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inotuzumab ozogamicin
Inotuzumab ozogamicin is an antibody-drug conjugate, consisting of inotuzumab, an anti-CD22 IgG4 antibody linked to a cytotoxic component (N-acetyl-gamma-calicheamicin).
Steady state concentration was achieved by cycle 4.
| PPB | 97% |
The cytotoxic component is primarily metabolized through non-enzymatic reduction.
| Half-life | 12.3 days |
Monotherapy for the treatment of adults with relapsed or refractory CD22-positive* B-cell precursor acute lymphoblastic leukemia (ALL)
(*determined by a validated assay)
Emetogenic Potential:
The following adverse effects were from the phase III relapsed or refractory ALL trial and occurred in ≥ 1% of patients who received inotuzumab ozogamicin.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | QT interval prolonged (6%) (also PR prolongation) | E D | |||
| Gastrointestinal | Abdominal pain (23%) | E | |||
| Anorexia (12%) | E | ||||
| Constipation (16%) | E | ||||
| Diarrhea (17%) | E | ||||
| Mucositis (13%) | E | ||||
| Nausea, vomiting (31%) (2% severe) | I | ||||
| General | Fatigue (35%) | E | |||
| Fever, chills (32%) (3% severe) | I | ||||
| Hematological | Myelosuppression ± infection, bleeding (51%) (48% severe) | E | |||
| Hepatobiliary | ↑ Amylase / lipase (9%) (4% severe) | E | |||
| ↑ LFTs (26%) (severe 10%) | E | ||||
| Veno-occlusive disease (VOD; 3-23%) or Sinusoidal Obstruction Syndrome (SOS) | E D | ||||
| Hypersensitivity | Infusion related reaction (2%) (Grade 1-2) | I | |||
| Immune | Antibody response (3%) | E D | |||
| Metabolic / Endocrine | Tumor lysis syndrome (2%) | E | |||
| Nervous System | Headache (28%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.
** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)
The most common side effects for inotuzumab ozogamicin include myelosuppression ± infection, bleeding, ↑ LFTs, fatigue, ↑ amylase / lipase, fever/chills, nausea/vomiting, headache, abdominal pain and constipation.
Infusion-reaction reactions were ≤ grade 2 in severity. They generally occurred in cycle 1 shortly after the end of inotuzumab ozogamicin infusion.
Patients at risk of tumour lysis syndrome (TLS) should have appropriate prophylaxis and be monitored closely.
Inotuzumab ozogamicin is associated with QT and PR prolongation. Risk factors include: female gender, age ≥ 65 years, baseline QT/QTc prolongation, congenital long QT syndromes, family history of sudden cardiac death at < 50 years of age, cardiac disease, history of arrhythmias, electrolyte disturbances, acute neurologic events, autonomic neuropathy, or diabetes.
Bacterial, viral and fungal infections were reported, and may be severe.
Hepatotoxicity, including severe and fatal hepatic Veno-occlusive disease (VOD)/ Sinusoidal obstruction syndrome (SOS) were observed. VOD/SOS has occurred up to 56 days after the last dose, while time from hematopoietic stem cell transplant (HSCT) to VOD/SOS onset was 15 days (range: 3-57 days). Risk is increased with:
- prior VOD/SOS or have serious ongoing hepatic disease
- prior HSCT
- subsequent HSCT (especially conditioning with 2 alkylating agents and last total bilirubin level ≥ ULN before follow-up HSCT)
- Increased age, history of liver disease and/or hepatitis before treatment, later salvage lines and a greater number of treatment cycles
Higher post-HSCT non-relapse mortality rate was observed in the inotuzumab arm (39% vs 23%), but more inotuzumab patients received HSCT (48% vs 22%). The most common causes of post-HSCT non-relapse mortality were VOD/SOS and infections.
Anti-inotuzumab ozogamicin antibodies were observed, but were not neutralizing and did not affect drug clearance after treatment. The impact of these antibodies on efficacy and safety are unknown.
Refer to protocol by which patient is being treated.
Hypokalemia, hypomagnesemia and hypocalcemia should be corrected before inotuzumab ozogamicin administration.
Patients at risk for tumour lysis syndrome should receive adequate hydration, prophylaxis and be monitored closely.
For patients with circulating lymphoblasts, cytoreduction is recommended prior to the first dose (to a peripheral blast count ≤ 10,000/mm3) with a combination of hydroxyurea, steroids and/or vincristine.
Consider prophylactic anti-infectives.
Pre-medications (prophylaxis for infusion reaction):
- Corticosteroid, antipyretic, and antihistamine are recommended prior to each dose.
Cycle 1 (q21 or 28 days†):
| Day 1 | Day 8* | Day 15* | |
| Dose for all patients (mg/m2 IV) | 0.8 | 0.5 | 0.5 |
† Cycle length may be extended up to 28 days for patients who achieve CR (complete remission) or CRi (complete remission with incomplete hematologic recovery), and/or to allow for recovery from toxicity.
* +/- 2 days (maintain at least 6 days between doses)
Subsequent cycles (q28 days):
For patients who achieved CR** or CRi^:
| inotuzumab ozogamicin dose (mg/m2 IV) | ||
| Day 1 | Day 8* | Day 15* |
| 0.5 | 0.5 | 0.5 |
For patients who did not achieve CR** or CRi^:
| inotuzumab ozogamicin dose (mg/m2 IV) | ||
| Day 1 | Day 8* | Day 15* |
| 0.8 | 0.5 | 0.5 |
* +/- 2 days (maintain at least 6 days between doses)
** CR defined as < 5% blasts in bone marrow and absence of peripheral blood leukemic blasts, platelets ≥ 100 and ANC ≥ 1, and resolution of any extramedullary disease
^ CRi defined as < 5% blasts in bone marrow and absence of peripheral blood leukemic blasts, platelets < 100 and ANC < 1, and resolution of any extramedullary disease
Two cycles of treatment in total are recommended. Consider a total of 3 cycles for patients who do not achieve a CR or CRi and MRD negativity after 2 cycles.
For patients with CR or CRi and MRD negativity who are not proceeding with HSCT, may give up to 6 cycles.
Discontinue treatment if CR or CRi is not achieved within 3 cycles.
Hematologic toxicities:
Doses within a treatment cycle (e.g. days 8 and/or 15) do not need to be held due to neutropenia or thrombocytopenia.
| If prior to inotuzumab ozogamicin treatment: | Blood counts during cycle | Action (for next cycle) |
| ANC ≥ 1 x 109/L | ANC decreases | Hold next cycle until ANC ≥ 1 x 109/L |
| Platelets ≥ 50 x 109/L* | Platelet count decreases | Hold next cycle until Platelets ≥ 50 x 109/L |
| ANC < 1 x 109/L and/or platelets* < 50 x 109/L | ANC or platelet count decreases | Hold next cycle until at least one of the following occurs:
|
*platelet count used for dosing should be independent of transfusion.
**based on most recent bone marrow assessment
Non-hematologic toxicities:
Dose interruptions within a cycle (e.g. days 8 and/or 15) are recommended for non-hematologic toxicities.
Non-Hematologic Toxicity | Action | Dosing at Restart (if applicable) | |||
If dose held for ≤ 7 days (within a cycle) | If dose held for ≥ 7 days | If dose held for ≥ 14 days | If dose held for > 28 days | ||
Bilirubin > 1.5 x ULN and AST/ALT > 2.5 x ULN | Hold until Bilirubin ≤ 1.5 x ULN and AST/ALT ≤ 2.5 x ULN (except in Gilbert's syndrome or hemolysis) | Hold next dose (maintain a minimum of 6 days between doses) | Omit next dose within the cycle | ↓ total dose by 25% for the subsequent cycle. 2nd occurrence: Reduce the number of doses to 2 per cycle for subsequent cycles. 3rd occurrence: Discontinue | Discontinue |
Other ≥ Grade 2 non-hematologic | Hold until ≤grade 1 or baseline before each dose | ||||
VOD/SOS or other severe liver toxicity | Discontinue | Not applicable | |||
Management of Infusion-related reactions:
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
| Grade | Management | Re-challenge |
| 1 or 2 |
Restart:
|
|
| 3 or 4 |
|
|
| Bilirubin | AST/ALT | Starting Dose | |
| ≤ 1.5 x ULN | and | ≤ 2.5 x ULN | No adjustment required |
| > 1.5 x ULN | and | > 2.5 x ULN | Limited data; if not due to Gilbert's syndrome or hemolysis, do not treat. |
| Creatinine Clearance (mL/min) | Starting Dose |
| ≥ 30 (mild to moderate) | No adjustment required |
| 15 to 29 (severe) | Limited data; use with caution |
| ESRD | No data |
No adjustment in starting dose is needed. No overall safety and efficacy differences between patients who were < 65 or ≥ 65 years of age. Increased age was associated with an increased risk of (VOD)/sinusoidal obstruction syndrome (SOS) after hematopoietic stem cell transplant.
No significant effects of gender on inotuzumab ozogamicin disposition
No significant effects of ethnicity on inotuzumab ozogamicin disposition.
Safety and efficacy have not been established.
- Inotuzumab ozogamicin is light sensitive; protect from light during reconstitution, dilution and administration.
- Reconstitute inotuzumab ozogamicin using sterile water for injection according to instructions in the product monograph.
- Further dilute the reconstituted drug in 0.9% sodium chloride solution, to a total volume of 50mL. Final concentration should be between 0.01 to 0.1 mg/mL.
- Do not shake the drug. Gently invert the drug container to mix.
- The diluted solution does not require filtration. If a filter is needed, polyethersulfone (PES), polyvinylidene fluoride (PVDF) or hydrophilic polysulfone (HPS)-based filters are recommended. Do not use filters made of nylon or mixed cellulose ester (MCE).
- Compatible with PVC, (DEHP or non-DEHP containing), polyolefin, or ethylene vinyl acetate (EVA) containers or infusion lines.
- The diluted solution may be refrigerated or stored at room temperature. (Refer to the product monograph for storage times.)
- If the diluted solution is refrigerated, it should remain at room temperature for about 1 hour before administration (protect from light).
- Infuse the diluted solution for 1 hour at a rate of 50 mL/hour.
- During administration, protect the infusion bag from light using an UV light-blocking cover (e.g. amber, dark brown or green bags or aluminum foil). The infusion line does not need to be protected from light.
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
- Hypersensitivity to this drug or to any of its components
Other Warnings/Precautions:
- Not recommended for use in CD22-negative B-cell precursor ALL patients
- Use with caution in:
- patients with a history of or risk factors for QTc prolongation or Torsade de pointes, who are taking medications known to prolong the QT interval, or
- have electrolyte disturbances or pre-existing conduction system abnormalities, or
- patients who have experienced prior VOD/SOS or patients with ongoing severe liver disease, or
- patients who are older, have had a previous HSCT, in later lines of salvage and/or a previous history of liver disease and/or hepatitis
- Avoid using conditioning regimens containing 2 alkylating agents, to decrease risk of VOD/SOS after HSCT.
- Vaccination with live vaccines is not recommended for at least 2 weeks before starting inotuzumab ozogamicin treatment, during treatment and until B-lymphocyte recovery after the final cycle.
- Inotuzumab ozogamicin has moderate influence on the ability to drive and use machines. Caution is recommended when performing these activities as patients may experience fatigue during treatment.
Pregnancy and Lactation:
- Genotoxicity: Yes
- Embryotoxicity: Yes
Inotuzumab ozogamicin is not recommended for use in pregnancy. Female patients (and their male partners) should use adequate contraception during treatment, and for at least 8 months after the last dose. Male patients with partners of childbearing potential should use adequate contraception during treatment and for at least 5 months after the last dose.
- Breastfeeding:
Breastfeeding is not recommended during treatment and for at least 2 months after the last dose.
- Fertility effects:
Fertility may be impaired
Concurrent use with cytoreductive drugs such as hydroxyurea, GCSF, and P-gp inhibitors had no apparent effect on inotuzumab.
Co-administration with inhibitors or inducers of CYP or UGT drug metabolizing enzymes are unlikely to alter exposure to the cytotoxic component (N-acetyl-gamma-calicheamicin dimethylhydrazide). Inotuzumab ozogamicin and its cytotoxic moiety have low potential to inhibit or induce certain CYP enzymes.
N-acetyl-gamma-calicheamicin dimethylhydrazide had a low potential to inhibit the activities of UGT drug metabolizing enzymes and drug transporters such as P-gp, BCRP, OAT1, OCT2, OAT3, OATP1B1 and OATP1B3.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, sunitinib, methadone, chloroquine, clarithromycin, haloperidol, fluconazole, moxifloxacin, domperidone, ondansetron, etc) | ↑ risk of significant QT prolongation | Additive | If possible, discontinue other QT prolonging drugs and use alternatives that do not prolong QT. If unavoidable, monitor closely. |
| Drugs that prolong PR interval (e.g. antiarrhythmics, beta blockers, non-dihydropyridine Ca channel blockers, digoxin, some HIV protease inhibitors, sphingosine-1 phosphate receptor modulators) | ↑ risk of significant PR prolongation | Additive | Caution |
| Drugs that decrease electrolyte levels | ↑ risk of arrhythmias | Avoid to the extent possible |
| Monitor Type | Monitor Frequency |
|---|---|
CBC | Baseline and before each dose |
Liver function tests | Baseline, before and after each dose; more frequent if hepatotoxicity is suspected |
Renal function tests | Baseline and before each cycle |
Electrolytes | Baseline and as clinically indicated |
Amylase and lipase | Baseline and as clinically indicated |
ECGs | Baseline and as clinically indicated; more frequent in patients at risk of prolonged QT/PR |
Infusion reactions | During and for at least 1 hour after the infusion |
Clinical toxicity assessment for tumour lysis syndrome, infection, bleeding, fatigue, GI effects, VOD/SOS | At each visit |
Post-HSCT patients | Monitor closely for hepatotoxicity and infection. Monitor liver function tests closely during the first month post-HSCT, then less frequently after |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
High Cost Therapy Funding Program
- Inotuzumab Ozogamicin (Inpatient) - Relapsed or Refractory Acute Lymphoblastic Leukemia
- Inotuzumab Ozogamicin (Outpatient) - Relapsed or Refractory Acute Lymphoblastic Leukemia
Inotuzumab ozogamicin (Besponsa) Product Monograph. Pfizer Canada Inc., March 15, 2018.
Prescribing information: inotuzumab ozogamicin (Besponsa). Pfizer Inc. (US), March 2018.
July 2023 Updated NDFP and HCTFP forms
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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