Dinutuximab

Dinutuximab
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Unitxin

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Black Box Warning

WARNING: SERIOUS INFUSION REACTIONS AND NEUROPATHY See full prescribing information for complete Boxed Warning. Infusion Reactions Serious and potentially life-threatening infusion reactions occurred in 26% of patients treated with Unituxin. Administer required prehydration and premedication including antihistamines prior to each Unituxin infusion. Monitor patients closely for signs and symptoms of an infusion reaction during and for at least four hours following completion of each Unituxin infusion. Immediately interrupt Unituxin for severe infusion reactions and permanently discontinue Unituxin for anaphylaxis (2.2, 2.3, 5.1). Neuropathy Unituxin causes severe neuropathic pain 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 was observed in adults. Resolution of motor neuropathy was not documented in all cases. Discontinue Unituxin for severe unresponsive pain, severe sensory neuropathy, or moderate to severe peripheral motor neuropathy (2.2, 2.3, 5.2).

Overview

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Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Unituxin is a GD2-binding monoclonal antibody indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

17.5 mg/m2/day as a diluted intravenous infusion over 10 to 20 hours for 4 consecutive days for up to 5 cycles. (2.1, 2.4) DOSAGE FORMS AND STRENGTHS

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Dinutuximab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Contraindications

History of anaphylaxis to dinutuximab. (4)

Warnings

WARNING: SERIOUS INFUSION REACTIONS AND NEUROPATHY See full prescribing information for complete Boxed Warning. Infusion Reactions Serious and potentially life-threatening infusion reactions occurred in 26% of patients treated with Unituxin. Administer required prehydration and premedication including antihistamines prior to each Unituxin infusion. Monitor patients closely for signs and symptoms of an infusion reaction during and for at least four hours following completion of each Unituxin infusion. Immediately interrupt Unituxin for severe infusion reactions and permanently discontinue Unituxin for anaphylaxis (2.2, 2.3, 5.1). Neuropathy Unituxin causes severe neuropathic pain 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 was observed in adults. Resolution of motor neuropathy was not documented in all cases. Discontinue Unituxin for severe unresponsive pain, severe sensory neuropathy, or moderate to severe peripheral motor neuropathy (2.2, 2.3, 5.2).

Capillary leak syndrome and hypotension: Administer required prehydration and monitor patients closely during treatment. Depending upon severity, manage by interruption, infusion rate reduction, or permanent discontinuation. (5.3, 5.4) Infection: Interrupt until resolution of systemic infection. (5.5) Neurological Disorders of the Eye: Interrupt for dilated pupil with sluggish light reflex or other visual disturbances and permanently discontinue for recurrent eye disorders or loss of vision. (5.6) Bone marrow suppression: Monitor peripheral blood counts during Unituxin therapy. (5.7) Electrolyte abnormalities: Monitor serum electrolytes closely. (5.8) Atypical hemolytic uremic syndrome: Permanently discontinue Unituxin and institute supportive management. (5.9) Embryo-Fetal toxicity: May cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. (5.10, 8.1, 8.3)

Adverse Reactions

Clinical Trials Experience

The most common adverse drug reactions (≥ 25%) are pain, pyrexia, thrombocytopenia, lymphopenia, infusion reactions, hypotension, hyponatremia, increased alanine aminotransferase, anemia, vomiting, diarrhea, hypokalemia, capillary leak syndrome, neutropenia, urticaria, hypoalbuminemia, increased aspartate aminotransferase, and hypocalcemia. (5, 6.1)

The most common serious adverse reactions (≥ 5%) are infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome. (5, 6.1)

To report SUSPECTED ADVERSE REACTIONS, contact United Therapeutics Corp. at 1-866-458-6479 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in clinical practice.

The data described below reflect exposure to Unituxin at the recommended dose and schedule in 1021 patients with high-risk neuroblastoma enrolled in an open label, randomized (Study 1) or single arm clinical trials (Study 2 and Study 3). Prior to enrollment, patients received therapy consisting of induction combination chemotherapy, maximum feasible surgical resection, myeloablative consolidation chemotherapy followed by autologous stem cell transplant, and radiation therapy to residual soft tissue disease. Patients received Unituxin in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2) and 13-cis-retinoic acid (RA). Treatment commenced within 95 days post autologous stem cell transplant in Study 1, within 210 days of autologous stem cell transplant in Study 2, and within 110 days of autologous stem cell transplant in Study 3.

Study 1

In a randomized, open label, multi-center study (Study 1), 134 patients received dinutuximab in combination with GM-CSF, IL-2 and RA (Unituxin/RA group), including 109 randomized patients and 25 patients with biopsy-proven residual disease who were non-randomly assigned to receive dinutuximab. A total of 106 randomized patients received RA alone (RA group) [see DOSAGE AND ADMINISTRATION (2) and CLINICAL STUDIES (14)]. Patients had a median age at enrollment of 3.8 years (range: 0.94 to 15.3 years), and were predominantly male (60%) and White (82%). In Study 1, adverse reactions of Grade 3 or greater severity were comprehensively collected, but adverse reactions of Grade 1 or 2 severity were collected sporadically and laboratory data were not comprehensively collected.

Approximately 71% of patients in the Unituxin/RA group and 77% of patients in the RA group completed planned treatment. The most common reason for premature discontinuation of study therapy was adverse reactions in the Unituxin/RA group (19%) and progressive disease (17%) in the RA group.

The most common adverse drug reactions (≥ 25%) in the Unituxin/RA group were pain, pyrexia, thrombocytopenia, lymphopenia, infusion reactions, hypotension, hyponatremia, increased alanine aminotransferase, anemia, vomiting, diarrhea, hypokalemia, capillary leak syndrome, neutropenia, urticaria, hypoalbuminemia, increased aspartate aminotransferase, and hypocalcemia. The most common serious adverse reactions (≥ 5%) in the Unituxin/RA group were infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome.

Table 5 lists the adverse reactions reported in at least 10% of patients in the Unituxin/RA group for which there was a between group difference of at least 5% (all grades) or 2% (Grade 3 or greater severity).

6.2 Immunogenicity As with all therapeutic proteins, patients treated with Unituxin may develop anti-drug antibodies. In clinical studies, 52 of 284 (18%) patients from Study 2 and 13 of 103 (13%) patients from Study 3 tested positive for anti-dinutuximab binding antibodies. Neutralizing antibodies were detected in 3.6% of patients who were tested for anti-dinutuximab binding antibodies in Study 2 and Study 3. However, due to the limitations of the assay, the incidence of neutralizing antibodies may not have been reliably determined.

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

Postmarketing Experience

There is limited information regarding Dinutuximab Postmarketing Experience in the drug label.

Drug Interactions

No drug-drug interaction studies have been conducted with dinutuximab.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): Risk Summary

Based on its mechanism of action, Unituxin may cause fetal harm when administered to a pregnant woman [see CLINICAL PHARMACOLOGY (12.1)]. There are no studies in pregnant women and no reproductive studies in animals to inform the drug-associated risk. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dinutuximab in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Dinutuximab during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Dinutuximab in women who are nursing.

Pediatric Use

8.4 Pediatric Use 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 five 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 one cycle of RA alone. Patients randomized to the RA arm received up to six cycles of RA monotherapy. Study 1 demonstrated an improvement in event-free survival and overall survival in patients in the Unituxin/RA arm compared to those in the RA arm [see ADVERSE REACTIONS (6), CLINICAL PHARMACOLOGY (12), CLINICAL STUDIES (14)].

Geriatic Use

The safety and effectiveness of Unituxin in geriatric patients have not been established.

Gender

There is no FDA guidance on the use of Dinutuximab with respect to specific gender populations.

Race

There is no FDA guidance on the use of Dinutuximab with respect to specific racial populations.

Renal Impairment

Unituxin has not been studied in patients with renal impairment.

Hepatic Impairment

Unituxin has not been studied in patients with hepatic impairment.

Females of Reproductive Potential and Males

Contraception

Females

Unituxin may cause fetal harm [see USE IN SPECIFIC POPULATIONS (8.1)]. Advise females of reproductive potential to use effective contraception during treatment and for two months after the last dose of Unituxin.

Immunocompromised Patients

There is no FDA guidance one the use of Dinutuximab in patients who are immunocompromised.

Lactation

Risk Summary

There is no information available on the presence of dinutuximab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. However, human IgG is present in human milk. Because of the potential for serious adverse reactions in a breastfed infant, advise a nursing woman to discontinue breastfeeding during treatment with Unituxin.

Administration and Monitoring

Administration

There is limited information regarding Dinutuximab Administration in the drug label.

Monitoring

There is limited information regarding Dinutuximab Monitoring in the drug label.

IV Compatibility

Injection: 17.5 mg/5 mL (3.5 mg/mL) in a single-use vial. (3)

Overdosage

There is limited information regarding Dinutuximab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Dinutuximab Pharmacology in the drug label.

Mechanism of Action

Mechanism of Action Dinutuximab binds to the glycolipid GD2. This glycolipid is expressed on neuroblastoma cells and on normal cells of neuroectodermal origin, including the central nervous system and peripheral nerves. Dinutuximab binds to cell surface GD2 and induces cell lysis of GD2-expressing cells through antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

Structure

There is limited information regarding Dinutuximab Structure in the drug label.

Pharmacodynamics

There is limited information regarding Dinutuximab Pharmacodynamics in the drug label.

Pharmacokinetics

The pharmacokinetics of dinutuximab was evaluated by a population pharmacokinetic analysis in a clinical study of Unituxin in combination with GM-CSF, IL-2, and RA. In this study, 27 children with high-risk neuroblastoma (age: 3.9±1.9 years) received up to 5 cycles of Unituxin at 17.5 mg/m2/day as an intravenous infusion over 10 to 20 hours for 4 consecutive days every 28 days. The observed maximum plasma dinutuximab concentration (Cmax) was 11.5 mcg/mL [20%, coefficient of variation (CV)]. The mean volume of distribution at steady state (Vdss) was 5.4 L (28%). The clearance was 0.21 L/day (62%) and increased with body size. The terminal half-life was 10 days (56%).

No formal pharmacokinetic studies were conducted in patients with renal or hepatic impairment.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility No animal studies have been conducted to evaluate the carcinogenic or mutagenic potential of dinutuximab.

Dedicated studies examining the effects of dinutuximab on fertility in animals have not been conducted. No clear effects on reproductive organs were observed in general toxicology studies conducted in rats.

13.2 Animal Toxicology and/or Pharmacology Non-clinical studies suggest that dinutuximab-induced neuropathic pain is mediated by binding of the antibody to the GD2 antigen located on the surface of peripheral nerve fibers and myelin and subsequent induction of CDC and ADCC activity.

Clinical Studies

There is limited information regarding Dinutuximab Clinical Studies in the drug label.

How Supplied

Unituxin is supplied in a carton containing one 17.5 mg/5 mL (3.5 mg/mL) single-use vial.

NDC 66302-014-01

Store Unituxin vials under refrigeration at 2°C to 8°C until time of use. Do not freeze or shake the vial. Keep the vial in the outer carton in order to protect from light.

Storage

There is limited information regarding Dinutuximab Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

Serious Infusion Reactions Inform patients and caregivers of the risk of serious infusion reactions and anaphylaxis and to immediately report any signs or symptoms, such as facial or lip swelling, urticaria, difficulty breathing, lightheadedness or dizziness that occur during or within 24 hours following the infusion [see WARNINGS AND PRECAUTIONS (5.1)].

Pain and Peripheral Neuropathy Inform patients and caregivers of the risk of severe pain and peripheral sensory and motor neuropathy and to promptly report severe or worsening pain and signs and symptoms of neuropathy such as numbness, tingling, burning, or weakness [see WARNINGS AND PRECAUTIONS (5.2)].

Capillary Leak Syndrome Inform patients and caregivers of the risk of capillary leak syndrome and to immediately report any signs or symptoms [see WARNINGS AND PRECAUTIONS (5.3)].

Hypotension Inform patients and caregivers of the risk of hypotension during the infusion and to immediately report any signs or symptoms [see WARNINGS AND PRECAUTIONS (5.4)].

Infection Inform patients and caregivers of the risk of infection following treatment and to immediately report any signs or symptoms [see WARNINGS AND PRECAUTIONS (5.5)].

Neurological Disorders of the Eye Inform patients and caregivers of the risk of neurological disorders of the eye and to promptly report signs or symptoms such as blurred vision, photophobia, ptosis, diplopia, or unequal pupil size [see WARNINGS AND PRECAUTIONS (5.6)].

Bone Marrow Suppression Inform patients and caregivers of the risk of bone marrow suppression, and to promptly report signs or symptoms of anemia, thrombocytopenia, or infection [see WARNINGS AND PRECAUTIONS (5.7)].

Electrolyte Abnormalities Inform patients and caregivers of the risk of electrolyte abnormalities including hypokalemia, hyponatremia, and hypocalcemia, and to report any signs or symptoms such as seizures, heart palpitations, and muscle cramping [see WARNINGS AND PRECAUTIONS (5.8)].

Atypical Hemolytic Uremic Syndrome Inform patients and caregivers of the risk of hemolytic uremic syndrome and to report any signs or symptoms such as fatigue, dizziness, fainting, pallor, edema, decreased urine output, or hematuria [see WARNINGS AND PRECAUTIONS (5.9)].

Embryo-Fetal Toxicity Advise women of reproductive potential of the potential risk to the fetus if administered during pregnancy and the need for use of effective contraception during and for at least two months after completing therapy [see WARNINGS AND PRECAUTIONS (5.10)].

Precautions with Alcohol

Alcohol-Dinutuximab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Dinutuximab Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Dinutuximab Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Overview

Dinutuximab (tradename Unituxin) is a drug developed by United Therapeutics for the treatment of high-risk neuroblastoma in pediatric patients. It was approved for use by the United States Food and Drug Administration for use on March 10, 2015.