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warnings and cautions
5 WARNINGS AND PRECAUTIONS Increased Risk of Neoplasm: Second neoplasms have occurred in childhood cancer survivors. Monitor patients with preexisting tumors for progression or recurrence. ( 5.3 ) Glucose Intolerance and Diabetes Mellitus: HUMATROPE may decrease insulin sensitivity, particularly at higher doses. Monitor glucose levels periodically in all patients receiving HUMATROPE, especially in patients with existing diabetes mellitus or at risk for development. ( 5.4 ) Intracranial Hypertension (IH): Has been reported usually within 8 weeks of initiation. Perform fundoscopic examinations prior to initiation and periodically thereafter. If papilledema occurs, stop treatment. ( 5.5 ) Hypersensitivity: Serious hypersensitivity reactions may occur. In the event of an allergic reaction, seek prompt medical attention. ( 5.6 ) Fluid Retention: May occur in adults and may be dose dependent. ( 5.7 ) Hypoadrenalism: Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid 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 somatropins. 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 somatropins. 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 in patients with known hypersensitivity to metacresol or glycerin [see Dosage and Administration ( 2.4 ), 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. Slipped capital femoral epiphysis may lead to osteonecrosis. Cases of slipped capital femoral epiphysis with or without osteonecrosis have been reported in pediatric patients with short stature receiving somatropin. Evaluate pediatric patients receiving HUMATROPE with the onset of a limp or complaints of hip or knee pain for slipped capital femoral epiphysis and osteonecrosis and manage accordingly. 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 somatropins. 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 somatropins. Pancreatitis should be considered in patients who develop abdominal pain. 5.13 Lipoatrophy When somatropins 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.
6 ADVERSE REACTIONS The following important adverse reactions are also described elsewhere in the labeling: Increased mortality in patients with acute critical illness [see Warnings and Precautions ( 5.1 )] Fatalities in children with Prader-Willi syndrome [see Warnings and Precautions ( 5.2 )] Neoplasms [see Warnings and Precautions ( 5.3 )] Glucose intolerance and diabetes mellitus [see Warnings and Precautions ( 5.4 )] Intracranial hypertension [see Warnings and Precautions ( 5.5 )] Severe hypersensitivity [see Warnings and Precautions ( 5.6 )] Fluid retention [see Warnings and Precautions ( 5.7 )] Hypoadrenalism [see Warnings and Precautions ( 5.8 )] Hypothyroidism [see Warnings and Precautions ( 5.9 )] Slipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions ( 5.10 )] Progression of preexisting scoliosis in pediatric patients [see Warnings and Precautions ( 5.11 )] Pancreatitis [see Warnings and Precautions ( 5.12 )] Lipoatrophy [see Warnings and Precautions ( 5.13 )] 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 2 . Table 2: 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 3 . A similar increase in otitis media was observed in an 18-month placebo-controlled study. Table 3: 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 4 . 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 4: 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 5 . 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 5: 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 with GH deficiency 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 6 (adult-onset patients) and in Table 7 (childhood-onset patients). Table 6: 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 7: 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 Postmarketing Experience The following adverse reactions have been identified during post-approval use of somatropin or 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 somatropins 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 Musculoskeletal and connective tissue disorders — Osteonecrosis in pediatric patients Neoplasia — Leukemia has been reported in a small number of GH deficient pediatric patients treated with somatropin
adverse reactions table
<table ID="t02" width="100%" styleCode="Noautorules"><caption>Table 2: 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 </caption><col width="63.900%" align="left"/><col width="36.100%" align="left"/><tfoot><tr><td colspan="2" align="left" valign="top"><paragraph styleCode="footnote"><sup>a</sup> Dose=0.06 mg/kg 3 times per week for up to 8 years. </paragraph></td></tr><tr><td colspan="2" align="left" valign="top"><paragraph styleCode="footnote"><sup>b</sup> n=1 </paragraph></td></tr></tfoot><tbody><tr><td align="left" valign="middle" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Adverse Reaction</content></td><td align="center" valign="middle" styleCode="Toprule Botrule Rrule"><content styleCode="bold">HUMATROPE</content><content styleCode="bold"><sup>a</sup></content> <content styleCode="bold">(n=314)</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Hypothyroidism </td><td align="center" valign="middle" styleCode="Botrule Rrule">25% </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Allergic reaction </td><td align="center" valign="middle" styleCode="Botrule Rrule">11% </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Arthralgia </td><td align="center" valign="middle" styleCode="Botrule Rrule">6% </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Bone disorder </td><td align="center" valign="middle" styleCode="Botrule Rrule">4% </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Edema </td><td align="center" valign="middle" styleCode="Botrule Rrule">4% </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Injection site pain/reaction </td><td align="center" valign="middle" styleCode="Botrule Rrule">4% </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Neoplasm/tumor </td><td align="center" valign="middle" styleCode="Botrule Rrule">2% </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Cardiovascular disorders </td><td align="center" valign="middle" styleCode="Botrule Rrule">1% </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Thyroid disorders </td><td align="center" valign="middle" styleCode="Botrule Rrule">1% </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Intracranial hypertension </td><td align="center" valign="middle" styleCode="Botrule Rrule">0%<sup>b</sup></td></tr></tbody></table>