4.1. Therapeutic indications

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

4.2. Posology and method of administration

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

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

Premedication with a corticosteroid, antihistamine, and acetaminophen (or paracetamol) is recommended 1 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 as hydration, administration of antihyperuricemic or other agents for treatment of hyperuricaemia should be taken (see section 4.4).

Posology

Induction

The recommended dose of MYLOTARG is 3 mg/m2/dose (up to a maximum of one 5 mg vial) infused over a 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 following recommended dosing: DNR 35 mg/m2/day on Days 1 and 2, and AraC 1 g/m2 every 12 hours, on Day 1 to Day 3.

Consolidation

For patients experiencing a complete remission (CR) following induction, defined as fewer than 5% blasts in a normocellular marrow and an absolute neutrophil count (ANC) of more than 1.0 × 109 cells/L with a platelet count of 100 × 109/L or more in the peripheral blood in the absence of transfusion, up to 2 consolidation courses of intravenous DNR (60 mg/m2 for 1 day [first course] or 2 days [second course]) in combination with intravenous AraC (1 g/m2 per 12 hours, infused over 2 hours on Day 1 to Day 4) with intravenous MYLOTARG (3 mg/m2/dose infused over 2 hours up to a maximum dose of one 5 mg vial on Day 1) are recommended.

Table 1. Dosing regimens for MYLOTARG in combination with chemotherapy

Treatment course

MYLOTARG

daunorubicin

cytarabine

Inductiona

3 mg/m2/dose (up to a maximum of one 5 mg vial) on Days 1, 4, and 7

60 mg/m2/day on Day 1 to Day 3

200 mg/m2/day on Day 1 to Day 7

Second induction (if required)

MYLOTARG should not be administered during second induction.

35 mg/m2/day on Day 1 to Day 2

1 g/m2/every 12 hours on Day 1 to Day 3

Consolidation Course 1a,b

3 mg/m2/dose (up to a maximum of one 5 mg vial) on Day 1

60 mg/m2/day on Day 1

1 g/m2/every 12 hours on Day 1 to Day 4

Consolidation Course 2a,b

3 mg/m2/dose (up to a maximum of one 5 mg vial) on Day 1

60 mg/m2/day on Day 1 to Day 2

1 g/m2/every 12 hours on Day 1 to Day 4

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 recommended either with leukapheresis, oral hydroxyurea or AraC with or without hydroxyurea to reduce the peripheral white blood cell (WBC) count 48 hours prior to administration of MYLOTARG.

If AraC is used for leukoreduction with or without hydroxyurea in patients with previously untreated, de novo hyperleukocytic AML receiving MYLOTARG in combination therapy, apply the following modified schedule (Table 2):

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

Treatment course

MYLOTARG

daunorubicin

cytarabine

hydroxyurea

Inductiona

3 mg/m2/dose (up to a maximum of one 5 mg vial) on Days 3, 6, and 9

60 mg/m2/day on Day 3 to Day 5

200 mg/m2/day on Day 1 to Day 7

Day 1 (as per standard medical 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 (see section 4.4). Management of some adverse drug reactions may require dose interruptions or permanent discontinuation 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

(Platelets < 100 000/mm3 at the planned start date of the consolidation course)

• Postpone start of consolidation course.

• If platelet count recovers to ≥ 100 000/mm3 within 14 days 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 start date of the consolidation course: MYLOTARG should not be re-introduced and consolidation therapy should consist of DNR and AraC only.

• If platelet count recovery remains < 50 000/mm3 for greater than 14 days consolidation therapy should be re-evaluated and a BMA should be performed to re-assess the patients' status.

Persistent neutropenia

• If neutrophil count does not recover to greater than 500/mm3 within 14 days following the planned start date of the consolidation cycle (14 days after haematologic recovery following previous cycle), discontinue MYLOTARG (do not 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 AST and/or 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.

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

Infusion related reactions

Interrupt the infusion and institute appropriate medical management based on the severity of symptoms. Patients should be monitored until signs and symptoms completely resolve and infusion may resume.

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

Other severe or life-threatening non-haematologic toxicities

Delay treatment with MYLOTARG until recovery to a severity of no more than mild.

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

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

Special populations

Hepatic impairment

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).

Renal impairment

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

Elderly

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

Paediatric population

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 can be made.

Method of administration

MYLOTARG is for intravenous use and must be reconstituted and diluted before administration (see section 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 a 2-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, see section 6.6.

4.3. Contraindications

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

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered 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 been reported 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 severe hepatic 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 may include elevations in ALT, AST, total bilirubin, and alkaline phosphatase, which should be monitored prior to 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 develop abnormal liver tests, more frequent monitoring of liver tests and clinical signs and symptoms of hepatotoxicity is recommended. For patients who proceed to HSCT, close monitoring of liver tests is recommended during the post-HSCT period, as appropriate. No definitive relationship was found between VOD and time of HSCT relative to higher MYLOTARG monotherapy doses, however, the ALFA-0701 study recommended an interval of 2 months between the last dose of MYLOTARG and HSCT.

Management of signs or symptoms of hepatic toxicity may require a dose interruption, or discontinuation of MYLOTARG (see section 4.2). In patients who experience VOD/SOS, MYLOTARG should be discontinued 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). There have been reports of fatal infusion reactions in the post-marketing setting. Signs and symptoms of infusion related reactions may include fever and chills, and less frequently hypotension, tachycardia, and respiratory symptoms that may occur during the first 24 hours after administration. Infusion of MYLOTARG should be performed under close clinical monitoring, including pulse, blood pressure, and temperature. Premedication with 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 develop evidence of severe reactions, especially dyspnoea, bronchospasm, or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinuation of treatment should be strongly considered for patients who develop signs or symptoms of anaphylaxis, including severe respiratory symptoms or clinically significant hypotension (see section 4.2).

Myelosuppression

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 and bleeding/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, patients should be monitored for signs and symptoms of infection, bleeding/haemorrhage, or other effects of myelosuppression. Routine clinical and laboratory surveillance testing during and after treatment is indicated.

Management of patients with severe infection, bleeding/haemorrhage, or other effects of myelosuppression, including severe neutropenia or persistent thrombocytopenia, may require a dose delay or permanent discontinuation of MYLOTARG (see section 4.2).

Tumour lysis syndrome (TLS)

In clinical studies, TLS was reported (see section 4.8). Fatal reports of TLS complicated by acute renal failure 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 count to below 30 000/mm3 prior to administration of MYLOTARG to reduce the risk of inducing TLS (see section 4.2).

Patients should be monitored for signs and symptoms of TLS and treated according to standard medical practice. Appropriate measures to help prevent the development of tumour lysis-related hyperuricaemia, such as hydration, administration of antihyperuricemics (e.g., allopurinol) or other agents for treatment of hyperuricaemia (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-risk cytogenetics, with uncertainty regarding the size of the effect in patients with adverse cytogenetics (see section 5.1). For patients being treated with MYLOTARG in combination with daunorubicin and cytarabine for newly diagnosed de novo AML, when cytogenetics testing results become available it should be considered whether the potential benefit of continuing treatment with MYLOTARG outweighs the risks for the individual patient (see section 5.1).

Contraception

Women of childbearing potential, or partners of females of childbearing potential should be advised to use 2 methods of effective contraception during treatment with MYLOTARG for at least 7 months (females) or 4 months (males) after the last dose (see section 4.6).

Excipients

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 (see sections 4.2 and 6.6), and this should be considered in relation to the total sodium from all sources that will be administered to the patient.

4.5. Interaction with other medicinal products and other forms of interaction

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

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

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 use 2 methods of effective contraception during treatment with MYLOTARG for at least 7 months (females) or 4 months (males) after the last dose.

Pregnancy

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

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

Breast-feeding

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 adverse drug reactions in breast-fed children, women should not breast-feed during treatment with MYLOTARG and for at least 1 month after the final dose (see section 5.3).

Fertility

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

4.7. Effects on ability to drive and use machines

MYLOTARG has moderate influence on the ability to drive and use machines. Patients should be advised they may experience fatigue, dizziness and headache during treatment with MYLOTARG (see section 4.8). Therefore, caution should be exercised when driving or operating machines.

4.8. Undesirable effects

Summary of the safety profile

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

In the combination therapy study ALFA-0701, clinically relevant serious adverse drug reactions were hepatotoxicity, including VOD/SOS (3.8%), haemorrhage (9.9%), severe infection (41.2%), and tumour lysis syndrome (1.5%). In monotherapy studies (Studies 201/202/203), clinically relevant serious adverse drug reactions 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 included infection (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 and infection. 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 most frequent adverse drug reactions (> 30%) included infection (50.0%), febrile neutropenia (40.0%) and haemorrhage (32.0%).

The most frequent (≥ 1%) adverse drug reactions that led to permanent discontinuation in the combination therapy study were thrombocytopenia, VOD, haemorrhage and infection. The most frequent (≥ 1%) adverse drug reactions that led to permanent discontinuation in monotherapy studies (Studies 201/202/203) were infection, haemorrhage, multi-organ failure, and VOD. The adverse drug reactions that led to permanent discontinuation 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, defined using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.

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

System organ class

Frequency

Preferred term

MYLOTARG + daunorubicin + cytarabine (N=131)

daunorubicin + cytarabine (N=137)

All grades

%

Grade 3/4

%

All grades

%

Grade 3/4

%

Infections and infestations

Very common

Infection*a

77.9

76.3

77.4

74.4

Vascular disorders

Very common

Haemorrhage*b

90.1

20.6

78.1

8.8

Hepatobiliary disorders

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) decreased

98.5

90.7

97.8

89.6

Neutrophils decreased

97.7

96.1

98.5

97.0

Hyperglycaemia

92.0

19.2

91.1

17.8

Aspartate aminotransferase (AST) increased

89.2

14.0

73.9

9.0

Prothrombin time increased

84.8

3.3

89.1

0

Activated partial thromboplastin time prolonged

80.0

6.4

57.5

5.5

Alkaline phosphatase increased

79.7

13.3

68.9

5.3

Alanine aminotransferase (ALT) increased

78.3

10.9

81.3

15.7

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 liver disease*.

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

System organ class

Frequency

Preferred term

All grades

%

Grade 3/4

%

Infections and infestations

Very common

Infection*a

68.2

32.8

Blood and lymphatic system disorders

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

Immune system disorders

Common

Infusion related reactionh

7.6

3.6

Metabolism and nutrition disorders

Very common

Hyperglycaemiai

11.2

6.9

Decreased appetite

27.1

6.1

Common

Tumour lysis syndrome**

2.5

1.8

Nervous system disorders

Very common

Headache

38.3

12.3

Cardiac disorders

Very common

Tachycardiaj

13.0

4.3

Vascular disorders

Very common

Haemorrhage*k

67.1

23.8

Hypotensionl

20.2

14.8

Hypertensionm

17.3

10.5

Respiratory, thoracic and mediastinal disorders

Very common

Dyspnoean

27.4

12.6

Unknown

Interstitial pneumonia*

Gastrointestinal disorders

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*

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders

Very common

Rashu

19.9

5.8

Common

Erythemav

9.4

2.2

Pruritus

5.4

0.4

Renal and urinary disorders

Unknown

Haemorrhagic cystitis*

General disorders and administration site 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

Investigations

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%), Gastrointestinal infection (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 infections including 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 pain upper, Abdominal discomfort, and Abdominal tenderness.

p. Stomatitis includes the following reported PTs: Mucosal inflammation, Oropharyngeal pain, Stomatitis, Mouth ulceration, Oral pain, Oral mucosal blistering, Aphthous stomatitis, Tongue ulceration, Glossodynia, Oral mucosal erythema, 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 liver disease*#.

t. Hepatic function abnormal includes the following reported PTs: Liver function test abnormal and Hepatic function abnormal.

u. Rash includes the following reported PTs: Rash, Dermatitis#, Dermatitis allergic#, Dermatitis bullous, Dermatitis contact, Dermatitis exfoliative#, Drug eruption, Pruritus allergic# and Rash erythematous#, Rash macular#, Rash maculo 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, Generalised oedema, and Periorbital oedema.

y. Fatigue includes the following reported PTs: Fatigue, Asthenia, Lethargy, and Malaise.

Description of selected adverse reactions

Hepatotoxicity, including hepatic VOD/SOS

In the combination therapy study, VOD and hepatic laboratory abnormalities were collected. Additional characterisation 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 following treatment, 2 (1.5%) of these reactions were fatal (see Table 5). Five (3.8%) of these VOD reactions occurred within 28 days of any dose of gemtuzumab ozogamicin. One VOD event occurred more than 28 days of last dose of gemtuzumab ozogamicin; with 1 of these events occurring a few days after having started an HSCT conditioning regimen. The median time from the last gemtuzumab ozogamicin dose to onset of VOD was 9 days (range: 2-298 days). VOD was also reported in 2 patients who received MYLOTARG as a follow-up therapy following relapse of AML after chemotherapy treatment in the control arm of the combination therapy study. Both of these patients experienced VOD more than 28 days after the last dose of gemtuzumab ozogamicin. 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 and hyperbilirubinemia). 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 5 hepatotoxicity.

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

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

Myelosuppression

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

During the induction phase, 109 (83.2%) and 99 (75.6%) patients had platelet recovery to counts of 50 000/mm3 and 100 000/mm3, respectively. The median times to platelet recovery to counts of 50 000/mm3 and 100 000/mm3 were 34 and 35 days, respectively. During the consolidation 1 phase, 92 (94.8%) and 71 (73.2%) patients had a platelet recovery to counts of 50 000/mm3 and 100 000/mm3, respectively. The median times to platelet recovery to counts of 50 000/mm3 and 100 000/mm3 were 32 and 35 days, respectively. During the consolidation 2 phase, 80 (97.6%) and 70 (85.4%) patients had a platelet recovery to counts of 50 000/mm3 and 100 000/mm3, respectively. The median times to platelet recovery to counts of 50 000/mm3 and 100 000/mm3 were 36.5 and 43 days, respectively.

Thrombocytopenia with platelet counts < 50 000/mm3 persisting 45 days after the start of therapy for responding patients (CR and incomplete platelet recovery [CRp]) occurred in 22 (20.4%) of patients. The number 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 and 10 [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/mm3 and 1 000/mm3 was 25 days. In the consolidation 1 phase of therapy, 94 (96.9%) patients had neutrophil recovery to counts of 500/mm3, and 91 (94%) patients recovered to counts of 1 000/mm3. The median times to neutrophil recovery to ANC of 500/mm3 and 1 000/mm3 were 21 and 25 days, respectively. In the consolidation 2 phase of therapy, 80 (97.6%) patients had neutrophil recovery to counts of 500/mm3, and 79 (96.3%) patients recovered to counts of 1 000/mm3. The median times to neutrophil recovery to ANC of 500/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 of gemtuzumab ozogamicin in combination with chemotherapy (N=131), 102 (77.9%) patients experienced all causality severe (Grade ≥ 3) infections. Treatment-related death due to septic shock was reported in 1 (0.8%) patients. Fatal severe infection was reported in 2 (1.53%) patients in the MYLOTARG arm and 4 (2.92%) patients in the control arm.

In the combination therapy study (N=131), all grades and Grade 3/4 bleeding/haemorrhagic reactions were reported in 118 (90.1%) and 27 (20.6%) patients, respectively. The most frequent Grade 3 bleeding/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 reactions were 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. The most 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-19 pneumonia 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 and traumatic intracranial haemorrhage Grade 4 in 1 patient, each). No fatal bleeding/haemorrhagic events were reported.

Management of patients with severe infection, bleeding/haemorrhage, or other effects of myelosuppression, including severe neutropenia or persistent thrombocytopenia, may require a dose delay or permanent discontinuation of MYLOTARG (see sections 4.2 and 4.4).

Immunogenicity

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 measure neutralizing 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 or conjugated calicheamicin. None of the patients experienced anaphylaxis, hypersensitivity or other clinical sequelae related to ADA. There was no evidence that the presence of ADA had a direct association with any potential safety issues.

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

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

Paediatric population

Previously untreated AML

The safety and efficacy of MYLOTARG in children and adolescents with previously untreated AML below the 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 gemtuzumab ozogamicin 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 safety profile was similar with that observed in the other studies of gemtuzumab ozogamicin combined with intensive chemotherapy in adult patients with de novo AML. However, the optimal dose of gemtuzumab ozogamicin for paediatric patients was not established, since in Study AAML0531 during the second intensification period after the second dose of gemtuzumab ozogamicin, a larger proportion of patients in the gemtuzumab ozogamicin arm experienced prolonged neutrophil recovery time (> 59 days) as compared with the 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 ozogamicin combined with induction therapy (cytarabine plus either mitoxantrone or liposomal daunorubicin) in 54 children ≥12 months of age with newly diagnosed AML, the safety profile was similar with that observed in the other studies of gemtuzumab ozogamicin combined with intensive chemotherapy in adult and paediatric patients with de novo AML. The rate of infection for all grades was 57.4%. The most frequently reported 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 were febrile 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% of patients did not recover neutrophil count to 1 000/mm3 and 11.1% of patients did not recover a non-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% of patients.

Relapsed or refractory AML

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

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

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

Monotherapy

Combinationa

Fractionatedb MYLOTARG

Non-fractionatedb MYLOTARG

Fractionatedb MYLOTARG

Non-fractionatedb MYLOTARG

Number of studies

N per study (range)

Ratec (%)

Number of studies

N per study (range)

Rate (%)

Number of studies

N per study (range)

Rate (%)

Number of studies

N per study (range)

Rate (%)

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%

Myelosuppressione

Almost all patients (> 90 %) experienced myelosuppression across studies

a: 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 dose ranging 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-Tukey double arcsine transformation prior to combining studies, and the estimated combined rate was back-transformed using the harmonic mean of 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 days for platelets and 30-37 days for neutrophils.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No cases of overdose with MYLOTARG were reported in clinical experience. Single doses higher than 9 mg/m2 in adults were not tested. Treatment of MYLOTARG overdose should consist of general supportive measures.