BLINATUMOMAB Drug Interactions: What You Need to Know

INTERACTIONS No formal drug interaction studies have been conducted with BLINCYTO. Initiation of BLINCYTO treatment causes transient release of cytokines that may suppress CYP450 enzymes. The highest drug-drug interaction risk is during the first 9 days of the first cycle and the first 2 days of the second cycle in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index. In these patients, monitor for toxicity (e.g., warfarin) or drug concentrations (e.g., cyclosporine). Adjust the dose of the concomitant drug as needed [see Clinical Pharmacology (12.2 , 12.3) ] .

BLINCYTO is contraindicated in patients with known hypersensitivity to blinatumomab or to any component of the product formulation. Known hypersensitivity to blinatumomab or to any component of the product formulation. ( 4 )

AND PRECAUTIONS Infections: Monitor patients for signs or symptoms; treat appropriately. ( 5.3 ) Effects on Ability to Drive and Use Machines: Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered. ( 5.6 ) Pancreatitis: Evaluate patients who develop signs and symptoms of pancreatitis. Management of pancreatitis may require either temporary interruption or discontinuation of BLINCYTO. ( 5.8 ) Preparation and Administration Errors: Strictly follow instructions for preparation (including admixing) and administration. ( 5.10 )

Benzyl Alcohol

Toxicity in Neonates: Use BLINCYTO prepared with preservative-free saline for neonates. BLINCYTO solution containing benzyl alcohol is not recommended for patients weighing less than 5.4 kg. ( 5.12 , 8.4 ) Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.13 , 8.1 , 8.3 )

5.1 Cytokine Release Syndrome Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. The median time to onset of CRS was 2 days after the start of infusion and the median time to resolution of CRS was 5 days among cases that resolved. Manifestations of CRS include fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin, and disseminated intravascular coagulation (DIC). The manifestations of CRS after treatment with BLINCYTO overlap with those of infusion reactions, capillary leak syndrome (CLS), and hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS). Evaluation for HLH/MAS should be considered when CRS is atypical or prolonged, or when features of macrophage activation are present. Using all of these terms to define CRS in clinical trials of BLINCYTO, CRS was reported in 15% of patients with relapsed or refractory ALL, in 7% of patients with MRD-positive ALL, and in 16% of patients receiving BLINCYTO cycles in the consolidation phase of therapy <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Monitor patients for signs or symptoms of these events. Advise outpatients on BLINCYTO to contact their healthcare professional for signs and symptoms associated with CRS. If severe CRS occurs, interrupt BLINCYTO until CRS resolves. Discontinue BLINCYTO permanently if life-threatening CRS occurs. Administer corticosteroids for severe or life-threatening CRS <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> .

5.2 Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome BLINCYTO can cause serious or life-threatening neurologic toxicity, including ICANS <span class="opacity-50 text-xs">[see Adverse Reactions 6.1 ]</span> . The incidence of neurologic toxicities in clinical trials was approximately 65% <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Among patients that experienced a neurologic toxicity, the median time to the first event was within the first 2 weeks of BLINCYTO treatment. The most common (≥ 10%) manifestations of neurological toxicity were headache, and tremor; the neurological toxicity profile varied by age group <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4 , 8.5) ]</span> .

Grade

3 or higher neurological toxicities following initiation of BLINCYTO administration occurred in approximately 13% of patients and included encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Manifestations of neurological toxicity included cranial nerve disorders. The majority of neurologic toxicities resolved following interruption of BLINCYTO, but some resulted in treatment discontinuation. The incidence of signs and symptoms consistent with ICANS in clinical trials was 7.5%. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. There is limited experience with BLINCYTO in patients with active ALL in the central nervous system (CNS) or a history of neurologic events. Patients with a history or presence of clinically relevant CNS pathology were excluded from clinical studies. Patients with Down Syndrome may have a higher risk of seizures with BLINCYTO therapy; consider seizure prophylaxis prior to initiation of BLINCYTO for these patients. Monitor patients receiving BLINCYTO for signs and symptoms of neurological toxicities, including ICANS. Advise outpatients on BLINCYTO to contact their healthcare professional if they develop signs or symptoms of neurological toxicities. Management of neurologic toxicity may require interruption or discontinuation of BLINCYTO as recommended and/or treatment with corticosteroids [see Dosage and Administration (2.4) ] .

5.3 Infections In patients with ALL receiving BLINCYTO in clinical studies, serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections were observed in approximately 25% of patients, some of which were life-threatening or fatal <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . As appropriate, administer prophylactic antibiotics and employ surveillance testing during treatment with BLINCYTO. Monitor patients for signs and symptoms of infection and treat appropriately.

5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS), which may be life-threatening or fatal, has been observed in patients receiving BLINCYTO <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Appropriate prophylactic measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used for the prevention of TLS during BLINCYTO treatment. Monitor for signs or symptoms of TLS. Management of these events may require either temporary interruption or discontinuation of BLINCYTO <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> .

5.5 Neutropenia and Febrile Neutropenia Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in patients receiving BLINCYTO <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . Monitor laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion. Interrupt BLINCYTO if prolonged neutropenia occurs.

5.6 Effects on Ability to Drive and Use Machines Due to the potential for neurologic events, including seizures and ICANS, patients receiving BLINCYTO are at risk for loss of consciousness <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) ]</span> . Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.

5.7 Elevated Liver Enzymes Treatment with BLINCYTO was associated with transient elevations in liver enzymes <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . In patients with ALL receiving BLINCYTO in clinical studies, the median time to onset of elevated liver enzymes was 3 days. The majority of these transient elevations in liver enzymes were observed in the setting of CRS. For the events that were observed outside the setting of CRS, the median time to onset was 19 days.

Grade

3 or greater elevations in liver enzymes occurred in approximately 7% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and total blood bilirubin prior to the start of and during BLINCYTO treatment. Interrupt BLINCYTO if the transaminases rise to greater than 5 times the upper limit of normal or if total bilirubin rises to more than 3 times the upper limit of normal .

5.8 Pancreatitis Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical studies and the postmarketing setting <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . Evaluate patients who develop signs and symptoms of pancreatitis. Management of pancreatitis may require either temporary interruption or discontinuation of BLINCYTO and dexamethasone <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> .

5.9 Leukoencephalopathy Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients with prior treatment with cranial irradiation and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown.

5.10 Preparation and Administration Errors Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration strictly to minimize medication errors (including underdose and overdose) <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) and Instructions for Use ]</span> .

5.11 Immunization The safety of immunization with live viral vaccines during or following BLINCYTO therapy has not been studied. Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.

5.12 Benzyl Alcohol Toxicity in Neonates Serious adverse reactions, including fatal reactions and the &quot;gasping syndrome,&quot; have been reported in very low birth weight (VLBW) neonates born weighing less than 1500 g, and early preterm neonates (infants born less than 34 weeks gestational age) who received intravenous drugs containing benzyl alcohol as a preservative. Early preterm VLBW neonates may be more likely to develop these reactions, because they may be less able to metabolize benzyl alcohol <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span> . Use the preservative-free preparations of BLINCYTO where possible in neonates. When prescribing BLINCYTO (with preservative) for neonatal patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative), other products containing benzyl alcohol or other excipients (e.g., ethanol, propylene glycol) which compete with benzyl alcohol for the same metabolic pathway. Monitor neonatal patients receiving BLINCYTO (with preservative) for new or worsening metabolic acidosis. The minimum amount of benzyl alcohol at which serious adverse reactions may occur in neonates is not known. The BLINCYTO 72-Hour bag (with preservative) and 96-Hour bag (with preservative) contain 2.5 mg of benzyl alcohol per mL, and the 7-Day bag (with preservative) contains 7.4 mg of benzyl alcohol per mL. The administration of BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span> .

5.13 Embryo-Fetal Toxicity Based on its mechanism of action, BLINCYTO may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with BLINCYTO and for 48 hours after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) ]</span> .