HUMATROPE *Somatropin* 36 IU (12MG)

HUMATROPE®
[somatropin (rDNA ORIGIN)] for Injection

DESCRIPTION

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.

Vial

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.

Cartridge

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.

INDICATIONS

Pediatric Patients

HUMATROPE is indicated for the treatment of pediatric patients with:

  • growth failure due to inadequate secretion of endogenous growth hormone (GH),
  • short stature associated with Turner syndrome,
  • Idiopathic Short Stature (ISS), height standard deviation score (SDS) <-2.25, and associated with growth rates unlikely to permit attainment of adult height in the normal range,
  • short stature or growth failure in short stature homeobox-containing gene (SHOX) deficiency,
  • short stature born small for gestational age (SGA) with no catch-up growth by 2 years to 4 years of age.

Adult Patients

HUMATROPE is indicated for the replacement of endogenous GH in adults with GH deficiency.

DOSAGE AND ADMINISTRATION

Administration And Use Instructions

  • Therapy with HUMATROPE should be supervised by a physician who is experienced in the diagnosis and management of patients with the conditions for which HUMATROPE is indicated [see INDICATIONS AND USAGE].
  • Fundoscopic examination should be performed routinely before initiating treatment with HUMATROPE to exclude preexisting papilledema, and periodically thereafter [see WARNINGS AND PRECAUTIONS].
  • Leave HUMATROPE at room temperature for 10 minutes prior to administration.
  • Administer HUMATROPE by subcutaneous injection to the back of the upper arm, abdomen, buttock, or thigh with regular rotation of injection sites to avoid lipoatrophy.

Pediatric Dosage

  • Individualize dosage for each patient based on the growth response.
  • Divide the calculated weekly HUMATROPE dosage into equal doses given either 6 or 7 days per week.
  • The recommended weekly dose in milligrams (mg) per kilogram (kg) of body weight for pediatric patients is:
    • Pediatric GH Deficiency: 0.18 mg/kg/week to 0.3 mg/kg/week (0.026 to 0.043 mg/kg/day)
    • Turner Syndrome: Up to 0.375 mg/kg/week (up to.054 mg/kg/day)
    • Idiopathic Short Stature: Up to 0.37 mg/kg/week (up to 0.053 mg/kg/day)
    • SHOX Deficiency: 0.35 mg/kg/week (0.05 mg/kg/day)
    • Small for Gestational Age (SGA): Up to 0.47 mg/kg/week (up to 0.067 mg/kg/day)
      • In very short pediatric patients, height SDS less than -3, and older pubertal pediatric patients consider initiating treatment with a larger dose of HUMATROPE (up to 0.067 mg/kg/day). Consider a gradual reduction in dosage if substantial catch-up growth is observed during the first few years of therapy. In pediatric patients less than 4 years of age with less severe short stature, baseline height SDS values between -2 and -3, consider initiating treatment at 0.033 mg/kg/day and titrate the dose as needed.
  • Assess compliance and evaluate other causes of poor growth such as hypothyroidism, under-nutrition, advanced bone age and antibodies to recombinant human GH if patients experience failure to increase height velocity, particularly during the first year of treatment.
  • Discontinue HUMATROPE for stimulation of linear growth once epiphyseal fusion has occurred [see CONTRAINDICATIONS].

Adult Dosage

  • Patients who were treated with somatropin for GH deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin for GH deficient adults.
  • Consider using a lower starting dose and smaller dose increment increases for geriatric patients as they may be at increased risk for adverse reactions with HUMATROPE than younger individuals [see Use In Specific Populations].
  • Women may require higher doses and patients receiving oral estrogen may require higher doses [see DRUG INTERACTIONS].
  • Administer the prescribed dose daily.
  • Either of two HUMATROPE dosing regimens may be used:
    • Non-weight based:
      • Initiate HUMATROPE with a dose of approximately 0.2 mg/day (range, 0.15 mg/day to 0.3 mg/day) and increase the dose every 1-2 months by increments of approximately 0.1 mg/day to 0.2 mg/day, according to individual patient requirements based on the clinical response and serum insulin-like growth factor 1 (IGF-1) concentrations.
      • Use the patient’s clinical response, adverse reactions, and determination of age-and gender-adjusted serum IGF-1 concentrations as guidance in dose titration.
      • Maintenance dosages will vary considerably from person to person, and between male and female patients.
    • Weight-based:
      • Initiate HUMATROPE at 0.006 mg/kg daily and increase the dose according to individual patient requirements to a maximum of 0.0125 mg/kg daily.
      • Use the patient’s clinical response, adverse reactions, and determination of age-and gender-adjusted serum IGF-1 concentrations as guidance in dose titration.
      • Maintenance dosages will vary considerably from person to person, and between male and female patients
      • Not recommended for obese patients as they are more likely to experience adverse reactions with this regimen.

Reconstitution Of Vials

  • Reconstitute the 5-mg vial of HUMATROPE with 1.5 to 5 mL of Diluent for HUMATROPE.
    • Inject the diluent into the vial by aiming the stream of liquid gently against the vial wall. Swirl the vial (do not shake) with a gentle rotary motion until the powder is completely dissolved into liquid and the solution is clear.
    • Inspect visually for particulate matter and discoloration. If the resulting solution is cloudy or contains particulate matter do not use.
  • Vials of HUMATROPE are stable for up to 14 days when reconstituted with Diluent for HUMATROPE and refrigerated at 36° to 46°F (2° to 8°C). Do not leave reconstituted vials at room temperature more than 30 minutes per day. Avoid freezing the reconstituted vial of HUMATROPE. Protect HUMATROPE from light during storage.
  • For patients with known hypersensitivity to the Diluent for HUMATROPE [see WARNINGS AND PRECAUTIONS], reconstitute the vial with Sterile Water for Injection. Use only one dose per vial, use immediately and discard the unused portion.

Reconstitution Of Cartridges

  • Each HUMATROPE cartridge is designed for use only with the appropriate corresponding HumatroPen®.
    • Reconstitute each cartridge of HUMATROPE using only the diluent syringe that accompanies the cartridge. Do not shake. The reconstituted solution should be clear.
    • Inspect visually for particulate matter and discoloration. If the resulting solution is cloudy or contains particulate matter do not use.
    • The somatropin concentrations for the reconstituted HUMATROPE cartridges are as follows:

 

Cartridge Somatropin Concentration
6 mg 2.08 mg/mL
12 mg 4.17 mg/mL
24 mg 8.33 mg/mL

 

  • Reconstituted cartridges of HUMATROPE are stable for up to 28 days when refrigerated at 36° to 46°F (2° to 8°C). Do not leave at room temperature more than 30 minutes per day. Avoid freezing the reconstituted cartridge. Protect HUMATROPE from light during storage.
  • For patients with known hypersensitivity to the diluent supplied with the HUMATROPE cartridge [see WARNINGS AND PRECAUTIONS], do not use HUMATROPE cartridge. Use the HUMATROPE vial and reconstitute with Sterile Water for Injection [see DOSAGE AND ADMINISTRATION].

HOW SUPPLIED

Dosage Forms And Strengths

HUMATROPE for injection is a white lyophilized powder available in the following vial and cartridge sizes:

  • 5 mg vial and a 5-mL vial of Diluent for HUMATROPE
  • 6 mg cartridge (gold) and a prefilled syringe of Diluent for HUMATROPE
  • 12 mg cartridge (teal) and a prefilled syringe of Diluent for HUMATROPE
  • 24 mg cartridge (purple) and a prefilled syringe of Diluent for HUMATROPE

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

 

Storage And Handling

Vials

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.

Cartridges

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.

SIDE EFFECTS

The following important adverse reactions are also described elsewhere in the labeling:

Clinical Studies Experience

Because clinical studies are conducted under varying conditions, adverse reaction rates observed during the clinical studies performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical studies performed with a different somatropin formulation, and may not reflect the adverse reaction rates observed in practice.

Pediatric Patients

Growth Failure Due To Inadequate Secretion Of Endogenous Growth Hormone

In an uncontrolled open-label study, 314 treatment-naive children aged >2 years who had GH deficiency were treated with HUMATROPE (0.06 mg/kg 3 times per week) for up to 8 years. Adverse reactions of special interest are reported in Table 1.

Table 1: Adverse Reactions of Special Interest Occurring in Humatrope-Treated Patients with Growth Failure Due to Inadequate Secretion of Endogenous Growth Hormone in an Open-label Study for Up to 8 Years

 

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
Dose=0.06 mg/kg 3 times per week for up to 8 years.
b n=1

 

Short Stature Associated With Turner Syndrome

In a randomized, concurrent-controlled (untreated), open-label study until attainment of adult height, the adverse reactions of special interest occurring in 74 patients treated with Humatrope at dose 0.3 mg/kg/week (mean duration 4.1 years) and in 62 untreated patients (mean duration 3.7 years) are reported in Table 2. A similar increase in otitis media was observed in an 18-month placebo-controlled study.

Table 2: Adverse Reactions of Special Interest Occurring in Patients with Turner Syndrome in an Open-labelStudy Until Attainment of Adult Height

 

Untreated
(n=62)
HUMATROPE
(n=74)
Surgical procedure 27% 45%
Otitis media 26% 43%
Ear disorders 5% 18%

 

Idiopathic Short Stature

Adverse reactions occurring in a randomized, placebo-controlled study of HUMATROPE treatment (0.22 mg/kg/week) until attainment of adult height (mean duration of HUMATROPE treatment 3.7 years, mean duration of placebo treatment 3.3 years) are reported in Table 3. Mean fasting serum insulin concentration increased by 10% in the HUMATROPE treatment group at the end of treatment relative to baseline, but remained within the normal reference range.

Table 3: Adverse Reactions Occurring in Patients with Idiopathic Short Stature Treated with HUMATROPE in a Randomized Placebo-controlled Study

 

Placebo
(n=31)
HUMATROPE
(n=37)
Scoliosis 13% 19%
Otitis media 7% 16%
Hyperlipidemia 3% 8%
Gynecomastia 3% 5%
Hip pain 0 3%
Arthralgia 3% 11%
Arthrosis 7% 11%
Myalgia 13% 24%
Hypertension 0 3%

 

In a dose-response study (239 patients treated for 2 years), among HUMATROPE dose groups [0.24 mg/kg/week (n=78), 0.37 mg/kg/week (n=83), 0.24 mg/kg/week for the first year and 0.37 mg/kg/week thereafter (n=78)], mean fasting blood glucose, mean glycosylated hemoglobin, and the incidence of elevated fasting blood glucose concentrations were similar. One patient developed glucose intolerance and high serum HbA1c.

Short Stature Or Growth Failure In SHOX Deficiency

Adverse reactions of special interest from a 2-year randomized, open-label study with HUMATROPE (0.35 mg/kg/wk) compared to no treatment are presented in Table 4. During the 2-year study period, the proportion of patients who had at least one IGF-I concentration greater than 2.0 SD above the age-and gender-appropriate mean was 10 of 27 (37%) for the HUMATROPE-treated group vs. 0 of 24 patients (0%) for the untreated group. The proportion of patients who had at least one IGFBP-3 concentration greater than 2.0 SD above the age and gender appropriate mean was 16 of 27 (59%) for the HUMATROPE treated group vs. 7 of 24 (29%) for the untreated group.

Table 4: Adverse Reactions of Special Interest Occurring in Patients with SHOX Deficiency By Treatment 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%
Percentage calculated for males only: Untreated (0/1), HUMATROPE (1/12)

 

Small For Gestational Age (SGA) With No Catch-up Growth By Age 2-4 Years

In a 2-year, multicenter, randomized study, 193 pediatric patients were treated with 2 different HUMATROPE treatment regimens: a fixed dose of 0.067 mg/kg/day (FHD group) or an individually adjusted dose regimen (IAD group; starting dose 0.035 mg/kg/day which could be increased as early as Month 3 to 0.067 mg/kg/day based on a validated growth prediction model). Reported adverse reactions included: common childhood infectious diseases, otitis media, headaches, and slipped capital femoral epiphysis (n=1. Six patients (4 in the FHD group and 2 in the IAD group whose dose was increased from 0.035 mg/kg/day to 0.067 mg/kg/day [one at Month 3 and one at Year 1]) had impaired fasting glucose at Year 2. Two of 6 had impaired fasting glucose during the study, and one discontinued HUMATROPE at month 15 as a consequence. At study completion, 20-25% of patients had serum IGF-I SDS values > +2.

The following adverse reactions were reported from an observational study of 340 pediatric patients who received HUMATROPE with an average dosage of 0.041 mg/kg/day (maximum dose: 0.084 mg/kg/day) for an average of 3.0 years: type 2 diabetes mellitus (n=1), carpal tunnel syndrome (n=1) and an exacerbation of preexisting scoliosis (n=1).

Adult Patients

Adult-Onset GH Deficiency

In the first 6 months of controlled blinded studies during which patients received either HUMATROPE or placebo, patients who received HUMATROPE experienced an increase in edema (17% vs. 4%) and peripheral edema (12% vs. 0%). Edema, muscle pain, joint pain, and joint disorder were reported early in therapy and tended to be transient or responsive to dosage titration.

Two of 113 patients developed carpal tunnel syndrome after beginning maintenance therapy without a low dose (0.00625 mg/kg/day) lead-in phase. Symptoms abated in these patients after dosage reduction.

Adverse reactions with ≥5% overall occurrence rate during 12 or 18 months of replacement therapy with HUMATROPE are shown in Table 5 (adult-onset patients) and in Table 6 (childhood-onset patients).

Table 5: Adverse Reactions with ≥5% Overall Occurrence in Adult-Onset Growth Hormone-Deficient Patients Treated with HUMATROPE for 18 Months as Compared with 6-Month Placebo and 12-Month HUMATROPE Exposure

 

Adverse Reaction 18 Months Exposure [Placebo (6 Months)/Humatrope (12 Months)]
(n=44)
18 Months Humatrope Exposure
(n=52)
Edema 11% 21%
Arthralgia 14% 17%
Paresthesia 14% 17%
Myalgia 9% 14%
Pain 14% 14%
Peripheral edema 18% 12%
Headache 7% 8%
Hypertension 5% 8%
Joint disorder 2% 6%
Rhinitis 11% 13%
Back pain 9% 10%
Acne 0% 6%
Surgical procedure 2% 6%
Flu syndrome 7% 4%

 

Childhood-Onset GH Deficiency

Two double-blind, placebo-controlled studies were conducted in 67 adult patients who had received previous somatropin treatment during childhood. Patients were randomized to receive either placebo injections or HUMATROPE (0.00625 mg/kg/day for the first 4 weeks, then 0.0125 mg/kg/day thereafter) for the first 6 months, followed by open-label use of HUMATROPE for the next 12 months for all patients. During the placebo-controlled phase (first 6 months) of the study, elevations of serum glutamic oxaloacetic transferase were reported more for HUMATROPE-treated (13% vs. 0%) than placebo-treated patients.

Table 6: Adverse Reactions with ≥5% Overall Occurrence in Childhood-Onset Growth Hormone-Deficient Patients Treated with HUMATROPE for 18 Months as Compared with 6-Month Placebo and 12-Month HUMATROPE Exposure

 

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%
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase

 

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to HUMATROPE with the incidence of antibodies to other products may be misleading.

In a clinical study with HUMATROPE during the first 6 months of HUMATROPE therapy in 314 naive patients, 1.6% developed specific antibodies to HUMATROPE (binding capacity ≥0.02 mg/L). None had antibody concentrations which exceeded 2 mg/L. Throughout 8 years of this same study, two patients (0.6%) had binding capacity >2 mg/L. Neither patient demonstrated a decrease in growth velocity at or near the time of increased antibody production. It has been reported that growth attenuation from pituitary-derived GH may occur when antibody concentrations are >1.5 mg/L.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of HUMATROPE. Because these adverse events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Severe Hypersensitivity Reactions – Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products

Neurologic – Headaches (common in pediatric patients and occasional in adults)

Skin – Increase in size or number of cutaneous nevi

Endocrine – Gynecomastia

Gastrointestinal – Pancreatitis

Metabolic – New-onset type 2 diabetes mellitus

Neoplasia – Leukemia has been reported in a small number of GH deficient pediatric patients treated with somatropin

Drug Interactions

Description

HUMATROPE®
[somatropin (rDNA ORIGIN)] for Injection

DESCRIPTION

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.

Vial

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.

Cartridge

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.