Blincyto

Blincyto

blinatumomab

Manufacturer:

Amgen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Blinatumomab.
Description
Each BLINCYTO package contains 1 vial BLINCYTO and 1 vial IV Solution Stabilizer.
BLINCYTO (blinatumomab) is a bispecific CD19-directed CD3 T-cell engager that binds to CD19 (expressed on cells of B-lineage origin) and CD3 (expressed on T cells). BLINCYTO is produced in Chinese hamster ovary cells. It consists of 504 amino acids and has a molecular weight of approximately 54 kilodaltons.
BLINCYTO is supplied in a single-dose vial as a sterile, preservative-free, white to off-white lyophilized powder for intravenous administration. Each single-dose vial of BLINCYTO contains 35 mcg blinatumomab, citric acid monohydrate (3.35 mg), lysine hydrochloride (23.23 mg), polysorbate 80 (0.64 mg), trehalose dihydrate (95.5 mg), and sodium hydroxide to adjust pH to 7.0. After reconstitution with 3 mL of preservative-free Sterile Water for Injection, USP, the resulting concentration is 12.5 mcg/mL blinatumomab.
IV Solution Stabilizer is supplied in a single-dose vial as a sterile, preservative-free, colorless to slightly yellow, clear solution. Each single-dose vial of IV Solution Stabilizer contains citric acid monohydrate (52.5 mg), lysine hydrochloride (2283.8 mg), polysorbate 80 (10 mg), sodium hydroxide to adjust pH to 7.0, and water for injection.
Action
Pharmacology: Mechanism of Action: Blinatumomab is a bispecific CD19-directed CD3 T-cell engager that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells. It activates endogenous T cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B cells. Blinatumomab mediates the formation of a synapse between the T-cell and the tumor cell, upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T cells, which result in redirected lysis of CD19+cells.
Pharmacodynamics: During the continuous intravenous infusion over 4 weeks, the pharmacodynamic response was characterized by T-cell activation and initial redistribution, reduction in peripheral B cells, and transient cytokine elevation.
Peripheral T-cell redistribution (i.e., T-cell adhesion to blood vessel endothelium and/or transmigration into tissue) occurred after start of BLINCYTO infusion or dose escalation. T-cell counts initially declined within 1 to 2 days and then returned to baseline levels within 7 to 14 days in the majority of patients. Increase of T-cell counts above baseline (T-cell expansion) was observed in few patients.
Peripheral B-cell counts decreased to less than or equal to 10 cells/microliter during the first treatment cycle at doses ≥ 5 mcg/m2/day or ≥ 9 mcg/day in the majority of patients. No recovery of peripheral B-cell counts was observed during the 2-week BLINCYTO-free period between treatment cycles.
Incomplete depletion of B cells occurred at doses of 0.5 mcg/m2/day and 1.5 mcg/m2/day and in a few patients at higher doses.
Cytokines including IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α, and IFN-γ were measured, and IL-6, IL-10, and IFN-γ were elevated. The highest elevation of cytokines was observed in the first 2 days following start of BLINCYTO infusion. The elevated cytokine levels returned to baseline within 24 to 48 hours during the infusion. In subsequent treatment cycles, cytokine elevation occurred in fewer patients with lesser intensity compared to the initial 48 hours of the first treatment cycle.
Clinical Studies: MRD-positive B-cell Precursor ALL: BLAST Study: The efficacy of BLINCYTO was evaluated in an open-label, multicenter, single-arm study (BLAST Study) that included patients who were ≥ 18 years of age, had received at least 3 chemotherapy blocks of standard ALL therapy, were in hematologic complete remission (defined as < 5% blasts in bone marrow, absolute neutrophil count > 1 Gi/L, platelets > 100 Gi/L) and had MRD at a level of ≥ 0.1% using an assay with a minimum sensitivity of 0.01%. BLINCYTO was administered at a constant dose of 15 mcg/m2/day (equivalent to the recommended dosage of 28 mcg/day) intravenously for all treatment cycles. Patients received up to 4 cycles of treatment. Dose adjustment was possible in case of adverse events.
The treated population included 86 patients in first or second hematologic complete remission (CR1 or CR2). The demographics and baseline characteristics are shown in Table 1. The median number of treatment cycles was 2 (range: 1 to 4). Following treatment with BLINCYTO, 45 out of 61 (73.8%) patients in CR1 and 14 out of 25 (56.0%) patients in CR2 underwent allogeneic hematopoietic stem cell transplantation in continuous hematologic complete remission. (See Table 1.)

Click on icon to see table/diagram/image

Efficacy was based on achievement of undetectable MRD within one cycle of BLINCYTO treatment and hematological relapse-free survival (RFS). The assay used to assess MRD response had a sensitivity of 0.01% for 6 patients and < 0.005% for 80 patients. Overall, undetectable MRD was achieved by 70 patients (81.4%: 95% CI: 71.6%, 89.0%). The median hematological RFS was 22.3 months. Table 2 shows the MRD response and hematological RFS by remission number. (See Table 2.)

Click on icon to see table/diagram/image

Undetectable MRD was achieved by 65 of 80 patients (81.3%: 95% CI: 71.0%, 89.1%) with an assay sensitivity of at least 0.005%. The estimated median hematological RFS among the 80 patients using the higher sensitivity assay was 24.2 months (95% CI: 17.9, NE).
Relapsed/Refractory B-cell Precursor ALL: TOWER Study: The efficacy of BLINCYTO was compared to standard of care (SOC) chemotherapy in a randomized, open-label, multicenter study (TOWER Study). Eligible patients were ≥ 18 years of age with relapsed or refractory B-cell precursor ALL [> 5% blasts in the bone marrow and refractory to primary induction therapy or refractory to last therapy, untreated first relapse with first remission duration < 12 months, untreated second or later relapse, or relapse at any time after allogeneic hematopoietic stem cell transplantation (alloHSCT)]. BLINCYTO was administered at 9 mcg/day on Days 1-7 and 28 mcg/day on Days 8-28 for Cycle 1, and 28 mcg/day on Days 1-28 for Cycles 2-5 in 42-day cycles and for Cycles 6-9 in 84-day cycles. Dose adjustment was possible in case of adverse events. SOC chemotherapy included fludarabine, cytarabine arabinoside, and granulocyte colony-stimulating factor (FLAG); high-dose cytarabine arabinoside (HiDAC); high-dose methotrexate- (HDMTX) based combination; or clofarabine/clofarabine-based regimens.
There were 405 patients randomized 2:1 to receive BLINCYTO or investigator-selected SOC chemotherapy. Randomization was stratified by age (< 35 years vs. ≥ 35 years of age), prior salvage therapy (yes vs. no), and prior alloHSCT (yes vs. no) as assessed at the time of consent. The demographics and baseline characteristics were well-balanced between the two arms (see Table 3).

Click on icon to see table/diagram/image

Of the 271 patients randomized to the BLINCYTO arm, 267 patients received BLINCYTO treatment. The median number of treatment cycles was two (range: 1 to 9 cycles); 267 (99%) received Cycles 1-2 (induction), 86 (32%) received Cycles 3-5 (consolidation), and 27 (10%) received Cycles 6-9 (continued therapy). Of the 134 patients on the SOC arm, 25 dropped out prior to start of study treatment, and 109 patients received a median of 1 treatment cycle (range: 1 to 4 cycles).
The determination of efficacy was based on overall survival (OS). The study demonstrated statistically significant improvement in OS for patients treated with BLINCYTO as compared to SOC chemotherapy. See figure and Table 4 as follows for efficacy results from the TOWER Study. (See figure and Table 4.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Study MT103-211: Study MT103-211 was an open-label, multicenter, single-arm study. Eligible patients were ≥ 18 years of age with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL (relapsed with first remission duration of ≤12 months in first salvage or relapsed or refractory after first salvage therapy or relapsed within 12 months of alloHSCT, and had ≥10% blasts in bone marrow).
BLINCYTO was administered as a continuous intravenous infusion. The recommended dose for this study was determined to be 9 mcg/day on Days 1-7 and 28 mcg/day on Days 8-28 for Cycle 1, and 28 mcg/day on Days 1-28 for subsequent cycles. Dose adjustment was possible in case of adverse events. The treated population included 185 patients who received at least 1 infusion of BLINCYTO; the median number of treatment cycles was 2 (range: 1 to 5). Patients who responded to BLINCYTO but later relapsed had the option to be retreated with BLINCYTO. Among treated patients, the median age was 39 years (range: 18 to 79 years), 63 out of 185 (34.1%) had undergone HSCT prior to receiving BLINCYTO, and 32 out of 185 (17.3%) had received more than 2 prior salvage therapies.
Efficacy was based on the complete remission (CR) rate, duration of CR, and proportion of patients with an MRD-negative CR/CR with partial hematological recovery (CR/CRh*) within 2 cycles of treatment with BLINCYTO. Table 5 shows the efficacy results from this study. The HSCT rate among those who achieved CR/CRh* was 39% (30 out of 77). (See Table 5.)

Click on icon to see table/diagram/image

ALCANTARA Study: The efficacy of BLINCYTO for treatment of Philadelphia chromosome-positive B-cell precursor ALL was evaluated in an open-label, multicenter, single-arm study (ALCANTARA Study). Eligible patients were ≥ 18 years of age with Philadelphia chromosome-positive B-cell precursor ALL, relapsed or refractory to at least 1 second generation or later tyrosine kinase inhibitor (TKI), or intolerant to second generation TKI, and intolerant or refractory to imatinib mesylate.
BLINCYTO was administered at 9 mcg/day on Days 1-7 and 28 mcg/day on Days 8-28 for Cycle 1, and 28 mcg/day on Days 1-28 for subsequent cycles. Dose adjustment was possible in case of adverse events.
The treated population included 45 patients who received at least one infusion of BLINCYTO; the median number of treatment cycles was 2 (range: 1 to 5). The demographics and baseline characteristics are shown in Table 6. (See Table 6.)

Click on icon to see table/diagram/image

Efficacy was based on the complete remission (CR) rate, duration of CR, and proportion of patients with an MRD-negative CR/CR with partial hematological recovery (CR/CRh*) within 2 cycles of treatment with BLINCYTO. Table 7 shows the efficacy results from ALCANTARA Study. Five of the 16 responding (31%) patients underwent allogeneic HSCT in CR/CRh* induced with BLINCYTO. There were 10 patients with documented T315I mutation; four achieved CR within 2 cycles of treatment with BLINCYTO. (See Table 7.)

Click on icon to see table/diagram/image

Study MT103-205: Study MT103-205 was an open-label, multicenter, single-arm study in pediatric patients with relapsed or refractory B-cell precursor ALL (second or later bone marrow relapse, any marrow relapse after allogeneic HSCT, or refractory to other treatments, and had > 25% blasts in bone marrow). BLINCYTO was administered at 5 mcg/m2/day on Days 1-7 and 15 mcg/m2/day on Days 8-28 for Cycle 1, and 15 mcg/m2/day on Days 1-28 for subsequent cycles. Dose adjustment was possible in case of adverse events. Patients who responded to BLINCYTO but later relapsed had the option to be retreated with BLINCYTO.
Among the 70 treated patients, the median age was 8 years (range: 7 months to 17 years), 40 out of 70 (57.1%) had undergone allogeneic HSCT prior to receiving BLINCYTO, and 39 out of 70 (55.7%) had refractory disease. The median number of treatment cycles was 1 (range: 1 to 5).
Twenty-three out of 70 (32.9%) patients achieved CR/CRh* within the first 2 treatment cycles with 17 out of 23 (73.9%) occurring within Cycle 1 of treatment. See Table 8 for the efficacy results from the study. The HSCT rate among those who achieved CR/CRh* was 48% (11 out of 23). (See Table 8.)

Click on icon to see table/diagram/image

Pharmacokinetics: The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 90 mcg/m2/day (approximately equivalent to 9 to 162 mcg/day) in adult patients. Following continuous intravenous infusion, the steady-state serum concentration (Css) was achieved within a day and remained stable over time. The increase in mean Css values was approximately proportional to the dose in the range tested. At the clinical doses of 9 mcg/day and 28 mcg/day for the treatment of relapsed or refractory ALL, the mean (SD) Css was 228 (356) pg/mL and 616 (537) pg/mL, respectively.
Distribution: The estimated mean (SD) volume of distribution based on terminal phase (Vz) was 4.35 (2.45) L with continuous intravenous infusion of blinatumomab.
Metabolism: The metabolic pathway of blinatumomab has not been characterized. Like other protein therapeutics, BLINCYTO is expected to be degraded into small peptides and amino acids via catabolic pathways.
Elimination: The estimated mean (SD) systemic clearance with continuous intravenous infusion in patients receiving blinatumomab in clinical studies was 3.11 (2.98) L/hour. The mean (SD) half-life was 2.10 (1.41) hours. Negligible amounts of blinatumomab were excreted in the urine at the tested clinical doses.
Gender, Age, and Body Surface Area: Results of population pharmacokinetic analyses indicate that age (0.62 to 80 years of age) and gender do not influence the pharmacokinetics of blinatumomab. Body surface area (0.4 to 2.70 m2) influences the pharmacokinetics of blinatumomab, however the clinical relevance of this effect is unknown.
Hepatic Impairment: No formal pharmacokinetic studies using BLINCYTO have been conducted in patients with hepatic impairment.
Renal Impairment: No formal pharmacokinetic studies of blinatumomab have been conducted in patients with renal impairment.
Pharmacokinetic analyses showed an approximately 2-fold difference in mean blinatumomab clearance values between patients with moderate renal impairment (CrCL ranging from 30 to 59 mL/min, N = 21) and normal renal function (CrCL more than 90 mL/min, N = 215). However, high interpatient variability was discerned (CV% up to 96.8%), and clearance values in renal impaired patients were essentially within the range observed in patients with normal renal function. There is no information available in patients with severe renal impairment (CrCL less than 30 mL/min) or patients on hemodialysis.
Drug Interactions: Transient elevation of cytokines may suppress CYP450 enzyme activities [see Interactions and Pharmacodynamics as previously mentioned].
Specific Populations: Pediatrics: The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 30 mcg/m2/day in pediatric patients. At the recommended doses, the mean (SD) steady-state concentration (Css) values were 162 (179) and 533 (392) pg/mL at 5 and 15 mcg/m2/day doses, respectively. The estimated mean (SD) volume of distribution (Vz), clearance (CL) and terminal half-life (t1/2,z) were 3.14 (2.97) L/m2, 1.88 (1.90) L/hour/m2 and 2.04 (1.35) hours, respectively.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: No carcinogenicity or genotoxicity studies have been conducted with blinatumomab.
No studies have been conducted to evaluate the effects of blinatumomab on fertility. A murine surrogate molecule had no adverse effects on male and female reproductive organs in a 13-week repeat-dose toxicity study in mice.
Indications/Uses
MRD-positive B-cell Precursor ALL: BLINCYTO is indicated for the treatment of B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% in adults.
This indication is approved based on MRD response rate and hematological relapse-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
Relapsed or Refractory B-cell Precursor ALL: BLINCYTO is indicated for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
Dosage/Direction for Use
Treatment of MRD-positive B-cell Precursor ALL: A treatment course consist 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).
See Table 9 for the recommended dose by patient weight and schedule. Patients greater than or equal to 45 kg receive a fixed-dose. (See Table 9.)

Click on icon to see table/diagram/image

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.
Intrathecal chemotherapy prophylaxis is recommended before and during Blincyto therapy to prevent central nervous system ALL relapse.
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: See 24-Hour or 48-Hour Infusion of BLINCYTO as follows for infusion over 24 hours or 48 hours.
Treatment of Relapsed or Refractory B-cell Precursor ALL: A 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).
See Table 10 for the recommended dose by patient weight and schedule. Patients greater than or equal to 45 kg receive a fixed-dose and for patients less than 45 kg, the dose is calculated using the patient’s body surface area (BSA). (See Table 10.)

Click on icon to see table/diagram/image

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.
Intrathecal chemotherapy prophylaxis is recommended before and during Blincyto therapy to prevent central nervous system ALL relapse.
Premedicate with dexamethasone: 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.
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.
For administration of BLINCYTO: See 24-Hour or 48-Hour Infusion of BLINCYTO as follows for infusion over 24 hours or 48 hours.
Dosage 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. (See Table 11.)

Click on icon to see table/diagram/image

Preparation: 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) [see Preparation and Administration Errors under Precautions].
BLINCYTO can be infused over 24 hours (preservative-free) or 48 hours (preservative-free). The choice between these options for the infusion duration should be made by the treating physician considering the frequency of the infusion bag changes and the weight of the patient.
For preparation, reconstitution, and administration of BLINCYTO: See 24-Hour or 48-Hour Infusion of BLINCYTO as follows for infusion over 24 hours or 48 hours.
Aseptic Preparation: Strictly observe aseptic technique when preparing the solution for infusion since BLINCYTO vials do not contain antimicrobial preservatives. To prevent accidental contamination, prepare BLINCYTO according to aseptic standards, including but not limited to: Prepare BLINCYTO in a USP <797> compliant facility.
Prepare BLINCYTO in an ISO Class 5 laminar flow hood or better.
Ensure that the admixing area has appropriate environmental specifications, confirmed by periodic monitoring.
Ensure that personnel are appropriately trained in aseptic manipulations and admixing of oncology drugs.
Ensure that personnel wear appropriate protective clothing and gloves.
Ensure that gloves and surfaces are disinfected.
Package Content: 1 package BLINCYTO includes 1 vial of BLINCYTO and 1 vial of IV Solution Stabilizer.
Do not use IV Solution Stabilizer for reconstitution of BLINCYTO. IV Solution Stabilizer is provided with the BLINCYTO package and is used to coat the IV bag prior to addition of reconstituted BLINCYTO to prevent adhesion of BLINCYTO to IV bags and IV tubing.
More than 1 package of BLINCYTO may be needed to prepare some of the prescribed doses.
Incompatibility Information: BLINCYTO is incompatible with di-ethylhexylphthalate (DEHP) due to the possibility of particle formation, leading to a cloudy solution.
Use polyolefin, PVC DEHP-free, or ethyl vinyl acetate (EVA) infusion bags/pump cassettes.
Use polyolefin, PVC DEHP-free, or EVA IV tubing sets.
24-Hour or 48-Hour Infusion of BLINCYTO: Preparation of BLINCYTO Infusion Bag for 24- or 48-Hour Infusion: Verify the prescribed dose and infusion duration for each BLINCYTO infusion bag. To minimize errors, use the specific volumes described in Tables 12 to 14 to prepare the BLINCYTO infusion bag.
Table 12 for patients weighing greater than or equal to 45 kg.
Tables 13 and 14 for patients weighing less than 45 kg.
Aseptically add 270 mL 0.9% Sodium Chloride Injection, USP to the IV bag.
Aseptically transfer 5.5 mL IV Solution Stabilizer to the IV bag containing 0.9% Sodium Chloride Injection, USP. Gently mix the contents of the bag to avoid foaming. Discard the vial containing the unused IV Solution Stabilizer.
Aseptically transfer reconstituted BLINCYTO [see Reconstitution of BLINCYTO as follows] into the IV bag containing 0.9% Sodium Chloride Injection, USP and IV Solution Stabilizer. Gently mix the contents of the bag to avoid foaming.
Refer to Tables 12 to 14 for the specific volume of reconstituted BLINCYTO.
Under aseptic conditions, attach the IV tubing to the IV bag with the sterile 0.2 micron in-line filter.
Ensure that the IV tubing is compatible with the infusion pump.
Remove air from the IV bag. This is particularly important for use with an ambulatory infusion pump. Prime the IV tubing only with the prepared solution for infusion. Do not prime with 0.9% Sodium Chloride Injection, USP.
Store at 2°C to 8°C if not used immediately [see Storage Requirements under Storage]. (See Tables 12, 13 and 14.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Reconstitution of BLINCYTO: Add 3 mL of preservative-free Sterile Water for Injection, USP by directing the water along the walls of the BLINCYTO vial and not directly on the lyophilized powder (resulting in a final BLINCYTO concentration of 12.5 mcg/mL).
Do not reconstitute BLINCYTO with IV Solution Stabilizer.
Gently swirl contents to avoid excess foaming. Do not shake.
Visually inspect the reconstituted solution for particulate matter and discoloration during reconstitution and prior to infusion. The resulting solution should be clear to slightly opalescent, colorless to slightly yellow. Do not use if solution is cloudy or has precipitated.
Administration: 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 Preparation of BLINCYTO Infusion Bag for 24- or 48-Hour Infusion as previously mentioned] 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, nonpyrogenic, 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.
Overdosage
Overdoses 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 [see Cytokine Release Syndrome under Precautions and Adverse Reactions].
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 [see Preparation and Administration Errors under Precautions]. 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 [see Treatment of MRD-positive B-cell Precursor ALL under Dosage & Administration].
Contraindications
BLINCYTO is contraindicated in patients with known hypersensitivity to blinatumomab or to any component of the product formulation.
Warnings
CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES.
Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO and treat with corticosteroids as recommended [see Dosage Adjustments under Dosage & Administration, Cytokine Release Syndrome under Precautions].
Neurological toxicities, which may be severe, life-threatening, or fatal, occurred in patients receiving BLINCYTO. Interrupt or discontinue BLINCYTO as recommended [see Dosage Adjustments under Dosage & Administration, Neurological Toxicities under Precautions].
Special Precautions
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 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. Administer corticosteroids for severe or life-threatening CRS [see Dosage Adjustments under Dosage & Administration].
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 Use in Children and Use in Elderly as follows]. 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 [see Dosage Adjustments under Dosage & Administration].
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 with BLINCYTO. 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 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 [see Dosage Adjustments under Dosage & Administration].
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 [see Postmarketing Experience under Adverse Reactions].
Evaluate patients who develop signs and symptoms of pancreatitis. Management of pancreatitis may require either temporary interruption or discontinuation of BLINCYTO and dexamethasone [see Dosage Adjustments under Dosage & Administration].
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) [see Preparation under Dosage & Administration].
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.
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 [see Neurological Toxicities as previously mentioned]. 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.
Use in Children: 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. The efficacy has also been established based on extrapolation from adequate and well-controlled studies in adults with MRD-positive B-cell precursor ALL.
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 Clinical Trials Experience under Adverse Reactions]. 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.
Use in Elderly: 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 Neurological Toxicities and Infections as previously mentioned].
Use In Pregnancy & Lactation
Pregnancy: Risk Summary: Based on its mechanism of action, BLINCYTO may cause fetal harm including B-cell lymphocytopenia when administered to a pregnant woman [see Pharmacology: Mechanism of Action under Actions]. 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 as follows). Advise pregnant women of the potential risk to a fetus.
The background rate of major birth defects and miscarriage is unknown for the indicated population. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
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 [see Immunization under Precautions].
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 [see Pregnancy as previously mentioned].
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.
Adverse Reactions
The following clinically significant adverse reactions are discussed in greater detail in other sections of the label: Cytokine Release Syndrome [see Cytokine Release Syndrome under Precautions].
Neurological Toxicities [see Neurological Toxicities under Precautions].
Infections [see Infections under Precautions].
Tumor Lysis Syndrome [see Tumor Lysis Syndrome under Precautions].
Neutropenia and Febrile Neutropenia [see Neutropenia and Febrile Neutropenia under Precautions].
Effects on Ability to Drive and Use Machines [see Effects on Ability to Drive and Use Machines under Precautions].
Elevated Liver Enzymes [see Elevated Liver Enzymes under Precautions].
Pancreatitis [see Pancreatitis under Precautions].
Leukoencephalopathy [see Leukoencephalopathy under Precautions].
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).
Table 15 summarizes the adverse reactions occuring at a ≥10% incidence for any grade or ≥5% incidence for Grade 3 or higher. (See Table 15.)

Click on icon to see table/diagram/image

Additional adverse reactions in patients with MRD-positive ALL that did not meet the threshold criteria for inclusion in Table 15 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 as follows reflect exposure to BLINCYTO in a randomized, open-label, active-controlled 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.
The adverse reactions occurring at a ≥ 10% incidence for any grade or ≥ 5% incidence for Grade 3 or higher in the BLINCYTO-treated patients in first cycle of therapy are summarized in Table 16. (See Table 16.)

Click on icon to see table/diagram/image

Selected laboratory abnormalities worsening from baseline Grade 0-2 to treatment-related maximal Grade 3-4 in first cycle of therapy are shown in Table 17. (See Table 17.)

Click on icon to see table/diagram/image

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, hypoesthesia, 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.
Postmarketing Experience: The following adverse reactions have been identified during post approval use of BLINCYTO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone [see Pancreatitis under Precautions].
Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of BLINCYTO has been evaluated using either an electrochemiluminescence detection technology (ECL) or an enzyme-linked immunosorbent assay (ELISA) screening immunoassay for the detection of binding anti-blinatumomab antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.
In clinical studies, less than 2% of patients treated with BLINCYTO tested positive for binding anti-blinatumomab antibodies. Of patients who developed anti-blinatumomab antibodies, 7 out of 9 (78%) had in vitro neutralizing activity. Anti-blinatumomab antibody formation may affect pharmacokinetics of BLINCYTO.
The detection of anti-blinatumomab 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 the incidence of antibodies to blinatumomab with the incidence of antibodies to other products may be misleading.
Drug 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 Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions].
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.
Storage Requirements: The information in Table 18 indicates the storage time for the reconstituted BLINCYTO vial and prepared infusion bag.
Store lyophilized BLINCYTO and IV Solution Stabilizer vials for a maximum of 8 hours at room temperature in the original carton to protect from light [see previously mentioned]. (See Table 18.)

Click on icon to see table/diagram/image
Patient Counseling Information
Cytokine Release Syndrome (CRS): Advise patients of the risk of CRS and infusion reactions, and to contact their healthcare professional for signs and symptoms associated with CRS or infusion reactions (pyrexia, fatigue, nausea, vomiting, chills, hypotension, rash, and wheezing) [see Cytokine Release Syndrome under Precautions and Clinical Trials Experience under Adverse Reactions].
Neurological Toxicities: Advise patients of the risk of neurological toxicities, and to contact their healthcare professional for signs and symptoms associated with this event (convulsions, speech disorders, and confusion) [see Neurological Toxicities under Precautions and Clinical Trials Experience under Adverse Reactions].
Infections: Advise patients of the risk of infections, and to contact their healthcare professional for signs or symptoms of infection [see Infections under Precautions and Clinical Trials Experience under Adverse Reactions].
Inform patients of the importance of keeping the skin clean around the intravenous catheter to reduce the risk of infection.
Pancreatitis: Advise patients of the risk of pancreatitis and to contact their healthcare provider for signs or symptoms of pancreatitis which include severe and persistent stomach pain, with or without nausea and vomiting [see Pancreatitis under Precautions and Postmarketing Experience under Adverse Reactions].
Driving and Engaging in Hazardous Occupations: 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. Patients should be advised that they may experience neurological events [see Effects on Ability to Drive and Use Machines under Precautions].
Infusion Pump Errors: Inform patients they should not adjust the setting on the infusion pump. Any changes to pump function may result in dosing errors. If there is a problem with the infusion pump or the pump alarms, patients should contact their doctor or nurse immediately.
ATC Classification
L01XC19 - blinatumomab ; Belongs to the class of monoclonal antibodies, other antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
Powd for infusion 35 mcg (sterile, preservative-free, white to off-white lyophilized powder in single-dose vial) x 1's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in