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 (eg, warfarin) or drug concentrations (eg, cyclosporine).

Adjust the dose of the concomitant drug as needed 

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide). 

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)   .

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).

Infections

Advise patients of the risk of infections, and to contact their healthcare professional for signs or symptoms of infection 

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 .

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  

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.

BLINCYTO® (blinatumomab) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799

 CLINICAL PHARMACOLOGY

1. 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.

.2. 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 (ie, 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.

3.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/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.

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.

 USE IN SPECIFIC POPULATIONS

1.Pregnancy Risk Summary

Based on its mechanism of action, BLINCYTO may cause fetal harm including B-cell lymphocytopenia when administered to a pregnant woman .

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.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.

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 .

2.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

3.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.

4.Pediatric Use                                                                                                              The safety and efficacy of BLINCYTO have been established in pediatric patients.

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 ALLReactions.

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.

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  

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 .

5.Geriatric Use                                                                                                                 Of the total number of patients with relapsed or refractory ALL in clinical studies of BLINCYTO, treated at the recommended dose and schedule, approximately 12% were 65 and over, while 3% 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 neurological toxicities, including cognitive disorder, encephalopathy, confusion, and serious infections [see Warnings and Precautions 

 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 ].

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 Administration (2.1)]