Padcev

Package leaflet: Information for the patient

Padcev 20 mg powder for concentrate for solution for infusion, 30 mg powder for concentrate for solution for infusion

enfortumab vedotin
This medicinal product is subject to additional monitoring. This will allow for rapid identification of new safety information. You can help by reporting any side effects you experience while taking this medicine. See the end of section 4 for information on how to report side effects.
Please read this leaflet carefully before you are given this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor.
• If you experience any side effect, including those not listed in this leaflet, talk to your doctor. See section 4.

Contents of this leaflet

1. What Padcev is and what it is used for
2. What you need to know before you are given Padcev
3. How to use Padcev
4. Possible side effects
5. How to store Padcev
6. Contents of the pack and other information

1. What Padcev is and what it is used for

Padcev contains the active substance enfortumab vedotin, which consists of a monoclonal antibody linked to a cytotoxic agent designed to destroy cancer cells. The monoclonal antibody recognizes specific cancer cells and releases the cytotoxic agent inside these cells.
This medicine is used alone or in combination with pembrolizumab in adults to treat a type of cancer called bladder cancer (urothelial cancer). Padcev is given to patients when their cancer has spread or cannot be surgically removed.
When used alone, Padcev is administered to patients who have already been treated with an immunotherapeutic medicine and also with a platinum-containing chemotherapy regimen.
This medicine may be given in combination with pembrolizumab. It is important that you also read the package leaflet for this other medicine. If you have any doubts, consult your doctor.

2. What you need to know before you are given Padcev

Do not receive Padcev

• if you are allergic to enfortumab vedotin or to any of the other ingredients of this medicine (listed in section 6). Warnings and precautions Contact your doctor immediately if:
• you experience any of the following symptoms of a skin reaction:
  • rash or itching that continues to worsen or reappears after treatment,
  • blistering or peeling of the skin,
• painful sores or ulcers in your mouth, nose, throat, or genital area,
• fever or flu-like symptoms,
• or swollen lymph nodes.

These could be signs of a severe skin reaction, which may occur during treatment with this medicine, particularly during the first few weeks of treatment. Skin reactions may occur more frequently when this medicine is administered together with pembrolizumab. In such cases, your doctor will monitor you and may give you a medicine to treat the skin condition. Your doctor may also suspend treatment until symptoms improve. If the skin reaction worsens, your doctor may discontinue treatment.
You will also find this information in the Patient Medication Guide included in the package. It is important that you carry this Patient Medication Guide with you and show it to every healthcare provider you see.

• you experience any symptoms of high blood sugar, including frequent urination, increased thirst, blurred vision, confusion, drowsiness, loss of appetite, breath with a fruity odour, nausea, vomiting, or stomach pain. During treatment, you may develop high blood sugar.
• you have lung problems (pneumonitis/interstitial lung disease) or if symptoms develop or worsen, including difficulty breathing, shortness of breath, or cough. These lung problems may occur more frequently when this medicine is administered together with pembrolizumab. In such cases, your doctor may suspend treatment until symptoms improve or reduce the dose. If symptoms worsen, your doctor may discontinue treatment.
• you have, or think you may have, an infection. Some infections may be serious and could be life-threatening.
• you experience any symptoms of nerve problems (neuropathy), such as numbness, tingling, or a pins-and-needles sensation in your hands or feet, or muscle weakness. In such cases, your doctor may suspend treatment until symptoms improve or reduce the dose. If symptoms worsen, your doctor may discontinue treatment.
• you develop eye problems, such as dry eyes, during treatment. You may develop dry eye problems during treatment with Padcev.

Children and adolescents
This medicine must not be used in children and adolescents under 18 years of age.
Other medicines and Padcev
Inform your doctor if you are taking, have recently taken, or might take any other medicines.
Inform your doctor if you are taking medicines for fungal infections (e.g. ketoconazole) as they may increase the amount of Padcev in your blood. If you regularly take these medicines, your doctor may switch you to a different medicine to use during treatment.
Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you may be pregnant, or are planning a pregnancy, consult your doctor before starting treatment with this medicine.
You must not use this medicine if you are pregnant. Padcev could harm the unborn baby.
If you are a woman of childbearing potential starting treatment with this medicine, you must use an effective method of contraception during treatment with Padcev and for at least 6 months after stopping treatment.
It is not known whether this medicine passes into breast milk and could harm the baby. Do not breastfeed during treatment and for at least 6 months after stopping Padcev.
Men taking this medicine are advised to freeze and store sperm samples before starting treatment. Men are advised to avoid fathering a child during treatment with this medicine and for at least 4 months after the last dose.
Driving and using machines
Do not drive or operate machinery if you do not feel well during treatment.

3. How to use Padcev

You will be administered Padcev in a hospital or clinic under the supervision of a physician
specialized in these treatments.
Dose of Padcev you will receive
When used alone, the recommended dose of this medicinal product is 1.25 mg/kg on Days 1,
8, and 15 of a 28-day cycle. When used in combination with pembrolizumab, the recommended dose of this
medicinal product is 1.25 mg/kg on Days 1 and 8 of a 21-day cycle. Your doctor will decide how many
treatment cycles you will need.
Method of administration of Padcev
You will receive Padcev as a 30-minute intravenous infusion. Padcev will be added to an infusion bag containing glucose, sodium chloride, or lactated Ringer's solution prior to use.
If you miss a dose of Padcev
It is very important that you keep all your appointments to receive Padcev. If you miss an appointment,
ask your doctor when to schedule your next dose.
If you stop administration of Padcev
Do not stop treatment with Padcev unless you have discussed it first with your doctor. Stopping
treatment may interrupt the medicine's effect.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some possible side effects could be serious:

• Skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, and other severe skin rashes such as drug reaction with eosinophilia and systemic symptoms [DRESS], symmetric drug-related intertriginous and flexural exanthema [SDRIFE]). Immediately inform your doctor if you experience any of the following signs of a severe skin reaction: rash or itching that continues to worsen or reappears after treatment, blisters or peeling of the skin, painful sores or ulcers in the mouth, nose, throat, or genital area, fever or flu-like symptoms, or swollen lymph nodes (frequency not known).

• High blood sugar (hyperglycaemia). Immediately inform your doctor if you experience any symptoms of high blood sugar, including: frequent urination, increased thirst, blurred vision, confusion, drowsiness, loss of appetite, fruity-smelling breath, nausea, vomiting, or stomach pain (may affect more than 1 in 10 people).

• A serious diabetes complication with high levels of ketones in the blood that can make the blood more acidic (diabetic ketoacidosis) (frequency not known).

• Lung problems (pneumonia/interstitial lung disease). Immediately inform your doctor if you develop or worsening symptoms, including difficulty breathing, shortness of breath, or cough (may affect up to 1 in 10 people).

• Nerve problems (peripheral neuropathy such as motor neuropathy, sensorimotor neuropathy, paresthesia, hypoesthesia, and muscle weakness). Immediately inform your doctor if you experience numbness, tingling, or a "pins and needles" sensation in your hands or feet, or muscle weakness (may affect more than 1 in 10 people).

• Leakage of Padcev from the vein into surrounding tissues at the infusion site (extravasation). Immediately inform your doctor or seek medical assistance if you notice any redness, swelling, itching, or discomfort at the infusion site. If Padcev leaks out of the injection site or vein and reaches the skin and surrounding tissues, it may cause a reaction at the infusion site. These reactions can occur immediately after an infusion, but sometimes they may occur days after the infusion (may affect up to 1 in 10 people).

• Severe infection (sepsis) when bacteria and their toxins circulate in the blood causing organ damage (may affect up to 1 in 10 people).

• Lung infection (pneumonia) (may affect up to 1 in 10 people).

• Infusion-related reaction. Medicines of this type (monoclonal antibodies) can cause infusion-related reactions, such as:

  • low blood pressure
  • swelling of the tongue
  • difficulty breathing (dyspnoea)
  • fever
  • chills
  • skin redness (flushing)
  • itching
  • rash
  • feeling unwell (nausea)
  • general feeling of discomfort (malaise)

These types of reactions usually occur from a few minutes to several hours after completion of the infusion. However, they may also occur more than several hours after the infusion, although this is rare. Infusion-related reactions may affect up to 1 in 10 people.

Other possible side effects

The following side effects have been reported with Padcev alone:

Very common (may affect more than 1 in 10 people):

• low red blood cell count (anaemia)
• nausea, diarrhoea, and vomiting
• fatigue
• loss of appetite
• altered taste
• dry eyes
• hair loss
• weight loss
• dry or itchy skin
• rash
• flat or red bumps on the skin
• increased liver enzymes (aspartate aminotransferase [AST] or alanine aminotransferase [ALT])

Common (may affect up to 1 in 10 people):

• abnormal gait (gait disturbance)
• red eyes
• hives on the skin
• red skin
• inflamed, itchy, cracked, and rough skin patches
• redness and tingling on palms or soles of feet
• skin peeling
• mouth ulcers
• rash with accompanying symptoms: itching, redness, bumps or red spots on the skin, fluid-filled blisters, large blisters, skin lesions
• low platelet levels in the blood which may cause bleeding and bruising (thrombocytopenia)

Uncommon (may affect up to 1 in 100 people):

• skin irritation
• burning sensation of the skin
• nerve function problems causing unusual sensations or movement problems
• reduction in muscle size
• blood-filled blisters
• allergic skin reaction
• rash with accompanying symptoms: bull's-eye-like spots, skin peeling, flat fluid-filled blister
• peeling of the skin all over the body
• inflammation in skin folds, including the groin
• blisters or blister-like lesions on the skin
• inflammation or itching affecting only legs and feet

Not known (frequency cannot be estimated from the available data):

• low white blood cell count with or without fever
• abnormal lightening or darkening of the skin (skin hyperpigmentation, skin lightening, pigmentary changes)

The following side effects have been reported with Padcev in combination with pembrolizumab:

Very common (may affect more than 1 in 10 people):

• low red blood cell count (anaemia)
• nausea, diarrhoea, and vomiting
• fatigue
• loss of appetite
• altered taste
• dry eyes
• hair loss
• weight loss
• dry or itchy skin
• flat or red bumps on the skin
• increased liver enzymes (aspartate aminotransferase [AST] or alanine aminotransferase [ALT])
• reduced activity of the thyroid gland (hypothyroidism)

Common (may affect up to 1 in 10 people):

• abnormal gait (gait disturbance)
• red eyes
• hives on the skin
• red skin
• rash
• inflamed, itchy, cracked, and rough skin patches
• redness and tingling on palms or soles of feet
• skin peeling
• mouth ulcers
• rash with accompanying symptoms: bull's-eye-like spots, itching, redness, bumps or red spots on the skin, fluid-filled blisters, large blisters, skin lesions
• increased lipase (a blood test used to monitor the pancreas)
• inflammation of the muscles (myositis)
• low platelet levels in the blood which may cause bleeding and bruising (thrombocytopenia)

Uncommon (may affect up to 1 in 100 people):

• skin irritation
• burning sensation of the skin
• nerve function problems causing unusual sensations or movement problems
• allergic skin reaction
• rash with accompanying symptoms: skin peeling, flat fluid-filled blister
• peeling of the skin all over the body
• inflammation in skin folds, including the groin
• blisters or blister-like lesions on the skin
• inflammation or itching affecting only legs and feet

Not known (frequency cannot be estimated from the available data):

• low white blood cell count with or without fever
• abnormal lightening or darkening of the skin (skin hyperpigmentation, skin lightening, pigmentary changes)

Reporting of side effects

If you get any side effects, including ones not listed in this leaflet, talk to your doctor. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Padcev

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and on the label of the
vial after Exp./EXP.
The expiry date refers to the last day of that month.
Store in a refrigerator (from 2 °C to 8 °C). Do not freeze.
Do not store any unused infusion solution for later use. Unused medicine and waste material
must be disposed of in accordance with local regulations.

6. Package contents and other information

What Padcev contains

• The active substance is enfortumab vedotin.
• One 20 mg vial of powder for concentrate for infusion solution contains 20 mg of enfortumab vedotin.
• One 30 mg vial of powder for concentrate for infusion solution contains 30 mg of enfortumab vedotin.
• After reconstitution, each mL of solution contains 10 mg of enfortumab vedotin.

The other components are histidine, monohydrate histidine hydrochloride, trehalose dihydrate, and polysorbate 20.
Description of the appearance of Padcev and contents of the pack
Padcev powder for concentrate for infusion solution is a white to off-white lyophilized powder.
Padcev is supplied in a carton containing 1 glass vial.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Astellas Pharma Europe B.V.
Sylviusweg 62
2333 BE Leiden
The Netherlands
Manufacturer:
Astellas Ireland Co. Ltd
Killorglin
Co. Kerry
V93 FC86
Ireland
For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:
België/Belgique/Belgien Lietuva
Astellas Pharma B.V. Branch Astellas Pharma d.o.o.
Tél/Tel: +32 (0) 2 5580710 Tel.: +370 37 408 681
България Luxembourg/Luxemburg
Астелас Фарма ЕООД Astellas Pharma B.V. Branch
Teл.: +359 2 862 53 72 Belgique/Belgien
Tél/Tel: +32 (0)2 5580710
Česká republika Magyarország
Astellas Pharma s.r.o. Astellas Pharma Kft.
Tel: +420 221 401 500 Tel.: +36 1 577 8200
Danmark Malta
Astellas Pharma a/s Astellas Pharmaceuticals AEBE
Tlf: +45 43 430355 Tel: +30 210 8189900
Deutschland Nederland
Astellas Pharma GmbH Astellas Pharma B.V.
Tel.: +49 (0)89 454401 Tel: +31 (0)71 5455745
Eesti Norge
Astellas Pharma d.o.o. Astellas Pharma
Tel: +372 6 056 014 Tlf: +47 66 76 46 00
Ελλάδα Österreich
Astellas Pharmaceuticals AEBE Astellas Pharma Ges.m.b.H.
Τηλ : +30 210 8189900 Tel.: +43 (0)1 8772668
España Polska
Astellas Pharma S.A. Astellas Pharma Sp.z.o.o.
Tel: +34 91 4952700 Tel.: +48 225451 111
France Portugal
Astellas Pharma S.A.S. Astellas Farma, Lda.
Tél: +33 (0)1 55917500 Tel: +351 21 4401300
Hrvatska România
Astellas d.o.o. S.C. Astellas Pharma SRL
Tel: +385 1670 0102 Tel: +40 (0)21 361 04 95
Ireland Slovenija
Astellas Pharma Co. Ltd. Astellas Pharma d.o.o.
Tel: +353 (0)1 4671555 Tel: +386 14011400
Ísland Slovenská republika
Vistor hf Astellas Pharma s.r.o.
Sími: +354 535 7000 Tel: +421 2 4444 2157
Italia Suomi/Finland
Astellas Pharma S.p.A. Astellas Pharma
Tel: +39 (0)2 921381 Puh/Tel: +358 (0)9 85606000
Κύπρος Sverige
Ελλάδα Astellas Pharma AB
Astellas Pharmaceuticals AEBE Tel: +46 (0)40-650 15 00
Τηλ : +30 210 8189900
Latvija United Kingdom (Northern Ireland)
Astellas Pharma d.o.o. Astellas Pharma Co., Limited
Tel: +371 67 619365 Tel: +353 (0)1 4671555
Free call from Northern Ireland: 0800783 5018
Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu.

The following information is intended exclusively for healthcare professionals:

Traceability
In order to improve the traceability of biological medicinal products, the name and batch number of the administered medicinal product must be clearly recorded.

Instructions for preparation and administration
Reconstitution in the single-dose vial

1. Follow appropriate procedures for handling and disposal of antineoplastic medicinal products.
2. Use appropriate aseptic technique for reconstitution and preparation of solutions for administration.
3. Calculate the recommended dose based on patient weight to determine the number and dosage (20 mg or 30 mg) of vials required.
4. Reconstitute each vial as follows, directing the stream of sterile water for injection preferably onto the vial wall rather than directly onto the lyophilized powder:
   a. 20 mg vial: add 2.3 mL of sterile water for injection to obtain a solution of 10 mg/mL of enfortumab vedotin.
   b. 30 mg vial: add 3.3 mL of sterile water for injection to obtain a solution of 10 mg/mL of enfortumab vedotin.
5. Gently rotate each vial until the contents are completely dissolved. Allow the reconstituted vial(s) to stand for at least 1 minute until air bubbles disappear. Do not shake the vial. Avoid exposure to direct sunlight.
6. Visually inspect the solution for particulate matter and discoloration. The reconstituted solution should be clear to slightly opalescent, colourless to pale yellow, and free of visible particles. Discard any vial showing visible particles or apparent discoloration.

Dilution in the infusion bag

7. Withdraw the calculated dose volume of reconstituted solution from the vial(s) and transfer it into an infusion bag.
8. Dilute enfortumab vedotin with either dextrose 50 mg/mL (5%), sodium chloride 9 mg/mL (0.9%), or Ringer's lactate solution for injection. The infusion bag size should allow addition of sufficient diluent to achieve a final concentration of 0.3–4 mg/mL of enfortumab vedotin.

The diluted solution for administration of enfortumab vedotin is compatible with intravenous infusion bags made of polyvinyl chloride (PVC), ethylene vinyl acetate, polyolefins such as polypropylene (PP), or polyethylene (PE) intravenous bottles, modified glycol polyethylene terephthalate, and infusion sets made of PVC with plasticizers (bis(2-ethylhexyl) phthalate (DEHP) or tris(2-ethylhexyl) trimellitate (TOTM)), PE, and with filter membranes (pore size: 0.2–1.2 μm) made of polyethersulfone, polyvinylidene difluoride, or mixed cellulose esters.

9. Mix the diluted solution by gentle inversion. Do not shake the bag. Avoid exposure to direct sunlight.
10. Prior to use, visually inspect the infusion bag for particulate matter or discoloration. The reconstituted solution should be clear to slightly opalescent, colourless to pale yellow, and free of visible particles. Do not use the infusion bag if particulate matter or discoloration is observed.
11. Discard any unused solution remaining in the single-dose vials.

Administration

12. Administer the infusion over 30 minutes through an intravenous line. Do not administer as an intravenous push or bolus.

No incompatibilities have been observed with closed system transfer devices made of acrylonitrile butadiene styrene (ABS), acrylic, activated carbon, ethylene propylene diene monomer, methacrylate ABS, polycarbonate, polyisoprene, polyoxymethylene, PP, silicone, stainless steel, or thermoplastic elastomers for the reconstituted solution.

13. Do not co-administer other medicinal products in the same infusion line.
14. In-line filters or syringe filters (pore size: 0.2–1.2 μm, recommended materials: polyethersulfone, polyvinylidene difluoride, mixed cellulose esters) are recommended during administration.

Disposal
Padcev is for single use only.
Any unused medicinal product and waste materials derived from this medicinal product must be disposed of in accordance with local regulations.

ANNEX IV
SCIENTIFIC CONCLUSIONS AND REASONS FOR THE CHANGE TO THE TERMS OF THE
MARKETING AUTHORISATION(S)

Scientific conclusions
Taking into account the assessment by the Pharmacovigilance Risk Assessment Committee (PRAC) of the Periodic Safety Update Report (PSUR) for enfortumab vedotin, the scientific conclusions of the PRAC are as follows:

In light of available data on pneumonia from clinical trials and spontaneous reports, including in some cases a close temporal relationship and a positive de-challenge, the PRAC considers that there is at least a reasonable possibility of a causal relationship between enfortumab vedotin and pneumonia. The PRAC concluded that the product information for medicinal products containing enfortumab vedotin should be amended accordingly.

In light of available data on thrombocytopenia from clinical trials and spontaneous reports, including in some cases a close temporal relationship and a positive de-challenge, the PRAC considers that there is at least a reasonable possibility of a causal relationship between enfortumab vedotin and thrombocytopenia. The PRAC concluded that the product information for medicinal products containing enfortumab vedotin should be amended accordingly.

Having reviewed the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the overall conclusions and the rationale of the recommendation.

Reasons for the change to the terms of the marketing authorisation(s)
Based on the scientific conclusions for enfortumab vedotin, the CHMP considers that the benefit-risk balance of the medicinal product(s) containing enfortumab vedotin remains unchanged, subject to the proposed amendments to the product information.
The CHMP recommends a change to the terms of the marketing authorisation(s).