Besponsa

BESPONSA is indicated for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

Dosage Forms And Strengths

For Injection: 0.9 mg as a white to off-white lyophilized powder in a single-dose vial for reconstitution and further dilution.

BESPONSA (inotuzumab ozogamicin) for Injection is supplied as a white to off-white lyophilized powder in a single-dose vial for reconstitution and further dilution. Each vial delivers 0.9 mg inotuzumab ozogamicin. Each carton (NDC 0008-0100-01) contains one single-dose vial.

Storage And Handling

Refrigerate (2-8°C; 36-46°F) BESPONSA vials and store in the original carton to protect from light. Do not freeze.

BESPONSA is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

REFERENCES

1. OSHA Hazardous Drugs. OSHA. [Accessed on 3 May 2017, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

Manufactured by: Pfizer, Wyeth Pharmaceuticals Inc, A Subsidiary Of Pfizer Inc, Philadelphia,PA 19101. Revised: Aug 2017

Inotuzumab ozogamicin has the following uses:

Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate (ADC) indicated for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).1

• If you have an allergy to Besponsa or any part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are taking any drugs that can cause a certain type of heartbeat that is not normal (prolonged QT interval). There are many drugs that can do this. Ask your doctor or pharmacist if you are not sure.
• If you are breast-feeding. Do not breast-feed while you take Besponsa or for 2 months after your last dose.

This is not a list of all drugs or health problems that interact with this medicine.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take Besponsa with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

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 bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• 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.
• Feeling very tired or weak.
• Dizziness or passing out.
• A type of abnormal heartbeat (prolonged QT interval) can happen with this medicine. Call your doctor right away if you have a fast heartbeat, a heartbeat that does not feel normal, or if you pass out.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take Besponsa or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to Besponsa. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate (ADC) consisting of 3 components: 1) the recombinant humanized immunoglobulin class G subtype 4 (IgG4) kappa antibody inotuzumab, specific for human CD22, 2) N-acetyl-gamma-calicheamicin that causes double-stranded DNA breaks, and 3) an acid-cleavable linker composed of the condensation product of 4-(4'-acetylphenoxy)-butanoic acid (AcBut) and 3-methyl-3-mercaptobutane hydrazide (known as dimethylhydrazide) that covalently attaches N-acetyl-gamma-calicheamicin to inotuzumab.

Inotuzumab ozogamicin has an approximate molecular weight of 160 kDa. The average number of calicheamicin derivative molecules conjugated to each inotuzumab molecule is approximately 6 with a distribution from 2–8. Inotuzumab ozogamicin is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the semisynthetic calicheamicin derivative is produced by microbial fermentation followed by synthetic modification.

Besponsa (inotuzumab ozogamicin) for Injection is supplied as a sterile, white to off-white, preservative-free, lyophilized powder for intravenous administration. Each single-dose vial delivers 0.9 mg inotuzumab ozogamicin. Inactive ingredients are polysorbate 80 (0.36 mg), sodium chloride (2.16 mg), sucrose (180 mg), and tromethamine (8.64 mg). After reconstitution with 4 mL of Sterile Water for Injection, USP, the final concentration is 0.25 mg/mL of inotuzumab ozogamicin with a deliverable volume of 3.6 mL (0.9 mg) and a pH of approximately 8.0.

Patients With Relapsed or Refractory ALL – INO-VATE ALL

The safety and efficacy of Besponsa were evaluated in INO-VATE ALL (NCT01564784) a randomized (1:1), open-label, international, multicenter study in patients with relapsed or refractory ALL. Patients were stratified at randomization based on duration of first remission (< 12 months or ≥ 12 months, salvage treatment (Salvage 1 or 2) and patient age at randomization (< 55 or ≥ 55 years). Eligible patients were ≥ 18 years of age with Philadelphia chromosome-negative or Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL. All patients were required to have ≥ 5% bone marrow blasts and to have received 1 or 2 previous induction chemotherapy regimens for ALL. Patients with Philadelphia chromosome-positive B-cell precursor ALL were required to have disease that failed treatment with at least 1 tyrosine kinase inhibitor and standard chemotherapy. Table 1 shows the dosing regimen used to treat patients.

Among all 326 patients who were randomized to receive Besponsa (N=164) or Investigator's choice of chemotherapy (N=162), 215 patients (66%) had received 1 prior treatment regimen for ALL and 108 patients (33%) had received 2 prior treatment regimens for ALL. The median age was 47 years (range: 18–79 years), 276 patients (85%) had Philadelphia chromosome-negative ALL, 206 patients (63%) had a duration of first remission < 12 months, and 55 patients (17%) had undergone a HSCT prior to receiving Besponsa or Investigator's choice of chemotherapy. The two treatment groups were generally balanced with respect to the baseline demographics and disease characteristics.

All evaluable patients had B-cell precursor ALL that expressed CD22, with ≥ 90% of evaluable patients exhibiting ≥ 70% leukemic blast CD22 positivity prior to treatment, as assessed by flow cytometry performed at a central laboratory.

The efficacy of Besponsa was established on the basis of CR, the duration of CR, and proportion of MRD-negative CR (< 1 × 10-4 of bone marrow nucleated cells by flow cytometry) in the first 218 patients randomized. CR, duration of remission (DoR), and MRD results in the initial 218 randomized patients were consistent with those seen in all 326 randomized patients.

Among the initial 218 randomized patients, 64/88 (73%) and 21/88 (24%) of responding patients per EAC achieved CR/CRi in Cycles 1 and 2, respectively, in the Besponsa arm, and 29/32 (91%) and 1/32 (3%) of responding patients per EAC achieved a CR/CRi in Cycles 1 and 2, respectively, in the Investigator's choice of chemotherapy arm.

Table 8 shows the efficacy results from this study.

Among the initial 218 patients, as per EAC assessment, 32/109 patients (29%) in the Besponsa arm achieved complete remission with partial hematologic recovery (CRh; defined as <5% blasts in the bone marrow, ANC > 0.5 × 109/L, and platelet counts > 50 × 109/L but not meeting full recovery of peripheral blood counts) versus 6/109 patients (6%) in the Investigator's choice of chemotherapy arm, and 71/109 patients (65%) in the Besponsa arm achieved CR/CRh versus 25/109 patients (23%) in the Investigator's choice of chemotherapy arm.

Overall, 79/164 patients (48%) in the Besponsa arm and 35/162 patients (22%) in the Investigator's choice of chemotherapy arm had a follow-up HSCT.

Figure 1 shows the analysis of overall survival (OS). The analysis of OS did not meet the pre-specified boundary for statistical significance.

Figure 1. Kaplan-Meier Curve for Overall Survival (Intent-to-Treat Population)

Pfizer

NDC 0008-0100-01

Besponsa™
(inotuzumab ozogamicin)
for Injection

0.9 mg/vial

For Intravenous Infusion Only

Reconstitution and dilution
required.

No Preservatives

One Single-Dose Vial.
Discard unused portion.

Rx only

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Feeling tired or weak.
• Headache.
• Upset stomach or throwing up.
• Belly pain.
• Not hungry.
• Loose stools (diarrhea).
• Hard stools (constipation).
• Mouth irritation or mouth sores.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Some side effects of Besponsa may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

>10%

Thrombocytopenia (51%)

Neutropenia (49%)

Infection (48%)

Neutropenia, grade 3 or higher (48%)

Thrombocytopenia, grade 3 or higher (42%)

Anemia (36%)

Leukopenia (35%)

Fatigue (35%)

Hemorrhage (33%)

Leukopenia, grade 3 or higher (33%)

Pyrexia (32%)

Nausea (31%)

Headache (28%)

Infection, grade 3 or higher (28%)

Febrile neutropenia (26%)

Transaminases increased (26%)

Anemia, grade 3 or higher (24%)

Abdominal pain (23%)

Hyperbilirubinemia (21%)

Gamma-glutamyltransferase increased (21%)

Lymphopenia (18%)

Diarrhea (17%)

Constipation (16%)

Lymphopenia, grade 3 or higher (16%)

Vomiting (15%)

Stomatitis (13%)

Alkaline phosphatase increased (13%)

Decreased appetite (12%)

Chills (11%)

1-10%

Grade 3 or higher

• Gamma-glutamyltransferase increased (10%)
• Transaminases increased (7%)
• Hemorrhage (5%)
• Fatigue (5%)
• Hyperbilirubinemia (5%)
• Pyrexia (3%)
• Abdominal pain (3%)
• Headache (2%)
• Alkaline phosphatase increased (2%)
• Stomatitis (2%)
• Nausea (2%)
• Decreased appetite (1%)
• Vomiting (1%)
• Diarrhea (1%)

Mechanism of Action

CD22-directed antibody-drug conjugate (ADC) recognizes human CD22; small molecule, N-acetyl-gamma-calicheamicin, is a cytotoxic agent that covalently attaches to antibody via a linker

Nonclinical data suggest anticancer activity of inotuzumab ozogamicin is due to binding of ADC to CD22-expressing tumor cells, followed by internalization of ADC-CD22 complex, and ultimately activating N-acetyl-gamma-calicheamicin 19 dimethylhydrazide, which induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death

Absorption

Peak plasma concentration: 308 ng/mL

AUC: 100,000 ng·h/mL

Steady-state drug concentration was achieved by cycle 4

Distribution

Protein bound: 97%

Vd: ~12 L

Metabolism

N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolized via nonenzymatic reduction

Elimination

Clearance, steady state: 0.0333 L/h

Half-life: 12.3 days