Genotropin
(somatropin)Dosage & Administration
GENOTROPIN should be administered subcutaneously
Genotropin Prescribing Information
Pediatric Patients
GENOTROPIN is indicated for the treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone.
GENOTROPIN is indicated for the treatment of pediatric patients who have growth failure due to Prader-Willi syndrome (PWS). The diagnosis of PWS should be confirmed by appropriate genetic testing [see Contraindications (4)].
GENOTROPIN is indicated for the treatment of growth failure in pediatric patients born small for gestational age (SGA) who fail to manifest catch-up growth by age 2 years.
GENOTROPIN is indicated for the treatment of growth failure associated with Turner syndrome.
GENOTROPIN is indicated for the treatment of idiopathic short stature (ISS), also called non-growth hormone-deficient short stature, defined by height standard deviation score (SDS) ≤-2.25, and associated with growth rates unlikely to permit attainment of adult height in the normal range, in pediatric patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other causes associated with short stature that should be observed or treated by other means.
Adult Patients
GENOTROPIN is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who meet either of the following two criteria:
Adult Onset (AO): Patients who have growth hormone 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 growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes.
Patients who were treated with somatropin for growth hormone deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin therapy at the reduced dose level recommended for growth hormone deficient adults. According to current standards, confirmation of the diagnosis of adult growth hormone deficiency in both groups involves an appropriate growth hormone provocative test with two exceptions: (1) patients with multiple other pituitary hormone deficiencies due to organic disease; and (2) patients with congenital/genetic growth hormone deficiency.
The weekly dose should be divided into 6 or 7 subcutaneous injections. GENOTROPIN must not be injected intravenously.
Therapy with GENOTROPIN should be supervised by a physician who is experienced in the diagnosis and management of pediatric patients with growth failure associated with growth hormone deficiency (GHD), Prader-Willi syndrome (PWS), Turner syndrome (TS), those who were born small for gestational age (SGA) or Idiopathic Short Stature (ISS), and adult patients with either childhood onset or adult onset GHD.
Dosing of Pediatric Patients
General Pediatric Dosing Information
The GENOTROPIN dosage and administration schedule should be individualized based on the growth response of each patient.
Response to somatropin therapy in pediatric patients tends to decrease with time. However, in pediatric patients, the failure to increase growth rate, particularly during the first year of therapy, indicates the need for close assessment of compliance and evaluation for other causes of growth failure, such as hypothyroidism, undernutrition, advanced bone age and antibodies to recombinant human GH (rhGH).
Treatment with GENOTROPIN for short stature should be discontinued when the epiphyses are fused.
Pediatric Growth Hormone Deficiency (GHD)
Generally, a dose of 0.16 to 0.24 mg/kg body weight/week is recommended.
Prader-Willi Syndrome
Generally, a dose of 0.24 mg/kg body weight/week is recommended.
Turner Syndrome
Generally, a dose of 0.33 mg/kg body weight/week is recommended.
Idiopathic Short Stature
Generally, a dose up to 0.47 mg/kg body weight/week is recommended.
Small for Gestational Age 1
Generally, a dose of up to 0.48 mg/kg body weight/week is recommended.
- 1
- Recent literature has recommended initial treatment with larger doses of somatropin (e.g., 0.48 mg/kg/week), 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 0.24 mg/kg/week) 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., 0.24 mg/kg/week), 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.
Dosing of Adult Patients
Adult Growth Hormone Deficiency (GHD)
Either of two approaches to GENOTROPIN 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 GHD registration trials, the recommended dosage at the start of treatment is not more than 0.04 mg/kg/week. The dose may be increased according to individual patient requirements to not more than 0.08 mg/kg/week at 4–8 week intervals. 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. In order to reach the defined treatment goal, estrogen-replete women may need higher doses than men. Oral estrogen administration may increase the dose requirements in women.
Preparation and Administration
The GENOTROPIN 5 and 12 mg cartridges are color-coded to help ensure proper use with the GENOTROPIN PEN delivery device. The 5 mg cartridge has a green tip to match the green pen window on the Pen 5, while the 12 mg cartridge has a purple tip to match the purple pen window on the Pen 12.
Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. GENOTROPIN MUST NOT BE INJECTED if the solution is cloudy or contains particulate matter. Use it only if it is clear and colorless.
GENOTROPIN may be given in the thigh, buttocks, or abdomen; the site of SC injections should be rotated daily to help prevent lipoatrophy.
GENOTROPIN is a white, lyophilized powder available as:
- •
- For injection: 5 mg or 12 mg in a single-patient-use two-chamber cartridge
- •
- For injection: 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 1 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, or 2 mg in a single‑dose Growth Hormone Delivery Device containing a two-chamber cartridge (GENOTROPIN MINIQUICK)
Pregnancy
Risk Summary
Limited available data with somatropin use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes. In animal studies (rats and rabbits), there was no evidence of embryo‑fetal or neonatal harm following somatropin administration during organogenesis at doses approximately 24 times and 19 times the recommended human therapeutic levels, respectively, based on body surface area (see Data).
The estimated background risk of 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.
Data
Animal Data
Animal reproduction studies with somatropin during the period of organogenesis at doses of 0.3, 1, and 3.3 mg/kg/day administered subcutaneously (SC) in pregnant rats and 0.08, 0.3, and 1.3 mg/kg/day administered intramuscularly in pregnant rabbits were not teratogenic (highest doses approximately 24 times and 19 times the recommended human therapeutic levels, respectively, based on body surface area).
In perinatal and postnatal studies in rats, somatropin doses of 0.3, 1, and 3.3 mg/kg/day produced growth‑promoting effects in the dams but not in the fetuses. Young rats at the highest dose showed increased weight gain during suckling but the effect was not apparent by 10 weeks of age. No adverse effects were observed on gestation, morphogenesis, parturition, lactation, postnatal development, or reproductive capacity of the offspring due to somatropin.
Lactation
Risk Summary
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 breastfeed infant have been reported. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for GENOTROPIN and any potential adverse effects on the breastfed infant from GENOTROPIN or from the underlying maternal condition.
Pediatric Use
Safety and effectiveness of GENOTROPIN in pediatric patients have been established in growth failure due to Prader-Willi syndrome (PWS), growth failure in children born small for gestational age (SGA) with no catch-up growth by age 2 years, growth failure associated with Turner syndrome, idiopathic short stature (ISS) and growth failure due to inadequate secretion of endogenous growth hormone.
Growth Failure Due to Prader-Willi Syndrome (PWS)
Safety and effectiveness of GENOTROPIN have been established in pediatric patients with growth failure due to Prader-Willi syndrome based on data from two randomized, open-label, controlled clinical trials with GENOTROPIN in 43 pediatric patients. 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 [see Contraindications (4), Warnings and Precautions (5.2), Clinical Studies (14.2)].
Short Stature in Pediatric Patients Born Small for Gestational Age (SGA) with No Catch-up Growth by Age 2
Safety and effectiveness of GENOTROPIN have been established in pediatric patients with short stature born SGA with no catch-up growth based on data from 4 randomized, open-label, controlled clinical trials with GENOTROPIN in 209 pediatric patients [see Clinical Studies (14.3)].
Short Stature associated with Turner Syndrome
Safety and effectiveness of GENOTROPIN have been established in pediatric patients with short stature associated with Turner syndrome based on data from two randomized, open-label, clinical trials with GENOTROPIN in 38 pediatric patients [see Clinical Studies (14.4)].
Idiopathic Short Stature (ISS)
Safety and effectiveness of GENOTROPIN have been established in pediatric patients with ISS based on data from one randomized, open-label, clinical trial with GENOTROPIN in 102 pediatric patients [see Clinical Studies (14.5)].
Geriatric Use
The safety and effectiveness of GENOTROPIN in patients aged 65 and over have not been evaluated in clinical studies. Elderly patients may be more sensitive to the action of GENOTROPIN, and therefore may be more prone to develop adverse reactions. A lower starting dose and smaller dose increments should be considered for older patients [see Dosage and Administration (2.2)].
GENOTROPIN is contraindicated in patients with:
• 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 [see Warnings and Precautions (5.1)].
• 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 [see Warnings and Precautions (5.2)].
• 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 growth hormone 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.
• Hypersensitivity
GENOTROPIN is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. The 5 mg and 12 mg presentations of GENOTROPIN lyophilized powder contain m-cresol as a preservative. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropins [see Warnings and Precautions (5.6)].
• Diabetic Retinopathy
Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.
• Closed Epiphyses
Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses.
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 amounts of somatropin [see Contraindications (4)]. Two placebo-controlled clinical trials in non-growth hormone 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 mg/day) compared to those receiving placebo. 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 having acute critical illnesses should be weighed against the potential risk.
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)].
Neoplasms
In childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent GHD and were treated with somatropin, an increased risk of a second neoplasm 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 [see Contraindications (4)].
Monitor all patients with a history of GHD secondary to an intracranial neoplasm routinely while on somatropin therapy for progression or recurrence of the tumor.
Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, practitioners should thoroughly consider the risks and benefits of starting somatropin in these patients. If treatment with somatropin is initiated, these patients should be carefully monitored for development of neoplasms.
Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes, of preexisting nevi.
Impaired Glucose Tolerance 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 during somatropin treatment. New-onset Type 2 diabetes mellitus has been reported. 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 (i.e., insulin or oral/injectable agents) may require adjustment when somatropin therapy is instituted in these patients.
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 somatropin to exclude preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed by fundoscopy 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 and Prader-Willi 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 [see Contraindications (4)].
Fluid Retention
Fluid retention during somatropin replacement therapy in adults may 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 somatropin treatment [see Drug Interactions (7.1)].
Hypothyroidism
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 growth hormone deficiency, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Therefore, patients treated with somatropin should have periodic thyroid function tests and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated.
Slipped Capital Femoral Epiphyses in Pediatric Patients
Slipped capital femoral epiphyses may occur more frequently in patients with endocrine disorders (including GHD 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.
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 Turner syndrome patients. 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.
Otitis Media and Cardiovascular Disorders in Turner Syndrome
Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since 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., stroke, aortic aneurysm/dissection, hypertension) as these patients are also at risk for these conditions.
Lipoatrophy
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 (2.3)].
Laboratory Tests
Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and IGF-I may increase during somatropin therapy.
Pancreatitis
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 persistent severe abdominal pain.