Dinutuximab

Unituxin (dinutuximab) is 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 [see Clinical Studies (14) ] . 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. ( 1 )

Injection: 17.5 mg/5 mL (3.5 mg/mL) as a clear and colorless to slightly opalescent solution in a single-dose vial. Injection: 17.5 mg/5 mL (3.5 mg/mL) in a single-dose vial. ( 3 )

Unituxin is contraindicated in patients with a history of anaphylaxis to dinutuximab. History of anaphylaxis to dinutuximab. ( 4 )

Neurological Disorders of the Eye: Interrupt Unituxin for dilated pupil with sluggish light reflex or other visual disturbances and permanently discontinue Unituxin for recurrent eye disorders or loss of vision. ( 5.2 ) Prolonged Urinary Retention and Transverse Myelitis: Permanently discontinue Unituxin and institute supportive care. ( 5.2 ) Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Permanently discontinue Unituxin and institute supportive care for signs and symptoms of RPLS. ( 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 ) Bone Marrow Suppression: Monitor peripheral blood counts during Unituxin therapy. ( 5.6 ) Electrolyte Abnormalities: Monitor serum electrolytes closely. ( 5.7 ) Atypical Hemolytic Uremic Syndrome: Permanently discontinue Unituxin and institute supportive management. ( 5.8 ) Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.9 , 8.1 , 8.3 )

5.1 Serious Infusion Reactions Serious infusion reactions requiring urgent intervention, including blood pressure support, bronchodilator therapy, corticosteroids, infusion rate reduction, infusion interruption, or permanent discontinuation of Unituxin, included facial and upper airway edema, dyspnea, bronchospasm, stridor, urticaria, and hypotension. Infusion reactions generally occurred during or within 24 hours of completing the Unituxin infusion. Due to overlapping signs and symptoms, it was not possible to distinguish between infusion reactions and hypersensitivity reactions in some cases. In Study 1, Severe (Grade 3 or 4) infusion reactions occurred in 35 (26%) patients in the Unituxin/13-cis-retinoic acid (RA) group compared to 1 (1%) patient receiving RA alone. Severe urticaria occurred in 17 (13%) patients in the Unituxin/RA group but did not occur in the RA group. Serious adverse reactions consistent with anaphylaxis and resulting in permanent discontinuation of Unituxin occurred in 2 (1%) patients in the Unituxin/RA group. Additionally, 1 (0.1%) patient had multiple cardiac arrests and died within 24 hours after having received Unituxin in Study 2. Prior to each Unituxin dose, administer required intravenous hydration and premedication with antihistamines, analgesics, and antipyretics [see Dosage and Administration (2.2) ] . Monitor patients closely for signs and symptoms of infusion reactions during and for at least 4 hours following completion of each Unituxin infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. For mild to moderate infusion reactions, such as transient rash, fever, rigors, and localized urticaria, that respond promptly to antihistamines or antipyretics, decrease the Unituxin infusion rate and monitor closely. Immediately interrupt or permanently discontinue Unituxin and institute supportive management for severe or prolonged infusion reactions. Permanently discontinue Unituxin and institute supportive management for life-threatening infusion reactions [see Dosage and Administration (2.3) ] .

5.2 Neurotoxicity Pain In Study 1, 114 (85%) patients treated in the Unituxin/RA group experienced pain despite pre-treatment with analgesics, including morphine sulfate infusion. Severe (Grade 3) pain occurred in 68 (51%) patients in the Unituxin/RA group compared to 5 (5%) patients in the RA group. Pain typically occurred during the Unituxin infusion and was most commonly reported as abdominal pain, generalized pain, extremity pain, back pain, neuralgia, musculoskeletal chest pain, and arthralgia. Premedicate with analgesics, including intravenous opioids, prior to each dose of Unituxin and continue analgesics until 2 hours following completion of Unituxin [see Dosage and Administration (2.2) ] . For severe pain, decrease the Unituxin infusion rate to 0.875 mg/m 2 /hour. Discontinue Unituxin if pain is not adequately controlled despite infusion rate reduction and institution of maximum supportive measures [see Dosage and Administration (2.3) ] . Peripheral Neuropathy In Study 1, severe (Grade 3) peripheral sensory neuropathy occurred in 2 (1%) patients and severe peripheral motor neuropathy occurred in 2 (1%) patients in the Unituxin/RA group. No patients treated with RA alone experienced severe peripheral neuropathy. The duration and reversibility of peripheral neuropathy occurring in Study 1 was not documented. In Study 3, no patients experienced peripheral motor neuropathy. Among the 9 (9%) patients who experienced peripheral sensory neuropathy of any severity, the median (min, max) duration of peripheral sensory neuropathy was 9 (3, 163) days. In a study of a related anti-GD2 antibody conducted in 12 adult patients with metastatic melanoma, 2 (13%) patients developed severe motor neuropathy. One patient developed lower extremity weakness and inability to ambulate that persisted for approximately 6 weeks. Another patient developed severe lower extremity weakness resulting in an inability to ambulate without assistance that lasted for approximately 16 weeks and neurogenic bladder that lasted for approximately 3 weeks. Complete resolution of motor neuropathy was not documented in this case. Permanently discontinue Unituxin in patients with peripheral motor neuropathy of Grade 2 or greater severity, Grade 3 sensory neuropathy that interferes with daily activities for more than 2 weeks, or Grade 4 sensory neuropathy [see Dosage and Administration (2.3) ] . Neurological Disorders of the Eye Neurological disorders of the eye experienced by 2 or more patients treated with Unituxin in Studies 1, 2, or 3 included blurred vision, photophobia, mydriasis, fixed or unequal pupils, optic nerve disorder, eyelid ptosis, and papilledema. In Study 1, 3 (2%) patients in the Unituxin/RA group experienced blurred vision, compared to no patients in the RA group. Diplopia, mydriasis, and unequal pupillary size occurred in 1 patient each in the Unituxin/RA group, compared to no patients in the RA group. The duration of eye disorders occurring in Study 1 was not documented. In Study 3, eye disorders occurred in 16 (15%) patients, and in 3 (3%) patients resolution of the eye disorder was not documented. Among the cases with documented resolution, the median duration of eye disorders was 4 days (range: 0, 221 days). Interrupt Unituxin in patients experiencing dilated pupil with sluggish light reflex or other visual disturbances that do not cause visual loss. Upon resolution and if continued treatment with Unituxin is warranted, decrease the Unituxin dose by 50%. Permanently discontinue Unituxin in patients with recurrent signs or symptoms of an eye disorder following dose reduction and in patients who experience loss of vision [see Dosage and Administration (2.3) ] . 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 [see Dosage and Administration (2.3) and Postmarketing Experience (6.2) ] . 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 [see Dosage and Administration (2.3) and Postmarketing Experience (6.2) ] . Reversible Posterior Leukoencephalopathy Syndrome Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has occurred in patients treated with Unituxin. […]

The following adverse reactions are discussed in greater detail in other sections of the labeling: Serious Infusion Reactions [see Boxed Warning and Warnings and Precautions (5.1) ] Neurotoxicity, including Pain, Peripheral Neuropathy, Neurological Disorders of the Eye, Prolonged Urinary Retention, Transverse Myelitis, and Reversible Posterior Leukoencephalopathy Syndrome [see Boxed Warning and Warnings and Precautions (5.2) ] Capillary Leak Syndrome [see Warnings and Precautions (5.3) ] Hypotension [see Warnings and Precautions (5.4) ] Infection [see Warnings and Precautions (5.5) ] Bone Marrow Suppression [see Warnings and Precautions (5.6) ] Electrolyte Abnormalities [see Warnings and Precautions (5.7) ] Atypical Hemolytic Uremic Syndrome [see Warnings and Precautions (5.8) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.9) ] 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.

6.1 Clinical Trials Experience 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, multicenter study (Study 1), 134 patients received Unituxin 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 Unituxin. 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). Table 5: Selected Adverse Reactions Occurring in at Least 10% of Patients in the Unituxin/RA Group in Study 1 Adverse Reaction Includes adverse reactions that occurred in at least 10% of patients in the Unituxin/RA group with at least a 5% (All Grades) or 2% (Grades 3 to 5) absolute higher incidence in the Unituxin/RA group compared to the RA group. , Adverse drug reactions were graded using CTCAE version 3.0. Unituxin/RA (N=134) RA (N=106) All Grades (%) Grades 3 to 4 (%) All Grades (%) Grades 3 to 4 (%) General Disorders and Administration Site Conditions Pain Includes preferred terms abdominal pain, abdominal pain upper, arthralgia, back pain, bladder pain, bone pain, chest pain, facial pain, gingival pain, infusion related reaction, musculoskeletal chest pain, myalgia, neck pain, neuralgia, oropharyngeal pain, pain, pain in extremity, and proctalgia. 85 51 16 6 Pyrexia 72 40 27 6 Edema 17 0 0 0 Blood and Lymphatic System Disorders Based on investigator reported adverse reactions. Thrombocytopenia 66 39 43 25 Lymphopenia 62 51 36 20 Anemia 51 34 22 16 Neutropenia 39 34 16 13 Immune System Disorders Infusion reactions 60 25 9 1 Vascular Disorders Hypotension 60 16 3 0 Capillary leak syndrome One Grade 5 adverse reaction. 40 23 1 0 Hemorrhage Includes preferred terms gastrointestinal hemorrhage, hematochezia, rectal hemorrhage, hematemesis, upper gastrointestinal hemorrhage, hematuria, hemorrhage urinary tract, renal hemorrhage, epistaxis, respiratory tract hemorrhage, disseminated intravascular coagulation, catheter site hemorrhage, hemorrhage, and hematoma. 17 6 6 3 Hypertension 14 2 7 1 Metabolism and Nutrition Disorders Hyponatremia 58 23 12 4 Hypokalemia 43 37 4 2 Hypoalbuminemia 33 7 3 0 Hypocalcemia 27 7 0 0 Hypophosphatemia 20 8 3 0 Hyperglycemia 18 6 4 1 Hypertriglyceridemia 16 1 11 1 Decreased appetite 15 10 5 4 Hypomagnesemia 12 2 1 0 Investigations Increased alanine aminotransferase 56 23 31 3 Increased aspartate aminotransferase 28 10 7 0 Increased serum creatinine 15 2 6 0 Increased weight 10 0 0 0 Gastrointestinal Disorders Vomiting 46 6 19 3 Diarrhea 43 13 15 1 Nausea 10 2 3 1 Skin and Subcutaneous Tissue Disorders Urticaria 37 13 3 0 Respiratory, Thoracic and Mediastinal Disorders Hypoxia 24 12 2 1 Cardiac Disorders Tachycardia Includes preferred terms tachycardia and sinus tachycardia. 19 2 1 0 Infections and Infestations Sepsis 18 16 9 9 Device related infection 16 16 11 11 Renal and Urinary Disorders Proteinuria 16 0 3 1 Nervous System Disorders Peripheral neuropathy 13 3 6 0 Table 6 compares the per-patient incidence of selected adverse reactions occurring during cycles containing Unituxin in combination with GM-CSF (Cycles 1, 3, and 5) with cycles containing Unituxin in combination with IL-2 (Cycles 2 and 4). Table 6: Comparison of Adverse Events by Treatment Cycle in the Unituxin/RA Group in Study 1 Preferred Term Includes preferred terms with a per-patient incidence of at least 20% in the Unituxin and RA group for either IL-2 or GM-CSF containing cycles. , Adverse drug reactions were graded using CTCAE version 3.0. All Grades Severe GM-CSF N=134 (%) IL-2 Seven patients who received GM-CSF in Cycle 1 discontinued prior to starting Cycle 2. […]

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

8.1 Pregnancy 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 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

8.2 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.

8.3 Females and Males of Reproductive Potential 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 2 months after the last dose of Unituxin.

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 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/m 2 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.

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

8.6 Renal Impairment Unituxin has not been studied in patients with renal impairment.

8.7 Hepatic Impairment Unituxin has not been studied in patients with hepatic impairment.

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).