Consumer medicine information

Enhertu

Trastuzumab deruxtecan

BRAND INFORMATION

Brand name

Enhertu

Active ingredient

Trastuzumab deruxtecan

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Enhertu.

SUMMARY CMI

ENHERTU®

Consumer Medicine Information (CMI) summary

The full CMI on Page 2 has more details. If you are worried about using this medicine, speak to your doctor or nurse.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI (page 2) for further details.

1. Why am I using ENHERTU?

ENHERTU contains the active ingredient trastuzumab deruxtecan. ENHERTU is used to treat adults who have:

  • HER2-positive breast cancer that has spread to other parts of the body or cannot be taken out by surgery and who have also received prior treatment with trastuzumab and a taxane for metastatic disease, or have received one prior treatment for breast cancer that has come back during or within 6 months of completing treatment for their early-stage breast cancer.
  • HER2-low breast cancer that cannot be removed by surgery or that has spread to other parts of your body (metastatic) and who have received prior chemotherapy for metastatic disease, or your disease has returned during or within 6 months of completing adjuvant chemotherapy (after surgery). If the breast cancer is also hormone receptor positive (HR+), you should have received hormonal therapy. A test may be performed to make sure ENHERTU is right for you.

For more information, see Section 1 in the full CMI.

2. What should I know before I use ENHERTU?

Before you are given ENHERTU, tell your doctor if you have or have had any lung problems, any kidney problems, any heart problems or any blood problems (low blood count). Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2 in the full CMI.

3. What if I am taking other medicines?

Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines. See Section 3 in the full CMI.

4. How is ENHERTU given to me?

ENHERTU will be given to you in a hospital or clinic by a doctor or nurse. See Section 4 in the full CMI.

5. What should I know while receiving ENHERTU?

Things you should do
  • Remind any doctor, dentist or nurse you visit that you are receiving ENHERTU.
  • Keep your appointments with your doctor, so that you do not miss a dose and progress is monitored.
  • Use effective contraception to avoid becoming pregnant while being treated with ENHERTU.
Things you should not do
  • Do not stop using ENHERTU suddenly, unless you have discussed this with your doctor.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how ENHERTU affects you.
Call your doctor straight away
  • If you experience any of the serious side effects listed in Section 6 in the full CMI.
  • If you have cough, shortness of breath, fever, or other new or worsening breathing problems.
  • If you become pregnant while using ENHERTU.
Looking after your medicine
  • ENHERTU will be stored by the healthcare professionals at the hospital or clinic where you receive treatment.

For more information, see Section 5 in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, some can be minor and temporary. However, some side effects may be serious and possibly fatal, therefore will need immediate medical attention. See Section 6 in the full CMI and, if you need to, ask your doctor if you have any further questions about side effects. Tell your doctor if you experience any side effects, including those not listed in this leaflet.

For more information, including what to do if you have any side effects, see Section 6 in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

ENHERTU®

Active ingredient: trastuzumab deruxtecan

Consumer Medicine Information (CMI)

This leaflet provides important information about using ENHERTU. You should also speak to your doctor or nurse if you would like further information or if you have any concerns or questions about using ENHERTU.

Where to find information in this leaflet:

1. Why am I using ENHERTU?
2. What should I know before I use ENHERTU?
3. What if I am taking other medicines?
4. How is ENHERTU given to me?
5. What should I know while receiving ENHERTU?
6. Are there any side effects?
7. Product details

1. Why am I using ENHERTU?

ENHERTU contains the active ingredient trastuzumab deruxtecan. ENHERTU is made up of a monoclonal antibody connected to a medicine intended to kill cancer cells. The monoclonal antibody delivers the medicine to cancer cells that express HER2 proteins. Once ENHERTU enters the cell, the medicine becomes active and kills the cancer cells.

ENHERTU is used to treat adults who have:

  • HER2-positive breast cancer that has spread to other parts of the body or cannot be taken out by surgery and who have also received prior treatment with trastuzumab and a taxane for metastatic disease, or have received one prior treatment for breast cancer that has come back during or within 6 months of completing treatment for their early-stage breast cancer.
  • HER2-low breast cancer that cannot be removed by surgery or that has spread to other parts of your body (metastatic) and who have received prior chemotherapy for metastatic disease, or your disease has returned during or within 6 months of completing adjuvant chemotherapy (after surgery). If the breast cancer is also hormone receptor positive (HR+), you should have received hormonal therapy. A test may be performed to make sure ENHERTU is right for you.

2. What should I know before I use ENHERTU?

Warnings and precautions

Check with your doctor if you:

  • have or have had any lung problems, any kidney problems, any heart problems or any blood problems (low blood count).

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 5 (What should I know while receiving ENHERTU?) and Section 6 (Are there any side effects?).

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Pregnancy

  • ENHERTU is not recommended if you are pregnant because this medicine may cause harm to the unborn baby.
  • Tell your doctor before using ENHERTU if you are pregnant, think you may be pregnant or are planning to have a baby.
  • Use effective contraception to avoid becoming pregnant while you are being treated with ENHERTU. Talk to your doctor about the best contraception for you.
  • Females should continue to take contraception for at least 7 months after your last dose of ENHERTU. Talk to your doctor before stopping your contraception.
  • Male patients with a female partner who could become pregnant should use effective contraception during treatment and for at least 4 months after the last dose of ENHERTU.
  • If you do become pregnant during treatment with ENHERTU, tell your doctor right away.

Breastfeeding

  • You should not breastfeed during treatment with ENHERTU.
  • You should not breastfeed for at least 7 months after your last treatment of ENHERTU.
  • It is not known whether the ingredients in ENHERTU pass into breast milk. Talk to your doctor about this.

Fertility

  • Talk to your doctor about sperm storage before treatment with ENHERTU because the medicine may reduce your fertility. Do not freeze or donate sperm throughout the treatment period, and for at least 4 months after the final dose of ENHERTU.

Children and adolescents

ENHERTU is not recommended for anyone under the age of 18 years.

3. What if I am taking other medicines?

Tell your doctor if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Check with your doctor if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ENHERTU.

4. How is ENHERTU given to me?

How you are given ENHERTU

ENHERTU will be given to you in a hospital or clinic.

  • The recommended dose of ENHERTU is 5.4 mg for every kilogram of your body weight, every 3 weeks.
  • Your doctor or nurse will give you ENHERTU through an infusion into your vein (IV).
  • Your first infusion will be given to you over 90 minutes. If you have no problems with the first infusion, the infusion on your next visits may be given over 30 minutes.
  • Your doctor will decide how many treatments you need.
  • Before each ENHERTU infusion, your doctor may give you medicines to help prevent nausea and vomiting.
  • If you experience infusion-related symptoms, your doctor or nurse may slow, interrupt or stop your treatment.

If you miss an appointment to get ENHERTU

  • Call your doctor right away to reschedule your appointment.
  • It is very important that you do not miss a dose of this medicine.

If you stop receiving ENHERTU

  • Do not stop treatment with ENHERTU unless you have discussed this with your doctor.
  • If you have any further questions about your treatment, ask your doctor.

5. What should I know while receiving ENHERTU?

Things you should do

  • Remind any doctor, dentist or nurse you visit that you are receiving ENHERTU.
  • Keep your appointments with your doctor, so that you do not miss a dose and progress is monitored.
  • Tell your doctor or nurse if you are taking other medicines, vitamins or supplements.
  • Tell your doctor if you experience any side effects, including those not listed in this leaflet.
  • Use effective contraception to avoid becoming pregnant while being treated with ENHERTU (see Contraception below).

Call your doctor straight away if you:

  • have cough, shortness of breath, fever, or other new or worsening breathing problems. These may be symptoms of a serious and potentially fatal lung disease (interstitial lung disease [ILD] and/or pneumonitis). Patients with a history of this lung disease or kidney problems may have increased risk of developing interstitial lung disease. Your doctor may have to monitor your lungs while you are taking this medicine.
  • have chills, fever, sores in your mouth, stomach pain or pain when urinating. These may be symptoms of an infection caused by low levels of a type of white blood cell called neutrophils (neutropenia).
  • have new or worsening shortness of breath, cough, tiredness, swelling of your ankles or legs, irregular heartbeat, sudden weight gain, dizziness, or loss of consciousness. These may be symptoms of a problem with your heart's ability to pump blood (left ventricular ejection fraction [LVEF] decrease).
  • become pregnant while using ENHERTU.
  • experience any of the serious side effects listed in Section 6 (Are there any side effects?).

Things you should not do

  • Do not stop using ENHERTU suddenly, unless you have discussed this with your doctor.

Contraception

Use effective contraception to avoid becoming pregnant while being treated with ENHERTU.

Females should continue to take contraception for at least 7 months after your last dose of ENHERTU.

Men with a female partner who may become pregnant should use effective contraception:

  • during treatment and
  • for at least 4 months after the last dose of ENHERTU.

Talk to your doctor about the best contraception for you or before stopping your contraception.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ENHERTU affects you.

It is not expected that ENHERTU affects your ability to drive or use machines. Be careful if you feel tired, dizzy, or have a headache.

Looking after your medicine

ENHERTU will be stored by the healthcare professionals at the hospital or clinic where you receive treatment.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, some can be minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor if you have any further questions about side effects.

Tell your doctor if you experience any side effects, including those not listed in this leaflet.

While you are taking ENHERTU

  • Your doctor will carry out tests before and during your treatment with ENHERTU
  • Depending on the side effects you experience, your doctor may decide to lower your dose, temporarily stop your treatment or permanently stop your treatment.

Serious side effects

Serious side effectsWhat to do
  • cough, shortness of breath (dyspnoea), fever, or other new or worsening breathing problems as these may be symptoms of a lung problem (interstitial lung disease/pneumonitis).
  • chills, fever, sores in your mouth, stomach pain or pain when urinating as these may be symptoms of an infection caused by low levels of a type of white blood cell called neutrophils (neutropenia).
  • new onset or worsening shortness of breath, cough, tiredness, swelling of your ankles or legs, irregular heartbeat, sudden weight gain, dizziness, or loss of consciousness as these may be symptoms of a problem with your heart's ability to pump blood (left ventricular ejection fraction [LVEF] decrease).
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these symptoms because some of them may be signs of a serious or possibly fatal condition. See Section 5 (What should I know while receiving ENHERTU?). Getting medical treatment right away may help keep these problems from becoming more serious.

You may experience the following side effects:

Very common (may affect more than 1 in 10 people)What to do
  • Nausea
  • Feeling tired (fatigue)
  • Vomiting
  • Hair loss (alopecia)
  • Constipation
  • Feeling less hungry
  • Diarrhoea
  • Coughing
  • Stomach (abdominal) pain
  • Headache
  • Fever (pyrexia)
  • Infections of the nose, nasal passages, throat, voice box and vocal cords
  • Sores in or around your mouth (stomatitis)
  • Difficulty breathing (dyspnoea)
  • Indigestion (dyspepsia)
  • Severe nosebleeds (epistaxis)
  • Lung problems (interstitial lung disease/pneumonitis)
  • Rash
  • Dizziness
  • Pain in muscles and bone
  • Weight loss
  • Decrease in the number of red blood cells (anaemia)
  • Decrease in the number of neutrophils (neutropenia)
  • Decrease in the number of platelets (thrombocytopenia)
  • Decrease in the number of white blood cells (leukopenia)
  • Decrease in the number of lymphocytes (lymphopenia)
  • Blood tests showing increased level of liver enzymes such as transaminases (aspartate aminotransferase, alanine aminotransferase, gammaglutamyltransferase). These are liver function tests that indicate abnormality.
  • Low potassium in the blood (hypokalaemia)
Speak to your doctor if you have any of these very common side effects and they worry you.
Common (may affect up to 1 in 10 people)What to do
  • Reactions related to the infusion of the medicine
  • Itching (pruritus)
  • Darkening of the skin (skin hyperpigmentation)
  • Bad taste in mouth (dysgeusia)
  • Excessive gas in the stomach or intestine, bloating and breaking wind (abdominal distension and flatulence)
  • Inflammation of the stomach (gastritis)
  • Feeling thirsty, dry mouth(dehydration)
  • Blurry vision
  • Dry eye
  • Abnormal blood test (increased levels of blood bilirubin, blood creatinine or blood alkaline phosphatase)
Speak to your doctor if you have any of these common side effects and they worry you.

Tell your doctor if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor before you decide to stop taking any of your medicines.

7. Product details

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

What ENHERTU contains

Active ingredient
(main ingredient)		Trastuzumab deruxtecan
Other ingredients
(inactive ingredients)		Histidine, histidine hydrochloride monohydrate, sucrose, and polysorbate 80

What ENHERTU looks like

ENHERTU (Aust R 343262) is a white to yellowish-white lyophilised powder supplied in a clear amber vial with a rubber stopper, aluminium seal and plastic flip-off cap.

Each carton contains 1 vial.

Who distributes ENHERTU

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
MACQUARIE PARK NSW 2113
Telephone: 1800 805 342

This leaflet was prepared in May 2024

ENHERTU® is a trademark of the Daiichi Sankyo Company limited, used under license by AstraZeneca.

© AstraZeneca, 2024

VV-RIM-01450360 v7.0

Published by MIMS July 2024

BRAND INFORMATION

Brand name

Enhertu

Active ingredient

Trastuzumab deruxtecan

Schedule

S4

 

1 Name of Medicine

Trastuzumab deruxtecan.

2 Qualitative and Quantitative Composition

One vial of lyophilized powder for concentrate for solution for infusion delivers 100 mg of trastuzumab deruxtecan. After reconstitution, one vial of 5 mL solution delivers 20 mg/mL of trastuzumab deruxtecan (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 yellowish-white lyophilized powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Metastatic breast cancer.

HER2-positive.

Enhertu as monotherapy, is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who previously received:
trastuzumab and a taxane for metastatic disease; or
one prior anti-HER2-based regimen and developed disease recurrence during or within six months of completing neo-adjuvant or adjuvant therapy.

HER2-low.

Enhertu is indicated for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-negative) breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.
Patients with hormone receptor positive (HR+) breast cancer should additionally have received and no longer be considered eligible for endocrine therapy.

4.2 Dose and Method of Administration

Do not substitute Enhertu for or with trastuzumab or trastuzumab emtansine. In order to prevent medicinal product errors, it is important to check the vial labels to ensure that the medicinal product being prepared and administered is Enhertu (trastuzumab deruxtecan) and not trastuzumab or trastuzumab emtansine.

Patient selection for HER2-low metastatic breast cancer.

Select patients for treatment of unresectable or metastatic HER2-low breast cancer based on IHC 1+ or IHC 2+/ISH-negative tumor status by using a TGA approved or notified assay performed by a NATA accredited laboratory.
The recommended dose of Enhertu is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.
The initial dose should be administered as a 90-minute intravenous infusion. If the initial infusion is well tolerated, subsequent doses of Enhertu may be administered as 30-minute infusions.
The infusion rate of Enhertu should be slowed or interrupted if the patient develops infusion-related symptoms. Enhertu should be permanently discontinued in case of severe infusion reactions.

Premedication.

Enhertu is emetogenic [see Section 4.8 Adverse Effects (Undesirable Effects)], which includes delayed nausea and/or vomiting. Prior to each dose of Enhertu, patients should be premedicated with a combination regimen of two or three medicinal products (e.g. dexamethasone with either a 5-HT3 receptor antagonist and/or an NK1 receptor antagonist, as well as other medicinal products as indicated) for prevention of chemotherapy-induced nausea and vomiting.

Dose modifications.

Management of adverse reactions may require temporary interruption, dose reduction, or treatment discontinuation of Enhertu as per guidelines provided in Table 1 and Table 2.
Enhertu dose should not be re-escalated after a dose reduction is made.

Delayed or missed dose.

If a planned dose is delayed or missed, it should be administered as soon as possible without waiting until the next planned cycle. The schedule of administration should be adjusted to maintain a 3-week interval between doses. The infusion should be administered at the dose and rate the patient tolerated in the most recent infusion.

Special patient populations.

Use in the elderly.

No dose adjustment of Enhertu is required in patients aged 65 years or older.

Paediatric use.

The safety and efficacy in children and adolescents below 18 years of age have not been established as there is no relevant use in the paediatric population for the indication of metastatic breast cancer.

Renal impairment.

No dose adjustment is required in patients with mild (creatinine clearance [CLcr] ≥ 60 and < 90 mL/min) or moderate (CLcr ≥ 30 and < 60 mL/min) renal impairment. Limited data are available in patients with severe renal impairment. A higher incidence of Grade 1 and 2 ILD/pneumonitis leading to an increase in discontinuation of therapy has been observed in patients with moderate renal impairment. Patients with moderate or severe renal impairment should be monitored carefully (see Section 4.4 Special Warnings and Precautions for Use, Interstitial lung disease/pneumonitis). The recommended dosage of Enhertu has not been established for patients with severe renal impairment (CLcr < 30 mL/min).

Hepatic impairment.

No dose adjustment is required in patients with mild (total bilirubin ≤ ULN and any AST > ULN or total bilirubin > 1 to 1.5 times ULN and any AST) hepatic impairment. There are insufficient data to make a recommendation on dose adjustment in patients with moderate (total bilirubin > 1.5 to 3 times ULN and any AST) hepatic impairment. No data are available in patients with severe (total bilirubin > 3 to 10 times ULN and any AST) hepatic impairment.

Method of administration.

Enhertu is for intravenous use. It must be reconstituted and diluted by a healthcare professional and administered as an intravenous infusion. Enhertu must not be administered as an intravenous push or bolus.
In order to prevent medicinal product errors, it is important to check the vial labels to ensure that the medicinal product being prepared and administered is Enhertu (trastuzumab deruxtecan) and not trastuzumab or trastuzumab emtansine.
Appropriate procedures for the preparation of chemotherapeutic medicinal products should be used. Appropriate aseptic technique should be used for the following reconstitution and dilution procedures.

Reconstitution.

Reconstitute immediately before dilution.
More than one vial may be needed for a full dose. Calculate the dose (mg), the total volume of reconstituted Enhertu solution required, and the number of vial(s) of Enhertu needed.
Reconstitute each 100 mg vial using a sterile syringe to slowly inject 5 mL of sterile water for injection into each vial to obtain a final concentration of 20 mg/mL.
Swirl the vial gently until completely dissolved. Do not shake.
If not used immediately, store the reconstituted Enhertu vials in a refrigerator at 2°C to 8°C for up to 24 hours from the time of reconstitution, protected from light. Do not freeze.
The product does not contain a preservative. Discard unused Enhertu after 24 hours refrigerated.

Dilution.

Calculation to determine the volume of reconstituted Enhertu (mL) to be further diluted.
Withdraw the calculated amount from the vial(s) using a sterile syringe. Inspect the reconstituted solution for particulates and discoloration. The solution should be clear and colourless to light yellow. Do not use if visible particles are observed or if the solution is cloudy or discoloured.
Dilute the calculated volume of reconstituted Enhertu in an infusion bag containing 100 mL of 5% dextrose solution. Do not use sodium chloride solution (see Section 6.2 Incompatibilities). An infusion bag made of polyvinylchloride or polyolefin (copolymer of ethylene and polypropylene) is recommended.
Gently invert the infusion bag to thoroughly mix the solution. Do not shake.
Cover the infusion bag to protect from light.
If not used immediately, store at room temperature for up to 4 hours including preparation and infusion or in a refrigerator at 2°C to 8°C for up to 24 hours, protected from light. Do not freeze.
Discard any unused portion left in the vial.

Administration.

If the prepared infusion solution was stored refrigerated (2°C to 8°C), it is recommended that the solution be allowed to equilibrate to room temperature prior to administration protected from light.
Administer Enhertu as an intravenous infusion only with a 0.20 or 0.22 micron in-line polyethersulfone (PES) or polysulfone (PS) filter. Do not administer as an intravenous push or bolus.
Cover the infusion bag to project from light.
Do not mix Enhertu with other medicinal products or administer other medicinal products through the same intravenous line.

4.3 Contraindications

None.

4.4 Special Warnings and Precautions for Use

Interstitial lung disease/pneumonitis.

Cases of interstitial lung disease (ILD) and/or pneumonitis, have been reported with Enhertu [see Section 4.8 Adverse Effects (Undesirable Effects)]. Patients should be advised to immediately report cough, dyspnoea, fever, and/or any new or worsening respiratory symptoms. Patients should be monitored for signs and symptoms of ILD/pneumonitis. Evidence of ILD/pneumonitis should be promptly investigated. Patients with suspected ILD/pneumonitis should be evaluated by radiographic imaging. Consultation with a pulmonologist should be considered. For asymptomatic (Grade 1) ILD/pneumonitis, consider corticosteroid treatment (e.g. ≥ 0.5 mg/kg/day prednisolone or equivalent). Enhertu should be withheld until recovery to Grade 0 and may be resumed according to instructions in Table 2 (see Section 4.2). For symptomatic ILD/pneumonitis (Grade 2 or greater), promptly initiate systemic corticosteroid treatment (e.g. ≥ 1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks. Enhertu should be permanently discontinued in patients who are diagnosed with symptomatic (Grade 2 or greater) ILD/pneumonitis (see Section 4.2 Dose and Method of Administration). Patients with a history of ILD/pneumonitis or with moderate or severe renal impairment may be at increased risk of developing ILD/pneumonitis and should be monitored carefully (see Section 4.2 Dose and Method of Administration).
In clinical studies, of the 1287 patients with unresectable or metastatic breast cancer treated with Enhertu 5.4 mg/kg, ILD occurred in 12.8% of patients as determined by independent review. Most ILD cases were Grade 1 (3.3%), Grade 2 (7.6%), or Grade 3 (0.9%). Fatal outcomes occurred in 6.1% of patients treated with Enhertu. Median time to first onset was 5.8 months (range: 0.9 to 31.5).

Neutropenia.

Cases of neutropenia, including febrile neutropenia, were reported in clinical studies of Enhertu. Complete blood counts should be monitored prior to initiation of Enhertu and prior to each dose, and as clinically indicated. Based on the severity of neutropenia, Enhertu may require dose interruption or reduction (see Section 4.2 Dose and Method of Administration).
Of the 1287 patients with unresectable or metastatic breast cancer who received Enhertu 5.4 mg/kg, a decrease in neutrophil count was reported in 35.7% of patients and 17.5% had Grade 3 or 4 events. Median time to first onset of decreased neutrophil count was 50 days (range: 1 to 972). Febrile neutropenia was reported in 0.9% of patients.

Left ventricular ejection fraction decrease.

Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies. LVEF should be assessed prior to initiation of Enhertu and at regular intervals during treatment as clinically indicated. LVEF decrease should be managed through treatment interruption. Enhertu should be permanently discontinued if LVEF of less than 40% or absolute decrease from baseline of greater than 20% is confirmed. Enhertu should be permanently discontinued in patients with symptomatic congestive heart failure (CHF) (see Section 4.2 Dose and Method of Administration).
In the 1287 patients with unresectable or metastatic breast cancer who received Enhertu 5.4 mg/kg, 53 cases (4.1%) of LVEF decrease were reported. No decreases of LVEF to less than 20% were observed. Treatment with Enhertu has not been studied in patients with LVEF less than 50% prior to initiation of treatment.

Embryo fetal toxicity.

Enhertu can cause fetal harm when administered to a pregnant woman. In post-marketing reports, use of trastuzumab, a HER2 receptor antagonist, during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Based on findings in animals and its mechanism of action, the topoisomerase I inhibitor component of Enhertu can also cause embryo-fetal harm when administered to a pregnant woman (see Section 4.6 Fertility, Pregnancy and Lactation).
The pregnancy status of females of reproductive potential should be verified prior to the initiation of Enhertu. The patient should be informed of the potential risks to the fetus. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 7 months following the last dose of Enhertu. Male patients with female partners of reproductive potential should be advised to use effective contraception during treatment with Enhertu and for at least 4 months after the last dose of Enhertu (see Section 4.6 Fertility, Pregnancy and Lactation).

Use in the elderly.

Please see Section 4.2 Dose and Method of Administration, Use in the elderly.

Paediatric use.

Please see Section 4.2 Dose and Method of Administration, Paediatric use.

Effects on laboratory tests.

Please see Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effects of other medicinal products on the pharmacokinetics of Enhertu.

In vitro studies indicate that the released topoisomerase I inhibitor is a substrate of the following transporters: P-glycoprotein (P-gp), OATP1B1, OATP1B3, MATE2K, MRP1, and BCRP. Inhibitors of these transporters could increase plasma concentrations of the released topoisomerase I inhibitor.
Coadministration of ritonavir (200 mg twice daily from day 17 of cycle 2 to day 21 of cycle 3), a dual inhibitor of OATP1B/CYP3A, increased exposure (AUC) of trastuzumab deruxtecan by 19% and the released topoisomerase I inhibitor by 22%.
Coadministration of itraconazole (200 mg twice daily from day 17 of cycle 2 to day 21 of cycle 3), a strong CYP3A inhibitor, increased exposure (AUC) of trastuzumab deruxtecan by 11% and the released topoisomerase I inhibitor by 18%.
Coadministration with ritonavir, a dual inhibitor of OATP1B/CYP3A, or with itraconazole, a strong CYP3A inhibitor, resulted in no clinically meaningful increase in exposures of trastuzumab deruxtecan or the released topoisomerase I inhibitor. No dose adjustment is required during coadministration of trastuzumab deruxtecan with drugs that are inhibitors of OATP1B or CYP3A.
No clinically meaningful interaction is expected with drugs that are inhibitors of P-gp, MATE2-K, MRP1, or BCRP transporters.

Effects of Enhertu on the pharmacokinetics of other medicinal products.

In vitro studies indicate that the topoisomerase I inhibitor does not inhibit or induce major CYP450 enzymes, including CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A. In vitro studies indicate that the topoisomerase I inhibitor does not inhibit OAT3, OCT1, OCT2, OATP1B3, MATE1, MATE2-K, P-gp, BCRP, or BSEP transporters, but has an inhibitory effect on OAT1 and OATP1B1 with IC50 values of 12.7 and 14.4 micromol/L, respectively, which are significantly higher than steady-state Cmax (0.01 micromol/L) of topoisomerase I inhibitor at 5.4 mg/kg dose administered every 3 weeks. No clinically meaningful drug-drug interaction is expected with drugs that are substrates of OAT1 or OATP1B1 transporters.

4.6 Fertility, Pregnancy and Lactation

Women of childbearing potential.

Pregnancy status of women of childbearing potential should be verified prior to initiation of Enhertu.

Effects on fertility.

No dedicated fertility studies have been conducted with trastuzumab deruxtecan. Repeat-dose toxicity studies with trastuzumab deruxtecan (intravenous dosing once every 3 weeks) revealed adverse changes to the male reproductive organs in rats and monkeys. In rats, treatment resulted in decreased testes and epididymides weights and spermatid retention at ≥ 20 mg/kg (3.3x the clinical AUC at the maximum recommended clinical dose for trastuzumab deruxtecan and 0.14x for the topoisomerase inhibitor) and tubular degeneration in testes and aspermia at 197 mg/kg (22x the clinical AUC for trastuzumab deruxtecan and 1.3x for the topoisomerase inhibitor). In monkeys, decreased spermatids in seminiferous tubules in the testes were noted at 30 mg/kg (6.5x the clinical AUC for trastuzumab deruxtecan 0.44x for the topoisomerase inhibitor). These changes in the testes of monkeys showed reversibility. Based on results from animal toxicity studies, Enhertu may impair male reproductive function and fertility.
It is not known whether trastuzumab deruxtecan or its metabolites are found in seminal fluid. Before starting treatment, male patients should be advised to seek counselling on sperm storage. Male patients must not freeze or donate sperm throughout the treatment period, and for at least 4 months after the final dose of Enhertu.

Contraception in males and females.

Women of childbearing potential should use effective contraception during treatment with Enhertu and for at least 7 months following the last dose. Men with female partners of childbearing potential should use effective contraception during treatment with Enhertu and for at least 4 months following the last dose.
(Category D)
Trastuzumab deruxtecan can cause fetal harm when administered to a pregnant woman. There are no available data on the effects of trastuzumab deruxtecan in pregnant women. However, in post-marketing reports, use of trastuzumab, a HER2 receptor antagonist, during pregnancy resulted in cases of oligohydramnios manifesting as fatal pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Based on findings in animals and its mechanism of action, the topoisomerase I inhibitor component of trastuzumab deruxtecan can also cause embryo-fetal harm when administered to a pregnant woman.
There were no animal reproductive or developmental toxicity studies conducted with trastuzumab deruxtecan. Based on results from general animal toxicity studies, trastuzumab deruxtecan and the topoisomerase I inhibitor component were toxic to rapidly dividing cells (lymphatic/haematopoietic organs, intestine, or testes), and the topoisomerase I inhibitor was genotoxic, suggesting the potential for embryotoxicity and teratogenicity.
Administration of Enhertu to pregnant women is not recommended, and patients should be informed of the potential risks to the fetus before they become pregnant. Women who become pregnant must immediately contact their doctor. If a woman becomes pregnant during treatment with Enhertu or within 7 months following the last dose of Enhertu, close monitoring is recommended.
 It is not known if trastuzumab deruxtecan is excreted in human milk. Since many medicinal products are excreted in human milk and because of the potential for serious adverse reactions in breastfeeding infants, women should discontinue breastfeeding prior to initiating treatment with Enhertu. Women may begin breastfeeding 7 months after concluding treatment.

4.7 Effects on Ability to Drive and Use Machines

Enhertu is not expected to affect patients' ability to drive or use machines. Due to potential adverse reactions such as fatigue, headache and dizziness [see Section 4.8 Adverse Effects (Undesirable Effects)], patients should be advised to use caution when driving or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials experience.

As clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Metastatic breast cancer.

Summary of adverse drug reactions during clinical trials.

The safety of Enhertu 5.4 mg/kg was evaluated in a pooled analysis of 1287 patients with unresectable or metastatic breast cancer in Study DS8201-A-J101 (Breast Cancer cohort, n=71), DESTINY-Breast01 (n=184), DESTINY-Breast02 (n=404), DESTINY-Breast03 (n=257), and DESTINY-Breast04 (n=371). The median duration of treatment was 10 months (range 0.2 to 45.1).
The pooled study population characteristics were as follows: the median age was 55.5 years (range 22 to 96); 99.5% were female; 49.2% were White, 40.8% were Asian, 2.6% were Black or African American; and 56.6% had an Eastern Cooperative Oncology Group (ECOG) performance status 0 and 43.3% had an ECOG performance status of 1. The studies excluded patients with a history of treated ILD or ILD at screening and patients with a history of clinically significant cardiac disease.
In the pooled studies, the most common adverse reactions (frequency ≥ 20%) were nausea (75.8%), fatigue (58.3%), vomiting (43.7%), alopecia (39.9%), neutropenia (35.7%), constipation (35.3%), anaemia (34.7%), decreased appetite (32%), diarrhoea (29.2%), transaminases increased (27.5%), musculoskeletal pain (27.2%), thrombocytopenia (24.7%), leukopenia (23.9%), and abdominal pain (20.6%). In the pooled studies, the most common serious adverse reactions (frequency > 1%) were interstitial lung disease (3.7%), vomiting (1.5%), anaemia (1.1%), and nausea (1.1%). There were 14 (1.1%) patients with adverse reactions leading to death, 13 attributed to ILD (1.0%), and 1 attributed to febrile neutropenia (0.1%).
Dose interruptions due to adverse reactions occurred in 32.7% of patients treated with Enhertu. The most frequent adverse reactions (> 2%) associated with dose interruption were neutropenia (14%), fatigue (5.1%), anaemia (4.8%), leukopenia (4.1%), thrombocytopenia (3.2%), upper respiratory tract infection (2.8%), and interstitial lung disease (2.5%). Dose reductions occurred in 20.9% of patients treated with Enhertu. The most frequent adverse reactions (> 2%) associated with dose reduction were nausea (5.2%), fatigue (5.1%), neutropenia (3.6%), and thrombocytopenia (2.2%). Discontinuation of therapy due to an adverse reaction occurred in 12.4% of patients treated with Enhertu. The most frequent adverse reaction (> 2%) associated with permanent discontinuation was interstitial lung disease (9.5%).

Tabulated list of adverse reactions.

The adverse reactions in patients with unresectable or metastatic breast cancer who received at least one dose of Enhertu 5.4 mg/kg are presented in Table 3. The adverse reactions are listed by Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) and categories of frequency. Frequency categories are defined as 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), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Adverse events in individual clinical trials.

DESTINY-Breast03.

The safety of Enhertu was evaluated in DESTINY-Breast03 in 257 patients with unresectable or metastatic HER2-positive breast cancer (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The median duration of treatment was 14.3 months (range: 0.7 to 29.8) in the Enhertu group and 6.9 months (range: 0.7 to 25.1) in the trastuzumab emtansine group.
In DESTINY-Breast03 (N=257), the most common adverse reactions (frequency ≥ 20%) were nausea (75.9%), fatigue (49.4%), vomiting (49.0%), neutropenia (42.8%), alopecia (37.0%), constipation (34.2%), anaemia (32.7%), transaminases increased (31.5%), musculoskeletal pain (31.1%), leukopenia (30.4%), decreased appetite (29.2%), diarrhoea (29.2%), thrombocytopenia (25.7%), headache (21.8%), and abdominal pain (21.0%). The most common serious adverse reactions (frequency > 1%) were interstitial lung disease (2.3%) and vomiting (1.9%).
In DESTINY-Breast03, dose interruptions due to adverse reactions occurred in 34.2% of patients treated with Enhertu. The most frequent adverse reactions (> 2%) associated with dose interruption were neutropenia (16.7%), leukopenia (5.1%), thrombocytopenia (4.3%), fatigue (4.3%), anaemia (3.5%), nausea (3.1%), and interstitial lung disease (2.7%). Dose reductions occurred in 19.8% of patients treated with Enhertu. The most frequent adverse reactions (> 2%) associated with dose reduction were nausea (6.2%), neutropenia (3.5%), and fatigue (3.1%). Discontinuation of therapy due to an adverse reaction occurred in 10.5% of patients treated with Enhertu. The most frequent adverse reaction (> 2%) associated with permanent discontinuation was ILD (8.2%). See Table 4.
Other clinically relevant adverse reactions reported in less than 10% of patients were:
Respiratory, thoracic and mediastinal disorders: dyspnoea (8%).
Skin and subcutaneous tissue disorders: pruritus (8%) and skin hyperpigmentation (6%) (grouped term includes PTs of skin hyperpigmentation, skin discoloration, and pigmentation disorder).
Nervous system disorders: dysgeusia (6%).
Metabolism and nutrition disorders: dehydration (4.3%).
Eye disorders: vision blurred (3.5%).
Injury, poisoning and procedural complications: infusion-related reactions (2.3%) (grouped term includes PTs of hypersensitivity, infusion-related reactions).
Blood and lymphatic system disorders: febrile neutropenia (0.8%). See Table 5.

DESTINY-Breast02.

The safety of Enhertu was evaluated in 404 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of Enhertu 5.4 mg/kg in DESTINY-Breast02 (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Enhertu was administered by intravenous infusion once every three weeks. The median duration of treatment was 11 months (range: 0.7 to 45) for patients who received Enhertu.
Serious adverse reactions occurred in 26% of patients receiving Enhertu. Serious adverse reactions in > 1% of patients who received Enhertu were COVID-19, ILD, pneumonia, vomiting, fatigue, and nausea. Fatalities due to adverse reactions occurred in 2.5% of patients including pneumonitis (2 patients), acute myeloid leukaemia, brain oedema, COVID-19, haemorrhage, hepatitis B, malignant pleural effusion, pneumonia, and vasogenic cerebral oedema (one patient each).
Enhertu was permanently discontinued in 20% of patients, of which ILD accounted for 9%. Dose interruptions due to adverse reactions occurred in 45% of patients treated with Enhertu. The most frequent adverse reactions (> 2%) associated with dose interruption were neutropenia, COVID-19, anaemia, fatigue, leukopenia, upper respiratory tract infection, and thrombocytopenia. Dose reductions occurred in 25% of patients treated with Enhertu. The most frequent adverse reactions (> 2%) associated with dose reduction were fatigue, nausea, neutropenia, and vomiting.
The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were nausea, decreased white blood cell count, decreased haemoglobin, decreased neutrophil count, fatigue, decreased lymphocyte count, decreased platelet count, increased alanine aminotransferase, vomiting, increased aspartate aminotransferase, alopecia, increased blood alkaline phosphatase, constipation, decreased appetite, hypokalaemia, diarrhoea, musculoskeletal pain, increased blood bilirubin, abdominal pain, and headache.
Table 6 and Table 7 summarise common adverse reactions and laboratory abnormalities observed in DESTINY-Breast02.
Other clinically relevant adverse reactions reported in less than 10% of patients in the Enhertu-treated group were:
Respiratory, thoracic and mediastinal disorders: dyspnea (8%) and epistaxis (8%);
Skin and subcutaneous tissue disorders: rash (8%) [including rash, pustular rash, maculo-papular rash, and pruritic rash], pruritis (5%), skin hyperpigmentation (5%) [including skin hyperpigmentation and pigmentation disorder];
Nervous system disorders: dizziness (8%) and dysgeusia (8%);
Cardiac disorders: asymptomatic left ventricular ejection fraction decrease (4.2%) [see Section 4.4 Special Warnings and Precautions for Use];
Eye disorders: dry eye (6%) and blurred vision [including blurred vision and visual impairment] (3%);
Metabolism and nutrition disorders: dehydration (2.7%);
Injury, poisoning and procedural complications: infusion-related reactions (1.2%);
Blood and lymphatic system disorders: febrile neutropenia (0.3%).

DESTINY-Breast01 and study DS8201-A-J101.

The safety of Enhertu has been evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2 positive breast cancer who received at least one dose of Enhertu 5.4 mg/kg in DESTINY Breast01 and Study DS8201-A-J101.
Table 5 lists adverse drug reactions, with incidences regardless of investigators assessment of causality, reported in this patient population. Enhertu was administered by intravenous infusion once every three weeks. The median duration of treatment was 9.8 months (range: 0.7 to 37.1).
In Enhertu treated patients (n=234), the median age was 56 years (range 28 to 96); 99.6% were female; 50.9% were White, 41.5% were Asian, 3.0% were Black or African American; and 57.7% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 and 41.9% had an ECOG performance status of 1. The studies excluded patients with a history of treated ILD or ILD at screening and patients with a history of clinically significant cardiac disease.
The most common adverse reactions (frequency ≥ 20%) were nausea, fatigue, vomiting alopecia, constipation, decreased appetite, anaemia, neutropenia, diarrhoea, thrombocytopaenia, cough, leukopenia, and headache (see Table 8). The most common National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v.4.03) Grade ≥ 3 adverse reactions (frequency > 1%) were neutropenia, anaemia, nausea, fatigue, leukopenia, lymphopenia, vomiting, thrombocytopaenia, hypokalaemia, ILD, diarrhoea, febrile neutropenia, dyspnoea, abdominal pain, decreased appetite, and alanine aminotransferase increased (see Table 8). In six patients (2.6%) ILD led to death.
Dose interruptions due to adverse reactions occurred in 25% of patients treated with Enhertu. The most frequent adverse reactions (> 2%) associated with dose interruption were neutropenia (14.5%), anaemia (3.4%), upper respiratory tract infection (3.0%), leukopenia (3.0%), ILD (2.6%), thrombocytopaenia (2.6%), and fatigue (2.1%). Dose reductions occurred in 15% of patients treated with Enhertu. The most frequent adverse reactions (> 2%) associated with dose reduction were fatigue (3.8%), nausea (3.4%), and neutropenia (3.4%). Discontinuation of therapy due to an adverse reaction occurred in 11% of patients treated with Enhertu. The most frequent adverse reaction (> 2%) associated with permanent discontinuation was ILD (9.4%).
Other clinically relevant adverse reactions reported in less than 10% of patients were:
Injury, poisoning and procedural complications: infusion-related reactions (2.6%);
Blood and lymphatic system disorders: febrile neutropenia (1.7%). See Table 9.

DESTINY-Breast04.

The safety of Enhertu was evaluated in DESTINY-Breast04 in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-negative) breast cancer (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The median duration of treatment was 8.2 months (range: 0.2 to 33.3) in the Enhertu group and 3.5 months (range: 0.3 to 17.6) in the chemotherapy group.
In patients treated with Enhertu in DESTINY-Breast04 (N=371), the most common adverse reactions (frequency ≥ 20%) were nausea (76.0%), fatigue (53.6%), vomiting (40.4%), alopecia (39.6%), anaemia (38.5%), constipation (34.0%), neutropenia (34.0%), transaminases increased (32.3%), decreased appetite (31.8%), diarrhoea (27.0%), musculoskeletal pain (26.7%), thrombocytopenia (25.6%), and leukopenia (24.0%). Please see Table 5. The most common serious adverse reactions (frequency > 1%) were ILD/pneumonitis (4.3%), dyspnoea (1.3%), musculoskeletal pain (1.3%), anaemia (1.1%), febrile neutropenia (1.1%), nausea (1.1%), pyrexia (1.1%), and vomiting (1.1%). There were 5 (1.3%) patients with adverse reactions leading to death, 3 attributed to ILD (0.8%) and 1 (0.3%) each for dyspnoea and febrile neutropenia.
Dose interruptions due to adverse reactions occurred in 25.9% of patients treated with Enhertu. The most frequent adverse reactions (> 2%) associated with dose interruption were neutropenia (9.2%), fatigue (5.1%), anaemia (4.6%), leukopenia (3.5%), ILD/pneumonitis (3.0%), transaminases increased (3.0%), and blood bilirubin increased (2.2%). Dose reductions occurred in 19.9% of patients treated with Enhertu. The most frequent adverse reactions (> 2%) associated with dose reduction were fatigue (4.6%), nausea (4.6%), thrombocytopenia (3.5%), and neutropenia (3.0%). Discontinuation of therapy due to an adverse reaction occurred in 11.1% of patients treated with Enhertu. The most frequent adverse reaction (> 2%) associated with permanent discontinuation was ILD/pneumonitis (8.4%). See Table 10.
Other clinically relevant adverse reactions reported in less than 10% of patients treated with Enhertu:
Nervous system disorders: dysgeusia (10%).
Respiratory, thoracic and mediastinal disorders: cough (10%).
Gastrointestinal disorders: abdominal distension (5%), gastritis (2.7%), flatulence (2.4%).
Eye disorders: blurred vision (4.9%) (grouped term includes PTs of blurred vision and visual impairment).
Skin and subcutaneous tissue disorders: pruritus (3.2%) and skin hyperpigmentation (2.7%) (grouped term includes PTs of skin hyperpigmentation, skin discoloration, and pigmentation disorder).
Metabolism and nutrition disorders: dehydration (1.9%).
Blood and lymphatic system disorders: febrile neutropenia (1.1%).
Injury, poisoning and procedural complications: infusion-related reactions (0.5%) (grouped term includes PTs of injection site reaction and chills). See Table 11.

Immunogenicity.

As with all therapeutic proteins, there is a potential for immunogenicity. Across all doses evaluated in clinical studies, 2.1% (47/2213) of evaluable patients developed antibodies against trastuzumab deruxtecan following treatment with Enhertu. The incidence of treatment-emergent neutralizing antibodies against trastuzumab deruxtecan was 0.1% (2/2213). There was no association between development of antibodies and allergic-type reactions.

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.

4.9 Overdose

There is no information on overdose with trastuzumab deruxtecan. In the event of overdose, patients should be monitored, and appropriate supportive care should be given.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Trastuzumab deruxtecan, is a HER2-targeted antibody-drug conjugate (ADC). The antibody is a humanised anti-HER2 IgG1 attached to deruxtecan, a topoisomerase I inhibitor bound by a tetrapeptide-based cleavable linker. The ADC is stable in plasma under in vitro conditions. Following binding to HER2 on tumour cells, trastuzumab deruxtecan undergoes internalization and intracellular linker cleavage by lysosomal enzymes. Upon release, the membrane-permeable topoisomerase I inhibitor causes DNA damage and apoptotic cell death. The topoisomerase I inhibitor, an exatecan derivative, is approximately 10 times more potent than SN38, the active metabolite of irinotecan.

Pharmacodynamic effects.

The administration of multiple doses of trastuzumab deruxtecan (6.4 mg/kg every 3 weeks) did not show any clinically meaningful effect on the QTc interval in an open-label, single-arm study in 51 patients with HER2-expressing metastatic breast cancer.

Clinical trials.

Metastatic breast cancer.

DESTINY-Breast03.

The efficacy and safety of Enhertu were demonstrated in a Phase 3, randomised, multicentre, open-label, active-controlled study: DESTINY-Breast03.
The study included adult patients with unresectable or metastatic HER2-positive breast cancer who received prior trastuzumab and taxane therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy. Archival breast tumour samples were required to show HER2 positivity defined as HER2 IHC 3+ or ISH-positive. The study excluded patients with a history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening, patients with symptomatic brain metastases, patients with a history of clinically significant cardiac disease, and patients with prior treatment with an anti-HER2 antibody-drug conjugate in the metastatic setting. Patients were randomised 1:1 to receive either Enhertu 5.4 mg/kg (N=261) or trastuzumab emtansine 3.6 mg/kg (N=263) by intravenous infusion every three weeks. Randomisation was stratified by hormone receptor status, prior treatment with pertuzumab, and history of visceral disease. Treatment was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity.
The primary efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR) based on RECIST v1.1. Overall survival (OS) was a key secondary efficacy outcome measure. Confirmed objective response rate (ORR) was a secondary endpoint.
Demographic and baseline disease characteristics were similar between treatment arms. Of the 524 patients randomised, the median age was 54 years (range 20 to 83); female (99.6%); Asian (59.9%), White (27.3%), Black or African American (3.6%); Eastern Cooperative Oncology Group (ECOG) performance status 0 (62.8%) or 1 (36.8%); hormone receptor status (positive: 51.9%); presence of visceral disease (73.3%); presence of brain metastases at baseline (15.6%), and 48.3% of patients received one line of prior systemic therapy in the metastatic setting. The percentage of patients who had not received prior treatment for metastatic disease was 9.5%.
At the prespecified interim analysis for PFS (data cut-off 21 May 2021) based on 245 events (73% of total events planned for final analysis), the study demonstrated a statistically significant improvement in PFS per BICR in patients randomised to Enhertu compared to trastuzumab emtansine. The median PFS per BICR was not reached in the Enhertu arm and was 6.8 months in the trastuzumab emtansine comparator arm (HR=0.28; 95% CI: 0.22, 0.37). Overall survival (OS) was immature at the time of analysis and median OS was not reached. The median duration of follow-up was 16.2 months (range: 0.0 to 32.7) in the Enhertu arm and 15.3 months (range: 0.0 to 31.3) in the trastuzumab emtansine arm.
At the overall survival analysis (data cutoff 25 July 2022) the study also demonstrated statistically significant improvement in OS and median OS was not reached. An updated PFS per BICR was provided at the time of this OS analysis. The median duration of follow-up was 28.4 months (range: 0.0 to 46.9) in the Enhertu arm and 26.5 months (range: 0.0 to 45.0) in the trastuzumab emtansine arm.
Efficacy results are summarised in Table 12 and Figure 1 and Figure 2.
Similar PFS results were observed across prespecified subgroups including prior pertuzumab therapy, hormone receptor status, presence of brain metastases, and presence of visceral disease.

DESTINY-Breast02.

The efficacy and safety of Enhertu were evaluated in study DESTINY-Breast02, a Phase 3, randomised, multicentre, open-label, active-controlled study that enrolled patients with unresectable or metastatic HER2-positive breast cancer.
The study included adult patients with unresectable or metastatic HER2 positive breast cancer who were resistant or refractory to prior trastuzumab emtansine and had documented radiologic progression during or after their most recent treatment or within 6 months after completing adjuvant therapy. Archival breast tumour samples were required to show HER2 positivity defined as HER2 IHC 3+ or ISH positive. The study excluded patients with a history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening, patients with untreated and symptomatic brain metastases and patients with a history of clinically significant cardiac disease. Patients were randomised 2:1 to receive either Enhertu 5.4 mg/kg (N=406) by intravenous infusion every three weeks or treatment of physician's choice (N=202, trastuzumab plus capecitabine or lapatinib plus capecitabine). Randomisation was stratified by hormone receptor status, prior treatment with pertuzumab, and history of visceral disease. Treatment was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity.
The primary efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR) based on RECIST v1.1. Overall survival (OS) was a key secondary efficacy outcome measure. Confirmed objective response rate (ORR) was a secondary objective.
Demographic and baseline disease characteristics were similar between treatment arms. Of the 608 patients randomised, the median age was 54 years (range 22 to 88); female (99.2%); White (63.2%), Asian (29.3%), Black or African American (2.8%); ECOG performance status 0 (57.4%) or 1 (42.4%); hormone receptor status (positive: 58.6%); presence of visceral disease (78.3%); presence of brain metastases at baseline (18.1%), and 4.9% of patients received one line of prior systemic therapy in the metastatic setting.
The study demonstrated a statistically significant improvement in PFS per BICR and OS in patients randomised to Enhertu compared to treatment of physician's choice. The median duration of follow-up was 21.5 months (range: 0.1 to 45.6) in the Enhertu arm and 18.6 months (range: 0.0 to 45.7) in the TPC arm.
Efficacy results are summarized in Table 13, Figure 3 and Figure 4.
Similar PFS results were observed across prespecified subgroups including prior pertuzumab therapy, hormone receptor status, presence of visceral disease, and presence of brain metastases.

DESTINY-Breast01.

The efficacy and safety of Enhertu were demonstrated in a Phase 2, single-agent, open-label, multicentre study: DESTINY-Breast01.
The study included adult patients with unresectable or metastatic HER2-positive breast cancer who had received two or more prior anti-HER2 regimens, including trastuzumab emtansine (100%), trastuzumab (100%), and pertuzumab (65.8%). Archival breast tumour samples were required to show HER2 positivity defined as HER2 IHC 3+ or ISH-positive. The study excluded patients with a history of treated ILD or ILD at screening and patients with a history of clinically significant cardiac disease. Enhertu was administered by intravenous infusion at 5.4 mg/kg once every three weeks until disease progression, death, withdrawal of consent, or unacceptable toxicity. The primary efficacy outcome measure was confirmed objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) in the intent-to-treat (ITT) population as evaluated by independent central review. Duration of response (DOR) and progression-free survival (PFS) were additional outcome measures.
DESTINY-Breast01 (N = 184) baseline demographic and disease characteristics were: median age 55 years (range 28 to 96); female (100%); White (54.9%), Asian (38.0%), Black or African American (2.2%); Eastern Cooperative Oncology Group (ECOG) performance status 0 (55.4%) or 1 (44.0%); hormone receptor status (positive: 52.7%); presence of visceral disease (91.8%); median number of prior therapies in the metastatic setting: 5 (range: 2 to 17); prior pertuzumab therapy (65.8%); sum of diameters of target lesions (< 5 cm: 42.4%, ≥ 5 cm: 50.0%).
Efficacy results based on a data cut-off of 26 Mar 2021 with a median duration of follow-up of 26.5 months and median duration of treatment of 10.1 months are summarised in Table 14.
Consistent antitumor activity was observed with Enhertu regardless of prior pertuzumab therapy and hormone receptor status. In DESTINY-Breast01, the subgroup of patients who received prior pertuzumab therapy had a confirmed ORR of 66% (95% CI: 57, 75), and those who did not receive prior pertuzumab therapy had a confirmed ORR of 57% (95% CI: 43, 69). The subgroup of patients who were hormone receptor positive at baseline had a confirmed ORR of 60% (95% CI: 49, 70), and those who were hormone receptor negative at baseline had a confirmed ORR of 68% (95% CI: 56, 77).

DESTINY-Breast04.

The efficacy and safety of Enhertu were evaluated in study DESTINY-Breast04, a phase 3, randomised, multicentre, open label study that enrolled 557 adult patients with unresectable or metastatic HER2-low breast cancer. The study included 2 cohorts: 494 hormone receptor positive (HR+) patients and 63 hormone receptor negative (HR-) patients. HER2-low expression was defined as IHC 1+ or IHC 2+/ISH-negative, as determined by the PATHWAY/VENTANA anti-HER-2/neu (4B5) evaluated at a central laboratory. Patients must have received chemotherapy in the metastatic setting or have developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. Patients who were HR+ must have received at least one endocrine therapy or be ineligible for endocrine therapy. Patients were randomised 2:1 to receive either Enhertu 5.4 mg/kg (N=373) by intravenous infusion every three weeks or physician's choice of chemotherapy (N=184, eribulin 51.1%, capecitabine 20.1%, gemcitabine 10.3%, nab paclitaxel 10.3%, or paclitaxel 8.2%). Randomisation was stratified by HER2 IHC status of tumour samples (IHC 1+ or IHC 2+/ISH-negative), number of prior lines of chemotherapy in the metastatic setting (1 or 2), and HR status/prior CDK4/6i treatment (HR+ with prior CDK4/6 inhibitor treatment, HR+ without prior CDK4/6 inhibitor treatment, or HR-). Treatment was administered until disease progression, death, withdrawal of consent, or unacceptable toxicity. The study excluded patients with a history of ILD/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening and clinically significant cardiac disease. Patients were also excluded for untreated or symptomatic brain metastases or ECOG performance status > 1.
The primary efficacy outcome measure was PFS in patients with HR+ breast cancer assessed by BICR based on RECIST v1.1. Key secondary efficacy outcome measures were PFS assessed by BICR based on RECIST v1.1 in the overall population (all randomised HR+ and HR- patients), OS in HR+ patients, and OS in the overall population. ORR, DOR, and PROs were secondary endpoints.
Demographics and baseline tumour characteristics were similar between treatment arms. Of the 557 patients randomised, the median age was 56.5 years (range: 28.4 to 80.5); 23.5% were age 65 or older; 99.6% were female and 0.4% were male; 47.9% were White, 40.0% were Asian, and 1.8% were Black or African American. Patients had an ECOG performance status of 0 (54.8%) or 1 (45.2%) at baseline; 57.6% were IHC 1+, 42.4% were IHC 2+/ISH-negative; 69.8% had liver metastases, 32.9% had lung metastases, and 5.7% had brain metastases. In the metastatic setting, patients had a median of 3 prior lines of systemic therapy (range: 1 to 9) with 57.6% having 1 and 40.9% having 2 prior chemotherapy regimens; 3.9% were early progressors (progression in the neo/adjuvant setting). In HR+ patients, the median number of prior lines of endocrine therapy was 2 (range: 0 to 9) and 70% had prior CDK4/6i treatment.
The study demonstrated a statistically significant and clinically meaningful improvement in OS and PFS in patients randomised to Enhertu compared to chemotherapy in both the HR+ cohort and the overall population.
Efficacy results are summarised in Table 15 and Figure 5 and Figure 6.
Consistent OS and PFS benefit was observed across prespecified subgroups, including HR status, prior CDK4/6i treatment, number of prior chemotherapies, and IHC 1+ and IHC 2+/ISH-negative status. In the HR subgroup, median OS was 18.2 months (95% CI: 13.6, not estimable) in patients randomised to Enhertu compared to 8.3 months (95% CI: 5.6, 20.6) in patients randomised to chemotherapy with a hazard ratio of 0.48 (95% CI: 0.24, 0.95). Median PFS was 8.5 months (95% CI: 4.3, 11.7) in patients randomised to Enhertu and 2.9 months (95% CI: 1.4, 5.1) in patients randomised to chemotherapy with a hazard ratio of 0.46 (95% CI: 0.24, 0.89).
For HR+ patients receiving Enhertu, health-related quality-of-life was maintained throughout treatment, with the EORTC-QLQ-C30 Global Health status/QoL (primary PRO scale of interest) mean score remaining stable over time up to and including cycle 33.
In addition, the time to definitive deterioration (TTDD) in HR+ patients was longer in the Enhertu arm compared to the chemotherapy arm for all prespecified scales of the EORTC-QLQ-C30 (global health status, pain symptoms, physical functioning, emotional functioning, and social functioning), suggesting that Enhertu maintains quality of life longer than chemotherapy in patients with unresectable or metastatic HER2-low breast cancer. Of note, in the QLQ-C30 global health status scale, the median TTDD by at least 10 points in global health status/global QoL scale score was 7.6 months (95% CI: 5.8, 9.2) in the Enhertu arm versus 5.1 months (95% CI: 3.1, 6.9) in the chemotherapy arm (stratified hazard ratio: 0.71 [95% CI: 0.56, 0.92]). In the QLQ C30 pain symptom subscale, the median TTDD by at least 10 points in pain symptoms was 9.7 months (95% CI: 8.5, 11.1) in the Enhertu arm versus 4.4 months (95% CI: 2.8, 6.2) in the chemotherapy arm (stratified hazard ratio: 0.51 [95% CI: 0.39, 0.65]). These results are consistent with the primary result and confirm the QoL benefit of Enhertu versus chemotherapy for patients with metastatic HER2-low breast cancer.

5.2 Pharmacokinetic Properties

The pharmacokinetics of trastuzumab deruxtecan was evaluated in patients with cancer. At the recommended dosage of Enhertu, the geometric mean (coefficient of variation [CV]%) Cmax of trastuzumab deruxtecan and DXd were 133 microgram/mL (19%) and 4.7 nanogram/mL (43%), respectively, and the AUC of trastuzumab deruxtecan and DXd were 780 microgram.day/mL (27%) and 29 nanogram.day/mL (42%), respectively, based on population pharmacokinetic analysis.

Distribution.

Based on population pharmacokinetic analysis, the volume of distribution of the central compartment (Vc) of trastuzumab deruxtecan was estimated to be 2.68 L.
In vitro, the mean human plasma protein binding of the topoisomerase I inhibitor was approximately 97%.
In vitro, the blood to plasma concentration ratio of the topoisomerase I inhibitor was approximately 0.6.

Metabolism.

Trastuzumab deruxtecan undergoes intracellular cleavage by lysosomal enzymes to release the active topoisomerase I inhibitor.
The humanised HER2 IgG1 monoclonal antibody is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
In vitro metabolism studies in human liver microsomes indicate that the topoisomerase I inhibitor is metabolized mainly by CYP3A4 via oxidative pathways.

Excretion.

Based on population pharmacokinetic analysis, following intravenous administration of trastuzumab deruxtecan, the clearance of trastuzumab deruxtecan was estimated to be 0.4 L/day and the clearance of the topoisomerase I inhibitor was 18.4 L/h. The apparent elimination half-life (t1/2) of trastuzumab deruxtecan and released topoisomerase I inhibitor was approximately 5.7 days. Moderate accumulation (approximately 35% in cycle 3 compared to cycle 1) of trastuzumab deruxtecan was observed.
Following intravenous administration of the topoisomerase I inhibitor to rats, the major excretion pathway was faeces via the biliary route. The topoisomerase I inhibitor was the most abundant component in urine, faeces, and bile. Following single intravenous administration of trastuzumab deruxtecan (6.4 mg/kg) to monkeys, unchanged released topoisomerase I inhibitor was the most abundant component in urine and faeces.

Linearity/nonlinearity.

The exposure of trastuzumab deruxtecan and released topoisomerase I inhibitor when administered intravenously increased in proportion to dose in the 3.2 mg/kg to 8.0 mg/kg dose range (approximately 0.6 to 1.5 times the recommended dose) with low to moderate interindividual variability.

Specific populations.

Age, race, ethnicity, sex and body weight.

Based on population pharmacokinetic analysis, age (20-96 years), race, ethnicity, sex and body weight did not have a clinically meaningful effect on exposure of trastuzumab deruxtecan or released topoisomerase I inhibitor.

Renal impairment.

No dedicated renal impairment study was conducted. Based on population pharmacokinetic analysis including patients with mild (creatinine clearance [CLcr] ≥ 60 and < 90 mL/min) or moderate (CLcr ≥ 30 and < 60 mL/min) renal impairment (estimated by Cockcroft-Gault), the pharmacokinetics of the released topoisomerase I inhibitor was not affected by mild to moderate renal impairment as compared to normal renal function (CLcr ≥ 90 mL/min).

Hepatic impairment.

No dedicated hepatic impairment study was conducted. Based on population pharmacokinetic analysis, higher levels of AST and total bilirubin resulted in a lower clearance of topoisomerase I inhibitor. The impact of these changes is not expected to be clinically meaningful.

5.3 Preclinical Safety Data

Genotoxicity.

The topoisomerase I inhibitor component of trastuzumab deruxtecan was clastogenic in both an in vivo rat bone marrow micronucleus assay and an in vitro Chinese hamster lung chromosome aberration assay and was not mutagenic in an in vitro bacterial reverse mutation assay.

Carcinogenicity.

Carcinogenicity studies have not been conducted with trastuzumab deruxtecan.

6 Pharmaceutical Particulars

6.1 List of Excipients

Histidine, histidine hydrochloride monohydrate, sucrose, and polysorbate 80.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Sodium chloride solution for infusion must not be used for reconstitution or dilution since it may cause particulate formation.

6.3 Shelf Life

Unopened vial.

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.

Reconstituted solution.

It is recommended that the reconstituted solution be used immediately. If not used immediately, the reconstituted solution may be stored in a refrigerator at 2°C to 8°C for up to 24 hours from the time of reconstitution, protected from light.

Diluted solution.

It is recommended that the diluted solution be used immediately. If not used immediately, the diluted solution may be stored at room temperature for up to 4 hours or in a refrigerator at 2°C to 8°C for up to 24 hours, protected from light. These storage times start from the time of dilution.

6.4 Special Precautions for Storage

Store vials in a refrigerator (2°C to 8°C) until time of reconstitution.
Do not freeze.
For storage conditions after reconstitution and dilution of the medicinal product, see Section 6.3 Shelf Life.

6.5 Nature and Contents of Container

Enhertu is provided in 10 mL Type 1 amber borosilicate glass vial sealed with a fluoro-resin laminated butyl rubber stopper, and a polypropylene/aluminium yellow flip-off crimp cap.
Each carton contains 1 glass vial.

6.6 Special Precautions for Disposal

Product is for single use in one patient only. Discard any residue. In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Trastuzumab deruxtecan is an antibody-drug conjugate (ADC) composed of three components: 1) a humanised anti-HER2 IgG1 monoclonal antibody (mAb) with the same amino acid sequence as trastuzumab, covalently linked to 2) a topoisomerase I inhibitor, an exatecan derivative, via 3) a tetrapeptide-based cleavable linker. Deruxtecan is composed of the linker and the topoisomerase I inhibitor.
The antibody is produced in Chinese hamster ovary cells by recombinant DNA technology and the topoisomerase I inhibitor and linker are produced by chemical synthesis. Approximately 8 molecules of deruxtecan are attached to each antibody molecule.

Chemical structure.


CAS number.

1826843-81-5.

7 Medicine Schedule (Poisons Standard)

Prescription only medicine (Schedule 4).

Summary Table of Changes