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.

UNITUXIN (BLA-125516)

(DINUTUXIMAB)

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

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09/29/2020 (SUPPL-25)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Immunogenicity

(Additions and/or revisions underlined)

As with all therapeutic proteins, there is a 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 in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Among the 418 patients who were treated with Unituxin in combination with GM-CSF, IL-2, and RA in Study 2, Study 3 and Study DIV-NB-201, 86 patients (20.6%) tested positive for anti- dinutuximab antibodies (ADA). Of the 86 ADA positive patients, 45 (52.3%) tested positive for neutralizing antibodies.

Among the 27 patients who were treated with Unituxin in combination with lenalidomide and isotretinoin in Study NANT 2011-04, 13 patients (48.1%) tested positive for ADA. Of the 13 ADA positive patients, 2 (15.4%) also tested positive for neutralizing antibodies.

The clearance of dinutuximab was 60% higher for the ADA positive patients than the ADA negative patients. The presence of ADA did not have a clinically significant effect on the incidence or severity of adverse reactions. There were insufficient number of patients with ADA to determine whether ADA alters the efficacy of Unituxin.

8 Use in Specific Populations

Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of Unituxin as part of multi-agent, multimodality therapy have been established in pediatric patients with high-risk neuroblastoma based on results of an open-label, randomized (1:1) trial conducted in 226 patients aged 11 months to 15 years (median age

3.8 years) (Study 1). Prior to enrollment, patients achieved at least a partial response to prior first-line therapy for high-risk neuroblastoma consisting of induction combination chemotherapy, maximum feasible surgical resection, myeloablative consolidation chemotherapy followed by autologous stem cell transplant, and received radiation therapy to residual soft tissue disease. Patients randomized to the Unituxin/13-cis-retinoic acid (RA) arm (Unituxin/RA) received up to 5 cycles of Unituxin in combination with alternating cycles of granulocyte-macrophage colony- stimulating factor (GM-CSF) and interleukin-2 (IL-2) plus RA, followed by 1 cycle of RA alone. Patients randomized to the RA arm received up to 6 cycles of RA monotherapy. Study 1 demonstrated an improvement in event-free survival (EFS) and overall survival (OS) in patients in the Unituxin/RA arm compared to those in the RA arm [see Adverse Reactions (6), Clinical Pharmacology (12), and Clinical Studies (14)].

Juvenile Animal Toxicity Data

Juvenile monkeys (13 to 18 months of age at study start) received dinutuximab daily via intravenous infusion for 4 consecutive days over five 28-day cycles at doses of 1, 3, or 10 mg/kg. Monkeys also received morphine during infusion for pain management. At the high dose of

10 mg/kg (approximately equal to the 17.5 mg/m2 clinical dose), mild degeneration of nerve fibers in the brain (medulla oblongata) and moderate degeneration of nerve fibers in the spinal cord (cervical, thoracic, and lumbar) were present. Mild neuronal and nerve fiber degeneration were also present in the dorsal root ganglia (cervical, thoracic, and lumbar). Nerve fiber degeneration in the spinal cord and neuronal degeneration in dorsal root ganglia persisted

6 months after the end of dosing, though at lower severity. At the 10 mg/kg dose level, nerve conduction velocity (NCV) analysis showed motor and sensory NCV decreases of less than 10% compared to vehicle controls, starting on Day 27 and continuing to Day 83. Sensory NCV decreases were still present at the end of the dosing period but were on a trend towards recovery 6 months after the end of dosing.

03/01/2017 (SUPPL-11)

Approved Drug Label (PDF)

Boxed Warning

Neurotoxicity replaces Neuropathy in all instances.

Additions and/or revisions underlined:

WARNING: SERIOUS INFUSION REACTIONS AND NEUROTOXICITY Infusion Reactions

… Neurotoxicity

Unituxin causes serious neurologic adverse reactions including severe neuropathic pain and peripheral neuropathy.

Severe neuropathic pain occurs in the majority of patients. Administer intravenous opioid prior to, during, and for 2 hours following completion of the Unituxin infusion.

In clinical studies of patients with high-risk neuroblastoma, Grade 3 peripheral sensory neuropathy occurred in 2% to 9% of patients. In clinical studies of Unituxin and related GD2-binding antibodies, severe motor neuropathy has occurred. Resolution of motor neuropathy did not occur in all cases. Discontinue Unituxin for severe unresponsive pain, severe sensory neuropathy, and moderate to severe peripheral motor neuropathy.

5 Warnings and Precautions

5.2 Neurotoxicity

Subheading title replaces Pain and Peripheral Neuropathy

Peripheral Neuropathy

… Permanently discontinue Unituxin in patients with peripheral motor neuropathy of Grade 2 or greater severity, Grade 3 sensory neuropathy that interferes …

Prolonged Urinary Retention

Urinary retention that persists for weeks to months following discontinuation of opioids has occurred in patients treated with Unituxin Permanently discontinue Unituxin in patients with urinary retention that does not resolve following discontinuation of opioids.

Transverse Myelitis

Transverse myelitis has occurred in patients treated with Unituxin. Promptly evaluate any patient with signs or symptoms of transverse myelitis such as weakness, paresthesia, sensory loss, or incontinence. Permanently discontinue Unituxin in patients who develop transverse myelitis.

Reversible Posterior Leukoencephalopathy Syndrome

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has occurred in patients treated with Unituxin. Institute appropriate medical treatment and permanently discontinue Unituxin in patients with signs and symptoms of RPLS (e.g., severe headache, hypertension, visual changes, lethargy, or seizures).

6 Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Serious Infusion Reactions
Neurotoxicity, including Pain, Peripheral Neuropathy, Neurological Disorders of the Eye, Prolonged Urinary Retention, Transverse Myelitis, and Reversible Posterior Leukoencephalopathy Syndrome
Capillary Leak Syndrome

6.3 Postmarketing Experience

(Newly added subsection)

The following adverse reactions have been identified during post-approval use of Unituxin. Because these 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.

Neurotoxicity: prolonged urinary retention, transverse myelitis, and reversible posterior leukoencephalopathy syndrome (RPLS).

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

PATIENT COUNSELING INFORMATION

Pain, Peripheral Neuropathy, Prolonged Urinary Retention, and Transverse Myelitis Inform patients and caregivers of the risk of severe pain, sensory and motor neuropathy, prolonged urinary retention, and transverse myelitis, and to promptly report severe or worsening pain and signs and symptoms such as numbness, tingling, burning, weakness, or inability to urinate.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) (newly added information)

Inform patients and caregivers of the risk of RPLS and to immediately report signs or symptoms such as severe headache, hypertension, visual changes, lethargy, or seizures.

Capillary Leak Syndrome …