1 INDICATIONS AND USAGE
1.1 Pediatric Patients
Growth Hormone Deficiency — Humatrope is indicated for the treatment of pediatric patients who have growth failure due to inadequate secretion of endogenous growth hormone (GH).
Short Stature Associated with Turner Syndrome — Humatrope is indicated for the treatment of short stature associated with Turner syndrome [see Clinical Studies (14.2)].
Idiopathic Short Stature — Humatrope is indicated for the treatment of idiopathic short stature, also called non-GH-deficient short stature, defined by height SDS ≤-2.25 and associated with growth rates unlikely to permit attainment of adult height in the normal range, in pediatric patients for whom diagnostic evaluation excludes other causes of short stature that should be observed or treated by other means [see Clinical Studies (14.3)]; SDS = standard deviation scores.
SHOX Deficiency — Humatrope is indicated for the treatment of short stature or growth failure in children with short stature homeobox-containing gene (SHOX) deficiency [see Clinical Studies (14.4)].
Small for Gestational Age — Humatrope is indicated for the treatment of growth failure in children born small for gestational age (SGA) who fail to demonstrate catch-up growth by age two to four years [see Clinical Studies (14.5)].
1.2 Adult Patients
Humatrope is indicated for the replacement of endogenous GH in adults with GH deficiency who meet either of the following two criteria [see Clinical Studies (14.1)]:
Adult-Onset (AO): Patients who have GH deficiency, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or
Childhood-Onset (CO): Patients who were GH deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes.
Patients who were treated with somatropin for GH deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin therapy at the reduced dose level recommended for GH deficient adults. According to current standards, confirmation of the diagnosis of adult GH deficiency in both groups involves an appropriate GH provocative test with two exceptions: (1) patients with multiple other pituitary hormone deficiencies due to organic disease; and (2) patients with congenital/genetic GH deficiency.
2 DOSAGE AND ADMINISTRATION
For subcutaneous injection.
Therapy with Humatrope should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with short stature associated with GH deficiency, Turner syndrome, idiopathic short stature, SHOX deficiency, small for gestational age birth, or adult patients with either childhood-onset or adult-onset GH deficiency.
Vial — Each 5-mg vial of Humatrope should be reconstituted with 1.5 to 5 mL of Diluent for Humatrope. The diluent should be injected into the vial of Humatrope by aiming the stream of liquid gently against the vial wall. Following reconstitution, the vial should be swirled with a GENTLE rotary motion until the contents are completely dissolved. DO NOT SHAKE. The resulting solution should be clear. If the solution is cloudy or contains particulate matter, the contents MUST NOT be injected.
If sensitivity to the diluent should occur, the vials may be reconstituted with Bacteriostatic Water for Injection (Benzyl Alcohol preserved), USP or Sterile Water for Injection, USP. When Humatrope is reconstituted with Bacteriostatic Water for Injection, USP, the solution should be kept refrigerated at 36° to 46°F (2° to 8°C) and used within 14 days. It is important to note that benzyl alcohol used as a preservative in Bacteriostatic Water has been associated with toxicity in newborns. Therefore, Bacteriostatic Water for Injection must not be used to reconstitute Humatrope for use in a newborn infant. When Humatrope is to be administered to a newborn infant it should be reconstituted with the diluent provided or, if the infant is sensitive to the diluent, Sterile Water for Injection, USP. When reconstituted with Sterile Water for Injection the solution should be kept refrigerated at 36° to 46°F (2° to 8°C) and used within 24 hours.
Cartridge — The Humatrope cartridge has been designed for use only with the Humatrope injection device. Each cartridge of Humatrope should be reconstituted using only the diluent syringe that accompanies the cartridge and should not be reconstituted with the Diluent for Humatrope provided with Humatrope vials. The reconstituted solution should be clear. If the solution is cloudy or contains particulate matter, the contents MUST NOT be injected. Humatrope cartridges should not be used if the patient is allergic to metacresol or glycerin.
The somatropin concentrations for the reconstituted Humatrope cartridges are as follows:
6 mg cartridge (gold)
12 mg cartridge (teal)
24 mg cartridge (purple)
[See How Supplied (16.2) and Information for the Patient for comprehensive directions on Humatrope cartridge reconstitution].
2.2 General Administration Guidelines
For all indications, the following general principles for administration should be followed:
When using the Humatrope vial the septum of the vial should be wiped with an alcoholic antiseptic solution before and after each injection to prevent contamination of the contents by repeated needle insertions. Sterile disposable syringes and needles should be used. The volume of the syringe should be small enough so that the prescribed dose can be withdrawn from the vial with reasonable accuracy.
When using the Humatrope cartridge a sterile disposable needle should be used for each injection.
Humatrope should be administered by subcutaneous injection with regular rotation of injection sites to avoid lipoatrophy.
For pediatric patients the calculated weekly Humatrope dosage should be divided into equal doses given either 6 or 7 days per week.
For adult patients the prescribed dose should be administered daily.
2.3 Dosing for Pediatric Patients
The Humatrope dosage and administration schedule should be individualized for each patient based on the growth response. Failure to increase height velocity, particularly during the first year of treatment, should prompt close assessment of compliance and evaluation of other causes of poor growth, such as hypothyroidism, under-nutrition, advanced bone age and antibodies to recombinant human growth hormone. Response to somatropin treatment tends to decrease with time. Somatropin treatment for stimulation of linear growth should be discontinued once epiphyseal fusion has occurred.
The recommended weekly dosages in milligrams (mg) per kilogram (kg) of body weight for pediatric patients are:
a Recent literature has recommended initial treatment with larger doses of somatropin (e.g., 0.067 mg/kg/day), especially in very short children (i.e., height SDS <–3), and/or older pubertal children, and that a reduction in dosage (e.g., gradually towards 0.033 mg/kg/day) should be considered if substantial catch-up growth is observed during the first few years of therapy. On the other hand, in younger SGA children (e.g., approximately <4 years) (who respond the best in general) with less severe short stature (i.e., baseline height SDS values between -2 and -3), consideration should be given to initiating treatment at a lower dose (e.g., 0.033 mg/kg/day), and titrating the dose as needed over time. In all children, clinicians should carefully monitor the growth response, and adjust the somatropin dose as necessary.
Growth hormone deficiency
0.026 to 0.043 mg/kg/day (0.18 to 0.30 mg/kg/week)
up to 0.054 mg/kg/day (0.375 mg/kg/week)
Idiopathic short stature
up to 0.053 mg/kg/day (0.37 mg/kg/week)
0.050 mg/kg/day (0.35 mg/kg/week)
Small for gestational age
up to 0.067 mg/kg/day (0.47 mg/kg/week)a
2.4 Dosing for Patients with Adult Growth Hormone Deficiency
Either of two approaches to Humatrope dosing may be followed: a non-weight-based regimen or a weight-based regimen.
Non-weight based — based on published consensus guidelines, a starting dose of approximately 0.2 mg/day (range, 0.15-0.30 mg/day) may be used without consideration of body weight. This dose can be increased gradually every 1-2 months by increments of approximately 0.1-0.2 mg/day, according to individual patient requirements based on the clinical response and serum insulin-like growth factor I (IGF-I) concentrations. The dose should be decreased as necessary on the basis of adverse events and/or serum IGF-I concentrations above the age- and gender-specific normal range. Maintenance dosages vary considerably from person to person, and between male and female patients.
Weight-based — based on the dosing regimen used in the original adult GH deficiency registration trials, the recommended dosage at the start of treatment is not more than 0.006 mg/kg (6 μg/kg) daily. The dose may be increased according to individual patient requirements to a maximum of 0.0125 mg/kg (12.5 μg/kg) daily. Clinical response, side effects, and determination of age- and gender-adjusted serum IGF-I concentrations should be used as guidance in dose titration.
A lower starting dose and smaller dose increments should be considered for older patients, who are more prone to the adverse effects of somatropin than younger individuals. In addition, obese individuals are more likely to manifest adverse effects when treated with a weight-based regimen. Estrogen-replete women may need higher doses than men. Oral estrogen administration may increase the dose requirements in women.
3 DOSAGE FORMS AND STRENGTHS
Humatrope is a sterile, 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 cartridges should be used only with the appropriate corresponding pen device.
4.1 Acute Critical Illness
Treatment with pharmacologic amounts of somatropin is contraindicated 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. Two placebo-controlled clinical trials in non-GH deficient adult patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (41.9% vs. 19.3%) among somatropin-treated patients (doses 5.3-8.0 mg/day) compared to those receiving placebo [see Warnings and Precautions (5.1)].
4.2 Prader-Willi Syndrome in Children
Somatropin is contraindicated in patients with Prader-Willi syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe respiratory impairment. There have been reports of sudden death when somatropin was used in such patients. Humatrope is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome. [See Warnings and Precautions (5.2)].
4.3 Active Malignancy
In general, somatropin is contraindicated in the presence of active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of recurrent activity. Since GH deficiency may be an early sign of the presence of a pituitary tumor (or, rarely, other brain tumors), the presence of such tumors should be ruled out prior to initiation of treatment. Somatropin should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor.
4.4 Diabetic Retinopathy
Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.
4.5 Closed Epiphyses
Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses.
Humatrope is contraindicated in patients with a known hypersensitivity to somatropin or diluent. Localized reactions are the most common hypersensitivity reactions.
5 WARNINGS AND PRECAUTIONS
5.1 Acute Critical Illness
Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic doses of somatropin [see Contraindications (4.1)]. The safety of continuing somatropin treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with somatropin in patients experiencing acute critical illnesses should be weighed against the potential risk.
5.2 Prader-Willi Syndrome in Children
There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin. If, during treatment with somatropin, patients show signs of upper airway obstruction (including onset of, or increased, snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with Prader-Willi syndrome treated with somatropin should also have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively[see Contraindications (4.2)]. Humatrope is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome.
Patients with preexisting tumors or GH deficiency secondary to an intracranial lesion should be examined routinely for progression or recurrence of the underlying disease process. In pediatric patients, clinical literature has revealed no relationship between somatropin replacement therapy and central nervous system (CNS) tumor recurrence or new extracranial tumors. However, in childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients treated with somatropin after their first neoplasm. Intracranial tumors, in particular meningiomas, in patients treated with radiation to the head for their first neoplasm, 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.
Patients should be monitored carefully for any malignant transformation of skin lesions (e.g., changes in preexisting cutaneous nevi).
5.4 Glucose Intolerance and Diabetes Mellitus
Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a result, previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked, and new onset type 2 diabetes mellitus has been reported in patients taking somatropin. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, 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 during somatropin therapy. The doses of antihyperglycemic drugs (e.g., insulin or oral agents) may require adjustment when somatropin therapy is instituted in these patients.
5.5 Intracranial Hypertension
Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea, and/or vomiting has been reported in a small number of patients treated with somatropin products. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating treatment with somatropin to exclude preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed by funduscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin can be restarted at a lower dose after IH-associated signs and symptoms have resolved. Patients with Turner syndrome may be at increased risk for the development of IH.
5.6 Fluid Retention
Fluid retention during somatropin replacement therapy in adults may frequently occur. Clinical manifestations of fluid retention are usually transient and dose dependent.
Patients with hypopituitarism (multiple pituitary hormone deficiencies) should have their other hormonal replacement treatments closely monitored during somatropin treatment.
Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response in children. Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism. In patients with GH deficiency, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Therefore, patients treated with somatropin should have periodic thyroid function tests performed, and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated.
5.9 Slipped Capital Femoral Epiphysis in Pediatric Patients
Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including pediatric GH deficiency and Turner syndrome) or in patients undergoing rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated.
5.10 Progression of Preexisting Scoliosis in Pediatric Patients
Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases growth rate, patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis. However, somatropin has not been shown to increase the occurrence of scoliosis. Skeletal abnormalities including scoliosis are commonly seen in untreated patients with Turner syndrome. Scoliosis is also commonly seen in untreated patients with Prader-Willi syndrome. Physicians should be alert to these abnormalities, which may manifest during somatropin therapy.
5.11 Otitis Media and Cardiovascular Disorders in Patients with Turner Syndrome
Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders, as these patients have an increased risk of ear and hearing disorders. Somatropin treatment may increase the occurrence of otitis media in patients with Turner syndrome. In addition, patients with Turner syndrome should be monitored closely for cardiovascular disorders (e.g., hypertension, aortic aneurysm or dissection, stroke) as patients with Turner syndrome are also at increased risk for these conditions.
Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment, with some evidence supporting a greater risk in children compared with adults. Published literature indicates that girls who have Turner syndrome may be at greater risk than other somatropin-treated children. Pancreatitis should be considered in any somatropin-treated patient, especially a child, who develops abdominal pain.
5.13 Local and Systemic Reactions
When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. This can be avoided by rotating the injection site [see Dosage and Administration (2.2)]. As with any protein, local or systemic allergic reactions may occur. Parents/patients should be informed that such reactions are possible and that prompt medical attention should be sought if allergic reactions occur.
5.14 Laboratory Tests
Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone and IGF-I may increase after somatropin therapy.
6 ADVERSE REACTIONS
6.1 Most Serious and/or Most Frequently Observed Adverse Reactions
This list presents the most seriousa and/or most frequently observedb adverse reactions during treatment with somatropin (including events observed in patients who received brands of somatropin other than Humatrope):
aSudden death in pediatric patients with Prader-Willi syndrome who had risk factors including severe obesity, history of upper airway obstruction or sleep apnea and unidentified respiratory infection [see Contraindications (4.2) and Warnings and Precautions (5.2)]
aIntracranial tumors, in particular meningiomas, in teenagers/young adults treated with radiation to the head for a first neoplasm who subsequently receive somatropin [see Contraindications (4.3) and Warnings and Precautions (5.3)]
aPancreatitis [see Warnings and Precautions (5.12)]
a,bGlucose intolerance including impaired glucose tolerance/impaired fasting glucose as well as overt diabetes mellitus [see Warnings and Precautions (5.4)]
aIntracranial hypertension [see Warnings and Precautions (5.5)]
aSignificant diabetic retinopathy [see Contraindications (4.4)]
aSlipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.9)]
aProgression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.10)]
bFluid retention manifested by edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias [see Warnings and Precautions (5.6)]
aUnmasking of latent central hypothyroidism [see Warnings and Precautions (5.8)]
aInjection site reactions/rashes and lipoatrophy (as well as rare generalized hypersensitivity reactions) [see Warnings and Precautions (5.13)]
6.2 Clinical Trials Experience
Because clinical trials are conducted under varying conditions, adverse reaction rates observed during the clinical trials performed with one somatropin formulation cannot always be directly compared to the rates observed during the clinical trials performed with a second somatropin formulation, and may not reflect the adverse reaction rates observed in practice.
As with all protein pharmaceuticals, a small percentage of patients may develop antibodies to the protein. During the first 6 months of Humatrope therapy in 314 naive patients, only 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.
In addition to an evaluation of compliance with the treatment program and of thyroid status, testing for antibodies to somatropin should be carried out in any patient who fails to respond to therapy.
In studies with GH deficient pediatric patients, injection site pain was reported infrequently. A mild and transient edema, which appeared in 2.5% of patients, was observed early during the course of treatment.
In a randomized, concurrent-controlled, open-label trial, there was a statistically significant increase in the occurrence of otitis media (43% vs. 26%), ear disorders (18% vs. 5%) and surgical procedures (45% vs. 27%) in patients receiving Humatrope compared with untreated control patients (Table 1). A similar increase in otitis media was observed in an 18-month placebo-controlled trial.
Idiopathic Short Stature
In a randomized, placebo-controlled study of Humatrope treatment (0.22 mg/kg/week) to adult height in patients with idiopathic short stature, the adverse events reported in Humatrope-treated patients (Table 2) were similar to those observed in other pediatric populations treated with Humatrope. Mean serum glucose concentration did not change during Humatrope treatment. Mean fasting serum insulin concentration increased 10% in the Humatrope treatment group at the end of treatment relative to baseline, but remained within the normal reference range. For the same duration of treatment, the mean fasting serum insulin concentration decreased by 2% in the placebo group. The occurrence rates of above-range values for glucose, insulin, and HbA1c were similar in the Humatrope (somatropin)- and placebo-treated groups. No patient developed diabetes mellitus. Consistent with the known mechanism of growth hormone action, Humatrope-treated patients had greater mean increases, relative to baseline, in serum insulin-like growth factor-I (IGF-I) than placebo-treated patients at each study observation. However, there was no significant difference between the Humatrope and placebo treatment groups in the proportion of patients who had at least one serum IGF-I concentration more than 2.0 SD above the age- and gender-appropriate mean (Humatrope: 9 of 35 patients [26%]; placebo: 7 of 28 patients [25%]).