Consumer medicine information

Mylotarg

Gemtuzumab ozogamicin

BRAND INFORMATION

Brand name

Mylotarg

Active ingredient

Gemtuzumab ozogamicin

Schedule

What is in this leaflet

This leaflet answers some common questions about MYLOTARG. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking MYLOTARG against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What MYLOTARG is used for

MYLOTARG contains the active ingredient gemtuzumab ozogamicin. It belongs to a group of medicines called antineoplastic agents that target cancer cells.

MYLOTARG is used to treat patients aged 15 years and above with acute myeloid leukaemia (AML). AML is a cancer of the blood and bone marrow in which the bone marrow makes immature white blood cells in high numbers. These abnormal cells crowd the bone marrow, preventing it from making normal blood cells.

This medicine works by stopping the abnormal growth of these cells and destroying them.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

Before you are given MYLOTARG

When you must not be given it

Do not receive MYLOTARG if you have an allergy to:

any medicine containing gemtuzumab ozogamicin
any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives.

Do not receive this medicine if you are pregnant. It may affect your developing baby if you take it during pregnancy.

Do not breast-feed if you are receiving this medicine. It is not known if MYLOTARG passes into breast milk and there is a possibility that your baby may be affected.

MYLOTARG should not be used in children and adolescents under 15 years of age. Limited information is available on MYLOTARG treatment in these patients.

Do not receive this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If you are not sure whether you should start receiving this medicine, talk to your doctor.

Before you start to be given it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

liver problems

MYLOTARG may cause, during or after treatment, a potentially life-threatening condition called hepatic venoocclusive disease, in which the blood vessels in the liver become damaged and obstructed by blood clots which may include fluid retention, rapid weight gain, increased liver size (which may be painful), and ascites (excessive accumulation of fluid in the abdominal cavity).

kidney problems
allergic reaction
an infection
bleeding
anaemia
an infusion reaction

Tell your doctor if you have had any of the following symptoms during or shortly after being given MYLOTARG

fever, chills, hot flush, dizziness or lightheadedness, rash or trouble breathing
nausea, vomiting, diarrhoea, changes in heartbeat, decreased urine or blood in urine, muscle weakness or cramps.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. It is unlikely that you will be given this medicine if you are pregnant or trying to become pregnant, as it may harm your unborn baby. Your doctor can discuss with you the risks and benefits involved.

You must avoid becoming pregnant or fathering a child if you are receiving MYLOTARG.

It is not known whether this medicine passes into breast milk.

You must not breast-feed during treatment with MYLOTARG and for at least 1 month after your last dose.

Seek advice from your doctor regarding fertility preservation before treatment. Fertility may be compromised by treatment with MYLOTARG.

If you have not told your doctor about any of the above, tell him/her before you start receiving MYLOTARG.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including:

all prescription medicines
all medicines, vitamins, herbal supplements or natural therapies you buy without a prescription from a pharmacy, supermarket, naturopath or health food shop.

Some medicines may be affected by MYLOTARG or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

How MYLOTARG is given

MYLOTARG is given in "cycles". The first MYLOTARG treatment cycle is made up of a single MYLOTARG dose given on Day 1, Day 4 and Day 7 in Week 1 (Induction cycle).

The second and third MYLOTARG treatment cycles are made up of a single MYLOTARG dose given on Day 1 (Consolidation cycle).

A doctor or nurse will give you your MYLOTARG dose gradually over 2 hours through a drip in your vein (intravenous infusion).

How much is given

Your doctor will calculate how much you need to be given.

This will depend on your height and weight and may also depend on your condition and how you have responded to previous treatment.

Medicines given before each cycle

Before each treatment with MYLOTARG you will be given other medicines (premedication) to help reduce symptoms such as fever, chills or hot flush, known as infusion reactions, and other possible side effects.

How long it is given

You will receive between one and three cycles of MYLOTARG in combination with chemotherapy. The first cycle is called Induction. The second and third cycles are called Consolidation. If the medicine works well after the Induction cycle, you may receive the two Consolidation cycles. If you do not respond to the medicine after the first cycle your treatment will be stopped.

Your doctor will discuss with you how long your treatment will last.

If you forget a treatment

If you miss a treatment, contact your doctor or nurse as soon as possible to make a new appointment.

If you take too much (overdose)

It is unlikely that you will be given too much MYLOTARG, as your dose will be calculated and given to you in a specialised setting under the supervision of a doctor.

If an overdose is suspected, immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital. You may need urgent medical attention.

While you are being given MYLOTARG

Things you must do

If you (or your partner) become pregnant while you are being given this medicine, tell your doctor immediately. You must avoid becoming pregnant or fathering a child.

Use a proven method of birth control (contraception) during treatment with MYLOTARG if you can become pregnant or if you can father a child. You must continue to use 2 methods of effective contraception during treatment and for at least 7 months (women) or at least 4 months (men) after the last dose of MYLOTARG.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are being treated with MYLOTARG.

Tell all doctors, dentists and pharmacists who treat you that you are being given this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are being given this medicine. It may affect other medicines used during surgery.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor will take regular blood tests to make sure MYLOTARG is working and to check for side effects.

In particular, your blood counts and liver function will need to be checked before each treatment.

Your doctor will also monitor you for signs and symptoms of infection, bleeding and respiratory effects.

Your doctor may change your dose, interrupt or completely stop treatment with this medicine if you have certain side effects.

Your doctor may also lower your dose based on your response to treatment.

Things to be careful of

Be careful driving or operating machinery until you know how MYLOTARG affects you. This medicine may cause fatigue in some people. If you feel tired, do not drive, operate machinery or do anything else that could be dangerous.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly. Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are receiving MYLOTARG.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by this list of possible. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or nurse immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

rapid weight gain, pain in the upper right side of your abdomen (stomach), swelling of your abdomen
- These could be symptoms of a very serious and potentially fatal condition called venoocclusive liver disease.
- If you receive MYLOTARG either before or after a stem cell transplant (a process that involves replacing blood-forming cells called stem cells that are diseased or have been damaged by anti-cancer medicines) you have an increased chance of getting this side effect.
- If you have abnormal liver function you may have an increased chance of getting this side effect.
fever, chills, hot flush, dizziness or lightheadedness, rash or trouble breathing during or shortly after the MYLOTARG infusion (infusion-related reactions)
shortness of breath, wheezing, coughing, difficulty breathing, changes in the colour of your skin to a blue tinge, feeling of heaviness or congestion in lungs
fever, sweating and chills
- These could be signs of an infection which may be serious and potentially fatal.
bruising easily or getting nose bleeds on a regular basis
symptoms in the stomach and intestines (for example, nausea, vomiting, diarrhoea), heart (for example, changes in the rhythm), kidney (for example, decreased urine, blood in urine), and nerves and muscles (for example, muscle spasms, weakness, cramps)
- These could be signs of a serious condition known as tumour lysis syndrome, which is caused by chemical disturbances in the blood due to the breakdown of dying cancer cells.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor as soon as possible if you notice any of the following:

bleeding
fatigue and shortness of breath
fever
pain in the abdomen.

The above list includes signs of serious side effects that may require urgent medical attention.

Tell your doctor or nurse if you notice any of the following:

nausea (feeling sick)
vomiting
fatigue
headache
mouth ulcer, redness or pain
diarrhoea
abdominal pain
decreased appetite
general weakness
constipation
high or low blood pressure
skin itching, redness, rash or blistering
irregular or racing heart rhythm
high blood sugar
a yellowish colour of the skin, eyes, and other tissues.

The above list includes the more common side effects of your medicine.

Some side effects (for example, changes in your liver function) can only be found when your doctor does tests from time to time to check your progress.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After receiving MYLOTARG

Storage

MYLOTARG must be kept in the original packaging in a refrigerator, protected from light, before it is time to use it.

Your doctor, nurse or pharmacist will prepare the infusion for you before you are given it.

Your doctor, nurse and pharmacist have more information on how to store and prepare MYLOTARG

Disposal

Your doctor, nurse or pharmacist will dispose of any left-over medicine.

Product description

What it looks like

MYLOTARG is a white or off-white powder or cake supplied in a glass vial.

Before MYLOTARG is given, the powder is mixed with sterile water and diluted with a solution of sodium chloride.

Each MYLOTARG carton contains 1 vial.

Ingredients

MYLOTARG contains 5 mg of gemtuzumab as the active ingredient.

dextran 40
dibasic sodium phosphate
monobasic sodium phosphate monohydrate
sodium chloride
sucrose

This medicine contains less than 1 mmol sodium (23 mg) per dose.

Supplier

MYLOTARG is supplied in Australia by:

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizermedinfo.com.au

® Registered Trademark

This leaflet was prepared in January 2022.

AUST R 316671

Published by MIMS February 2022

BRAND INFORMATION

Brand name

Mylotarg

Active ingredient

Gemtuzumab ozogamicin

Schedule

1 Name of Medicine

Gemtuzumab ozogamicin.

2 Qualitative and Quantitative Composition

Each single-dose vial contains 5 mg gemtuzumab ozogamicin.
After reconstitution, the concentrated solution contains 1 mg/mL gemtuzumab ozogamicin (see Section 4.2 Dose and Method of Administration).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection.
White to off-white cake or powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Mylotarg is indicated for combination therapy with standard anthracycline and cytarabine (AraC) for the treatment of patients age 15 years and above with previously untreated, de novo CD33-positive acute myeloid leukaemia (AML), except acute promyelocytic leukaemia (APL) (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties).

4.2 Dose 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.
Premedication with a corticosteroid, antihistamine, and acetaminophen (or paracetamol) is recommended 1 hour prior to Mylotarg dosing to help ameliorate infusion related symptoms (see Section 4.4 Special Warnings and Precautions for Use).
Appropriate measures to help prevent the development of tumour lysis-related hyperuricaemia such as hydration, administration of antihyperuricaemic or other agents for treatment of hyperuricaemia must be taken (see Section 4.4 Special Warnings and Precautions for Use).
Mylotarg must be reconstituted and diluted before administration (see Section 4.2 Dose and Method of Administration, Instructions for use and handling).

Traceability.

In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded in the patient file.

Dosage.

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 of the induction chemotherapy cycle.
If a second induction is required, Mylotarg should not be administered during second induction therapy. Only standard anthracycline and cytarabine (AraC) should be administered during the second induction cycle.

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 x 10⁹ cells/L with a platelet count of 100 x 10⁹/L or more in the peripheral blood in the absence of transfusion, the recommended dose of Mylotarg is 3 mg/m²/dose (up to a maximum dose of one 5 mg vial) infused over a 2 hour period on Day 1 of the consolidation chemotherapy cycle. See Table 1.

Method of administration.

Mylotarg is for intravenous use and must be reconstituted and diluted before administration (see Section 4.2 Dose and Method of Administration). Administer Mylotarg intravenously by infusion over a 2 hour period under close clinical monitoring, including pulse, blood pressure, and temperature. Do not administer Mylotarg as an intravenous push or bolus (see Section 4.2 Dose and Method of Administration, Instructions for use and handling).

Dosage adjustment.

Schedule modification for hyperleukocytosis. In patients with hyperleukocytic (leukocyte count > 30,000/mm³) AML, cytoreduction is recommended either with leukapheresis, oral hydroxyurea or AraC with or without hydroxyurea to reduce the peripheral white blood cell (WBC) count 48 hours prior to administration of Mylotarg (see Section 4.4 Special Warnings and Precautions for Use).
If AraC is used for leukoreduction with or without hydroxyurea in patients with previously untreated, de novo hyperleukocytic AML receiving Mylotarg in combination therapy, treatment of hyperleukocytosis with AraC should begin on Day 1 with Mylotarg given at 3 mg/m²/dose (up to a maximum of one 5 mg vial) on days 3, 6, and 9 of standard induction chemotherapy, adapted in accordance with standard medical practice (see Table 2 and Table 3 for additional dose modification information).
Dose modification for adverse reactions. Dose modification of Mylotarg is recommended based on individual safety and tolerability (see Section 4.4 Special Warnings and Precautions for Use). Management of some adverse reactions may require dose interruptions or permanent discontinuation of Mylotarg (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
Tables 2 and 3 show the dose modification guidelines for haematologic and non-haematologic toxicities, respectively.

Special populations.

Use in patients with hepatic impairment.

No adjustment of the starting dose is required in patients with hepatic impairment defined by total bilirubin ≤ 2 x upper limit of normal (ULN) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x ULN. Postpone Mylotarg until recovery of total bilirubin to ≤ 2 x ULN and AST and ALT to ≤ 2.5 x ULN prior to each dose (see Table 3; see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Use in patients with renal impairment.

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

Elderly patients.

No adjustment to dose of Mylotarg is required in elderly patients (≥ 65 years) (see Section 5.2 Pharmacokinetic Properties).

Paediatric population.

The safety and efficacy of Mylotarg in combination with chemotherapy in the paediatric population (< 15 years) with newly-diagnosed AML have not been established. Currently available data are described, see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties; Section 5.2 Pharmacokinetic Properties, but no recommendation on a posology can be made.

Instructions for use and handling.

Use appropriate aseptic technique for the reconstitution and dilution procedures. Mylotarg is light sensitive and should be protected from light (including ultraviolet light) during reconstitution, dilution and administration.

Reconstitution.

Calculate the dose (mg) of Mylotarg required.
Prior to reconstitution, allow the vial to reach room temperature (below 25°C) for approximately 5 minutes. Reconstitute each 5 mg vial with 5 mL of water for injections to obtain a single use solution of 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 may contain 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 to 16 hours in a refrigerator (2°C-8°C) or up to 3 hours at room temperature (below 25°C). Protect from light and do not freeze.

Dilution.

Calculate the required volume of the reconstituted solution needed to obtain the appropriate dose according to patient body surface area. Withdraw this amount from the vial using a syringe. Mylotarg vials contain 5 mg of drug product with no overfill. When reconstituted to a 1 mg/mL concentration as directed, the extractable content of the vial is 4.5 mg (4.5 mL). Protect from light. Product is for single use in one patient only. Discard any residue.
Doses must be mixed to a concentration between 0.075 mg/mL to 0.234 mg/mL according to the following instructions:
Doses less than 3.9 mg must be prepared for administration by syringe. Add the reconstituted Mylotarg solution to a syringe with sodium chloride 9 mg/mL (0.9%) solution for injection to a final concentration between 0.075 mg/mL to 0.234 mg/mL. Protect from light.
Doses greater than or equal to 3.9 mg are to be diluted in a syringe or an intravenous bag in an appropriate volume of sodium chloride 9 mg/mL (0.9%) solution for injection to ensure a final concentration between 0.075 mg/mL to 0.234 mg/mL. Protect from light.
Gently invert the infusion container to mix the diluted solution. Do not shake.
Following dilution with sodium chloride 9 mg/mL (0.9%) solution for injection, Mylotarg solution should be infused immediately. If not used immediately, the diluted solution may be stored up to 18 hours in a refrigerator (2°C-8°C) and up to 6 hours at room temperature (below 25°C). The allowed time at room temperature (below 25°C) includes the time required for preparation of the diluted solution, equilibration, if needed, and administration to the patient. The maximum time from preparation of the diluted solution through administration should not exceed 24 hours. The diluted solution must be protected from light for the duration of the storage period. Do not freeze.
It is recommended that the infusion container be made of polyvinyl chloride (PVC) with DEHP, ethylene vinyl acetate (EVA) or polyolefin (polypropylene and/or polyethylene).

Administration.

Filtration of the diluted solution is required. An in-line, low protein-binding 0.2 micron polyethersulphone (PES) filter must be used for infusion of Mylotarg.
Doses administered by syringe must utilize small bore infusion lines (microbore) with an in line, low protein-binding 0.2 micron polyethersulphone (PES) filter.
During the infusion, the intravenous bag or syringe must be protected from light (including ultraviolet light) using a 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 6 hour room temperature (below 25°C) storage period. Infusion lines made of PVC (DEHP- or non DEHP-containing), polyurethane or polyethylene are recommended.
The total in-use period for Mylotarg should not exceed 18 hours from the start of reconstitution through completion of administration.
Do not mix Mylotarg with, or administer as an infusion with, other medicinal products.
For information on dilution, storage, and infusion, see Section 6.4 Special Precautions for Storage.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

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

Hepatotoxicity, including life-threatening, and sometimes fatal hepatic VOD/SOS events, was reported (see Section 4.8 Adverse Effects (Undesirable Effects)).
Hepatotoxicity, including VOD/SOS events, has been reported in association with the use of Mylotarg as a single agent, and as part of a combination chemotherapy regimen, in patients without a history of liver disease or haematopoietic stem cell transplant (HSCT).
Based on an analysis of potential risk factors, adult patients who received Mylotarg as monotherapy, either before or after an HSCT, and patients with moderate or severe hepatic impairment are at increased risk for developing VOD/SOS (see Section 4.8 Adverse Effects (Undesirable Effects)).
Death from liver failure and from VOD/SOS have been reported in patients who received Mylotarg. Due to the risk of VOD/SOS, monitor closely for signs and symptoms of VOD/SOS; these may include elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, and alkaline phosphatase, which should be monitored prior to each dose of Mylotarg, 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/SOS 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 Dose and Method of Administration). In patients who experience VOD/SOS, discontinue Mylotarg and treat according to standard medical practice.

Infusion related reactions (including anaphylaxis).

In clinical studies with Mylotarg, infusion related reactions, including anaphylaxis were reported (see Section 4.8 Adverse Effects (Undesirable Effects)). There have been reports of fatal infusion reactions in the postmarketing 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. Perform infusion of Mylotarg 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 Dose and Method of Administration). Interrupt infusion immediately for patients who develop evidence of severe reactions, especially dyspnea, bronchospasm, or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinuation of Mylotarg 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 Dose and Method of Administration).

Myelosuppression.

In clinical studies with Mylotarg, neutropenia, thrombocytopenia, anaemia, leukopenia, febrile neutropenia, lymphopenia, and pancytopenia, some of which were life-threatening or fatal, were reported (see Section 4.8 Adverse Effects (Undesirable Effects)). Complications associated with neutropenia and thrombocytopenia may include infections and bleeding/haemorrhagic events, respectively. Infections and bleeding/haemorrhagic events were reported, some of which were life threatening or fatal.
Monitor complete blood counts prior to each dose of Mylotarg and monitor patients for signs and symptoms of infection, bleeding/haemorrhage, or other effects of myelosuppression during treatment with Mylotarg. Routine clinical and laboratory surveillance testing during and after treatment with Mylotarg 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 Dose and Method of Administration).

Tumour lysis syndrome (TLS).

In clinical studies with Mylotarg, TLS was reported (see Section 4.8 Adverse Effects (Undesirable Effects)). Fatal reports of TLS complicated by acute renal failure have been reported in the postmarketing 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 Dose and Method of Administration).
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 antihyperuricaemic (e.g. allopurinol) or other agents for treatment of hyperuricaemia (e.g. rasburicase) must be taken.

Use in 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 effect in patients with adverse cytogenetics (see Section 5.1 Pharmacodynamic Properties). For patients being treated with Mylotarg in combination with standard chemotherapy for newly-diagnosed de novo AML, when cytogenetics testing results become available consider whether the potential benefit of continuing treatment with Mylotarg outweighs the risks for the individual patient.

Use in the elderly.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties.

Paediatric use.

See Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties.

Effects on laboratory tests.

No formal drug-laboratory interaction studies have been conducted with Mylotarg.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No clinical drug interaction studies have been performed with Mylotarg.

Effect of other drugs on gemtuzumab ozogamicin.

In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide is primarily metabolized via nonenzymatic reduction. Therefore, coadministration of Mylotarg with inhibitors or inducers of cytochrome P450 (CYP) or uridine diphosphate glucuronosyltransferase (UGT) drug metabolizing enzymes are unlikely to alter the exposure to N-acetyl gamma calicheamicin dimethyl hydrazide.
Based on population PK analyses, the combination of gemtuzumab ozogamicin with hydroxyurea, DNR, and AraC is not predicted to cause clinically meaningful changes in the PK of hP67.6 or unconjugated calicheamicin.

Effect of Mylotarg on other drugs.

Effect on CYP substrates.

In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide and gemtuzumab ozogamicin had a low potential to inhibit the activities of CYP1A2, CYP2A6 (tested only using gemtuzumab ozogamicin), CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 at clinically relevant concentrations. In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide and gemtuzumab ozogamicin had a low potential to induce the activities of CYP1A2, CYP2B6, and CYP3A4 at clinically relevant concentrations.

Effect on UGT substrates.

In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide had a low potential to inhibit the activities of UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 at clinically relevant concentrations.

Effect on drug transporter substrates.

In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide had a low potential to inhibit the activities of P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance associated protein (MRP) 2, multidrug and toxin extrusion protein (MATE)1 and MATE2K, organic anion transporter (OAT)1 and OAT3, organic cation transporter (OCT) 1 and OCT 2, and organic anion transporting polypeptide (OATP)1B1 and OATP1B3 at clinically relevant concentrations.

Effect on co-administered chemotherapeutic agents.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Based on nonclinical findings, male and female fertility may be compromised by treatment with Mylotarg. Both men and women should seek advice for fertility preservation before treatment.
Marked impairment of male fertility was observed in rats at all dose levels of gemtuzumab ozogamicin tested (≥ 0.12 mg/m²/day intravenously), associated with decreased sperm count, reduced sperm motility and increased abnormal sperm. Effects were more severe 9 weeks post-treatment compared to immediately after the end of treatment, related to damage to spermatogonia and spermatocytes during dosing and the time-course for spermatogenesis, but there was evidence of reversibility. Toxicity to the male reproductive tract was observed with gemtuzumab ozogamicin in rats and monkeys with no NOAEL established. Findings included degeneration of seminiferous tubules in the testis; luminal cellular debris, oligospermia and epithelial degeration in the epididymis; and atrophy, duct ectasia, and sperm stasis in the seminal vesicle.
In female rats, the incidence of pregnancy was unaffected following treatment with gemtuzumab ozogamicin at intravenous doses up to 1.08 mg/m²/day. However, slightly lower numbers of corpora lutea were observed at 1.08 mg/m²/day and embryolethality occurred at ≥ 0.36 mg/m²/day (99 and 32 times the exposure of patients after the third 3 mg /m² dose, based on plasma AUC) in the presence of maternotoxicity. Adverse effects on the female reproductive tract (atrophy in the ovary, oviduct, uterus and cervix) with the potential to disrupt normal menstrual cycling were observed in monkeys treated at ≥ 6.6 mg/m²/week for 12 weeks. Dosing at 2.2 mg/m²/week (67 times the exposure in patients) did not adversely affect reproductive tissues in female monkeys.
(Category D)
There are no or very limited data for the use of gemtuzumab ozogamicin in pregnant women.
Gemtuzumab ozogamicin caused embryofetal lethality (increased post-implantation loss and decreased live litter size) and malformations (missing or shortened digits, absent aortic arch, misshapen or shortened forelimb long bones, misshapen scapula, absent vertebral centrum and fused sternebrae) with daily intravenous administration at 0.36 mg/m²/day in pregnant rats. At 0.15 mg/m²/day fetal weight was reduced, the incidence of wavy ribs was increased and ossification was impaired. The findings occurred at maternotoxic doses but may reflect direct toxicity to the embryo/fetus. No adverse effects on embryofetal development were observed in the rat at 0.06 mg/m²/day (approximately 4 times the exposure in patients after the third 3 mg/m² dose, based on plasma AUC).
Mylotarg must not be used during pregnancy unless the potential benefit to the mother outweighs the potential risks to the fetus. 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 fetus. 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 effective contraception during treatment with Mylotarg for at least 7 months (females) or 4 months (males) after the last dose.
There is no information regarding the presence of Mylotarg in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for adverse reactions in breastfed infants, women should not breastfeed during treatment with Mylotarg and for at least 1 month after the final dose.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effect of Mylotarg on the ability to drive and use machines have been performed. Fatigue has been reported during treatment with Mylotarg (see Section 4.8 Adverse Effects (Undesirable Effects)). Therefore, caution should be exercised when driving or operating machines.

4.8 Adverse Effects (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 4. Information about adverse drug reactions from monotherapy studies and post-marketing experience is presented Table 5 in order to provide full characterisation of adverse reactions.
In the combination therapy study ALFA-0701, clinically relevant serious adverse reactions were hepatotoxicity, including VOD/SOS (3.8%), haemorrhage (9.9%), severe infection (41.2%), and TLS (1.5%). In monotherapy studies, clinically relevant serious adverse reactions also included infusion related reactions (2.5%), thrombocytopenia (21.7%), and neutropenia (34.3%).
The most common adverse reactions (> 30%) in the combination therapy study were haemorrhage and infection. In monotherapy studies the most common adverse reactions (> 30%) included pyrexia, nausea, infection, chills, haemorrhage, vomiting, thrombocytopenia, fatigue, headache, stomatitis, diarrhoea, abdominal pain, and neutropenia.
The most frequent (≥ 1%) adverse reactions that led to permanent discontinuation in the combination therapy study were thrombocytopenia, VOD, haemorrhage and infection. The most frequent (≥ 1%) adverse reactions that led to permanent discontinuation in monotherapy studies were infection, haemorrhage, multi-organ failure, and VOD.

Tabulated list of adverse reactions.

Tables 4 and 5 show the adverse reactions reported in patients with previously untreated de novo AML who received Mylotarg in a combination study and in patients with AML who received Mylotarg in monotherapy studies, respectively.
The adverse 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 reactions are presented in order of decreasing seriousness.

Description of selected adverse drug 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 4). 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.
Based on an analysis of potential risk factors, adult patients who received Mylotarg as monotherapy, patients who had received an HSCT prior to gemtuzumab ozogamicin exposure were 2.6 times more likely (95% CI: 1.448, 4.769) to develop VOD compared to patients without HSCT prior to treatment with gemtuzumab ozogamicin; patients who had received an HSCT following treatment with gemtuzumab ozogamicin were 2.9 times more likely (95% CI: 1.502, 5.636) to develop VOD compared to patients without HSCT following treatment with gemtuzumab ozogamicin; and patients who had moderate/severe hepatic impairment at baseline were 8.7 times more likely (95% CI: 1.879, 39.862) to develop VOD compared to patients without moderate/severe hepatic impairment at baseline.
Patients should be monitored for hepatotoxicity as recommended (see Section 4.4 Special Warnings and Precautions for Use). Management of signs or symptoms of hepatic toxicity may require a dose interruption, or discontinuation of Mylotarg (see Section 4.2 Dose and Method of Administration).
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.

Platelet and neutrophil recovery.

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.

Infections.

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.

Bleeding/haemorrhagic events.

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).
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 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).
Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity.
In clinical studies of Mylotarg in patients with relapsed or refractory AML, the immunogenicity of Mylotarg was evaluated using 2 enzyme-linked immunosorbent assays (ELISAs).
Patients in the Phase 2 trials did not develop antidrug antibodies (ADAs) and only 2 patients in a Phase 1 trial developed antibodies against the calicheamicin-linker complex, 1 of whom had reduced hP67.6 plasma concentrations. Overall, the incidence rate of ADA development after Mylotarg treatment was < 1% across the 4 clinical studies with ADA data. Definitive conclusions cannot be drawn between the presence of antibodies and potential impact on efficacy and safety due to the limited number of patients with positive ADAs.
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.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

Paediatric population.

The safety and efficacy of Mylotarg in children and adolescents below the age of 15 years has not been established (see Section 4.2 Dose and Method of Administration).
In the completed randomised paediatric Phase 3 Children's Oncology Group (COG) Study AAML0531 (see Section 5.1 Pharmacodynamic Properties) 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%).

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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Gemtuzumab ozogamicin is a CD33-directed ADC. Gemtuzumab is a humanised immunoglobulin class G subtype 4 (IgG4) antibody which specifically recognizes human CD33. The antibody portion (hP67.6) binds specifically to the CD33 antigen, a sialic acid dependent adhesion protein found on the surface of myeloid leukaemic blasts and immature normal cells of myelomonocytic lineage, but not on normal haematopoietic stem 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. Nonclinical data suggest that the anticancer activity of gemtuzumab ozogamicin is due to the binding of the ADC to CD33 expressing cancer cells, followed by internalization of the ADC CD33 complex, and the intracellular release of N-acetyl gamma calicheamicin dimethyl hydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl gamma calicheamicin dimethyl hydrazide induces double-stranded DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.

Pharmacodynamic (PD) effects.

In vitro cytotoxicity assays showed that gemtuzumab ozogamicin was effective at selectively killing CD33-positive human leukaemia cell line (HL 60) target cells. In nonclinical murine models, gemtuzumab ozogamicin demonstrates antitumour effects in the HL 60 human promyelocytic leukaemia xenograft tumour in athymic mice. Combining DNR and AraC chemotherapy with gemtuzumab ozogamicin was effective in eliminating disease and prolonging survival in nonclinical AML models, with synergistic activity evident.
Saturation of a high percentage of CD33 antigenic sites is presumed to be required for maximum delivery of calicheamicin to leukaemic blast cells. Several single agent studies measured target (CD33) saturation post Mylotarg dose in patients with relapsed and refractory AML. Across all studies, near maximal peripheral 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.

Clinical trials.

In a Phase 3 trial (ALFA-0701) the combination of Mylotarg + AraC + DNR was compared to AraC + DNR. Combination therapy with Mylotarg + chemotherapy resulted in a statistically significant improvement in Event-Free Survival (EFS) compared to the chemotherapy combination alone. There was no significant improvement in rates of Overall Survival (OS) or CR demonstrated in Mylotarg combination therapy compared to the chemotherapy combination alone.
ALFA-0701 study of previously untreated patients with de novo AML. The efficacy and safety of Mylotarg were evaluated in a multicenter, randomized, open label, Phase 3 study comparing the addition of Mylotarg to a standard chemotherapy induction regimen of daunorubicin and cytarabine (DA) versus DA alone. Eligible patients were between 50 and 70 years of age with previously untreated de novo AML. Patients with acute promyelocytic leukaemia (APL, AML3) and patients with AML arising from myelodysplastic syndrome (MDS) or secondary AML were excluded from the study.
Patients were randomized (1:1) to receive induction therapy consisting of DNR (60 mg/m² on Days 1 to 3) and AraC (200 mg/m² on Days 1 to 7) (DA) with (N = 135) or without (N = 136) Mylotarg 3 mg/m² (up to maximum of one vial) on Days 1, 4, and 7. Patients who did not achieve a response after first induction could receive a second induction with DNR and AraC alone, consisting of DNR 35 mg/m²/day on Days 1 and 2 and AraC 1 g/m² every 12 hours on Day 1 to Day 3. Patients with response received consolidation therapy with 2 courses of treatment including DNR (60 mg/m² on Day 1 of consolidation course 1; 60 mg/m² on Days 1 and 2 of consolidation course 2) and AraC (1 g/m² every 12 hours on Days 1 to 4) with or without Mylotarg 3 mg/m² (up to a maximum of one vial) on Day 1 according to their initial randomisation. Patients who experienced remission were also eligible for allogeneic transplantation. An interval of at least 2 months between the last dose of Mylotarg and transplantation was recommended.
The primary endpoint was EFS. The secondary endpoints included CR and CRp rates, Relapse Free Survival (RFS), OS, and safety of the combination DA with or without Mylotarg.
EFS was measured from randomisation to induction failure, relapse, or death due to any cause. Per protocol, induction failure was defined as failure to achieve CR or CRp in induction, and date of induction failure was defined as date of marrow evaluation after the last course of induction. Remission was assessed by the investigators and classified as CR defined as fewer than 5% blasts in a normocellular marrow and an ANC of more than 1 x 10⁹/L with a platelet count of more than 100 x 10⁹/L in the peripheral blood in the absence of transfusion; and CRp, defined as CR with residual thrombocytopenia (platelets ≤ 100 x 10⁹/L).
In total, 271 patients were randomized in this study with 135 to induction treatment of 3+7 DA plus fractionated 3 mg/m² x 3 doses of Mylotarg and 136 to 3+7 DA alone (see Section 4.2 Dose and Method of Administration). A second course of 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 CR after 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 experienced remission were also eligible for allogeneic transplantation. An interval of at least 2 months between the last dose of Mylotarg and transplantation was recommended.
Safety data consisting of selected treatment emergent adverse events (TEAEs) considered most important for understanding the safety profile of Mylotarg as well as all adverse events (AEs) that led to the permanent discontinuation of treatment were retrospectively collected. The selected TEAEs consisted of all grades haemorrhages, all grades VOD/SOS and severe infections.
Overall, the median age of patients was 62 years and most patients (87.8%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1 at baseline. Baseline characteristics were balanced between treatment arms with the exception of gender as a higher percentage of males 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 LeukemiaNet (ELN) risk classifications, respectively. CD33 expression on AML blasts by flow cytometry harmonized from local laboratory results was determined in 194/271 (71.6%) patients overall. Few patients (13.7%) had low CD33 expression (less than 30% of blasts).
The trial met its primary objective of demonstrating that Mylotarg added in fractionated doses (3 mg/m² x 3) to standard induction chemotherapy for patients with previously untreated de novo AML resulted in a statistically significant and clinically meaningful improvement in EFS. Median EFS was 17.3 months (95% confidence interval [CI]: 13.4 30.0) in the Mylotarg arm versus 9.5 months (95% CI: 8.1 12.0) in the DA alone arm; hazard ratio (HR) 0.562 (95% CI: 0.415 0.762); 2 sided p = 0.0002 by log-rank test. EFS results derived from investigator assessment are summarized in Table 6, and the Kaplan Meier plot is shown in Figure 1.

Use in AML with adverse-risk cytogenetics. In subgroup analyses in ALFA-0701, the addition of Mylotarg to standard combination chemotherapy did not improve EFS in the subgroup of patients having adverse-risk cytogenetics (HR 1.11; 95% CI: 0.63, 1.95). EFS and OS analyzed by cytogenetic risk classification and cytogenetic/molecular risk classification are presented in Table 7 and Table 8.

Paediatric population.

Paediatric study.

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), and young adults (6.3% of patients); mean age was 8.9 years (range: 0-29 years), patients with de novo AML were randomly assigned to either standard 5-course chemotherapy alone or to the same chemotherapy with 2 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 a reduced relapse risk, with a trend towards longer OS in the Mylotarg arm which was not statistically significant (3 years: 72.4% versus 67.6%; HR 0.904; 95% CI: 0.721, 1.133; p = 0.3799). However, it was also found that increased toxicity (post-remission toxic mortality) was observed in patients with low-risk AML which was attributed to the prolonged neutropenia that occurred after receiving gemtuzumab ozogamicin during intensification Course 2 (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)). Overall, 29 (5.5%) of patients in the Mylotarg arm and 15 (2.8%) patients in the comparator arm died during remission. Thus, the optimal dose of gemtuzumab ozogamicin for paediatric patients was not established (see Section 4.2 Dose and Method of Administration).
Cardiac electrophysiology. There are limited data available to describe the effects of gemtuzumab ozogamicin on cardiac electrophysiology.

5.2 Pharmacokinetic Properties

Gemtuzumab ozogamicin is an ADC composed of CD33 directed monoclonal antibody (hP67.6) that is covalently linked to the cytotoxic agent N-acetyl-gamma calicheamicin. The pharmacokinetics (PK) of gemtuzumab ozogamicin is described by measuring PK characteristics of the antibody (hP67.6) as well as total and unconjugated calicheamicin derivatives. Given that the hP67.6 portion renders target selectivity on the intact molecule, and that Mylotarg dosages are reported in terms of milligrams of protein (hP67.6), the hP67.6 concentration results are reported as the primary PK measures. After gemtuzumab ozogamicin binds to CD33 it is internalised and N-acetyl calicheamicin is released by hydrolytic cleavage. Determination of PK parameters for unconjugated calicheamicin was limited due to the low systemic concentration levels.
No clinical PK data have been collected using the fractionated regimen; however, the PK have been simulated using the population PK model. Although the total dose of the fractionated dosing regimen is half of that of the original dosing regimen (9 versus 18 mg/m²), the predicted total area under the plasma concentration time curve (AUC) of hP67.6 over the course of treatment is 25%, and maximum observed concentration (C_max) is 24%, of the values for original 9 mg/m² dosing regimen, since the PK is nonlinear. When gemtuzumab ozogamicin is administered at 3 mg/m² on Days 1, 4, and 7, the C_max of hP67.6, which would occur at the end of infusion, is predicted to be 0.38 mg/L following the first dose and increased to 0.63 mg/L after the third dose.

Distribution.

In vitro, the binding of N-acetyl gamma calicheamicin dimethyl hydrazide to human plasma proteins is approximately 97%. In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide is a substrate of P-glycoprotein (P-gp). Population PK analyses found the total volume of distribution of hP67.6 antibody (sum of V1 [10 L] and V2 [15 L]) was found to be approximately 25 L.

Metabolism.

The primary metabolic pathway of gemtuzumab ozogamicin is anticipated to be hydrolytic release of N-acetyl gamma calicheamicin dimethyl hydrazide. In vitro studies demonstrated that N-acetyl gamma calicheamicin dimethyl hydrazide is extensively metabolized, primarily via nonenzymatic reduction of the disulphide moiety. The activity (cytotoxicity) of the resultant metabolites is expected to be significantly attenuated. In patients, unconjugated calicheamicin plasma levels were typically low, with a predicted geometric mean C_max of 1.5 nanogram/mL following the third dose.

Excretion.

Based on population PK analyses, the predicted clearance (CL) value of hP67.6 from plasma was 3 L/h immediately after the first dose and then 0.3 L/h. The terminal plasma half-life (t½) for hP67.6 was predicted to be approximately 160 hours for a typical male patient at the recommended dose level (3 mg/m²) of Mylotarg.

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 Mylotarg disposition.

Hepatic impairment.

No formal PK studies of Mylotarg have been conducted in patients with hepatic impairment.
Based on a population PK analysis, the clearance of gemtuzumab ozogamicin (hP67.6 antibody and unconjugated calicheamicin) is not expected to be affected by mild hepatic impairment status, as defined by National Cancer Institute Organ Dysfunction Working Group (NCI ODWG). The analysis included 405 patients in the following NCI ODWG impairment status categories: mild (B1, n = 58 and B2, n = 19), moderate (C, n = 6) and normal hepatic function (n = 322) (see Section 4.2 Dose and Method of Administration). The PK of gemtuzumab ozogamicin has not been studied in patients with severe hepatic impairment (see Section 4.2 Dose and Method of Administration).

Renal impairment.

No formal PK studies of gemtuzumab ozogamicin have been conducted in patients with renal impairment.
Based on population PK analysis in 406 patients, the clearance of gemtuzumab ozogamicin in patients with mild renal impairment (creatinine clearance [CL_cr] 60-89 mL/min; n = 149 or moderate renal impairment (CL_cr 30 59 mL/min; n = 47), was similar to patients with normal renal function (CL_cr ≥ 90 mL/min; n = 209). The impact of severe renal impairment on PK of gemtuzumab ozogamicin could not be assessed, since data are available from a single patient only (CL_cr 15-29 mL/min; n = 1).

Geriatric use.

Use of Mylotarg in combination with DNR and AraC in newly-diagnosed adult patients with de novo AML is supported by a randomized, controlled trial that included 50 patients greater than or equal to 65 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

Paediatric use.

The results of the population modelling showed that the PK behaviour of gemtuzumab ozogamicin (hP67.6 antibody and unconjugated calicheamicin) is similar between adult and paediatric AML patients following the 9 mg/m² dosing regimen.

5.3 Preclinical Safety Data

Genotoxicity.

Gemtuzumab ozogamicin was clastogenic in vivo in the bone marrow of mice. This is consistent with the known induction of DNA breaks by calicheamicin and other enediyne antitumour antibiotics. N-acetyl gamma calicheamicin dimethyl hydrazide (the released cytotoxin) was mutagenic in the bacterial reverse mutation assay and clastogenic in the in vitro micronucleus assay in human TK6 (lymphoblastoid) cells.

Carcinogenicity.

Formal carcinogenicity studies have not been conducted with gemtuzumab ozogamicin. After 6 weeks of administration of gemtuzumab ozogamicin to rats, preneoplastic lesions (minimal to slight oval cell hyperplasia) were observed in the liver at 7.2 mg/m²/week (approximately 54 times the exposure in patients after the third 3 mg/m² dose based on plasma AUC₁₆₈). Preneoplastic and neoplastic lesions have been observed in the livers of rats with other antibody-calicheamicin conjugates.

6 Pharmaceutical Particulars

6.1 List of Excipients

Dextran 40, dibasic sodium phosphate, monobasic sodium phosphate monohydrate, sodium chloride, sucrose.

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Unopened vials.

Store at 2°C - 8°C (Refrigerate. Do not freeze). Store in the original carton and protect from light.

Reconstituted and 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 25°C).
The diluted solution may be stored up to 18 hours in a refrigerator (2°C -8°C) and up to 6 hours at room temperature (below 25°C). The allowed time at room temperature (below 25°C) includes the time required for preparation of the diluted solution, equilibration, if needed and administration to the patient. The maximum time from preparation of the diluted solution through administration should not exceed 24 hours.

6.5 Nature and Contents of Container

Amber Type 1 glass vial, with butyl rubber stopper and crimp seal with flip-off cap containing 5 mg gemtuzumab ozogamicin.
Each carton contains 1 single-dose vial containing sterile, preservative-free, white to off-white lyophilized cake or powder.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Gemtuzumab ozogamicin is an antibody-drug conjugate (ADC) composed of the CD33-directed monoclonal antibody (hP67.6; recombinant humanized immunoglobulin [Ig] G4, kappa antibody produced by mammalian cell culture in NS0 cells) that is covalently linked to the cytotoxic agent N-acetyl gamma calicheamicin. Gemtuzumab ozogamicin consists of conjugated and unconjugated gemtuzumab. The conjugated molecules differ in the number of activated calicheamicin derivative moieties attached to gemtuzumab. The number of conjugated calicheamicin derivatives per gemtuzumab molecule ranges from predominantly 0 to 6, with an average of 2 to 3 moles of calicheamicin derivative per mole of gemtuzumab.

CAS number.

220578-59-6.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

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