ZOMACTON is a recombinant human growth hormone indicated for: Pediatric: 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), short stature or growth failure in short stature homeobox-containing gene (SHOX) deficiency, and short stature born small for gestational age (SGA) with no catch-up growth by 2 years to 4 years.
( 1.1 ) Adult: Replacement of endogenous GH in adults with GH deficiency ( 1.2 )
1.1Pediatric Patients
ZOMACTON 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 (HSDS) ≤-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.
1.2Adult Patients
ZOMACTON is indicated for the replacement of endogenous GH in adults with GH deficiency.
Contraindications
ZOMACTON is contraindicated in patients with: Acute critical illness after open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure due to the risk of increased mortality with use of pharmacologic doses of somatropin [see Warnings and Precautions (5.1) ] . Pediatric patients with Prader-Willi syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe respiratory impairment due to the risk of sudden death [see Warnings and Precautions (5.2) ] .
Active malignancy [see Warnings and Precautions (5.3) ] . Known hypersensitivity to somatropin or to any excipients of ZOMACTON. Systemic hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with postmarketing use of somatropins [see Dosage and Administrations (2.4) , Warnings and Precautions (5.6) ] . Active proliferative or severe non-proliferative diabetic retinopathy. Pediatric patients with closed epiphyses.
Acute critical illness ( 4 , 5.1 ) Pediatric patients with Prader-Willi syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe respiratory impairment due to risk of sudden death ( 4 , 5.2 ) Active malignancy ( 4 ) Hypersensitivity to ZOMACTON, its excipients, or diluents ( 4 ) Active proliferative or severe non-proliferative diabetic retinopathy ( 4 ) Pediatric patients with closed epiphyses ( 4 )
Increased Risk of Neoplasm: Second neoplasms have occurred in childhood cancer survivors. Monitor patients with preexisting tumors for progression or recurrence. ( 5.3 ) Glucose Intolerance and Diabetes Mellitus: ZOMACTON may decrease insulin sensitivity, particularly at higher doses. Monitor glucose levels periodically in all patients receiving ZOMACTON, especially in patients with existing diabetes mellitus or at risk for development.
( 5.4 ) Intracranial Hypertension (IH): Has been reported usually within 8 weeks of initiation. Perform fundoscopic examinations prior to initiation and periodically thereafter. If papilledema occurs, stop treatment. ( 5.5 ) Hypersensitivity: Serious hypersensitivity reactions may occur. In the event of an allergic reaction, seek prompt medical attention. ( 5.6 ) Fluid Retention: May occur in adults and may be dose dependent.
( 5.7 ) Hypoadrenalism: Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism. ( 5.8 ) Hypothyroidism: Monitor thyroid function periodically as hypothyroidism may occur or worsen after initiation of somatropin. ( 5.9 ) Slipped Capital Femoral Epiphysis in Pediatric Patients: May occur; evaluate patients with onset of a limp or hip/knee pain.
( 5.10 ) Progression of Preexisting Scoliosis in Pediatric Patients: Monitor patients with scoliosis for progression. ( 5.11 ) Pancreatitis: Has been reported; consider pancreatitis in patients with abdominal pain, especially pediatric patients. ( 5.12 ) Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative: Serious and fatal adverse reactions can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including the diluent for ZOMACTON 5 mg.
If administering ZOMACTON 5 mg to infants, reconstitute with 0.9% sodium chloride injection. ( 5.13 )
5.1Increased 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 (4) ] . 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.
5.2Sudden 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 (4) ] .
ZOMACTON is not indicated for the treatment of pediatric patients who have growth failure due to Prader-Willi syndrome.
5.3Increased Risk of Neoplasms Active Malignancy
There is an increased risk of malignancy progression with somatropin treatment in patients with active malignancy [see Contraindications (4) ]. 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.
5.4Glucose 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.
5.5Intracranial 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. 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.
5.6Severe 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) ] .
5.7Fluid Retention
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.
5.8Hypoadrenalism
Patients receiving somatropin th
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Interactions
Table 7 includes a list of drugs with clinically important drug interactions when administered concomitantly with ZOMACTON and instructions for preventing or managing them. Table 7: Clinically Important Drug Interactions with ZOMACTON Glucocorticoids Clinical Impact: Microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1) is required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue.
ZOMACTON inhibits 11βHSD-1. Consequently, individuals with untreated GH deficiency have relative increases in 11βHSD-1 and serum cortisol. Initiation of ZOMACTON may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. Intervention: Patients treated with glucocorticoid replacement for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of ZOMACTON [seeWarnings and Precautions (5.8)].
Examples: Cortisone acetate and prednisone may be affected more than others since conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1. Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment Clinical Impact: Pharmacologic glucocorticoid therapy and supraphysiologic glucocorticoid treatment may attenuate the growth promoting effects of ZOMACTON in pediatric patients.
Intervention: Carefully adjust glucocorticoid replacement dosing in pediatric patients receiving glucocorticoid treatments to avoid both hypoadrenalism and an inhibitory effect on growth. Cytochrome P450-Metabolized Drugs Clinical Impact: Limited published data indicate that somatropin treatment increases cytochrome P450 (CP450)-mediated antipyrine clearance. ZOMACTON may alter the clearance of compounds known to be metabolized by CP450 liver enzymes.
Intervention: Careful monitoring is advisable when ZOMACTON is administered in combination with drugs metabolized by CP450 liver enzymes. Oral Estrogen Clinical Impact: Oral estrogens may reduce the serum IGF-1 response to ZOMACTON. Intervention: Patients receiving oral estrogen replacement may require greater ZOMACTON dosages [seeDosage and Administration (2.2)] . Insulin and/or Other Hypoglycemic Agents Clinical Impact: Treatment with ZOMACTON may decrease insulin sensitivity, particularly at higher doses.
Intervention: Patients with diabetes mellitus may require adjustment of their doses of insulin and/or other hypoglycemic agents [seeWarnings and Precautions (5.4)]. Glucocorticoids: Patients treated with glucocorticoid for hypoadrenalism may require an increase in their maintenance or stress doses following initiation of ZOMACTON ( 7 ) Pharmacologic Glucocorticoid Therapy and Supraphysiologic Glucocorticoid Treatment: Adjust glucocorticoid replacement dosing in pediatric patients receiving glucocorticoid treatment to avoid both hypoadrenalism and an inhibitory effect on growth.
( 7 ) Cytochrome P450-Metabolized Drugs: ZOMACTON may alter the clearance. Monitor carefully if used with ZOMACTON ( 7 ) Oral Estrogen: Larger doses of ZOMACTON may be required ( 7 ) Insulin and/or Other Hypoglycemic Agents: Dose adjustment of insulin or hypoglycemic agent may be required ( 5.4 , 7 )
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary 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 (5.13) and Use in Specific Populations (8.4) ]. 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.
Adverse reactions
The following important adverse reactions are also described elsewhere in the labeling: Increased mortality in patients with acute critical illness [see Warnings and Precautions (5.1) ] Fatalities in pediatric patients with Prader-Willi syndrome [see Warnings and Precautions (5.2) ] Neoplasms [see Warnings and Precautions (5.3) ] Glucose intolerance and diabetes mellitus [see Warnings and Precautions (5.4) ] Intracranial hypertension [see Warnings and Precautions (5.5) ] Severe hypersensitivity [see Warnings and Precautions (5.6) ] Fluid retention [see Warnings and Precautions (5.7) ] Hypoadrenalism [see Warnings and Precautions (5.8) ] Hypothyroidism [see Warnings and Precautions (5.9) ] Slipped capital femoral epiphysis in pediatric patients [see Warnings and Precautions (5.10) ] Progression of preexisting scoliosis in pediatric patients [see Warnings and Precautions (5.11) ] Pancreatitis [see Warnings and Precautions (5.12) ] Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative [see Warnings and Precautions (5.13) ] Lipoatrophy [see Warnings and Precautions (5.14) ] Common adverse reactions reported in adult and pediatric patients include: upper respiratory infection, fever, pharyngitis, headache, otitis media, edema, arthralgia, paresthesia, myalgia, carpal tunnel syndrome, peripheral edema, flu syndrome, hypothyroidism, hyperglycemia, and impaired glucose tolerance.
( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Ferring Pharmaceuticals Inc. at 1-888-337-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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 different approved 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 ZOMACTON was evaluated in 164 pediatric patients with short stature due to GHD in an open-label study for 24 weeks.
The subjects ranged in age from 2.1 to 17.7 years with a mean of 10.8 years. One hundred twenty (73%) of the subjects were male and 44 (27%) were female. Two subjects were Asian, 12 were Black, 130 were Caucasian, and 20 were categorized as 'other'. Table 1: Adverse Reactions ≥ 5% in Pediatric Patients with Growth Failure Due to GHD Treated with ZOMACTON through 24 Weeks Adverse Reaction 24 Week Exposure to ZOMACTON (n=164) Upper respiratory infection 32% Fever 16% Pharyngitis 12% Headache 11% Otitis Media 10% Increased cough 9% Abdominal pain 7% Anemia 6% Maculopapular rash 6% Diarrhea 5% Pain 5% Rhinitis 5% All pediatric patients were carefully observed for signs or laboratory abnormalities of hypothyroidism.
Fifteen patients had T4 values which occasionally fell below the central laboratory's lower limit of normal; T4 levels rose to normal when tested during the next visit for all patients except one who continued to be monitored. Six of the 15 patients received thyroxine therapy before and throughout the study period, and thyroxine dose adjustments were made during the study in 3/6 subjects. In studies with GH deficient pediatric patients, injection site pain was reported in 1.6% of patients.
A mild and transient edema, which appeared in 1.6% of patients, was observed early during the course of treatment. Short Stature Associated with Turner Syndrome In a randomized, concurrent-controlled, open-label study, there was an increase in the occurrence of otitis media, ear disorders and surgical procedures in patients receiving another somatropin product at a dose of 0.3 mg/kg/week, compared with untreated control patients (Table 2).
A similar increase in otitis media was observed in an 18-month placebo-controlled study. Table 2: Adverse Reactions Occurring in Patients with Turner Syndrome Treated with 0.3 mg/kg/week of Another Somatropin product During a
4.7Year Randomized Open-Label Study Untreated (n=62) Somatropin (n=74)
Surgical procedure 27% 45% Otitis media 26% 43% Ear disorders 5% 18% Idiopathic Short Stature Adverse reactions from a randomized, placebo-controlled study of another somatropin product dosed at 0.22 mg/kg/week are presented in Table 3. Mean fasting serum insulin concentration increased 10% in the group treated with another somatropin product 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 Another Somatropin product during a
4.4Year Randomized Placebo-Controlled Study Adverse Reactions Placebo (n=31) Another
Somatropin product (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 with 239 patients treated for 2 years, mean fasting blood glucose, mean glycosylated hemoglobin, and the incidence of elevated fasting blood glucose concentrations were similar among dose groups. One patient developed glucose intolerance and high serum HbA 1c .
Short Stature or Growth Failure in SHOX Deficiency Adverse reactions from a 2-year open-label study with another somatropin product compared to no treatment are presented in Table 4. During the study, the proportion of patients who had at least one IGF-1 concentration greater than
2.0 SD above the age- and gender-appropriate mean was 37.0% for the somatropin-treated group vs. 0% patients 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 59% for the somatropin treated group vs. 29% for the untreated group. Table 4: Adverse Reactions Occurring in Patients with SHOX Deficiency Treated with Another Somatropin product for 2 years Untreated (n=25) Another Somatropin product (n=27) Arthralgia 8% 11% Gynecomastia 0% 8% Excessive number of cutaneous nevi 0% 7% Scoliosis 0% 4% Small for Gestational Age (SGA) with No Catch-up Growth by 2 Years to 4 Years of Age In a 2-year study, 193 pediatric patients were treated with another somatropin product using 2 different 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).
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 1 discontinued treatment at month 15 as a consequence.
At study completion, 20-25% of patients had serum IGF-1 SDS values > +2. The following adverse reactions were reported from an observational study of 340 pediatric patients who received another somatropin product with an average dosage of 0.041 mg/kg/day for an average of 3 years: type 2 diabetes mellitus (n=1), carpal tunnel syndrome (n=1) and exacerbation of preexisting scoliosis (n=1). Adult Patients Adult-Onset GH Deficiency In the first 6 months of controlled blinded trials during which patients received either another somatropin product or placebo, patients who received this other somatropin product experienced a statistically significant increase in edema (another somatropin product 17% vs. placebo 4%, p=0.043) and peripheral edema (12% vs. 0%, respectively, p=0.017).
Edema, muscle pain, joint pain, and joint disorder were reported early in therapy and tended to be transient or responsive to dosage tit
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
SOMATROPIN 4.8MG/VIAL
Official product information
Drugs@FDA lists the approved labels, letters and reviews for application BLA019774.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
