Humatrope

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.

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 Cartridges

• Each single-patient-use 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 in Table 1:               

    Table 1: Somatropin Concentration of HUMATROPE Cartridges.

    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.

Pregnancy

Lactation

Pediatric Use

Safety and effectiveness of HUMATROPE in pediatric patients have been established in growth failure due to inadequate secretion of endogenous growth hormone, short stature associated with Turner syndrome, idiopathic short stature (ISS), short stature or growth failure in SHOX deficiency, and short stature in children born small for gestational age (SGA) with no catch-up growth by 2 years to 4 years of age.

Geriatric Use

The safety and effectiveness of HUMATROPE in patients aged 65 years and over has not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of somatropin, and therefore may be more prone to development of adverse reactions. A lower starting dose and smaller dose increments should be considered for older patients [see Dosage and Administration ].

Acute Critical Illness

Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic doses of somatropin [see Contraindications ]. 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.

Sudden Death in Pediatric Patients with Prader-Willi Syndrome

There have been reports of sudden death after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin. If, during treatment with somatropin, patients show signs of upper airway obstruction (including onset of, or increased, snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with Prader-Willi syndrome treated with somatropin should also have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively [see Contraindications ]. HUMATROPE is not indicated for the treatment of pediatric patients who have growth failure due to Prader-Willi syndrome.

Increased Risk of Neoplasms

Glucose Intolerance and Diabetes Mellitus

Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses. New onset type 2 diabetes mellitus has been reported in patients taking somatropin. Previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked. Monitor glucose levels periodically in all patients receiving HUMATROPE, especially in those with risk factors for diabetes mellitus, such as obesity, Turner syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely. The doses of antidiabetic agents may require adjustment when HUMATROPE is initiated.

Intracranial Hypertension

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with somatropins. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose. Fundoscopic examination should be performed routinely before initiating treatment with HUMATROPE to exclude preexisting papilledema, and periodically thereafter. If papilledema is observed by fundoscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with HUMATROPE can be restarted at a lower dose after IH-associated signs and symptoms have resolved. Patients with Turner syndrome may be at increased risk for the development of IH.

Severe Hypersensitivity

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropins. Patients and caregivers should be informed that such reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs. Do not use HUMATROPE in patients with known hypersensitivity to somatropin or any of the excipients in HUMATROPE. Do not use HUMATROPE cartridges in patients with known hypersensitivity to metacresol or glycerin [see Dosage and Administration , Contraindications ].

Fluid Retention

Fluid retention during somatropin replacement therapy may frequently occur. Clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paresthesia) are usually transient and dose dependent.

Hypoadrenalism

Patients receiving somatropin therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of HUMATROPE treatment. Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism [see Drug Interactions ].

Hypothyroidism

Undiagnosed/untreated hypothyroidism may prevent an optimal response to HUMATROPE, in particular, the growth response in pediatric patients. Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism. In patients with GH deficiency, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Therefore, patients treated with somatropin should have periodic thyroid function tests performed, and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated.

Slipped Capital Femoral Epiphysis in Pediatric Patients

Slipped capital femoral epiphysis may occur more frequently in patients undergoing rapid growth. Evaluate pediatric patients with the onset of a limp or complaints of hip or knee pain.

Progression of Preexisting Scoliosis in Pediatric Patients

Somatropin increases the growth rate, and progression of existing scoliosis can occur in patients who experience rapid growth. Somatropin has not been shown to increase the occurrence of scoliosis. Monitor patients with a history of scoliosis for progression of scoliosis.

Pancreatitis

Cases of pancreatitis have been reported in pediatric patients and adults receiving somatropins. The risk may be greater risk in pediatric patients compared with adults. Published literature indicates that girls who have Turner syndrome may be at greater risk than other pediatric patients receiving somatropins. Pancreatitis should be considered in patients who develop abdominal pain.

Lipoatrophy

When somatropins are administered subcutaneously at the same site over a long period of time, tissue atrophy may result. Rotate injection sites when administering HUMATROPE to reduce this risk [see Dosage and Administration ].

Laboratory Tests

Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone and IGF-I may increase after HUMATROPE therapy.