi syndrome. 5.3 increased risk of neoplasms active malignancy there is an increased risk of malignancy progression with somatropin treatment in patients with active malignancy [see contraindications ( 4 )]. any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with humatrope. discontinue humatrope if there is evidence of recurrent activity. risk of second neoplasm in pediatric patients an increased risk of a second neoplasm in pediatric cancer survivors who were treated with radiation to the brain/head and who developed subsequent gh deficiency and were treated with somatropin has been reported. intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. in adults, it is unknown whether there is any relationship between somatropin replacement therapy and cns tumor recurrence. monitor all patients receiving humatrope who have a history of gh deficiency secondary to an intracranial neoplasm for progression or recurrence of the tumor. new malignancy during treatment because pediatric patients with certain rare genetic causes of short stature have an increased risk of developing malignancies, thoroughly consider the risks and benefits of starting humatrope in these patients. if humatrope is initiated, carefully monitor patients for development of neoplasms. monitor all patients receiving humatrope carefully for increased growth, or potential malignant changes, of preexisting nevi. advise patients/caregivers to report marked changes in behavior, onset of headaches, vision disturbances and/or changes in skin pigmentation or changes in the appearance of pre-existing nevi. 5.4 glucose intolerance and diabetes mellitus treatment with somatropin may decrease insulin sensitivity, particularly at higher doses. new onset type 2 diabetes mellitus has been reported in patients taking somatropin. previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked. monitor glucose levels periodically in all patients receiving humatrope, especially in those with risk factors for diabetes mellitus, such as obesity, turner syndrome, or a family history of diabetes mellitus. patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely. the doses of antidiabetic agents may require adjustment when humatrope is initiated. 5.5 intracranial hypertension intracranial hypertension (ih) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with somatropin products. symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. in all reported cases, ih-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose. fundoscopic examination should be performed routinely before initiating treatment with humatrope to exclude preexisting papilledema, and periodically thereafter. if papilledema is observed by fundoscopy during somatropin treatment, treatment should be stopped. if somatropin-induced ih is diagnosed, treatment with humatrope can be restarted at a lower dose after ih-associated signs and symptoms have resolved. patients with turner syndrome may be at increased risk for the development of ih. 5.6 severe hypersensitivity serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products. patients and caregivers should be informed that such reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs. do not use humatrope in patients with known hypersensitivity to somatropin or any of the excipients in humatrope. do not use humatrope cartridges or the diluent supplied with humatrope vials in patients with known hypersensitivity to metacresol or glycerin [see dosage and administration ( 2.4 , 2.5 ), contraindications ( 4 )] . 5.7 fluid retention fluid retention during somatropin replacement therapy may frequently occur. clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paresthesia) are usually transient and dose dependent. 5.8 hypoadrenalism patients receiving somatropin therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. in addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of humatrope treatment. monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism [see drug interactions ( 7 )]. 5.9 hypothyroidism undiagnosed/untreated hypothyroidism may prevent an optimal response to humatrope, in particular, the growth response in pediatric patients. patients with turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism. in patients with gh deficiency, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. therefore, patients treated with somatropin should have periodic thyroid function tests performed, and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated. 5.10 slipped capital femoral epiphysis in pediatric patients slipped capital femoral epiphysis may occur more frequently in patients undergoing rapid growth. evaluate pediatric patients with the onset of a limp or complaints of hip or knee pain. 5.11 progression of preexisting scoliosis in pediatric patients somatropin increases the growth rate, and progression of existing scoliosis can occur in patients who experience rapid growth. somatropin has not been shown to increase the occurrence of scoliosis. monitor patients with a history of scoliosis for progression of scoliosis. 5.12 pancreatitis cases of pancreatitis have been reported in pediatric patients and adults receiving somatropin products. the risk may be greater risk in pediatric patients compared with adults. published literature indicates that girls who have turner syndrome may be at greater risk than other pediatric patients receiving somatropin products. pancreatitis should be considered in patients who develop abdominal pain. 5.13 lipoatrophy when somatropin products are administered subcutaneously at the same site over a long period of time, tissue atrophy may result. rotate injection sites when administering humatrope to reduce this risk [see dosage and administration ( 2.1 )] . 5.14 laboratory tests serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone and igf-i may increase after humatrope therapy.

( 2.3 ) see full prescribing information for reconstitution instructions. ( 2.4 , 2.5 ) 2.1 administration and use instructions therapy with humatrope should be supervised by a physician who is experienced in the diagnosis and management of patients with the conditions for which humatrope is indicated [see indications and usage ( 1 )] . fundoscopic examination should be performed routinely before initiating treatment with humatrope to exclude preexisting papilledema, and periodically thereafter [see warnings and precautions ( 5.5 )] . leave humatrope at room temperature for 10 minutes prior to administration. administer humatrope by subcutaneous injection to the back of the upper arm, abdomen, buttock, or thigh with regular rotation of injection sites to avoid lipoatrophy. 2.2 pediatric dosage individualize dosage for each patient based on the growth response. divide the calculated weekly humatrope dosage into equal doses given either 6 or 7 days per week. the recommended weekly dose in milligrams (mg) per kilogram (kg) of body weight for pediatric patients is: pediatric gh deficiency: 0.18 mg/kg/week to 0.3 mg/kg/week (0.026 to 0.043 mg/kg/day) turner syndrome: up to 0.375 mg/kg/week (up to.054 mg/kg/day) idiopathic short stature: up to 0.37 mg/kg/week (up to 0.053 mg/kg/day) shox deficiency: 0.35 mg/kg/week (0.05 mg/kg/day) small for gestational age (sga): up to 0.47 mg/kg/week (up to 0.067 mg/kg/day) in very short pediatric patients, height sds less than -3, and older pubertal pediatric patients consider initiating treatment with a larger dose of humatrope (up to 0.067 mg/kg/day). consider a gradual reduction in dosage if substantial catch-up growth is observed during the first few years of therapy. in pediatric patients less than 4 years of age with less severe short stature, baseline height sds values between -2 and -3, consider initiating treatment at 0.033 mg/kg/day and titrate the dose as needed. assess compliance and evaluate other causes of poor growth such as hypothyroidism, under-nutrition, advanced bone age and antibodies to recombinant human gh if patients experience failure to increase height velocity, particularly during the first year of treatment. discontinue humatrope for stimulation of linear growth once epiphyseal fusion has occurred [see contraindications ( 4 )] . 2.3 adult dosage patients who were treated with somatropin for gh deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin for gh deficient adults. consider using a lower starting dose and smaller dose increment increases for geriatric patients as they may be at increased risk for adverse reactions with humatrope than younger individuals [see use in specific populations ( 8.5 )] . women may require higher doses and patients receiving oral estrogen may require higher doses [see drug interactions ( 7 )] . administer the prescribed dose daily. either of two humatrope dosing regimens may be used: non-weight based: initiate humatrope with a dose of approximately 0.2 mg/day (range, 0.15 mg/day to 0.3 mg/day) and increase the dose every 1-2 months by increments of approximately 0.1 mg/day to 0.2 mg/day, according to individual patient requirements based on the clinical response and serum insulin-like growth factor 1 (igf-1) concentrations. use the patient's clinical response, adverse reactions, and determination of age- and gender-adjusted serum igf-1 concentrations as guidance in dose titration. maintenance dosages will vary considerably from person to person, and between male and female patients. weight-based: initiate humatrope at 0.006 mg/kg daily and increase the dose according to individual patient requirements to a maximum of 0.0125 mg/kg daily. use the patient's clinical response, adverse reactions, and determination of age- and gender-adjusted serum igf-1 concentrations as guidance in dose titration. maintenance dosages will vary considerably from person to person, and between male and female patients not recommended for obese patients as they are more likely to experience adverse reactions with this regimen. 2.4 reconstitution of vials reconstitute the 5-mg vial of humatrope with 1.5 to 5 ml of diluent for humatrope. inject the diluent into the vial by aiming the stream of liquid gently against the vial wall. swirl the vial (do not shake) with a gentle rotary motion until the powder is completely dissolved into liquid and the solution is clear. inspect visually for particulate matter and discoloration. if the resulting solution is cloudy or contains particulate matter do not use. vials of humatrope are stable for up to 14 days when reconstituted with diluent for humatrope and refrigerated at 36° to 46°f (2° to 8°c). do not leave reconstituted vials at room temperature more than 30 minutes per day. avoid freezing the reconstituted vial of humatrope. protect humatrope from light during storage. for patients with known hypersensitivity to the diluent for humatrope [see warnings and precautions ( 5.6 )] , reconstitute the vial with sterile water for injection. use only one dose per vial, use immediately and discard the unused portion. 2.5 reconstitution of cartridges each humatrope cartridge is designed for use only with the appropriate corresponding humatropen ® . reconstitute each cartridge of humatrope using only the diluent syringe that accompanies the cartridge. do not shake. the reconstituted solution should be clear. inspect visually for particulate matter and discoloration. if the resulting solution is cloudy or contains particulate matter do not use. the somatropin concentrations for the reconstituted humatrope cartridges are as follows: cartridge somatropin concentration 6 mg 2.08 mg/ml 12 mg 4.17 mg/ml 24 mg 8.33 mg/ml reconstituted cartridges of humatrope are stable for up to 28 days when refrigerated at 36° to 46°f (2° to 8°c). do not leave at room temperature more than 30 minutes per day. avoid freezing the reconstituted cartridge. protect humatrope from light during storage. for patients with known hypersensitivity to the diluent supplied with the humatrope cartridge [see warnings and precautions ( 5.6 )] , do not use humatrope cartridge. use the humatrope vial and reconstitute with sterile water for injection [see dosage and administration ( 2.4 )] .

utions ( 5.14 )] common adverse reactions reported in adult and pediatric patients include: upper respiratory infection, fever, pharyngitis, headache, otitis media, edema, arthralgia, paresthesia, myalgia, carpal tunnel syndrome, peripheral edema, flu syndrome, hypothyroidism, hyperglycemia, and impaired glucose tolerance. ( 6 ) to report suspected adverse reactions, contact eli lilly and company at 1-800-lillyrx (1-800-545-5979) or fda at 1-800-fda-1088 or www.fda.gov/medwatch . 6.1 clinical studies experience because clinical studies are conducted under varying conditions, adverse reaction rates observed during the clinical studies performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical studies performed with a different somatropin formulation, and may not reflect the adverse reaction rates observed in practice. pediatric patients growth failure due to inadequate secretion of endogenous growth hormone in an uncontrolled open-label study, 314 treatment-naive children aged >2 years who had gh deficiency were treated with humatrope (0.06 mg/kg 3 times per week) for up to 8 years. adverse reactions of special interest are reported in table 1 . table 1: adverse reactions of special interest occurring in humatrope-treated patients with growth failure due to inadequate secretion of endogenous growth hormone in an open-label study for up to 8 years a dose=0.06 mg/kg 3 times per week for up to 8 years. b n=1 adverse reaction humatrope a (n=314) hypothyroidism 25% allergic reaction 11% arthralgia 6% bone disorder 4% edema 4% injection site pain/reaction 4% neoplasm/tumor 2% cardiovascular disorders 1% thyroid disorders 1% intracranial hypertension 0% b short stature associated with turner syndrome in a randomized, concurrent-controlled (untreated), open-label study until attainment of adult height, the adverse reactions of special interest occurring in 74 patients treated with humatrope at dose 0.3 mg/kg/week (mean duration 4.1 years) and in 62 untreated patients (mean duration 3.7 years) are reported in table 2 . a similar increase in otitis media was observed in an 18-month placebo-controlled study. table 2: adverse reactions of special interest occurring in patients with turner syndrome in an open-label study until attainment of adult height untreated (n=62) humatrope (n=74) surgical procedure 27% 45% otitis media 26% 43% ear disorders 5% 18% idiopathic short stature adverse reactions occurring in a randomized, placebo-controlled study of humatrope treatment (0.22 mg/kg/week) until attainment of adult height (mean duration of humatrope treatment 3.7 years, mean duration of placebo treatment 3.3 years) are reported in table 3 . mean fasting serum insulin concentration increased by 10% in the humatrope treatment group at the end of treatment relative to baseline, but remained within the normal reference range. table 3: adverse reactions occurring in patients with idiopathic short stature treated with humatrope in a randomized placebo-controlled study placebo (n=31) humatrope (n=37) scoliosis 13% 19% otitis media 7% 16% hyperlipidemia 3% 8% gynecomastia 3% 5% hip pain 0 3% arthralgia 3% 11% arthrosis 7% 11% myalgia 13% 24% hypertension 0 3% in a dose-response study (239 patients treated for 2 years), among humatrope dose groups [0.24 mg/kg/week (n=78), 0.37 mg/kg/week (n=83), 0.24 mg/kg/week for the first year and 0.37 mg/kg/week thereafter (n=78)], mean fasting blood glucose, mean glycosylated hemoglobin, and the incidence of elevated fasting blood glucose concentrations were similar. one patient developed glucose intolerance and high serum hba 1c . short stature or growth failure in shox deficiency adverse reactions of special interest from a 2-year randomized, open-label study with humatrope (0.35 mg/kg/wk) compared to no treatment are presented in table 4 . during the 2-year study period, the proportion of patients who had at least one igf-i concentration greater than 2.0 sd above the age- and gender-appropriate mean was 10 of 27 (37%) for the humatrope-treated group vs. 0 of 24 patients (0%) for the untreated group. the proportion of patients who had at least one igfbp-3 concentration greater than 2.0 sd above the age and gender appropriate mean was 16 of 27 (59%) for the humatrope treated group vs. 7 of 24 (29%) for the untreated group. table 4: adverse reactions of special interest occurring in patients with shox deficiency by treatment group in an open-label study a percentage calculated for males only: untreated (0/1), humatrope (1/12) untreated (n=25) humatrope (n=27) arthralgia 8% 11% gynecomastia a 0% 8% excessive number of cutaneous nevi 0% 7% scoliosis 0% 47% small for gestational age (sga) with no catch-up growth by age 2-4 years in a 2-year, multicenter, randomized study, 193 pediatric patients were treated with 2 different humatrope treatment regimens: a fixed dose of 0.067 mg/kg/day (fhd group) or an individually adjusted dose regimen (iad group; starting dose 0.035 mg/kg/day which could be increased as early as month 3 to 0.067 mg/kg/day based on a validated growth prediction model). reported adverse reactions included: common childhood infectious diseases, otitis media, headaches, and slipped capital femoral epiphysis (n=1. six patients (4 in the fhd group and 2 in the iad group whose dose was increased from 0.035 mg/kg/day to 0.067 mg/kg/day [one at month 3 and one at year 1]) had impaired fasting glucose at year 2. two of 6 had impaired fasting glucose during the study, and one discontinued humatrope at month 15 as a consequence. at study completion, 20-25% of patients had serum igf-i sds values > +2. the following adverse reactions were reported from an observational study of 340 pediatric patients who received humatrope with an average dosage of 0.041 mg/kg/day (maximum dose: 0.084 mg/kg/day) for an average of 3.0 years: type 2 diabetes mellitus (n=1), carpal tunnel syndrome (n=1) and an exacerbation of preexisting scoliosis (n=1). adult patients adult-onset gh deficiency in the first 6 months of controlled blinded studies during which patients received either humatrope or placebo, patients who received humatrope experienced an increase in edema (17% vs. 4%) and peripheral edema (12% vs. 0%). edema, muscle pain, joint pain, and joint disorder were reported early in therapy and tended to be transient or responsive to dosage titration. two of 113 patients developed carpal tunnel syndrome after beginning maintenance therapy without a low dose (0.00625 mg/kg/day) lead-in phase. symptoms abated in these patients after dosage reduction. adverse reactions with ≥5% overall occurrence rate during 12 or 18 months of replacement therapy with humatrope are shown in table 5 (adult-onset patients) and in table 6 (childhood-onset patients). table 5: adverse reactions with ≥5% overall occurrence in adult-onset growth hormone-deficient patients treated with humatrope for 18 months as compared with 6-month placebo and 12-month humatrope exposure adverse reaction 18 months exposure [placebo (6 months)/humatrope (12 months)] (n=44) 18 months humatrope exposure (n=52) edema 11% 21% arthralgia 14% 17% paresthesia 14% 17% myalgia 9% 14% pain 14% 14% peripheral edema 18% 12% headache 7% 8% hypertension 5% 8% joint disorder 2% 6% rhinitis 11% 13% back pain 9% 10% acne 0% 6% surgical procedure 2% 6% flu syndrome 7% 4% childhood-onset gh deficiency two double-blind, placebo-controlled studies were conducted in 67 adult patients who had received previous somatropin treatment during childhood. patients were randomized to receive either placebo injections or humatrope (0.00625 mg/kg/day for the first 4 weeks, then 0.0125 mg/kg/day thereafter) for the first 6 months, followed by open-label use of humatrope for the next 12 months for all patients. during the placebo-controlled phase (first 6 months) of the study, elevations of serum glutamic oxaloacetic transferase were reported more for humatrope-treated (13% vs. 0%) than placebo-treated patients. table 6: adverse reactions with ≥5% overall occurrence in childhood-onset growth hormone-deficient patients treated with humatrope for 18 months as compared with 6-month placebo and 12-month humatrope exposure a abbreviations: alt=alanine aminotransferase; ast=aspartate aminotransferase adverse reaction 18 months exposure [placebo (6 months)/humatrope (12 months)] (n=30) 18 months humatrope exposure (n=32) ast a increased 7% 13% headache 7% 9% asthenia 3% 6% edema 10% 6% myalgia 7% 6% pain 10% 6% alt a increased 7% 6% flu syndrome 10% 16% cough increased 0% 6% hypesthesia 0% 6% rhinitis 7% 6% respiratory disorder 7% 3% gastritis 7% 0% pharyngitis 7% 3% 6.2 immunogenicity as with all therapeutic proteins, there is potential for immunogenicity. the detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. for these reasons, comparison of the incidence of antibodies to humatrope with the incidence of antibodies to other products may be misleading. in a clinical study with humatrope during the first 6 months of humatrope therapy in 314 naive patients, 1.6% developed specific antibodies to humatrope (binding capacity ≥0.02 mg/l). none had antibody concentrations which exceeded 2 mg/l. throughout 8 years of this same study, two patients (0.6%) had binding capacity >2 mg/l. neither patient demonstrated a decrease in growth velocity at or near the time of increased antibody production. it has been reported that growth attenuation from pituitary-derived gh may occur when antibody concentrations are >1.5 mg/l. 6.3 postmarketing experience the following adverse reactions have been identified during post-approval use of humatrope. because these adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. severe hypersensitivity reactions — serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products neurologic — headaches (common in pediatric patients and occasional in adults) skin — increase in size or number of cutaneous nevi endocrine — gynecomastia gastrointestinal — pancreatitis metabolic — new-onset type 2 diabetes mellitus neoplasia — leukemia has been reported in a small number of gh deficient pediatric patients treated with somatropin

isone may be effected more than others since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βhsd-1. non-replacement glucocorticoid treatment in pediatric patients clinical impact: non-replacement glucocorticoid treatment, including supraphysiologic glucocorticoid treatment, may attenuate the growth promoting effects of humatrope in pediatric patients. intervention: carefully adjust glucocorticoid dosing in pediatric patients receiving glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth. cytochrome p450-metabolized drugs clinical impact: limited published data indicate that somatropin treatment increases cytochrome p450 (cp450)-mediated antipyrine clearance. humatrope may alter the clearance of compounds known to be metabolized by cp450 liver enzymes. intervention: careful monitoring is advisable when humatrope is administered in combination with drugs metabolized by cp450 liver enzymes. oral estrogen clinical impact: oral estrogens may reduce the serum igf-1 response to humatrope. intervention: patients receiving oral estrogen may require greater humatrope dosages [see dosage and administration ( 2.3 )] . insulin and/or other hypoglycemic agents clinical impact: treatment with humatrope may decrease insulin sensitivity, particularly at higher doses. intervention: patients with diabetes mellitus may require adjustment of their doses of insulin and/or other hypoglycemic agents [see warnings and precautions ( 5.4 )]. replacement glucocorticoid treatment: patients treated with glucocorticoids for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of humatrope. ( 7 ) non-replacement glucocorticoid treament in pediatric patients: adjust glucocorticoid dosing in pediatric patients receiving glucocorticoid treatment to avoid both hypoadrenalism and an inhibitory effect on growth. ( 7 ) cytochrome p450-metabolized drugs: humatrope may alter the clearance. monitor carefully if used with humatrope. ( 7 ) oral estrogen: patients may require larger doses of humatrope. ( 7 ) insulin and/or other hypoglycemic agents: dose adjustment of insulin or hypoglycemic agent may be required. ( 5.4 , 7 )

and any potential adverse effects on the breastfed infant from humatrope or from the underlying maternal condition. 8.4 pediatric use safety and effectiveness of humatrope in pediatric patients have been established in growth failure due to inadequate secretion of endogenous growth hormone, short stature associated with turner syndrome, idiopathic short stature (iss), short stature or growth failure in shox deficiency, and short stature in children born small for gestational age (sga) with no catch-up growth by 2 years to 4 years of age. growth failure due to inadequate secretion of endogenous growth hormone safety and effectiveness of humatrope have been established in pediatric patients with growth failure due to growth hormone deficiency based on data from an open-label, uncontrolled, multicenter study with humatrope in 314 pediatric patients conducted for up to 8 years [see clinical studies ( 14.1 )] . short stature associated with turner syndrome safety and effectiveness of humatrope have been established in pediatric patients with short stature associated with turner syndrome based on data from one long-term, randomized, open-label, multicenter, concurrently controlled study; two long-term, open-label multicenter, historically controlled us studies; and one long-term, randomized, us dose-response study with humatrope in 181 pediatric patients [see clinical studies ( 14.2 )] . idiopathic short stature (iss) safety and effectiveness of humatrope have been established in pediatric patients with iss based on data from two randomized, multicenter studies, one placebo-controlled study and one dose-response study with humatrope in 310 pediatric patients [see clinical studies ( 14.3 )] . short stature or growth failure in shox deficiency safety and effectiveness of humatrope have been established in pediatric patients with short stature or growth failure in shox deficiency based on data from a randomized, controlled, two-year, three-arm, open-label study with humatrope in 52 pediatric patients [see clinical studies ( 14.4 )] . short stature in children born small for gestational age (sga) with no catch-up growth by 2 years to 4 years of age safety and effectiveness of humatrope have been established in pediatric patients with short stature born sga with no catch-up growth based on data from two clinical studies with humatrope in 214 pediatric patients [see clinical studies ( 14.5 )] . 8.5 geriatric use the safety and effectiveness of humatrope in patients aged 65 years and over has not been evaluated in clinical studies. elderly patients may be more sensitive to the action of somatropin, and therefore may be more prone to development of adverse reactions. a lower starting dose and smaller dose increments should be considered for older patients [see dosage and administration ( 2.3 )] .

m one long-term, randomized, open-label, multicenter, concurrently controlled study; two long-term, open-label multicenter, historically controlled us studies; and one long-term, randomized, us dose-response study with humatrope in 181 pediatric patients [see clinical studies ( 14.2 )] . idiopathic short stature (iss) safety and effectiveness of humatrope have been established in pediatric patients with iss based on data from two randomized, multicenter studies, one placebo-controlled study and one dose-response study with humatrope in 310 pediatric patients [see clinical studies ( 14.3 )] . short stature or growth failure in shox deficiency safety and effectiveness of humatrope have been established in pediatric patients with short stature or growth failure in shox deficiency based on data from a randomized, controlled, two-year, three-arm, open-label study with humatrope in 52 pediatric patients [see clinical studies ( 14.4 )] . short stature in children born small for gestational age (sga) with no catch-up growth by 2 years to 4 years of age safety and effectiveness of humatrope have been established in pediatric patients with short stature born sga with no catch-up growth based on data from two clinical studies with humatrope in 214 pediatric patients [see clinical studies ( 14.5 )] .

(0.033 mg/kg body weight) in healthy volunteers (10 males, 10 females) resulted in an increased median igf-1 level from 202 ng/ml (men) and 107 ng/ml (women) predose to maximal level of 362 ng/ml (men) and 234 ng/ml (women) after a median of 21 hours (men) and 14 hours (women). 12.3 pharmacokinetics absorption humatrope has been studied following intramuscular, subcutaneous, and intravenous administration in healthy adult subjects. a single subcutaneous dose administration of humatrope 0.1 mg/kg (0.27 iu/kg) in healthy subjects (n= 8) resulted in a mean (sd) c max of 63.3 (18.2) ng/ml at median t max of 4.0 (range 3 to 8) hours. the absolute bioavailability of somatropin is 75% after subcutaneous administration. distribution the mean (sd) volume of distribution of somatropin after single dose subcutaneous injection of 0.1 mg/kg (0.27 iu/kg) in healthy subjects is about 0.96 (0.3) l/kg. elimination metabolism — extensive metabolism studies have not been conducted. the metabolic fate of somatropin involves classical protein catabolism in both the liver and kidneys. in renal cells, at least a portion of the breakdown products of somatropin is returned to the systemic circulation. excretion — in healthy subjects, mean somatropin clearance is 0.18 (0.03) l/hr/kg following subcutaneous administration. the mean half-life of subcutaneous somatropin is 3.8 (1.4) hours. the long half-life observed after subcutaneous administration is due to slow absorption from the injection site. urinary excretion of intact humatrope has not been measured. small amounts of somatropin have been detected in the urine of pediatric patients following replacement therapy. specific populations geriatric patients — the pharmacokinetics of humatrope have not been studied in patients greater than 65 years of age. pediatric patients — the pharmacokinetics of humatrope in pediatric patients are similar to those of adults. male and female patients — no gender-specific pharmacokinetic studies have been performed with humatrope. the available literature indicates that the pharmacokinetics of somatropin are similar in men and women. patients with renal or hepatic impairment — no studies have been performed with humatrope.

l/hr/kg following subcutaneous administration. the mean half-life of subcutaneous somatropin is 3.8 (1.4) hours. the long half-life observed after subcutaneous administration is due to slow absorption from the injection site. urinary excretion of intact humatrope has not been measured. small amounts of somatropin have been detected in the urine of pediatric patients following replacement therapy. specific populations geriatric patients — the pharmacokinetics of humatrope have not been studied in patients greater than 65 years of age. pediatric patients — the pharmacokinetics of humatrope in pediatric patients are similar to those of adults. male and female patients — no gender-specific pharmacokinetic studies have been performed with humatrope. the available literature indicates that the pharmacokinetics of somatropin are similar in men and women. patients with renal or hepatic impairment — no studies have been performed with humatrope.

es and one long-term, randomized, us dose-response study were conducted to evaluate the efficacy of humatrope for treatment of short stature due to turner syndrome. the randomized, open-label, canadian study compared near-adult height outcomes for humatrope-treated patients to those of a concurrent control group who received no injections. the humatrope-treated patients received a dosage of 0.3 mg/kg/week given in divided doses 6 times per week from a mean age of 11.7 years for a mean duration of 4.7 years. puberty was induced with a standardized estrogen regimen initiated at 13 years of age for both treatment groups. in two of the us studies, the effect of long-term treatment with humatrope (0.375 mg/kg/week given in divided doses either 3 times per week or daily) on adult height was determined by comparing adult heights in the treated patients with those of age-matched historical controls with turner syndrome who received no growth-promoting therapy. puberty was induced with a standardized estrogen regimen initiated after 14 years of age in one study; in the second study patients treated early (before 11 years of age) were randomized to begin pubertal induction at either age 12 (n=26) or 15 (n=29) years (conjugated estrogens, 0.3 mg escalating to 0.625 mg daily); those whose treatment was initiated after 11 years of age began estrogen replacement after 1 year of treatment with humatrope. in the third us study, a randomized, blinded dose-response study, patients were treated from a mean age of 10.9 years for a mean duration of 5.5 years with a weekly humatrope dosage of either 0.27 mg/kg or 0.36 mg/kg administered in divided doses 3 or 6 times weekly. in summary, patients with turner syndrome (total n=249 from the 4 studies above) treated to adult height achieved average height gains ranging from 5.0 to 8.3 cm. see table 8 . table 8: height gain results a of somatropin studies in patients with turner syndrome a data shown are mean values. b rct: randomized controlled trial; mht: matched historical controlled trial; rdt: randomized dose-response trial. c analysis of covariance (ancova) vs. controls: ancova models with gh (0.27 or 0.36 mg/kg/wk) included covariates of baseline age (all studies), baseline height (all studies), study site (all studies), mid-parental height (all studies) and karyotype (us1 and us2 only), baseline bone age (us2 only) or estrogen (low dose or placebo for us3 only). d group a: gh age <11 yr, estrogen is initiated at age 15. e group b: gh age <11 yr, estrogen is initiated at age 12. f group c: gh age >11 yr, estrogen is initiated at after 12 month of treatment with humatrope. study group study design b somatropin treated number at adult height gh age (yr) estrogen age (yr) gh duration (yr) adult height gain (cm) c canadian rct 27 11.7 13 4.7 5.4 us 1 mht 17 9.1 15.2 7.6 7.4 us 2 a d mht 29 9.4 15 6.1 8.3 b e mht 26 9.6 12.3 5.6 5.9 c f mht 51 12.7 13.7 3.8 5 us 3 rdt 99 10.9 8-13.5 5.5 5.7 14.3 pediatric patients with idiopathic short stature (iss) two randomized, multicenter studies, one placebo-controlled and one dose-response, were conducted in pediatric patients with idiopathic short stature. the diagnosis of idiopathic short stature was made after excluding other known causes of short stature, as well as gh deficiency. the placebo-controlled study enrolled 71 pediatric patients (55 males, 16 females) 9 to 15 years old (mean age 12.4 ± 1.5 years), with short stature, 68 of whom received placebo (n=31) or humatrope (n=37). patients were predominately prepubertal (tanner i, 45%) or in early puberty (tanner ii, 47%) at baseline. in this double-blind study, patients received subcutaneous injections of either humatrope 0.222 mg/kg/week, or placebo given in divided doses 3 times per week until height velocity decreased to ≤1.5 cm/year (“final height”). final height measurements were available for 33 subjects (22 treated with humatrope, 11 treated with placebo) after a mean treatment duration of 4.4 years (range 0.1-9.1 years). results are presented in table 9 . the number of patients whose final height was above the 5th percentile of the general population height standard for age and sex was significantly greater in the humatrope group than the placebo group (41% vs. 0%), as was the number of patients who gained at least 1 sds unit in height across the duration of the study (50% vs. 0%). table 9: baseline height characteristics and effect of humatrope on final height in placebo-controlled study ab a for final height population. b abbreviations: bph=baseline predicted height; ci=confidence interval; fh=final height; na=not applicable; sds=standard deviation score. c assessed using a one-way analysis of variance (anova) with effect for treatment. d placebo n=10 as one patient was missing bph. e assessed using analysis of covariance (ancova) with baseline predicted height sds as the covariate. placebo (n=11) mean (sd) humatrope (n=22) mean (sd) treatment effect mean (95%ci b ) p-value baseline height sds -2.8 (0.6) -2.7 (0.6) na b 0.77 c bph sds -2.3 (0.8) -2.1 (0.7) na 0.53 c,d final height sds -2.3 (0.6) -1.8 (0.8) 0.51 (0.10, 0.92) 0.017 e fh b sds - baseline height sds 0.4 (0.2) 0.9 (0.7) 0.51 (0.04, 0.97) 0.034 e fh sds - bph sds -0.1 (0.6) 0.3 (0.6) 0.46 (0.02, 0.89) 0.043 d,e the dose-response study included 239 pediatric patients (158 males, 81 females), 5 to 15 years old, (mean age 9.8 ± 2.3 years). mean ± sd baseline characteristics included: height sds -3.21 ± 0.70, predicted adult height sds -2.63 ± 1.08, and height velocity sds -1.09 ± 1.15. all but 3 patients were prepubertal. patients were randomized to one of three humatrope treatment groups: 0.24 mg/kg/week (n=78); 0.24 mg/kg/week for 1 year, followed by 0.37 mg/kg/week (n=78); and 0.37 mg/kg/week (n=83). height velocity was assessed in each treatment group during the first 2 years of therapy. after completing the initial 2-year dose-response phase of the study, 50 patients were followed to final height. after 2 years of treatment, patients who received the humatrope dosage of 0.37 mg/kg/week (n=71) had a significantly greater increase in mean height velocity than patients who received 0.24 mg/kg/week (n=68), (4.04 vs. 3.27 cm/year respectively (anova p=0.003). a total of 12 patients who received 0.37 mg/kg/week and 10 patients who received 0.24 mg/kg/week treatment had missing 2 year treatment data. the mean difference between final height and baseline predicted height was 7.2 cm for patients who received humatrope 0.37 mg/kg/week and 5.4 cm for patients who received 0.24 mg/kg/week. the results are presented in table 10 . while no patient had height above the 5th percentile in any dosage group at baseline, 82% (n=14) of the 17 patients who received 0.37 mg/kg/week and 47% (n=8) of the 17 patients who received 0.24 mg/kg/week achieved final heights above the 5th percentile of the general population height standards. table 10: idiopathic short stature study results: final height minus baseline predicted height a a abbreviations: fh=final height; ph=predicted height; ci=confidence interval; cm=centimeters. placebo-controlled study 3x per week dosing dose response study 6x per week dosing placebo (n=10) humatrope 0.22 mg/kg (n=22) humatrope 0.24 mg/kg (n=13) humatrope 0.24/0.37 mg/kg (n=13) humatrope 0.37 mg/kg (n=13) fh - baseline ph mean (95% ci), cm -0.7 (-3.6, 2.3) +2.2 (0.4, 3.9) +5.4 (2.8, 7.9) +6.7 (4.1, 9.2) +7.2 (4.6, 9.8) 14.4 pediatric patients with short stature or growth failure in shox deficiency a randomized, controlled, two-year, three-arm, open-label study was conducted to evaluate the efficacy of humatrope for treatment of short stature in pediatric patients with shox deficiency who were not gh–deficient. a total of 52 patients (24 male, 28 female) with shox deficiency, 3 to 12.3 years of age, were randomized to either a humatrope-treated arm (27 patients; mean age 7.3 ± 2.1 years) or an untreated control arm (25 patients; mean age 7.5 ± 2.7 years). to determine the comparability of treatment effect between patients with shox deficiency and patients with turner syndrome, the third study arm enrolled 26 patients with turner syndrome, 4.5 to 11.8 years of age (mean age 7.5 ± 1.9 years) who received humatrope treatment. all patients were prepubertal at study entry. patients in the humatrope-treated group(s) received daily subcutaneous injections of 0.05 mg/kg of humatrope, equivalent to 0.35 mg/kg/week. patients in the untreated group received no injections. one untreated patient discontinued the study during the first year. the results are presented in table 11 ; the mean first-year height velocity of treated patients with shox deficiency was significantly greater than that of the untreated patients (mean between-group difference = 3.5 [95% ci: 2.8 – 4.2] cm/year, p<0.001). table 11: summary of results in patients with shox deficiency and turner syndrome a positive values favor humatrope b p<0.001 (assessed using analysis of covariance [ancova] with covariates of treatment group, léri-weill syndrome, sex and baseline age). c p<0.001 (assessed using ancova with covariates of treatment group and baseline height [cm]). d p<0.001 (assessed using ancova with covariates of treatment group and baseline height sds). e p=0.003 calculated using fisher's exact test. shox deficiency turner syndrome untreated (n=24) mean (sd) humatrope (n=27) mean (sd) treatment difference a mean (95% ci) humatrope (n=26) mean (sd) height velocity (cm/yr) 1 st year 5.2 (1.1) 8.7 (1.6) b +3.5 (2.8, 4.2) 8.9 (2.0) 2 nd year 5.4 (1.2) 7.3 (1.1) b +2.0 (1.3, 2.6) 7.0 (1.1) height gain (cm) baseline to 1 st year 5.4 (1.2) 9.1 (1.5) c +3.7 (2.9, 4.5) 8.9 (1.9) baseline to 2 nd year 10.5 (1.9) 16.4 (2.0) c +5.8 (4.6, 7.1) 15.7 (2.7) height sds gain baseline to 1 st year 0.1 (0.5) 0.7 (0.5) d +0.5 (0.3, 0.8) 0.8 (0.5) baseline to 2 nd year 0.2 (0.5) 1.2 (0.7) d +1.0 (0.7, 1.3) 1.2 (0.7) patients with height sds > -2.0 at 2 years 1 (4%) 11 (41%) e -- 8 (31%) 14.5 pediatric patients with short stature born small for gestational age (sga) who fail to demonstrate catch-up growth by age 2 - 4 years the height increases would be considered similar if the lower bound of the 95% confidence interval (ci) for the mean difference between the groups (iad – fhd) was greater than -0.5 height sds. a 2-year, open-label, multicenter, european study enrolled 193 prepubertal, non-gh deficient children with mean chronological age 6.8 ± 2.4 years (range: 3 to 12.3). study entry criteria included birth weight <10th percentile and/or birth length sds <-2 for gestational age, and height sds for chronological age ≤-3. exclusion criteria included syndromal conditions (e.g., turner syndrome), chronic disease (e.g., diabetes mellitus), and active tumors. the primary objective was to compare the increase from baseline in height sds after 1 year of treatment when humatrope is administered according to an individually adjusted dose (iad) regimen with a fixed high dose (fhd) regimen. patients were randomized to either a fhd (0.067 mg/kg/day [0.47 mg/kg/week]; n=99) or an iad treatment group (n=94). the initial humatrope dosage in the iad treatment group was 0.035 mg/kg/day (0.25 mg/kg/week). the dosage was increased to 0.067 mg/kg/day in those patients in the iad group whose 1-year height gain predicted at month 3 was <0.75 height sds (n=40) or whose actual height gain measured at year 1 was <0.75 height sds (n=11). the results are presented in table 12 , the increase from baseline in height sds in the iad group was non-inferior to that in the fhd group at year 1 (mean between-group difference = -0.3 sds [95% ci: -0.4, -0.2 sds]). the results were similar when children who entered puberty during the study were removed from the analysis. data is shown for the efficacy analysis population that included all patients who received at least 1 dose of humatrope and had at least 1 post randomization height measurement. approximately 85% of the randomized patients completed 2 years of therapy. table 12: results for height sds and change from baseline in height sds at year 1 and year 2 after humatrope treatment of short children born sga who fail to demonstrate catch-up growth a a abbreviations: iad=individually adjusted dose; fhd=fixed high dose; sd=standard deviation; sds=standard deviation score b least squares mean difference ± standard error and 95% confidence interval based on ancova model with treatment and gender as fixed effects, and baseline height sds, baseline chronological age, baseline bone age, and mid-parental target height sds as covariates. c only children with actual height measurements were included in the year 1 and year 2 analyses. iad group 0.035 to 0.067 mg/kg/day mean (sd) fhd group 0.067 mg/kg/day mean (sd) iad – fhd groupdifference± se (95% ci) b baseline (n=86) -3.9 (0.6) (n=93) -3.9 (0.7) -0.0 ± 0.1 (-0.2, 0.2) year 1 height sds change from baseline (n=86) c -3.0 (0.7) 0.9 (0.4) (n=93) c -2.7 (0.7) 1.1 (0.4) -0.3 ± 0.1 (-0.4, -0.2) p-value <0.001 year 2 height sds change from baseline (n=82) c -2.5 (0.8) 1.4 (0.5) (n=88) c -2.2 (0.7) 1.6 (0.5) -0.3 ± 0.1 (-0.4, -0.1) an open-label, multicenter, single arm study was conducted in france, during which 35 prepubertal, non-gh deficient children were treated for 2 years with humatrope 0.067 mg/kg/day (0.47 mg/kg/week). mean chronological age at baseline was 9.3 ± 0.9 years (range: 6.7 to 10.8). additional study entry criteria included birth length sds <-2 or <3rd percentile for gestational age, and height sds for chronological age <-2. exclusion criteria included syndromal conditions (e.g., turner syndrome), and chronic disease (e.g., diabetes mellitus). all 35 patients completed the study. mean height sds increased from a baseline value of -2.7 (sd 0.5) to -1.5 (sd 0.6) after 2 years of humatrope treatment. 14.6 adult patients with growth hormone deficiency two multicenter studies in patients with adult-onset gh deficiency (n=98) and two studies in patients with childhood-onset gh deficiency (n=67) were designed to assess the effects of replacement therapy with humatrope. adult-onset patients and childhood-onset patients differed by diagnosis (organic vs. idiopathic pituitary disease), body size (average vs. small [mean height (171 cm vs 161 cm) and weight (85 kg vs 64 kg)]), and age (mean 44 vs. 29 years).each study included a 6-month randomized, blinded, placebo-controlled phase, during which approximately half of the patients received placebo injections, while the other half received humatrope injections. the humatrope dosages for all studies were identical: 1 month of treatment at 0.00625 mg/kg/day followed by 0.0125 mg/kg/day for the next 5 months. the 6-month, double-blind phase was followed by 12 months of open-label humatrope treatment for all patients. the primary efficacy measures were body composition (lean body mass and fat mass) and lipid parameters [total cholesterol, high-density lipoprotein (hdl) and low-density lipoprotein (ldl)]. lean body mass was determined by bioelectrical impedance analysis (bia), validated with potassium 40. body fat was assessed by bia and sum of skinfold thickness. lipid subfractions were analyzed by standard assay methods in a central laboratory. in patients with adult-onset gh deficiency, humatrope treatment (vs. placebo) resulted in an increase in mean lean body mass (2.59 vs. -0.22 kg, p<0.001) and a decrease in body fat (-3.27 vs. 0.56 kg, p<0.001). similar changes were seen in childhood-onset gh deficient patients. these changes in lean body mass persisted throughout the 18-month period for both the adult-onset and childhood-onset groups; the changes in fat mass persisted in the childhood-onset group. serum concentrations of hdl cholesterol which were low at baseline (mean, 31.0 mg/dl and 33.9 mg/dl in adult-onset (n=46) and childhood-onset (n=30) patients, respectively) had increased by the end of 18 months of humatrope treatment (mean change of 13.7 and 11.1 mg/dl for the adult-onset (n=40) and childhood-onset (n=21) groups, respectively p<0.001; there was no adjustment for missing data). total cholesterol and ldl did not show significant difference from baseline results by the end of 18 months of humatrope treatment. in an additional 2-year, open-label, randomized study, 149 patients with childhood-onset gh deficiency who had completed pediatric somatropin therapy, had attained final height (height velocity <1 cm/yr) and were confirmed to be gh-deficient as young adults, were randomized to receive humatrope 0.0125 mg/kg/day (n=59), humatrope 0.025 mg/kg/day (n=58), or no treatment (control) (n=32). total bone mineral content (bmc) increased by 5.2% ± 3.9% in the control group (n=28 for those with bmc measurements), 7.0% ± 7.2% in the humatrope 0.025 mg/kg/day group (n=51) and 8.0% ± 8.9% in the humatrope 0.0125 mg/kg/day group (n=51). for the treatment effect versus control group, p=0.012 (anova); there was no statistically significant difference between the 2 humatrope dose groups. a significant overall treatment effect (anova, p=0.037) was seen for the percentage change in lumbar spine bmc, but not for femoral neck or hip.

tis may develop and to report to their healthcare provider any new onset of abdominal pain. hypoadrenalism - advise patients/caregivers who have or who are at risk for pituitary hormone deficiency(s) that hypoadrenalism may develop and to report to their healthcare provider if they experience hyperpigmentation, extreme fatigue, dizziness, weakness, or weight loss. hypothyroidism - advise patients/caregivers that undiagnosed/untreated hypothyroidism may prevent an optimal response to humatrope. advise patients/caregivers they may require periodic thyroid function tests. intracranial hypertension - advise patients/caregivers to report to their healthcare provider any visual changes, headache, and nausea and/or vomiting. hypersensitivity reactions – advise patients/caregivers that serious systemic hypersensitivity reactions (anaphylaxis and angioedema) are possible and that prompt medical attention should be sought if an allergic reaction occurs. glucose intolerance/ diabetes mellitus – advise patients/caregivers that new onset impaired glucose intolerance/diabetes mellitus or exacerbation of preexisting diabetes mellitus can occur and monitoring of blood glucose during treatment with humatrope may be needed. administration – counsel patients and parents that they should never share a humatropen with another person, even if the needle is changed. sharing of the pen between patients may pose a risk of transmission of infection. marketed by: lilly usa, llc, indianapolis, in 46285, usa copyright © 1987, 2019, eli lilly and company. all rights reserved. htr-0004-uspi-20191028