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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
ZOMACTON (BLA-019774)
(SOMATROPIN RECOMBINANT)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
04/02/2024 (SUPPL-63)
4 Contraindications
Additions and/or revisions underlined:
…
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)].
…
07/19/2018 (SUPPL-48)
4 Contraindications
(additions underlined)
…
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.
…
Known hypersensitivity to somatropin or any of the excipients in ZOMACTON. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropin products
…
5 Warnings and Precautions
5.12 Pancreatitis(additions underlined)
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.
(additions underlined)
Active Malignancy
There is an increased risk of malignancy progression with somatropin treatment in patients with active malignancy. 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.
(addition underlined)
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.
(additions underlined)
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.
6 Adverse Reactions
6.1 Clinical Trials Experience(extensive additions, please refer to label)
8 Use in Specific Populations
8.1 Pregnancy(additions underlined)
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.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.
(additions underlined)
Risk Summary
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. 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.
…
(additions underlined)
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.
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 long term, open-label multicenter, historically controlled US studies; and one long-term, randomized, US dose-response study with another somatropin product in 181 pediatric patients.
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.
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.
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.
Toxicity (Gasping Syndrome) with Benzyl Alcohol-Preserved Solution
…
07/19/2018 (SUPPL-49)
4 Contraindications
(additions underlined)
…
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.
…
Known hypersensitivity to somatropin or any of the excipients in ZOMACTON. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropin products
…
5 Warnings and Precautions
5.12 Pancreatitis(additions underlined)
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.
additions underlined)
Active Malignancy
There is an increased risk of malignancy progression with somatropin treatment in patients with active malignancy. 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.
(addition underlined)
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.
(additions underlined)
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.
6 Adverse Reactions
6.1 Clinical Trials Experience(extensive additions, please refer to label)
8 Use in Specific Populations
8.1 Pregnancy(additions underlined)
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.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.
(additions underlined)
Risk Summary
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. 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.
…
(additions underlined)
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.
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 long term, open-label multicenter, historically controlled US studies; and one long-term, randomized, US dose-response study with another somatropin product in 181 pediatric patients.
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.
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.
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.
Toxicity (Gasping Syndrome) with Benzyl Alcohol-Preserved Solution
…
07/19/2018 (SUPPL-50)
4 Contraindications
(additions underlined)
…
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.
…
Known hypersensitivity to somatropin or any of the excipients in ZOMACTON. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropin products
…
5 Warnings and Precautions
5.12 Pancreatitis(additions underlined)
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.
(additions underlined)
Active Malignancy
There is an increased risk of malignancy progression with somatropin treatment in patients with active malignancy. 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.
(addition underlined)
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.
(additions underlined)
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.
6 Adverse Reactions
6.1 Clinical Trials Experience(extensive additions, please refer to label)
8 Use in Specific Populations
8.1 Pregnancy(additions underlined)
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.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.
(additions underlined)
Risk Summary
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. 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.
…
(additions underlined)
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.
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 long term, open-label multicenter, historically controlled US studies; and one long-term, randomized, US dose-response study with another somatropin product in 181 pediatric patients.
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.
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.
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.
Toxicity (Gasping Syndrome) with Benzyl Alcohol-Preserved Solution
…
07/19/2018 (SUPPL-51)
4 Contraindications
(additions underlined)
…
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.
…
Known hypersensitivity to somatropin or any of the excipients in ZOMACTON. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropin products
…
5 Warnings and Precautions
5.12 Pancreatitis(additions underlined)
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.
(additions underlined)
Active Malignancy
There is an increased risk of malignancy progression with somatropin treatment in patients with active malignancy. 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.
(addition underlined)
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.
(additions underlined)
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.
6 Adverse Reactions
6.1 Clinical Trials Experience(extensive additions, please refer to label)
8 Use in Specific Populations
8.1 Pregnancy(additions underlined)
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.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.
(additions underlined)
Risk Summary
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. 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.
…
(additions underlined)
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.
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 long term, open-label multicenter, historically controlled US studies; and one long-term, randomized, US dose-response study with another somatropin product in 181 pediatric patients.
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.
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.
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.
Toxicity (Gasping Syndrome) with Benzyl Alcohol-Preserved Solution
…
01/30/2018 (SUPPL-29)
4 Contraindications
4 CONTRAINDICATIONS(Additions and/or revisions are underlined)
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.
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 death.
Active malignancy due to an increased risk of second neoplasm..
Hypersensitivity to ZOMACTON, any of its excipients, or its accompanying diluents. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropin products.
Active proliferative or severe non-proliferative diabetic retinopathy.
Pediatric patients with closed epiphyses.
5 Warnings and Precautions
5.1 Increased Mortality in Patients with Acute Critical Illness(Subsection title has been revised; additions
and/or revisions are underlined)
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 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.
(New subsection title has been added; additions and/or revisions are underlined)
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.
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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.
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Cases of pancreatitis have been reported in pediatric patients and adults receiving somatropin. The risk may be greater in pediatric patients compared with adults. Pancreatitis should be considered in patients who develop abdominal pain.
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When administering ZOMACTON 5 mg to infants, reconstitute with normal saline, not the diluent provided. Only one dose should be used per vial and the reconstituted product should be discarded after use.
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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.
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Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone and IGF-1 may increase after ZOMACTON treatment.
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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. …
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In childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent GH deficiency 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 Monitor all patients receiving ZOMACTON who have a history of GH deficiency secondary to an intracranial neoplasm for progression or recurrence of the tumor.
ecause pediatric patients 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 ZOMACTON in these patients. If ZOMACTON is initiated, these patients should be carefully monitored for development of neoplasms. ZOMACTON is not indicated for the treatment of non- GH deficient pediatric patients with short stature.
Monitor 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.
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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 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.
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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. ZOMACTON is not indicated for the treatment of pediatric patients who have growth failure due to Turner syndrome.
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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.
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Undiagnosed or untreated hypothyroidism may prevent an optimal response to ZOMACTON, in particular, the growth response in pediatric patients. 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.
6 Adverse Reactions
6 ADVERSE REACTIONS(Additions and/or revisions are underlined)
The following important adverse reactions are also described elsewhere in the labeling:
- Increased mortality in patients with acute critical illness
- Fatalities in pediatric patients with Prader-Willi syndrome
- Neoplasms
- Glucose intolerance and diabetes mellitus
- Intracranial hypertension
- Severe hypersensitivity
- Fluid retention
- Hypoadrenalism
- Hypothyroidism
- Slipped capital femoral epiphysis in pediatric patients
- Progression of preexisting scoliosis in pediatric patients
- Pancreatitis
- Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preservative
- Lipoatrophy
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As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ZOMACTON in the studies described below with the incidence of antibodies in other studies or to other products may be misleading
In a clinical trial with another recombinant growth hormone during the first 6 months of somatropin therapy in 314 naive patients, 1.6% developed specific antibodies to somatropin (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.
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Severe Hypersensitivity Reactions — Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema
Neurologic — Headaches (common in pediatric patients and occasional in adults).
Skin — Increase in size or number of cutaneous nevi
Endocrine — Gynecomastia.
Gastrointestinal — Pancreatitis
Metabolic — New-onset type 2 diabetes mellitus
Neoplasia — Leukemia has been reported in a small number of GH deficient pediatric patients treated with somatropin, somatrem (methionylated rhGH), and GH of pituitary origin.
7 Drug Interactions
7 DRUG INTERACTIONS(Table has been added; please refer to label)
8 Use in Specific Populations
8.1 Pregnancy(Newly added subsection, additions are underlined)
Limited available data with somatropin use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes. 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. 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.
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Risk Summary
The ZOMACTON 5mg diluent contains benzyl alcohol. If ZOMACTON 5mg is needed during lactation, reconstitute with normal saline, 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.
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When administering ZOMACTON 5 mg to infants, reconstitute with normal saline, not the diluent provided. Only one dose should be used per vial and the reconstituted product should be discarded after use.
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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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Newly added subsection, additions are underlined)
Advise the patient to read the FDA-approved patient labeling (Instructions for Use).
- Neoplasms – 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.
- Fluid Retention - 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/paraesthesias) and to report to their healthcare provider any of these signs or symptoms occur during treatment with ZOMACTON.
- Pancreatitis - Advise patients/caregivers that pancreatitis may develop and to report to their healthcare provider any new onset abdominal pain.
- Hypoadrenalism - Advise 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.
- Hypothyroidism - Advise patients/caregivers that undiagnosed/untreated hypothyroidism may prevent an optimal response to ZOMACTON. Advise patients/caregivers they may require periodic thyroid function tests.
- Intracranial Hypertension - Advise patients/caregivers to report to their healthcare provider any visual changes, headache, and nausea and/or vomiting.
- Hypersensitivity Reactions – 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.
- Glucose Intolerance/ 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.
- Women of Reproductive Potential – 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.
12/13/2016 (SUPPL-38)
4 Contraindications
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ZOMACTON is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropin products.
5 Warnings and Precautions
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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 ofsomatropin . 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 to 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 experiencing acute critical illnesses should be weighed against the potential risk.
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.
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.
6 Adverse Reactions
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Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products.
09/30/2016 (SUPPL-36)
4 Contraindications
(addition underlined)
ZOMACTON is contraindicated for use in patients with hypersensitivity to somatropin or
to any of the excipients.