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MYLOTARG (gemtuzumab ozogamicin)
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1 Health Professional Information
1 INDICATIONS
MYLOTARG (gemtuzumab ozogamicin for injection) is indicated for:
- Combination therapy with daunorubicin (DNR) and cytarabine (AraC) for the treatment of adult patients with previously untreated, de novo CD33-positive acute myeloid leukemia (AML), except acute promyelocytic leukemia
1.1 Pediatrics
Based on the data submitted and reviewed by Health Canada, the safety and efficacy of MYLOTARG in combination with chemotherapy in pediatric patients with newly‑diagnosed AML has not been established; therefore, Health Canada has not authorized an indication for pediatric use (see WARNINGS AND PRECAUTIONS, Special Populations).
1.2 Geriatrics
Use of MYLOTARG in combination with DNR and AraC in newly-diagnosed adult patients with de novo AML is supported by a randomized, controlled trial that included 50 patients greater than or equal to 65 years of age. No overall differences in safety or effectiveness were observed in this trial between these subjects and younger subjects (see WARNINGS AND PRECAUTIONS, Special Populations).
2 Contraindications
MYLOTARG (gemtuzumab ozogamicin for injection) is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Dosage Forms, Strengths, Composition and Packaging.
3 Serious Warnings And Precautions Box
Serious Warnings and Precautions
- Hepatotoxicity, including venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS) which may be severe, life-threatening or fatal, has been observed in patients receiving MYLOTARG (gemtuzumab ozogamicin). Monitor frequently for signs and symptoms of VOD after treatment with MYLOTARG (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Hepatotoxicity, including VOD/SOS)
- Myelosuppression/cytopenias, and complications including infections and bleeding/hemorrhagic events, which may be severe, life-threatening or fatal, were reported in patients receiving MYLOTARG (see WARNINGS AND PRECAUTIONS, Hematologic, Myelosuppression/cytopenia)
- Tumor lysis syndrome (TLS), which may be severe, life-threatening or fatal, has been observed in patients receiving MYLOTARG (see WARNINGS AND PRECAUTIONS, General, Tumor lysis syndrome)
- Infusion-related reactions (see WARNINGS AND PRECAUTIONS, General, Infusion-related reactions)
4 Dosage And Administration
4.1 Dosing Considerations
- MYLOTARG (gemtuzumab ozogamicin for injection) should be administered under the supervision of a physician experienced in the use of anticancer medicinal products and in an environment where full resuscitation facilities are immediately available.
- MYLOTARG should be used only in patients eligible to receive intensive induction chemotherapy.
- Premedication with a corticosteroid, antihistamine, and acetaminophen is recommended 1 hour prior to MYLOTARG dosing to help ameliorate infusion related symptoms (see WARNINGS AND PRECAUTIONS).
- Appropriate measures to help prevent the development of tumor lysis-related hyperuricemia such as hydration, administration of antihyperuricemic or other agents for treatment of hyperuricemia must be taken (see WARNINGS AND PRECAUTIONS).
- For patients with hyperleukocytosis (leukocyte count >30,000/mm3), cytoreduction is recommended prior to administration of MYLOTARG (see Table 2).
- MYLOTARG must be reconstituted and diluted before administration. For instructions on reconstitution and dilution of the medicinal product before administration, see DOSAGE AND ADMINISTRATION, Reconstitution.
4.2 Recommended Dose and Dosage Adjustment
A treatment course including MYLOTARG in combination therapy for adults with newly diagnosed de novo CD33-positive acute myeloid leukemia (AML) consists of 1 induction cycle and 2 consolidation cycles.
Induction
The recommended dose of MYLOTARG is 3 mg/m2/dose (up to a maximum of one 4.5 mg vial) infused over a 2‑hour period on Days 1, 4, and 7 in combination with daunorubicin (DNR), 60 mg/m2/day infused over 30 minutes on Day 1 to Day 3, and cytarabine (AraC) 200 mg/m2/day by continuous infusion on Day 1 to Day 7.
For patients requiring a second induction cycle, do NOT administer MYLOTARG during the second induction cycle. Only DNR and AraC should be administered during the second induction cycle, at the following recommended dosing: DNR 35 mg/m2/day on Days 1 and 2, and AraC 1 g/m2 every 12 hours, on Day 1 to Day 3.
Consolidation
For patients experiencing a complete remission (CR) following induction, defined as fewer than 5% blasts with no Auer rods in the bone marrow and the absence of peripheral blood leukemic blasts, full recovery of peripheral blood counts (absolute neutrophil count [ANC] of more than 1.0 x 109 cells/L, and platelet count of more than 100 x 109/L), transfusion independence and resolution of any extramedullary disease, up to 2 consolidation courses of intravenous DNR (60 mg/m2 for 1 day [first course] or 2 days [second course]) in combination with intravenous AraC (1000 mg/m2 per 12 hours, infused over 2 hours on Day 1 to Day 4) with intravenous MYLOTARG (3 mg/m2/dose infused over 2 hours up to a maximum dose of one 4.5 mg vial on Day 1) are recommended. Table 1 shows dosing regimens for MYLOTARG in combination with chemotherapy.
| |||
Treatment Course | MYLOTARG | Daunorubicin | Cytarabine |
|---|---|---|---|
Inductiona,c | 3 mg/m2/dose (up to a maximum dose of one 4.5 mg vial) on Days 1,4, and 7 | 60 mg/m2/day on Days 1‑3 | 200 mg/m2/day on Days 1‑7 |
Second induction (if required) | Do NOT administer MYLOTARG during the second induction cycle. | 35 mg/m2/day on Day 1 to Day 2 | 1 g/m2/every 12 hours Day 1 to Day 3 |
Consolidation Course 1a,b,c | 3 mg/m2/dose (up to a maximum dose of one 4.5 mg vial) on Day 1 | 60 mg/m2/day on Day 1 | 1 g/m2/every 12 hours from Days 1‑4 |
Consolidation Course 2a,b,c | 3 mg/m2/dose (up to a maximum dose of one 4.5 mg vial) on Day 1 | 60 mg/m2/day on Days 1‑2 | 1 g/m2/every 12 hours from Days 1‑4 |
Dose and schedule modifications
Hepatic Impairment:
No adjustment to dose of MYLOTARG is required in patients with hepatic impairment defined by total bilirubin ≤2-times the ULN, and AST and/or ALT ≤2.5-times ULN. Delay treatment with MYLOTARG until recovery of total bilirubin to ≤2-times ULN and, AST and ALT to ≤2.5-times ULN prior to each dose. MYLOTARG has not been studied in patients with hepatic impairment defined by total bilirubin >2-times the ULN, or AST or ALT >2.5-times ULN (see Dose modification for adverse reactions and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).
Renal Impairment:
No adjustment to dose of MYLOTARG is required in patients with mild to moderate renal impairment. MYLOTARG has not been studied in patients with severe renal impairment (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).
Pediatric Population:
MYLOTARG dosing has not been established in pediatric patients with de novo AML (see INDICATIONS).
Schedule modification for hyperleukocytosis
In patients with hyperleukocytic (leukocyte count >30,000/mm3) AML, cytoreduction is recommended either with leukapheresis, oral hydroxyurea, or AraC with or without hydroxyurea to reduce the peripheral white blood cell (WBC) count 48 hours prior to administration of MYLOTARG (see WARNINGS AND PRECAUTIONS, General).
If AraC is used for leukoreduction with or without hydroxyurea in patients with previously untreated, de novo hyperleukocytic AML receiving MYLOTARG in combination therapy, apply the following modified schedule (Table 2):
| ||||
Treatment Course | MYLOTARG | Daunorubicin | Cytarabine | Hydroxyurea |
|---|---|---|---|---|
Inductiona | 3 mg/m2/dose (up to a maximum dose of one 4.5 mg vial) on Days 3, 6, and 9 | 60 mg/m2/day on Days 3‑5 | 200 mg/m2/day on Days 1‑7 | Day 1 (as per standard medical practice) |
Dose modification for adverse reactions
Monitor blood counts frequently through resolution of cytopenias. Monitor blood counts and chemistries at least three times per week through recovery from treatment-related toxicities. Dose modification of MYLOTARG is recommended based on individual safety and tolerability (see WARNINGS AND PRECAUTIONS). Management of some adverse reactions may require dose interruptions or permanent discontinuation of MYLOTARG (see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS).
Table 3 shows the dose modification guidelines for hematologic and nonhematologic toxicities.
| |
Hematologic and Nonhematologic Toxicities | Recommended Action |
|---|---|
Persistent thrombocytopenia |
|
Persistent neutropenia |
|
VOD/SOS |
|
Total bilirubin greater than 2 × ULN, or AST and/or ALT greater than 2.5 × ULN |
|
Infusion related reactions |
|
Other severe or life-threatening nonhematologic toxicities |
|
4.3 Administration
Administer MYLOTARG intravenously by infusion over a 2 hour period under close clinical monitoring, including pulse, blood pressure, and temperature. Do not administer MYLOTARG as an intravenous push or bolus.
4.4 Reconstitution
Use appropriate aseptic technique for the reconstitution and dilution procedures. MYLOTARG is light sensitive and should be protected from light during reconstitution, dilution,
and administration.
Reconstitution
- Calculate the dose (mg) of MYLOTARG required.
- Prior to reconstitution, allow the vial to reach room temperature (below 25°C) for approximately 5 minutes. Reconstitute each vial with 5 mL of water for injections to obtain a single-use solution of 1 mg/mL of gemtuzumab ozogamicin that delivers 4.5 mL (4.5 mg).
- Gently swirl the vial to aid dissolution. Do not shake.
- Inspect the reconstituted solution for particulates and discoloration. The reconstituted solution may contain small white to off-white, opaque to translucent, and amorphous to fiber-like particles.
- MYLOTARG contains no bacteriostatic preservatives.
- If the reconstituted solution cannot be used immediately, it may be stored in the original vial for up to 16 hours in a refrigerator (2°C-8°C) or up to 3 hours at room temperature (below 30°C). Protect from light and do not freeze.
Dilution
- Calculate the required volume of the reconstituted solution needed to obtain the appropriate dose according to patient body surface area. Withdraw this amount from the vial using a syringe. MYLOTARG vials are filled with 5 mg of drug product with a 0.5 mL overfill. When reconstituted to a 1 mg/mL concentration as directed, the minimum extractable content of the vial is 4.5 mg (4.5 mL). Protect from light. Discard any unused reconstituted solution left in the vial.
- Doses must be mixed to a concentration between 0.075 mg/mL to 0.234 mg/mL according to the following instructions:
- Doses less than 3.9 mg must be prepared for administration by syringe. Add the reconstituted MYLOTARG solution to a syringe with sodium chloride 9 mg/mL (0.9%) solution for injection to a final concentration between 0.075 mg/mL to 0.234 mg/mL. Protect from light.
- Doses greater than or equal to 3.9 mg are to be diluted in a syringe or an intravenous bag in an appropriate volume of sodium chloride 9 mg/mL (0.9%) solution for injection to ensure a final concentration between 0.075 mg/mL to 0.234 mg/mL. Protect from light.
- Gently invert the infusion container to mix the diluted solution. Do not shake.
- Following dilution with sodium chloride 9 mg/mL (0.9%) solution for injection, MYLOTARG solution should be infused immediately. If not used immediately, the diluted solution may be stored up to 18 hours in a refrigerator (2‑8°C) and up to 6 hours at room temperature (below 30°C). The allowed time at room temperature (below 30°C) includes the time required for preparation of the diluted solution, equilibration, if needed, and administration to the patient. The maximum time from preparation of the diluted solution through administration should not exceed 24 hours. Protect from light and do not freeze.
- It is recommended that the infusion container be made of polyvinyl chloride (PVC) with DEHP, ethylene vinyl acetate (EVA) or polyolefin (polypropylene and/or polyethylene).
Administration
- Filtration of the diluted solution is required. An in-line, low protein-binding 0.2 micron polyethersulphone (PES) filter must be used for infusion of MYLOTARG.
- Doses administered by syringe must utilize small bore infusion lines (microbore) with an in-line, low protein-binding 0.2 micron polyethersulphone (PES) filter.
- During the infusion, the intravenous bag or syringes need to be protected from light using a light (including ultraviolet light) blocking cover. The infusion line does not need to be protected from light.
- Infuse the diluted solution for 2 hours. The infusion must be completed prior to the end of the allowed 6‑hour storage of the diluted solution at room temperature (below 30°C). Infusion lines made of PVC (DEHP- or non DEHP-containing), polyurethane or polyethylene are recommended.
- Flush the intravenous line after each dose with 0.9% sodium chloride.
Do not mix MYLOTARG with, or administer as an infusion with, other medicinal products.
4.5 Missed Dose
Management of some adverse reactions may require dose interruptions or permanent discontinuation of MYLOTARG (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Table 3).
5 Overdosage
Treatment of MYLOTARG (gemtuzumab ozogamicin for injection) overdose should consist of general supportive measures.
For management of a suspected drug overdose, contact your regional poison control centre.
6 Dosage Forms, Strengths, Composition And Packaging
| Route of Administration | Dosage Form / Strength/Composition | Non-medicinal Ingredients |
|---|---|---|
| Intravenous infusion | White to off-white lyophilized cake or powder containing one 4.5 mg single-use vial | Dextran 40; Dibasic sodium phosphate, anhydrous; Monobasic sodium phosphate, monohydrate; Sodium chloride; Sucrose |
The container is an amber Type 1 glass vial, with butyl rubber stopper and crimp seal with flip-off cap. Each carton contains 1 vial.
7 Description
MYLOTARG (gemtuzumab ozogamicin for injection) is an antibody-drug conjugate (ADC) composed of the CD33-directed monoclonal antibody (hP67.6; recombinant humanized immunoglobulin [Ig] G4, kappa antibody produced by mammalian cell culture in NS0 cells) that is covalently linked to the cytotoxic agent N-acetyl gamma calicheamicin. Gemtuzumab ozogamicin consists of conjugated and unconjugated gemtuzumab. The conjugated molecules differ in the number of activated calicheamicin derivative moieties attached to gemtuzumab. The number of conjugated calicheamicin derivatives per gemtuzumab molecule ranges from predominantly zero to 6, with an average of 2 to 3 moles of calicheamicin derivative per mole of gemtuzumab.
8 Warnings And Precautions
Please see the Serious Warnings and Precautions Box at the Beginning of Part 1: Health Professional Information.
General
Infusion-related reactions (including anaphylaxis)
Life-threatening or fatal infusion-related reactions, including anaphylaxis, have been reported in clinical studies and in the postmarketing setting with MYLOTARG (gemtuzumab ozogamicin for injection; see ADVERSE REACTIONS, Clinical Trial Adverse Reactions). These can occur during or within 24 hours following infusion of MYLOTARG. Signs and symptoms of infusion-related reactions may include fever and chills, and less frequently hypotension, tachycardia, and respiratory symptoms. Perform infusion of MYLOTARG under close clinical monitoring, including pulse, blood pressure, and temperature.
Premedication with a corticosteroid, antihistamine, and acetaminophen is recommended 1 hour prior to MYLOTARG dosing (see DOSAGE AND ADMINISTRATION, Dosing Considerations). Interrupt infusion immediately for patients who develop evidence of severe reactions, especially dyspnea, bronchospasm, or clinically significant hypotension. Patients should be monitored during infusion and for at least 1 hour following infusion, or until signs and symptoms completely resolve. Discontinue MYLOTARG treatment in patients who develop signs or symptoms of anaphylaxis, including severe respiratory symptoms or clinically significant hypotension (see DOSAGE AND ADMINISTRATION, Dose and schedule modifications).
Tumor lysis syndrome (TLS)
Fatal reports of TLS complicated by acute renal failure with MYLOTARG have been reported in the postmarketing setting. In clinical studies with MYLOTARG, TLS was reported (see ADVERSE REACTIONS). In patients with hyperleukocytic acute myeloid leukemia (AML) leukoreduction should be considered with hydroxyurea or leukapheresis to reduce the peripheral WBC count to below 30,000/mm3 prior to administration of MYLOTARG to reduce the risk of inducing TLS (see DOSAGE AND ADMINISTRATION, Dose and schedule modifications).
Patients should be monitored for signs and symptoms of TLS and treated according to standard medical practice. Appropriate measures to help prevent the development of tumor lysis-related hyperuricemia such as hydration, administration of antihyperuricemic (e.g., allopurinol) or other agents for treatment of hyperuricemia (e.g., rasburicase) must be taken.
Carcinogenesis and Mutagenesis
Formal carcinogenicity studies have not been conducted with gemtuzumab ozogamicin (see NON-CLINICAL TOXICOLOGY).
Cardiovascular
QT interval prolongation has been observed in patients treated with other drugs containing calicheamicin. QT interval prolongation has been observed in patients that have been treated with MYLOTARG. No clinical study has been performed to determine the risk of QT interval prolongation with MYLOTARG. When administering MYLOTARG to patients who have a history of or predisposition for QTc prolongation, who are taking medicinal products that are known to prolong QT interval, and in patients with electrolyte disturbances, obtain electrocardiograms (ECGs) and electrolytes prior to the start of treatment and as needed during administration.
Driving and Operating Machinery
No studies on the effect of MYLOTARG on the ability to drive and use machines have been
performed. Fatigue has been reported during treatment with MYLOTARG (see ADVERSE REACTIONS). MYLOTARG may affect one’s ability to drive or operate a vehicle or potentially dangerous machinery.
Hematologic
Myelosuppression/cytopenia
With MYLOTARG treatment, life-threatening or fatal infections and bleeding/hemorrhagic events were reported. In clinical studies with MYLOTARG, neutropenia, thrombocytopenia, anemia, leukopenia, febrile neutropenia, lymphopenia, and pancytopenia, some of which were life-threatening or fatal, were reported (see ADVERSE REACTIONS, Clinical Trial Adverse Reactions). Complications associated with neutropenia and thrombocytopenia may include infections and bleeding/hemorrhagic events, respectively.
Persistent thrombocytopenia and more frequent platelet transfusions have been observed in patients treated with MYLOTARG.
Monitor complete blood counts prior to and following each dose of MYLOTARG and monitor patients for signs and symptoms of infection, bleeding/hemorrhage, or other effects of myelosuppression during treatment with MYLOTARG. Blood counts should be frequently monitored after treatment with MYLOTARG until resolution of cytopenias. Routine clinical and laboratory surveillance testing during and after treatment with MYLOTARG is indicated.
Management of patients with severe infection, bleeding/hemorrhage, or other effects of myelosuppression, including severe neutropenia or persistent thrombocytopenia, may require a dose delay or permanent discontinuation of MYLOTARG (see DOSAGE AND ADMINISTRATION, Dose and schedule modifications).
Hepatic/Biliary/Pancreatic
Hepatotoxicity, including hepatic venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS)
Life-threatening or fatal hepatotoxicity events, including VOD/SOS and hepatic failure, have been reported in patients treated with MYLOTARG (see ADVERSE REACTIONS, Clinical Trial Adverse Reactions).
Hepatotoxicity, including VOD/SOS events, has been reported in association with the use of MYLOTARG 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). Based on an analysis of potential risk factors, adult patients who received MYLOTARG as monotherapy, either before or after an HSCT, and patients with moderate or severe hepatic impairment are at increased risk for developing VOD/SOS (see ADVERSE REACTIONS, Clinical Trial Adverse Reactions).
Due to the risk of VOD/SOS, monitor patients closely for signs and symptoms of VOD/SOS. These may include elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, and alkaline phosphatase, which should be monitored prior to each dose of MYLOTARG. In addition, monitor for hepatomegaly (which may be painful), rapid weight gain,and ascites. Monitoring only total bilirubin may not identify all patients at risk of VOD/SOS. For patients who develop abnormal liver tests, more frequent monitoring of liver tests and clinical signs and symptoms of hepatotoxicity is recommended.
For patients who proceed to HSCT, close monitoring of liver tests is recommended during the post-HSCT period, as appropriate. Although no definitive relationship was found between VOD/SOS and time of HSCT relative to higher MYLOTARG monotherapy doses, the ALFA-0701 study recommended an interval of 2 months between the last dose of MYLOTARG and HSCT.
Management of signs or symptoms of hepatic toxicity may require a dose interruption or discontinuation of MYLOTARG (see DOSAGE AND ADMINISTRATION, Dose and schedule modifications). In patients who experience VOD/SOS, discontinue MYLOTARG and treat according to standard medical practice.
Monitoring and Laboratory Tests
Hepatic
Due to the risk of VOD/SOS, monitor closely for signs and symptoms of
VOD/SOS. These may include ALT, AST, total bilirubin, and alkaline phosphatase, which should be monitored prior to each dose of MYLOTARG. In addition, monitor for hepatomegaly (which may be painful), rapid weight gain, and ascites. Monitoring only total bilirubin may not identify all patients at risk of VOD/SOS. For patients who develop abnormal liver tests, more frequent monitoring of liver tests and clinical signs and symptoms of hepatotoxicity is recommended. For patients who proceed to HSCT, close monitoring of liver tests is recommended during the post-HSCT period, as appropriate (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Hepatotoxicity, including VOD/SOS).
Hematologic
Monitor complete blood counts prior to and following each dose of MYLOTARG and monitor patients for signs and symptoms of infection, bleeding/hemorrhage, or other effects of myelosuppression during treatment with MYLOTARG. Blood counts should be frequently monitored after treatment with MYLOTARG until resolution of cytopenias. Routine clinical and laboratory surveillance testing during and after treatment with MYLOTARG is indicated (see WARNINGS AND PRECAUTIONS, Hematologic, Myelosuppression/cytopenia).
Infusion-related reactions
Perform infusion of MYLOTARG under close clinical monitoring, including pulse, blood pressure, and temperature. Infusion-related reactions should be monitored during the infusion and for at least 1 hour after the end of the infusion, or until signs and symptoms have completely resolved. (see WARNINGS AND PRECAUTIONS, General, Infusion related reactions).
Tumor Lysis Syndrome
Patients should be monitored for signs and symptoms of TLS and treated according to standard medical practice (see WARNINGS AND PRECAUTIONS, General, Tumor lysis syndrome).
Sexual Health
Reproduction
Women of childbearing potential should be advised to avoid becoming pregnant while receiving MYLOTARG.
Advise women of childbearing potential to use 2 methods of effective contraception during treatment with MYLOTARG, and for at least 7 months after the last dose. Advise men with female partners of childbearing potential to use 2 methods of effective contraception during treatment with MYLOTARG and for at least 4 months after the last dose.
Fertility
There is no information regarding the effects of MYLOTARG on the fertility in patients. Based on nonclinical findings in animals, male and female fertility may be compromised by treatment with
MYLOTARG (see NON-CLINICAL TOXICOLOGY, Reproductive Toxicity). Both men and women should seek advice for fertility preservation before treatment.
8.1 Special Populations
8.1.1 Pregnant Women
There are very limited data for the use of MYLOTARG (gemtuzumab ozogamicin for injection) in pregnant patients. Based on its mechanism of action and nonclinical safety findings in animals, MYLOTARG could cause embryo-fetal harm when administered to a pregnant woman. In addition, studies in animals have shown developmental toxicity (see NON-CLINICAL TOXICOLOGY, Developmental Toxicity).
MYLOTARG is not recommended during pregnancy and in women of childbearing potential not using contraception.
8.1.2 Breast-feeding
There is no information regarding the presence of MYLOTARG or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because many drugs are excreted in human milk precaution should be exercised. Due to the potential for adverse reactions in breastfed infants, women should not breastfeed during treatment with MYLOTARG and for at least 1 month after the final dose.
8.1.3 Pediatrics
The safety and efficacy of MYLOTARG in combination with chemotherapy in the pediatric population with newly-diagnosed AML have not been established. Based on the data submitted and reviewed by Health Canada, the safety and efficacy of MYLOTARG in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use (see INDICATIONS).
8.1.4 Geriatrics
No adjustment to dose of MYLOTARG is required in elderly patients (≥65 years) (see INDICATIONS).
9 Аdverse Reactions
9.1 Adverse Reaction Overview
The following adverse reactions associated with MYLOTARG (gemtuzumab ozogamicin for injection) are discussed in detail under WARNINGS AND PRECAUTIONS. Appropriate management and dosing considerations regarding these adverse events are outlined under DOSAGE AND ADMINISTRATION: Dose modification for adverse reactions.
- Infusion-related reactions
- Tumour lysis syndrome (TLS)
- Myelosuppression/cytopenia, including infection and bleeding/haemorrhagic events
- Hepatotoxicity, including VOD/SOS
In the combination therapy study ALFA-0701, in patients who received MYLOTARG in combination with DNR and AraC, 67.2% experienced a serious adverse reaction. Selected clinically relevant serious adverse reactions were hepatotoxicity, including VOD/SOS (3.8%), haemorrhage (9.9%), severe infection (41.2%), and TLS (1.5%). The most common (>2%) serious adverse reactions with MYLOTARG included: thrombocytopenia, bronchopulmonary aspergillosis, septic shock, febrile bone marrow aplasia, bacterial sepsis, acute kidney injury, pneumonia, sepsis, acute respiratory distress syndrome, Escherichia sepsis, acute myeloid leukemia, venooclusive disease, hepatocellular injury, cholestatic liver injury, febrile neutropenia, mucosal inflammation, disease progression, and enterococcal sepsis.
The most common selected adverse reactions (>30%, grouped terms) in the combination therapy study were haemorrhage and infection. The most frequently (≥10%) reported adverse reactions were epistaxis, purpura, haematoma, device-related infection, petechiae, catheter site haemorrhage, blood blister, haematuria, gingival bleeding, mouth haemorrhage, thrombocytopenia, haemoptysis, device-related sepsis and bronchopulmonary aspergillosis. The most frequent (≥1%) adverse reactions that led to permanent discontinuation in the combination therapy study were thrombocytopenia, VOD, haemorrhage, and infection.
Fatal adverse reactions were experienced by 7 (5.3%) patients who received MYLOTARG and 5 (3.6 %) patients in the control arm. In the MYLOTARG arm, these deaths were due to: VOD, septic shock, subdural haematoma, cerebral haematoma, and intracranial haematoma. In the control arm, these deaths were due to septic shock and cerebral haemorrhage. The occurrence of deaths within 28 days of last dose of any study treatment was 6 events (4.6%) in the MYLOTARG arm and 5 events (3.6%) in the control arms.
Information about adverse drug reactions from monotherapy studies is presented in order to provide full characterization of adverse drug reactions. In monotherapy studies, clinically relevant serious adverse reactions also included infusion related reactions (2.5%), thrombocytopenia (21.7%), and neutropenia (34.3). In monotherapy studies the most common adverse reactions (>30%) included pyrexia, nausea, infection, chills, haemorrhage, vomiting, thrombocytopenia, fatigue, headache, stomatitis, diarrhoea, abdominal pain, and neutropenia. The most frequent (≥1%) adverse reactions that led to permanent discontinuation in monotherapy studies were infection, haemorrhage, multi-organ failure, and VOD.
9.2 Clinical Trial Adverse Reactions
Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
The overall safety profile of MYLOTARG is based on data from patients with acute myeloid leukaemia (AML) from the combination therapy study ALFA-0701, monotherapy studies, and from post-marketing experience. In the combination therapy study, safety data consisting of selected treatment emergent adverse events (TEAEs) considered most important for understanding the safety profile of MYLOTARG included all grades haemorrhages, all grades venoocclusive disease (VOD), and severe infections. All of these TEAEs were determined to be adverse drug reactions.
The safety evaluation of MYLOTARG (3 mg/m2 on Days 1, 4 and 7) in combination with daunorubicin and cytarabine in adult patients with previously untreated de novo acute myeloid leukemia (AML) is based on data from the ALFA-0701 (n=271) study (see CLINICAL TRIALS). The study was designed to compare the clinical efficacy and safety of patients treated with MYLOTARG in combination with daunorubicin (DNR) and cytarabine (AraC; MYLOTARG arm; N=135) versus patients treated with DNR and AraC alone (control arm; N=136). The age of patients in this study ranged from 50-70, with a median of 62 years. In this study, 131 patients were treated with MYLOTARG plus DNR and AraC. During the induction course, 123 (93.9%) received the 3 fractionated doses. MYLOTARG was received by 91 (69.5%) of patients during the first consolidation course and 64 (48.9%) of patients during the second consolidation course.
Table 5 shows the adverse drug reactions occurring ≥1% from the ALFA-0701 study reported in patients with previously untreated de novo AML who received MYLOTARG in combination.
| MYLOTARG + | Daunorubicin + | ||
|---|---|---|---|---|
System Organ Class Adverse Reaction | All Grades | Grade 3/4 | All Grades | Grade 3/4 |
Blood and lymphatic system disorders |
|
|
|
|
Thrombocytopenia | 15.3 | 14.5 | 0 | 0 |
Ear and labyrinth disorders |
|
|
|
|
Ear haemorrhage | 1.5 | 0 | 0 | 0 |
Eye disorders |
|
|
|
|
Conjunctival haemorrhage | 8.4 | 0 | 2.2 | 0 |
Eye haemorrhage | 3.1 | 0 | 0.7 | 0 |
Retinal haemorrhage | 2.3 | 1.5 | 0 | 0 |
Gastrointestinal disorders |
|
|
|
|
Anal haemorrhage | 1.5 | 0 | 0.7 | 0 |
Gingival bleeding | 17.6 | 1.5 | 8.8 | 0 |
Haematemesis | 5.3 | 3.1 | 2.2 | 0 |
Haematochezia | 4.6 | 0.8 | 5.8 | 0 |
Haemorrhoidal haemorrhage | 2.3 | 0 | 2.2 | 0 |
Lip haemorrhage | 3.8 | 0 | 1.5 | 0.7 |
Melaena | 5.3 | 1.5 | 0 | 0 |
Mouth haemorrhage | 16.0 | 0.8 | 4.4 | 0 |
Rectal haemorrhage | 6.9 | 1.5 | 6.6 | 0.7 |
Tongue blistering | 1.5 | 0 | 0 | 0 |
Tongue haematoma | 2.3 | 0.8 | 0.7 | 0 |
General disorders and administration site conditions |
|
|
|
|
Catheter site haematoma | 8.4 | 0 | 5.1 | 0 |
Catheter site haemorrhage | 22.1 | 1.5 | 20.4 | 0.7 |
Infusion site haemorrhage | 1.5 | 0 | 0 | 0 |
Puncture site haemorrhage | 5.3 | 0.8 | 2.2 | 0 |
Hepatobiliary disorders |
|
|
|
|
Venoocclusive liver disease | 4.6 | 2.3 | 0 | 0 |
Infections and infestations |
|
|
|
|
Device related infection | 24.43 | 24.43 | 24.09 | 24.09 |
Bronchopulmonary aspergillosis | 10.69 | 10.69 | 6.57 | 6.57 |
Device related sepsis | 10.69 | 10.69 | 10.95 | 10.95 |
Bacterial sepsis | 9.16 | 9.16 | 2.92 | 2.92 |
Septic shock | 9.16 | 7.63 | 5.84 | 8.76 |
Staphylococcal sepsis | 6.87 | 6.87 | 10.22 | 10.22 |
Streptococcal sepsis | 6.87 | 6.87 | 2.92 | 2.92 |
Enterococcal sepsis | 4.58 | 4.58 | 0.73 | 0.73 |
Escherichia bacteraemia | 4.58 | 4.58 | 2.92 | 2.92 |
Escherichia sepsis | 4.58 | 4.58 | 3.65 | 3.65 |
Sepsis | 4.58 | 4.58 | 2.92 | 2.92 |
Klebsiella sepsis | 3.82 | 3.82 | 2.92 | 2.92 |
Pneumonia | 3.82 | 3.82 | 4.38 | 4.38 |
Clostridium difficile colitis | 3.05 | 3.05 | 2.19 | 2.19 |
Staphylococcal bacteraemia | 3.05 | 3.05 | 1.46 | 1.46 |
Aspergillus infection | 2.29 | 2.29 | 2.19 | 2.19 |
Candida sepsis | 2.29 | 2.29 | 2.92 | 2.92 |
Cellulitis | 2.29 | 2.29 | 1.46 | 1.46 |
Clostridium difficile infection | 2.29 | 2.29 | 3.65 | 3.65 |
Escherichia urinary tract infection | 2.29 | 2.29 | 1.46 | 1.46 |
Candida infection | 1.53 | 1.53 | 0 | 0 |
Lung infection | 1.53 | 1.53 | 1.46 | 1.46 |
Pseudomonal sepsis | 1.53 | 1.53 | 0 | 0 |
Streptococcal bacteraemia | 1.53 | 1.53 | 0.73 | 0.73 |
Streptococcal infection | 1.53 | 1.53 | 0.73 | 0.73 |
Urinary tract infection | 1.53 | 1.53 | 6.57 | 6.57 |
Anal abscess | 1.53 | 1.53 | 0.73 | 0.73 |
Injury, poisoning, and procedural complications |
|
|
|
|
Contusion | 3.8 | 0 | 2.2 | 0 |
Post-procedural haemorrhage | 6.9 | 0 | 2.9 | 0.7 |
Procedural haemorrhage | 1.5 | 0 | 0.7 | 0 |
Subdural haematoma | 1.5 | 0 | 0 | 0 |
Wound haemorrhage | 1.5 | 0.8 | 2.2 | 0 |
Investigations |
|
|
|
|
Blood urine present | 1.5 | 0 | 0.7 | 0 |
Renal and urinary disorders |
|
|
|
|
Haematuria | 19.1 | 2.3 | 10.2 | 0.7 |
Reproductive system and breast disorders |
|
|
|
|
Metrorrhagia | 2.3 | 0 | 4.4 | 0 |
Vaginal haemorrhage | 1.5 | 0.8 | 0 | 0 |
Respiratory, thoracic and mediastinal disorders |
|
|
|
|
Epistaxis | 62.6 | 1.5 | 36.5 | 0 |
Haemoptysis | 14.5 | 3.1 | 9.5 | 1.5 |
Pulmonary alveolar haemorrhage | 3.1 | 2.3 | 0.7 | 0 |
Skin and subcutaneous tissue disorders |
|
|
|
|
Blood blister | 22.1 | 0.8 | 8.0 | 0 |
Petechiae | 22.9 | 1.5 | 16.8 | 1.5 |
Purpura | 26.0 | 1.5 | 14.6 | 2.2 |
Vascular disorders |
|
|
|
|
Haematoma | 25.2 | 1.5 | 17.5 | 0.7 |
Haemorrhage | 4.6 | 1.5 | 4.4 | 0 |
Table 6 summarizes the selected adverse reactions reported in patients with previously untreated de novo AML who received MYLOTARG in a combination.
| ||||
System Organ Class | MYLOTARG + | Daunorubicin + | ||
|---|---|---|---|---|
All Grades | Grade 3/4 | All Grades | Grade 3/4 | |
Infections and infestations | ||||
Infection*,a | 77.9 | 76.3 | 77.4 | 74.5 |
Vascular disorders | ||||
Haemorrhage*,b | 90.1 | 20.6 | 78.1 | 8.8 |
Hepatobiliary disorders | ||||
Venoocclusive liver disease*,c | 4.6 | 2.3 | 1.5 | 1.5 |
Hepatotoxicity, including hepatic VOD/SOS
In the combination therapy study in patients with previously untreated de novo AML treated with fractionated doses of MYLOTARG in combination with chemotherapy (N=131), hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic VOD/SOS events, was reported. Hepatotoxicity with fatal outcome occurred in 5 (3.7%) patients in the combination therapy study and in 1 (0.7%) patient in the control arm.
In the combination therapy study (N=131), VOD events were reported in 6 (4.6%) patients during or following treatment, 2 (1.5%) of these events were fatal. Five (3.8%) of these VOD events occurred within 28 days of last dose of MYLOTARG. One VOD event occurred more than 28 days of last dose of MYLOTARG; with 1 of these events occurring a few days after having started a HSCT conditioning regimen. The median time from the last MYLOTARG dose to onset of VOD was 9 days (range: 2-298 days). VOD was also reported in 2 patients who received MYLOTARG as a follow-up therapy following relapse of AML after chemotherapy treatment in the control arm of the combination therapy study. Both of these patients experienced VOD more than 28 days after the last dose of MYLOTARG treatment. One of these patients experienced VOD 25 days after the subsequent HSCT. In the control arm receiving chemotherapy without ever receiving MYLOTARG, there were zero VOD events.
Based on an analysis of potential risk factors, adult patients who received MYLOTARG as monotherapy, patients who had received an HSCT prior to gemtuzumab ozogamicin exposure were 2.6 times more likely (95% CI: 1.448, 4.769) to develop VOD compared to patients without HSCT prior to treatment with gemtuzumab ozogamicin; patients who had received an HSCT following treatment with gemtuzumab ozogamicin were 2.9 times more likely (95% CI: 1.502, 5.636) to develop VOD compared to patients without HSCT following treatment with gemtuzumab ozogamicin; and patients who had moderate/severe hepatic impairment at baseline were 8.7 times more likely (95% CI: 1.879, 39.862) to develop VOD compared to patients without moderate/severe hepatic impairment at baseline.
Patients should be monitored for hepatotoxicity (see WARNINGS AND PRECAUTIONS). Management of signs or symptoms of hepatic toxicity may require a dose interruption or discontinuation of MYLOTARG (see DOSAGE AND ADMINISTRATION, Dose and schedule modifications).
Myelosuppression/cytopenia
In the combination therapy study in patients with previously untreated de novo AML treated with fractionated doses of MYLOTARG in combination with chemotherapy, Grade 3/4 decreases in leukocytes, neutrophils, and platelets were observed in 131 (100%), 124 (96.1%), and 131 (100%) patients, respectively. In the control group (N=137), Grade 3/4 decreases in leukocytes, neutrophils, and platelets were observed in 135 (99.3%), 131 (97.0%), and 136 (100.0%), respectively.
During the induction phase, 109 (83.2%) and 99 (75.6%) patients receiving Mylotarg had platelet recovery to counts of 50,000/mm3 and 100,000/mm3, respectively. In the control arm, 118 patients (86.1%) had platelet recovery to 50,000/mm3 and 111 patients (81.0%) had platelet recovery to 100,000/mm3.The median times to platelet recovery to counts of 50,000/mm3 and 100,000/mm3 were 34 and 35 days, respectively for patients receiving MYLOTARG, and 29.0 and 30.0 days for the patients in the control arm. During the Consolidation 1 phase, 92 (94.8%) and 71 (73.2%) patients receiving MYLOTARG had a platelet recovery to counts of 50,000/mm3, and 100,000/mm3, respectively, while 86 (88.7%) and 80 (82.5%) patients in the control arm had platelet recovery to counts of 50,000/mm3, and 100,000/mm3. The median times to platelet recovery to counts of 50,000/mm3 and 100,000/mm3 were 32 and 35 days, respectively for patients receiving MYLOTARG and 27.0 and 28.0 days for those in the control arm. During the Consolidation 2 phase, 80 (97.6%) and 70 (85.4%) patients receiving Mylotarg had a platelet recovery to counts of 50,000/mm3 and 100,000/mm3, respectively. The median times to platelet recovery to counts of 50,000/mm3 and 100,000/mm3 were 36.5 and 43 days, respectively. In the control arm during the Consolidation 2 phase, 85 (95.5%) and 82 (92.1%) patients had a platelet recovery to counts of 50,000/mm3 and 100,000/mm3, respectively. The median times to platelet recovery to counts of 50,000/mm3 and 100,000/mm3 were 30.0 and 32.0 days, respectively. Platelet recovery to both counts of 50,000/mm3 and 100,000/mm3 was longer for patients who received MYLOTARG through all treatment phases compared to patients in the control arm.
Thrombocytopenia with platelet counts <50,000/mm3 persisting 45 days after the start of therapy for responding patients (CR and complete remission with incomplete platelet recovery [CRp]) occurred in 22 (20.4%) patients receiving MYLOTARG and 2 (2.0%) patient in the control arm. The number of patients with persistent thrombocytopenia remained similar across treatment courses (8 [7.4%] patients at the induction phase, 8 [8.5%] patients at the Consolidation 1 phase, and 10 [13.2%] patients at the Consolidation 2 phase). In the control arm, persistent thrombocytopenia was experienced by 1 (1.0%) patient in the induction phase, no patients at the Consolidation 1 phase, and 2 (2.4%) patients at the Consolidation 2 phase.
During the induction phase, 121 (92.4%) and 118 (90.1%) patients had a documented neutrophil recovery to ANC of 500/mm3 and 1000/mm3, respectively. The median time to neutrophil recovery to ANC of 500/mm3 and 1000/mm3 was 25 days. In the control arm during the induction phase, 125 (91.2%) and 120 (87.6%) patients had a documented neutrophil recovery to ANC of 500/mm3 and 1000/mm3, respectively. The median time to neutrophil recovery to ANC of 500/mm3 and 1000/mm3 was 24.0 and 25.0 days, respectively. In the Consolidation 1 phase of therapy, 94 (96.9%) patients had neutrophil recovery to counts of 500/mm3, and 91 (94%) patients recovered to counts of 1000/mm3. The median times to neutrophil recovery to ANC of 500/mm3 and 1000/mm3 were 21 and 25 days, respectively. In the control arm during the Consolidation 1 phase, 94 (96.9%) and 89 (91.8%) patients had a documented neutrophil recovery to ANC of 500/mm3 and 1000/mm3, respectively. The median time to neutrophil recovery to ANC of 500/mm3 and 1000/mm3 was 22.0 and 24.0 days, respectively. In the Consolidation 2 phase of therapy, 80 (97.6%) patients had neutrophil recovery to counts of 500/mm3, and 79 (96.3%) patients recovered to counts of 1000/mm3. The median times to neutrophil recovery to ANC of 500/mm3 and 1000/mm3 were 22 and 27 days, respectively. In the control arm during the Consolidation 2 phase, 88 (98.9%) and 88 (98.9%) patients had a documented neutrophil recovery to ANC of 500/mm3 and 1000/mm3, respectively. The median time to neutrophil recovery to ANC of 500/mm3 and 1000/mm3 was 22.0 and 26.0 days, respectively.
In the combination therapy study, in patients with de novo AML treated with fractionated doses of MYLOTARG in combination with chemotherapy (N=131), 102 (77.9%) patients experienced all-causality severe (Grade ≥3) infections. In the control arm, 106 (77.4%) patients experienced all-causality severe (Grade ≥3) infections. Treatment-related death due to septic shock was reported in 1 (0.8%) patient receiving MYLOTARG and in 3 patients (2.2%) in the control arm.
In the combination therapy study (N=131), all grades and Grade 3/4 bleeding/haemorrhagic events were reported in 118 (90.1%) and 27 (20.6%) patients, respectively. The most frequent Grade 3 bleeding/haemorrhagic events were haematemesis (3.1%), haemoptysis (3.1%), and haematuria (2.3%). Grade 4 bleeding/haemorrhagic events were reported in 4 (3.1%) patients (gastrointestinal haemorrhage, haemorrhage, and pulmonary alveolar haemorrhage [2 patients]). Fatal bleeding/haemorrhagic events were reported in 3 (2.3%) patients (cerebral haematoma, intracranial haematoma, and subdural haematoma). In the control arm, all grades and Grade 3/4 bleeding/haemorrhagic events were reported in 107 (78.1%) and 12 (8.8%) patients, respectively. The most frequent Grade 3 bleeding/haemorrhagic event was purpura (2.2%). Fatal bleeding/haemorrhagic events were reported in 1 (0.7%) patient (cerebral haemorrhage).
Management of patients with severe infection, bleeding/haemorrhage, or other effects of myelosuppression, including severe neutropenia or persistent thrombocytopenia, may require a dose delay or permanent discontinuation of MYLOTARG (see DOSAGE AND ADMINISTRATION, Dose and schedule modifications and WARNINGS AND PRECAUTIONS, Hematologic).
Immunogenicity
Immunogenicity was not assessed in the ALFA-0701 study of patients treated with MYLOTARG in combination with DNR and AraC. The data regarding immunogenicity with MYLOTARG is limited. As with all therapeutic proteins, there is potential for immunogenicity. In clinical studies of MYLOTARG in patients with relapsed or refractory AML, the immunogenicity of MYLOTARG was evaluated using 2 enzyme-linked immunosorbent assays (ELISAs).
Patients in the Phase 2 trials did not develop antidrug antibodies (ADAs) and only 2 patients in a Phase 1 trial developed antibodies against the calicheamicin-linker complex, 1 of whom had reduced hP67.6 plasma concentrations. Overall, the incidence rate of ADA development after MYLOTARG treatment was <1% across the 4 clinical studies with ADA data. Definitive conclusions cannot be drawn between the presence of antibodies and potential impact on efficacy and safety due to the limited number of patients with positive antidrug antibodies.
The detection of ADAs is highly dependent on the sensitivity and specificity of the assay. The incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, circulating drug concentrations, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to MYLOTARG with the incidence of antibodies to other products may be misleading.
9.3 Less Common Clinical Trial Adverse Reactions
Additional clinically significant less common events include the following adverse drug reactions and discontinuations due to adverse events:
Blood and lymphatic system disorders: Febrile neutropenia
Cardiac disorders: Acute coronary syndrome
Hepatobiliary disorders: Cholecystitis acute, Hepatitis cholestatic, Hepatotoxicity
Nervous system disorders: Cerebral hematoma, Peripheral neuropathy
Renal and urinary disorders: Acute kidney injury, Renal failure
9.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data
Table 7 summarizes hematologic and chemistry laboratory abnormalities by treatment arm for patients treated in ALFA-0701.
| |||||||
Laboratory Abnormality | N | MYLOTARG + | N | Daunorubicin + | |||
|---|---|---|---|---|---|---|---|
All Grades | Grade 3/4 | All Grades | Grade 3/4 | ||||
Haematology | |||||||
Activated partial thromboplastin time prolonged | 125 | 80.0 | 6.4 | 127 | 57.5 | 5.5 | |
Haemoglobin decreased | 130 | 100 | 86.2 | 136 | 100 | 89.7 | |
Lymphocytes (absolute) decreased | 129 | 98.5 | 90.7 | 135 | 97.8 | 89.6 | |
Neutrophils decreased | 129 | 97.7 | 96.1 | 135 | 98.5 | 97.0 | |
Platelets decreased | 131 | 100 | 100 | 136 | 100 | 100 | |
Prothrombin time increased | 92 | 84.8 | 3.3 | 92 | 89.1 | 0 | |
White blood cells decreased | 131 | 100 | 100 | 136 | 99.3 | 99.3 | |
Chemistry | |||||||
Alanine aminotransferase (ALT) increased | 129 | 78.3 | 10.9 | 134 | 81.3 | 15.7 | |
Alkaline phosphatase increased | 128 | 79.7 | 13.3 | 132 | 68.9 | 5.3 | |
Aspartate aminotransferase (AST) increased | 129 | 89.2 | 14.0 | 134 | 73.9 | 9.0 | |
Blood bilirubin increased | 126 | 51.6 | 7.1 | 132 | 50.8 | 3.8 | |
Glucose decreased | 125 | 23.2 | 0.8 | 135 | 11.9 | 1.5 | |
Hyperglycaemia | 125 | 92.0 | 19.2 | 135 | 91.1 | 17.8 | |
Hyperuricemia | 117 | 32.5 | 2.6 | 123 | 28.5 | 0 | |
Phosphate decreased | 129 | 89.2 | 65.1 | 134 | 69.4 | 40.3 | |
Potassium decreased | 130 | 93.1 | 57.7 | 135 | 82.2 | 31.1 | |
Sodium decreased | 130 | 90.0 | 44.6 | 135 | 85.9 | 27.4 | |
9.5 Post-Market Adverse Reactions
The following adverse drug reactions have been identified during post-approval use of MYLOTARG. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal disorders: Neutropenic colitis*
Infections and infestations: Fungal lung infections including Pulmonary mycosis and Pneumocystis jirovecii pneumonia*; and bacterial infections including Stenotrophomonas
infection
Renal and urinary disorders: Haemorrhagic cystitis*
Respiratory, thoracic and mediastinal disorders: Interstitial pneumonia*
* including fatal events
10 Drug Interactions
10.1 Overview
No clinical drug interaction studies have been performed with MYLOTARG (gemtuzumab ozogamicin for injection).
10.2 Drug-Drug Interactions
Effect of other drugs on gemtuzumab ozogamicin
In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide is primarily metabolized via nonenzymatic reduction. Therefore, coadministration of MYLOTARG with inhibitors or inducers of cytochrome P450 (CYP) or uridine diphosphate glucuronosyltransferase (UGT) drug metabolizing enzymes are unlikely to alter the exposure to N-acetyl gamma calicheamicin dimethyl hydrazide.
No clinical drug interaction studies have been performed. Based on population PK analyses, the combination of gemtuzumab ozogamicin with hydroxyurea, daunorubicin (DNR) and cytarabine (AraC) is not predicted to cause clinically meaningful changes in the pharmacokinetics (PK) of hP67.6 or unconjugated calicheamicin.
Effect of gemtuzumab ozogamicin on other drugs
Effect on CYP substrates
In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide and gemtuzumab ozogamicin had a low potential to inhibit the activities of CYP1A2, CYP2A6 (tested only using gemtuzumab ozogamicin), CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 at clinically relevant concentrations. In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide and gemtuzumab ozogamicin had a low potential to induce the activities of CYP1A2, CYP2B6, and CYP3A4 at clinically relevant concentrations.
Effect on UGT substrates
In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide had a low potential to inhibit the activities of UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 at clinically relevant concentrations.
Effect on drug transporter substrates
In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide had a low potential to inhibit the activities of P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance associated protein (MRP) 2, multidrug and toxin extrusion protein (MATE)1 and MATE2K, organic anion transporter (OAT)1 and OAT3, organic cation transporter (OCT) 1 and OCT 2, and organic anion transporting polypeptide (OATP)1B1 and OATP1B3 at clinically relevant concentrations.
Effect on AraC and DNR
No clinical drug interaction studies have been performed. Based on population PK analyses, the combination of gemtuzumab ozogamicin with DNR and AraC is not predicted to cause clinically meaningful changes in the PK of these agents.
10.3 Drug-Food Interactions
Interactions with food have not been established.
10.4 Drug-Herb Interactions
Interactions with herbal products have not been established.
10.5 Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.
11 Action And Clinical Pharmacology
11.1 Mechanism of Action
MYLOTARG (gemtuzumab ozogamicin for injection) is a CD33-directed ADC. Gemtuzumab is a humanized immunoglobulin class G subtype 4 (IgG4) antibody which specifically recognizes human CD33. The antibody portion (hP67.6) binds specifically to the CD33 antigen, a sialic acid-dependent adhesion protein found on the surface of myeloid leukemic blasts and immature normal cells of myelomonocytic lineage, but not on normal hematopoietic stem cells. The small molecule, N-acetyl gamma calicheamicin dimethyl hydrazide, is a cytotoxic semisynthetic natural product. N-acetyl gamma calicheamicin dimethyl hydrazide is covalently attached to the antibody via an AcBut (4-(4'-acetylphenoxy) butanoic acid linker. Nonclinical data suggest that 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, and the intracellular release of N-acetyl gamma calicheamicin dimethyl hydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl gamma calicheamicin dimethyl hydrazide induces double-stranded DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.
11.2 Pharmacodynamics
In vitro cytotoxicity assays showed that gemtuzumab ozogamicin was effective at selectively killing human leukemia cell line (HL-60) target cells. In nonclinical murine models, gemtuzumab ozogamicin demonstrates antitumor effects in the HL-60 human promyelocytic leukemia xenograft tumor in athymic mice. Combining DNR and AraC chemotherapy with gemtuzumab ozogamicin was effective in eliminating disease and prolonging survival in nonclinical acute myeloid leukemia (AML) models.
Saturation of a high percentage of CD33 antigenic sites is presumed to be required for maximum delivery of calicheamicin to leukemic blast cells. Near maximal peripheral CD33 saturation was observed across studies after gemtuzumab ozogamicin dosing at dose levels of 2 mg/m2 and above.
11.3 Pharmacokinetics
Gemtuzumab ozogamicin is an ADC composed of CD33-directed monoclonal antibody (hP67.6) that is covalently linked to the cytotoxic agent N-acetyl-gamma calicheamicin dimethyl hydrazide. The pharmacokinetic (PK) of gemtuzumab ozogamicin is described by measuring PK characteristics of the antibody (hP67.6) as well as total and unconjugated calicheamicin derivatives. Given that the hP67.6 portion renders target selectivity on the intact molecule, and that MYLOTARG dosages are reported in terms of milligrams of protein (hP67.6), the hP67.6 concentration results are reported as the primary PK measures. After gemtuzumab ozogamicin binds to the target it is internalized and N-acetyl calicheamicin dimethyl hydrazide is released by hydrolytic cleavage. Determination of PK parameters for unconjugated calicheamicin was limited due to the low systemic concentration levels.
No clinical PK data have been collected using the fractionated regimen; however, the PK have been simulated using the population PK model. Although the total dose of the fractionated dosing regimen is half of that of the original dosing regimen (9 versus 18 mg/m2), the predicted total area under the plasma concentration time curve (AUC) of hP67.6 over the course of treatment is 25%, and maximum observed concentration (Cmax) is 24%, of the values for original 9 mg/m2 dosing regimen, since the PK is nonlinear. When gemtuzumab ozogamicin is administered at 3 mg/m2 on Days 1, 4, and 7, the Cmax of hP67.6, which would occur at the end of infusion, is predicted to be 0.38 mg/L following the first dose and increased to 0.63 mg/L after the third dose.
Distribution: In vitro, the binding of N-acetyl gamma calicheamicin dimethyl hydrazide to human plasma proteins is approximately 97%. In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide is a substrate of P-glycoprotein (P-gp). Population PK analyses found the total volume of distribution of hP67.6 antibody (sum of V1 [10 L] and V2 [15 L]) to be approximately 25 L.
Metabolism: The primary metabolic pathway of gemtuzumab ozogamicin is anticipated to be hydrolytic release of N-acetyl gamma calicheamicin dimethyl hydrazide. In vitro studies demonstrated that N-acetyl gamma calicheamicin dimethyl hydrazide is extensively metabolized, primarily via nonenzymatic reduction of the disulfide moiety. The activity (cytotoxicity) of the resultant metabolites is expected to be significantly attenuated. In patients, unconjugated calicheamicin plasma levels were typically low, with a predicted geometric mean Cmax of 1.5 ng/mL (95% CI: 1.4, 1.6) following the third dose.
Elimination: Based on population PK analyses, the predicted clearance (CL) parameter value of hP67.6 from plasma was 3 L/h immediately after the first dose and then 0.3 L/h. The terminal plasma half-life (t½) for hP67.6 was predicted to be approximately 160 hours for a typical adult male patient at the recommended dose level (3 mg/m2) of MYLOTARG.
Age, race, and gender: Based on a population PK analysis, age, race, and gender did not significantly affect MYLOTARG disposition.
Hepatic Impairment: No formal PK studies of MYLOTARG have been conducted in patients with hepatic impairment.
Based on a population PK analysis, the clearance parameter of gemtuzumab ozogamicin (hP67.6 antibody and unconjugated calicheamicin) is not expected to be affected by mild hepatic impairment status, as defined by National Cancer Institute Organ Dysfunction Working Group (NCI ODWG). The analysis included 405 patients in the following NCI ODWG impairment status categories: mild (B1, n=58 and B2, n=19), moderate (C, n=6) and normal hepatic function (n=322). The PK of gemtuzumab ozogamicin has not been studied in patients with severe hepatic impairment (see DOSAGE AND ADMINISTRATION, Dosing Considerations).
Renal Impairment: No formal PK studies of gemtuzumab ozogamicin have been conducted in patients with renal impairment (see DOSAGE AND ADMINISTRATION, Dosing Considerations).
Based on population PK analysis in 406 patients, the clearance parameter of gemtuzumab ozogamicin in patients with mild renal impairment (CLcr 60-89 mL/min; n=149) or moderate renal impairment (CLcr 30-59 mL/min; n=47), was similar to patients with normal renal function (CLcr ≥90 mL/min; n=209). The impact of severe renal impairment on PK of gemtuzumab ozogamicin could not be assessed, since data are available from a single patient only (CLcr 15-29 mL/min; n=1).
12 Storage, Stability And Disposal
Store in refrigerator (2°C to 8°C).
Do not freeze.
Store the vial in the original carton to protect from light.
Following reconstitution and dilution, the solution should be protected from light and should be used immediately. If the product cannot be used immediately, the diluted solution may be stored up to 18 hours in a refrigerator (2°C to 8°C) and up to 6 hours at room temperature (below 30°C). The allowed time at room temperature (below 30°C) includes the time required for preparation of the diluted solution, equilibration, if needed, and administration to the patient. The maximum time from preparation of the diluted solution through administration should not exceed 24 hours (see DOSAGE AND ADMINISTRATION, Reconstitution).
13 Special Handling Instructions
Use appropriate aseptic technique for the reconstitution and dilution procedures (see DOSAGE AND ADMINISTRATION, Reconstitution). MYLOTARG (gemtuzumab ozogamicin for injection) is light sensitive and should be protected from light during reconstitution, dilution, and administration.
Control #: 255008
September 20, 2021
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