DINUTUXIMAB Drug Interactions: What You Need to Know

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

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

AND PRECAUTIONS 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.2) ]</span> . 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. Institute appropriate medical treatment and permanently discontinue Unituxin in patients with signs and symptoms of RPLS (eg, severe headache, hypertension, visual changes, lethargy, or seizures) [see Dosage and Administration (2.3) and Postmarketing Experience (6.2) ] .

5.3 Capillary Leak Syndrome In Study 1, severe (Grade 3 to 5) capillary leak syndrome occurred in 31 (23%) patients in the Unituxin/RA group and in no patients treated with RA alone. Additionally, capillary leak syndrome was reported as a serious adverse reaction in 9 (6%) patients in the Unituxin/RA group and in no patients treated with RA alone. Immediately interrupt or discontinue Unituxin and institute supportive management in patients with symptomatic or severe capillary leak syndrome <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.4 Hypotension In Study 1, severe (Grade 3 or 4) hypotension occurred in 22 (16%) patients in the Unituxin/RA group compared to no patients in the RA group. Prior to each Unituxin infusion, administer required intravenous hydration. Closely monitor blood pressure during Unituxin treatment. Immediately interrupt or discontinue Unituxin and institute supportive management in patients with symptomatic hypotension, systolic blood pressure (SBP) less than lower limit of normal for age, or SBP that is decreased by more than 15% compared to baseline <span class="opacity-50 text-xs">[see Dosage and Administration (2.2 , 2.3) ]</span> .

5.5 Infection In Study 1, severe (Grade 3 or 4) bacteremia requiring intravenous antibiotics or other urgent intervention occurred in 17 (13%) patients in the Unituxin/RA group compared to 5 (5%) patients treated with RA alone. Sepsis occurred in 24 (18%) patients in the Unituxin/RA group and in 10 (9%) patients in the RA group. Monitor patients closely for signs and symptoms of systemic infection and temporarily discontinue Unituxin in patients who develop systemic infection until resolution of the infection <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.6 Bone Marrow Suppression In Study 1, severe (Grade 3 or 4) thrombocytopenia (39% vs. 25%), anemia (34% vs. 16%), neutropenia (34% vs. 13%), and febrile neutropenia (4% vs. 0 patients) occurred more commonly in patients in the Unituxin/RA group compared to patients treated with RA alone. Monitor peripheral blood counts closely during therapy with Unituxin.

5.7 Electrolyte Abnormalities In Study 1, electrolyte abnormalities occurring in at least 25% of patients who received Unituxin/RA included hyponatremia, hypokalemia, and hypocalcemia. Severe (Grade 3 or 4) hypokalemia and hyponatremia occurred in 37% and 23% of patients in the Unituxin/RA group, respectively, compared to 2% and 4% of patients in the RA group. In a study of a related anti-GD2 antibody conducted in 12 adult patients with metastatic melanoma, 2 (13%) patients developed syndrome of inappropriate antidiuretic hormone secretion resulting in severe hyponatremia. Monitor serum electrolytes daily during therapy with Unituxin.

5.8 Atypical Hemolytic Uremic Syndrome Hemolytic uremic syndrome in the absence of documented infection and resulting in renal insufficiency, electrolyte abnormalities, anemia, and hypertension occurred in 2 patients enrolled in Study 2 following receipt of the first cycle of Unituxin. Atypical hemolytic uremic syndrome recurred following rechallenge with Unituxin in 1 patient. Permanently discontinue Unituxin and institute supportive management for signs of hemolytic uremic syndrome <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.9 Embryo-Fetal Toxicity Based on its mechanism of action, Unituxin may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment, and for 2 months after the last dose of Unituxin <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) and Clinical Pharmacology (12.1) ]</span> .