Included as part of the "PRECAUTIONS" Section
Increased Mortality In Patients With 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 trials 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 mg/day-8 mg/day) compared to those receiving placebo. The safety of continuing ZOMACTON treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. ZOMACTON 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]. ZOMACTON is not indicated for the treatment of pediatric patients who have growth failure due to Prader-Willi syndrome.
Increased Risk Of Neoplasms
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 ZOMACTON. Discontinue ZOMACTON if there is evidence of recurrent activity.
Risk Of Second Neoplasm In Pediatric Patients
There is 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. 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 ZOMACTON who have a history of GH deficiency secondary to an intracranial neoplasm for progression or recurrence of the tumor.
New Malignancy During Treatment
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 ZOMACTON in these patients. If ZOMACTON is initiated, these patients should be carefully monitored for development of neoplasms.
Monitor all patients receiving ZOMACTON 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.
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 ZOMACTON, 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 ZOMACTON 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. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin. In all reported cases, IH-associated signs and symptoms resolved rapidly after cessation of therapy or a reduction of the somatropin dose. Fundoscopic examination should be performed routinely before initiating treatment with ZOMACTON to exclude preexisting papilledema, and periodically thereafter. If papilledema is observed by fundoscopy, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with ZOMACTON 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 [see CONTRAINDICATIONS].
Fluid retention during somatropin replacement therapy in adults may frequently occur. Clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paresthesias) 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 ZOMACTON. Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism [see DRUG INTERACTIONS].
Undiagnosed or untreated hypothyroidism may prevent response to ZOMACTON, in particular, the growth response in pediatric patients. Patients with Turner syndrome have an 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 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.
Cases of pancreatitis have been reported in pediatric patients and adults receiving somatropin. The risk may be greater 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. Pancreatitis should be considered in patients who develop abdominal pain.
Risk Of Serious Adverse Reactions In Infants Due To Benzyl Alcohol Preserved Solution
Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including the bacteriostatic 0.9% sodium chloride diluent provided with ZOMACTON 5 mg. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations.
When administering ZOMACTON 5 mg to infants, reconstitute with 0.9% sodium chloride injection, not with the diluent provided. Use only one dose per vial and discard the unused portion [see Use In Specific Populations].
When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. Rotate injection sites when administering ZOMACTON to reduce this risk [see DOSAGE AND ADMINISTRATION].
Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone and IGF-1 may increase after ZOMACTON treatment.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Instructions for Use).
Advise childhood cancer survivors/caregivers that individuals treated with brain/head radiation are at increased risk of secondary neoplasms and as a precaution need to be monitored for recurrence. 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.
Advise patients that fluid retention during ZOMACTON replacement therapy in adults may frequently occur. Inform patients of the clinical manifestations of fluid retention (e.g. edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paresthesias) and to report to their healthcare provider any of these signs or symptoms occur during treatment with ZOMACTON.
Advise patients/caregivers that pancreatitis may develop and to report to their healthcare provider any new onset abdominal pain.
Advise patients/caregivers that undiagnosed/untreated hypothyroidism may prevent an optimal response to ZOMACTON. Advise patients/caregivers they may require periodic thyroid function tests.
Advise patients/caregivers to report to their healthcare provider any visual changes, headache, and nausea and/or vomiting.
Advise patients/caregivers that serious systemic hypersensitivity reactions (anaphylaxis and angioedema) are possible and that prompt medical attention should be sought if an allergic reaction occurs.
Diabetes Mellitus – Advise patients/caregivers that new onset impaired glucose intolerance/diabetes mellitus or exacerbation of preexisting diabetes mellitus can occur and monitoring of blood glucose during treatment with ZOMACTON may be needed.
Instruct patients to inform their healthcare provider if they are pregnant or planning to become pregnant as they may potentially require the use of a different formulation of ZOMACTON.
HypoadrenalismAdvise patients/caregivers who have or who are at risk for pituitary hormone deficiency(s) that hypoadrenalism may develop and to report to their healthcare provider if they experience hyperpigmentation, extreme fatigue, dizziness, weakness, or weight loss.
Females Of Reproductive Potential
Carcinogenesis, Mutagenesis, Impairment Of Fertility
ZOMACTON has shown no potential for mutagenicity in the Ames Test. Carcinogenesis and fertility studies have not been conducted with ZOMACTON.
Use In Specific Populations
The ZOMACTON 5 mg diluent contains benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a pregnant woman, benzyl alcohol exposure in the fetus is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs [see WARNINGS AND PRECAUTIONS and Pediatric Use]. Therefore, if ZOMACTON 5mg is needed during pregnancy, reconstitute with 0.9% sodium chloride injection, use only one dose per vial, and discard the unused portion, or use a ZOMACTON 10 mg benzyl alcohol-free formulation.
Limited published data do not report an association with somatropin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when somatropin is used in pregnancy. Published reports indicate that somatropin does not cross the placenta. Animal reproduction studies have not been conducted with ZOMACTON.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.
The ZOMACTON 5mg diluent contains benzyl alcohol. Because benzyl alcohol is rapidly metabolized by a lactating woman, benzyl alcohol exposure in the breastfed infant is unlikely. However, adverse reactions have occurred in premature neonates and low birth weight infants who received intravenously administered benzyl alcohol-containing drugs [see WARNINGS AND PRECAUTIONS and Pediatric Use]. If ZOMACTON 5mg is needed during lactation, reconstitute with 0.9% sodium chloride injection, use only one dose per vial, and discard after use or use a ZOMACTON 10 mg benzyl alcohol-free formulation.
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 on the breastfed infant have been reported with somatropin. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZOMACTON and any potential adverse effects on the breastfed child from ZOMACTON or from the underlying maternal condition.
Safety and effectiveness of ZOMACTON 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.
Growth Failure due to Inadequate Secretion of Endogenous Growth Hormone
Safety and effectiveness of ZOMACTON have been established in pediatric patients with growth failure due to growth hormone deficiency based on data from a multi-center, open-label study in 164 pediatric patients conducted for a two-year period [see Clinical Studies].
Short Stature Associated with Turner Syndrome
Safety and effectiveness of ZOMACTON have been established in pediatric patients with short stature associated with Turner syndrome based on data from one long-term, randomized, open-label, Canadian multicenter, concurrently controlled study; two longterm, open-label multicenter, historically controlled US studies; and one long-term, randomized, US dose-response study with another somatropin product in 181 pediatric patients [see Clinical Studies].
Idiopathic Short Stature (ISS)
Safety and effectiveness of ZOMACTON 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 another somatropin product in 310 pediatric patients [see Clinical Studies].
Short Stature or Growth Failure in SHOX Deficiency
Safety and effectiveness of ZOMACTON 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 another somatropin product in 52 pediatric patients [see Clinical Studies].
Short Stature in Children Born Small for Gestational Age (SGA) with No Catch-up Growth by Age 2 Years to 4 Years of Age
Safety and effectiveness of ZOMACTON have been established in pediatric patients with short stature born SGA with no catch-up growth based on data from two clinical studies with another somatropin product in 228 pediatric patients [see Clinical Studies].
Toxicity (Gasping Syndrome) with Benzyl Alcohol-Preserved Solution
Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 mg/kg/day to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 mmol/L to 1.378 mmol/L). The maximal daily uptake of benzyl alcohol is 39 mg at ZOMACTON doses of 0.067 mg/kg/day.
Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. When administering ZOMACTON 5 mg to infants, reconstitute with 0.9% sodium chloride injection, not with the diluent provided. Use only one dose per vial and discard the unused portion [see WARNINGS AND PRECAUTIONS].
The safety and effectiveness of somatropin 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 geriatric patients [see DOSAGE AND ADMINISTRATION].