MYLOTARG 5mg powder for concentrate infusion solution medication leaflet

MYLOTARG 5 mg powder for concentrate for solution for infusion

One vial of powder for concentrate for solution for infusion contains 5 mg gemtuzumab ozogamicin.

After reconstitution (see section 6.6), the concentrated solution contains 1 mg/mL gemtuzumab ozogamicin.

Gemtuzumab ozogamicin is an antibody-drug conjugate (ADC) composed of the CD33-directed monoclonalantibody (hP67.6; recombinant humanised immunoglobulin [Ig] G4, kappa antibody produced bymammalian cell culture in NS0 cells) that is covalently linked to the cytotoxic agent

N-acetyl gamma calicheamicin.

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion (powder for concentrate).

White to off-white cake or powder.

MYLOTARG is indicated for combination therapy with daunorubicin (DNR) and cytarabine (AraC) for thetreatment of patients aged 15 years and above with previously untreated, de novo CD33-positive acutemyeloid leukaemia (AML), except acute promyelocytic leukaemia (APL) (see sections 4.4 and 5.1).

MYLOTARG should be administered under the supervision of a physician experienced in the use ofanticancer medicinal products and in an environment where full resuscitation facilities are immediatelyavailable.

MYLOTARG should be used only in patients eligible to receive intensive induction chemotherapy.

Premedication with a corticosteroid, antihistamine, and acetaminophen (or paracetamol) is recommended1 hour prior to dosing to help ameliorate infusion-related symptoms (see section 4.4).

Appropriate measures to help prevent the development of tumour lysis-related hyperuricaemia, such ashydration, administration of antihyperuricemic or other agents for treatment of hyperuricaemia should betaken (see section 4.4).

Induction

The recommended dose of MYLOTARG is 3 mg/m2/dose (up to a maximum of one 5 mg vial) infused overa 2-hour period on Days 1, 4, and 7 in combination with DNR 60 mg/m2/day infused over 30 minutes on

Day 1 to Day 3, and AraC 200 mg/m2/day by continuous infusion on Day 1 to Day 7.

If a second induction is required, MYLOTARG should not be administered during second induction therapy.

Only DNR and AraC should be administered during the second induction cycle, at the followingrecommended 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 ina normocellular marrow and an absolute neutrophil count (ANC) of more than 1.0 × 109 cells/L with aplatelet count of 100 × 109/L or more in the peripheral blood in the absence of transfusion, up to 2consolidation courses of intravenous DNR (60 mg/m2 for 1 day [first course] or 2 days [second course]) incombination with intravenous AraC (1 g/m2 per 12 hours, infused over 2 hours on Day 1 to Day 4) withintravenous MYLOTARG (3 mg/m2/dose infused over 2 hours up to a maximum dose of one 5 mg vial on

Day 1) are recommended.

Table 1. Dosing regimens for MYLOTARG in combination with chemotherapy

MYLOTARG daunorubicin cytarabinecourse3 mg/m2/dose (up to aa 60 mg/m2/day on Day 1 to 200 mg/m2/day on Day 1

Induction maximum of one 5 mg

Day 3 to Day 7vial) on Days 1, 4, and 7

Second MYLOTARG should not35 mg/m2/day on Day 1 to 1 g/m2/every 12 hours oninduction (if be administered during

Day 2 Day 1 to Day 3required) second induction.

3 mg/m2/dose (up to a

Consolidation 1 g/m2/every 12 hours ona,b maximum of one 5 mg 60 mg/m2/day on Day 1

Course 1 Day 1 to Day 4vial) on Day 13 mg/m2/dose (up to a

Consolidation 60 mg/m2/day on Day 1 to 1 g/m2/every 12 hours ona,b maximum of one 5 mg

Course 2 Day 2 Day 1 to Day 4vial) on Day 1

a. See Table 3 and Table 4 for dose modification information.

b. For patients experiencing a complete remission (CR) following induction.

Dose and schedule modifications

Schedule modification for hyperleukocytosis

In patients with hyperleukocytic (leukocyte count ≥ 30 000/mm3) AML, cytoreduction is recommendedeither with leukapheresis, oral hydroxyurea or AraC with or without hydroxyurea to reduce the peripheralwhite blood cell (WBC) count 48 hours prior to administration of MYLOTARG.

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 followingmodified schedule (Table 2):

Table 2. Schedule modification for the treatment of hyperleukocytosis with cytarabine

MYLOTARG daunorubicin cytarabine hydroxyureacourse3 mg/m2/dose (up to a 2 2 Day 1 (as per60 mg/m /day on 200 mg/m /day on

Inductiona maximum of one 5 mg standard medical

Day 3 to Day 5 Day 1 to Day 7vial) on Days 3, 6, and 9 practice)

See Table 1 for dose recommendations for consolidation course.

a. See Table 3 and Table 4 for additional dose modification information.

Dose modification for adverse drug reactions

Dose modification of MYLOTARG is recommended based on individual safety and tolerability (seesection 4.4). Management of some adverse drug reactions may require dose interruptions or permanentdiscontinuation of MYLOTARG (see sections 4.4 and 4.8).

Tables 3 and 4 show the dose modification guidelines for haematological and non-haematological toxicities,respectively.

Table 3. Dose modifications for haematological toxicities

Haematological toxicities Dose modifications

Persistent thrombocytopenia - Postpone start of consolidation course.(Platelets < 100 000/mm3 at theplanned start date of the - If platelet count recovers to ≥ 100 000/mm3 within 14 daysconsolidation course) following the planned start date of the consolidation course:

initiate consolidation therapy (see as described in Table 1).

- If platelet count recovers to < 100 000/mm3 and≥ 50 000/mm3 within 14 days following the planned startdate of the consolidation course: MYLOTARG should notbe re-introduced and consolidation therapy should consist of

DNR and AraC only.

- If platelet count recovery remains < 50 000/mm3 for greaterthan 14 days consolidation therapy should be re-evaluatedand a BMA should be performed to re-assess the patients’status.

Persistent neutropenia - If neutrophil count does not recover to greater than 500/mm3within 14 days following the planned start date of theconsolidation cycle (14 days after haematologic recoveryfollowing previous cycle), discontinue MYLOTARG (donot administer MYLOTARG in the consolidation cycles).

Abbreviations: AML=acute myeloid leukaemia; AraC=cytarabine; BMA=bone marrow aspirate,

DNR=daunorubicin.

Table 4. Dose modifications for non-haematological toxicities

Non-haematological toxicities Dose modifications

VOD/SOS Discontinue MYLOTARG (see section 4.4).

Total bilirubin > 2 × ULN and Postpone MYLOTARG until recovery of total bilirubin to ≤ 2 × ULN

AST and/or ALT > 2.5 × ULN and AST and ALT to ≤ 2.5 × ULN prior to each dose.

Consider omitting scheduled dose if delayed more than 2 daysbetween sequential infusions.

Infusion related reactions Interrupt the infusion and institute appropriate medical managementbased on the severity of symptoms. Patients should be monitored untilsigns and symptoms completely resolve and infusion may resume.

Consider permanent discontinuation of treatment for severe orlife-threatening infusion reactions (see section 4.4).

Other severe or life-threatening Delay treatment with MYLOTARG until recovery to a severity of nonon-haematologic toxicities more than mild.

Consider omitting scheduled dose if delayed more than 2 daysbetween sequential infusions.

Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; SOS=sinusoidal obstructionsyndrome; ULN=upper limit of normal; VOD=venoocclusive disease.

No adjustment of the starting dose is required in patients with hepatic impairment defined by total bilirubin≤ 2 × upper limit of normal (ULN) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT)≤ 2.5 × ULN. Postpone MYLOTARG until recovery of total bilirubin to ≤ 2 × ULN and AST and ALT to≤ 2.5 × ULN prior to each dose (see Table 4, sections 4.4 and 5.2).

No dose adjustment is required in patients with mild to moderate renal impairment. MYLOTARG has notbeen studied in patients with severe renal impairment. MYLOTARG does not undergo renal clearance, thepharmacokinetics in patients with severe renal impairment is unknown (see section 5.2).

No dose adjustment is required in elderly patients (≥ 65 years) (see section 5.2).

The safety and efficacy of MYLOTARG in patients less than 15 years of age has not been established.

Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology canbe made.

MYLOTARG is for intravenous use and must be reconstituted and diluted before administration (seesection 6.6). When reconstituted to a 1 mg/mL concentration, the extractable content of one vial is 4.5 mg(4.5 mL). The reconstituted and diluted solution should be administered intravenously by infusion over a2-hour period under close clinical monitoring, including pulse, blood pressure, and temperature.

MYLOTARG should not be administered as an intravenous push or bolus (see section 6.6).

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

Hepatotoxicity, including hepatic venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS)

Hepatotoxicity, including life-threatening, and sometimes fatal hepatic failure and VOD/SOS have beenreported in patients treated with MYLOTARG (see section 4.8).

Based on an analysis of potential risk factors, adult patients who received MYLOTARG as monotherapy,either before or after an haematopoietic stem cell transplant (HSCT), and patients with moderate or severehepatic impairment are at increased risk for developing VOD (see section 4.8).

Due to the risk of VOD/SOS, signs and symptoms of VOD/SOS should be closely monitored; these mayinclude elevations in ALT, AST, total bilirubin, and alkaline phosphatase, which should be monitored priorto each dose of MYLOTARG, 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 developabnormal liver tests, more frequent monitoring of liver tests and clinical signs and symptoms ofhepatotoxicity is recommended. For patients who proceed to HSCT, close monitoring of liver tests isrecommended during the post-HSCT period, as appropriate. No definitive relationship was found between

VOD and time of HSCT relative to higher MYLOTARG monotherapy doses, however, the ALFA-0701study 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 section 4.2). In patients who experience VOD/SOS, MYLOTARG should bediscontinued and patients treated according to standard medical practice.

Infusion related reactions (including anaphylaxis)

In clinical studies infusion related reactions, including anaphylaxis were reported (see section 4.8). Therehave been reports of fatal infusion reactions in the post-marketing setting. Signs and symptoms of infusionrelated reactions may include fever and chills, and less frequently hypotension, tachycardia, and respiratorysymptoms that may occur during the first 24 hours after administration. Infusion of MYLOTARG should beperformed under close clinical monitoring, including pulse, blood pressure, and temperature. Premedicationwith a corticosteroid, antihistamine and acetaminophen (or paracetamol) is recommended 1 hour prior to

MYLOTARG dosing (see section 4.2). Infusion should be interrupted immediately for patients who developevidence of severe reactions, especially dyspnoea, bronchospasm, or clinically significant hypotension.

Patients should be monitored until signs and symptoms completely resolve. Discontinuation of treatmentshould be strongly considered for patients who develop signs or symptoms of anaphylaxis, including severerespiratory symptoms or clinically significant hypotension (see section 4.2).

In clinical studies, neutropenia, thrombocytopenia, anaemia, leukopenia, febrile neutropenia, lymphopenia,and pancytopenia, some of which were life-threatening or fatal, were reported (see section 4.8).

Complications associated with neutropenia and thrombocytopenia may include infections andbleeding/haemorrhagic reactions respectively. Infections and bleeding/haemorrhagic reactions were reported,some of which were life-threatening or fatal.

Complete blood counts should be monitored prior to each dose of MYLOTARG. During treatment, patientsshould be monitored for signs and symptoms of infection, bleeding/haemorrhage, or other effects ofmyelosuppression. Routine clinical and laboratory surveillance testing during and after treatment isindicated.

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 permanentdiscontinuation of MYLOTARG (see section 4.2).

In clinical studies, TLS was reported (see section 4.8). Fatal reports of TLS complicated by acute renalfailure have been reported in the post-marketing setting. In patients with hyperleukocytic AML,leukoreduction should be considered with hydroxyurea or leukapheresis to reduce the peripheral WBC countto below 30 000/mm3 prior to administration of MYLOTARG to reduce the risk of inducing TLS (seesection 4.2).

Patients should be monitored for signs and symptoms of TLS and treated according to standard medicalpractice. Appropriate measures to help prevent the development of tumour lysis-related hyperuricaemia, suchas hydration, administration of antihyperuricemics (e.g., allopurinol) or other agents for treatment ofhyperuricaemia (e.g., rasburicase) must be taken.

AML with adverse-risk cytogenetics

The efficacy of MYLOTARG has been shown in AML patients with favourable- and intermediate-riskcytogenetics, with uncertainty regarding the size of the effect in patients with adverse cytogenetics (seesection 5.1). For patients being treated with MYLOTARG in combination with daunorubicin and cytarabinefor newly diagnosed de novo AML, when cytogenetics testing results become available it should beconsidered whether the potential benefit of continuing treatment with MYLOTARG outweighs the risks forthe individual patient (see section 5.1).

Women of childbearing potential, or partners of females of childbearing potential should be advised to use2 methods of effective contraception during treatment with MYLOTARG for at least 7 months (females) or4 months (males) after the last dose (see section 4.6).

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

This medicinal product may be further prepared for administration with sodium-containing solutions (seesections 4.2 and 6.6), and this should be considered in relation to the total sodium from all sources that willbe administered to the patient.

No clinical drug interaction studies have been conducted with MYLOTARG. See section 5.2 for availabledata from in vitro studies.

Women of childbearing potential should be advised to avoid becoming pregnant while receiving

MYLOTARG.

Women of childbearing potential, or partners of females of childbearing potential should be advised to use2 methods of effective contraception during treatment with MYLOTARG for at least 7 months (females) or4 months (males) after the last dose.

There are no or limited amount of data from the use of gemtuzumab ozogamicin in pregnant women. Studiesin animals have shown reproductive toxicity (see section 5.3).

MYLOTARG must not be used during pregnancy unless the potential benefit to the mother outweighs thepotential risks to the foetus. Pregnant women, or patients becoming pregnant whilst receiving gemtuzumabozogamicin, or treated male patients as partners of pregnant women, must be apprised of the potential hazardto the foetus.

There is no information regarding the presence of gemtuzumab ozogamicin or its metabolites in human milk,the effects on the breast-fed child, or the effects on milk production. Because of the potential for adversedrug reactions in breast-fed children, women should not breast-feed during treatment with MYLOTARG andfor at least 1 month after the final dose (see section 5.3).

There is no information on fertility in patients. Based on non-clinical findings, male and female fertility maybe compromised by treatment with gemtuzumab ozogamicin (see section 5.3). Both men and women shouldseek advice on fertility preservation before treatment.

MYLOTARG has moderate influence on the ability to drive and use machines. Patients should be advisedthey may experience fatigue, dizziness and headache during treatment with MYLOTARG (see section 4.8).

Therefore, caution should be exercised when driving or operating machines.

The overall safety profile of MYLOTARG is based on data from patients with acute myeloid leukaemia fromthe combination therapy study ALFA-0701, monotherapy studies, and from post-marketing experience. Inthe combination therapy study, safety data consisting of selected treatment emergent adverse events (TEAEs)considered most important for understanding the safety profile of MYLOTARG consisted of all gradeshaemorrhages, all grades VOD, and severe infections. All of these TEAEs were determined to be adversedrug reactions. Because of this limited data collection, laboratory data from the combination therapy studyare included in Table 5. Information about adverse drug reactions from monotherapy studies using thenon-fractionated regimen (Studies 201/202/203) and post-marketing experience is presented in Table 6 andthe monotherapy study B1761031 using the fractionated regimen is presented in the section below in order toprovide full characterisation of adverse drug reactions.

In the combination therapy study ALFA-0701, clinically relevant serious adverse drug reactions werehepatotoxicity, including VOD/SOS (3.8%), haemorrhage (9.9%), severe infection (41.2%), and tumour lysissyndrome (1.5%). In monotherapy studies (Studies 201/202/203), clinically relevant serious adverse drugreactions also included infusion related reactions (2.5%), thrombocytopenia (21.7%), and neutropenia(34.3%). In the monotherapy study B1761031, clinically relevant serious adverse drug reactions includedinfection (30.0%), febrile neutropenia (22.0%), pyrexia (6.0%), haemorrhage (4.0%), thrombocytopenia(4.0%), anaemia (2.0%), and tachycardia (2.0%).

The most common adverse drug reactions (> 30%) in the combination therapy study were haemorrhage andinfection. In monotherapy studies (Studies 201/202/203) the most common adverse drug reactions (> 30%)included pyrexia, nausea, infection, chills, haemorrhage, vomiting, thrombocytopenia, fatigue, headache,stomatitis, diarrhoea, abdominal pain, and neutropenia. In the monotherapy study B1761031 the mostfrequent adverse drug reactions (> 30%) included infection (50.0%), febrile neutropenia (40.0%) andhaemorrhage (32.0%).

The most frequent (≥ 1%) adverse drug reactions that led to permanent discontinuation in the combinationtherapy study were thrombocytopenia, VOD, haemorrhage and infection. The most frequent (≥ 1%) adversedrug reactions that led to permanent discontinuation in monotherapy studies (Studies 201/202/203) wereinfection, haemorrhage, multi-organ failure, and VOD. The adverse drug reactions that led to permanentdiscontinuation in monotherapy study B1761031 were infection and pyrexia.

Tabulated list of adverse drug reactions

The adverse drug reactions are presented by system organ class (SOC) and frequency categories, definedusing the following convention: very common (³ 1/10), common (³ 1/100 to < 1/10), uncommon (³ 1/1 000 to< 1/100), rare (³ 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from theavailable data). Within each frequency grouping, adverse drug reactions are presented in order of decreasingseriousness.

Table 5. Selected** adverse drug reactions in patients who received MYLOTARG in combinationtherapy study (ALFA-0701)

MYLOTARG + daunorubicin daunorubicin

System organ class + cytarabine (N=131) + cytarabine (N=137)

Frequency

Preferred term All grades Grade 3/4 All grades Grade 3/4% % % %

Very common

Infection*a 77.9 76.3 77.4 74.4

Very common

Haemorrhage*b 90.1 20.6 78.1 8.8

Common

Venoocclusive liver disease*c 4.6 2.3 1.5 1.5

Investigations ***

Very common

Haemoglobin decreased 100 86.2 100 89.7

Platelets decreased 100 100 100 100

White blood cells decreased 100 100 99.3 99.3

Lymphocytes (absolute) 98.5 90.7 97.8 89.6decreased

Neutrophils decreased 97.7 96.1 98.5 97.0

Hyperglycaemia 92.0 19.2 91.1 17.8

Aspartate aminotransferase 89.2 14.0 73.9 9.0(AST) increased

Prothrombin time increased 84.8 3.3 89.1 0

Activated partial 80.0 6.4 57.5 5.5thromboplastin time prolonged

Alkaline phosphatase 79.7 13.3 68.9 5.3increased

Alanine aminotransferase 78.3 10.9 81.3 15.7(ALT) increased

Blood bilirubin increased 51.6 7.1 50.8 3.8

Hyperuricaemia 32.5 2.6 28.5 0

Abbreviations: N=number of patients; PT=preferred term.

*Including fatal outcome.

**Only selected safety data were collected in this study of newly diagnosed AML.

***Frequency is based on laboratory values (Grade per NCI CTCAE v4.03).

a. Infection includes Sepsis and Bacteraemia (53.4%), Fungal infection (15.3%), Lower respiratory tract infection(5.3%), Bacterial infection (9.2%), Gastrointestinal infection (8.4%), Skin infection (2.3%), and Other infections(28.4%).

b. Haemorrhage includes Central nervous system haemorrhage (3.1%), Upper gastrointestinal haemorrhage (33.6%),

Lower gastrointestinal haemorrhage (17.6%), Subcutaneous haemorrhage (60.3%), Other haemorrhage (64.9%), and

Epistaxis (62.6%).

c. Venoocclusive liver disease includes the following reported PTs: Venoocclusive disease and Venoocclusive liverdisease*.

Table 6. Adverse drug reactions in patients who received MYLOTARG in monotherapy*** studiesand post-marketing

System organ class All grades Grade 3/4

Frequency % %

Preferred term

Very common

Infection*a 68.2 32.8

Very common

Febrile neutropenia 19.1 11.6

Thrombocytopeniab 48.4 48.0

Neutropeniac 30.3 29.2

Anaemiad 27.1 24.2

Leukopeniae 26.7 26.7

Common

Pancytopeniaf 5.0 4.3

Lymphopeniag 3.6 3.2

Common

Infusion related reactionh 7.6 3.6

Very common

Hyperglycaemiai 11.2 6.9

Decreased appetite 27.1 6.1

Common

Tumour lysis syndrome** 2.5 1.8

Very common

Headache 38.3 12.3

Very common

Tachycardiaj 13.0 4.3

Very common

Haemorrhage*k 67.1 23.8

Hypotensionl 20.2 14.8

Hypertensionm 17.3 10.5

Respiratory, thoracic and mediastinaldisorders

Very common

Dyspnoean 27.4 12.6

Unknown

Interstitial pneumonia*

Very common

Vomiting 60.6 33.6

Diarrhoea 33.9 14.8

Abdominal paino 33.2 7.2

Nausea 71.1 39.3

Stomatitisp 36.1 12.3

Constipation 25.3 5.0

Common

Ascites 2.9 0.4

Dyspepsia 8.7 1.1

Oesophagitis 1.8 0.7

Unknown

Neutropenic colitis*

Very common

Transaminases increasedq 24.5 18.8

Hyperbilirubinaemiar 13.0 10.5

Common

Venoocclusive liver disease*s 2.9 1.1

Hepatomegaly 2.5 0.7

Jaundice 2.2 1.1

Hepatic function abnormalt 2.5 1.4

Gamma-glutamyltransferase increased 1.8 0.7

Uncommon

Hepatic failure*# 0.4 0.4

Budd-Chiari syndrome# 0.4 0.4

Very common

Rashu 19.9 5.8

Common

Erythemav 9.4 2.2

Pruritus 5.4 0.4

Unknown

Haemorrhagic cystitis*

General disorders and administrationsite conditions

Very common

Pyrexiaw 82.7 52.3

Oedemax 21.3 3.2

Fatiguey 41.2 11.2

Chills 67.9 17.3

Common

Multi-organ failure* 2.2 0.7

Very common

Blood lactate dehydrogenase increased 16.6 7.2

Common

Blood alkaline phosphate increased 8.7 6.1

*Including fatal outcome.

**Including fatal adverse drug reactions in the post-marketing setting.

***MYLOTARG in the treatment of relapsed AML (9 mg/m2) (Studies 201/202/203).#Singular cases.

Abbreviation: PT=preferred term.

a. Infection includes Sepsis and Bacteraemia (25.6%), Fungal infection (10.5%), Lower respiratory tract infection(13.0%), Upper respiratory tract infection (4.3%), Bacterial infection (3.6%), Viral infection (24.2%), Gastrointestinalinfection (3.3%), Skin infection (7.9%), and Other infections (19.5%). Post-marketing (frequency category unknown)fungal lung infections including Pulmonary mycosis and Pneumocystis jirovecii pneumonia*; and bacterial infectionsincluding Stenotrophomonas infection were also reported.

b. Thrombocytopenia includes the following reported PTs: Platelet count decreased and Thrombocytopenia*.

c. Neutropenia includes the following reported PTs: Neutropenia, Granulocytopenia and Neutrophil count decreased.

d. Anaemia includes the following reported PTs: Anaemia and Haemoglobin decreased.

e. Leukopenia includes the following reported PTs: Leukopenia and White blood cell count decreased.

f. Pancytopenia includes the following reported PTs: Pancytopenia and Bone marrow failure.g. Lymphopenia includes the following reported PTs: Lymphopenia and Lymphocyte count decreased.h. Infusion related reaction includes the following reported PTs: Infusion related reaction, Urticaria, Hypersensitivity,

Bronchospasm, Drug hypersensitivity, and Injection site urticaria#.i. Hyperglycaemia includes the following reported PTs: Hyperglycaemia and Blood glucose increased#.j. Tachycardia includes the following reported PTs: Tachycardia, Sinus tachycardia, Heart rate increased#, and

Supraventricular tachycardia#.k. Haemorrhages include Central nervous system haemorrhage (5.1%), Upper gastrointestinal haemorrhage (21.3%),

Lower gastrointestinal haemorrhage (15.2%), Subcutaneous haemorrhage (28.5%), Other haemorrhage (32.9%), and

Epistaxis (28.5%).

l. Hypotension includes the following reported PTs: Hypotension and Blood pressure decreased.m. Hypertension includes the following reported PTs: Hypertension and Blood pressure increased.n. Dyspnoea includes the following reported PTs: Dyspnoea and Dyspnoea exertional.o. Abdominal pain includes the following reported PTs: Abdominal pain, Abdominal pain lower, Abdominal painupper, Abdominal discomfort, and Abdominal tenderness.

p. Stomatitis includes the following reported PTs: Mucosal inflammation, Oropharyngeal pain, Stomatitis, Mouthulceration, Oral pain, Oral mucosal blistering, Aphthous stomatitis, Tongue ulceration, Glossodynia, Oral mucosalerythema, Glossitis#, and Oropharyngeal blistering#.

q. Transaminases increased includes the following reported PTs: Transaminases increased, Hepatocellular injury,

Alanine aminotransferase increased, Aspartate aminotransferase increased, and Hepatic enzyme increased.

r. Hyperbilirubinaemia includes the following reported PTs: Blood bilirubin increased and Hyperbilirubinaemia.s. Venoocclusive liver disease includes the following reported PTs: Venoocclusive disease and Venoocclusive liverdisease*#.t. Hepatic function abnormal includes the following reported PTs: Liver function test abnormal and Hepatic functionabnormal.u. Rash includes the following reported PTs: Rash, Dermatitis#, Dermatitis allergic#, Dermatitis bullous, Dermatitiscontact, Dermatitis exfoliative#, Drug eruption, Pruritus allergic# and Rash erythematous#, Rash macular#, Rashmaculo papular, Rash papular, Rash pruritic, Rash vesicular#.

v. Erythema includes the following reported PTs: Catheter site erythema, Erythema and Infusion site erythema#.w. Pyrexia includes the following reported PTs: Pyrexia, Body temperature increased, and Hyperthermia.x. Oedema includes the following reported PTs: Oedema, Face oedema, Oedema peripheral, Swelling face, Generalisedoedema, and Periorbital oedema.y. Fatigue includes the following reported PTs: Fatigue, Asthenia, Lethargy, and Malaise.

Hepatotoxicity, including hepatic VOD/SOS

In the combination therapy study, VOD and hepatic laboratory abnormalities were collected. Additionalcharacterisation of hepatotoxicity adverse reactions is provided from the monotherapy studies.

In the combination therapy study (N=131), VOD was reported in 6 (4.6%) patients during or followingtreatment, 2 (1.5%) of these reactions were fatal (see Table 5). Five (3.8%) of these VOD reactions occurredwithin 28 days of any dose of gemtuzumab ozogamicin. One VOD event occurred more than 28 days of lastdose of gemtuzumab ozogamicin; with 1 of these events occurring a few days after having started an HSCTconditioning regimen. The median time from the last gemtuzumab ozogamicin dose to onset of VOD was9 days (range: 2-298 days). VOD was also reported in 2 patients who received MYLOTARG as a follow-uptherapy following relapse of AML after chemotherapy treatment in the control arm of the combinationtherapy study. Both of these patients experienced VOD more than 28 days after the last dose of gemtuzumabozogamicin. One of these patients experienced VOD 25 days after the subsequent HSCT.

In the monotherapy study B1761031, no VOD events were reported for any patient. However, 1 (2.0%)patient had fatal capillary leak syndrome with symptoms consistent with VOD (ascites andhyperbilirubinemia). The Grade 3 hepatotoxicity events included gamma-glutamyltransferase increased(4.0%), alanine aminotransferase increased (2.0%), aspartate aminotransferase increased (2.0%),hypoalbuminemia (2.0%) and transaminases increased (2.0%). No patients had Grade 4 or Grade 5hepatotoxicity.

Based on an analysis of potential risk factors, adult patients who received non-fractionated MYLOTARG asmonotherapy, patients who had received an HSCT prior to gemtuzumab ozogamicin exposure were 2.6 timesmore likely (95% confidence interval [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 followingtreatment with gemtuzumab ozogamicin were 2.9 times more likely (95% CI: 1.502, 5.636) to develop VODcompared to patients without HSCT following treatment with gemtuzumab ozogamicin; and patients whohad moderate/severe hepatic impairment at baseline were 8.7 times more likely (95% CI: 1.879, 39.862) todevelop VOD compared to patients without moderate/severe hepatic impairment at baseline.

Patients should be monitored for hepatotoxicity as recommended in section 4.4. Management of signs orsymptoms of hepatic toxicity may require a dose interruption, or discontinuation of MYLOTARG (seesection 4.2).

In the combination therapy study in patients with previously untreated de novo AML treated withfractionated doses of gemtuzumab ozogamicin in combination with chemotherapy, Grade 3/4 decreases inleukocytes, neutrophils, and platelets were observed in 131 (100%), 124 (96.1%), and 131 (100%) patients,respectively.

During the induction phase, 109 (83.2%) and 99 (75.6%) patients had platelet recovery to counts of50 000/mm3 and 100 000/mm3, respectively. The median times to platelet recovery to counts of 50 000/mm3and 100 000/mm3 were 34 and 35 days, respectively. During the consolidation 1 phase, 92 (94.8%) and71 (73.2%) patients had a platelet recovery to counts of 50 000/mm3 and 100 000/mm3, respectively. Themedian times to platelet recovery to counts of 50 000/mm3 and 100 000/mm3 were 32 and 35 days,respectively. During the consolidation 2 phase, 80 (97.6%) and 70 (85.4%) patients had a platelet recovery tocounts of 50 000/mm3 and 100 000/mm3, respectively. The median times to platelet recovery to counts of50 000/mm3 and 100 000/mm3 were 36.5 and 43 days, respectively.

Thrombocytopenia with platelet counts < 50 000/mm3 persisting 45 days after the start of therapy forresponding patients (CR and incomplete platelet recovery [CRp]) occurred in 22 (20.4%) of patients. Thenumber of patients with persistent thrombocytopenia remained similar across treatment courses(8 [7.4%] patients at the induction phase and 8 [8.5%] patients at the consolidation 1 phase and10 [13.2%] 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 1 000/mm3, respectively. The median time to neutrophil recovery to ANC of 500/mm3and 1 000/mm3 was 25 days. In the consolidation 1 phase of therapy, 94 (96.9%) patients had neutrophilrecovery to counts of 500/mm3, and 91 (94%) patients recovered to counts of 1 000/mm3. The median timesto neutrophil recovery to ANC of 500/mm3 and 1 000/mm3 were 21 and 25 days, respectively. In theconsolidation 2 phase of therapy, 80 (97.6%) patients had neutrophil recovery to counts of 500/mm3, and79 (96.3%) patients recovered to counts of 1 000/mm3. The median times to neutrophil recovery to ANC of500/mm3 and 1 000/mm3 were 22 and 27 days, respectively.

In the combination therapy study, in patients with de novo AML treated with fractionated doses ofgemtuzumab ozogamicin in combination with chemotherapy (N=131), 102 (77.9%) patients experienced allcausality severe (Grade ≥ 3) infections. Treatment-related death due to septic shock was reported in1 (0.8%) patients. Fatal severe infection was reported in 2 (1.53%) patients in the MYLOTARG arm and4 (2.92%) patients in the control arm.

In the combination therapy study (N=131), all grades and Grade 3/4 bleeding/haemorrhagic reactions werereported in 118 (90.1%) and 27 (20.6%) patients, respectively. The most frequent Grade 3bleeding/haemorrhagic reactions were haematemesis (3.1%), haemoptysis (3.1%), and haematuria (2.3%).

Grade 4 bleeding/haemorrhagic reactions were reported in 4 (3.1%) patients (gastrointestinal haemorrhage,haemorrhage, and pulmonary alveolar haemorrhage [2 patients]). Fatal bleeding/haemorrhagic reactionswere reported in 3 (2.3%) patients (cerebral haematoma, intracranial haematoma, and subdural haematoma).

In the monotherapy study B1761031 (N=50), Grade 3/4 infections were reported in 10 (20%) patients. Themost frequent (≥ 5.0%) reported Grade 3/4 infections were sepsis and pneumonia in 3 (6.0%) patients, each.

Six (6) (12.0%) patients had Grade 5 infection (sepsis in 4 [8.0%], atypical pneumonia, and COVID-19pneumonia in 1 [2.0%] patient, each). All grade bleeding/haemorrhagic events were reported in 16 (32.0%)patients. Grade 3/4 haemorrhagic events occurred in 2 (4.0%) patients (gastric haemorrhage Grade 3 andtraumatic intracranial haemorrhage Grade 4 in 1 patient, each). No fatal bleeding/haemorrhagic events werereported.

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 permanentdiscontinuation of MYLOTARG (see sections 4.2 and 4.4).

As with all therapeutic proteins, there is potential for immunogenicity.

The anti-drug antibody (ADA) against MYLOTARG was evaluated using electrochemiluminescence (ECL)method. For patients whose ADA samples were tested positive, a cell-based assay was developed to measureneutralizing antibody (NAb) against MYLOTARG.

In the monotherapy study B1761031 in 50 treated adult patients with relapsed or refractory CD33-positive

AML, the incidence of ADA and NAb was 12.0% (6/50) and 2.0% (1/50), respectively. The presence of

ADA had no statistically significant or clinically relevant effects on PK of total hP67.6 antibody orconjugated calicheamicin. None of the patients experienced anaphylaxis, hypersensitivity or other clinicalsequelae related to ADA. There was no evidence that the presence of ADA had a direct association with anypotential safety issues.

In the dose finding part of MyeChild 01 study in 54 treated paediatric patients ≥12 months of age with newlydiagnosed AML, the overall ADA incidence across cohorts was 2% (1/49). No AESI-infusion-relatedreactions were reported for the ADA positive patient.

The detection of ADAs is highly dependent on the sensitivity and specificity of the assay. The incidence ofantibody positivity in an assay may be influenced by several factors, including assay methodology,circulating gemtuzumab ozogamicin concentrations, sample handling, timing of sample collection,concomitant treatments and underlying disease. For these reasons, comparison of incidence of antibodies togemtuzumab ozogamicin with the incidence of antibodies to other products may be misleading.

Previously untreated AML

The safety and efficacy of MYLOTARG in children and adolescents with previously untreated AML belowthe age of 15 years has not been established (see section 4.2).

In the completed randomised paediatric Phase 3 Study AAML0531 (see section 5.1) of gemtuzumabozogamicin combined with intensive first-line therapy in 1 063 newly diagnosed children (93.7% of patients< 18 years of age), and young adults (6.3% of patients) with de novo AML aged 0 to 29 years, the safetyprofile was similar with that observed in the other studies of gemtuzumab ozogamicin combined withintensive chemotherapy in adult patients with de novo AML. However, the optimal dose of gemtuzumabozogamicin for paediatric patients was not established, since in Study AAML0531 during the secondintensification period after the second dose of gemtuzumab ozogamicin, a larger proportion of patients in thegemtuzumab ozogamicin arm experienced prolonged neutrophil recovery time (> 59 days) as compared withthe comparator arm (21.0% versus 11.5%), and more patients died during remission (5.5% versus 2.8%).

In the dose finding part of the paediatric study MyeChild 01 (see section 5.1) of gemtuzumab ozogamicincombined with induction therapy (cytarabine plus either mitoxantrone or liposomal daunorubicin) in54 children ≥12 months of age with newly diagnosed AML, the safety profile was similar with that observedin the other studies of gemtuzumab ozogamicin combined with intensive chemotherapy in adult andpaediatric patients with de novo AML. The rate of infection for all grades was 57.4%. The most frequentlyreported ADRs ≥Grade 3 for all cohorts were febrile neutropenia (92.6%), thrombocytopenia (90.7%),neutropenia (87.0%) and anaemia (83.3%). The most frequently reported serious ADRs for all cohorts werefebrile neutropenia (29.6%) and infection (14.8%). Serious febrile neutropenia was experienced by 13.3%,15.0% and 57.9% of patients in cohorts 1, 2 and 3, respectively. By day 45 post Course 1 or 2, 27.8% ofpatients did not recover neutrophil count to 1 000/mm3 and 11.1% of patients did not recover anon-transfusion dependent platelet count to 80 000/mm3 due to documented bone marrow aplasia/hypoplasia.

VOD occurred during the post-transplant period in 13% of patients. Fatal VOD was observed in 1.9% ofpatients.

Relapsed or refractory AML

The safety and efficacy of MYLOTARG in paediatric patients with relapsed or refractory AML has not beenestablished (see sections 4.1 and 4.2).

Safety results observed in a systematic literature review of studies evaluating MYLOTARG in paediatricpatients (see section 5.1), are presented in Table 7.

Table 7. Safety results from a systematic literature review in paediatric patients with relapsed orrefractory AML who received MYLOTARG

Monotherapy Combinationa

Fractionatedb Non-fractionatedb Fractionatedb Non-fractionatedb

MYLOTARG MYLOTARG MYLOTARG MYLOTARG

Number N per Ratec Number N per Rate Number N per Rate Number N per Rateof study (%) of study (%) of study (%) of study (%)studies (range) studies (range) studies (range) studies (range)

VOD 1 6 0 10 5, 30 6.8 2 3, 17 0 5 5, 84 4.4

VOD post HSCT Not reported 5 4, 14 19.1 2 3, 8 0 2 12, 28 14.7

Deathd 1 6 0 4 6, 29 10.8 Not reported 3 5, 45 6.5

Infection 5 studies; N per study (range) 12-30; 28.4% 4 studies; N per study (range) 12-84; 42.2%

Myelosuppression Almost all patients (> 90 %) experienced myelosuppression across studiesea: When MYLOTARG was given in combination, cytarabine was part of the combination studied in 8 out of the 9 studies.b: Fractionated dosing refers to MYLOTARG dose of 3 mg/m2 on days 1, 4, 7. Non-fractionated dosing refers to MYLOTARG (total doseranging 1.8 mg/m2 - 9 mg/m2) 2 times during a cycle at least 14 days apart.c: Rates across studies were estimated using inverse variance weighting with fixed effects. Proportions were transformed using Freeman-Tukeydouble arcsine transformation prior to combining studies, and the estimated combined rate was back-transformed using the harmonic meanof study sample sizes.

d: Within 30 days from the last dose of MYLOTARG.e: Where analysed, median recovery (defined as 20 x 109/L or 50 x 109/L for platelets and 0.5 x 109/L for neutrophils) ranged from 42-48 daysfor platelets and 30-37 days for neutrophils.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

No cases of overdose with MYLOTARG were reported in clinical experience. Single doses higher than9 mg/m2 in adults were not tested. Treatment of MYLOTARG overdose should consist of general supportivemeasures.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies and antibody drug conjugates,other monoclonal antibodies and antibody drug conjugates, ATC code: L01FX02

Gemtuzumab ozogamicin is a CD33-directed ADC. Gemtuzumab is a humanised immunoglobulin class Gsubtype 4 (IgG4) antibody which specifically recognises human CD33. The antibody portion bindsspecifically to the CD33 antigen, a sialic acid-dependent adhesion protein found on the surface of myeloidleukaemic blasts and immature normal cells of myelomonocytic lineage, but not on normal haematopoieticstem cells. The small molecule, N-acetyl gamma calicheamicin, is a cytotoxic semisynthetic natural product.

N-acetyl gamma calicheamicin is covalently attached to the antibody via an AcBut (4-(4-acetylphenoxy)butanoic acid) linker. Non-clinical data suggest that the anticancer activity of gemtuzumab ozogamicin is dueto the binding of the ADC to CD33-expressing cancer cells, followed by internalisation of the ADC-CD33complex, and the intracellular release of N-acetyl gamma calicheamicin dimethyl hydrazide via hydrolyticcleavage of the linker. Activation of N-acetyl gamma calicheamicin dimethyl hydrazide inducesdouble-stranded DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.

Saturation of a high percentage of CD33 antigenic sites is presumed to be required for maximum delivery ofcalicheamicin to leukaemic blast cells. Several single agent studies measured CD33 saturationpost-MYLOTARG dose in patients with relapsed and refractory AML. Across all studies, near maximalperipheral CD33 saturation was observed post-MYLOTARG dose at all dose levels of 2 mg/m² and above,suggesting that a low dose of gemtuzumab ozogamicin is sufficient to bind all available CD33 sites.

ALFA-0701 study of previously untreated patients with de novo AML

The efficacy and safety of MYLOTARG were evaluated in a multicentre, randomised, open-label Phase 3study comparing the addition of MYLOTARG to a standard chemotherapy induction regimen ofdaunorubicin and cytarabine (DA) versus DA alone. Eligible patients were between 50 and 70 years of agewith previously untreated de novo AML (Study ALFA-0701). Patients with acute promyelocytic leukaemia(APL, AML3) and patients with AML arising from myelodysplastic syndrome (MDS) or secondary AMLwere excluded from the study.

The primary endpoint was event-free survival (EFS). The secondary endpoints included CR and CRp rates,relapse-free survival (RFS), overall survival (OS), and safety of the combination DA with or without

MYLOTARG.

In total, 271 patients were randomised in this study with 135 to induction treatment of 3+7 DA plusfractionated 3 mg/m2 × 3 doses of MYLOTARG and 136 to 3+7 DA alone (see section 4.2). A second courseof induction therapy with DA but without MYLOTARG, regardless of the randomisation arm, was allowed.

Patients in either arm who did not receive the second course of induction therapy and did not achieve a CRafter induction could receive a salvage course comprised of idarubicin, AraC, and granulocyte colony-stimulating factor (G-CSF).

Patients with CR or CRp received consolidation therapy with 2 courses of treatment including DNR and

AraC with or without MYLOTARG according to their initial randomisation. Patients who experiencedremission were also eligible for allogeneic transplantation. An interval of at least 2 months between the lastdose of MYLOTARG and transplantation was recommended.

Overall, the median age of patients was 62 years (range 50 to 70 years) and most patients (87.8%) had an

Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1 at baseline. Baselinecharacteristics were balanced between treatment arms with the exception of gender as a higher percentage ofmales were enrolled in the MYLOTARG arm (54.8%) than in the DA alone arm (44.1%). Overall, 59.0%and 65.3% of patients had documented favourable/intermediate-risk disease by the National Comprehensive

Cancer Network (NCCN) and European LeukaemiaNet (ELN) 2010 risk classifications, respectively. CD33expression on AML blasts by flow cytometry harmonised from local laboratory results was determined in194/271 (71.6%) patients overall. Few patients (13.7%) had low CD33 expression (less than 30% of blasts).

The study met its primary objective of demonstrating that MYLOTARG added in fractionated doses(3 mg/m2 × 3 doses) to standard induction chemotherapy for patients with previously untreated de novo AMLresulted in a statistically significant and clinically meaningful improvement in EFS. Median EFS was17.3 months (95% CI: 13.4, 30.0) in the MYLOTARG arm versus 9.5 months (95% CI: 8.1, 12.0) in the DAalone arm; hazard ratio (HR) 0.562 (95% CI: 0.415, 0.762); 2-sided p=0.0002 by log-rank test. Efficacy datafrom ALFA-0701 study are summarised in Table 8, and the Kaplan-Meier plot for EFS is shown in Figure 1.

Table 8. Efficacy results from study ALFA-0701 (mITT population)

MYLOTARG +daunorubicin + cytarabine daunorubicin + cytarabine

Event-free survival (by Investigator) N=135 N=136

Number of events, n (%) 73 (54.1) 102 (75.0)

Median EFS in months [95% CI]a, 17.3 [13.4, 30.0] 9.5 [8.1, 12.0]2-year EFS probability[95% CI]b 42.1 [32.9, 51.0] 18.2 [11.1, 26.7]3-year EFS probability [95% CI]b 39.8 [30.2, 49.3] 13.6 [5.8, 24.8]

Hazard ratio [95% CI]c 0.562 [0.415, 0.762]p-valued 0.0002

Relapse-free survival (by Investigator) N=110 N=100

Number of events, n (%) 49 (44.5) 66 (66.0)

Median RFS in months [95% CI]a 28.0 [16.3, NE] 11.4 [10.0, 14.4]

Hazard ratio [95% CI] c 0.526 [0.362, 0.764]p-valued 0.0006

Overall survival N=135 N=136

Number of deaths, n (%) 80 (59.3) 88 (64.7)

Median OS in months [95% CI]a 27.5 [21.4, 45.6] 21.8 [15.5, 27.4]

Hazard ratio [95% CI]c 0.807 [0.596, 1.093]p-valued 0.1646

Response rate (by Investigator) N=135 N=136

Overall response % [95% CI]e 81.5 [73.89, 87.64] 73.5 [65.28, 80.72]

CR 70.4 69.9

CRp 11.1 3.7

Risk difference [95% CI]f 7.95[-3.79, 19.85]p-valueg 0.1457

Based on the primary definition of EFS: event dates (induction failure, relapse, or death) determined by investigatorassessment.

The mITT population included all patients who were randomised, unless withdrawal of consent prior to start of treatmentand were analysed according to initial randomisation arm.

Abbreviations: CR=complete remission; CRp=complete remission with incomplete platelet recovery; CI=confidenceinterval; EFS=event-free survival; mITT=modified intent-to-treat; n=number; N=number; NE= not estimable; OS=overallsurvival; RFS=relapse-free survival.

a. Median estimated by Kaplan-Meier method; CI based on the Brookmeyer-Crowley method with log-log transformation.

b. Estimated from Kaplan-Meier curve. Probability (%) calculated by the product-limit method; CI calculated from the log-log transformation of survival probability using a normal approximation and the Greenwood formula.

c. Based on the Cox proportional hazards model Versus daunorubicin + cytarabine.

d. 2-sided p-value from the log-rank test.

e. Response defined as CR+CRp.

f. Overall response difference; CI based on Santner and Snell method.g. Based on Fisher’s exact test.

Figure 1. Kaplan-Meier plot of event-free survival by investigator assessment fromstudy ALFA-0701 (mITT population)

Abbreviations: C=cytarabine; D=daunorubicin; GO=gemtuzumab ozogamicin; mITT=modified intent-to-treat.

Use in AML with adverse-risk cytogenetics

In subgroup analyses in ALFA-0701, the addition of MYLOTARG to standard combination chemotherapydid not improve EFS in the subgroup of patients having adverse-risk cytogenetics (HR 1.11; 95% CI: 0.63,1.95). EFS and OS analysed by cytogenetic risk classification and cytogenetic/molecular risk classificationare presented in Table 9 and Table 10 below.

Table 9. Event-free survival by investigator assessment by AML risk classifications from study

ALFA-0701 (mITT Population)

MYLOTARG + daunorubicin +daunorubicin + cytarabinecytarabine

Cytogenetics (favourable/intermediate), N 94 95

Number of events, n (%) 44 (46.8) 68 (71.6)

Median EFS in months [95% CI]a 22.5 [15.5, NE] 11.6 [8.3, 13.7]

Hazard ratio [95% CI]b 0.460 [0.313, 0.676]p-valuec < 0.0001

Cytogenetics (unfavourable), N 27 30

Number of events, n (%) 23 (85.2) 26 (86.7)

Median EFS in months [95% CI]a 4.5 [1.1, 7.4] 2.8 [1.6, 8.7]

Hazard ratio [95% CI]b 1.111 [0.633, 1.949]p-valuec 0.7151

ELN (favourable/intermediate), N 86 91

Number of events, n (%) 40 (46.5) 63 (69.2)

Median EFS in months [95% CI]a 22.5 [15.5, NE] 12.2 [8.5, 14.3]

Hazard ratio [95% CI]b 0.485 [0.325, 0.724]p-valuec 0.0003

ELN (poor/adverse), N 37 36

Number of events, n (%) 27 (73.0) 32 (88.9)

Median EFS in months [95% CI]a 7.4 [3.7, 14.3] 4.0 [1.7, 8.6]

Hazard ratio [95% CI]b 0.720 [0.430, 1.205]p-valuec 0.2091

The ALFA-0701 study was not designed to prospectively evaluate the benefit of MYLOTARG in subgroups; analysis arepresented for descriptive purposes only.

Based on the primary definition of EFS: event dates (induction failure, relapse, or death) determined by investigatorassessment.

The mITT population included all patients who were randomised, unless withdrawal of consent prior to start of treatment andwere analysed according to initial randomisation arm.

Abbreviations: AML =acute myeloid leukaemia; CI=confidence interval; EFS=event-free survival; ELN=European

LeukaemiaNet; mITT=modified intent-to-treat; n=number; N=number; NE=not estimable.

a. Median estimated by Kaplan-Meier method; CI based on the Brookmeyer and Crowley Method with log-logtransformation.

b. Based on the Cox Proportional Hazards Model Versus daunorubicin+cytarabine.

c. 2-sided p-value from the log-rank test.

Table 10. Overall survival by AML risk classifications from study ALFA-0701 (mITT Population)

MYLOTARG + daunorubicin +daunorubicin + cytarabinecytarabine

Cytogenetics (favourable/intermediate), N 94 95

Number of deaths, n (%) 51 (54.3) 57 (60.0)

Median OS in months [95% CI]a 38.6 [24.4, NE] 26.0 [18.9, 39.7]

Hazard ratio [95% CI]b 0.747 [0.511, 1.091]p-valuec 0.1288

Cytogenetics (unfavourable), N 27 30

Number of deaths, n (%) 24 (88.9) 24 (80.0)

Median OS in months [95% CI]a 12.0 [4.2, 14.2] 13.5 [9.4, 27.3]

Hazard ratio [95% CI]b 1.553 [0.878, 2.748]p-valuec 0.1267

ELN (favourable/intermediate), N 86 91

Number of deaths, n (%) 44 (51.2) 53 (58.2)

Median OS in months [95% CI]a 45.6 [25.5, NE] 26.9 [19.3, 46.5]

Hazard ratio [95% CI]b 0.730 [0.489, 1.089]p-valuec 0.1216

ELN (poor/adverse), N 37 36

Number of deaths, n (%) 31 (83.8) 29 (80.6)

Median OS in months [95% CI]a 13.2 [7.0, 18.5] 13.5 [10.8, 19.8]

Hazard ratio [95% CI]b 1.124 [0.677, 1.867]p-valuec 0.6487

The ALFA-0701 study was not designed to prospectively evaluate the benefit of MYLOTARG in subgroups; analysis arepresented for descriptive purposes only.

The mITT population included all patients who were randomised, unless withdrawal of consent prior to start of treatment andwere analysed according to initial randomisation arm.

Abbreviations: AML=acute myeloid leukaemia; CI=confidence interval; ELN=European LeukaemiaNet; mITT=modifiedintent-to-treat; n=number; N=number; NE=not estimable; OS=Overall Survival

a. Median estimated by Kaplan-Meier method; CI based on the Brookmeyer and Crowley Method with log-logtransformation.

b. Based on the Cox Proportional Hazards Model Versus daunorubicin + cytarabine.

c. 2-sided p-value from the log-rank test.

Previously untreated AML

COG AAML0531

In a randomised study (COG AAML0531) that evaluated standard chemotherapy alone or combined with

MYLOTARG in 1 063 newly diagnosed children with AML (93.7% of patients < 18 years of age), andyoung adults (6.3% of patients); mean age was 8.9 years (range: 0-29 years), patients with de novo AMLwere randomly assigned to either standard 5-course chemotherapy alone or to the same chemotherapy with2 doses of MYLOTARG (3 mg/m2/dose) administered once in induction Course 1 and once in intensification

Course 2. The study showed that addition of MYLOTARG to intensive chemotherapy improved EFS(3 years: 50.6% versus 44.0%; HR 0.838; 95% CI: 0.706, 0.995; p=0.0431) in de novo AML owing to areduced relapse risk, with a trend towards longer OS in the MYLOTARG arm which was not statisticallysignificant (3 years: 72.4% versus 67.6%; HR 0.904; 95% CI: 0.721, 1.133; p=0.3799). However, it was alsofound that increased toxicity (post-remission toxic mortality) was observed in patients with low-risk AMLwhich was attributed to the prolonged neutropenia that occurred after receiving gemtuzumab ozogamicinduring intensification Course 2 (see sections 4.2 and 4.8). Overall, 29 (5.5%) of patients in the MYLOTARGarm and 15 (2.8%) patients in the comparator arm died during remission. Thus, the optimal dose ofgemtuzumab ozogamicin for paediatric patients was not established (see section 4.2).

MyeChild 01

The major dose finding part of the paediatric study MyeChild 01 investigated the number of doses of

MYLOTARG 3 mg/m2 (up to a maximum of 3 doses; each dose was capped at one 5 mg vial/dose) whichcan be combined safely with cytarabine plus either mitoxantrone or liposomal daunorubicin in inductiontherapy. Key inclusion criteria included patients ≥12 months and <18 years of age at trial entry and diagnosisof AML/high risk MDS (>10% blasts in the bone marrow)/isolated myeloid sarcoma with no prior therapy.

There were 3 cohorts that varied by the number of MYLOTARG infusions during the induction phase:

Cohort 1 (n=15): Patients received a single dose of MYLOTARG (3 mg/m2) on day 4 of Course 1 ofinduction chemotherapy. Cohort 2 (n=20): Patients received a single dose of MYLOTARG (3 mg/m2) ondays 4 and 7 of Course 1 of induction chemotherapy. Cohort 3 (n=19): Patients received a single dose of

MYLOTARG (3 mg/m2) on days 4, 7 and 10 of Course 1 of induction chemotherapy. Among 55 enrolledpatients, 30 (54.5%) patients were 2 years to <12 years of age, 32 (58.2%) patients were male and the medianage of all patients was 7.0 (range: 1, 17) years. Though efficacy was a secondary endpoint, best overallresponse (CR+CRi) among patients treated (n=54) was achieved in 49 (90.7%; 95% CI: 79.7%, 96.9%)patients (cohort 1, 80.0%, cohort 2, 95.0%, cohort 3, 94.7%). MRD negativity was reported in 35 (71.4%)patients after Course 2 of treatment (cohort 1, 58.3%, cohort 2, 78.9%, cohort 3, 72.2%). The MyeChild 01study is ongoing. The optimal dose of gemtuzumab ozogamicin for paediatric patients is not yet established(see section 4.2).

Relapsed or refractory AML

A systematic literature review of studies was conducted to evaluate MYLOTARG in paediatric patients withrelapsed or refractory AML, which included 454 patients receiving MYLOTARG either as a monotherapy(single or fractionated dosing) or combination therapy from 16 published papers plus the US Expanded

Access Study (see section 4.8). The median study size was 15 patients, with a range of 5-105 patients. Theoverall minimum and maximum ages range from 0 years to 22.3 years, with an overall median age of8.7 years at the time of treatment.

Most studies were in the compassionate use setting (70.6%). MYLOTARG was given as monotherapy in47.1%, part of a combination in 23.5%, and in both settings in 29.4% of the studies. Total dosing of

MYLOTARG ranged from 1.8 mg/m2 to 9 mg/m2. When MYLOTARG was given in combination, acytarabine based regimen was used in 8 of the 9 studies. In 23.5% of the studies the majority of patientsreceived fractionated (3 mg/m2 on Day 1, 4, 7) doses of MYLOTARG, while in 35.3% of the studies doseshigher than 3 mg/m2 were given. MYLOTARG was given as induction treatment in most studies (82.4%).

With MYLOTARG monotherapy, the response rate (CR/CRp/CRi; weighted average across studies) was33.3% with fractionated dosing (1 study) and 24.3% with non-fractionated dosing (9 studies). In thecombination setting, the response rate was 49.0% with non-fractionated MYLOTARG (3 studies) and 38.8%with fractionated MYLOTARG (2 studies).

Safety information on myelosuppression, infections, VOD overall and VOD post-HSCT, and death, whichare known adverse events for MYLOTARG (see section 4.8 and Table 7), was obtained from literature.

Limitations of this analysis include the small sample size of some studies, heterogeneity of the studies, andthe lack of control data in this setting.

The effect of MYLOTARG on corrected QT interval was evaluated in monotherapy study B1761031, in50 adult patients with relapsed or refractory CD33-positive AML. At therapeutic plasma concentrations, thelargest mean QTcF interval change from baseline was 5.10 msec (90% CI: 2.15, 8.06 msec). There were nopatients with a maximum QTcF increase from baseline of > 60 msec and no patients had a QTcF > 480 msec.

One (1) event each of atrial fibrillation (Grade 3) and supraventricular tachycardia (Grade 3) occurred in thesame patient. No Grade 4 or Grade 5 cardiac conduction adverse events were reported.

Based on the concentration-QTc interval analysis, the expected median change in QTcF from baseline fortotal hP67.6 antibody was 0.842 msec (95% CI: -1.93, 3.51 msec) at an average observed plasma Cmax. Forunconjugated calicheamicin, the expected median change in QTcF from baseline was 0.602 msec (95%

CI: -2.17, 2.72 msec) at an approximate observed plasma Cmax following administration at the recommendeddosing regimen of MYLOTARG.

Gemtuzumab ozogamicin is an antibody-drug conjugate (ADC) composed of CD33-directed monoclonalantibody (hP67.6) that is covalently linked to the cytotoxic agent N-acetyl-gamma calicheamicin. Thepharmacokinetics (PK) of gemtuzumab ozogamicin is described by measuring PK characteristics of theantibody (hP67.6) as well as conjugated and unconjugated calicheamicin derivatives.

Clinical PK data were collected following a monotherapy dosing regimen (3 mg/m2 up to one 5 mg vial on

Days 1, 4, 7) of MYLOTARG in adult patients with relapsed/refractory AML. Exposures as measured bygeometric mean AUC336 and Cmax following multiple doses for conjugated calicheamicin and total hP67.6antibody were 461 500 pg∙hr/mL and 11 740 pg/mL; 26 820 ng∙hr/mL and 585.6 ng/mL, respectively. The

PK data for unconjugated calicheamicin are not presented due to instability issues in plasma.

In vitro, the binding N-acetyl gamma calicheamicin dimethyl hydrazide to human plasma proteins isapproximately 97%. In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide is a substrate of

P-glycoprotein (P-gp). In patients, the total volume of distribution of hP67.6 antibody (sum of V1 [13.0 L]and V2 [6.91 L]) was found to be approximately 20 L.

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 metabolised, primarily via nonenzymaticreduction of the disulphide moiety. The activity (cytotoxicity) of the resultant metabolites is expected to besignificantly attenuated.

Effect of other medicinal products on gemtuzumab ozogamicin

In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide is primarily metabolised via nonenzymaticreduction. Therefore, coadministration of gemtuzumab ozogamicin with inhibitors or inducers of cytochrome

P450 (CYP) or uridine diphosphate glucuronosyltransferase (UGT) drug metabolising enzymes are unlikelyto alter exposure to N-acetyl gamma calicheamicin dimethyl hydrazide.

Based on population pharmacokinetic (PK) analyses, the combination of gemtuzumab ozogamicin withhydroxyurea, DNR, and AraC is not predicted to cause clinically meaningful changes in the PK of hP67.6 orunconjugated calicheamicin.

Effect of gemtuzumab ozogamicin on other medicinal products

Effect on CYP substrates

In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide and gemtuzumab ozogamicin had a lowpotential to inhibit the activities of CYP1A2, CYP2A6 (tested only using gemtuzumab ozogamicin),

CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 at clinically relevant concentrations. Invitro, N-acetyl gamma calicheamicin dimethyl hydrazide and gemtuzumab ozogamicin had a low potential toinduce 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 associatedprotein (MRP) 2, multidrug and toxin extrusion protein (MATE)1 and MATE2K, organic anion transporter(OAT)1 and OAT3, organic cation transporter (OCT)1 and OCT2, and organic anion transportingpolypeptide (OATP)1B1 and OATP1B3 at clinically relevant concentrations.

Effect on co-administered chemotherapeutic agents

Based on population pharmacokinetic (PK) analyses, the combination of gemtuzumab ozogamicin with DNRand AraC is not predicted to cause clinically meaningful changes in the PK of these agents.

Gemtuzumab ozogamicin PK was well characterised by a 2-compartment model with linear andtime-dependent clearance components. In 50 patients with relapsed or refractory AML following amonotherapy dosing regimen (3 mg/m2 up to one 5 mg vial on Days 1, 4, 7) of MYLOTARG, the clearanceof total hP67.6 antibody was 0.288 L/h, and the terminal elimination half-life (t½) was estimated to be 96.6 h.

Pharmacokinetics in specific groups of subjects or patients

Age, race, and gender

Based on a population PK analysis, age, race, and gender did not significantly affect gemtuzumabozogamicin disposition.

No formal PK studies of gemtuzumab ozogamicin have been conducted in patients with hepatic impairment.

Based on a population PK analysis, the clearance of gemtuzumab ozogamicin (hP67.6 antibody andunconjugated 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 included405 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) (see section 4.2).

No formal PK studies of gemtuzumab ozogamicin have been conducted in patients with renal impairment.

Based on a population PK analysis in 406 patients, the clearance of gemtuzumab ozogamicin in patients withmild renal impairment (creatinine clearance [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 PK of gemtuzumab ozogamicin has not been studied in patients with severe renal impairment.

Clinical PK data were collected following a dosing regimen (3 mg/m2 up to one 5 mg vial on Days 4, 7 and10) of MYLOTARG with induction therapy in pediatric patients ≥12 months of age with newly diagnosed

AML. Exposures as measured by geometric mean AUCtau and Cmax following the third dose for conjugatedcalicheamicin and total hP67.6 antibody were 777 300 pg.hr/mL and 24 340 pg/mL; 46 500 ng.hr/mL and1 336 ng/mL, respectively.

The main toxicities occurred in the liver, bone marrow and lymphoid organs, haematology parameters(decreased RBC mass and WBC counts, mainly lymphocytes), kidney, eye and male and female reproductiveorgans. Effects on liver, kidney and male reproductive organs in rats, and on lymphoid tissues in monkeys(approximately 18 times for rats, and 36 times for monkeys, the human clinical exposure after the thirdhuman dose of 3 mg/m2 based on AUC168) were not reversible. Effects on female reproductive organs andthe eye in monkeys were adverse in the 12-week study (approximately 193 and 322 times, respectively, thehuman clinical exposure after the third human dose of 3 mg/m2 based on AUC168). The relevance of theirreversible animal findings to humans is uncertain. Nervous system effects have not been observed inanimals after administration of MYLOTARG. Nervous system alterations were identified in rats with otherantibody-calicheamicin conjugates.

Gemtuzumab ozogamicin was found to be clastogenic. This is consistent with the known induction of DNAbreaks by calicheamicin and other enediyne antitumour antibiotics. N-acetyl gamma calicheamicin DMH(the released cytotoxin) was found to be mutagenic and clastogenic.

Formal carcinogenicity studies have not been conducted with gemtuzumab ozogamicin. In toxicity studies,rats developed preneoplastic lesions (minimal to slight oval cell hyperplasia) in the liver approximately54 times the human clinical exposure after the third human dose of 3 mg/m2 based on AUC168. There were nopreneoplastic or neoplastic lesions observed in monkeys up to approximately 115 times the human clinicalexposure after the third human dose of 3 mg/m2 based on AUC168. The relevance of these animal findings tohumans is uncertain.

In a female rat fertility study slightly lower numbers of corpora lutea and increased embryolethality wereobserved in the presence of maternal toxicity (approximately 9.7 times the human clinical exposure after thethird human dose of 3 mg/m2 based on AUC168). Effects on the reproductive tract of female monkeys wereobserved in the 12-week study (atrophy of the ovary, oviduct, uterus, and cervix; approximately 193 timesthe human clinical exposure after the third dose of 3 mg/m2).

In a male fertility study, effects on male reproduction included lower spermatogonia and spermatocytes,decreases in testicular spermatids and epididymal sperm, vacuolation of the nucleus in spermatids, and/orappearance of giant cells. Additional findings included effects on the testes, epididymides and mammarygland as well as fertility. When male rats were mated again after a 9-week non-dosing period, effects onsperm and fertility were worse but there was partial recovery of the lower spermatogonia and spermatocytesin the testes. Effects on male rat reproductive organs were partially reversible or not reversible (seesection 4.6). Male reproductive effects (testes, epididymides, seminal vesicles) in monkeys were observed atapproximately 66 times the human clinical exposure after the third dose of 3 mg/m2.

In an embryo-foetal toxicity study lower foetal body weight, higher incidence of foetal wavy ribs, and lowerincidence of foetal skeletal ossification were observed. Increased embryolethality and foetal morphologicalanomalies included digital malformations, absence of the aortic arch, anomalies in the long bones in theforelimbs, misshapen scapula, absence of a vertebral centrum, and fused sternebrae. Increasedembryolethality was also observed in the presence of maternal toxicity. The lowest dose with embryo-foetaleffects correlated with 9.7 times the human clinical exposure after the third human dose of 3 mg/m2, basedon AUC168 (see section 4.6).

Dextran 40

Sucrose

Sodium chloride

Sodium dihydrogen phosphate monohydrate

Disodium hydrogen phosphate anhydrous

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Unopened vial5 years

Reconstituted and diluted solution

Protect the reconstituted and diluted MYLOTARG solutions from light. The solutions should be usedimmediately. Do not freeze the reconstituted or diluted solution.

If the product cannot be used immediately:

- Following reconstitution, the original vial may be stored up to 16 hours in a refrigerator (2°C-8°C)or up to 3 hours at room temperature (below 30°C).

- The diluted solution may be stored up to 18 hours in a refrigerator (2°C-8°C) and up to 6 hours atroom temperature (below 30°C). The allowed time at room temperature (below 30°C) includes thetime required for preparation of the diluted solution, equilibration, if needed, and administration tothe patient. The maximum time from preparation of the diluted solution through administrationshould not exceed 24 hours.

Store in a refrigerator (2°C-8°C).

Do not freeze.

Store the vial in the original carton to protect from light.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Amber Type 1 glass vial, with butyl rubber stopper and crimp seal with flip-off cap containing 5 mggemtuzumab ozogamicin.

Each carton contains 1 vial.

Use appropriate aseptic technique for the reconstitution and dilution procedures. MYLOTARG is lightsensitive and should be protected from ultraviolet light during reconstitution, dilution, and administration.

- Calculate the dose (mg) of MYLOTARG required.

- Prior to reconstitution, allow the vial to reach room temperature (below 30°C) for approximately5 minutes. Reconstitute each 5 mg vial with 5 mL of water for injections to obtain a single-use solutionof 1 mg/mL of gemtuzumab ozogamicin.

- Gently swirl the vial to aid dissolution. Do not shake.

- Inspect the reconstituted solution for particulates and discolouration. The reconstituted solution maycontain small white to off-white, opaque to translucent, and amorphous to fibre-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 to16 hours in a refrigerator (2°C-8°C) or up to 3 hours at room temperature (below 30°C). Protect fromlight and do not freeze.

- Calculate the required volume of the reconstituted solution needed to obtain the appropriate doseaccording to patient body surface area. Withdraw this amount from the vial using a syringe.

MYLOTARG vials contain 5 mg of medicinal product with no overfill. When reconstituted to a 1mg/mL concentration as directed, the extractable content of the vial is 4.5 mg (4.5 mL). Protect fromlight. 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 thefollowing instructions:

o 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 injectionto a final concentration between 0.075 mg/mL to 0.234 mg/mL. Protect from light.

o Doses greater than or equal to 3.9 mg are to be diluted in a syringe or an intravenous bag in anappropriate volume of sodium chloride 9 mg/mL (0.9%) solution for injection to ensure a finalconcentration 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 solutionshould be infused immediately. If not used immediately, the diluted solution may be stored up to18 hours in a refrigerator (2°C-8°C) and up to 6 hours at room temperature (below 30°C). The allowedtime at room temperature (below 30°C) includes the time required for preparation of the dilutedsolution, equilibration, if needed, and administration to the patient. The maximum time from preparationof the diluted solution through administration should not exceed 24 hours. Protect from light and do notfreeze.

- 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).

- Filtration of the diluted solution is required. An in-line, low protein-binding 0.2 micronpolyethersulphone (PES) filter must be used for infusion of MYLOTARG.

- Doses administered by syringe must utilize small bore infusion lines (microbore) with an in-line, lowprotein-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 allowed6-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 arerecommended.

Do not mix MYLOTARG with, or administer as an infusion with, other medicinal products.

See also section 6.3 for dilution, storage, and infusion information.

Toxic waste disposal procedures prescribed for anticancer medicinal products must be used.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/18/1277/001

Date of first authorisation: 19 April 2018

Date of latest renewal: 15 November 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.