Consumer medicine information

Besponsa

Inotuzumab ozogamicin

BRAND INFORMATION

Brand name

Besponsa

Active ingredient

Inotuzumab ozogamicin

Schedule

What is in this leaflet

This leaflet answers some common questions about Besponsa.

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 receiving Besponsa against the benefits it is expected to have for you.

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

Keep this leaflet. You may need to read it again.

What Besponsa is used for

The active ingredient in Besponsa is inotuzumab ozogamicin. It belongs to a group of medicines called antineoplastic agents that target cancer cells.

Besponsa is used to treat adults with acute lymphoblastic leukaemia (ALL). ALL is a cancer of the blood where the cells that help protect your body from infection and foreign materials (white blood cells) grow uncontrollably.

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.

Use in children

The safety and effectiveness of this medicine in children and adolescents under the age of 18 years have not been established.

Before you are given Besponsa

When you must not be given it

Do not receive Besponsa if you:

have had severe confirmed venoocclusive disease (a condition in which the blood vessels in the liver become damaged and blocked by blood clots) or you currently have this disease
have serious ongoing liver disease (e.g., cirrhosis [a condition in which the liver does not function properly due to long-term damage], nodular regenerative hyperplasia [a condition with signs and symptoms of portal hypertension that can be caused by chronic use of medicines], active hepatitis [a disease characterised by inflammation of the liver]).

Do not receive Besponsa if you have an allergy to:

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

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 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 receive 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
heart problems
an infection or fever or bruising easily or getting nose bleeds on a regular basis.

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

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 involved.

You must avoid becoming pregnant or fathering a child if you are being treated with Besponsa.

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

You should not breast-feed during treatment with Besponsa and for at least 2 months after your last dose.

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

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 Besponsa 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.

There are certain periods before, during and after Besponsa treatment where live vaccines are not recommended. Your doctor will advise you.

How Besponsa is given

Besponsa is given in "cycles". One Besponsa treatment cycle is made up of a single Besponsa dose given each week for 3 weeks.

A doctor or nurse will give you your Besponsa dose gradually over 1 hour 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 Besponsa, 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

If the medicine works well and you are going to receive a stem cell transplant, you may receive 2 cycles or a maximum of 3 cycles of treatment. If the medicine works well, but you are not going to receive a stem cell transplant, you may receive up to a maximum of 6 cycles of treatment. If you do not respond to the medicine within 3 cycles, 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 are given too much (overdose)

It is unlikely that you will be given too much Besponsa, 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 Besponsa

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 Besponsa if you can become pregnant or if you can father a child. You must continue to use effective birth control for at least 8 months (women) or at least 5 months (men) after the last dose of Besponsa.

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

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.

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor will take regular blood tests to make sure Besponsa 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 your heart rhythm, the levels of certain electrolytes (such as calcium, magnesium, potassium) in your blood, and the level of enzymes (known as amylase and lipase) in your blood.

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 Besponsa 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.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are being given Besponsa.

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 side effects. 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 are over 65 years of age, have a prior history of liver disease and/or hepatitis, have previously received 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), and/or have received several prior treatments, you have an increased chance of getting this side effect.
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
fever, chills, hot flush, dizziness or lightheadedness, rash or trouble breathing during or shortly after the Besponsa infusion (infusion-related reactions)
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.
dizziness, feeling lightheaded, or fainting
- These could be signs of a heart rhythm disorder that can cause serious irregular heart rhythms.

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
diarrhoea
constipation
headache
general weakness
a yellowish colour of the skin, eyes, and other tissues
mouth ulcer, redness or pain
decreased appetite.

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 nurse if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

After receiving Besponsa

Storage

Besponsa 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. They may give it to you straight away or within 8 hours after the start of preparation.

Your doctor, nurse and pharmacist have more information on how to store Besponsa.

Disposal

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

Product description

What it looks like

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

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

Each Besponsa carton contains 1 vial.

Ingredients

Besponsa contains 1 mg of inotuzumab ozogamicin as the active ingredient.

It also contains:

sucrose
trometamol
polysorbate 80
sodium chloride.

Supplier

Besponsa is supplied in Australia by:

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free number: 1800 675 229

Australian registration

AUST R 288135

Date of preparation

This leaflet was prepared in February 2021.

® = Registered Trademark

Published by MIMS April 2021

BRAND INFORMATION

Brand name

Besponsa

Active ingredient

Inotuzumab ozogamicin

Schedule

1 Name of Medicine

Inotuzumab ozogamicin (rch).

2 Qualitative and Quantitative Composition

Besponsa (inotuzumab ozogamicin) is a CD22-directed antibody-drug conjugate (ADC) consisting of 3 components:
1) a recombinant humanised immunoglobulin class G subtype 4 (IgG4) kappa antibody inotuzumab, produced in Chinese hamster ovary cells by recombinant deoxyribonucleic acid (DNA) technology, specific for human CD22;
2) a semisynthetic calicheamicin derivative, N-acetyl-gamma-calicheamicin, produced by microbial fermentation followed by synthetic modification, that causes double-stranded DNA breaks; and
3) an acid cleavable linker composed of the condensation product of 4-(4'-acetylphenoxy)-butanoic acid (AcBut) and 3-methyl-3-mercaptobutane hydrazide (known as dimethylhydrazide) that covalently attaches N-acetyl-gamma-calicheamicin to inotuzumab.
Each vial contains 1 mg inotuzumab ozogamicin.
After reconstitution with 4 mL of sterile water for injection, 1 mL of solution contains 0.25 mg inotuzumab ozogamicin. The drug product pH is approximately 8.0.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection.
Besponsa is supplied for intravenous infusion as 1 mg (protein equivalent) of white to off-white lyophilised cake or powder in a single dose vial for reconstitution and dilution.

4 Clinical Particulars

4.1 Therapeutic Indications

Besponsa is indicated for the treatment of adults with relapsed or refractory CD22‐positive B-cell precursor acute lymphoblastic leukaemia (ALL).

4.2 Dose and Method of Administration

Use of Besponsa should be initiated and supervised by a physician experienced in the treatment of haematological malignancies.

Premedication.

For patients with circulating lymphoblasts, cytoreduction with a combination of hydroxyurea, steroids, and/or vincristine to a peripheral blast count ≤ 10,000/mm³ is recommended prior to the first dose.
Premedication with a corticosteroid, antipyretic, and antihistamine is recommended prior to dosing (see Section 4.4 Special Warnings and Precautions for Use, Infusion related reactions). Patients should be observed during and for at least 1 hour after the end of infusion for symptoms of infusion related reactions (see Section 4.4 Special Warnings and Precautions for Use, Infusion related reactions).

Recommended dosage regimen.

Besponsa should be administered in 3- to 4-week cycles.
For patients proceeding to HSCT, the recommended duration of treatment with Besponsa is 2 cycles. A third cycle may be considered for those patients who do not achieve a CR or CRi and MRD negativity after 2 cycles (see Section 4.4 Special Warnings and Precautions for Use, Hepatotoxicity, including venoocclusive liver disease (VOD)/sinusoidal obstruction syndrome (SOS)).
For patients not proceeding to HSCT, a maximum of 6 cycles may be administered.
Any patients who do not achieve a CR or CRi within 3 cycles should discontinue treatment.
Table 1 shows the recommended dosing regimens.
For the first cycle, the recommended total dose of Besponsa for all patients is 1.8 mg/m² per cycle, administered as 3 divided doses on Days 1 (0.8 mg/m²), 8 (0.5 mg/m²), and 15 (0.5 mg/m²). Cycle 1 is 3 weeks in duration, but may be extended to 4 weeks if the patient achieves a CR or CRi, and/or to allow recovery from toxicity.
For subsequent cycles, the recommended total dose of Besponsa is 1.5 mg/m² per cycle, administered as 3 divided doses on Days 1 (0.5 mg/m²), 8 (0.5 mg/m²), and 15 (0.5 mg/m²) for patients who achieve a CR or CRi or 1.8 mg/m² per cycle given as 3 divided doses on Days 1 (0.8 mg/m²), 8 (0.5 mg/m²), and 15 (0.5 mg/m²) for patients who do not achieve a CR or CRi. Subsequent cycles are 4 weeks in duration.

Dosage adjustments.

Dose modification of Besponsa may be required based on individual safety and tolerability (see Section 4.4 Special Warnings and Precautions for Use). Management of some adverse drug reactions may require dosing interruptions and/or dose reductions, or permanent discontinuation of Besponsa (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)). If the dose is reduced due to Besponsa-related toxicity, the dose must not be re-escalated.
Table 2 and Table 3 show the dose modification guidelines for haematologic and nonhaematologic toxicities, respectively. Besponsa doses within a treatment cycle (i.e. Days 8 and/or 15) do not need to be interrupted due to neutropenia or thrombocytopenia, but dosing interruptions within a cycle are recommended for nonhaematologic toxicities.

Table 4 shows the dose modification guidelines depending on the duration of dosing interruptions due to toxicity.

Children and adolescents.

The safety and efficacy of Besponsa in children and adolescents (< 18 years) have not been established.

Use in hepatic impairment.

No adjustment to the starting dose is required when administering Besponsa to patients with hepatic impairment defined by total bilirubin ≤ 1.5 x ULN and AST/ALT ≤ 2.5 x ULN (see Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic impairment).
There is limited safety information available in patients with hepatic impairment defined by total bilirubin > 1.5 x ULN and AST/ALT > 2.5 x ULN prior to dosing. Interrupt dosing until recovery of total bilirubin to ≤ 1.5 x ULN and AST/ALT to ≤ 2.5 x ULN prior to each dose unless due to Gilbert's syndrome or haemolysis (see Table 1). Permanently discontinue treatment if total bilirubin does not recover to ≤ 1.5 x ULN or AST/ALT does not recover to ≤ 2.5 x ULN (see Table 1; see Section 4.4 Special Warnings and Precautions for Use, Hepatotoxicity, including venoocclusive liver disease (VOD)/sinusoidal obstruction syndrome (SOS)).

Use in renal impairment.

No adjustment to the starting dose is required when administering Besponsa to patients with mild, moderate, or severe renal impairment (CLcr 60-89 mL/min, 30-59 mL/min, or 15-29 mL/min, respectively) (see Section 5.2 Pharmacokinetic Properties, Special populations, Renal impairment). The safety and efficacy of Besponsa have not been studied in patients with end-stage renal disease.

Use in the elderly.

No adjustment to the starting dose is required based on age (see Section 5.2 Pharmacokinetic Properties, Special populations, Age, race and gender).
Increased age may be associated with an increased risk of VOD/SOS after HSCT (see Section 4.4 Special Warnings and Precautions for Use, Hepatotoxicity, including venoocclusive liver disease (VOD)/sinusoidal obstruction syndrome (SOS)).

Instructions for reconstitution, dilution and administration.

Administer Besponsa intravenously by infusion over 1 hour. Do not administer Besponsa as an intravenous push or bolus.
Use appropriate aseptic technique for the reconstitution and dilution procedures. Besponsa (which has a density of 1.02 g/mL at 20°C) is light sensitive and should be protected from ultraviolet light during reconstitution, dilution, and administration.
The maximum time from reconstitution through the end of administration should be ≤ 8 hours, with ≤ 4 hours between reconstitution and dilution.

Reconstitution.

Calculate the dose (mg) and number of vials of Besponsa required.
Reconstitute each 1 mg vial with 4 mL of sterile water for injection to obtain a solution of 0.25 mg/mL of Besponsa.
Gently swirl the vial to aid dissolution. Do not shake.
Inspect the reconstituted solution for particulates and discolouration. The reconstituted solution should be clear to slightly cloudy, colourless, and essentially free of visible foreign matter.
Besponsa contains no bacteriostatic preservatives. The reconstituted solution should be used immediately. If the reconstituted solution cannot be used immediately, it may be refrigerated (2-8°C) for up to 4 hours. 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(s) using a syringe. Protect from light. Discard any unused reconstituted Besponsa solution left in the vial.
Add the reconstituted solution to an infusion container with 0.9% sodium chloride for injection to a total nominal volume of 50 mL. The final concentration should be between 0.01 and 0.1 mg/mL. Protect from light. An infusion container made of polyvinyl chloride (PVC) (di(2-ethylhexyl) phthalate [DEHP]- or non-DEHP-containing), polyolefin (polypropylene and/or polyethylene), or ethylene vinyl acetate (EVA) is recommended.
Gently invert the infusion container to mix the diluted solution. Do not shake.
The diluted solution should be used immediately or stored at room temperature (20-25°C) or refrigerated (2-8°C). The maximum time from reconstitution through the end of administration should be ≤ 8 hours, with ≤ 4 hours between reconstitution and dilution. Protect from light and do not freeze.

Administration.

If the diluted solution is refrigerated (2-8°C), the solution should be allowed to equilibrate at room temperature (20-25°C) for approximately 1 hour prior to administration.
Filtration of the diluted solution is not required. However, if the diluted solution is filtered, polyethersulfone (PES)-, polyvinylidene fluoride (PVDF)-, or hydrophilic polysulfone (HPS) based filters are recommended. Do not use filters made of nylon or mixed cellulose ester (MCE).
Protect the intravenous bag from light using an ultraviolet light-blocking cover (i.e. amber, dark brown, or green bags or aluminium foil) during infusion. The infusion line does not need to be protected from light.
Infuse the diluted solution for 1 hour at a rate of 50 mL/h at room temperature (20-25°C). Protect from light. Infusion lines made of PVC (DEHP or non DEHP containing), polyolefin (polypropylene and/or polyethylene), or polybutadiene are recommended.
Do not mix Besponsa or administer as an infusion with other medicinal products.
Besponsa contains no antimicrobial preservative and is for use in one patient on one occasion only.
Table 9 (see Section 6.4 Special Precautions for Storage) contains a summary of storage times and conditions for reconstitution, dilution, and administration of Besponsa.

4.3 Contraindications

Hypersensitivity to inotuzumab ozogamicin or to any of the excipients.
Patients who have experienced prior confirmed severe or ongoing venoocclusive liver disease/sinusoidal obstruction syndrome (VOD/SOS).
Patients with serious ongoing hepatic disease (e.g. cirrhosis, nodular regenerative hyperplasia, active hepatitis).

4.4 Special Warnings and Precautions for Use

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

In a randomised clinical study of Besponsa in patients with relapsed or refractory ALL (B1931022), hepatotoxicity, including severe, life threatening, and sometimes fatal hepatic VOD/SOS was observed in 23/164 patients (14%) in the Besponsa arm during or following treatment or following a HSCT after completion of treatment. VOD was reported up to 56 days after the last dose during treatment or during follow-up without an intervening HSCT. The median time from subsequent HSCT to onset of VOD was 15 days (range: 3-57 days). In the Besponsa arm, among the 79 patients who proceeded to a subsequent HSCT, VOD was reported in 18/79 patients (23%), and among all 164 patients treated, VOD was reported in 5/164 patients (3%) during study therapy or in follow-up without an intervening HSCT (see Section 4.8 Adverse Effects (Undesirable Effects)).
In Study B1931022, increases in liver tests, were reported. Grade 3/4 AST, ALT, and total bilirubin abnormal liver tests occurred in 7/160 (4%), 7/161 (4%), and 8/161 patients (5%), respectively (see Section 4.8 Adverse Effects (Undesirable Effects)).
Some patients may be at increased risk for developing VOD/SOS.
Patients who have experienced prior VOD/SOS or have serious ongoing hepatic liver disease (e.g. cirrhosis, nodular regenerative hyperplasia, active hepatitis) may be at increased risk for worsening of liver disease, including developing VOD/SOS, following treatment with Besponsa.
Prior HSCT may be associated with an increased risk of VOD/SOS (see Section 4.8 Adverse Effects (Undesirable Effects)).
Among patients who proceed to HSCT, use of HSCT conditioning regimens containing 2 alkylating agents and last total bilirubin level ≥ ULN before follow up HSCT are significantly associated with an increased risk of VOD/SOS after HSCT. Other factors that may also be associated with an increased risk of VOD/SOS after HSCT include increased age, a history of liver disease and/or hepatitis before treatment, later salvage lines, and a greater number of treatment cycles.
Due to the risk of VOD/SOS, especially after HSCT, monitor closely for signs and symptoms of VOD/SOS; these may include elevations in total bilirubin, hepatomegaly (which may be painful), rapid weight gain, and ascites. Monitoring only total bilirubin may not identify all patients at risk of VOD/SOS. In all patients, monitor liver tests, including alanine aminotransferase (ALT), AST, total bilirubin, and alkaline phosphatase, prior to and following each dose of Besponsa. 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, monitor liver tests closely during the first month post-HSCT, then less frequently thereafter, according to standard medical practice. Elevation of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of Besponsa (see Section 4.2 Dose and Method of Administration, Dosage adjustments).
Patients who have experienced prior confirmed severe or ongoing VOD/SOS or patients with serious ongoing liver disease (e.g. cirrhosis, nodular regenerative hyperplasia, active hepatitis) should not be treated with Besponsa (see Section 4.3 Contraindications).
Carefully consider the benefit/risk before administering Besponsa to patients who have experienced mild/moderate VOD/SOS or patients with less serious ongoing hepatic disease. If these patients are treated with Besponsa, monitor closely for signs and symptoms of VOD/SOS and permanently discontinue treatment if VOD/SOS occurs (see Section 4.2 Dose and Method of Administration, Dosage adjustments).
Particular attention should be paid when administering Besponsa to patients who are older, have had a prior HSCT, are in later lines of salvage, or have a prior history of liver disease and/or hepatitis. Due to the risk of VOD/SOS, for patients proceeding to HSCT, the duration of treatment with inotuzumab ozogamicin is 2 cycles; a third cycle should be considered for those patients who do not achieve a CR or CRi and MRD negativity after 2 cycles (see Section 4.2 Dose and Method of Administration, Recommended dosage regimen). Avoid the use of HSCT conditioning regimens containing 2 alkylating agents.
Permanently discontinue treatment if VOD/SOS occurs (see Section 4.2 Dose and Method of Administration, Dosage adjustments). If severe VOD/SOS occurs, treat according to standard medical practice.

Increased risk of post-transplant non-relapse mortality.

In study B1931022, a higher post-HSCT non-relapse mortality rate was observed in patients receiving Besponsa compared to the Investigator's choice of chemotherapy arm, resulting in a higher Day 100 post-HSCT mortality rate.
Monitor closely for toxicities post-HSCT, including signs and symptoms of infection and VOD/SOS (see Section 4.8 Adverse Effects (Undesirable Effects)).

Myelosuppression/cytopenias.

In study B1931022, neutropenia, thrombocytopenia, anaemia, leukopenia, febrile neutropenia, lymphopenia, and pancytopenia, some of which were life-threatening, were reported (see Section 4.8 Adverse Effects (Undesirable Effects)).
Complications associated with neutropenia and thrombocytopenia (including infections and bleeding/haemorrhagic events, respectively) were reported in some patients (see Section 4.8 Adverse Effects (Undesirable Effects)). Infections, including serious infections, some of which were life-threatening or fatal, were reported. Fatal infections included pneumonia, neutropenic sepsis, sepsis, septic shock, and pseudomonal sepsis. Bacterial, viral, and fungal infections were also reported.
Monitor complete blood counts prior to each dose of Besponsa and monitor for signs and symptoms of infection, bleeding/haemorrhage, or other effects of myelosuppression during treatment with Besponsa. As appropriate, administer prophylactic anti-infectives and employ surveillance testing during and after treatment with Besponsa. Management of patients with severe infection, bleeding/haemorrhage, or other effects of myelosuppression, including severe neutropenia or thrombocytopenia, may require dosing interruption, dose reduction, or permanent discontinuation of Besponsa (see Section 4.2 Dose and Method of Administration, Dosage adjustments).

Infusion related reactions.

In study B1931022, infusion related reactions were reported (see Section 4.8 Adverse Effects (Undesirable Effects)). Infusion related reactions generally occurred in Cycle 1 shortly after the end of the Besponsa infusion and resolved spontaneously or with medical management.
Premedication with a corticosteroid, antipyretic, and antihistamine is recommended prior to dosing (see Section 4.2 Dose and Method of Administration, Premedication).
Monitor patients closely during and for at least 1 hour after the end of infusion for the potential onset of infusion related reactions, including symptoms such as hypotension, hot flush, rash, or breathing problems. If an infusion related reaction occurs, interrupt the infusion and institute appropriate medical management. Depending on the severity of the infusion related reaction, consider discontinuation of the infusion or administration of steroids and antihistamines. For severe or life-threatening infusion reactions, permanently discontinue Besponsa (see Section 4.2 Dose and Method of Administration, Dosage adjustments).

Tumour lysis syndrome.

In study B1931022, tumour lysis syndrome (TLS), which may be life-threatening or fatal, was reported (see Section 4.8 Adverse Effects (Undesirable Effects)). TLS occurred shortly after the end of the Besponsa infusion and resolved with medical management.
Monitor for signs and symptoms of TLS and treat according to standard medical practice.

QT interval prolongation.

In study B1931022, increases in QTcF interval of ≥ 60 msec from baseline were measured in some patients. No patient had QTcF values > 500 msec (see Section 5.1 Pharmacodynamic Properties, Cardiac electrophysiology). Grade 2 QT prolongation was reported. No Grade ≥ 3 QT prolongation or event of Torsade de Pointes were reported (see Section 4.8 Adverse Effects (Undesirable Effects)).
Besponsa should be administered with caution in patients who have a history of, or predisposition for QT interval prolongation, who are taking medicinal products that are known to prolong QT interval, and in patients with electrolyte disturbances (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Electrocardiograms (ECGs) and electrolytes should be obtained prior to the start of treatment and periodically monitored during treatment (see Section 5.1 Pharmacodynamic Properties, Cardiac electrophysiology).

Increased amylase and lipase.

In study B1931022, increases in amylase and lipase were reported in 8 (5%) and 15 (9%) patients receiving Besponsa, respectively (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored for increases in amylase and lipase. Potential hepatobiliary disease should be evaluated and treated according to standard medical practice.

Immunisations.

The safety of immunisation with live viral vaccines during or following Besponsa therapy has not been studied. Vaccination with live viral vaccines is not recommended for at least 2 weeks prior to the start of Besponsa treatment, during treatment, and until recovery of B lymphocytes following the last treatment cycle.

Paediatric use.

The safety and efficacy of Besponsa in the paediatric population (< 18 years) have not been established.

Use in the elderly.

Based on a population pharmacokinetic analysis in 765 patients, no adjustment to the starting dose is required based on age (see Section 5.2 Pharmacokinetic Properties, Special populations, Age, race and gender).
In a randomised clinical study of Besponsa for the treatment of patients with ALL (B1931022), 30/164 (18%) patients treated with Besponsa were ≥ 65 years of age. Although no overall differences were observed in the safety and efficacy (CR/CRi and OS) of Besponsa between patients who were < 65 and ≥ 65 years of age, increased age may be associated with an increased risk of VOD/SOS after HSCT (see Section 4.4 Special Warnings and Precautions for Use, Hepatotoxicity, including venoocclusive liver disease (VOD)/sinusoidal obstruction syndrome (SOS)).

Use in hepatic impairment.

No adjustment to the starting dose is required when administering Besponsa to patients with hepatic impairment defined by total bilirubin ≤ 1.5 x ULN and AST/ALT ≤ 2.5 x ULN (see Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic impairment).
There is limited safety information available in patients with hepatic impairment defined by total bilirubin > 1.5 x ULN and AST/ALT > 2.5 x ULN prior to dosing. Management of such patients may require dosing interruption or permanent discontinuation of Besponsa (see Section 4.2 Dose and Method of Administration, Dosage adjustments; Section 4.4 Special Warnings and Precautions for Use, Hepatotoxicity, including venoocclusive liver disease (VOD)/sinusoidal obstruction syndrome (SOS)).

Use in renal impairment.

Effects on laboratory tests.

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

4.5 Interactions with Other Medicines and Other Forms of Interactions

No clinical drug interaction studies have been performed with Besponsa.
In a randomised clinical study of Besponsa in patients with relapsed or refractory ALL (B1931022), prolonged QT interval was observed with Besponsa (see Section 5.1 Pharmacodynamic Properties, Cardiac electrophysiology). Therefore, the concomitant use of Besponsa with medicinal products known to prolong QT interval or able to induce Torsades de Pointes should be carefully considered. Monitor the QT interval in case of combinations of such medicinal products (see Section 4.4 Special Warnings and Precautions for Use, QT interval prolongation).

Effect of other medicines on inotuzumab ozogamicin.

In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide is primarily metabolised via nonenzymatic reduction. Therefore, coadministration of Besponsa with inhibitors or inducers of cytochrome P450 (CYP) or uridine diphosphate glucuronosyltransferase (UGT) drug-metabolising enzymes are unlikely to alter exposure to N-acetyl-gamma-calicheamicin dimethylhydrazide.
Based on a population pharmacokinetic analysis in 736 patients, concomitant administration of cytoreductive drugs including hydroxyurea, granulocyte colony stimulating factors including filgrastim or lenograstim, and P-gp inhibitors, had no apparent effect on inotuzumab ozogamicin clearance.

Effect of inotuzumab ozogamicin on other medicines.

Effect on CYP substrates.

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

Effect on UGT substrates.

In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide 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 dimethylhydrazide had a low potential to inhibit the activities of P-gp, breast cancer resistance protein (BCRP), organic anion transporter (OAT)1 and OAT3, organic cation transporter (OCT)2, and organic anion transporting polypeptide (OATP)1B1 and OATP1B3 at clinically relevant concentrations.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In a female fertility and early embryonic development study, female rats received daily intravenous doses of inotuzumab ozogamicin up to 0.11 mg/m² for 2 weeks before mating through Day 7 of pregnancy. An increase in the proportion of resorptions and decrease in the number of viable embryos were observed at the 0.11 mg/m² dose level (approximately 3 times the exposure in patients at the maximum recommended dose, based on AUC). Additional findings in female reproductive organs occurred in repeat-dose toxicology studies and included decreased ovarian and uterine weights, and ovarian and uterine atrophy. Findings in male reproductive organs occurred in repeat-dose toxicology studies and included decreased testicular weights, testicular degeneration, hypospermia, and prostatic and seminal vesicle atrophy. Testicular degeneration and hypospermia were non-reversible following a 4-week non-dosing period. In the chronic studies of 26-weeks duration, adverse effects on reproductive organs occurred at ≥ 0.07 mg/m² in male rats (approximately 0.1 times the exposure in patients at the maximum recommended dose, based on AUC).
Based on these findings, female and male fertility may be compromised by treatment with Besponsa. Both men and women should seek advice for fertility preservation before treatment.
(Category D)
There are no data in pregnant women using Besponsa.
In a fertility and early embryonic development study in female rats, inotuzumab ozogamicin was administered intravenously daily for 2 weeks before mating through Day 7 of pregnancy, which resulted in embryo-fetal mortality in the presence of slight maternal toxicity at doses of 0.109 mg/m²/day with maternal systemic exposures (approximately 3 times the human clinical exposure based on AUC).
In embryo-fetal development studies in rats and rabbits, pregnant animals received daily intravenous doses up to 0.109 mg/m²/day or 0.145 mg/m²/day, respectively, during the period of organogenesis. The maternally toxic dose of 0.109 mg/m²/day was fetotoxic in rats, resulting in fetal growth retardation as evidenced by decreased fetal weights and delayed skeletal ossification. Slight fetal growth retardation in rats also occurred at 0.036 mg/m²/day (approximately 0.45 times the human clinical exposure based on AUC). At a dose of 0.145 mg/m²/day in rabbits (approximately 4 times the human clinical exposure based on AUC), there were no effects on embryo-fetal development.
Based on these findings and the genotoxic potential of inotuzumab ozogamicin (see Section 5.3 Preclinical Safety Data, Genotoxicity), Besponsa can cause embryo-fetal harm when administered to a pregnant woman.
Besponsa should not be used during pregnancy unless the potential benefit to the mother outweighs the potential risks to the fetus.
Women of childbearing potential should be advised to use effective contraception to avoid becoming pregnant during treatment with Besponsa and for at least 8 months after the last dose.
Men with female partners of childbearing potential should be advised to use effective contraception during treatment with Besponsa and for at least 5 months after the last dose.
Pregnant women, or patients becoming pregnant while receiving Besponsa, or treated male patients as partners of pregnant women, must be apprised of the potential risk to the fetus.
There are no data on the presence of inotuzumab ozogamicin or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. A risk to the newborn/infant cannot be excluded. Because of the potential for adverse reactions in breastfed infants, women should not breastfeed during treatment with Besponsa and for at least 2 months after the final dose.

4.7 Effects on Ability to Drive and Use Machines

No formal studies have been conducted on effects on the ability to drive and use machines. Patients should be advised that they may experience fatigue during treatment with Besponsa (see Section 4.8 Adverse Effects (Undesirable Effects)). Therefore, caution is recommended when driving or operating machines.

4.8 Adverse Effects (Undesirable Effects)

The adverse effects described in this section reflect exposure to Besponsa in 164 patients with relapsed or refractory ALL who participated in a randomised clinical study of Besponsa versus Investigator's choice of chemotherapy (FLAG, MXN/Ara-C, or HIDAC) (B1931022) (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In patients who received Besponsa, the median duration of treatment was 8.9 weeks (range: 0.1-26.4 weeks), with a median of 3 treatment cycles started in each patient. In patients who received Investigator's choice of chemotherapy, the median duration of treatment was 0.9 weeks (range: 0.1-15.6 weeks), with a median of 1 treatment cycle started in each patient.
In patients who received Besponsa, the most common (≥ 20%) adverse reactions were thrombocytopenia, neutropenia, infection, anaemia, leukopenia, fatigue, haemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinaemia.
In patients who received Besponsa, the most common (≥ 2%) serious adverse reactions were infection (23%), febrile neutropenia (11%, haemorrhage (5%), abdominal pain (3%), pyrexia (2%), VOD/SOS (2%), and fatigue (2%).
In patients who received Besponsa, the most common (≥ 2%) adverse reactions reported as the reason for permanent discontinuation were infection (6%), thrombocytopenia (2%), hyperbilirubinaemia (2%), transaminases increased (2%), and haemorrhage (2%); the most common (≥ 5%) adverse reactions reported as the reason for dosing interruption were neutropenia (17%), infection (10%), thrombocytopenia (10%), transaminases increased (6%), and febrile neutropenia (5%); the most common (≥ 1%) adverse reactions reported as the reason for dose reduction were neutropenia (1%), thrombocytopenia (1%), and transaminases increased (1%).

Tabular listing of adverse reactions.

Table 5 shows the adverse reactions with ≥ 10% incidence reported in patients with relapsed or refractory ALL who received Besponsa or Investigator's choice of chemotherapy (only adverse reactions with ≥ 10% incidence in the Besponsa arm are included).

Listing of additional adverse reactions.

Additional adverse reactions (all grades) that were reported in < 10% of patients treated with Besponsa included:

Blood and lymphatic system disorders.

Common: Pancytopenia (2%; includes the following preferred terms: bone marrow failure, febrile bone marrow aplasia, and pancytopenia).

Metabolism and nutrition disorders.

Common: Hyperuricaemia (4%), tumour lysis syndrome (2%; see text below; see Section 4.4 Special Warnings and Precautions for Use, Tumour lysis syndrome).

Gastrointestinal disorders.

Common: Abdominal distension (6%), ascites (4%).

Hepatobiliary disorders.

Common: VOD/SOS (3%), includes 1 patient with VOD/SOS that occurred at Day 56 (i.e. not within 42 days of Cycle 1 Day 1) with no intervening HSCT but does not include 18 patients with VOD/SOS that occurred after HSCT (see text below; see Section 4.4 Special Warnings and Precautions for Use, Hepatotoxicity, including venoocclusive liver disease (VOD)/sinusoidal obstruction syndrome (SOS)).

Investigations.

Common: Lipase increased (9%), amylase increased (5%), electrocardiogram QT prolonged (1%; see text below; see Section 4.4 Special Warnings and Precautions for Use, QT interval prolongation).

Injury, poisoning, and procedural complications.

Common: Infusion related reaction (2%; includes the following preferred terms: hypersensitivity and infusion related reaction) (see text below; see Section 4.4 Special Warnings and Precautions for Use, Infusion related reactions).

Description of selected adverse reactions.

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

In study B1931022, VOD/SOS was reported in 23/164 (14%) patients during or following treatment or following a HSCT after completion of treatment. Grade 3/4 AST, ALT, and total bilirubin abnormal liver tests occurred in 7/160 (4%), 7/161 (4%), and 8/161 (5%) patients, respectively.
Among all 164 patients treated, VOD/SOS was reported in 5/164 (3%) patients during study therapy or in follow-up without an intervening HSCT. Among the 79 patients who proceeded to a subsequent HSCT (8 of whom received additional salvage therapy after treatment with Besponsa before proceeding to HSCT), VOD/SOS was reported in 18/79 (23%) patients. Five of the 18 VOD/SOS events that occurred post-HSCT were fatal.
VOD/SOS was reported up to 56 days after the last dose during treatment or during follow-up without an intervening HSCT. The median time from HSCT to onset of VOD/SOS was 15 days (range: 3-57 days).
Of the 5 patients who experienced VOD/SOS during treatment with Besponsa but without an intervening HSCT, 2 patients had also received a HSCT before Besponsa treatment. Among patients who proceeded to HSCT, VOD/SOS was reported after the HSCT that followed treatment with Besponsa in 5/11 (46%) patients who received a HSCT both prior to and after Besponsa treatment and 13/68 (19%) patients who only received a HSCT after Besponsa treatment.
For clinical management of hepatotoxicity, including VOD/SOS, see Section 4.4 Special Warnings and Precautions for Use.

Increased risk of post-transplant non-relapse mortality.

In study B1931022, 79/164 patients (48%) in the Besponsa arm and 35/162 patients (22%) in the Investigator's choice of chemotherapy arm had a follow-up HSCT. Although the overall post-HSCT mortality rate was similar in the Besponsa arm and Investigator's choice of chemotherapy arm (51/79 [65%] and 23/35 [66%], respectively), the post-HSCT non-relapse mortality rate was higher in the Besponsa arm compared to the Investigator's choice of chemotherapy arm (31/79 [39%] and 8/35 [23%], respectively).
In the Besponsa arm, the most common causes of post-HSCT non-relapse mortality included VOD and infections. Five of the 18 VOD events that occurred post-HSCT were fatal. In the Besponsa arm, among patients with ongoing VOD at time of death, 6 patients died due to multiorgan failure (MOF) or infection (3 patients died due to MOF, 2 patients died due to infection, and 1 patient died due to MOF and infection).
For clinical management of the increased risk of post-transplant non-relapse mortality, see Section 4.4 Special Warnings and Precautions for Use.

Myelosuppression/cytopenias.

In study B1931022, thrombocytopenia and neutropenia were reported in 83/164 (51%) and 81/164 (49%) patients, respectively. Grade 3 thrombocytopenia and neutropenia were reported in 23/164 (14%) patients and 33/164 (20%) patients, respectively. Grade 4 thrombocytopenia and neutropenia were reported in 46/164 (28%) patients and 45/164 (27%) patients, respectively. Febrile neutropenia, which may be life-threatening, was reported in 43/164 (26%) patients.
For clinical management of myelosuppression/cytopenias, see Section 4.4 Special Warnings and Precautions for Use.

Complications associated with neutropenia and thrombocytopenia.

Infections, including serious infections, some of which were life-threatening or fatal, were reported in 79/164 (48%) patients. Fatal infections, including pneumonia, neutropenic sepsis, sepsis, septic shock, and pseudomonal sepsis, were reported in 8/164 (5%) patients. Bacterial, viral, and fungal infections were reported.
Bleeding/haemorrhagic events, mostly mild in severity, were reported in 54/164 (33%) patients. Grade 3/4 bleeding/haemorrhagic events were reported in 8/164 (5%) patients. One Grade 5 bleeding/haemorrhagic event (intra-abdominal haemorrhage) was reported in 1/164 (1%) patients. The most common bleeding event was epistaxis which was reported in 24/164 (15%) patients.
For clinical management of myelosuppression/cytopenias and associated complications, see Section 4.4 Special Warnings and Precautions for Use.

Infusion related reactions.

In study B1931022, infusion related reactions, all of which were Grade ≤ 2 in severity, were reported in 4/164 (2%) patients. These infusion related reactions generally occurred shortly after the end of the Besponsa infusion and resolved.
For clinical management of infusion related reactions, see Section 4.4 Special Warnings and Precautions for Use.

Tumour lysis syndrome.

In study B1931022, tumour lysis syndrome (TLS), which may be life-threatening or fatal, was reported in 4/164 (2%) patients. Grade 3/4 TLS was reported in 3/164 (2%) patients. TLS occurred shortly after the end of the Besponsa infusion and resolved with medical management.
For clinical management of TLS, see Section 4.4 Special Warnings and Precautions for Use.

QT interval prolongation.

In study B1931022, increases in QTcF interval of ≥ 60 msec from baseline were measured in 4/162 (3%) patients. No patient had QTcF values > 500 msec. Grade 2 QT prolongation was reported in 2/164 (1%) patients. No Grade ≥ 3 QT prolongation or event of Torsade de Pointes were reported.
For periodic monitoring of ECG and electrolyte levels, see Section 4.4 Special Warnings and Precautions for Use.

Laboratory abnormalities.

Table 6 shows the clinically important laboratory abnormalities reported in patients with relapsed or refractory ALL who received Besponsa or Investigator's choice of chemotherapy.

Immunogenicity.

In clinical studies of Besponsa in patients with relapsed or refractory ALL, 7/236 (3%) patients tested positive for anti-inotuzumab ozogamicin antibodies. No patient tested positive for neutralising anti-inotuzumab ozogamicin antibodies. In patients who tested positive for anti-inotuzumab ozogamicin antibodies, the presence of anti-inotuzumab ozogamicin antibodies did not affect clearance following Besponsa treatment.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Overdoses may result in adverse reactions that are consistent with the reactions observed at the recommended therapeutic dose (see Section 4.8 Adverse Effects (Undesirable Effects)). In the event of an overdose, the infusion should be temporarily interrupted and patients should be monitored for liver and haematological toxicities (see Section 4.2 Dose and Method of Administration). Reinitiation of Besponsa at the correct therapeutic dose should be considered when all toxicities have resolved.
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.

Inotuzumab ozogamicin is a CD22-targeted antibody-drug conjugate (ADC). Inotuzumab is a humanised IgG4 antibody which specifically recognises human CD22. The small molecule, N-acetyl-gamma-calicheamicin, is a cytotoxic agent that is covalently attached to the antibody via an acid-cleavable linker. Nonclinical data suggest that the anticancer activity of inotuzumab ozogamicin is due to the binding of the ADC to CD22-expressing tumour cells, followed by internalisation of the ADC-CD22 complex, and the intracellular release of N-acetyl-gamma-calicheamicin dimethylhydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl-gamma-calicheamicin dimethylhydrazide induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.

Pharmacodynamics.

Pharmacodynamic effects.

During the treatment period, the pharmacodynamic response to inotuzumab ozogamicin was characterised by the depletion of CD22-positive leukaemic blasts.

Cardiac electrophysiology.

Based on a pharmacokinetic exposure-response analysis in 250 patients with relapsed or refractory ALL or other haematologic malignancies who received 1.8 mg/m²/cycle inotuzumab ozogamicin administered as 3 divided doses on Days 1 (0.8 mg/m²), 8 (0.5 mg/m²), and 15 (0.5 mg/m²) of a 21- to 28-day cycle or 1.8 mg/m²/cycle administered once every 4 weeks, respectively, the median QT interval corrected for heart rate using Fridericia's formula (QTcF) increased by 2.53 milliseconds (msec) from baseline (97.5th percentile: 4.92 msec) at the average maximum observed concentration (C_max) estimated for patients with relapsed or refractory ALL (371 nanogram/mL) and by 3.87 msec from baseline (97.5^th percentile: 7.54 msec) at a 1.5 times higher average C_max (569 nanogram/mL).
In a randomised clinical study in patients with relapsed or refractory ALL (B1931022), increases in QTcF of ≥ 60 msec from baseline were measured in 4/162 (3%) patients in the Besponsa arm and 3/124 (2%) patients in the Investigator's choice of chemotherapy arm. Increases in QTcF of > 500 msec were observed in none of the patients in the Besponsa arm and 1/124 (1%) patients in the Investigator's choice of chemotherapy arm. Mean (90% confidence interval [CI]) maximum QTcF changes from baseline were 16.5 msec (14.3-18.7) in the Besponsa arm and 10.8 msec (8.0-13.6) in the Investigator's choice of chemotherapy arm. Central tendency analysis of the QTcF interval changes from baseline showed that the highest upper bound of the 2-sided 90% CI for QTcF was 21.1 msec (observed at Cycle 4/Day 1/1 hour) in the Besponsa arm and 21.2 msec (observed at Cycle 2/Day 1/1 hour) in the Investigator's choice of chemotherapy arm (see Section 4.4 Special Warnings and Precautions for Use, QT interval prolongation).

Clinical trials.

Patients with relapsed or refractory ALL who have received 1 or 2 prior treatment regimens for ALL - study B1931022.

The safety and efficacy of Besponsa in patients with relapsed or refractory ALL were evaluated in a randomised, open-label, international, multicentre, Phase 3 study (B1931022). Eligible patients were ≥ 18 years of age with Philadelphia chromosome-negative or Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL. All patients were required to have ≥ 5% bone marrow blasts and to have received 1 or 2 previous induction chemotherapy regimens for ALL. Patients with Philadelphia chromosome-positive B-cell precursor ALL were required to have disease that failed treatment with at least 1 tyrosine kinase inhibitor and standard chemotherapy. Table 1 (see Section 4.2 Dose and Method of Administration) shows the dosing regimen used to treat patients.
Among all 326 patients randomised to the study, 164 patients received Besponsa and 162 patients received Investigator's choice of chemotherapy.
Among the initial 218 patients who were randomised to receive Besponsa (N=109) or Investigator's choice of chemotherapy including fludarabine + cytarabine + granulocyte colony-stimulating factor (FLAG), mitoxantrone + cytarabine (MXN/Ara-C), or high dose cytarabine (HIDAC) (N=109), and who were assessed for complete remission/complete remission with incomplete haematologic recovery (CR/CRi) by the Endpoint Adjudication Committee (EAC), 142 (65%) patients had received 1 prior treatment regimen for ALL and 74 (34%) patients had received 2 prior treatment regimens for ALL. The median age was 47 years (range: 18-79 years), 186 (85%) patients had Philadelphia chromosome-negative ALL, 133 (61%) patients had a duration of first remission < 12 months, and 39 (18%) patients had undergone a haematopoietic stem cell transplant (HSCT) prior to receiving Besponsa or Investigator's choice of chemotherapy.
Among all 326 patients who were randomised to receive Besponsa (N=164) or Investigator's choice of chemotherapy (N=162), 215 (66%) patients had received 1 prior treatment regimen for ALL and 108 (33%) patients had received 2 prior treatment regimens for ALL. The median age was 47 years (range: 18-79 years), 276 (85%) patients had Philadelphia chromosome-negative ALL, 206 (63%) patients had a duration of first remission < 12 months, and 55 (18%) patients had undergone a HSCT prior to receiving Besponsa or Investigator's choice of chemotherapy. The two treatment groups were generally balanced with respect to the baseline demographics and disease characteristics.
All evaluable patients had B-cell precursor ALL that expressed CD22, with ≥ 90% of evaluable patients exhibiting ≥ 70% leukaemic blast CD22 positivity prior to treatment, as assessed by flow cytometry performed at a central laboratory.
The primary endpoints were CR/CRi, assessed by a blinded independent EAC, and overall survival (OS). The secondary endpoints included minimal residual disease (MRD) negativity, duration of remission (DoR), HSCT rate, and progression-free survival (PFS). CR/CRi, MRD, and DoR were analysed in the initial 218 randomised patients and OS, PFS, and HSCT rate were analysed in all 326 randomised patients.
Table 7 shows the efficacy results for CR/CRi, MRD-negativity, and DoR in the initial 218 patients from this study. Table 8 shows the efficacy results for OS, PFS, and HSCT rate in all 326 patients from this study.

Among the initial 218 randomised patients, 88/109 achieved CR/CRi as per EAC in the Besponsa arm (64/88 [73%] in Cycle 1; 21/88 [24%] in Cycle 2) and 32/109 achieved CR/CRi as per EAC in the Investigator's choice of chemotherapy arm (29/32 [91%] in Cycle 1; 1/32 [3%] in Cycle 2).
CR/CRi, MRD, and DoR results in the initial 218 randomised patients were consistent with those seen in all 326 randomised patients.
Among the 164 patients randomised to the Besponsa arm, 62 patients achieved and remained in CR/CRi and proceeded directly to HSCT with a median of 4.9 weeks (range: 3.4 - 7.1 weeks) between the last dose of Besponsa and proceeding to HSCT.
A total of 79/164 (48%) patients in the Besponsa arm and 36/162 (22%) patients in the Investigator's choice of chemotherapy arm had a follow-up HSCT. This included 70 and 18 patients in the Besponsa arm and Investigator's choice of chemotherapy arm, respectively, who proceeded directly to HSCT.
Figure 1 shows the analysis of overall survival (OS) (hazard ratio: 0.75; p=0.0105). Median OS was 7.7 months in the Besponsa arm and 6.2 months in the Investigator's choice of chemotherapy arm. Among all 326 randomised patients, the survival probability at 24 months was 22.8% in the Besponsa arm and 10.0% in the Investigator's choice of chemotherapy arm. The analysis of OS did not meet the pre-specified boundary for statistical significance.

Based on 04 January 2017 last subject last visit date.
Patient reported outcomes were measured using the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30). Besponsa resulted in significantly better estimated mean postbaseline scores (Besponsa and Investigator's choice of chemotherapy, respectively) in physical functioning (75.0 versus 68.1; p=0.0139), role functioning (64.7 versus 53.4; p=0.0065), social functioning (68.1 versus 59.8; p=0.0336), and appetite loss (17.6 versus 26.3; p=0.0193) compared to Investigator's choice of chemotherapy.

5.2 Pharmacokinetic Properties

In patients with relapsed or refractory ALL, steady-state exposure was achieved by Cycle 4. The mean C_max of inotuzumab ozogamicin was 308 nanogram/mL. The mean simulated total area under the concentration-time curve (AUC) per cycle was 100,000 nanogram.h/mL.

Distribution.

In vitro, the binding of N-acetyl-gamma-calicheamicin dimethylhydrazide to human plasma proteins is approximately 97%. In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide is a substrate of P-glycoprotein (P-gp). In humans, the total volume of distribution of inotuzumab ozogamicin was approximately 12 L.

Metabolism.

In vitro, N-acetyl-gamma-calicheamicin dimethylhydrazide was primarily metabolised via nonenzymatic reduction. In humans, N-acetyl-gamma-calicheamicin dimethylhydrazide serum levels were typically below the limit of quantitation.

Excretion.

Inotuzumab ozogamicin pharmacokinetics were well characterised by a 2-compartment model with linear and time-dependent clearance components. In 234 patients with relapsed or refractory ALL, the clearance of inotuzumab ozogamicin at steady state was 0.0333 L/h and the terminal half-life (t_½) was 12.3 days. Following administration of multiple doses, a 5.3 times accumulation of inotuzumab ozogamicin was predicted by Cycle 4.
Based on a population pharmacokinetic analysis in 765 patients, body surface area was found to significantly affect inotuzumab ozogamicin disposition. The dose of Besponsa is administered based on body surface area (see Section 4.2 Dose and Method of Administration).

Special populations.

Age, race and gender.

Based on a population pharmacokinetic analysis, age, race, and gender did not significantly affect inotuzumab ozogamicin disposition.

Hepatic impairment.

No formal pharmacokinetic studies of Besponsa have been conducted in patients with hepatic impairment.
Based on a population pharmacokinetic analysis in 765 patients, the clearance of inotuzumab ozogamicin in patients with hepatic impairment defined by National Cancer Institute Organ Dysfunction Working Group (NCI ODWG) category B1 (total bilirubin ≤ upper limit of normal [ULN] and aspartate aminotransferase [AST] > ULN; n=133) or B2 (total bilirubin > 1.0-1.5 x ULN and AST any level; n=17) was similar to patients with normal hepatic function (total bilirubin/AST ≤ ULN; n=611) (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment). In 3 patients with hepatic impairment defined by NCI ODWG category C (total bilirubin > 1.5-3 x ULN and AST any level) and 1 patient with NCI ODWG category D (total bilirubin > 3 x ULN and AST any level), inotuzumab ozogamicin clearance did not appear to be reduced.

Renal impairment.

No formal pharmacokinetic studies of Besponsa have been conducted in patients with renal impairment.
Based on a population pharmacokinetic analysis in 765 patients, the clearance of inotuzumab ozogamicin in patients with mild renal impairment (creatinine clearance [CLcr] 60-89 mL/min; n=237), moderate renal impairment (CLcr 30-59 mL/min; n=122), or severe renal impairment (CLcr 15-29 mL/min; n=4) was similar to patients with normal renal function (CLcr ≥ 90 mL/min; n=402) (see Section 4.4 Special Warnings and Precautions for Use, Use in renal impairment). The safety and efficacy of inotuzumab ozogamicin have not been studied in patients with end stage renal disease.

5.3 Preclinical Safety Data

Genotoxicity.

Inotuzumab ozogamicin was clastogenic in vivo in the bone marrow of male mice that received single intravenous doses ≥ 1.14 mg/m². This is consistent with the known induction of DNA breaks by calicheamicin. N-acetyl-gamma-calicheamicin dimethylhydrazide (the cytotoxic agent released from inotuzumab ozogamicin) was mutagenic in an in vitro bacterial reverse mutation (Ames) assay.

Carcinogenicity.

Formal carcinogenicity studies have not been conducted with inotuzumab ozogamicin. In intravenous toxicity studies, rats were dosed weekly for 4 or 26 weeks with inotuzumab ozogamicin at doses up to 4.07 mg/m²/week and 0.727 mg/m²/week, respectively. After 4 or 26 weeks of dosing, rats developed oval cell hyperplasia, altered cell foci, and hepatocellular adenomas in the liver at ≥ 0.073 mg/m²/week (approximately 0.1 times the human clinical exposure based on AUC). In 1 monkey, a focus of hepatocellular alteration was detected at 0.732 mg/m²/week (approximately 4 times the human clinical exposure based on AUC) at the end of the 26-week dosing period.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each vial contains the following inactive ingredients: trometamol, sucrose, polysorbate 80, sodium chloride.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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.
Besponsa contains no bacteriostatic preservatives. The reconstituted solution should be used immediately. If the reconstituted solution cannot be used immediately, it may be refrigerated (2-8°C) for up to 4 hours. Protect from light and do not freeze.
The diluted solution should be used immediately or stored at room temperature (20-25°C) or refrigerated (2-8°C). The maximum time from reconstitution through the end of administration should be ≤ 8 hours, with ≤ 4 hours between reconstitution and dilution. Protect from light and do not freeze.

6.4 Special Precautions for Storage

Store unopened vials in the original carton at 2-8°C (Refrigerate. Do not freeze) and protect from light until time of use.
Table 9 shows the storage times and conditions for reconstitution, dilution, and administration of Besponsa.

6.5 Nature and Contents of Container

Each carton contains 1 single-use vial containing 1 mg of sterile, preservative free, white to off-white lyophilised cake or powder for injection.
The container is a Type I amber glass vial with chlorobutyl rubber stoppers and crimp seals with a flip off cap.

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.

Chemical Name: Conjugate of humanised immunoglobulin class G subtype 4 (IgG4) monoclonal antibody with N-acetyl-calicheamicin (via a linker) with an average loading of 6 moles of calicheamicin derivative/mole of antibody.
Molecular weight: approximately 160 kDa with 6 calicheamicin derivatives.

CAS number.

CAS Registry Number: activated calicheamicin derivative: 174885-02-0.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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Consumer medicine information

Besponsa

Inotuzumab ozogamicin

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