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gemtuzumab ozogamicin
Gemtuzumab ozogamicin is a CD33-directed monoclonal antibody-drug conjugate (ADC). The antibody portion that recognizes the human CD33 antigen is covalently attached to a cytotoxic calicheamicin derivative, via a linker. The anticancer activity of gemtuzumab ozogamicin is due to the binding of the ADC to CD33-expressing tumor cells, followed by internalization of the ADC-CD33 complex. Following internalization, the calicheamicin derivative is released intracellularly and binds to DNA resulting in double strand breaks, inducing cell cycle arrest and apoptosis.
| PPB |
N-acetyl gamma calicheamicin dimethyl hydrazide: ~97% to human plasma proteins |
N-acetyl gamma calicheamicin dimethyl hydrazide is extensively metabolized, primarily through nonenzymatic reduction of the disulfide moiety.
| Active metabolites |
Yes, but activity of the metabolites is expected to be significantly attenuated |
| Half-life |
Based on a 3 mg/m2 dose: Antibody portion: ~160 hours |
| Clearance |
Antibody portion: 3 L/hour (after first dose); 0.3 L/hour. (after second dose) |
- Acute myeloid leukemia (AML)
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
The following table lists adverse effects that occurred in ≥ 1% of patients, in the phase III study with previously untreated de novo AML who received gemtuzumab ozogamicin as combination therapy. Incidences marked with “∞” were reported from monotherapy trials in newly diagnosed or relapsed/refractory AML. The table also includes severe or life-threatening adverse effects from post-marketing.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Acute coronary syndrome (rare) | E | |||
| Tachycardia (2%) (severe)∞ | E | ||||
| Dermatological | Rash (16%) ∞ | E | |||
| Gastrointestinal | Constipation (21%) ∞ | E | |||
| Diarrhea (2%) (severe)∞ | E | ||||
| Mucositis (2%) | E | ||||
| Nausea, vomiting (21%) ∞ | I | ||||
| General | Fatigue (46%) (12% severe)∞ | E | |||
| Hematological | Febrile neutropenia (18%) ∞ | E | |||
| Hemorrhage (90%) (e.g., upper or lower GI, subcut, pulmonary, epistaxis, hematuria, CNS and others) (23% ≥ grade 3) | E | ||||
| Myelosuppression (19%) (prolonged thrombocytopenia¥; 3% prolonged neutropenia†) (during induction) | E | ||||
| Hepatobiliary | Cholecystitis (rare) | E | |||
| Hepatotoxicity (13%) (≥ grade 3) | E | ||||
| Veno-occlusive disease (5%) (including sinusoidal obstruction syndrome) | E | ||||
| Infection | Infection (78%) (≥ grade 3) (including fungal infections) | E | |||
| Metabolic / Endocrine | Hyperuricemia (3%) | I E | |||
| Tumor lysis syndrome (2%) | I E | ||||
| Nervous System | Headache (19%) ∞ | E | |||
| Renal | Renal failure (rare) | 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)
¥Platelets < 50 × 109/L, lasting past cycle Day 42 in the absence of active leukemia.
†Neutrophils < 0.5 × 109/L, lasting past cycle Day 42 in the absence of active leukemia.
The most common side effects for gemtuzumab ozogamicin include hemorrhage, infection, fatigue, constipation, nausea, vomiting, headache, myelosuppression, febrile neutropenia, rash and hepatotoxicity.
Hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) events, was reported with the use of gemtuzumab ozogamicin as a single agent, and as part of a combination chemotherapy regimen, in patients without a history of liver disease or hematopoietic stem cell transplant (HSCT). In the combination therapy study, the median time to VOD onset was 9 days (range:2 to 298 days). Adults who receive gemtuzumab ozogamicin as monotherapy, either before or after an HSCT, and those with moderate to severe baseline hepatic impairment, appear to be at increased risk for VOD/SOS.
Gemtuzumab ozogamicin is myelosuppressive; neutropenia, thrombocytopenia, anemia, leukopenia, febrile neutropenia, lymphopenia, and pancytopenia, some of which were life-threatening or fatal, have been reported. Prolonged thrombocytopenia (>42 days post dose) has also been reported. Complications associated with neutropenia and thrombocytopenia may include infections and bleeding/hemorrhagic events. The median times for platelet recovery to 50 x 109/L and 100 x 109/L for the induction phase ranged from 34-35 days and platelet recovery for Consolidation 1 and 2 phases ranged from 32-43 days. The median times for neutrophil recovery to ANC of 0.5 x 109/L and 1 x 109/L for the induction phase was 25 days and neutrophil recovery for Consolidation 1 and 2 phases ranged from 21-27 days.
Life-threatening or fatal infections and bleeding/hemorrhagic events have been reported. Fatal bleeding events included CNS hematomas.
Life-threatening or fatal infusion-related reactions which may occur within 24 hours of gemtuzumab ozogamicin infusions, have been reported. Signs and symptoms of infusion related reactions may include fever and chills, and less frequently hypotension, tachycardia, and respiratory symptoms.
Refer to protocol by which patient is being treated.
Pre-medications (prophylaxis for infusion reaction):
Give 1 hour prior to gemtuzumab ozogamicin:
- a corticosteroid (e.g., 1 mg/kg methylprednisolone or equivalent)
- an antihistamine PO or IV (e.g., diphenhydramine 50 mg), and
- acetaminophen PO (e.g., acetaminophen 650 mg)
To prevent tumour lysis syndrome, initiate hydration and antihyperuricemic agent (or other agents for hyperuricemia) as necessary.
Cytoreduction is recommended prior to gemtuzumab ozogamicin administration if leukocyte count >30 x 109/L:
- Reduce peripheral WBC count 48 hours prior to administration of gemtuzumab ozogamicin according to institutional guidelines..
Combination therapy:
Note: A treatment course consists of 1 induction cycle and 2 consolidation cycles.
Induction:
Intravenous: 3 mg/m² (up to a maximum dose of 4.5 mg) Days 1, 4, and 7
(in combination with daunorubicin and cytarabine)
If cytarabine is used for leukoreduction with or without hydroxyurea, refer to the modified induction schedule in the product monograph.
For patients requiring a second induction cycle, do NOT administer gemtuzumab ozogamicin during the second induction cycle.
Consolidation (2 cycles):
Intravenous: 3 mg/m² (up to a maximum dose of 4.5 mg) Day 1
(in combination with cytarabine*, OR daunorubicin and cytarabine)
*based on NDFP form.
See CYTADAUN+GEMT for daunorubicin and cytarabine dosing or CYTA(HD)+GEMT for cytarabine dosing.
Hematologic Toxicities
|
Toxicity |
Recommended Action |
|
Persistent thrombocytopenia |
If platelet count does not recover to ≥100 x 109/L within 14 days following the anticipated start date of the consolidation cycle*:
|
|
Persistent neutropenia |
If neutrophil count does not recover to ≥0.5 x 109/L within 14 days following the anticipated start date of the consolidation cycle*:
|
*14 days after hematologic recovery following previous cycle
Non-Hematologic Toxicities
|
Toxicity |
Recommended Action |
|
|
VOD/SOS |
Discontinue |
|
| Total bilirubin > 2 × ULN, or AST and/or ALT > 2.5 × ULN |
Hold until recovery of:
Omit if delayed >2 days between sequential infusions |
|
| Infusion-related reactions | Mild to moderate |
Hold and initiate appropriate supportive care measures. With symptom resolution, consider resuming at ≤50% of the rate at which the reaction occurred. If symptoms recur, repeat procedure above. |
| Severe or life-threatening | Discontinue | |
| Other severe or life threatening nonhematologic toxicities |
Hold until recovery to a severity of no more than mild. Omit if delayed >2 days between sequential infusions. |
|
| Hepatic Impairment | Total bilirubin | AST | Gemtuzumab Ozogamicin Dose | |
|
Mild |
≤ ULN | and | >ULN | No dose adjustment required |
| >1 to 1.5 x ULN | Any | |||
| Moderate | >1.5 to 3 x ULN | Any | No data available | |
| Severe | >3 x ULN | Any |
| Creatinine Clearance (mL/min) | Gemtuzumab Ozogamicin Dose |
|
≥ 30 |
No dose adjustment required |
| < 30 | No data available |
No dose adjustment is required as no overall differences in safety or efficacy were observed between patients ≥ 65 years of age and younger patients.
Safety and efficacy of gemtuzumab ozogamicin have not been established.
-
Gemtuzumab ozogamicin is light sensitive; protect from light during reconstitution, dilution and administration.
-
Protect the IV bag/syringe from light using a light-blocking cover during infusion. The infusion line does not need to be protected from light.
-
Prior to reconstitution, allow gemtuzumab ozogamicin vials to reach room temperature (up to 30°C) for approximately 5 minutes.
-
Do not shake during reconstitution or dilution, gently swirl the vial or invert container to mix the solution.
-
Gemtuzumab ozogamicin vials are filled with 5 mg of drug product with a 0.5 mL overfill.
-
Dilute dose in 0.9% sodium chloride to a concentration between 0.075 mg/mL to 0.234 mg/mL:
-
To reduce the potential for drug adsorption, doses <3.9 mg must be diluted in a syringe and administered IV over 2 hours.
-
Doses greater ≥3.9 mg are to be diluted in a syringe or an IV infusion bag and administered IV over 2 hours.
-
-
Do not administer as an IV push or bolus.
-
Do not mix gemtuzumab ozogamicin with, or administer as an infusion with, other drugs.
-
Use PVC bags with DEHP, ethylene vinyl acetate (EVA) or polyolefin (polypropylene and/or polyethylene) and an in-line, low protein-binding 0.2 micron polyethersulphone (PES) filter for IV infusions.
-
For doses administered by syringe, use small bore infusion lines (microbore) with an in-line, low protein-binding 0.2 micron polyethersulphone (PES) filter.
-
Infuse the diluted solution using an infusion set made of polyvinyl chloride (PVC) with DEHP, PVC non-DEHP, polyethylene, or polyurethane.
-
Flush the IV line after each dose with 0.9% sodium chloride.
-
Monitor vital signs (pulse, blood pressure, and temperature) frequently during infusion and for at least 1 hour after the end of the infusion or until signs and symptoms of infusion-related-reactions completely resolve.
- Refrigerate unopened vials (2oC to 8oC); do not freeze and protect from light
- Patients who have a hypersensitivity to this drug or any of its components.
- Patients who have a history of or predisposition for QTc prolongation, who are taking medicinal products that are known to prolong QT interval and have electrolyte disturbances may be at increased risk for cardiac complications.
- Patients should use caution when driving or using machinery as fatigue, has been reported with treatment.
Other Drug Properties:
-
Carcinogenicity:
Unknown
-
Genotoxicity:
Yes
-
Clastogenicity:
Documented in animals
-
Embryotoxicity:
Probable
Gemtuzumab ozogamicin is not recommended for use in pregnancy. 2 methods of effective contraception should be used by both sexes during treatment, and for at least 7 months after the last dose in women and at least 4 months after the last dose in men.
-
Excretion into breast milk:
Unknown
Due to the potential for adverse reactions in the breastfed infant, breast-feeding is not recommended during treatment and for at least 1 month after the final dose.
-
Fertility effects:
Documented in animals
N-acetyl gamma calicheamicin dimethyl hydrazide is primarily metabolized via nonenzymatic reduction. Therefore, coadministration of gemtuzumab ozogamicin with inhibitors or inducers of cytochrome P450 (CYP) or uridine diphosphate glucuronosyltransferase (UGT) drug metabolizing enzymes are unlikely to alter the exposure to the calicheamicin derivative.
At clinically relevant concentrations, N-acetyl gamma calicheamicin dimethyl hydrazide had a low potential to inhibit drug transporters (e.g., P-gp, BCRP, OAT1 and OAT3, OCT2, OATP1B1, OATP1B3, BSEP and MRP2).
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests (ALT, AST, total bilirubin, and ALP) |
Baseline and prior to each dose; more frequently if clinically indicated, particularly if hepatotoxicity/VOD is suspected and/or in HSCT patients (including post-HSCT period). |
CBC |
Baseline, prior to and after each dose and ≥ 3 times/week until recovery from treatment-related toxicities. |
Serum chemistries, including creatinine and electrolytes |
Baseline, as clinically indicated and ≥ 3 times/week until recovery from treatment-related toxicities. |
ECG |
Baseline and as clinically indicated (in patients who are at risk or have a history of QT prolongation) |
| Clinical toxicity assessment for TLS, infusion related reactions, infection, bleeding/hemorrhage, cardiovascular, VOD/SOS, GI effects | At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
High Cost Therapy Funding Program ()
- Gemtuzumab Ozogamicin (Inpatient) - Previously Untreated Acute Myeloid Leukemia
- Gemtuzumab Ozogamicin (Outpatient) - Previously Untreated Acute Myeloid Leukemia
Amadori S, Suciu S, Selleslag D, et al. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016 Mar 20;34(9):972-9. doi: 10.1200/JCO.2015.64.0060. Epub 2016 Jan 25. PMID: 26811524.
Castaigne S, Pautas C, Terré C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study [published correction appears in Lancet. 2018 Feb 8;:]. Lancet. 2012;379(9825):1508-1516. doi:10.1016/S0140-6736(12)60485-1
Cortes, J.E., de Lima, M., Dombret, H. et al. Prevention, recognition, and management of adverse events associated with gemtuzumab ozogamicin use in acute myeloid leukemia. J Hematol Oncol 13, 137 (2020). https://doi.org/10.1186/s13045-020-00975-2
Gemtuzumab ozogamicin drug monograph. BC Cancer Agency, February 2021.
Lambert J, Pautas C, Terré C, et al. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019;104(1):113-119. doi:10.3324/haematol.2018.188888
Prescribing Information: MylotargTM (gemtuzumab ozogamicin). Wyeth Pharmaceuticlas LLC Pfizer (US) 2000.
Product Monograph: Mylotarg® (gemtuzumab ozogamicin), Wyeth LLC Pfizer Canada ULC, September 20, 2021.
Taksin AL, Legrand O, Raffoux E, et al. High efficacy and safety profile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the alfa group. Leukemia. 2007 Jan;21(1):66-71. doi: 10.1038/sj.leu.2404434
June 2022 No changes. Republished to appear on website.
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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