Blincyto

Blincyto^® (blinatumomab)

Brief Prescribing Information Please refer to the Summary of Product Characteristics before prescribing Blincyto.Pharmaceutical Form:   One Blincyto 35mcg single dose vial containing a sterile, preservative-free, white to off-white lyophilized powder and One IV Solution Stabilizer 10 mL single dose glass vial containing a sterile, preservative-free, colorless to slightly yellow, clear solution.  Do not use the IV Solution Stabilizer to reconstitute BLINCYTO. Indications: BLINCYTO is indicated for the treatment of MRD-positive B-cell precursor ALL BLINCYTO is indicated as monotherapy for the treatment of adults with Philadelphia chromosome negative CD19 positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission (CR) with minimal residual disease (MRD) greater than or equal to 0.1%. Relapsed or refractory B-cell precursor ALL BLINCYTO is indicated for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), Refer to SMPC for full information. Posology and method of administration: Posology; Treatment of MRD-Positive B-cell Precursor ALL  A treatment course consists of 1 cycle of BLINCYTO for induction followed by up to 3 additional cycles for consolidation.

A single cycle of treatment of BLINCYTO induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days) Refer to SMPC for full information. Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiations (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended. Premedicate with prednisone or equivalent for MRD-positive B-cell Precursor ALL. For adult patients, premedicate with prednisone 100 mg intravenously or equivalent (e.g., dexamethasone 16 mg) 1 hour prior to the first dose of BLINCYTO in each cycle. For administration of BLINCYTO: over 24 hours or 48 hours and over 7 days using Bacteriostatic 0.9% Sodium Chloride Injection Refer to SMPC for full information, USP (containing 0.9% benzyl alcohol). This option is available for patients weighing greater than or equal to 22 kg. It is not recommended for use in patients weighing less than 22 kg. Treatment of Relapsed or Refractory B-cell Precursor ALL treatment course consists of up to 2 cycles of BLINCYTO for induction followed by 3 additional cycles for consolidation and up to 4 additional cycles of continued therapy.  A single cycle of treatment of BLINCYTO induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days). A single cycle of treatment of BLINCYTO continued therapy consists of 28 days of continuous intravenous infusion followed by a 56-day treatment-free interval (total 84 days). Refer to SMPC for the recommended daily dose by patient weight. Special population: Pediatric Use The safety and efficacy of BLINCYTO have been established in pediatric patients with relapsed or refractory B-cell precursor ALL. Use of BLINCYTO is supported by a single-arm trial in pediatric

patients with relapsed or refractory B-cell precursor ALL. This study included pediatric patients in the following age groups: 10 infants (1 month up to less than 2 years), 40 children (2 years up to less than 12 years), and 20 adolescents (12 years to less than 18 years). No differences in efficacy were

observed between the different age subgroups. In general, the adverse reactions in BLINCYTO-treated pediatric patients were similar in type to those

seen in adult patients with relapsed or refractory B-cell precursor ALL, see section 4.8. Adverse reactions that were observed more frequently (≥ 10% difference) in the pediatric population compared to the adult population were pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs.24%), infusion-related reaction (49% vs. 34%), thrombocytopenia (34% vs. 21%), leukopenia (24% vs.11%) and weight increased (17% vs. 6%). In pediatric patients less than 2 years old (infants), the incidence of neurologic toxicities was not significantly different than for the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability. Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (17%). The steady-state concentrations of blinatumomab were comparable in adult and pediatric patients at the equivalent dose levels based on BSA-based regimens. Benzyl alcohol toxicity in pediatric patients Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. When prescribing BLINCYTO (with preservative) in pediatric patients consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative) (contains 7.4 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known, Refer to SMPC for full information. Due to the addition of bacteriostatic saline, 7-day bags of BLINCYTO solution for infusion contain benzyl alcohol and are not recommended for use in patients weighing less than 22 kg. Prepare BLINCYTO solution for infusion with preservative-free saline (24- or 48-hour bags) for use in patients weighing less than 22 kg,Geriatric use Of the total number of patients with ALL treated in clinical studies of BLINCYTO approximately 12% were 65 and over, while 2% were 75 and older. No overall differences in safety or effectiveness were observed between these patients and younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, elderly patients experienced a higher rate of serious infections and neurological toxicities, including cognitive disorder, encephalopathy, and confusion, see section. Method of administration: Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiation (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended. Premedicate with dexamethasone o For adult patients, premedicate with 20 mg dexamethasone 1 hour prior to the first dose of BLINCYTO of each cycle, prior to a step dose (such as Cycle 1 day 8), and when restarting an infusion after an interruption of 4 or more hours. o For pediatric patients, premedicate with 5 mg/m2 of dexamethasone, to a maximum dose of 20 mg prior to the first dose of BLINCYTO in the first cycle, prior to a step dose (such as Cycle 1 day 8), and when restarting an infusion after an interruption of 4 or more hours in the first cycle. 24-Hour or 48-Hour Infusion of BLINCYTO..  Administer BLINCYTO as a continuous intravenous infusion at a constant flow rate using an infusion pump. The pump should be programmable, lockable, non-elastomeric, and have an alarm.  Prepared BLINCYTO infusion bags, see section 6.6.1 should be infused over 24 hours or 48 hours. The starting volume (270 mL) is more than the volume administered to the patient (240 mL) to account for the priming of the IV tubing and to ensure that the patient will receive the full dose of BLINCYTO. Infuse BLINCYTO solution according to the instructions on the pharmacy label on the prepared bag at one of the following constant infusion rates:- Infusion rate of 10 mL/hour for a duration of 24 hours, OR - Infusion rate of 5 mL/hour for a duration of 48 hours. The BLINCYTO solution must be administered using IV tubing that contains a sterile, non-pyrogenic, low protein-binding, 0.2 micron in-line filter. Important Note: Do not flush the BLINCYTO infusion line or intravenous catheter, especially when changing infusion bags. Flushing when changing bags or at completion of infusion can result in excess dosage and complications thereof. When administering via a multi-lumen venous catheter, BLINCYTO should be infused through a dedicated lumen. At the end of the infusion, any unused BLINCYTO solution in the IV bag and IV tubing should be disposed of in accordance with local requirements. BLINCYTO Infusion Bag for 7 Day Infusion using Bacteriostatic Saline Administer BLINCYTO as a continuous intravenous infusion at a constant flow rate using an infusion pump. The pump should be programmable, lockable, non-elastomeric, and have an alarm. Prepared BLINCYTO infusion bags should be infused over 7 days, Refer to SMPC for full information.The final volume of infusion solution (110 mL) will be more than the volume administered to the patient (100 mL) to account for the priming of the IV tubing and to ensure that the patient will receive the full dose of BLINCYTO. Infuse BLINCYTO solution according to the instructions on the pharmacy label on the prepared bag at an infusion rate of 0.6 mL/hour for a duration of 7 days. Important Note: Do not flush the BLINCYTO infusion line or intravenous catheter, especially when changing infusion bags. Flushing when changing bags or at completion of infusion can result in excess dosage and complications thereof. When administering via a multi-lumen venous catheter, BLINCYTO should be infused through a dedicated lumen. At the end of the infusion, any unused BLINCYTO solution in the IV bag and IV tubing should be disposed of in accordance with local requirements. For instructions on the handling and preparation of the medicinal product before administration, Refer to SMPC for full information. Dose Adjustments If the interruption after an adverse event is no longer than 7 days, continue the same cycle to a total of 28 days of infusion inclusive of days before and after the interruption in that cycle. If an interruption due to an adverse event is longer than 7 days, start a new cycle. Contraindications BLINCYTO is contraindicated in patients with known hypersensitivity to blinatumomab or to any component of the product formulation. Special warnings and precautions for use 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. Manifestations of CRS include fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase, increased aspartate aminotransferase, 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 histiocytosis/macrophage activation syndrome (MAS). 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 and in 7% of patients with MRD-positive ALL. 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, Neurological Toxicities In patients with ALL receiving BLINCYTO in clinical studies, neurological toxicities have occurred

in approximately 65% of patients. Among patients that experienced a neurologic event, the median time to the first event was within the first 2 weeks of BLINCYTO treatment and the majority of events resolved. The most common (≥ 10%) manifestations of neurological toxicity were headache, and tremor; the neurological toxicity profile varied by age group, see section 4.2. Grade 3 or higher (severe, life-threatening, or fatal) 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 events resolved following interruption of BLINCYTO, but some resulted in treatment discontinuation. 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. Monitor patients receiving BLINCYTO for signs and symptoms of neurological toxicities. Advise outpatients on BLINCYTO to contact their healthcare professional if they develop signs or symptoms of neurological toxicities. Interrupt or discontinue BLINCYTO as recommended Refer to SMPC for full information.. 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. As appropriate, administer prophylactic antibiotics and employ surveillance testing during treatment withBLINCYTO. Monitor patients for signs and symptoms of infection and treat appropriately.Tumor Lysis Syndrome Tumor lysis syndrome (TLS), which may be life-threatening or fatal, has been observed in patients receiving BLINCYTO. Appropriate prophylactic measures, including pretreatment nontoxiccytoreduction 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, Refer to SMPC for full information. Neutropenia and Febrile Neutropenia Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in patients receiving BLINCYTO. 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. Elevated Liver Enzymes Treatment with BLINCYTO was associated with transient elevations in liver enzymes. 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. Pancreatitis Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical studies and the postmarketing setting. Evaluate patients who develop signs and symptoms of pancreatitis. Management of pancreatitis may require either temporary interruption or discontinuation of BLINCYTO and dexamethasone, Refer to SMPC for full information. 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. 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). 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. Risk of Serious Adverse Reactions in Pediatric Patients due to Benzyl Alcohol Preservative Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including BLINCYTO (with preservative). The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When prescribing BLINCYTO (with preservative) for pediatric patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative) (contains 7.4 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known. Due to the addition of bacteriostatic saline, 7-day bags of BLINCYTO solution for infusion with preservative contain benzyl alcohol and are not recommended for use in any patients weighing less than 22 kg, Refer to SMPC for full information. Interaction with other medicinal products and other forms of interaction: 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 sections 5.1 and 5.2. .Fertility, pregnancy and lactation: Pregnancy: Risk Based on its mechanism of action, BLINCYTO may cause fetal harm including B-cell lymphocytopenia when administered to a pregnant woman, see section 5.1. There are no data on the use of BLINCYTO in pregnant women. In animal reproduction studies, a murine surrogate molecule administered to pregnant mice crossed the placental barrier (see Data). Advise pregnant women of the potential risk to a fetus. Clinical Considerations: Fetal/Neonatal Adverse Reactions Due to the potential for B-cell lymphocytopenia in infants following exposure to BLINCYTO in-utero, the infant’s B lymphocytes should be monitored before the initiation of live virus vaccination. Data Animal Data Animal reproduction studies have not been conducted with blinatumomab. In embryo-fetal developmental toxicity studies, a murine surrogate molecule was administered intravenously to pregnant mice during the period of organogenesis. The surrogate molecule crossed the placental barrier and did not cause embryo-fetal toxicity or teratogenicity. The expected depletions of B and T cells were observed in the pregnant mice, but hematological effects were not assessed in fetuses.

Lactation. Risk Summary There is no information regarding the presence of blinatumomab in human milk, the effects on the breastfed infant, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from BLINCYTO, including B-cell lymphocytopenia, advise patients not to breastfeed during and for at least 48 hours after treatment with BLINCYTO.

Females and Males of Reproductive Potential Based on its mechanism of action, BLINCYTO may cause fetal harm when administered to a pregnant

woman. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating BLINCYTO treatment. Contraception Females Advise females of reproductive potential to use effective contraception during treatment and for at least 48 hours after the last dose of BLINCYTO. Fertility No studies have been conducted to evaluate the effects of blinatumomab on fertility. There were no effects on male or female mouse reproductive organs in 13-week toxicity studies with the murine surrogate molecule  Effects on ability to drive and use machines: Due to the potential for neurologic events, including seizures, patients receiving BLINCYTO are at risk for loss of consciousness.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. Undesirable effects: Refer to SMPC for full information . Cytokine Release Syndrome, Neurological Toxicities, Infections, Tumor Lysis Syndrome, Neutropenia and Febrile Neutropenia, Effects on Ability to Drive and Use Machines, Elevated Liver Enzymes, Pancreatitis, Leukoencephalopathy,  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 the rates observed in practice. MRD-positive B-cell Precursor ALL The safety of BLINCYTO in patients with MRD-positive B-cell precursor ALL was evaluated in two single-arm clinical studies in which 137 patients were treated with BLINCYTO. The median age of the study population was 45 years (range: 18 to 77 years). The most common adverse reactions (≥ 20%) were pyrexia, infusion-related reactions, headache, infections (pathogen unspecified), tremor, and chills. Serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥ 2%) included pyrexia, tremor, encephalopathy, aphasia, lymphopenia, neutropenia, overdose, device related infection, seizure, and staphylococcal infection. Adverse reactions of Grade 3 or higher were reported in 64% of patients. Discontinuation of therapy due to adverse reactions occurred in 17% of patients; neurologic events were the most frequently reported reasons for discontinuation. There were 2 fatal adverse events that occurred within 30 days of the end of BLINCYTO treatment (atypical pneumonia and subdural hemorrhage). Additional adverse reactions in patients with MRD-positive ALL that did not meet the threshold criteria for inclusion in Table 4 were: Blood and lymphatic system disorders: anemia General disorders and administration site conditions: edema peripheral, pain, and chest pain (includes chest pain and musculoskeletal chest pain) Hepatobiliary disorders: blood bilirubin increased Immune system disorders: hypersensitivity and cytokine release syndrome Infections and infestations: viral infectious disorders, bacterial infectious disorders, and fungal infectious disorders Injury, poisoning and procedural complications: medication error and overdose (includes overdose and accidental overdose) Investigations: blood alkaline phosphatase increased Musculoskeletal and connective tissue disorders: pain in extremity and bone pain Nervous system disorders: seizure (includes seizure and generalized tonic-clonic seizure), speech disorder, and hypoesthesia.

Psychiatric disorders: confusional state, disorientation, and depression. Respiratory, thoracic and mediastinal disorders: dyspnea and productive cough

Vascular disorders: hypertension (includes blood pressure increased and hypertension) flushing (includes flushing and hot flush), and capillary leak syndrome. Philadelphia Chromosome-negative Relapsed or Refractory B-cell Precursor ALL. The safety data described below reflect exposure to BLINCYTO in a randomized, open-label, activecontrolled clinical study (TOWER Study) in which 376 patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL were treated with BLINCYTO (n = 267) or standard of care (SOC) chemotherapy (n = 109). The median age of BLINCYTO-treated patients was 37 years (range: 18 to 80 years), 60% were male, 84% were White, 7% Asian, 2% were Black or African American, 2% were American Indian or Alaska Native, and 5% were Multiple/Other. The most common adverse reactions (≥ 20%) in the BLINCYTO arm were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia. Serious adverse reactions were reported in 62% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, sepsis, pneumonia, overdose, septic shock, CRS, bacterial sepsis, device related infection, and bacteremia. Adverse reactions of Grade 3 or higher were reported in 87% of patients. Discontinuation of therapy due to adverse reactions occurred in 12% of patients treated with BLINCYTO; neurologic events and infections were the most frequently reported reasons for discontinuation of treatment due to an adverse reaction. Fatal adverse events occurred in 16% of patients. The majority of the fatal events were infections. Relapsed or Refractory B-cell Precursor ALL Other important adverse reactions from pooled relapsed or refractory B-cell precursor ALL studies were: Blood and lymphatic system disorders: lymphadenopathy, hematophagic histiocytosis, and

leukocytosis (includes leukocytosis and white blood cell count increased) General disorders and administration site conditions: chills, chest pain (includes chest discomfort, chest pain, musculoskeletal chest pain, and non-cardiac chest pain), pain, body temperature increased, hyperthermia, and systemic inflammatory response syndrome Hepatobiliary disorders: hyperbilirubinemia (includes blood bilirubin increased and hyperbilirubinemia) Immune system disorders: hypersensitivity (includes hypersensitivity, anaphylactic reaction, angioedema, dermatitis allergic, drug eruption, drug hypersensitivity, erythema multiforme, and urticaria) Injury, poisoning and procedural complications: medication error and overdose (includes overdose, medication error, and accidental overdose) Investigations: weight increased, decreased immunoglobulins (includes immunoglobulins decreased, blood immunoglobulin A decreased, blood immunoglobulin G decreased, blood immunoglobulin M decreased, and hypogammaglobulinemia), blood alkaline phosphatase increased, and hypertransaminasemia Metabolism and nutrition disorders: tumor lysis syndrome Musculoskeletal and connective tissue disorders: back pain, bone pain, and pain in extremity Nervous system disorders: tremor (resting tremor, intention tremor, essential tremor, and tremor), altered state of consciousness (includes altered state of consciousness, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, stupor, and somnolence), dizziness, memory impairment, seizure (includes seizure, and atonic seizure), aphasia, cognitive disorder, speech disorder, paraesthesia, hypoesthesia, and encephalopathy and cranial nerve disorders (trigeminal neuralgia, trigeminal nerve disorder, sixth nerve paralysis, cranial nerve disorder, facial nerve disorder, and facial paresis). Psychiatric disorders: insomnia, disorientation, confusional state, and depression (includes depressed mood, depression, suicidal ideation, and completed suicide) Respiratory, thoracic and mediastinal disorders: dyspnea (includes acute respiratory failure, dyspnea, dyspnea exertional, respiratory failure, respiratory distress, bronchospasm, bronchial hyperreactivity, tachypnea, and wheezing), cough, and productive cough Vascular disorders: hypotension (includes blood pressure decreased, hypotension, hypovolemic shock, and circulatory collapse), hypertension (includes blood pressure increased, hypertension, and hypertensive crisis), flushing (includes flushing and hot flush), and capillary leak syndrome

Overdose: have been observed, including one adult patient who received 133-fold the recommended therapeutic dose of BLINCYTO delivered over a short duration. In the dose evaluation phase of the Phase 1/2 study in pediatric and adolescent patients with relapsed or refractory B-cell precursor ALL, one patient experienced a fatal cardiac failure event in the setting of life-threatening cytokine release syndrome (CRS) at a 30 mcg/m2/day (higher than the maximum tolerated/recommended) dose, Overdoses resulted in adverse reactions, which were consistent with the reactions observed at the recommended therapeutic dose and included fever, tremors, and headache. In the event of overdose, interrupt the infusion, monitor the patient for signs of toxicity, and provide supportive care, Consider re-initiation of BLINCYTO at the correct therapeutic dose when all toxicities have resolved and no earlier than 12 hours after interruption of the infusion, Refer to SMPC for full information .Special precautions for storage: Store BLINCYTO and IV Solution Stabilizer vials in the original package refrigerated at 2°C to 8°C and protect from light until time of use.  Do not freeze. Store and transport the prepared IV bag containing BLINCYTO solution for infusion at 2°C to 8°C conditions.  Ship in packaging that has been validated to maintain temperature of the contents at 2°C to 8°C.  Do not freeze. Nature and contents of container: Each BLINCYTO package contains:One BLINCYTO 35 mcg single dose vial containing a sterile, preservative-free, white to off-white lyophilized powder and One IV Solution Stabilizer 10 mL single dose glass vial containing a sterile, preservative-free, colorless to slightly yellow, clear solution.  Do not use the IV Solution Stabilizer to reconstitute BLINCYTO. Special precautions for disposal and other handling : Reconstitution and Preparation of Solution for Infusion: It is very important that the instructions for preparation (including admixing) and administration provided in this section are strictly followed to minimize medication errors (including underdose and overdose). Refer to SMPC for full information..Legal Category: POM. Administrative information: Date of PI: Mar 2018.  Marketing Authorisation Holder: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799. Registration number: Blincyto 35 MCG:  1-5058-17 . Local representative in Saudi Arabia:  Salehiya Trading Est. Address: P.O.Box 991, Riyadh 11421, Kingdom of Saudi Arabia. Tel: 00966 1 464 6955 Ext. 127.