Consumer medicine information

Padcev

Enfortumab vedotin

BRAND INFORMATION

Brand name

Padcev

Active ingredient

Enfortumab vedotin

Schedule

SUMMARY CMI

PADCEV^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about being given this medicine, speak to your doctor or pharmacist.

▼ This medicine is new. Please report side effects. See the full CMI for further details.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I being given PADCEV?

PADCEV contains the active ingredient enfortumab vedotin. PADCEV is used in adults to treat a kind of cancer called urothelial cancer (urothelial carcinoma). People get PADCEV when their cancer has spread or cannot be taken out by surgery.

For more information, see Section 1. Why am I being given PADCEV? in the full CMI.

2. What should I know before I am given PADCEV?

PADCEV should not be given if you have ever had an allergic reaction to enfortumab vedotin or any of the ingredients listed at the end of the CMI.

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. PADCEV should not be given to children and adolescents below 18 years of age.

For more information, see Section 2. What should I know before I am given PADCEV? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with PADCEV and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How am I given PADCEV?

Your doctor will give you PADCEV through an infusion (a drip) into a vein (intravenously) over 30 minutes.
You will get PADCEV once a week for 3 weeks in each 28 day period of treatment. Your doctor will decide how many treatments you need.

More instructions can be found in Section 4. How am I given PADCEV? in the full CMI.

5. What should I know while being given PADCEV?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are being given PADCEV. Tell your doctor if you have any symptoms of skin reactions, high blood sugar or diabetes, lung problems, nerve damage, or eye problems. Tell your doctor if you are taking any other medicines including but not limited to treatment for fungal infections (e.g., Ketoconazole). Additional medicines are listed in Section 3. What if I am taking other medicines? in the full CMI.
Things you should not do	It is very important that you do not miss a dose of this medicine (call your doctor if you cannot make it to your appointment to receive your next dose).
Driving or using machines	Be careful before you drive or use any machines or tools until you know how PADCEV affects you.
Looking after your medicine	You will not be asked to store PADCEV. It will usually be stored in the pharmacy or on the ward. Any unused portion of the solution will be disposed of by your doctor.

For more information, see Section 5. What should I know while being given PADCEV? in the full CMI.

6. Are there any side effects?

Some possible side effects may be serious, and can include skin reactions, high blood sugar levels, lung problems, nerve damage, and eye problems.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? 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.

WARNING:

SERIOUS SKIN REACTIONS

Tell your doctor right away if you have signs of a severe skin reaction: rash or itching that continues to get worse or comes back after treatment, skin blistering or peeling, painful sores or ulcers in mouth or nose, throat, or genital area, fever or flu-like symptoms or swollen lymph nodes.

FULL CMI

PADCEV^®

Active ingredient(s): enfortumab vedotin

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

1. Why am I being given PADCEV?
2. What should I know before I am given PADCEV?
3. What if I am taking other medicines?
4. How am I given PADCEV?
5. What should I know while being given PADCEV?
6. Are there any side effects?
7. Product details

1. Why am I being given PADCEV?

PADCEV contains the active ingredient enfortumab vedotin.

PADCEV is used in adults to treat urothelial carcinoma. PADCEV is given to people that have received an immunotherapy medicine and also received a platinum-containing chemotherapy medicine. People get PADCEV when their cancer has spread or cannot be taken out by surgery.

2. What should I know before I am given PADCEV?

Warnings

Do not use PADCEV if:

you are allergic to enfortumab vedotin, or any of the ingredients listed at the end of this leaflet.
always check the ingredients to make sure you can be given this medicine.

Check with your doctor if you:

have high blood sugar or diabetes
are currently experiencing numbness or tingling in your hands or feet
take any other medicines including but not limited to treatment for fungal infections (e.g., ketoconazole) as they can increase the amount of PADCEV in your blood. If you normally take these medicines, your doctor might change it and prescribe a different medicine for you during your treatment with PADCEV.

During treatment, you may be at risk of developing certain side effects. These side effects can sometimes become life-threatening and can lead to death. These side effects may happen anytime during treatment or even after your treatment has ended. You may experience more than one side effect at the same time.

It is important you understand these risks and how to monitor for them. See additional information under 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.

PADCEV may harm your unborn baby and should not be used during pregnancy.

If you are a woman starting PADCEV who is able to become pregnant, you should use effective contraception during treatment with PADCEV and for at least 7 months after stopping PADCEV.

If you are a man taking PADCEV whose partner is able to become pregnant, you should use effective contraception during treatment with PADCEV and for at least 6 months after stopping PADCEV.

It is not known if PADCEV passes into your breast milk and could harm your baby. You should not breastfeed during treatment with PADCEV and for at least 6 months after stopping PADCEV.

3.What if I am taking other medicines?

Tell your doctor or pharmacist 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.

Medicines that may interfere with the effect of PADCEV include but are not limited to medicines for treating:

bacterial infections (e.g., clarithromycin)
depression (e.g., nefazodone)
fungal infections (e.g., ketoconazole, voriconazole, posaconazole, itraconazole)
hepatitis C (e.g., boceprevir, telaprevir)
infections with the human immunodeficiency virus (HIV) (e.g., cobicistat, indinavir, nelfinavir, ritonavir, saquinavir).
epilepsy (e.g., carbamazepine, phenobarbital, phenytoin)
depression (e.g., escitalopram, fluoxetine, sertraline or the herbal medicine St. John's Wort (also known as Hypericum perforatum))
tuberculosis (e.g., rifampicin).

Do not take PADCEV with:

the supplement goldenseal (Hydrastis Canadensis).

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

4. How am I given PADCEV?

How much to take

PADCEV will be given to you by intravenous (IV) infusion into your vein over 30 minutes.

Your doctor will decide how much to use.

When to take PADCEV

You will receive your PADCEV over periods of time called cycles. Each PADCEV cycle is 28 days and you will receive PADCEV on days 1, 8 and 15 of every cycle.
Your doctor will decide how many treatment cycles you need.

If you forget to receive PADCEV

If you miss a dose, 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 are given too much PADCEV

As PADCEV is given to you under the supervision of your doctor, it is unlikely that you will be given too much. However, if you experience any side effects after being given PADCEV, tell your doctor immediately.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while being given PADCEV?

Things you should do

Call your doctor straight away if you:

have any of the following skin reaction symptoms: rash or itching that continues to get worse or comes back after treatment, skin blistering or peeling, painful sores or ulcers in mouth or nose, throat, or genital area, fever or flu-like symptoms or swollen lymph nodes. These may be signs of a severe skin reaction that can happen while receiving PADCEV, particularly during the first few weeks of your treatment. If it occurs, your doctor will monitor you and may give you a medicine to treat your condition. She or he may pause PADCEV treatment until symptoms are reduced. If your skin reaction worsens, your doctor may stop your PADCEV treatment.
have any symptoms of high blood sugar, including: frequent urination, increased thirst, blurred vision, confusion, drowsiness, loss of appetite, fruity smell on your breath, nausea, vomiting or stomach pain. You can develop high blood sugar during treatment with PADCEV.
have any symptoms of lung problems, including cough, shortness of breath or chest pain. If it occurs, your doctor may pause treatment until symptoms are improved or reduce your dose. If your symptoms worsen, your doctor may stop your treatment.
have any symptoms of nerve damage (neuropathy) such as numbness, tingling or a tingling sensation in your hands or feet or muscle weakness, burning, stabbing or shooting pain. If it occurs, your doctor may pause treatment until symptoms are improved or reduce your dose. If your symptoms worsen, your doctor may stop your PADCEV treatment.
have eye problems such as dry eyes during your treatment. You can develop certain eye problems while receiving PADCEV.

Remind any doctor, dentist or pharmacist you visit that you are being given PADCEV.

Driving or using machines

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

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

You will not be asked to store PADCEV. It will usually be stored in the fridge (at 2°C to 8°C) at the pharmacy or on the ward. Unused portion of the infusion solution will not be stored for reuse.

Getting rid of any unwanted medicine

Any unused medicine or waste material will be disposed of by your doctor in accordance with local requirements.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effects

What to do

Bleeding related:

low red blood cells (anaemia)
decreased white blood cell count

Stomach related:

nausea, diarrhoea and vomiting

General:

tiredness
abnormal walking (gait disturbance)
weight loss

Eating related:

decreased appetite
change in sense of taste

Eye related:

dry eye

Skin related:

hair loss

Liver related:

increased liver enzymes (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) (these are blood tests)

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Skin reactions:

Stevens-Johnson syndrome
toxic epidermal necrolysis
other severe rashes

Tell your doctor right away if you have any of these signs of a severe skin reaction:

rash or itching that continues to get worse or comes back after treatment
skin blistering or peeling
painful sores or ulcers in mouth or nose, throat, or genital area
fever or flu-like symptoms
swollen lymph nodes
(frequency not known).

High blood sugar (hyperglycaemia):

Tell your doctor right away if you have any symptoms of high blood sugar, including:

frequent urination
increased thirst
blurred vision
confusion
drowsiness
loss of appetite
fruity smell on your breath
nausea
vomiting
stomach pain

(may affect up to 1 in 10 people).

Respiratory symptoms and lung problems (lung inflammation):

cough
shortness of breath
chest pain

(frequency not known)

Nerve damage (peripheral neuropathy):

Tell your doctor right away if you get:

numbness
tingling or a tingling sensation in your hands or feet
muscle weakness,
burning, stabbing or shooting pain

(may affect up to 1 in 100 people).

Leakage of PADCEV out of your vein into the tissues around your infusion site (extravasation):

Tell your doctor or get medical help right away if you notice:

any redness, swelling, itching, or discomfort at the infusion site.

If PADCEV leaks from the injection site or the vein into the nearby skin and tissues, it could cause an infusion site reaction. These reactions can happen right after you receive an infusion, but sometimes may happen days after your infusion (may affect up to 1 in 100 people).

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist 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 or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What PADCEV contains

Active ingredient (main ingredient)	enfortumab vedotin
Other ingredients (inactive ingredients)	histidine, histidine hydrochloride monohydrate, trehalose dihydrate, and polysorbate 20

Do not take this medicine if you are allergic to any of these ingredients.

What PADCEV looks like

PADCEV 20 mg is a white to off-white powder for injection in a vial. (Aust R 355870).

PADCEV 30 mg is a white to off-white powder for injection in a vial. (Aust R 367410).

Who distributes PADCEV

Astellas Pharma Australia Pty Ltd
Suite 2.01, 2 Banfield Road
Macquarie Park NSW 2113
Tel: 1800 751 755 (Medical Information)
Email: [email protected] (Medical Information)
Website: www.astellas.com/au

This leaflet was prepared in May 2023.

Published by MIMS November 2023

BRAND INFORMATION

Brand name

Padcev

Active ingredient

Enfortumab vedotin

Schedule

1 Name of Medicine

Enfortumab vedotin.

2 Qualitative and Quantitative Composition

Each vial of powder for concentrate for infusion contains either 20 mg or 30 mg enfortumab vedotin. After reconstitution, each mL contains 10 mg of enfortumab vedotin.
Enfortumab vedotin is a Nectin-4 targeted antibody drug conjugate (ADC) comprised of a fully human IgG1 kappa antibody, conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable vc maleimidocaproyl linker.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection vial. White to off-white lyophilized powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Padcev as monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a platinum-containing chemotherapy and a programmed death receptor-1 or programmed death-ligand-1 inhibitor.

4.2 Dose and Method of Administration

General.

Prior to administration, the Padcev vial is reconstituted with Sterile Water for Injection (SWFI). The reconstituted solution is transferred to an intravenous infusion bag containing either sterile 5% Dextrose Injection, sterile 0.9% Sodium Chloride Injection or sterile Lactated Ringer's Injection for administration.
Product is for single use in one patient only. Discard any residue.
Treatment with Padcev should be initiated and supervised by a physician experienced in the use of anti-cancer therapies.

Dosage.

The recommended dose of Padcev is 1.25 mg/kg (up to a maximum of 125 mg for patients ≥ 100 kg) administered as an intravenous infusion over 30 minutes on days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. (See Table 1).

Dose modifications.

See Table 2.

Elderly.

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

Children.

The safety and efficacy of Padcev in pediatric patients have not been established.

Patients with renal impairment.

No dose adjustment is necessary in patients with mild [creatinine clearance (CrCL) > 60-90 mL/min], moderate (CrCL 30-60 mL/min) or severe (CrCL 15-< 30 mL/min) renal impairment. Padcev has not been evaluated in patients with end stage renal disease (see Section 5.2 Pharmacokinetic Properties).

Patients with hepatic impairment.

No dose adjustment is required in patients with mild hepatic impairment. Padcev has only been evaluated in a limited number of patients with moderate hepatic impairment and has not been evaluated in patients with severe hepatic impairment. As there is limited to no data available, use Padcev with caution in patients with moderate or severe hepatic impairment (total bilirubin > 1.5 x ULN and AST of any level) (see Section 5.2 Pharmacokinetic Properties).

Method of administration.

Reconstitution in single-dose vial.

1. Follow procedures for proper handling and disposal of anticancer drugs.
2. Use appropriate aseptic technique for reconstitution and preparation of dosing solutions.
3. Calculate the recommended dose based on the patient's weight to determine the number and strength (20 mg or 30 mg) of vials needed.
4. Reconstitute each vial as follows and, if possible, direct the stream of SWFI along the walls of the vial and not directly onto the lyophilized powder:
a. 20 mg vial: Add 2.3 mL of SWFI, resulting in 10 mg/mL Padcev.
b. 30 mg vial: Add 3.3 mL of SWFI, resulting in 10 mg/mL Padcev.
5. Slowly swirl each vial until the contents are completely dissolved. Allow the reconstituted vial(s) to settle for at least 1 minute until the bubbles are gone. Do not shake the vial.
6. Visually inspect the solution for particulate matter and discoloration. The reconstituted solution should be clear to slightly opalescent, colorless to light yellow and free of visible particles. Discard any vial with visible particles or discoloration.
7. Based upon the calculated dose amount, the reconstituted solution from the vial(s) should be added to the infusion bag immediately. This product does not contain a preservative. If not used immediately, reconstituted vials may be stored for up to 24 hours in refrigeration at 2°C to 8°C. Do not freeze. Discard unused vials with reconstituted solution beyond the recommended storage time.

Dilution in infusion bag.

8. Withdraw the calculated dose amount of reconstituted solution from the vial(s) and transfer into an infusion bag.
9. Dilute Padcev with either 5% Dextrose Injection, 0.9% Sodium Chloride Injection or Lactated Ringer's Injection. The infusion bag size should allow enough diluent to achieve a final concentration of 0.3 mg/mL to 4 mg/mL Padcev.
10. Mix diluted solution by gentle inversion. Do not shake the bag.
11. Visually inspect the infusion bag for any particulate matter or discoloration prior to use. The reconstituted solution should be clear to slightly opalescent, colorless to light yellow and free of visible particles. Do not use the infusion bag if particulate matter or discoloration is observed.
12. Discard any unused portion left in the single-dose vials.
13. The prepared infusion bag should not be stored longer than 16 hours under refrigeration at 2°C to 8°C including infusion time. Do not freeze.

Administration.

14. Administer the infusion over 30 minutes through an intravenous line. Do not administer as an IV push or bolus.
15. Do not co-administer other drugs through the same infusion line.

4.3 Contraindications

Padcev is contraindicated in patients with known hypersensitivity to enfortumab vedotin or to any of the excipients in the formulation (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Skin reactions.

Skin reactions are anticipated on-target events, as Nectin-4 is expressed in the skin.
Skin reactions, predominantly mild to moderate rash maculopapular, have occurred with Padcev. Severe cutaneous adverse reactions, including SJS and TEN, with fatal outcome have also occurred in patients treated with Padcev, predominantly during the first cycle of treatment.
Starting with the first cycle and throughout treatment, monitor patients for skin reactions. Consider appropriate treatment such as topical corticosteroids and antihistamines for mild to moderate skin reactions. For Grade 2 worsening skin reactions, consider withholding Padcev until toxicity is Grade ≤ 1. For severe (Grade 3) skin reactions, suspected SJS or TEN, withhold Padcev and consider referral for specialized care. Permanently discontinue Padcev for confirmed SJS or TEN; Grade 4 or recurrent Grade 3 skin reactions (see Section 4.2 Dose and Method of Administration).

Hyperglycaemia.

Hyperglycaemia and diabetic ketoacidosis (DKA) including fatal events, occurred in patients with and without pre-existing diabetes mellitus, treated with Padcev. Hyperglycaemia occurred more frequently in patients with pre-existing hyperglycaemia or a high body mass index (≥ 30 kg/m²) (see Section 4.8 Adverse Effects (Undesirable Effects)). Blood glucose levels should be monitored regularly in patients with or at risk for diabetes mellitus or hyperglycaemia. If blood glucose is elevated (> 13.9 mmol/L; > 250 mg/dL), withhold Padcev (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties).

Pneumonitis/interstitial lung disease.

Severe, life-threatening or fatal pneumonitis occurred in patients treated with Padcev. In clinical trials, 3.1% of the 680 patients treated with Padcev had pneumonitis of any grade and 0.7% had Grade 3-4. In clinical trials, the median time to onset of pneumonitis was 2.9 months (range: 0.6 to 6 months). Two patients (0.3%) on trial also experienced fatal events. Monitor patients for signs and symptoms indicative of pneumonitis/interstitial lung disease such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations. Withhold Padcev for patients who develop Grade 2 pneumonitis/interstitial lung disease and consider dose reduction. Permanently discontinue Padcev in all patients with Grade 3 or 4 pneumonitis/interstitial lung disease (see Section 4.2 Dose and Method of Administration).

Peripheral neuropathy.

Peripheral neuropathy, predominantly sensory, has occurred with Padcev, including Grade ≥ 3 reactions. Monitor patients for symptoms of new or worsening peripheral neuropathy as these patients may require a delay, dose reduction or discontinuation of Padcev (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties).

Ocular disorders.

Ocular disorders, predominantly dry eye, occurred in patients treated with Padcev. Severe (Grade 3) ocular disorders only occurred in 3 patients (0.4%).
Monitor patients for ocular disorders such as dry eye. Consider artificial tears for prophylaxis of dry eye and refer patient for ophthalmologic evaluation if ocular symptoms do not resolve or worsen.

Infusion site extravasation.

Skin and soft tissue injury following Padcev administration has been observed when extravasation occurred. Ensure good venous access prior to starting Padcev and monitor for possible infusion site extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.

Use in hepatic impairment.

Based on population pharmacokinetics analysis using data from clinical studies in patients with metastatic UC, there was no significant differences in enfortumab vedotin exposure and a 37% increase in MMAE AUC were observed in patients with mild hepatic impairment (total bilirubin 1 to 1.5 x ULN and AST of any level, or total bilirubin ≤ ULN and AST > ULN, n=65) compared to patients with normal hepatic function. As Padcev has only been studied in a limited number of patients with moderate hepatic impairment (n=3) and has not been evaluated in patients with severe hepatic impairment (total bilirubin > 1.5 x ULN and AST of any level), use Padcev with caution in these patients.

Use in renal impairment.

No significant differences in the safety and efficacy of Padcev in patients with mild (creatinine clearance; CrCL > 60-90 mL/min), moderate (CrCL 30-60 mL/min) and severe (CrCL 15-< 30 mL/min) renal impairment were observed. Enfortumab vedotin has not been evaluated in patients with end stage renal disease (CrCL < 15 mL/min) (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Pharmacokinetic characteristics in special populations).

Embryofetal toxicity and contraception.

Pregnant women should be informed of the potential risk to a fetus (see Section 4.6 Fertility, Pregnancy and Lactation). Females of reproductive potential should be advised to have a pregnancy test within 7 days prior to starting treatment with Padcev, to use effective contraception during treatment and for at least 7 months after stopping treatment. Males with female partners of reproductive potential should be advised to use effective contraception during treatment and for at least 6 months after the last dose of Padcev.

Use in the elderly.

No overall differences in safety or efficacy were observed between patients ≥ 65 years of age and younger patients (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties, Pharmacokinetic characteristics in special populations).

Paediatric use.

There is no relevant use of enfortumab vedotin in the paediatric population for the indication of LA or mUC.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Formal drug-drug interaction studies with enfortumab vedotin have not been conducted. To evaluate the drug-drug interaction potential of unconjugated MMAE, physiologically based pharmacokinetic (PBPK) modeling was conducted to predict the drug-drug interaction potential of enfortumab vedotin following co-administration with other drugs.

Effects of other medicines on Padcev.

Drug interactions with co-medications that are CYP3A4 inhibitors.

Concomitant use of enfortumab vedotin with ketoconazole (a combined P-gp and strong CYP3A inhibitor) is predicted to increase unconjugated MMAE C_max by 15% and AUC by 38%, with no change in ADC exposure. Closely monitor for adverse reactions when Padcev is given concomitantly with strong CYP3A4 inhibitors (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetic characteristics in special populations).

Co-administration with other CYP substrates.

In vitro studies indicated that clinical drug-drug interactions are unlikely to occur as a result of MMAE-mediated inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2D6. Unconjugated MMAE does not induce CYP1A2, CYP2B6 or CYP3A4/5.

Co-administration with drugs that are substrates of transporters.

In vitro data indicate that unconjugated MMAE is a P-gp substrate but does not inhibit P-gp at clinically relevant concentrations. Unconjugated MMAE was not a substrate or inhibitor for the BCRP, MRP2, OATP1B1, OATP1B3, OAT1, OCT2 or OAT3 transporters. Unconjugated MMAE was also not an inhibitor of BSEP or OCT1.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of Padcev on human male and female fertility have not been studied. MMAE, the cytotoxic moiety of enfortumab vedotin, acts via an aneugenic mechanism and may affect fertility. Results from a repeat-dose toxicity study in rats indicate the potential for enfortumab vedotin to impair male reproductive function and fertility.
In rats given weekly IV doses of ≥ 2 mg/kg enfortumab vedotin resulting in systemic exposures below the clinical exposure levels at the recommended clinical dose resulted in dose dependent testicular seminiferous tubule degeneration with abnormal lumen contents and hypospermia. These findings were partially reversed following a 24-week treatment-free period. Repeat dose studies in female rats at IV doses ≤ 5 mg/kg enfortumab vedotin (resulting in subclinical exposures) showed no histological abnormalities in female reproductive organs however, dedicated fertility studies have not been conducted. Therefore, men being treated with Padcev are advised to have sperm samples frozen and stored before treatment. Men being treated with Padcev are advised to use effective contraception during treatment with Padcev and not to father a child during treatment and for up to 6 months following the last dose. Effects on spermatogenesis cannot be excluded after a 6-month treatment-free period.
(Category D)
There are no adequate or well-controlled studies with Padcev in pregnant women. However, based on its mechanism of action and findings in animals, Padcev can cause fetal harm when administered to a pregnant woman. Padcev is contraindicated in pregnancy. MMAE, the main cytotoxic moiety of enfortumab vedotin, was shown to cross the placenta in rats. In pregnant rats, administration of MMAE (0.2 mg/kg IV) or enfortumab vedotin (2.5 mg/kg IV) during the period of organogenesis, caused embryofetal lethality and toxicity and included an increased incidence of resorptions, pre- and post-implantation loss, and decreased litter size. There was also a reduction in mean fetal weight and an increased incidence of fetal malformations (protruding tongue, malrotated hindlimbs, gastroschisis, agnathia, situs inversus, and malformed mandible, misaligned, fused and/or absent caudal vertebrae, split vertebrae, and shortened long bone, malrotated hindlimb, absent 4th digit of the forepaw asymmetric, fused, incompletely ossified and misshapen sternebrae, misshapen cervical arch and unilateral ossification of the thoracic centra). These adverse embryofetal development effects occurred at exposures less than that expected in patients receiving enfortumab vedotin. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Padcev. Consider obtaining a pregnancy test in females of childbearing potential within 7 days prior to initiating treatment with Padcev. Advise females of reproductive potential to use effective contraception during treatment with Padcev and for at least 7 months after the last dose. Padcev should not be used during pregnancy unless the benefit to the mother outweighs the potential risks to the fetus. If Padcev is used during pregnancy or if the patient becomes pregnant while receiving Padcev, the patient should be clearly advised on the potential risk to the fetus. See Effects on fertility section pertaining to advice for women whose male partners are being treated with Padcev.
It is unknown whether enfortumab vedotin or the cytotoxic moiety, MMAE, are excreted in human milk. No studies have been conducted to assess the impact of Padcev on milk production or its presence in breast milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in breastfeeding infants due to Padcev, a risk to breast-fed children cannot be excluded. Breastfeeding should be discontinued during Padcev treatment and for at least 6 months after the last dose.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

The safety of Padcev was evaluated as monotherapy in 680 patients who received at least one dose of Padcev 1.25 mg/kg in two phase 1 studies (EV-101 and EV-102), one phase 2 study (EV-201) and one phase 3 study (EV-301).
Serious adverse events occurred in 45% of patients. The most common serious adverse reactions (≥ 2%) were diarrhoea (2%) and hyperglycaemia (2%). Nineteen percent of patients permanently discontinued Padcev for adverse events; the most common adverse reaction (≥ 2%) leading to dose discontinuation was peripheral sensory neuropathy (4%). Adverse events leading to dose interruption occurred in 62% of patients; the most common adverse reactions (≥ 2%) leading to dose interruption were peripheral sensory neuropathy (15%), fatigue (7%), rash maculo-papular (4%), aspartate aminotransferase increased (4%), alanine aminotransferase increased (4%), anemia (3%), diarrhoea (3%) and hyperglycaemia (3%). Thirty five percent of patients required a dose reduction due to an adverse event; the most common adverse reactions (≥ 2%) leading to a dose reduction were peripheral sensory neuropathy (10%), fatigue (5%), rash maculo-papular (4%) and decreased appetite (2%).

Tabulated summary of adverse reactions.

Adverse reactions observed during clinical studies are listed in this section by frequency category. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). See Table 3.

Clinically relevant adverse reactions (< 10%) and frequencies of patients who received Padcev included:

Blood and lymphatic system disorders.

Not known: Neutropenia^*, febrile neutropenia^*, neutrophil count decreased^*.

General disorders and administration site conditions.

Common: Infusion site extravasation.

Nervous system disorders.

Common: Gait disturbance, hypoaesthesia, neuropathy peripheral, muscular weakness, paraesthesia, peripheral motor neuropathy, peripheral sensorimotor neuropathy.
Uncommon: Burning sensation, demyelinating polyneuropathy, dysaesthesia, motor dysfunction, muscle atrophy, neuralgia, neurotoxicity, peroneal nerve palsy, polyneuropathy, skin burning sensation, sensory loss.

Respiratory, thoracic, and mediastinal disorders.

Not known: Pneumonitis^*, interstitial lung disease^*.

Skin and subcutaneous tissue disorders.

Common: Blister, conjunctivitis, drug eruption, erythaema, eczema, dermatitis bullous, palmar-plantar erythrodysesthesia syndrome, rash erythaematous, rash macular, rash papular, rash pruritic, rash vesicular, skin exfoliation, stomatitis.
Uncommon: Blood blister, dermatitis, dermatitis allergic, dermatitis contact, dermatitis exfoliative generalised, erythaema multiforme, exfoliative rash, intertrigo, pemphigoid, rash maculovesicular, skin irritation, stasis dermatitis.
Not known: Epidermal necrosis^*, Stevens-Johnson syndrome^*, symmetrical drug-related intertriginous and flexural exanthaema^*, toxic epidermal necrolysis^*.
^*Adverse reactions of an unknown frequency have been identified during post approval use of enfortumab vedotin. Because these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Description of selected adverse reactions.

Skin reactions.

In clinical studies, skin reactions occurred in 55% (375) of the 680 patients treated with Padcev 1.25 mg/kg. Severe (Grade 3 or 4) skin reactions occurred in 13% (85) of patients and a majority of these reactions included rash maculo-papular, rash erythematous, rash or drug eruption. The median time to onset of severe skin reactions was 0.62 months (range: 0.1 to 6.4).
In the EV-201 (n=214) clinical study, of the patients who experienced skin reactions, 75% had complete resolution and 14% had partial improvement (see Section 4.4 Special Warnings and Precautions for Use).

Hyperglycaemia.

In clinical studies, hyperglycaemia occurred in 14% (98) of the 680 patients treated with Padcev 1.25 mg/kg. Seven percent of patients who received Padcev 1.25 mg/kg developed severe (Grade 3-4) hyperglycaemia. Two patients experienced fatal events, one event each of hyperglycaemia and diabetic ketoacidosis. The incidence of Grade 3-4 hyperglycaemia increased consistently in patients with higher body mass index and in patients with higher baseline haemoglobin A1C. The median time to onset of hyperglycaemia was 0.6 months (range: 0.1 to 20.3). Patients with baseline haemoglobin A1C ≥ 8% were excluded from clinical studies.
In the EV-201 (n=214) clinical study, at the time of their last evaluation, 61% of patients had complete resolution, and 19% of patients had partial improvement (see Section 4.4 Special Warnings and Precautions for Use).

Pneumonitis/interstitial lung disease.

In clinical studies, pneumonitis occurred in 15 (2.2%) and interstitial lung disease occurred in 2 (0.3%) of the 680 patients treated with Padcev 1.25 mg/kg. Less than 1% of patients experienced severe (Grade 3-4) pneumonitis or interstitial lung disease.

Peripheral neuropathy.

In clinical studies peripheral neuropathy occurred in 52% (352) of the 680 patients treated with Padcev 1.25 mg/kg. Four percent of patients experienced severe (Grade 3-4) peripheral neuropathy including sensory and motor events. The median time to onset of Grade ≥ 2 was 4.6 months (range: 0.1 to 15.8). Patients with pre-existing peripheral neuropathy Grade ≥ 2 were excluded from clinical studies.
In the EV-201 (n=214) clinical study, at the time of their last evaluation, 19% of patients had complete resolution, and 39% of patients had partial improvement (see Section 4.4 Special Warnings and Precautions for Use).

Ocular disorders.

In clinical studies, 14 (2.1%) patients interrupted, and 1 (0.1%) patient permanently discontinued treatment for ocular disorders. Severe (Grade 3) ocular disorders only occurred in 3 patients (0.4%). Thirteen percent of patients experienced dry eye symptoms during treatment with Padcev 1.25 mg/kg and the median time to onset was 1.7 months (range: 0 to 19.1) (see Section 4.4 Special Warnings and Precautions for Use).

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 known antidote for overdosage with Padcev. In case of overdosage, the patient should be closely monitored for adverse reactions, and supportive treatment should be administered as appropriate taking into consideration the half-life of 3.6 days (ADC) and 2.6 days (MMAE).
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

The clinical pharmacology of enfortumab vedotin was evaluated in patients with solid tumours who received enfortumab vedotin administered by intravenous infusion.

Pharmacodynamic effects.

In an exposure-response analysis, a higher exposure was associated with higher incidence of some adverse reactions (e.g. Grade ≥ 2 peripheral neuropathy, Grade ≥ 3 hyperglycaemia).

Cardiac electrophysiology.

The effect of Padcev on the duration of cardiac ventricular repolarization was evaluated in 17 patients with LA or metastatic urothelial carcinoma who received Padcev on Days 1, 8, and 15 of each 28-day cycle. Based on concentration - QTcF modeling, a population mean change in QTcF interval (change from baseline QTcF; upper 1-sided 95% CI) of 6.17 (10.5) msec was estimated to occur at a geometric mean C_max of 20.1 mcg/mL for the ADC. For MMAE, a population mean change in QTcF interval (upper 1-sided 95% CI) of -3.14 (9.52) msec was estimated to occur at a geometric mean C_max of 3.94 nanogram/mL. At the recommended dose of 1.25 mg/kg, Padcev had no large effect on QTc prolongation (> 20 msec).

Mechanism of action.

Enfortumab vedotin is an ADC targeting Nectin-4, an adhesion protein located on the surface of epithelial cells including urothelial cancer cells. It is comprised of a fully human IgG1-kappa antibody conjugated to the microtubule-disrupting agent, MMAE, via a protease-cleavable linker. Nonclinical data suggest that the anticancer activity of enfortumab vedotin is due to the binding of the ADC to Nectin-4-expressing cells, followed by internalisation of the ADC-Nectin-4 complex, and the release of MMAE via proteolytic cleavage. Release of MMAE disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptosis, and immunogenic cell death. MMAE released from enfortumab vedotin targeted cells can diffuse into nearby Nectin-4 low-expressing cells resulting in cytotoxic cell death.

Clinical studies.

Metastatic urothelial cancer.

EV-301.

The efficacy of enfortumab vedotin was evaluated in study EV-301, an open-label, randomized, phase 3, multicentre study that enrolled 608 patients with LA or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and a platinum containing chemotherapy. Patients were randomized 1:1 to receive either Padcev 1.25 mg/kg on Days 1, 8 and 15 of a 28-day cycle or one of the following chemotherapies as decided by the investigator: docetaxel (38%), paclitaxel (36%), or vinflunine (26%).
Patients were excluded from the study if they had active CNS metastases, ongoing sensory or motor neuropathy Grade ≥ 2, or uncontrolled diabetes defined as haemoglobin A1C (HbA1c) ≥ 8% or HbA1c ≥ 7% with associated diabetes symptoms.
The median age was 68 years (range: 30 to 88 years), 77% were male, and most patients were White (52%) or Asian (33%). All patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (40%) or 1 (60%). Eighty percent of patients had visceral metastases including 31% with liver metastases. Seventy-six percent of patients had urothelial carcinoma/transitional cell carcinoma (TCC) histology and 14% had urothelial carcinoma mixed. A total of 527 out of 608 subjects had evaluable Nectin-4 results; of these 527 subjects, 516 (98%) had detectable Nectin-4 (H-score > 0) as assessed by a validated immunohistochemistry (IHC) assay. A total of 76 (13%) of patients received ≥ 3 lines of prior systemic therapy. Fifty-two percent (314) of patients received prior PD-1 inhibitor, 47% (284) received prior PD-L1 inhibitor, and an additional 1% (9) patients received both PD-1 and PD-L1 inhibitors. Sixty-nine percent of patients did not respond to prior therapy with a PD-1 or PD-L1 inhibitor. Sixty-three percent (383) of patients received prior cisplatin-based regimens, 26% (159) received prior carboplatin-based regimens, and an additional 11% (65) received both cisplatin and carboplatin-based regimens.
The study demonstrated statistically significant improvements in Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR) for patients randomized to Padcev as compared to chemotherapy (PFS and ORR were evaluated by investigator assessment using RECIST v1.1). The median follow-up time for this study was 11.1 months (95% CI: 10.6 to 11.6). Patients randomized to the Padcev arm had a statistically significant improvement in OS compared to the chemotherapy arm with a median OS of 12.9 months versus 9 months, respectively (HR=0.702; 95% CI: 0.556, 0.886; 1-sided p-value: 0.00142). Patients randomized to receive Padcev experienced longer PFS compared to those randomized to receive chemotherapy with a median PFS of 5.6 months versus 3.7 months, respectively (HR=0.615; 95% CI: 0.505, 0.748; 1-sided p-value: ˂ 0.00001). Among the 288 patients randomized to receive Padcev with measurable disease at baseline, the ORR was 40.6% (117/288) (95% CI: 34.90, 46.54) compared with chemotherapy with an ORR of 17.9% (53/296) (95% CI: 13.71, 22.76). The median time to response in the Padcev arm was 1.87 months (95% CI: 1.1 to 5.7). Efficacy results were consistent across patient subgroups including age, geographic region, baseline ECOG PS, liver metastasis, preselected control therapy, primary site of tumour, prior lines of therapy in LA or metastatic setting and best response to prior PD1 or PD-L1.
Table 4 and Figures 1 and 2 summarize the efficacy results for EV-301.

Patient-reported quality of life (QoL) was assessed using the EORTC QLQ-C30. Over the first 12 weeks of treatment, patients treated with Padcev maintained overall quality of life compared with baseline and had less variability compared to chemotherapy. Further, patients treated with Padcev had statistically significant improvements in pain compared to chemotherapy, with an average difference in change from baseline of -5.73 (2-sided p < 0.05) at week 12. Fifty-two percent of patients treated with Padcev and 29% of patients treated with chemotherapy achieved a clinically meaningful confirmed improvement in pain (odds ratio [95% CI]: 2.76, [1.81; 4.22]) over the study period. These results should be interpreted in the context of the open-label study design with no adjustment for multiplicity.

5.2 Pharmacokinetic Properties

Distribution.

The mean estimate of steady state volume of distribution of ADC was 12.8 L following 1.25 mg/kg of enfortumab vedotin. In vitro, the binding of unconjugated MMAE to human plasma proteins ranged from 68% to 82%. Unconjugated MMAE is not likely to displace or to be displaced by highly protein-bound drugs. Unconjugated MMAE does not significantly partition into human red blood cells in vitro; the ratio of amount in blood to amount in plasma concentration is 0.926 to 0.976.

Metabolism.

Enfortumab vedotin is expected undergo catabolism in patients, resulting in the production of small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE related catabolites. In vitro data indicate that the metabolism of unconjugated MMAE occurs primarily via oxidation by CYP3A4.

Excretion.

The excretion of unconjugated MMAE occurs mainly in faeces with a smaller proportion in urine. After a single dose of another ADC that contained unconjugated MMAE, approximately 24% of the total unconjugated MMAE administered was recovered in faeces and urine as unchanged MMAE over a 1-week period. The majority of recovered unconjugated MMAE was excreted in faeces (72%). A similar excretion profile is expected for unconjugated MMAE after enfortumab vedotin administration.

Immunogenicity.

A total of 590 patients were tested for immunogenicity to Padcev 1.25 mg/kg; 15 patients were confirmed to be positive at baseline for anti-therapeutic antibody (ATA), and in patients that were negative at baseline (n=575), a total of 16 (2.8%) were positive postbaseline (13 transiently and 3 persistently). Due to the limited number of patients with antibodies against Padcev, no conclusions can be drawn concerning a potential effect of immunogenicity on efficacy or safety.