Drug Safety-related Labeling Changes (SrLC)

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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.

INCRELEX (BLA-021839)

(MECASERMIN RECOMBINANT)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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07/09/2025 (SUPPL-33)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Slipped Capital Femoral Epiphysis

Additions and/or revisions underlined:

Slipped capital femoral epiphysis can occur in patients who experience rapid growth. Slipped capital femoral epiphysis may lead to osteonecrosis. Cases of slipped capital femoral epiphysis with or without osteonecrosis have been reported in pediatric patients receiving products indicated to treat growth failure and/or short stature, including INCRELEX. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during INCRELEX therapy should be evaluated for slipped capital femoral epiphysis and osteonecrosis and managed accordingly.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:

. . .

What are the possible side effects of INCRELEX? INCRELEX may cause serious side effects, including:

. . .

A bone problem called slipped capital femoral epiphysis. This happens when the top of the upper leg (femur) slips apart. This may lead to a serious condition where bone tissue dies due to a lack of blood supply (osteonecrosis). Get medical help for your child right away if your child develops a limp or has hip or knee pain.

. . .

03/15/2024 (SUPPL-31)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Hypoglycemia

Additions and/or revisions underlined:

Severe hypolgycemia leading to hypolycemic seizures has been observed with INCRELEX treatment [see Adverse Reactions (6.1)]. Because INCRELEX has insulin-like hypoglycemic effects it should be administered shortly before or after (± 20 minutes) a meal or snack. Glucose monitoring and INCRELEX dose titration are recommended until a well-tolerated dose is established [see Dosage and Administration (2.1)] and subsequently as medically indicated. Special attention should be paid to small children because their oral intake may not be consistent. Patients should avoid engaging in any high- risk activities (e.g., driving, exercise, etc.) within 2 to 3 hours after dosing, particularly during the initiation of INCRELEX treatment until tolerability and a stable dose have been established [see Adverse Reactions (6.1)]. INCRELEX should not be administered when the meal or snack is omitted.

The dose of INCRELEX should never be increased to make up for one or more omitted doses.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

In clinical studies of 71 subjects with Primary IGFD treated for a mean duration of 3.9 years and representing 274 subject-years, no subjects withdrew from any clinical study because of adverse reactions. Adverse reactions to INCRELEX treatment that occurred in 5% or more of these study participants are listed below by organ class.

Metabolism and Nutrition Disorders: hypoglycemia

General Disorders and Administrative Site Conditions: lipohypertrophy, bruising

Infections and Infestations: otitis media, serous otitis media

Respiratory, Thoracic and Mediastinal Disorders: snoring, tonsillar hypertrophy

Nervous System Disorders: headache, dizziness, convulsions

Gastrointestinal Disorders: vomiting

Ear and Labyrinth Disorders: hypoacusis, fluid in middle ear, ear pain, abnormal tympanometry

Investigations: cardiac murmur

Musculoskeletal and Connective Tissue Disorders: arthralgia, pain in extremity

Blood and Lymphatic System Disorders: thymus hypertrophy

Surgical and Medical Procedures: ear tube insertion

…

12/03/2019 (SUPPL-24)

Approved Drug Label (PDF)

4 Contraindications

…

Malignant Neoplasia

INCRELEX is contraindicated in pediatric patients with malignant neoplasia or a history of malignancy.

5 Warnings and Precautions

5.1 Hypoglycemia

(addition underlined)

… Patients should avoid engaging in any high-risk activities (e.g., driving, exercise, etc.) within 2 to 3 hours after dosing, particularly during the initiation of INCRELEX treatment until tolerability and a stable dose have been established.

…

5.7 Malignant Neoplasia

(newly added subsection)

There have been postmarketing reports of malignant neoplasms in pediatric patients who have received treatment with INCRELEX . The cases of malignant neoplasms represented a variety of different malignancies. It is unknown whether there is any relationship between INCRELEX therapy and new occurrence of neoplasia. The occurrence of neoplasia was mostly reported in patients with rare genetic conditions of short stature associated with an increased risk of cancer, or in patients with other cancer predisposing conditions. The tumors were observed also more frequently in patients who received INCRELEX at higher than recommended doses, or at doses that produced serum IGF-1 levels above the normal reference ranges for age and sex.

Monitor all patients receiving INCRELEX carefully for development of neoplasms. Advise patients/caregivers to report development of new neoplasms. If malignant neoplasia develops, discontinue INCRELEX treatment.

5.8 Risk of Serious Adverse Reactions in Infants due to Benzyl Alcohol Preserved Solution

(additions and/or revisions underlined)

Serious and fatal adverse reactions including "gasping syndrome" can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including INCRELEX. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations.

Use of INCRELEX in infants is not recommended.

6 Adverse Reactions

6.3 Postmarketing Experience

(additions underlined)

…

Neoplasms Benign, Malignant and Unspecified (including cysts and polyps

Addition of the following to the bulleted line listing:

…

Slipped Capital Femoral Epiphysis
Progression of Preexisting Scoliosis
Malignant Neoplasia
Benzyl Alcohol

8 Use in Specific Populations

8.4 Pediatric Use

(additions underlined)

Toxicity (Gasping Syndrome) with Benzyl Alcohol

Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and infants in the intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 mg/kg/day to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 mmol/L to 1.378 mmol/L). INCRELEX contains 9 mg/mL benzyl alcohol as a preservative.

Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. Use of INCRELEX in infants is not recommended.

Safety and effectiveness in pediatric patients below the age of 2 years of age have not been established.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

Advise patients and/or caregivers to read the FDA-approved patient labeling (Patient Information) and Instructions for Use.

Counsel patients and/or parents that there have been occurrences of malignant neoplasia observed among pediatric patients who received treatment with INCRELEX. Instruct patients and/or parents to monitor for development of any new growth or symptoms of cancer and to report it immediately.

…Do not increase the dose of INCRELEX to make up for one or more omitted doses. INCRELEX therapy will be initiated at a low dose and the dose should be increased only if no hypoglycemia episodes have occurred after at least 7 days of dosing. Educate patients and caregivers on how to recognize the signs and symptoms of hypoglycemia.

…

PATIENT INFORMATION

(additions underlined)

…

What are the possible side effects of INCRELEX? INCRELEX may cause serious side effects, including:

…

Tumor Growths. Several cases of cancerous tumors have been observed in pediatric patients who received treatment with INCRELEX. Tell your doctor immediately if your child develops any new growths or symptoms of cancer.

…

01/18/2019 (SUPPL-21)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

There are no available data on INCRELEX use in pregnant women. Exposure to INCRELEX during pregnancy is unlikely because the drug is not indicated for use after epiphyseal closure. In animal reproduction studies, there were no observed embryo-fetal development abnormalities with intravenous administration of INCRELEX to pregnant rats and rabbits during fetal organogenesis given at exposures up to 11 and 3 times the maximum recommended human dose (MRHD) of 0.24 mg/kg/day based on body surface area (BSA), respectively.

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

Studies to assess embryo-fetal toxicity evaluated the effects of INCRELEX® during organogenesis in Sprague Dawley rats given 1, 4, and 16 mg/kg/day and in New Zealand White rabbits given 0.125, 0.5, and 2 mg/kg/day, administered intravenously. There were no observed embryo-fetal developmental abnormalities in rats given up to 16 mg/kg/day (11 times the MRHD] based on BSA] comparison). In the rabbit study, the NOAEL for fetal toxicity was 0.5 mg/kg/day (approximately equivalent to the MRHD based on BSA) due to an increase in fetal death at 2 mg/kg. INCRELEX® displayed no teratogenicity or maternal toxicity in rabbits given up to 2 mg/kg (83 times the MRHD based on BSA).

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

There is no information available on the presence of mecasermin in human or animal milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for INCRELEX and any potential adverse effects on the breast-fed child from INCRELEX or from the underlying maternal condition.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

(Extensive changes; please refer to labeling)

03/15/2016 (SUPPL-17)

Approved Drug Label (PDF)

6 Adverse Reactions

Immunogenicity

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 INCRELEX with the incidence of antibodies to other products may be misleading.
Anti-IGF-1 antibodies were present at one or more of the periodic assessments in 14 of 23 children with Primary IGFD treated for 2 years. However, no clinical consequences of these antibodies were observed (e.g., attenuation of growth).