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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.
NORDITROPIN (BLA-021148)
(SOMATROPIN RECOMBINANT)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
02/23/2018 (SUPPL-37)
4 Contraindications
(Additions and/or revisions are underlined)
NORDITROPIN 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 sudden death.
- Hypersensitivity to NORDITROPIN or any of its excipients…
5 Warnings and Precautions
5.1 Increased Mortality in Patients with Acute Critical Illness(Subsection title revised; additions and/or revisions are underlined)
…The safety of continuing NORDITROPIN treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established.
(Additions and/or revisions are underlined)
Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including GH deficiency and Turner syndrome) or in patients undergoing rapid growth. Evaluate pediatric patients with the onset of a limp or complaints of hip or knee pain.
(Additions and/or revisions are underlined)
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.
(Additions and/or revisions are underlined)
Cases of pancreatitis have been reported in pediatric patients and adults receiving somatropin products. There may be a greater risk in pediatric patients compared with adults. Published literature indicates that females who have Turner syndrome may be at greater risk than other pediatric patients receiving somatropin products. Pancreatitis should be considered in patients who develop persistent severe abdominal pain.
(Additions and/or revisions are underlined)
When somatropin products are administered subcutaneously at the same site over a long period of time, tissue atrophy may result. Rotate injection sites when administering NORDITROPIN to reduce this risk.
(Additions and/or revisions are underlined)
Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and IGF-I may increase after NORDITROPIN treatment.
(Subsection title revised; additions and/or revisions are 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 NORDITROPIN. Discontinue NORDITROPIN 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 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 NORDITROPIN who have a history of 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 NORDITROPIN in these patients. If NORDITROPIN is initiated, carefully monitor patients for development of neoplasms.
Monitor all patients receiving NORDITROPIN 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.
(Subsection title revised; additions and/or revisions are 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 NORDITROPIN, 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 NORDITROPIN is initiated.
(Additions and/or revisions are underlined)
…In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of NORDITROPIN treatment. Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism.
(Additions and/or revisions are underlined)
Undiagnosed/untreated hypothyroidism may prevent an optimal response to NORDITROPIN, in particular, the growth response in pediatric patients. Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism. In patients with GH deficiency, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment.
6 Adverse Reactions
(Additions and/or revisions are underlined)
The following important adverse reactions are also described elsewhere in the labeling:
Sudden death in children with Prader-Willi syndrome
Pancreatitis
(Extensive changes; please refer to labeling)
(Newly added subsection heading; additions and/or revisions are underlined)
In clinical trials, GH deficient pediatric patients receiving NORDITROPIN for up to 12 months were tested for induction of antibodies, and 0/358 patients developed antibodies with binding capacities above 2 mg/L. Amongst these patients, 165 had previously been treated with other somatropin formulations, and 193 were previously untreated naive patients. Eighteen of 76 children (~24%) treated with NORDITROPIN for short stature born SGA developed anti-rhGH antibodies.
(Additions and/or revisions are underlined)
Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune system disorders — Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema
Skin — Increase in size or number of cutaneous nevi
Endocrine disorders — Hypothyroidism
Metabolism and nutrition disorders — Hyperglycemia
Musculoskeletal and connective tissue disorders — Slipped capital femoral epiphysis — Legg-Calvé-Perthes disease
Investigations — Increase in blood alkaline phosphatase level — Decrease in serum thyroxin (T4) levels
Gastrointestinal — Pancreatitis
Neoplasm —Leukemia has been reported in a small number of GH deficient children treated with somatropin, somatrem (methionylated rhGH) and GH of pituitary origin.
7 Drug Interactions
(Additions and/or revisions are underlined)
Table 2 includes a list of drugs with clinically important drug interactions when administered concomitantly with NORDITROPIN and instructions for preventing or managing them.
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Risk Summary
Limited available data with somatropin use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, there was no evidence of fetal or neonatal harm when pregnant rats were administered subcutaneous NORDITROPIN during organogenesis or during lactation at doses approximately 10-times higher than the maximal clinical dose of 0.016 mg/kg, based on body surface area (see Data).
The estimated background risk of birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively.
Data
Animal Data
In an embryo-fetal development study, NORDITROPIN was administered via subcutaneous injection to pregnant rats from gestation Day 6 to 17, corresponding with the period of organogenesis. NORDITROPIN did not adversely affect fetal viability or developmental outcomes at maternal doses that were approximately 10-times the clinical dose of 0.016 mg/kg, based on body surface area.
In a pre- and post-natal development study in pregnant rats, NORDITROPIN was administered from gestation Day 17 through lactation Day 21 (weaning). No adverse developmental effects were observed in the offspring at doses up to 1.1 mg/kg (approximately 10 times the clinical dose of 0.016 mg/kg, based on body surface area.
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Risk Summary
There is no information regarding the presence of somatropin in human milk. Limited published data indicate that exogenous somatropin does not increase normal breastmilk concentrations of growth hormone. No adverse effects 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 NORDITROPIN and any potential adverse effects on the breastfed infant from NORDITROPIN or from the underlying maternal condition.
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Safety and effectiveness of NORDITROPIN in pediatric patients have been established in growth failure due to inadequate secretion of endogenous growth hormone, short stature associated with Noonan syndrome, short stature associated with Turner syndrome, short stature in children born small for gestational age (SGA) with no catch-up growth by age 2 years to 4 years of age, idiopathic short stature (ISS), and growth failure due to Prader Willi syndrome (PWS).
Growth Failure due to Inadequate Secretion of Endogenous Growth Hormone
Safety and effectiveness of NORDITROPIN have been established in pediatric patients with growth failure due to growth hormone deficiency in a multi-center, prospective, randomized, open-label, dose-response study in 111 pediatric patients conducted for a two- year period.
Short Stature associated with Noonan Syndrome
Safety and effectiveness of NORDITROPIN have been established in pediatric patients with Noonan syndrome in a prospective, open- label, randomized, parallel group study in 21 pediatric patients conducted for 2 years.
Safety and effectiveness of NORDITROPIN have been established in pediatric patients with short stature associated with Turner syndrome in two randomized, parallel group, open-label, multicenter studies in 87 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 NORDITROPIN have been established in pediatric patients with short stature born SGA with no catch-up growth in a multi-center, randomized, double-blind, two-arm study to final height in 53 pediatric patients and in a randomized study of 84 prepubertal, non-GHD, Japanese pediatric patients.
Idiopathic Short Stature (ISS)
Safety and effectiveness of NORDITROPIN have been established in pediatric patients with ISS based on data from a randomized, open-label clinical study with another somatropin product in 105 pediatric patients.
Growth Failure due to Prader Willi Syndrome (PWS)
Safety and effectiveness of NORDITROPIN have been established in pediatric patients with growth failure due to Prader Willi Syndrome based on data from two randomized, open label, controlled clinical trials with another somatropin product in pediatric patients. There have been reports of sudden death after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Advise the patient to read the FDA-approved patient labeling. (Patient Information and 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 NORDITROPIN 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 NORDITROPIN.
• 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 NORDITROPIN. 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 NORDITROPIN may be needed.
02/23/2018 (SUPPL-38)
4 Contraindications
(Additions and/or revisions are underlined)
NORDITROPIN 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 sudden death.
Hypersensitivity to NORDITROPIN or any of its excipients…
5 Warnings and Precautions
5.1 Increased Mortality in Patients with Acute Critical Illness(Subsection title revised; additions and/or revisions are underlined)
…The safety of continuing NORDITROPIN treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established.
(Additions and/or revisions are underlined)
Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including GH deficiency and Turner syndrome) or in patients undergoing rapid growth. Evaluate pediatric patients with the onset of a limp or complaints of hip or knee pain.
(Additions and/or revisions are underlined)
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.
(Additions and/or revisions are underlined)
Cases of pancreatitis have been reported in pediatric patients and adults receiving somatropin products. There may be a greater risk in pediatric patients compared with adults. Published literature indicates that females who have Turner syndrome may be at greater risk than other pediatric patients receiving somatropin products. Pancreatitis should be considered in patients who develop persistent severe abdominal pain.
(Additions and/or revisions are underlined)
When somatropin products are administered subcutaneously at the same site over a long period of time, tissue atrophy may result. Rotate injection sites when administering NORDITROPIN to reduce this risk.
(Additions and/or revisions are underlined)
Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and IGF-I may increase after NORDITROPIN treatment.
(Subsection title revised; additions and/or revisions are underlined)
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…
(Subsection title revised; additions and/or revisions are 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 NORDITROPIN. Discontinue NORDITROPIN 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 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 NORDITROPIN who have a history of 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 NORDITROPIN in these patients. If NORDITROPIN is initiated, carefully monitor patients for development of neoplasms.
Monitor all patients receiving NORDITROPIN 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.(Subsection title revised; additions and/or revisions are 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 NORDITROPIN, 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 NORDITROPIN is initiated.
(Additions and/or revisions are underlined)
…In addition, patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses following initiation of NORDITROPIN treatment. Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism.
(Additions and/or revisions are underlined)
Undiagnosed/untreated hypothyroidism may prevent an optimal response to NORDITROPIN, in particular, the growth response in pediatric patients. Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism. In patients with GH deficiency, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment.
6 Adverse Reactions
(Additions and/or revisions are underlined)
The following important adverse reactions are also described elsewhere in the labeling:
Sudden death in children with Prader-Willi syndrome
Pancreatitis
(Extensive changes; please refer to labeling)
(Newly added subsection heading; additions and/or revisions are underlined)
In clinical trials, GH deficient pediatric patients receiving NORDITROPIN for up to 12 months were tested for induction of antibodies, and 0/358 patients developed antibodies with binding capacities above 2 mg/L. Amongst these patients, 165 had previously been treated with other somatropin formulations, and 193 were previously untreated naive patients. Eighteen of 76 children (~24%) treated with NORDITROPIN for short stature born SGA developed anti-rhGH antibodies.
(Additions and/or revisions are underlined)
Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune system disorders — Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema
Skin — Increase in size or number of cutaneous nevi
Endocrine disorders — Hypothyroidism
Metabolism and nutrition disorders — Hyperglycemia
Musculoskeletal and connective tissue disorders — Slipped capital femoral epiphysis — Legg-Calvé-Perthes disease
Investigations — Increase in blood alkaline phosphatase level — Decrease in serum thyroxin (T4) levels
Gastrointestinal — Pancreatitis
Neoplasm —Leukemia has been reported in a small number of GH deficient children treated with somatropin, somatrem (methionylated rhGH) and GH of pituitary origin.
7 Drug Interactions
(Additions and/or revisions are underlined)
Table 2 includes a list of drugs with clinically important drug interactions when administered concomitantly with NORDITROPIN and instructions for preventing or managing them.
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Risk Summary
Limited available data with somatropin use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes. In animal reproduction studies, there was no evidence of fetal or neonatal harm when pregnant rats were administered subcutaneous NORDITROPIN during organogenesis or during lactation at doses approximately 10-times higher than the maximal clinical dose of 0.016 mg/kg, based on body surface area (see Data).
The estimated background risk of birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively.
Data
Animal Data
In an embryo-fetal development study, NORDITROPIN was administered via subcutaneous injection to pregnant rats from gestation Day 6 to 17, corresponding with the period of organogenesis. NORDITROPIN did not adversely affect fetal viability or developmental outcomes at maternal doses that were approximately 10-times the clinical dose of 0.016 mg/kg, based on body surface area.
In a pre- and post-natal development study in pregnant rats, NORDITROPIN was administered from gestation Day 17 through lactation Day 21 (weaning). No adverse developmental effects were observed in the offspring at doses up to 1.1 mg/kg (approximately 10 times the clinical dose of 0.016 mg/kg, based on body surface area.
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Risk Summary
There is no information regarding the presence of somatropin in human milk. Limited published data indicate that exogenous somatropin does not increase normal breastmilk concentrations of growth hormone. No adverse effects 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 NORDITROPIN and any potential adverse effects on the breastfed infant from NORDITROPIN or from the underlying maternal condition.
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Safety and effectiveness of NORDITROPIN in pediatric patients have been established in growth failure due to inadequate secretion of endogenous growth hormone, short stature associated with Noonan syndrome, short stature associated with Turner syndrome, short stature in children born small for gestational age (SGA) with no catch-up growth by age 2 years to 4 years of age, idiopathic short stature (ISS), and growth failure due to Prader Willi syndrome (PWS).
Growth Failure due to Inadequate Secretion of Endogenous Growth Hormone
Safety and effectiveness of NORDITROPIN have been established in pediatric patients with growth failure due to growth hormone deficiency in a multi-center, prospective, randomized, open-label, dose-response study in 111 pediatric patients conducted for a two- year period.
Short Stature associated with Noonan Syndrome
Safety and effectiveness of NORDITROPIN have been established in pediatric patients with Noonan syndrome in a prospective, open- label, randomized, parallel group study in 21 pediatric patients conducted for 2 years.
Safety and effectiveness of NORDITROPIN have been established in pediatric patients with short stature associated with Turner syndrome in two randomized, parallel group, open-label, multicenter studies in 87 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 NORDITROPIN have been established in pediatric patients with short stature born SGA with no catch-up growth in a multi-center, randomized, double-blind, two-arm study to final height in 53 pediatric patients and in a randomized study of 84 prepubertal, non-GHD, Japanese pediatric patients.
Idiopathic Short Stature (ISS)
Safety and effectiveness of NORDITROPIN have been established in pediatric patients with ISS based on data from a randomized, open-label clinical study with another somatropin product in 105 pediatric patients.
Growth Failure due to Prader Willi Syndrome (PWS)
Safety and effectiveness of NORDITROPIN have been established in pediatric patients with growth failure due to Prader Willi Syndrome based on data from two randomized, open label, controlled clinical trials with another somatropin product in pediatric patients. There have been reports of sudden death after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Advise the patient to read the FDA-approved patient labeling. (Patient Information and 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 NORDITROPIN 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 NORDITROPIN.
• 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 NORDITROPIN. 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 NORDITROPIN may be needed.
12/13/2016 (SUPPL-48)
4 Contraindications
(revision underlined)
• Hypersensitivity
Norditropin 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
(revision underlined)
• Hypersensitivity
Norditropin 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.
(addition 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 amounts of somatropin . Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (42% vs. 19%) among somatropin-treated patients (doses 5.3-8 mg/day) compared to those receiving placebo. The safety of continuing somatropin treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with somatropin in patients experiencing acute critical illnesses should be weighed against the potential risk.
(addition underlined)
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.
(New subsection added)
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.
(New subsection added)
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
The following important adverse reactions are also described elsewhere in the labeling:
• Increased mortality in patients with acute critical illness [see
• Fatalities in children with Prader-Willi syndrome [see
• 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
• Otitis media and cardiovascular disorders in patients with Turner syndrome
• Lipoatrophy
• Pancreatitis
(addition underlined)
Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNCELING INFORMATION(Revised, please refer to label)