Mylotarget

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MABTHERA (MYLOTARG)

Composition:

Active substance: gemtuzumab;

One vial contains 4.5 mg of gemtuzumab ozogamicin;

Excipients: sucrose, dextran 40, sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous.

Pharmaceutical form. Powder for concentrate for solution for infusion.

Basic physicochemical properties: lyophilized solid or powder, white or almost white.

Pharmacotherapeutic group

Antineoplastic agents. Monoclonal antibodies.

ATC code L01X C05.

Pharmacological Properties

Gemtuzumab ozogamicin is an antibody-drug conjugate (ADC) consisting of a monoclonal antibody directed against the CD33 antigen (hP67.6; recombinant humanized immunoglobulin [Ig] G4, kappa antibody produced in mammalian cell culture using NS0 cells), covalently linked to the cytotoxic agent N-acetyl-gamma-calicheamicin. Gemtuzumab ozogamicin consists of both conjugated and unconjugated gemtuzumab. The conjugated molecules differ in the number of activated calicheamicin derivative fragments attached to gemtuzumab. The number of calicheamicin derivative molecules conjugated per gemtuzumab molecule ranges from predominantly zero to six, with an average of 2 to 3 moles of calicheamicin derivative per 1 mole of gemtuzumab.

Mechanism of Action

The hP67.6 antibody recognizes the human CD33 antigen. The small molecule N-acetyl-gamma-calicheamicin is a cytotoxic agent covalently linked to the antibody via a linker. Preclinical studies indicate that the antitumor activity of gemtuzumab ozogamicin is mediated by binding of the ADC to tumor cells expressing the CD33 antigen, followed by internalization of the ADC-CD33 complex and intracellular release of N-acetyl-gamma-calicheamicin dimethylhydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl-gamma-calicheamicin dimethylhydrazide induces double-strand DNA breaks, leading to cell cycle arrest and apoptotic cell death.

Pharmacodynamics

High saturation levels of CD33 antigen markers are required for optimal delivery of calicheamicin to leukemic blast cells. In various studies, near-maximal peripheral CD33 saturation was observed after administration of gemtuzumab ozogamicin at doses ≥ 2 mg/m².

When administering a dose of 9 mg/m² of gemtuzumab ozogamicin (2 doses given 14 days apart), the risk of developing veno-occlusive disease (VOD) of the liver increases with higher Cmax of the first dose of gemtuzumab ozogamicin. An increased incidence of VOD was more frequently observed in patients with prior stem cell transplantation.

Clinical Studies

Newly diagnosed CD33-positive acute myeloid leukemia (AML)

Study ALFA-0701

The use of Mylotarg in combination with chemotherapy was evaluated in the ALFA-0701 study (NCT00927498), a multicenter, randomized, open-label phase 3 trial involving 271 patients with newly diagnosed de novo AML aged 50 to 70 years. Patients were randomized (1:1) to receive induction therapy consisting of daunorubicin (60 mg/m² on days 1–3) and cytarabine (200 mg/m² on days 1–7) (DA) with (n = 135) or without (n = 136) Mylotarg at a dose of 3 mg/m² (no more than one vial) on days 1, 4, and 7. Patients who did not achieve response after the first induction cycle had the option to receive a second induction cycle with daunorubicin (35 mg/m²/day on days 1 and 2) and cytarabine (1 g/m² every 12 hours on days 1–3), without Mylotarg. Responding patients received consolidation therapy consisting of two courses, including daunorubicin (60 mg/m² on day 1 of course 1; 60 mg/m² on days 1 and 2 of course 2) and cytarabine (1 g/m² every 12 hours on days 1–4), with or without Mylotarg at 3 mg/m² (no more than one vial) on day 1, according to initial randomization. Patients achieving remission were also eligible for allogeneic transplantation. An interval of at least 2 months between the last dose of Mylotarg and transplantation was recommended.

The median patient age was 62 years (range: 50–70 years), the population included 137 women and 134 men, and 88% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 at baseline. Baseline characteristics were balanced between treatment groups, except for sex—proportion of men was higher in the Mylotarg group (55%) compared to the DA group (44%). Overall, favorable/intermediate risk was documented in 59%, 65%, and 70% of patients according to National Comprehensive Cancer Network (NCCN), European LeukemiaNet (ELN), and cytogenetic risk classification, respectively, while high/unfavorable risk was observed in 33%, 27%, and 21% of patients, respectively. CD33 antigen expression on AML blast cells, assessed by flow cytometry and harmonized based on local laboratory results, was determined in 194 of 271 patients (72%). Low CD33 antigen expression (< 30% of blasts) was observed in several patients (14%), but no patient lacked CD33 antigen expression.

Efficacy was evaluated based on event-free survival (EFS), calculated from the date of randomization to the date of induction therapy failure, relapse, or death from any cause. According to the protocol, induction therapy failure was defined as failure to achieve complete remission (CR) or CR with incomplete platelet recovery (CRp) during induction therapy, and the date of induction therapy failure was defined as the date of bone marrow assessment after the last induction course. Median EFS was 17.3 months in the Mylotarg group compared to 9.5 months in the control group; hazard ratio (HR) was 0.56 (95% CI: 0.42–0.76); p-value by two-sided log-rank test was < 0.001.

In a sensitivity analysis of EFS (calculated from the date of randomization to failure to achieve CR during induction therapy, relapse, or death from any cause, using the date of randomization as the date of induction therapy failure), median EFS was 13.6 months with Mylotarg plus DA versus 8.8 months with DA alone; HR was 0.68 (95% CI: 0.51–0.91).

Study AAML0531

The use of Mylotarg in combination with chemotherapy was evaluated in study AAML0531 (NCT00372593), a multicenter, randomized trial involving 1063 patients with newly diagnosed AML aged 0 to 29 years. Patients were randomized to receive 5 cycles of chemotherapy with or without a single dose of Mylotarg (3 mg/m²/dose), administered once on day 6 of cycle 1 of induction therapy and once on day 7 of cycle 2 of intensification therapy. All patients proceeded to cycle 2 of induction therapy regardless of remission status after cycle 1 of induction therapy. Prior to initiation of subsequent therapy cycles, achievement of absolute neutrophil count (ANC) > 1 × 10⁹/L and platelet count > 75 × 10⁹/L was recommended in the absence of active disease. Patients who did not achieve remission after cycle 2 of induction therapy discontinued protocol therapy. All other patients proceeded to cycle 1 of intensification therapy. Patients with high and intermediate risk disease who had a 5/6 or 6/6 matched family donor (MFD) proceeded to hematopoietic stem cell transplantation (HSCT) after cycle 1 of intensification therapy. Patients with high-risk disease proceeded to HSCT from an alternative donor in the absence of an MFD. All patients with low-risk disease and any patients with high or intermediate risk disease without suitable donors proceeded to cycle 2 of intensification therapy with or without Mylotarg according to their initial randomization, followed by cycle 3 of intensification therapy. All patients in remission were to proceed to cycle 2 of intensification therapy or allogeneic HSCT. In cycle 2 of intensification therapy, patients received Mylotarg according to their initial randomization. Patients in remission after cycle 2 of intensification therapy proceeded to cycle 3 of intensification therapy.

A total of 532 patients were randomized to the Mylotarg plus chemotherapy group and 531 to the chemotherapy-only group. Overall, 94% of patients were under 18 years of age, and 6% were adults; median age was 9.0 years (range: 0–29 years). Men comprised 49% of study participants, women 51%, 73% were Caucasian, 11% Black, 5% Asian, 11% other racial groups or race not specified, and 18% were Hispanic. Distribution of patients in each risk group: low risk (23% vs 23%), intermediate risk (57% vs 57%), and high risk (15% vs 17%).

Evidence supporting efficacy was based on event-free survival (EFS), defined as the time from study enrollment to induction therapy failure, relapse, or death from any cause. Induction therapy failure was defined as inability to achieve complete response by the end of cycle 2 of induction therapy, and the date of induction therapy failure was defined as day 1 of the study. The hazard ratio for EFS was 0.84 (95% CI: 0.71–0.99). The estimated percentage of patients who remained free of induction therapy failure, relapse, or death at 5 years was 48% (95% CI: 43–52%) in the Mylotarg plus chemotherapy group compared to 40% (95% CI: 36–45%) in the chemotherapy-only group.

Study AML-19

The use of Mylotarg as monotherapy was evaluated in study AML-19 (NCT00091234), a multicenter, randomized, open-label phase 3 trial comparing Mylotarg with best supportive care (BSC) in patients with newly diagnosed AML aged over 75 years or aged 61–75 years with World Health Organization (WHO) performance status > 2 or unwillingness to receive intensive chemotherapy. Patients were randomized 1:1 and stratified by age (61–75 vs 76–80 vs ≥ 81 years), CD33-positive status of bone marrow blast cells (< 20% vs 20–80% vs > 80% vs unknown), baseline white blood cell count (< 30 × 10⁹/L vs ≥ 30 × 10⁹/L), WHO performance status (0–1 vs 2 vs 3–4), and study site.

During induction therapy, patients received Mylotarg at 6 mg/m² on day 1 and 3 mg/m² on day 8. Patients without signs of disease progression or significant toxicity after Mylotarg induction therapy received further outpatient treatment consisting of up to 8 treatment cycles with Mylotarg at 2 mg/m² on day 1 every 4 weeks. Patients continued therapy unless significant toxicity, relapse, or disease progression occurred. BSC included standard supportive care and use of hydroxyurea or other antimetabolites as palliative therapy.

A total of 118 patients were randomized to receive Mylotarg and 119 to receive BSC. Median patient age was 77 years (range: 62–88 years); most patients (65%) had a baseline WHO performance status of 0–1. Baseline characteristics were balanced between treatment groups, except for sex and cytogenetics. Compared to the BSC group, the Mylotarg group had a higher proportion of women (52% vs 39%) and patients with favorable/intermediate cytogenetic risk (50% vs 38%). The proportion of patients with unfavorable cytogenetics was similar in both groups (28% vs 27%). Fewer patients in the Mylotarg group lacked cytogenetic data (22% vs 35%). CD33 antigen expression on AML blast cells, assessed by flow cytometry at a central laboratory, was determined in 235 of 237 patients (99%); CD33 expression level was < 20% in 10% of patients.

Efficacy of Mylotarg was evaluated based on improvement in overall survival (OS). The hazard ratio (HR) for OS was 0.69 (95% CI: 0.53–0.90); p-value by two-sided log-rank test was 0.005. Median OS was 4.9 months in the Mylotarg group compared to 3.6 months in the control group.

Relapsed or Refractory CD33-Positive AML

Study MyloFrance-1

The efficacy of Mylotarg as monotherapy was evaluated in the MyloFrance-1 study, a non-comparative, open-label phase 2 trial in adult patients with CD33-positive AML in first relapse. Patients with secondary leukemia or prior autologous or allogeneic stem cell transplantation were excluded. Investigational treatment included one cycle of Mylotarg at 3 mg/m² on days 1, 4, and 7. Consolidation therapy included intravenous cytarabine every 12 hours for 3 days. Cytarabine dose was 3 g/m² for patients under 55 years of age and 1 g/m² for patients aged 55 years or older and/or with creatinine clearance < 50 mL/min. Hematopoietic stem cell transplantation (HSCT) was permitted after Mylotarg treatment, but HSCT was recommended to be delayed by at least 90 days after Mylotarg administration.

A total of 57 patients received Mylotarg treatment. Median patient age was 64 years (range: 22–80 years). Median duration of first remission was 10 months. Forty-four patients (78%) had intermediate-risk cytogenetics, and 12 patients (22%) had high-risk cytogenetics.

Efficacy of Mylotarg was evaluated based on complete remission (CR) rate and duration of remission. Fifteen patients (26%; 95% CI: 16–40%) achieved CR after one cycle of Mylotarg. Median relapse-free survival, calculated from the date of first documented CR to the date of relapse or death, was 11.6 months.

Pharmacokinetics

Clinical pharmacokinetic (PK) data for fractionated dosing regimens are lacking. After administration of a 9 mg/m² dose of gemtuzumab ozogamicin (2 doses given 14 days apart), Cmax after the first dose was 3.0 mg/L and increased to 3.6 mg/L after the second dose.

Distribution

N-acetyl-gamma-calicheamicin dimethylhydrazide is approximately 97% bound to human plasma proteins in vitro. Population PK analyses indicate that the total volume of distribution of the hP67.6 antibody (sum of V1 [6.31 L] and V2 [15.1 L]) in patients is approximately 21.4 L.

Elimination

The clearance (Cl) of the hP67.6 antibody from plasma was 0.35 L/h after the first dose and 0.15 L/h after the second dose; a reduction of approximately 60%. The terminal half-life (t½) of the hP67.6 antibody in plasma was 62 hours after the first dose and 90 hours after the second dose.

Metabolism

In vitro studies indicate that N-acetyl-gamma-calicheamicin dimethylhydrazide is actively metabolized primarily via non-enzymatic cleavage of the disulfide fragment.

Special Patient Populations

Age, race, sex, presence of mild or moderate renal impairment (creatinine clearance [CrCl] by Cockcroft-Gault formula 30–89 mL/min), or mild hepatic impairment had no clinically significant effect on the pharmacokinetics of gemtuzumab ozogamicin. The pharmacokinetics of gemtuzumab ozogamicin in patients with severe renal impairment (CrCl 15–29 mL/min) or moderate (total bilirubin > 1.5 × ULN [upper limit of normal] to 3.0 × ULN) and severe hepatic impairment (total bilirubin > 3 × ULN) is unknown.

Elderly Patients

The use of Mylotarg in combination with daunorubicin and cytarabine in adult patients with newly diagnosed de novo AML is supported by results from a randomized controlled trial involving 50 patients aged ≥ 65 years. No overall differences in safety or efficacy were observed between these patients and younger patients. The use of Mylotarg as monotherapy in adult patients with newly diagnosed AML is supported by results from a randomized controlled trial involving 118 patients treated with Mylotarg. All patients were over 60 years of age, and 65% were over 75 years of age. No overall differences in efficacy based on patient age were observed.

The use of Mylotarg as monotherapy for the treatment of relapsed or refractory AML is supported by results from a non-comparative study involving 27 patients aged 65 years or older. No overall differences in efficacy were observed between these patients and younger patients. In elderly patients, a higher incidence of fever and severe or higher-grade infections was observed.

Clinical characteristics

Indications

MyloTarg is indicated for:

• Treatment of newly diagnosed CD33-positive acute myeloid leukemia in adults and children aged 1 month and older.
• Treatment of relapsed or refractory CD33-positive acute myeloid leukemia in adults and children aged 2 years and older.

Contraindications

MyloTarg is contraindicated in patients with a history of hypersensitivity to the active substance, any of the excipients, or components of the product. Reported reactions included anaphylactic reactions (see sections "Special precautions" and "Adverse reactions").

Interaction with other medicinal products and other forms of interaction

Clinical studies on interactions with other medicinal products have not been conducted.

In vitro studies

At clinically relevant concentrations, gemtuzumab ozogamicin has a low potential for the following interactions.

Inhibition of cytochrome CYP450 enzymes: CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.

At clinically relevant concentrations, N-acetyl-gamma-kalicheamicin dimethylhydrazide has a low potential for the following interactions.

Inhibition of cytochrome CYP450 enzymes: CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5.

Induction of cytochrome CYP450 enzymes: CYP1A2, CYP2B6, and CYP3A4.

Inhibition of uridine diphosphate-glucuronosyltransferase (UGT) enzymes: UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7.

Inhibition of drug transporters: P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporters (OAT)1 and (OAT)3, organic cation transporter (OCT)2, organic anion transporting polypeptides (OATP)1B1 and OATP1B3.

Special Warnings and Precautions for Use

Hepatotoxicity, including veno-occlusive disease (VOD) of the liver

Hepatotoxicity, including life-threatening and sometimes fatal cases of VOD, has been reported in patients treated with Mylotarg as monotherapy or in combination with chemotherapy (see section "Adverse Reactions").

In the ALFA-0701 study, VOD was reported in 6 of 131 patients (5%) during or after treatment with Mylotarg, or after subsequent hematopoietic stem cell transplantation (HSCT). The median time from Mylotarg administration to onset of VOD was 9 days (range: 2–298 days); 5 cases occurred within 28 days of any Mylotarg dose, and 1 case occurred more than 28 days after the last Mylotarg dose. Three of the 6 VOD cases were fatal. VOD was also reported in 2 patients in the control arm of the ALFA-0701 study after receiving Mylotarg for treatment of relapsed AML.

In the MyloFrance-1 study (Mylotarg 3 mg/m² on days 1, 4, and 7), no cases of VOD were reported in any of the 57 patients during or after treatment or after subsequent HSCT following completion of Mylotarg therapy.

In the AAML0531 study, VOD was reported in 25 of 520 pediatric patients (5%) in the Mylotarg treatment arm. VOD was fatal in 2 patients. Among 187 pediatric patients who underwent HSCT in the Mylotarg treatment arm, VOD occurred within 30 days after HSCT in 20 patients (11%).

Based on data analyses from various studies, the risk of VOD was higher in adult patients receiving higher doses of Mylotarg as monotherapy, in patients with pre-existing moderate or severe hepatic impairment prior to Mylotarg administration, in patients receiving Mylotarg after HSCT, and in patients undergoing HSCT after Mylotarg therapy. The likelihood of developing VOD was 8.7 times higher in patients with pre-existing moderate/severe hepatic impairment compared to patients without moderate/severe hepatic impairment at baseline. The likelihood of developing VOD was 2.6 times higher in patients treated with Mylotarg for relapse after HSCT compared to patients without prior HSCT. The likelihood of developing VOD after HSCT was 2.9 times higher in patients who underwent HSCT after Mylotarg therapy compared to patients without HSCT after Mylotarg therapy. Although no association between VOD occurrence and timing of HSCT was identified when higher doses of Mylotarg were used as monotherapy, based on the ALFA-0701 study, it is recommended to maintain a 2-month interval between the last Mylotarg dose and HSCT. In the MyloFrance-1 study, no patient underwent HSCT within 3.5 months after Mylotarg therapy.

Prior to each Mylotarg administration, levels of ALT, AST, total bilirubin, and alkaline phosphatase should be determined. After Mylotarg therapy, frequent monitoring for signs and symptoms of VOD is required; these may include elevated ALT, AST, and total bilirubin levels, hepatomegaly (which may be tender), rapid weight gain, and ascites. Monitoring of total bilirubin alone may not be sufficient to identify all patients at risk of VOD. In case of abnormalities in liver function tests, increased frequency of monitoring liver function tests and clinical signs and symptoms of hepatotoxicity is recommended. Patients undergoing HSCT after Mylotarg therapy require frequent monitoring of liver function tests during the post-HSCT period.

To manage signs or symptoms of hepatotoxicity, temporary or permanent discontinuation of Mylotarg should be considered (see section "Dosage and Administration"). In case of VOD occurrence, Mylotarg must be permanently discontinued, and treatment should be initiated according to standard medical practice.

Infusion reactions (including anaphylactic reactions)

Life-threatening or fatal infusion reactions may occur during or within 24 hours after Mylotarg infusion (see section "Adverse Reactions"). Signs or symptoms of infusion reactions may include fever, chills, hypotension, tachycardia, hypoxia, and respiratory failure.

Premedication is required prior to Mylotarg infusion (see section "Dosage and Administration"). Frequent monitoring of vital signs is required during infusion. In case of infusion reaction, especially dyspnea, bronchospasm, or hypotension, the infusion must be immediately stopped. Patients should be monitored during and for at least 1 hour after completion of infusion or until signs and symptoms have fully resolved. In case of signs or symptoms of anaphylactic reactions, including severe respiratory symptoms or clinically significant hypotension, Mylotarg must be permanently discontinued (see section "Dosage and Administration").

Bleeding

Mylotarg is a myelosuppressive agent that may cause fatal or life-threatening bleeding due to prolonged thrombocytopenia. In the ALFA-0701 study (Mylotarg in combination with chemotherapy), bleeding events of all grades and grade 3–4 were reported in 118 of 131 patients (90%) and 27 of 131 patients (21%), respectively. Fatal bleeding events (including cerebral, intracranial, and subdural hematomas) were reported in 4 of 131 patients (3%). Thrombocytopenia with platelet counts < 50 × 10⁹/L lasting more than 42 days was reported in 19 patients (19%) during the induction therapy phase (see section "Adverse Reactions"). The proportion of patients with persistent thrombocytopenia increased with the number of treatment phases and was higher in patients receiving Mylotarg in combination with chemotherapy compared to those receiving chemotherapy alone (see section "Adverse Reactions").

In the AAML0531 study, fatal bleeding occurred in 3 of 520 pediatric patients (<1%). Grade 3 or 4 bleeding events were reported in 66 of 520 pediatric patients (13%) in the Mylotarg treatment arm.

In the AML-19 study (Mylotarg as monotherapy at 6 mg/m² on day 1 and 3 mg/m² on day 8), bleeding events of all grades and grade ≥3 were reported in 28 of 111 patients (25%) and 14 of 111 patients (13%), respectively. One fatal bleeding event was reported in 1 of 111 patients (1%). In the MyloFrance-1 study (Mylotarg as monotherapy at 3 mg/m²), grade 3 bleeding events were reported in 4 of 57 patients (7%), but no grade 4 bleeding events were reported in any patient.

Prior to each Mylotarg administration, complete blood count parameters should be determined, and frequent monitoring of complete blood count parameters is required after Mylotarg therapy until cytopenia resolves. During Mylotarg treatment, patients should be monitored for signs and symptoms of bleeding. In case of severe bleeding, hemorrhage, or persistent thrombocytopenia, Mylotarg administration should be delayed or permanently discontinued (see section "Dosage and Administration"), and supportive therapy should be provided according to standard practice.

QT interval prolongation

QT interval prolongation has been observed in patients treated with other calicheamicin-containing agents. Electrocardiography (ECG) and electrolyte levels should be monitored before initiation of Mylotarg therapy and as needed during treatment in patients with a history of QTc prolongation, those taking concomitant medications known to prolong the QT interval, or those with electrolyte imbalances.

Use in AML with adverse cytogenetic risk

Subgroup analyses from the ALFA-0701 study showed that adding Mylotarg to standard combination chemotherapy did not improve event-free survival in the subgroup of patients with adverse cytogenetic risk (hazard ratio [HR] 1.11; 95% confidence interval [CI]: 0.63, 1.95). In patients receiving Mylotarg in combination with daunorubicin and cytarabine for treatment of newly diagnosed de novo AML, the potential benefit of continuing Mylotarg therapy should be weighed against the risks for each individual patient after cytogenetic test results are available.

Embryo-fetal toxicity

Due to its mechanism of action and findings from animal studies, Mylotarg may cause harm to the fetus if administered to pregnant women. In animal studies, gemtuzumab ozogamicin caused embryo-fetal toxicity at exposures approximately 0.4-fold of the human exposure at the maximum recommended human dose based on area under the concentration-time curve (AUC) values.

Women of reproductive potential should be advised to use effective contraception during Mylotarg therapy and for at least 6 months after the last dose. Men with female partners of reproductive potential should be advised to use effective contraception during Mylotarg therapy and for at least 3 months after the last dose. Pregnant women should be informed of the potential risk to the fetus. Women should be advised to inform their physician if they become pregnant or suspect pregnancy during Mylotarg therapy (see sections "Pregnancy and Breastfeeding").

Traceability

In order to improve traceability of biological medicinal products, the name and batch number of the administered product should be clearly documented.

Sodium content

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free".

Use during Pregnancy or Breastfeeding

Pregnancy

Due to its mechanism of action, Mylotarg may cause harm to the fetus if administered to pregnant women. There are no data on Mylotarg use in pregnant women; therefore, the associated risk cannot currently be assessed. In reproductive toxicity studies in animals, gemtuzumab ozogamicin caused embryo-fetal toxicity, including structural abnormalities and developmental disturbances, when systemic exposure in the maternal organism was ≥0.4-fold of the human exposure at the maximum recommended dose based on AUC values. Patients should be informed of the potential risk to the fetus.

The expected background risk of major congenital malformations and miscarriage in the specified patient group is unknown. All pregnancies carry a background risk of birth defects, miscarriage, or other adverse outcomes. In the general U.S. population, the expected background risk of major congenital malformations and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Breastfeeding

There are no data on the presence of gemtuzumab ozogamicin or its metabolites in human breast milk, the effects on breastfed infants, or the effects on milk production. Due to the potential for serious adverse reactions in breastfed infants, women should be advised not to breastfeed during Mylotarg therapy and for at least 1 month after the last dose.

Women and Men of Reproductive Potential

Mylotarg may cause harm to the embryo or fetus if administered to a pregnant woman.

Before initiating Mylotarg therapy, women of reproductive potential should undergo a pregnancy test.

Contraception

Women

Women of reproductive potential should be advised to use effective contraception during Mylotarg therapy and for at least 6 months after the last dose.

Men

Men with female partners of reproductive potential should be advised to use effective contraception during Mylotarg therapy and for at least 3 months after the last dose.

Infertility

Women

Based on animal studies, Mylotarg may impair female fertility.

Men

Based on animal studies, Mylotarg may impair male fertility.

Effect on ability to drive and use machines

Mylotarg has a moderate effect on the ability to drive and use machines. Patients should be informed that fatigue, dizziness, or headache may occur during Mylotarg therapy (see section "Adverse Reactions"). Therefore, caution should be exercised when driving or operating machinery.

Administration and Dosage

Pre-medication and Administration Guidelines

Adult patients require pre-medication with acetaminophen 650 mg orally and diphenhydramine 50 mg intravenously 1 hour prior to administration of Mylotarg, as well as methylprednisolone 1 mg/kg or an equivalent corticosteroid in an equivalent dose 30 minutes prior to Mylotarg infusion.

Pediatric patients aged 1 month and older require pre-medication with acetaminophen 15 mg/kg (not exceeding 650 mg) and diphenhydramine 1 mg/kg (not exceeding 50 mg) 1 hour prior to Mylotarg administration, and methylprednisolone 1 mg/kg orally or intravenously 30 minutes prior to Mylotarg infusion. Additional doses of acetaminophen and diphenhydramine may be administered every 4 hours after the initial pre-medication. In case of any signs of infusion reaction such as fever, chills, hypotension, or dyspnea during or within 4 hours after completion of the infusion, the same dose of methylprednisolone or an equivalent corticosteroid should be re-administered (see section "Special Warnings and Precautions").

Appropriate measures should be taken to prevent tumor lysis syndrome.

In case of hyperleukocytosis (white blood cell count ≥ 30 × 10⁹/L), cytoreduction is recommended prior to administration of Mylotarg.

Recommended Dosage

Newly Diagnosed CD33-Positive de novo AML (Combination Therapy)

Adults

The recommended dose of Mylotarg for adults is 3 mg/m². The treatment course of Mylotarg as part of combination therapy in adults with newly diagnosed CD33-positive de novo AML consists of 1 induction cycle and 2 consolidation cycles.

During the induction cycle, the recommended dose of Mylotarg is 3 mg/m² (not exceeding one 4.5 mg vial) on days 1, 4, and 7, in combination with daunorubicin and cytarabine. In case a second induction cycle is required, Mylotarg is CONTRAINDICATED during the second induction cycle.

During the consolidation cycles, the recommended dose of Mylotarg is 3 mg/m² (not exceeding one 4.5 mg vial) on day 1, in combination with daunorubicin and cytarabine.

Children aged 1 month and older

The recommended dose of Mylotarg for children aged 1 month and older is:

• 3 mg/m² for patients with body surface area (BSA) ≥ 0.6 m²;
• 0.1 mg/kg for patients with BSA < 0.6 m².

For cycle 1 of induction therapy, Mylotarg is administered as a single dose in combination with standard chemotherapy. Mylotarg is not used in the second induction cycle (see section "Pharmacodynamics").

Mylotarg is not administered in the first or third intensification cycle. In cycle 2 of intensification, Mylotarg is administered as a single dose in combination with standard chemotherapy. The risks and potential benefits should be carefully evaluated before administering Mylotarg in cycle 2 of intensification (see section "Adverse Reactions").

Newly Diagnosed CD33-Positive AML (Monotherapy)

The treatment course of Mylotarg as monotherapy in adults with newly diagnosed CD33-positive AML includes 1 induction cycle and up to 8 subsequent therapy cycles.

During the induction cycle, the recommended dose of Mylotarg is 6 mg/m² (not limited to one 4.5 mg vial) as monotherapy on day 1 and 3 mg/m² (not limited to one 4.5 mg vial) on day 8.

During subsequent therapy cycles, the recommended dose of Mylotarg is 2 mg/m² (not limited to one 4.5 mg vial) as monotherapy on day 1 every 4 weeks.

Relapsed or Refractory CD33-Positive AML (Monotherapy)

The recommended dose of Mylotarg as monotherapy for the treatment of relapsed or refractory CD33-positive AML in adults and children aged 2 years and older is 3 mg/m² (not exceeding one 4.5 mg vial) on days 1, 4, and 7. Treatment of relapsed or refractory disease consists of one course of Mylotarg therapy (see section "Pharmacodynamics").

Dose Adjustment in Case of Toxicity

Complete blood counts should be monitored frequently until cytopenia resolves. Clinical and biochemical blood parameters should be monitored at least three times weekly until treatment-related toxicity resolves. Management of certain adverse reactions (see sections "Special Warnings and Precautions" and "Adverse Reactions") may require temporary or permanent discontinuation of Mylotarg. Table 1 provides guidance on dose adjustments for hematologic and non-hematologic toxicities.

Table 1. Dose modification in case of hematological and non-hematological toxicity
Hematological and non-hematological toxicity	Recommended actions
Patients receiving Mylotarg as part of combination therapy
Persistent thrombocytopenia	Adults: If platelet count does not recover to ≥ 100 × 10⁹/L within 14 days after the scheduled start date of consolidation therapy (14 days after normalization of blood counts following the previous cycle), Mylotarg must be permanently discontinued (Mylotarg is contraindicated during consolidation therapy) Children: Platelet count must be at least 75 × 10⁹/L prior to the next cycle (induction or intensification)
Persistent neutropenia	Adults: If neutrophil count does not recover to > 0.5 × 10⁹/L within 14 days after the scheduled start date of consolidation therapy (14 days after normalization of blood counts following the previous cycle), Mylotarg must be permanently discontinued (Mylotarg is contraindicated during consolidation therapy) Children: Neutrophil count must be at least 1 × 10⁹/L prior to the next cycle (induction or intensification)
All patients receiving Mylotarg (as monotherapy or as part of combination therapy)
VOD	Permanently discontinue Mylotarg (see section "Special precautions")
Total bilirubin > 2 × ULN or AST and/or ALT > 2.5 × ULN	Withhold Mylotarg until total bilirubin recovers to ≤ 2 × ULN and AST and ALT recover to ≤ 2.5 × ULN prior to each dose. If the delay between two consecutive infusions exceeds 2 days, omit the planned dose
Infusion reactions	Interrupt infusion and provide appropriate medical treatment. Administer acetaminophen, diphenhydramine, and/or methylprednisolone as needed (see section "Dosage and administration"). Provide supportive care as needed. For mild, moderate, or severe infusion reactions, after resolution of symptoms, consider resuming infusion at a rate no greater than half the rate that caused the reaction. If symptoms recur, repeat the above procedure. For severe infusion reactions or any life-threatening infusion reactions, permanently discontinue Mylotarg (see section "Special precautions")
Other severe or life-threatening non-hematological toxicity	Withhold Mylotarg until toxicity resolves to at least mild severity. If the delay between two consecutive infusions exceeds 2 days, omit the planned dose
Abbreviations: ALT — alanine aminotransferase; AST — aspartate aminotransferase; VOD — veno-occlusive disease; ULN — upper limit of normal.

Instructions for Reconstitution, Dilution, and Administration

During reconstitution and dilution procedures, appropriate aseptic techniques should be used. The reconstituted and diluted solution of Mylotarg should be protected from light.

Reconstitution

1. Mylotarg is a cytotoxic agent. Appropriate special handling and disposal procedures must be followed.
2. Calculate the required dose (mg) and the number of Mylotarg vials needed.
3. Allow vials to reach room temperature (up to 30 °C) for approximately 5 minutes before reconstitution.
4. Reconstitute the contents of each vial with 5 mL of sterile Water for Injection to achieve a concentration of 1 mg/mL of Mylotarg, resulting in a volume of 4.5 mL (4.5 mg).
5. Gently swirl the vial to aid dissolution. DO NOT SHAKE.
6. Inspect the reconstituted solution for particulate matter and discoloration. The reconstituted solution may contain small, translucent or opalescent, amorphous or fibrous particles, white or almost white in color.
7. Mylotarg does not contain bacteriostatic preservatives.
8. If not used immediately, the reconstituted solution may be stored in the original vial for up to 16 hours in a refrigerator (2–8 °C) or up to 3 hours at room temperature (up to 30 °C). PROTECT FROM LIGHT. DO NOT FREEZE.

Dilution

1. Calculate the required volume of reconstituted solution based on the patient’s body surface area to achieve the appropriate dose. Withdraw this volume from one or more vials using a syringe. PROTECT FROM LIGHT. Discard any unused reconstituted solution remaining in the vial.

Doses must be diluted to achieve a concentration between 0.075 mg/mL and 0.234 mg/mL according to the instructions below.

1. Doses < 3.9 mg should be prepared for administration using a syringe. Add the reconstituted Mylotarg solution to a syringe containing 0.9% Sodium Chloride Injection to achieve a final concentration between 0.075 mg/mL and 0.234 mg/mL. PROTECT FROM LIGHT.
2. Doses ≥ 3.9 mg should be diluted in a syringe or in a polyvinyl chloride (PVC) bag containing di(2-ethylhexyl)phthalate (DEHP), non-DEHP PVC, polyolefin, or ethylene-vinyl acetate, with an appropriate volume of 0.9% Sodium Chloride Injection to achieve a final concentration between 0.075 mg/mL and 0.234 mg/mL. PROTECT FROM LIGHT.
3. Gently invert the infusion container to mix the diluted solution. DO NOT SHAKE.
4. After dilution with 0.9% Sodium Chloride Injection, the Mylotarg solution should be administered immediately. If not used immediately, the diluted solution may be stored for up to 18 hours in a refrigerator (2–8 °C) and up to 6 hours at room temperature (up to 30 °C). The permitted room temperature storage period (up to 30 °C) includes the time required for preparation of the diluted solution, equilibration if necessary, and 2 hours required for patient administration. PROTECT FROM LIGHT and DO NOT FREEZE.

Administration

• Administer Mylotarg infusion using a 0.2-micron polyester sulfone (PES) filter.
• During infusion, protect the intravenous infusion bag from light using a light-protective covering. The infusion set does not require light protection.
• Administer the diluted solution over 2 hours using an infusion system made of polyvinyl chloride (PVC) with DEHP, non-DEHP PVC, polyethylene, or polyurethane. The infusion must be completed within the permitted 6-hour room temperature (up to 30 °C) storage period of the diluted solution.
• Mylotarg must not be mixed or co-administered with other medicinal products.

Children

The safety and efficacy of Mylotarg in combination with standard chemotherapy have been established in children aged 1 month and older with newly diagnosed de novo AML. The use of Mylotarg for this indication is supported by evidence of efficacy from adequately conducted and controlled studies in adults, along with supportive safety and efficacy data from study AAML0531 (NCT00372593) (see sections "Adverse Reactions", "Pharmacodynamics"). Study AAML0531 included patients in the following age groups: 2 patients aged < 27 days, 94 patients aged 28 days to < 2 years, 225 patients aged 2 to < 12 years, 175 patients aged 12 to < 18 years, and 36 patients aged ≥ 18 years in the Mylotarg plus chemotherapy group. The safety and efficacy of Mylotarg in combination with standard chemotherapy in children under 1 month of age with newly diagnosed de novo AML have not been established.

The safety and efficacy of Mylotarg as monotherapy in children with newly diagnosed AML have not been established.

The safety and efficacy of Mylotarg as monotherapy in pediatric patients with relapsed or refractory AML are supported by results from a non-comparative study involving 29 patients in the following age groups: 1 patient aged 1 month to < 2 years, 13 patients aged 2 to < 12 years, and 15 patients aged 12–18 years. A review of published case reports included an additional 96 patients aged 0.2 to 21 years. No differences in efficacy or safety based on patient age were observed. Information on this use is provided in the prescribing information. The safety and efficacy of Mylotarg as monotherapy in children under 2 years of age with relapsed or refractory AML have not been established.

Overdose

There have been no reported cases of Mylotarg overdose in clinical experience. Single doses exceeding 9 mg/m² have not been administered to adults. Management of Mylotarg overdose should consist of general supportive measures.

Adverse Reactions

The clinically significant adverse reactions listed below are discussed in detail in other sections of this instruction.

• Hepatotoxicity, including veno-occlusive disease (VOD) (see section "Special Warnings and Precautions for Use").
• Infusion reactions (see section "Special Warnings and Precautions for Use").
• Hemorrhage (see section "Special Warnings and Precautions for Use").

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, the frequency of adverse reactions observed in the clinical trials of one drug cannot be directly compared with that of another drug, and may not reflect the frequency observed in clinical practice.

Combination therapy for the treatment of newly diagnosed CD33-positive de novo AML

The safety of Mylotarg in combination with first-line therapy was evaluated in two prospective clinical trials: the ALFA-0701 trial in adults and the AAML0531 trial in children.

ALFA-0701 Study

The safety assessment of Mylotarg (3 mg/m² on days 1, 4, and 7 in combination with daunorubicin and cytarabine [DA]) in adults was based on the ALFA-0701 trial, in which 131 patients received Mylotarg in combination with DA and 137 patients received DA alone. In this study, 123 patients received all three scheduled doses of Mylotarg, while 7 patients missed at least one dose. The mean total administered dose during the induction cycle was 14.51 mg (range: 4.6–18.0 mg). Mylotarg was administered to 91 patients (70%) in the Mylotarg group during consolidation cycle 1 and to 64 patients (49%) during consolidation cycle 2.

Safety data, including information on individual adverse reactions occurring after the start of treatment (ARTAEs), considered most relevant for understanding the safety profile of Mylotarg, as well as all adverse reactions (ARs) leading to permanent discontinuation of treatment, were collected retrospectively. Individual ARTAEs included hemorrhage of all severity grades, VOD of all severity grades, and severe infections.

Treatment discontinuation due to any adverse reaction was reported in 31% of patients in the Mylotarg group compared to 7% in the DA group. The most frequent adverse reactions (≥1%) leading to permanent treatment discontinuation in patients receiving Mylotarg were thrombocytopenia (15%), VOD (3%), and septic shock (2%).

Fatal adverse reactions were reported in 8 patients (6%) in the Mylotarg group compared to 3 patients (2%) in the DA group. In the Mylotarg group, 3 patients died due to VOD, 4 patients died due to hemorrhage-related events (CNS hemorrhage, hemorrhagic shock), and 1 patient died due to suspected cardiac toxicity. In the DA group, 3 patients died due to sepsis.

Table 2. Selected adverse reactions of grade ≥ 3 in patients with newly diagnosed de novo AML in the ALFA-0701 study
Adverse reactions	Mylotarg + daunorubicin + cytarabine (n (%))	Daunorubicin + cytarabine (n (%))
Induction therapy	N = 131	N = 137
Infectiona	61 (47 %)	53 (39 %)
Bleedingb	24 (18 %)	12 (9 %)
Hepatic veno-occlusive diseasec	3 (2 %)	0
Consolidation therapy, cycle 1	N = 91	N = 103
Infectiona	50 (55 %)	43 (42 %)
Bleedingb	5 (5 %)	0
Hepatic veno-occlusive diseasec	0	0
Consolidation therapy, cycle 2	N = 64	N = 107
Infectiona	32 (50 %)	54 (50 %)
Bleedingb	4 (6 %)	0
Hepatic veno-occlusive diseasec	0	0
Abbreviations: AML — acute myeloid leukemia; N — number of patients; PT — preferred term. a Infection — grouped term including various PTs. b Bleeding — grouped term including various PTs. c The term "hepatic veno-occlusive disease" includes the following reported PTs: hepatic veno-occlusive disease, veno-occlusive disease.

All participants in the ALFA-0701 study experienced severe cases of neutropenia, thrombocytopenia, and anemia. The incidence of grade 3–4 thrombocytopenia, which was prolonged in the absence of active leukemia, was higher in patients who received Mylotarg treatment (Table 3).

Table 3. Prolonged cytopeniaa in the ALFA-0701 study
Adverse reactions	Mylotarg + daunorubicin + cytarabine (n/N (%))	Daunorubicin + cytarabine (n/N (%))
Induction therapy
Prolonged thrombocytopenia	19/101 (19 %)	7/97 (7 %)
Prolonged neutropenia	3/106 (3 %)	0/101 (0 %)
Consolidation therapy, cycle 1
Prolonged thrombocytopenia	21/87 (24 %)	6/91 (7 %)
Prolonged neutropenia	3/88 (3 %)	1/97 (1 %)
Consolidation therapy, cycle 2
Prolonged thrombocytopenia	22/62 (35 %)	25/103 (24 %)
Prolonged neutropenia	1/62 (2 %)	2/105 (2 %)
a Platelet count < 50 × 109/L or neutrophil count < 0.5 × 109/L persisting after day 42 of cycle in the absence of active leukemia.

Table 4 summarizes the abnormalities in individual biochemical parameters in patients who received treatment in the ALFA-0701 study.

Table 4. Biochemical laboratory parameters: abnormalities in patients with baseline grade ≤ 2 in the ALFA-0701 study
Abnormal laboratory parameters	Mylotarg + daunorubicin + cytarabine		Daunorubicin + cytarabine
	Patients (n) with grade ≤ 2 at baseline	Patients progressing to grade ≥ 3 (n (%))	Patients (n) with grade ≤ 2 at baseline	Patients progressing to grade ≥ 3 (n (%))
Hypophosphatemia	117	75 (64 %)	127	52 (41 %)
Hypokalemia	127	73 (57 %)	133	41 (31 %)
Hyponatremia	129	57 (44 %)	134	36 (27 %)
Elevated alkaline phosphatase	120	16 (13 %)	128	7 (5 %)
Elevated aspartate aminotransferase	126	18 (14 %)	132	11 (8 %)
Elevated alanine aminotransferase	124	13 (10 %)	132	20 (15 %)
Elevated blood bilirubin	119	9 (8 %)	126	5 (4 %)

Study AAML0531

The safety evaluation of Mylotarg in combination with chemotherapy in pediatric patients is based on data from study AAML0531 (see section "Pharmacodynamics"), in which patients were randomized to receive treatment (N = 520 in the Mylotarg plus chemotherapy group and N = 517 in the chemotherapy-only group). In the treatment arm of this study, 520 patients received cycle 1 of induction therapy and 326 patients received cycle 2 of intensification therapy.

Safety data collected included only non-hematologic adverse events of grade 3 or 4, fatal adverse events, VOD/SOS, and prolonged duration of neutropenia and thrombocytopenia.

Table 5 lists the adverse events of grade 3 or higher (≥ 5%) observed in the Mylotarg plus chemotherapy and chemotherapy-only groups among patients with newly diagnosed de novo AML in study AAML0531.

In the Mylotarg plus chemotherapy group, fatal adverse events (by MedDRA system organ class terms) included infection (14 [3%]), multi-organ failure (5 [1%]), anemia (1 [<1%]), and hemorrhage (3 [<1%]). In the chemotherapy-only group, fatal adverse events included infection (7 [1%]), multi-organ failure (6 [1%]), hepatic failure (1 [<1%]), arterial hypotension (3 [<1%]), and hemorrhage (3 [<1%]).

Table 5. Adverse reactions of grade 3 and higher (≥ 5%) in patients with newly diagnosed de novo AML in study AAML0531 during cycles of treatment with Mylotarg

Adverse Reactions	Induction, cycle 1		Intensification, cycle 2
	Mylostar + chemotherapy N = 520 n (%)	Chemotherapy alone N = 517 n (%)	Mylostar + chemotherapy N = 326 n (%)	Chemotherapy alone N = 304 n (%)
Infectiona	186 (36 %)	181 (35 %)	220 (67 %)	211 (69 %)
Febrile neutropenia	167 (32 %)	157 (30 %)	79 (24 %)	68 (22 %)
Decreased appetite	78 (15 %)	79 (15 %)	61 (19 %)	36 (12 %)
Hypoglycemia	59 (11 %)	55 (11 %)	36 (11 %)	28 (9 %)
Mucositisa	55 (11 %)	64 (12 %)	25 (8 %)	15 (5 %)
Hypoxia	35 (7 %)	26 (5 %)	19 (6 %)	22 (7 %)
Bleedinga	36 (7 %)	19 (4 %)	19 (6 %)	9 (3 %)
Increased transaminase levelsa	33 (6 %)	24 (5 %)	23 (7 %)	13 (4 %)
Diarrhea	21 (4 %)	36 (7 %)	15 (5 %)	10 (3 %)
Nausea	21 (4 %)	18 (4 %)	23 (7 %)	10 (3 %)
Arterial hypotension	16 (3 %)	26 (5 %)	28 (9 %)	23 (8 %)

A collective term encompassing various preferred terms.

The addition of Mylotarg to chemotherapy was associated with an increased incidence of prolonged thrombocytopenia and neutropenia, particularly during cycle 2 of intensification therapy. During cycle 2 of intensification therapy, prolonged thrombocytopenia (platelet count < 50 × 10⁹/L persisting beyond day 42 of the cycle in the absence of active leukemia) was observed in 64% (190/297) of patients in the Mylotarg plus chemotherapy group compared with 55% (146/264) in the chemotherapy-only group. Prolonged neutropenia (neutrophil count < 0.5 × 10⁹/L persisting beyond day 42 of the cycle in the absence of active leukemia) occurred in 47% (142/300) versus 43% (118/275) of patients, respectively. Prolonged cytopenias were associated with an increased number of fatal events during remission in the Mylotarg plus chemotherapy group (29 [5%]) compared with the chemotherapy-only group (15 [3%]).

VOD cases were reported in 25 (5%) patients in the Mylotarg plus chemotherapy group and in 25 (5%) patients in the chemotherapy-only group. VOD was fatal in 2 (<1%) and 7 (1%) patients in the Mylotarg plus chemotherapy and chemotherapy-only groups, respectively.

Monotherapy for the treatment of newly diagnosed CD33-positive AML

The safety profile of Mylotarg (6 mg/m², followed by 3 mg/m², with a 7-day interval between doses) as monotherapy is based on results from a randomized, open-label Phase 3 study (AML-19), which compared Mylotarg (N = 118) with best supportive care (BSC) (N = 119) in patients with previously untreated AML who were ineligible for intensive chemotherapy.

The overall incidence of adverse reactions of any grade in the AML-19 study was 87% in the Mylotarg group and 90% in the BSC group. The incidence of adverse reactions of grade ≥3 was 61% in the Mylotarg group and 68% in the BSC group. Fatal adverse reactions were reported in 19 patients (17%) in the Mylotarg group compared with 23 patients (20%) in the BSC group.

Table 6. Selected adverse reactions in the AML-19 study
Adverse reactions	Mylotarg n = 111		Optimal supportive therapy n = 114
	Any grade	Grade > 3	Any grade	Grade > 3
Hepatic disorders	57 (51 %)	8 (7 %)	52 (46 %)	7 (6 %)
Increased fatigue	51 (46 %)	13 (12 %)	69 (61 %)	24 (21 %)
Infection	49 (44 %)	39 (35 %)	48 (42 %)	39 (34 %)
Cardiac disorders	31 (28 %)	7 (6 %)	37 (33 %)	16 (14 %)
Bleeding	28 (25 %)	14 (13 %)	34 (30 %)	14 (12 %)
Febrile neutropenia	20 (18 %)	20 (18 %)	27 (24 %)	27 (24 %)
Metabolic disorders	18 (16 %)	4 (4 %)	17 (15 %)	7 (6 %)
Renal disorders	7 (6 %)	4 (4 %)	9 (8 %)	5 (4 %)

Monotherapy for the treatment of relapsed or refractory CD33-positive AML

The adverse reactions listed below were observed with Mylotarg administered as monotherapy at a dose of 3 mg/m² on days 1, 4, and 7 in 57 patients with relapsed AML in the MyloFrance-1 study. All 57 patients (100%) received the 3 planned doses of Mylotarg.

During the treatment period, treatment-emergent adverse reactions (TEARs) of grade 3 occurring after initiation of treatment and observed in >1% of patients included sepsis (32%), fever (16%), rash (11%), pneumonia (7%), hemorrhage (7%), mucositis (4%), pain (4%), diarrhea (2%), headache (2%), tachycardia (2%), and pulmonary edema (2%). No grade 4 toxicities were reported. TEARs of all grades occurring in >15% of patients included fever (79%), infection (42%), increased AST levels (40%), hemorrhage (23%), nausea and vomiting (21%), constipation (21%), mucositis (21%), headache (19%), increased ALT levels (16%), and rash (16%). No fatal infections were reported. Grade 1 or 2 hyperbilirubinemia occurred in 4 patients (7%). No cases of VOD were reported. Seven patients underwent HSCT after treatment with Mylotarg. Three patients received allogeneic optimal supportive care (OSC), and 4 patients received autologous OSC. No cases of VOD occurred after HSCT.

Post-marketing experience

The following adverse reactions have been identified during post-marketing use of Mylotarg. Because these reactions are reported voluntarily from a population of uncertain size, it is not always 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*; bacterial infections, including infections caused by Stenotrophomonas.

Renal and urinary disorders: hemorrhagic cystitis.*

Respiratory, thoracic and mediastinal disorders: interstitial pneumonia.*

* Including fatal cases.

Immunogenicity

All therapeutic proteins have potential for immunogenicity. The immunogenicity of Mylotarg has not been studied in clinical trials using the recommended dosing regimens.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

Shelf life. 5 years.

Storage conditions

Store in a refrigerator at 2–8 °C. Do not freeze. Keep in the original cardboard packaging to protect from light. Keep out of reach of children.

Packaging

4.5 mg in a vial. One vial per cardboard box.

Prescription status. Prescription only.

Manufacturer

Pharmacia and Upjohn Company LLC.

Manufacturer's address and location of operations

7000 Portage Road, Kalamazoo, Michigan (MI) 49001, USA.