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.

HUMATROPE (BLA-019640)

(SOMATROPIN RECOMBINANT)

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

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11/25/2025 (SUPPL-110)

Approved Drug Label (PDF)

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Each single-patient-use HUMATROPE cartridge is designed for use only with the appropriate corresponding HumatroPen® supplied separately.

. . .

07/09/2025 (SUPPL-111)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.10 Slipped Capital Femoral Epiphysis in Pediatric Patients

Additions and/or revisions underlined:

Slipped capital femoral epiphysis may occur more frequently in patients undergoing 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 with short stature receiving somatropin. Evaluate pediatric patients receiving HUMATROPE with the onset of a limp or complaints of hip or knee pain for slipped capital femoral epiphysis and osteonecrosis and manage accordingly.

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during post-approval use of somatropin or HUMATROPE. Because these adverse events 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.

. . .

Musculoskeletal and connective tissue disorders – Osteonecrosis in pediatric patients

. . .

12/08/2023 (SUPPL-108)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Subsection title revised:

Adult Patients with GH deficiency

…

Adverse reactions with greater than or equal to 5% overall occurrence rate during 12 or 18 months of replacement therapy with HUMATROPE are shown in Table 6 (adult-onset patients) and in Table 7 (childhood-onset patients).

7 Drug Interactions

Additions and/or revisions underlined:

Table 8 includes a list of drugs with clinically important drug interactions when administered concomitantly with HUMATROPE and instructions for preventing or managing them.

10/28/2019 (SUPPL-105)

Approved Drug Label (PDF)

4 Contraindications

(additions underlined)

HUMATROPE 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.

…

Active malignancy

…

5 Warnings and Precautions

5.11 Progression of Preexisting Scoliosis in Pediatric Patients

(additions underlined)

… Monitor patients with a history of scoliosis for progression of scoliosis.

5.2 Sudden Death in Pediatric Patients with Prader-Willi Syndrome

(addition 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.

…

5.3 Increased Risk of Neoplasms

(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 HUMATROPE. Discontinue HUMATROPE if there is evidence of recurrent activity.

…

New Malignancy During Treatment

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 HUMATROPE in these patients. If HUMATROPE is initiated, carefully monitor patients for development of neoplasms.

Monitor all patients receiving HUMATROPE carefully for increased growth, or potential malignant changes, of preexisting nevi. Advise patients/caregivers to report marked changes in behavior, onset of headaches, vision disturbances and/or changes in skin pigmentation or changes in the appearance of pre-existing nevi.

5.6 Severe Hypersensitivity

(additions underlined)

… Do not use HUMATROPE in patients with known hypersensitivity to somatropin or any of the excipients in HUMATROPE. Do not use HUMATROPE cartridges or the diluent supplied with HUMATROPE vials in patients with known hypersensitivity to metacresol or glycerin.

5.8 Hypoadrenalism

(additions underlined)

… HUMATROPE treatment. Monitor patients for reduced serum cortisol levels and/or need for glucocorticoid dose increases in those with known hypoadrenalism

6 Adverse Reactions

6.1 Clinical Trials Experience

(extensive revisions and additions, please refer to label for more information)

6.2 Immunogenicity

new subsection added)

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 HUMATROPE with the incidence of antibodies to other products may be misleading.

In a clinical study with HUMATROPE during the first 6 months of HUMATROPE therapy in 314 naive patients, 1.6% developed specific antibodies to HUMATROPE (binding capacity greater than or equal to 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.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

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 HUMATROPE.

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.

8.2 Lactation

(PLLR conversion)

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 related to somatropin in the breastfed infant have been reported. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HUMATROPE and any potential adverse effects on the breastfed infant from HUMATROPE or from the underlying maternal condition.

8.4 Pediatric Use

(new subsection added)

Safety and effectiveness of HUMATROPE 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 HUMATROPE have been established in pediatric patients with growth failure due to growth hormone deficiency based on data from an open-label, uncontrolled, multicenter study with HUMATROPE in 314 pediatric patients conducted for up to 8 years.

Short Stature Associated with Turner Syndrome

Safety and effectiveness of HUMATROPE have been established in pediatric patients with short stature associated with Turner syndrome based on data from one long-term, randomized, open-label, multicenter, concurrently controlled study; two long-term, open-label multicenter, historically controlled US studies; and one long-term, randomized, US dose-response study with HUMATROPE in 181 pediatric patients.

Idiopathic Short Stature (ISS)

Safety and effectiveness of HUMATROPE 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 HUMATROPE in 310 pediatric patients.

Short Stature or Growth Failure in SHOX Deficiency

Safety and effectiveness of HUMATROPE 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 HUMATROPE in 52 pediatric patients.

Short Stature in Children Born Small for Gestational Age (SGA) with No Catch-up Growth by 2 Years to 4 Years of Age

Safety and effectiveness of HUMATROPE have been established in pediatric patients with short stature born SGA with no catch-up growth based on data from two clinical studies with HUMATROPE in 214 pediatric patients.

10/28/2019 (SUPPL-91)

Approved Drug Label (PDF)

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

PATIENT COUNSELING INFORMATION

(section revised, additions 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 HUMATROPE 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 that occur during treatment with HUMATROPE.
Pancreatitis - Advise patients/caregivers that pancreatitis may develop and to report to their healthcare provider any new onset of 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 HUMATROPE. 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 HUMATROPE may be needed.
Administration – Counsel patients and parents that they should never share a HumatroPen with another person, even if the needle is changed. Sharing of the pen between patients may pose a risk of transmission of infection.

12/13/2016 (SUPPL-104)

Approved Drug Label (PDF)

4 Contraindications

Hypersensitivity

(revision underlined)

Humatrope 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

5.1 Acute Critical Illness

(additions 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 5.3-8.0 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.

5.6 Severe Hypersensitivity

(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.

5.8 Hypoadrenalism

(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

(additions underlined)

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

· Pancreatitis

· Lipoatrophy

6.2 Post-Marketing Experience

(addition underlined)

Other adverse events that have been reported in somatropin-treated patients include the following:

Severe Hypersensitivity Reactions — Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with postmarketing use of somatropin products.