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HUMATROPE®
[somatropin (rDNA ORIGIN)] for Injection
Humatrope (somatropin, rDNA origin, for injection) is a polypeptide hormone of recombinant DNA origin. Humatrope is synthesized in a strain of Escherichia coli that has been modified by the addition of the gene for human GH. The peptide is comprised of 191 amino acid residues and has a molecular weight of about 22,125 daltons. The amino acid sequence of the peptide is identical to that of human GH of pituitary origin.
Humatrope is a sterile, white, lyophilized powder intended for subcutaneous or intramuscular administration after reconstitution to its liquid form. Humatrope is a highly purified preparation. Phosphoric acid and/or sodium hydroxide may have been added to adjust the pH. Reconstituted solutions have a pH of approximately 7.5. This product is oxygen sensitive.
Each vial of Humatrope contains 5 mg somatropin (15 IU or 225 nanomoles); 25 mg mannitol; 5 mg glycine; and 1.13 mg dibasic sodium phosphate. Each vial is supplied in a combination package with an accompanying 5-mL vial of diluting solution (diluent). The diluent contains Water for Injection with 0.3% metacresol as a preservative and 1.7% glycerin.
Cartridges of Humatrope contain either 6 mg (18 IU), 12 mg (36 IU), or 24 mg (72 IU) of somatropin. Each Humatrope cartridge contains the following:
| Cartridge | |||
| 6 mg (gold) | 12 mg (teal) | 24 mg (purple) | |
| Component | |||
| Somatropin | 6 mg | 12 mg | 24 mg |
| Mannitol | 18 mg | 36 mg | 72 mg |
| Glycine | 6 mg | 12 mg | 24 mg |
| Dibasic sodium phosphate | 1.36 mg | 2.72 mg | 5.43 mg |
Each cartridge is supplied in a combination package with an accompanying syringe containing approximately 3 mL of diluting solution (diluent). The diluent contains Water for Injection; 0.3% metacresol as a preservative; and 1.7%, 0.29%, and 0.29% glycerin in the 6, 12, and 24 mg cartridges, respectively.
HUMATROPE is indicated for the treatment of pediatric patients with:
HUMATROPE is indicated for the replacement of endogenous GH in adults with GH deficiency.
| Cartridge | Somatropin Concentration |
| 6 mg | 2.08 mg/mL |
| 12 mg | 4.17 mg/mL |
| 24 mg | 8.33 mg/mL |
HUMATROPE for injection is a white lyophilized powder available in the following vial and cartridge sizes:
HUMATROPE for injection is a white lyophilized powder available in the following vial and cartridge sizes:
| NDC | Kit | HUMATROPE | Diluent |
| NDC 0002-7335-11 | Vial Kit | 5 mg vial | 5-mL vial of Diluent for HUMATROPE |
| NDC 0002-8147-01 | Cartridge Kit | 6 mg cartridge (gold) | prefilled syringe of Diluent for HUMATROPE |
| NDC 0002-8148-01 | Cartridge Kit | 12 mg cartridge (teal) | prefilled syringe of Diluent for HUMATROPE |
| NDC 0002-8149-01 | Cartridge Kit | 24 mg cartridge (purple) | prefilled syringe of Diluent for HUMATROPE |
Refrigerate vials of HUMATROPE and Diluent for HUMATROPE at 36° to 46°F (2° to 8°C). Avoid freezing Diluent for HUMATROPE. Protect HUMATROPE from light during storage.
Refrigerate cartridges of HUMATROPE and Diluent for HUMATROPE at 36° to 46°F (2° to 8°C). Avoid freezing Diluent for HUMATROPE. Protect HUMATROPE from light during storage.
Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA. Revised: Oct 2019
The following important adverse reactions are also described elsewhere in the labeling:
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.
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
| Adverse Reaction | HUMATROPEa (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 |
| a Dose=0.06 mg/kg 3 times per week for up to 8
years. b n=1 |
|
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-labelStudy Until Attainment of
Adult Height
| Untreated (n=62) |
HUMATROPE (n=74) |
|
| Surgical procedure | 27% | 45% |
| Otitis media | 26% | 43% |
| Ear disorders | 5% | 18% |
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 HbA1c.
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 Groupin an Open-label
Study
| Untreated (n=25) |
HUMATROPE (n=27) |
|
| Arthralgia | 8% | 11% |
| Gynecomastiaa | 0% | 8% |
| Excessive number of cutaneous nevi | 0% | 7% |
| Scoliosis | 0% | 47% |
| a Percentage calculated for males only: Untreated (0/1), HUMATROPE (1/12) | ||
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).
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% |
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
| Adverse Reaction | 18 Months Exposure [Placebo (6 Months)/Humatrope (12 Months)] (n=30) |
18 Months Humatrope Exposure (n=32) |
| ASTa 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% |
| a Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase | ||
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.
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
Table 7 includes a list of drugs with clinically important drug interactions when administered concomitantly with HUMATROPE and instructions for preventing or managing them.
Table 7: Clinically Important Drug Interactions with
HUMATROPE
| Replacement Glucocorticoid Treatment | |
| Clinical Impact: | Microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. HUMATROPE inhibits 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Initiation of HUMATROPE may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. |
| Intervention: | Patients treated with glucocorticoid replacement for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of HUMATROPE [see WARNINGS AND PRECAUTIONS]. |
| Examples: | Cortisone acetate and prednisone 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]. |
| 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]. |
HUMATROPE contains somatropin, which is not a controlled substance.
Inappropriate use of somatropin may result in significant negative health consequences.
Somatropin is not associated with drug related withdrawal adverse reactions.
Included as part of the PRECAUTIONS section.
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]. 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.
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]. HUMATROPE is not indicated for the treatment of pediatric patients who have growth failure due to Prader-Willi syndrome.
There is an increased risk of malignancy progression with somatropin treatment in patients with active malignancy [see CONTRAINDICATIONS]. 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.
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.
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.
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.
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, CONTRAINDICATIONS].
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.
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].
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.
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.
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.
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.
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].
Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone and IGF-I may increase after HUMATROPE therapy.
Advise the patient to read the FDA-approved patient labeling (Instructions for Use).
Carcinogenicity, mutagenicity and impairment of fertility studies have not been conducted with HUMATROPE.
Limited available data with somatropin use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes. Animal reproduction studies have not been conducted with HUMATROPE.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
There is no information regarding the presence of somatropin in human milk. Limited published data indicate that exogenous somatropin does not increase normal breastmilk concentrations of growth hormone. No adverse effects related to somatropin in the breastfed infant have been reported. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HUMATROPE and any potential adverse effects on the breastfed infant from HUMATROPE or from the underlying maternal condition.
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.
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].
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].
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].
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].
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].
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].
Acute overdosage could lead initially to hypoglycemia and subsequently to hyperglycemia. Overdose with somatropin is likely to cause fluid retention. Long-term overdosage could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess endogenous growth hormone.
HUMATROPE is contraindicated in patients with:
Somatropin binds to dimeric GH receptors located within the cell membranes of target tissue cells. This interaction results in intracellular signal transduction and subsequent induction of transcription and translation of GH-dependent proteins including IGF-1, IGF BP-3 and acid-labile subunit. Somatropin has direct tissue and metabolic effects or mediated indirectly by IGF-1, including stimulation of chondrocyte differentiation, and proliferation, stimulation of hepatic glucose output, protein synthesis and lipolysis.
Somatropin stimulates skeletal growth in pediatric patients with GHD as a result of effects on the growth plates (epiphyses) of long bones. The stimulation of skeletal growth increases linear growth rate (height velocity) in most somatropin-treated pediatric patients. Linear growth is facilitated in part by increased cellular protein synthesis.
Subcutaneous administration of a single dose of Humatrope (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).
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) Cmax of 63.3 (18.2) ng/mL at median Tmax of 4.0 (range 3 to 8) hours. The absolute bioavailability of somatropin is 75% after subcutaneous administration.
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.
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.
The pharmacokinetics of HUMATROPE have not been studied in patients greater than 65 years of age.
The pharmacokinetics of HUMATROPE in pediatric patients are similar to those of adults.
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.
No studies have been performed with HUMATROPE.
An open-label, uncontrolled, multicenter study with Humatrope was conducted in, 314 treatment-naive children aged >2 years who had GH deficiency. Patients were treated with HUMATROPE (0.06 mg/kg 3 times per week) for up to 8 years. The efficacy of HUMTROPE was assessed by evaluating height velocity. Mean increase in height velocity from baseline of 3.6 ± 1.9 cm/year to 8.8 ± 2.3 cm/year was achieved by 1 year of treatment. Height velocity remained increased above baseline for a small subset of patients (n=12) who remained on-study up to 8 years during the long-term extension phase (6.3 ± 2.5 cm/year at year 8 of treatment).
One long-term, randomized, open-label, Canadian multicenter, concurrently controlled study, two long-term, open-label multicenter, historically controlled US studies 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 Resultsa
of Somatropin Studies in Patients with Turner Syndrome
| Study | Group | Study Designb | 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 | Ad | MHT | 29 | 9.4 | 15 | 6.1 | 8.3 |
| Be | MHT | 26 | 9.6 | 12.3 | 5.6 | 5.9 | |
| Cf | MHT | 51 | 12.7 | 13.7 | 3.8 | 5 | |
| US 3 | RDT | 99 | 10.9 | 8-13.5 | 5.5 | 5.7 | |
| a Data shown are mean values. b RCT: randomized controlled trial; MHT: matched historical controlled trial; RDT: randomized dose-response trial. cAnalysis 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. |
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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-ControlledStudyab
| Placebo (n=11) Mean (SD) |
HUMATROPE (n=22) Mean (SD) |
Treatment Effect Mean (95%CIb) | p-value | |
| Baseline height SDS | -2.8 (0.6) | -2.7 (0.6) | NAb | 0.77c |
| BPH SDS | -2.3 (0.8) | -2.1 (0.7) | NA | 0.53c,d |
| Final height SDS | -2.3 (0.6) | -1.8 (0.8) | 0.51 (0.10, 0.92) | 0.017e |
| FHb SDS - baseline height SDS | 0.4 (0.2) | 0.9 (0.7) | 0.51 (0.04, 0.97) | 0.034e |
| FH SDS -BPH SDS | -0.1 (0.6) | 0.3 (0.6) | 0.46 (0.02, 0.89) | 0.043d,e |
| a For final height population. b Abbreviations: BPH=baseline predicted height; CI=confidence interval; FH=final height; NA=not applicable; SDS=standard deviation score. cAssessed 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. |
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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 Heighta
| 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) |
| a Abbreviations: FH=final height; PH=predicted height; CI=confidence interval; cm=centimeters. | |||||
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
| SHOX Deficiency | Turner Syndrome | |||
| Untreated (n=24) Mean (SD) |
HUMATROPE (n=27) Mean (SD) |
Treatment Differencea Mean (95% CI) | HUMATROPE (n=26) Mean (SD) |
|
| Height Velocity (cm/yr) | ||||
| 1st Year | 5.2 (1.1) | 8.7 (1.6)b | +3.5 (2.8, 4.2) | 8.9 (2.0) |
| 2nd 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 1st Year | 5.4 (1.2) | 9.1 (1.5)c | +3.7 (2.9, 4.5) | 8.9 (1.9) |
| Baseline to 2nd 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 1st Year | 0.1 (0.5) | 0.7 (0.5)d | +0.5 (0.3, 0.8) | 0.8 (0.5) |
| Baseline to 2nd 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%) |
| 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). cp<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. |
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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. 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. 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 AfterHUMATROPE Treatment of Short
Children Born SGA Who Fail to Demonstrate Catch-up Growtha
| 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) | (n=93) | -0.0 ± 0.1 |
| -3.9 (0.6) | -3.9 (0.7) | (-0.2, 0.2) | |
| Year 1 | (n=86)c | (n=93)c | -0.3 ± 0.1 |
| Height SDS | -3.0 (0.7) | -2.7 (0.7) | (-0.4, -0.2) |
| Change from baseline | 0.9 (0.4) | 1.1 (0.4) | p-value <0.001 |
| Year 2 | (n=82)c | (n=88)c | -0.3 ± 0.1 |
| Height SDS | -2.5 (0.8) | -2.2 (0.7) | (-0.4, -0.1) |
| Change from baseline | 1.4 (0.5) | 1.6 (0.5) | |
| 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. |
|||
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.
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.
Instructions for Use
HumatroPen® 6 mg
(HU-ma-tro-Pen 6 mg)
HUMATROPE® Delivery System Device for use with HUMATROPE (somatropin) 6 mg Cartridges
 |
Section 1: Read Section 1 completely before you move on to Section 2.
What you need to know about HumatroPen® 6 mg
Read this Instructions for Use including the “Commonly asked questions” section, at the end of this Instructions for Use, before you start using HumatroPen 6 mg and each time you get a new Pen. There may be new information. This information does not take the place of talking to your healthcare provider about your or your child’s medical condition or treatment.
Your healthcare provider should show you how to use HumatroPen (Pen) the right way before you use it for the first time. Ask your healthcare provider if you have any questions. If you are having problemsusing the HumatroPen 6 mg, call Lilly at 1-800-545-5979 or go to www.humatrope.com.
Introduction
Important information about HumatroPen 6 mg:
Information about needles used with HumatroPen 6 mg:
How do I care for HumatroPen 6 mg?
How do I store HumatroPen 6 mg with an attached cartridge?
When do I need to replace my HumatroPen?
Do not use your Pen for more than 3 years after first use or past the expiration date on the carton, whichever comes first.
Record the date the Pen was first used here: __ / __ / __.
Record the expiration date from your carton here: __ / __ / __.
Contact your healthcare provider if you need a new HumatroPen 6 mg, or when the Pen has been used for 3 years.
For more information, call Lilly at 1-800-545-5979 or go to www.humatrope.com.
HumatroPen 6 mg Parts
 |
Pen Needle Parts (Pen needles not included)
 |
Hidden Needle Cover (optional, included)
 |
Storage Case
 |
Section 2: Read Section 2 only after you have read Section 1.
Getting Started
New Cartridge Set-up
Step 2A - Check the Pen and Cartridge
 |
Important Notes:
 |
 |
Important Note:
Check the number on the front housing to make sure that it matches the Cartridge strength on the Cartridge label. If the
Pen and Cartridge do not match, contact your healthcare provider.
Step 2B - Attach the Cartridge
 |
 |
Important Note:
If the Cartridge is not completely attached, the screw may not move and cause you to inject the wrong dose.
Step 2C - Attach the needle
 |
 |
 |
Step 2D - Remove air from new Cartridge
 |
 |
Important Notes:
Step 2E - Continue on to Daily Use
Section 3: Now that you have done the 1 time only New Cartridge Set-up, follow Section 3 foreach of your daily injections.
Daily Use
Before your injection: Take the Pen out of the refrigerator and let it sit for 10 minutes before injecting to allow it to reach room temperature. Injecting medicine that is cold can cause  discomfort.
Step 3A - Check the Pen
 |
Important Note:
Do not use the Pen if any part of the Pen or Cartridge appears broken or damaged. Contact your healthcare provider.
 |
Important Note: Do not use the Cartridge past the expiration date.
 |
Important Note:
Check the number on the front housing to make sure that it matches the Cartridge strength on the Cartridge label. If the Pen and Cartridge do not match, contact your healthcare provider.
Step 3B - Attach a new disposable pen needle for each injection.
 |
 |
 |
Important Note: Talk to your healthcare provider about the right way to use the Pen, and the optional Hidden Needle Cover, the right sites to inject HUMATROPE, and how to rotate your injection sites. When using the Hidden Needle Cover with your HumatroPen, you must use a needle length of 5 mm or longer.
Read the Hidden Needle Cover Instructions for Use.
Step 3C - Dial and inject the dose
 |
 |
 |
 |
Important Note: It is possible to set a dose larger than the amount of HUMATROPE left in the Cartridge.
Step 3D - Remove and dispose of the needle
 |
 |
 |
Important Note: Do not remove this Cartridge from the Pen until the Cartridge is empty or needs to be replaced to help prevent you from giving the wrong dose.
Step 3E - Store Pen and Cartridge for next use
Commonly asked questions:
1. Do I need to perform the New Cartridge Setup before every dose?
2. What should I do if the Cartridge label and Pen do not match?
3. What should I do if the HUMATROPE is not clear?
4. Why are there air bubbles in the Cartridge?
5. What should I do if the screw does not move out when there is no Cartridge attached to the Pen?
6. What should I do if I cannot attach the Cartridge to the Pen body?
7. Why is it hard to push the injection button when I try to inject the dose?
8. What should I do if the dose knob does not go to zero (0) when I inject the dose?
9. What should I do if I see HUMATROPE leaking from the needle after I have finished the injection?
10. How can I tell when the injection is complete?
Disposing of used needles:
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
Instructions for Use
HumatroPen® 12 mg
(HU-ma-tro-Pen 12 mg) HUMATROPE® Delivery System Device for use with
HUMATROPE (somatropin) 12 mg Cartridges
 |
Section 1: Read Section 1 completely before you move on to Section 2.
What you need to know about HumatroPen® 12 mg
Read this Instructions for Use including the “Commonly asked questions” section, at the end of this Instructions for Use, before you start using HumatroPen 12 mg and each time you get a new Pen. There may be new information. This information does not take the place of talking to your healthcare provider about your or your child’s medical condition or treatment.
Your healthcare provider should show you how to use HumatroPen (Pen) the right way before you use it for the first time. Ask your healthcare provider if you have any questions. If you are having problems using the HumatroPen 12 mg, call Lilly at 1-800-545-5979 or go to www.humatrope.com.
Introduction
Important information about HumatroPen 12 mg:
Information about needles used with HumatroPen 12 mg:
How do I care for HumatroPen 12 mg?
How do I store HumatroPen 12 mg with an attached cartridge?
When do I need to replace my HumatroPen?
Do not use your pen for more than 3 years after the first use or past the expiration date on the carton, whichever comes first.
Record the date the Pen was first used here: __ / __ / __.
Record the expiration date from your carton here: __ / __ / __.
Contact your healthcare provider if you need a new HumatroPen 12 mg, or when the Pen has been used for 3 years.
For more information, call Lilly at 1-800-545-5979 or go to www.humatrope.com.
HumatroPen 12 mg Parts
 |
Pen Needle Parts (Pen needles not included)
 |
Hidden Needle Cover (optional, included)
 |
Storage Case
 |
Section 2: Read Section 2 only after you have read Section 1.
Getting Started
New Cartridge Set-up
Step 2A - Check the Pen and Cartridge
 |
Important Notes:
 |
 |
Important Note: Check the number on the front housing to make sure that it matches the Cartridge strength on the Cartridge label. If the Pen and Cartridge do not match, contact your healthcare provider.
Step 2B - Attach the Cartridge
 |
 |
Important Note: If the Cartridge is not completely attached, the screw may not move and cause you to inject the wrong dose.
Step 2C - Attach the needle
 |
 |
 |
Step 2D - Remove air from new Cartridge
 |
 |
Important Notes:
Step 2E - Continue on to Daily Use
Section 3: Now that you have done the 1 time only New Cartridge Set-up, follow Section 3 for each of your daily injections.
Daily Use
Before your injection: Take the Pen out of the refrigerator and let it sit for 10 minutes before injecting to allow it to reach room temperature. Injecting medicine that is cold can cause  discomfort.
Step 3A - Check the Pen
 |
Important Note: Do not use the Pen if any part of the Pen or Cartridge appears broken or damaged. Contact your healthcare provider.
 |
Important Note: Do not use the Cartridge past the expiration date.
 |
Important Note: Check the number on the front housing to make sure that it matches the Cartridge strength on the Cartridge label. If the Pen and Cartridge do not match, contact your healthcare provider.
Step 3B - Attach a new disposable pen needle for each injection.
 |
 |
 |
Important Note: Talk to your healthcare provider about the right way to use the Pen, and the optional Hidden Needle Cover, the right sites to inject HUMATROPE, and how to rotate your injection sites. When using the Hidden Needle Cover with your HumatroPen, you must use a needle length of 5 mm or longer.
Read the Hidden Needle Cover Instructions for Use.
Step 3C - Dial and inject the dose
 |
 |
 |
 |
Important Note: It is possible to set a dose larger than the amount of HUMATROPE left in the Cartridge.
Step 3D - Remove and dispose of the needle
 |
 |
 |
Important Note: Do not remove this Cartridge from the Pen until the Cartridge is empty or needs to be replaced to help prevent you from giving the wrong dose.
Step 3E - Store Pen and Cartridge for next use
Commonly asked questions:
1. Do I need to perform the New Cartridge Setup before every dose?
2. What should I do if the Cartridge label and Pen do not match?
3. What should I do if the HUMATROPE is not clear?
4. Why are there air bubbles in the Cartridge?
5. What should I do if the screw does not move out when there is no Cartridge attached to thePen?
6. What should I do if I cannot attach the Cartridge to the Pen body?
7. Why is it hard to push the injection button when I try to inject the dose?
8. What should I do if the dose knob does not go to zero (0) when I inject the dose?
9. What should I do if I see HUMATROPE leaking from the needle after I have finished the injection?
10. How can I tell when the injection is complete?
Disposing of used needles:
Instructions for Use
HumatroPen® 24 mg
(HU-ma-tro-Pen 24 mg) HUMATROPE® Delivery System Device for use with
HUMATROPE (somatropin) 24 mg Cartridges
 |
Section 1: Read Section 1 completely before you move on to Section 2.
What you need to know about HumatroPen® 24 mg
Read this Instructions for Use including the “Commonly asked questions” section, at the end of this Instructions for Use, before you start using HumatroPen 24 mg and each time you get a new Pen. There may be new information. This information does not take the place of talking to your healthcare provider about your or your child’s medical condition or treatment.
Your healthcare provider should show you how to use HumatroPen (Pen) the right way before you use it for the first time. Ask your healthcare provider if you have any questions. If you are having problems using the HumatroPen 24 mg, call Lilly at 1-800-545-5979 or go to www.humatrope.com.
Introduction
Important information about HumatroPen 24 mg:
Information about needles used with HumatroPen 24 mg:
How do I care for HumatroPen 24 mg?
How do I store HumatroPen 24 mg with an attached cartridge?
When do I need to replace my HumatroPen?
Do not use your pen for more than 3 years after the first use or past the expiration date on the carton, whichever comes first.
Record the date the Pen was first used here: __ / __ / __.
Record the expiration date from your carton here: __ / __ / __.
Contact your healthcare provider if you need a new HumatroPen 24 mg, or when the Pen has been used for 3 years.
For more information, call Lilly at 1-800-545-5979 or go to www.humatrope.com.
HumatroPen 24 mg Parts
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Pen Needle Parts (Pen needles not included)
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Hidden Needle Cover (optional, included)
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Storage Case
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Section 2: Read Section 2 only after you have read Section 1.
Getting Started
New Cartridge Set-up
Step 2A - Check the Pen and Cartridge
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Important Notes:
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Important Note:
Check the number on the front housing to make sure that it matches the Cartridge strength on the Cartridge label. If the Pen and Cartridge do not match, contact your healthcare provider.
Step 2B - Attach the Cartridge
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Important Note:
If the Cartridge is not completely attached, the screw may not move and cause you to inject the wrong dose.
Step 2C - Attach the needle
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Step 2D - Remove air from new Cartridge
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Important Notes:
Step 2E - Continue on to Daily Use
Section 3: Now that you have done the 1 time only New Cartridge Set-up, follow Section 3 foreach of your daily injections.
Daily Use
Before your injection: Take the Pen out of the refrigerator and let it sit for 10 minutes before injecting to allow it to reach room temperature. Injecting medicine that is cold can cause discomfort.
Step 3A - Check the Pen
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Important Note: Do not use the Pen if any part of the Pen or Cartridge appears broken or damaged. Contact your healthcare provider.
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Important Note: Do not use the Cartridge past the expiration date.
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Important Note: Check the number on the front housing to make sure that it matches the Cartridge the expiration date. strength on the Cartridge label. If the Pen and Cartridge do not match, contact your healthcare provider.
Step 3B - Attach a new disposable pen needle for each injection.
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Important Note: Talk to your healthcare provider about the right way to use the Pen, and the optional Hidden Needle Cover, the right sites to inject HUMATROPE, and how to rotate your injection sites. When using the Hidden Needle Cover with your HumatroPen, you must use a needle length of 5 mm or longer.
Read the Hidden Needle Cover Instructions for Use.
Step 3C - Dial and inject the dose
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Important Note: It is possible to set a dose larger than the amount of HUMATROPE left in the Cartridge.
Step 3D - Remove and dispose of the needle
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Important Note: Do not remove this Cartridge from the Pen until the Cartridge is empty or needs to be replaced to help prevent you from giving the wrong dose.
Step 3E - Store Pen and Cartridge for next use
Commonly asked questions:
1. Do I need to perform the New Cartridge Setup before every dose?
2. What should I do if the Cartridge label and Pen do not match?
3. What should I do if the HUMATROPE is not clear?
4. Why are there air bubbles in the Cartridge?
5. What should I do if the screw does not move out when there is no Cartridge attached to the Pen?
6. What should I do if I cannot attach the Cartridge to the Pen body?
7. Why is it hard to push the injection button when I try to inject the dose?
8. What should I do if the dose knob does not go to zero (0) when I inject the dose?
9. What should I do if I see HUMATROPE leaking from the needle after I have finished theinjection?
10. How can I tell when the injection is complete?
Disposing of used needles:
Instructions for Use
HUMATROPE®
(HU-ma-trope) (somatropin) for injection
Vial Kit
Read this Instructions for Use before you start using HUMATROPE and each time you get a new HUMATROPE vial. There may be new information. This information does not take the place of talking to your healthcare provider about your or your child’s medical condition or treatment.
Your healthcare provider should show you how to prepare, mix, measure, and inject HUMATROPE the right way before you use it for the first time. Ask your healthcare provider if you have any questions.
Do not share your syringes or needles with anyone else, even if the needle has been changed. You may giveother people a serious infection or get a serious infection from them.
HUMATROPE is not recommended for use by blind or visually impaired individuals without the help of a sighted individual trained on how to use it.
How should I store HUMATROPE?
You will need the following supplies to mix your HUMATROPE and give your injection (Figures A and B):
Before mixing your HUMATROPE, check the expiration date on the vial labels (See Figure A). Do not use any vial that has expired. Contact your healthcare provider or call Lilly at 1-800-545-5979 if either vial has expired.
Figure A
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Figure B
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Mixing the Vial of HUMATROPE:
Only mix HUMATROPE with the Diluent for HUMATROPE that comes in the package.
Do not use other solutions for mixing HUMATROPE unless instructed to do so by your healthcare provider.
Your healthcare provider will also tell you what size syringe and needle to use and how much Diluent to add to the vial of HUMATROPE.
Wash your hands with soap and water.
Step 1.
Figure C
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Step 2.
Figure D
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Step 3.
Figure E
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Step 4.
Figure F
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Step 5.
Figure G
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Step 6.
Figure H
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Step 7.
Figure I
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Step 8.
Figure J
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Step 9.
Figure K
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Step 10.
Step 11.
Figure L
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Step 12.
Preparing to give your Injection:
Step 13.
Step 14.
Step 15.
Step 16.
Step 17.
Step 18.
Step 19.
Step 20.
Injecting HUMATROPE:
Step 21.
Figure M
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Step 22.
Figure N
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Step 23.
Figure O
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Step 24.
Figure P
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Step 25.
Figure Q
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Step 26.
Step 27.
Step 28.
Disposing of used needles and syringes:
Instructions for Use
HUMATROPE®
(HU-ma-trope) (somatropin) for injection
Cartridge Kit
HUMATROPE cartridges are only to be used with HumatroPen® injection devices.
Read this Instructions for Use before you start using HUMATROPE Cartridge Kit and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your or your child’s medical condition or treatment.
Your healthcare provider should show you how to prepare, mix, measure, and inject HUMATROPE the right way before you use it for the first time. Ask your healthcare provider if you have any questions.
How should I store HUMATROPE?
Important:
HUMATROPE Cartridge Kit (See Figure A)
Note: There are 3 strengths of HUMATROPE Cartridges that have different amounts of HUMATROPE (6 mg, 12 mg, or 24 mg). Make sure that you have the Cartridge that your healthcare provider prescribed.
Mixing the HUMATROPE in the Cartridge
Only use the prefilled Diluent Syringe that comes with your HUMATROPE Cartridge Kit to mix the HUMATROPE in the Cartridge. Do not use the diluent that comes in the HUMATROPE vial box, or any other liquid.
HUMATROPE Cartridge Kit mixing Instructions
Parts Figure A
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Only use a HUMATROPE Cartridge Kit to prepare the HUMATROPE Cartridge.
*Note: The liquid (Diluent) should be clear, colorless, and free of particles and is shown as blue in the figure (See Figure A).
Preparing Your New HUMATROPE Cartridge
Start by thoroughly washing your hands.
Remove all contents from the tray.
Note: The HUMATROPE Cartridge is made for left or right handed use so you may handle it the way that is most comfortable for you.
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Hold the gray needle cover at the bottom of the Diluent Syringe.
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Pull the needle cover straight down to remove from the Diluent Syringe and throw it away. Do not push the plunger yet. It is okay if a drop of Diluent is seen. You do not have to release air from the Diluent Syringe.
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Hold the Cartridge, with the black triangles up toward the Diluent Syringe. Make sure the Cartridge and Diluent Syringe are facing each other in a straight line.
Do not insert the Cartridge at an angle.
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Push the Cartridge straight into the Diluent Syringe until it stops and the black triangles are covered inside the Diluent Syringe.
You may hear or feel a click.
Do not twist the Cartridge.
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Hold the Diluent Syringe and the Cartridge together with both hands. Push and release the plunger 2 or 3 times until the Diluent is in the Cartridge.
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Remove your thumb from the plunger and check that the Diluent Syringe is empty. It is normal for small drops of Diluent to remain in the Diluent Syringe.
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With your thumb off the plunger, pull Place the end cap on a hard, flat the Cartridge away from the Diluent surface. Push the Diluent Syringe
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Place the end cap and throw away the Diluent Syringe right away as instructed by your healthcare provider.
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Mix the medicine in the Cartridge by gently moving it in an up and down motion 10 times. Then let the Cartridge sit for 3 minutes.
Do not shake.
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Check the HUMATROPE liquid, it should be clear. If the liquid is clear, your Cartridge is now prepared and ready to be attached to your HumatroPen (See the Instructions for Use for HumatroPen 6 mg, 12 mg or 24 mg).
If the liquid is cloudy or contains particles, gently mix the medicine in the Cartridge 10 more times. Let the Cartridge sit for 5 more minutes. If the liquid still remains cloudy or contains particles, do not use the Cartridge. Contact your healthcare provider or call Lilly at 1-800-5455979 or go to www.humatrope.com.
If you have questions about preparing your HUMATROPE Cartridge, you should contact your healthcare provider.
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Talk to your healthcare provider about the right way to use your HUMATROPE Cartridge Kit and HumatroPen injection device, the right sites to inject HUMATROPE, and how to rotate your injection sites.
Disposing of used Diluent Syringes:
Instructions for Use
Hidden Needle Cover
For use with HumatroPen® (6 mg, 12 mg, or 24 mg)
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What you need to know about the Hidden Needle Cover
Read this Instructions for Use for the Hidden Needle Cover before you use it. There may be new information. This information does not take the place of talking to your healthcare provider about your or your child’s medical condition or treatment.
Your healthcare provider should show you how to use the Hidden Needle Cover with the HumatroPen the right way before you use it for the first time. Ask your healthcare provider if you have any questions. If you are having problemsusing the Hidden Needle Cover with the HumatroPen (6 mg, 12 mg or 24 mg) call Lilly at 1-800-545-5979 or go towww. Humatrope.com.
The Hidden Needle Cover allows you to give your injection with the needle hidden from view. Be sure the HumatroPen is set up by following the steps in the HumatroPen Instructions for Use.
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What kinds of needles can be used with the Hidden Needle Cover?
1. Be sure the HumatroPen cap is removed. Remove the paper tab and attach a new needle to the Cartridge,  and remove the outer needle cap and inner needle cap. Read Section 2A and 2B of the HumatroPen Instructions for Use for detailed instructions to set-up the HumatroPen. Read Section 2C of the HumatroPen Instructions for Use for detailed instructions to attach the needle. Follow your healthcare provider’s instructions on the safe handling of needles.
2. Confirm the Hidden Needle Cover is in the locked position. If it is not  locked, turn the slider so that the guide post is in the guide channel, in  the locked position, as shown.
Be sure to turn the slider to the locked position, do not push the slider. The Hidden Needle Cover should now be in the locked position. It is   important to make sure the slider is in the locked position to help avoid accidental needle sticks in the next step.
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3 Insert the Pen with attached Cartridge and needle straight into the locked Hidden Needle Cover by pushing firmly until it stops. Do not block the opening of the Hidden Needle Cover with your hand or fingers, while performing this step.
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4 Unlock the Hidden Needle Cover by turning the slider until the guide post is in the guide channel, in the unlocked position as shown. To avoid accidental needle sticks, be careful not to push the slider in after it is unlocked.
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5 Turn the dose knob to the prescribed dose.
If you turn past the prescribed dose, you can correct the dose by turning down to the right dose. The dose knob clicks as you turn it.
Do not dial your dose by counting clicks because you may dial the wrong dose.
Read the HumatroPen Instructions for Use: Step 3C “Dial and inject the dose” for detailed instructions on how to give your injection.
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6 Injections can be given in the following areas:
Talk to your healthcare provider about the right way to use HumatroPen, the right areas to give your injection, and injection site rotation.
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7 Insert the needle at a 90 degree angle as shown by your healthcare provider. The slider will move over the Hidden Needle Cover Body as the needle is inserted.
Place your thumb on the injection button, then slowly and firmly push the injection button until it stops moving. Continue to hold the injection button for 5 seconds, then remove the needle from the skin. The Hidden Needle Cover will automatically lock as you remove the needle from the skin.
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Check to make sure you see a 0.00 in the dose window. This means that the complete dose was injected.
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Important Note: It is possible to set a dose larger than the amount of HUMATROPE left in the Cartridge. At the end of the injection, the number in the dose window should be 0.00. If it is not, this is the amount of HUMATROPE you did not receive. Write this number down.
Remove the Hidden Needle Cover, needle and empty Cartridge from the Pen. Insert a new Cartridge, attach a new needle, and remove air from the new Cartridge. Attach the Hidden Needle Cover.
Complete your dose by injecting only the amount you did not receive. If you still do not think you received your full dose, do not take another dose. Call Lilly at 1-800-545-5979 or your healthcare provider for assistance.
8 After you have completed your injection confirm that the Hidden Needle Cover has returned to the locked position. Carefully pull the Hidden Needle Cover straight off to remove it from the Pen.
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Note: If the Hidden Needle Cover did not return to the locked position, you can still remove the Hidden Needle Cover from the Pen by pulling it straight off.
9 Read Step 3D “Remove and dispose of the needle” in the Instructions for Use for the HumatroPen.
10 Read Step 3E “Store Pen and Cartridge for next use” in the Instructions for Use for the HumatroPen.
11 Read “Commonly asked questions” in the Instructions for Use for the HumatroPen.
12 Read “Disposing of used needles” in the Instructions for Use for the HumatroPen.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
