Blinatumomab

Blinatumomab is a cancer medication that interferes with the growth and spread of cancer cells in the body.

Blinatumomab is used to treat a type of blood cancer called Philadelphia chromosome-negative B-precursor acute lymphoblastic leukemia (ALL). This medicine is given after other cancer treatments have been tried without success.

Blinatumomab was approved by the US Food and Drug Administration (FDA) on an "accelerated" basis. In clinical studies, blinatumomab produced complete remission in many people. However, further studies are needed to determine if this medicine can lengthen survival time.

Blinatumomab may also be used for purposes not listed in this medication guide.

Some side effects may occur during the injection. Tell your caregiver right away if you feel dizzy, nauseated, light-headed, chilled or feverish, or if you have a headache, skin rash, trouble breathing, or swelling in your face.

A serious side effect of blinatumomab is called cytokine release syndrome. Tell your caregivers right away if you have signs of this condition, which may include: high fever, nausea, sudden swelling or redness, or extreme tiredness.

Also tell your caregivers or seek emergency medical attention if you have slurred speech, confusion, loss of balance, or seizure (convulsions). These could be signs of life-threatening nerve problems.

You should not use blinatumomab if you are allergic to it.

To make sure blinatumomab is safe for you, tell your doctor if you have:

• a history of nerve problems (neurologic disorder), such as unexplained confusion, trouble speaking, or problems with balance;
• any type of infection; or
• if you have ever had a reaction while receiving a blinatumomab injection.

It is not known whether blinatumomab will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether blinatumomab passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

This medicine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Other drugs may interact with blinatumomab, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

>10%

Pyrexia (62%)

Other pathogen infections (44%)

Headache (36%)

Febrile neutropenia (25%)

Nausea (25%)

Peripheral edema (25%)

Hypokalemia (23%)

Rash (21%)

Tremor (20%)

Constipation (20%)

Diarrhea (20%)

Bacterial infections (19%)

Cough (19%)

Anemia (18%)

Fatigue (17%)

Neutropenia (16%)

Dyspnea (15%)

Abdominal pain (15%)

Chills (15%)

Fungal infections (15%)

Insomnia (15%)

Dizziness (14%)

Back pain (14%)

Vomiting (13%)

Viral infections (13%)

Pain in extremity (12%)

Hypomagnesemia (12%)

Increased ALT (12%)

Increased AST (11%)

Bone pain (11%)

Hyperglycemia (11%)

Increased weight (11%)

Thrombocytopenia (11%)

Chest pain (11%)

Cytokine release syndrome (11%)

Hypotension (11%)

1-10%

Arthralgias (10%)

Decreased appetite (10%)

Leukopenia (9%)

Pneumonia (9%)

Hypertension (8%)

Sepsis (7%)

Hypophosphatemia (6%)

Postmarketing Reports

Stomach pain

Pregnancy: Based on mechanism of action, therapy may cause fetal harm when administered to pregnant woman; verify pregnancy status of females of reproductive potential prior to initiating treatment

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

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

IV Preparation

Reconstituting vial

• Using a 5-mL syringe, reconstitute 1 vial using 3 mL of preservative-free sterile water for injection
• Do not reconstitute vial with IV solution stabilizer
• Direct sterile water for injection toward the side of the vial during reconstitution
• Gently swirl contents to avoid excess foaming
• Reconstituted solution should be clear to slightly opalescent; do not use if solution is cloudy or has precipitated
• Do not shake

IV admixture

• For 24 hr or 48 hr infusion (preservative free)
  • Specific admixing instructions are provided for each dose and infusion time
  • Aseptically add 270 mL of 0.9% NaCl to an empty bag; transfer 5.5 mL IV solution stabilizer to saline solution; see prescribing information for specific instructions for preparation
• For 7 day infusion (preservative containing)
  • Specific admixing instructions are provided for each dose and infusion time
  • Aseptically add 90 mL of bacteriostatic 0.9% NaCl to an empty bag; transfer 2.2 mL IV solution stabilizer to saline solution
  • Aseptically transfer reconstituted blinatumomab and 0.9% NaCl to diluted solution; final volume should be 110 mL; see prescribing information for specific instructions for preparation

IV Administration

Prime the IV line only with the prepared solution for infusion

Do not prime with 0.9% NaCl

Premedicate with dexamethasone 20 mg IV 1 hr prior to the first dose of each cycle, prior to a step dose (eg, Cycle 1 day 8), or when restarting an infusion after an interruption of ≥4 hr

Administer as a continuous IV infusion at a constant flow rate using an infusion pump; the pump should be programmable, lockable, non-elastomeric, and have an alarm

For 24 hr or 48 hr infusion

• Infusion bags should be infused over 24 hr or 48 hr (see preparation)
• Infuse the total 240 mL solution according to the instructions on the pharmacy label on the bag at one of the following constant infusion rates:
• -Infusion rate of 10 mL/hr for a duration of 24 hr, OR
• -Infusion rate of 5 mL/hr for a duration of 48 hr

For 7 day infusion

• Not recommended for patients weighing ≤22kg
• Infusion rate of 0.6 mL/hr for a duration of 7 days

All infusions must be administered using IV tubing that contains a sterile, nonpyrogenic, low protein-binding, 0.2 micron in-line filter

Infuse through a dedicated lumen

At the end of the infusion, any unused solution in the IV bag and IV lines should be disposed of in accordance with local requirements

Do NOT flush line

• Do not flush the infusion line, especially when changing infusion bags
• Flushing when changing bags or at completion of infusion can result in excess dosage

Storage

Protect from light

Unopened vial

• Store drug and IV solution stabilizer vials in the original package refrigerated at 2-8°C (36-46°F) and protect from light until time of use
• Do not freeze

Reconstituted vial

• Room temperature 23- 27°C (73-81°F): 4 hr
• Refrigerated 2-8°C (36-46°F): 24 hr

Prepared IV bag with stabilizer

• Room temperature 23- 27°C (73-81°F): 48 hr (includes infusion time)
• Refrigerated 2-8°C (36-46°F): 8 days

Blinatumomab is a prescription medicine used to treat a certain type of acute lymphoblastic leukemia (ALL). Acute lymphoblastic leukemia is a cancer of the blood in which a particular kind of white blood cell is growing out of control. 

Blinatumomab is a type of immunotherapy, a treatment that uses certain parts of a person’s immune system to destroy leukemia cells.

This medication comes in an injectable form to be given directly into the vein by continuous IV infusion for 4 weeks (28 days), followed by a 2 week break.

Common side effects include fever and headache. Do not drive, operate heavy machinery, or do other dangerous activities while you are receiving blinatumomab as it may cause dizziness, seizures, and confusion.

Blinatumomab is part of the drug class:

• Monoclonal antibodies

Before you receive blinatumomab, tell your healthcare provider about all of your medical conditions, including if you:

• are allergic to blinatumomab or to any of its ingredients
• have a history of neurological problems, such as seizures, confusion, trouble speaking or loss of balance.
• have an infection.
• have ever had an infusion reaction after receiving blinatumomab or other medications.
• are pregnant or plan to become pregnant. blinatumomab may harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with blinatumomab.
• are breastfeeding or plan to breastfeed. It is not known if blinatumomab passes into your breast milk. You and your healthcare provider should decide if you will take blinatumomab or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. 

Do not receive a "live" vaccine while using blinatumomab, or you could develop a serious infection. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine. Ask your doctor how soon it is safe for you to receive a vaccine after you stop using blinatumomab.

This medicine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Other drugs may interact with blinatumomab, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell your doctor about all your current medicines and any medicine you start or stop using.

No formal drug interaction studies to date.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Transient release of cytokines may result in suppression of CYP isoenzymes and potentially increase serum concentrations of drugs metabolized by CYP isoenzymes.1 8 Risk of drug interactions is highest during days 1–9 of cycle 1 and days 1–2 of cycle 2.1

Monitor for toxicity and/or changes in serum concentrations in patients receiving CYP substrates, particularly those with a low therapeutic index that require individualized dosing; adjust dosage of the CYP substrate as needed.1

Specific Drugs

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of high or low blood pressure like very bad headache or dizziness, passing out, change in eyesight.
• Signs or symptoms of depression, suicidal thoughts, emotional ups and downs, abnormal thinking, anxiety, or lack of interest in life.
• Chest pain or pressure.
• Shortness of breath.
• Swelling.
• Shakiness.
• Any unexplained bruising or bleeding.
• Feeling very tired or weak.
• Swollen gland.
• Memory problems or loss.
• Feeling confused.
• Feeling very sleepy.
• Flushing.
• Yellow skin or eyes.
• Patients with cancer who take this medicine may be at a greater risk of getting a bad health problem called tumor lysis syndrome (TLS). Sometimes, this has been deadly. Call your doctor right away if you have a fast heartbeat or a heartbeat that does not feel normal; any passing out; trouble passing urine; muscle weakness or cramps; upset stomach, throwing up, loose stools, or not able to eat; or feel sluggish.
• Very bad and sometimes deadly pancreas problems (pancreatitis) have happened with blinatumomab. Call your doctor right away if you have very bad stomach pain, very bad back pain, or very upset stomach or throwing up.

Blinatumomab is a bispecific T-cell engager (BiTE) which binds to CD19 expressed on B-cells and CD3 expressed on T-cells. It activates endogenous T cells by connecting CD3 in the T-cell receptor complex with CD19 on B-cells (malignant and benign), thus forming a cytolytic synapse between a cytotoxic T-cell and the cancer target B-cell (Topp 2014). Blinatumomab mediates the production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T cells, which result in lysis of CD19-positive cells.

Distribution

Pediatric patients 0 to 17 years: 3.14 ± 2.97 L/m2; Adults: 4.35 L

Excretion

Urine (negligible amounts)

Half-Life Elimination

Pediatric patients 0 to 17 years: 2.04 ± 1.35 hours; Adults: 2.1 hours

Concerns related to adverse effects:

• Bone marrow suppression: Neutropenia and neutropenic fever, including life-threatening episodes, have been reported. Monitor blood counts throughout therapy; may require therapy interruption if prolonged neutropenia occurs. Anemia and thrombocytopenia may also occur.

• Cytokine release syndrome: [US Boxed Warning]: Cytokine release syndrome (CRS), which may be life-threatening or fatal, has occurred. Interrupt or discontinue therapy as recommended. Infusion reactions have also occurred, and may be difficult to distinguish from CRS. CRS symptoms may include pyrexia, headache, nausea, weakness, hypotension, increased transaminases, and elevated total bilirubin. In some patients, disseminated intravascular coagulation (DIC), capillary leak syndrome (CLS), and hemophagocytic histiocytosis/macrophage activation syndrome (MAS) have been reported in the setting of CRS. Monitor closely for signs/symptoms of these conditions; may require therapy interruption or discontinuation. CRS which was life-threatening or fatal occurred rarely. The highest cytokine elevation was observed in the first 2 days following the start of infusion. In 1 study, patients with a high tumor burden (≥50% leukemic blasts or >15,000/mm3 peripheral blood leukemic blast counts), or elevated lactate dehydrogenase were pre-treated with dexamethasone (10 to 24 mg/m2/day for up to 5 days and concluding 3 days prior to initiating blinatumomab) to reduce the incidence of severe CRS (Topp 2015).

• Hepatotoxicity: Transient increases in liver enzymes (associated both with and without CRS) may occur during therapy. In patients with ALL, the median time to enzyme elevation was 3 to 19 days; grade 3 or higher elevations were observed in a small percentage of patients. Monitor ALT, AST, GGT, and total bilirubin at baseline and during treatment. Interrupt therapy if transaminases are >5 times ULN or if bilirubin is >3 times ULN.

• Infection: Serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-related infections have been reported in approximately one-fourth of patients with ALL in clinical trials (may be life-threatening or fatal). Consider prophylactic antibiotics if appropriate, and monitor closely for signs/symptoms of infection. Treat promptly if infection occurs.

• Leukoencephalopathy: Leukoencephalopathy (as seen on MRI) has been reported, particularly in those patients who received prior treatment with cranial irradiation and antileukemia chemotherapy (eg, high-dose methotrexate, intrathecal cytarabine).

• Neurotoxicity: [US Boxed Warning]: Neurological toxicities, which may be severe, life-threatening, or fatal, have occurred. Interrupt or discontinue therapy as recommended. Neurotoxicity has occurred in almost two-thirds of patients with ALL in clinical trials. The median time to onset was within the first 2 weeks of therapy. Common neurological symptoms include headache and tremor (symptoms may differ in children <2 years, and elderly patients have a higher incidence of neurotoxicity). Grade 3 or higher neurotoxicity (eg, encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders) has also been observed. Neurotoxicity may be managed with dexamethasone (Topp 2015). Patients are at risk for loss of consciousness due to neurologic events while taking blinatumomab; advise patients to avoid driving, participating in hazardous occupations, or operating heavy or dangerous machinery during treatment. Patients with a history of (or current) clinically relevant CNS pathology were excluded from clinical trials. Monitor patients for signs/symptoms of neurotoxicity; may require therapy interruption or discontinuation. The majority of symptoms resolved after interrupting therapy.

• Pancreatitis: Fatal cases of pancreatitis in patients receiving blinatumomab plus dexamethasone have been reported in the postmarketing setting. Monitor for signs/symptoms of pancreatitis; may require therapy interruption or discontinuation.

• Tumor lysis syndrome: Life-threatening or fatal tumor lysis syndrome (TLS) has been observed. Administer measures to prevent TLS (eg, pretreatment nontoxic cytoreduction and hydration during treatment). Monitor for signs/symptoms of TLS (eg, acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia); may require treatment interruption or discontinuation.

Concomitant drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Vaccines: Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to blinatumomab initiation, during treatment, and until immune system recovery following the last cycle of therapy.

Special populations:

• Elderly: Elderly patients experienced an increased rate of neurotoxicity (including cognitive disorder), encephalopathy, confusion, and serious infections as compared to patients <65 years.

• Pediatric: Pediatric patients experienced an increased rate of anemia, thrombocytopenia, vomiting, pyrexia, and hypertension as compared to adult patients. While the incidence of neurologic toxicities in patients <2 years of age did not differ from other age groups, the manifestations were different; reported toxicities were agitation, headache, insomnia, somnolence, and irritability.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Diluent may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling. Due to the addition of bacteriostatic saline, the 7-day infusion bags of blinatumomab contain benzyl alcohol and are not recommended for use in patients weighing <22 kg.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.

Other warnings/precautions:

• Safety issue: Preparation and administration errors have occurred. Do not flush infusion line, particularly when changing infusion bags or at completion of infusion; may result in overdose and complications. IV bag contains overfill and volume will be more than the volume administered to the patient to account for IV line priming and to ensure that the full dose is administered. Follow preparation and administration instructions carefully. Refer to manufacturer labeling for further information.

Animal reproductions studies have not been conducted. Based on the mechanism of action, blinatumomab may cause fetal harm when administered to a pregnant woman. Newborns exposed in utero may develop B-cell lymphocytopenia; monitor B-lymphocytes prior to administering live virus vaccines. Verify pregnancy status of women of reproductive potential prior to initiating treatment; effective contraception should be used during treatment and for at least 48 hours after the last dose.

US BOXED WARNINGS:
-CYTOKINE RELEASE SYNDROME (CRS): Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving this drug. Interrupt or discontinue therapy as recommended.
-NEUROLOGICAL TOXICITIES: Neurological toxicities, which may be severe and life-threatening, or fatal, have occurred in patients receiving this drug. Interrupt or discontinue therapy as recommended.

The safety and efficacy of this drug has not been established in patients less than 18 years of age.

Consult WARNINGS section for additional precautions.