Kisplyx: detailed information

Package leaflet: Information for the user

Kisplyx 4 mg hard capsules, 10 mg hard capsules

lenvatinib
Read all of this leaflet carefully before you start taking 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 or pharmacist.
This medicine has been prescribed for you only. Do not pass it on to other people, even if their symptoms seem identical to yours, as it may be harmful.
If you experience any side effect, including those not listed in this leaflet, inform your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet

What Kisplyx is and what it is used for
What you need to know before taking Kisplyx
How to take Kisplyx
Possible side effects
How to store Kisplyx
Contents of the pack and other information

1. What Kisplyx is and what it is used for

What Kisplyx is
Kisplyx is a medicine that contains the active substance lenvatinib. It is used in combination with
pembrolizumab as a first-line treatment for adults with advanced renal cell cancer (advanced kidney
cancer). It is also used in combination with everolimus to treat adults with advanced renal cell cancer
when other treatments (so-called "anti-VEGF therapy") have not succeeded in stopping the disease.

How Kisplyx works
Kisplyx blocks the action of proteins called tyrosine kinase receptors (RTKs), which are involved in the
development of new blood vessels that supply oxygen and nutrients to cells and help them grow. These
proteins may be present in high levels in tumour cells, and by inhibiting their activity, Kisplyx can slow
down the rate at which cancer cells multiply and the tumour grows, and help cut off the blood supply
that the tumour needs.

2. What you need to know before taking Kisplyx

Do not take Kisplyx

if you are allergic to lenvatinib or to any of the other ingredients of this medicine (listed in section 6).
if you are breastfeeding (see the section below on Contraception, pregnancy and breastfeeding).

Warnings and precautions
Talk to your doctor before taking Kisplyx if:

you have high blood pressure
you are a woman of childbearing potential (see the section “Contraception, pregnancy and breastfeeding” below)
you have previously had heart problems or stroke
you have liver or kidney problems
you have recently undergone surgery or radiotherapy
you need to undergo a surgical procedure. If you are scheduled for major surgery, your doctor may consider interrupting Kisplyx, as Kisplyx may affect wound healing. Kisplyx may be restarted once adequate wound healing has been established.
you are over 75 years of age
you belong to an ethnic group other than white or Asian
you weigh less than 60 kg
you have a history of abnormal passages forming (known as fistulas) between different organs in the body or from an organ to the skin
you have or have had an aneurysm (a bulge and weakening in the wall of a blood vessel) or a tear in the wall of a blood vessel.
you have or have had mouth, tooth, and/or jaw pain, swelling or ulcers in the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth. You may be advised to have a dental check-up before starting Kisplyx, as jaw bone damage (osteonecrosis) has been reported in patients treated with Kisplyx. If you need to undergo invasive dental treatment or oral surgery, inform your dentist that you are being treated with Kisplyx, especially if you are or have also been treated with injectable bisphosphonates (used to prevent or treat bone diseases).
you are taking or have taken medicines used to treat osteoporosis (anti-resorptive bone agents) or anticancer medicines that affect blood vessel formation (so-called angiogenesis inhibitors), as the risk of jaw bone damage may be higher.

Before taking Kisplyx, your doctor may perform certain blood tests, for example,
to monitor your blood pressure and liver or kidney function, and to check whether you have low levels
of salts and high levels of thyroid-stimulating hormone in the blood. Your doctor will discuss the results of these
tests with you and decide whether you can receive Kisplyx. You may require additional treatment with other
medicines, a lower dose of Kisplyx, or special monitoring due to an increased risk of adverse effects.
If you have any doubts, talk to your doctor before taking Kisplyx.
Children and adolescents
The use of Kisplyx is not currently recommended in children and adolescents under
18 years of age.
Other medicines and Kisplyx
Tell your doctor or pharmacist if you are taking, have recently taken, or might take
any other medicines, including herbal preparations and over-the-counter medicines.
Contraception, pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning to become pregnant, or are breastfeeding,
consult your doctor or pharmacist before taking this medicine.

Use highly effective contraceptive measures during treatment with this medicine and for at least one month after treatment ends.
Do not take Kisplyx if you are planning a pregnancy during treatment. This is because it may severely harm the unborn child.
If you become pregnant during treatment with Kisplyx, inform your doctor immediately. Your doctor will help you decide whether to continue treatment.
Do not breastfeed while taking Kisplyx. This is because the medicine passes into breast milk and may severely harm the breastfed infant.

Driving and using machines
Kisplyx may cause side effects that could impair your ability to drive or use
machinery. Avoid driving or operating machinery if you experience dizziness or fatigue.

3. How to take Kisplyx

Take this medicine exactly as your doctor has told you. If you have any doubts, consult your doctor or pharmacist.
Dosage

The recommended daily dose of Kisplyx is 20 mg once daily (two 10 mg capsules) in combination with pembrolizumab 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes.
The recommended daily dose of Kisplyx is 18 mg once daily (one 10 mg capsule and two 4 mg capsules) in combination with one 5 mg tablet of everolimus taken once daily.
If you have severe liver or kidney problems, the recommended daily dose of Kisplyx is 10 mg once daily (one 10 mg capsule) in combination with one 5 mg tablet of everolimus taken once daily. If you are receiving lenvatinib in combination with pembrolizumab, your doctor or pharmacist will verify the correct dose of pembrolizumab you should take.
Your doctor may reduce your dose if you experience side effects.

How to take the medicine

You may take the capsules with or without food.
Do not open the capsules to avoid exposure to the capsule contents.
Swallow the capsules whole with water. If you are unable to swallow the capsules whole, a liquid mixture may be prepared using water, apple juice, or milk. The liquid mixture may be administered orally or via a feeding tube. If administered via a feeding tube, the liquid mixture must be prepared with water only. If not used immediately after preparation, the liquid mixture may be stored in a covered container and refrigerated at a temperature between 2 °C and 8 °C for up to 24 hours. Shake the liquid mixture for 30 seconds after removing it from the refrigerator. If the liquid mixture is not used within 24 hours of preparation, it must be discarded.
Preparation and administration of the liquid mixture:
o Place the intact capsules corresponding to the prescribed dose (up to 5 capsules) into a small container (capacity of approximately 20 mL (4 teaspoons)) or into an oral dosing syringe (20 mL); do not break or crush the capsules.
o Add 3 mL of liquid to the container or oral dosing syringe. Wait 10 minutes to allow the capsule coating (outer surface) to dissolve, then mix or shake the mixture for 3 minutes until the capsules are completely dissolved.
- If preparing the liquid mixture in an oral dosing syringe, cap the syringe, remove the plunger, and use a second syringe or medicine dropper to add the liquid into the first syringe, then reinsert the plunger before mixing.
  o Drink the liquid mixture directly from the container or use an oral dosing syringe to administer it directly into the mouth or via a feeding tube.
  o Then, add an additional 2 mL of liquid to the container or oral dosing syringe using a second syringe or medicine dropper, mix or shake, and administer this mixture. Repeat this step at least twice, and continue until no visible residue remains, to ensure the entire dose is administered.
Take the capsules every day at approximately the same time.

How long to take Kisplyx
You will usually continue taking this medicine for as long as you are benefiting from it.
If you take more Kisplyx than you should
If you take more Kisplyx than you should, consult your doctor or pharmacist immediately. Take the medicine package with you.
If you forget to take Kisplyx
Do not take a double dose (two doses at the same time) to make up for a missed dose.
What you should do if you forget a dose depends on how long it is until your next dose.

If there are 12 hours or more until your next dose: take the missed dose as soon as you remember. Then take your next dose at the usual time.
If there are less than 12 hours until your next dose: skip the missed dose. Then take your next dose at the usual time.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. The following side effects may occur with this medicine.
Immediately inform your doctor if you notice any of the following side effects – urgent medical treatment may be required:

Numbness or weakness on one side of the body, severe headache, seizures, confusion, difficulty speaking, changes in vision or dizziness: these may be signs of stroke, bleeding in the brain, or effects on the brain due to a severe increase in blood pressure.
Chest pain or pressure, arm, back, neck or jaw pain, shortness of breath, rapid or irregular heartbeat, cough, bluish colouring of lips or fingers, feeling of extreme tiredness: these may be signs of a heart problem, blood clot in the lungs, or air leaking from the lungs into the chest cavity, preventing the lungs from expanding.
Severe stomach (abdominal) pain – this may be due to a perforation in the intestinal wall or a fistula (an abnormal connection between the intestine and another part of the body or the skin via a tube-like passage).
Black, tar-like stools or bleeding, or coughing up blood – these may be signs of internal bleeding.
Diarrhoea, feeling unwell and malaise – these are very common side effects, which may become serious if they lead to dehydration, potentially resulting in kidney failure. Your doctor may prescribe medicines to reduce these side effects.
Mouth, tooth and/or jaw pain, swelling or ulcers in the mouth, numbness or heaviness in the jaw, or loosening of a tooth; these could be signs of damage to the jawbone (osteonecrosis).

Immediately inform your doctor if any of the side effects listed below occur.
The following side effects may occur with this medicine when used alone:
Very common (may affect more than 1 in 10 people)

Low levels of platelets in the blood, which may lead to bruising and difficulty healing wounds
Decreased number of white blood cells in the blood
Underactive thyroid (fatigue, weight gain, constipation, feeling cold, dry skin) and changes in blood test results for thyroid-stimulating hormone levels (high)
Changes in blood test results regarding potassium levels (low) and calcium levels (low)
Changes in blood test results regarding magnesium levels (low) and cholesterol levels (high)
Loss of appetite or weight loss
Difficulty sleeping
Dizziness
Headache
Bleeding (most commonly nosebleeds, but also other types of bleeding, e.g. blood in urine, bruising, bleeding from gums or intestinal wall)
High or low blood pressure
Hoarseness
Nausea and vomiting, constipation, diarrhoea, abdominal pain, indigestion
Dry, sore or inflamed mouth, altered taste sensation
Increased levels of lipase and amylase (enzymes involved in digestion)
Changes in blood test results indicating liver function abnormalities
Redness, pain and swelling of the skin on hands and feet (palmar-plantar erythrodysesthesia)
Rash
Hair loss
Back pain
Joint or muscle pain
Changes in urine tests regarding protein levels (high) and urinary tract infections (urinating more frequently than usual and pain when passing urine)
Changes in blood test results indicating kidney function abnormalities and kidney failure
Feeling of extreme tiredness or weakness
Swelling of the legs

Common (may affect up to 1 in 10 people)

Loss of body fluids (dehydration)
Signs of stroke, including numbness or weakness on one side of the body, severe headache, seizures, confusion, difficulty speaking, changes in vision or dizziness
Palpitations
Heart problems or blood clots in the lungs (difficulty breathing, chest pain) or in other organs, which may include chest pain or pressure, arm, back, neck or jaw pain, shortness of breath, rapid or irregular heartbeat, cough, bluish colouring of lips or fingers, and feeling of extreme tiredness
Anal fistula (a small channel forming between the anus and surrounding skin)
Feeling of bloating or excess gas
Liver failure
Drowsiness, confusion, poor concentration, loss of consciousness, which may be signs of liver failure
Inflammation of the gallbladder
Dry skin, skin thickening and itching
Feeling unwell
A hole (perforation) in the stomach or intestine

Uncommon (may affect up to 1 in 100 people)

Painful infection or irritation near the anus
Severe pain in the upper left part of the abdomen, which may be associated with fever, chills, nausea and vomiting (splenic infarction)
Mini-stroke (transient ischaemic attack)
Severe difficulty breathing and chest pain caused by air leaking from the lung into the chest cavity, preventing the lung from expanding
Inflammation of the pancreas
Inflammation of the colon (colitis)
Liver damage
Damage to the jawbone (osteonecrosis)
Wound healing problems
Decreased secretion of hormones produced by the adrenal glands

Not known (the following side effects have been reported since Kisplyx was marketed,
but their frequency is unknown)

Widening and weakening of a blood vessel wall or a tear in the blood vessel wall (aneurysms and arterial dissections)
Other types of fistulas (an abnormal connection between different organs in the body or from the skin to an underlying structure, such as the throat and trachea). Symptoms depend on where the fistula is located. Inform your doctor if you experience new or unusual symptoms, such as coughing while swallowing.

The following side effects may occur with this medicine when administered in combination with everolimus:
Very common (may affect more than 1 in 10 people)

Low levels of platelets in the blood, which may lead to bruising and difficulty healing wounds
Decreased number of white blood cells in the blood
Underactive thyroid (fatigue, weight gain, constipation, feeling cold, dry skin) and changes in blood test results for thyroid-stimulating hormone levels (high)
Changes in blood test results regarding potassium levels (low) and calcium levels (low)
Changes in blood test results regarding magnesium levels (low) and cholesterol levels (high)
Loss of appetite or weight loss
Difficulty sleeping
Headache
Bleeding (most commonly nosebleeds, but also other types of bleeding, e.g. blood in urine, bruising, bleeding from gums or intestinal wall)
High blood pressure
Hoarseness
Nausea and vomiting, constipation, diarrhoea, abdominal pain, indigestion
Sore or inflamed mouth, altered taste sensation
Increased levels of lipase and amylase (enzymes involved in digestion)
Changes in blood test results indicating liver function abnormalities
Redness, pain and swelling of the skin on hands and feet (palmar-plantar erythrodysesthesia)
Rash
Back pain
Joint or muscle pain
Changes in urine tests regarding protein levels (high)
Changes in blood test results indicating kidney function abnormalities and kidney failure
Feeling of extreme tiredness or weakness
Swelling of the legs

Common (may affect up to 1 in 10 people)

Urinary tract infections (urinating more frequently than usual and pain when passing urine)
Loss of body fluids (dehydration)
Dizziness
Palpitations
Heart problems or blood clots in the lungs (difficulty breathing, chest pain) or in other organs, which may include chest pain or pressure, arm, back, neck or jaw pain, shortness of breath, rapid or irregular heartbeat, cough, bluish colouring of lips or fingers, and feeling of extreme tiredness
Low blood pressure
Severe difficulty breathing and chest pain caused by air leaking from the lung into the chest cavity, preventing the lung from expanding
Dry mouth
Feeling of bloating or excess gas
Inflammation of the gallbladder
Hair loss
Feeling unwell
A hole (perforation) in the stomach or intestine

Uncommon (may affect up to 1 in 100 people)

Painful infection or irritation near the anus
Signs of stroke, including numbness or weakness on one side of the body, severe headache, seizures, confusion, difficulty speaking, changes in vision or dizziness
Mini-stroke (transient ischaemic attack)
Inflammation of the pancreas
Anal fistula (a small channel forming between the anus and surrounding skin)
Inflammation of the colon (colitis)
Liver failure or signs of liver damage, including yellowing of the skin or whites of the eyes (jaundice), drowsiness, confusion, poor concentration
Damage to the jawbone (osteonecrosis)
Dry skin, skin thickening and itching
Wound healing problems
Other types of fistulas (an abnormal connection between different organs in the body or from the skin to an underlying structure, such as the throat and trachea). Symptoms depend on where the fistula is located. Inform your doctor if you experience new or unusual symptoms, such as coughing while swallowing
Decreased secretion of hormones produced by the adrenal glands

Not known (the following side effects have been reported since Kisplyx was marketed,
but their frequency is unknown)

Widening and weakening of a blood vessel wall or a tear in the blood vessel wall (aneurysms and arterial dissections)

The following side effects may occur with this medicine when administered in combination with pembrolizumab:
Very common (may affect more than 1 in 10 people)

Low levels of platelets in the blood, which may lead to bruising and difficulty healing wounds
Decreased number of white blood cells in the blood
Underactive thyroid (fatigue, weight gain, constipation, feeling cold, dry skin) and changes in blood test results for thyroid-stimulating hormone levels (high)
Changes in blood test results regarding potassium levels (low) and calcium levels (low)
Changes in blood test results regarding magnesium levels (low) and cholesterol levels (high)
Loss of appetite or weight loss
Difficulty sleeping
Dizziness
Headache
Bleeding (most commonly nosebleeds, but also other types of bleeding, e.g. blood in urine, bruising, bleeding from gums or intestinal wall)
High blood pressure
Hoarseness
Nausea and vomiting, constipation, diarrhoea, abdominal pain, indigestion
Dry, sore or inflamed mouth, altered taste sensation
Increased levels of lipase and amylase (enzymes involved in digestion)
Changes in blood test results indicating liver function abnormalities
Redness, pain and swelling of the skin on hands and feet (palmar-plantar erythrodysesthesia)
Rash
Back pain
Joint or muscle pain
Changes in urine tests regarding protein levels (high)
Changes in blood test results indicating kidney function abnormalities and kidney failure
Feeling of extreme tiredness or weakness
Swelling of the legs

Common (may affect up to 1 in 10 people)

Urinary tract infections (urinating more frequently than usual and pain when passing urine)
Loss of body fluids (dehydration)
Palpitations
Heart problems or blood clots in the lungs (difficulty breathing, chest pain) or in other organs, which may include chest pain or pressure, arm, back, neck or jaw pain, shortness of breath, rapid or irregular heartbeat, cough, bluish colouring of lips or fingers, and feeling of extreme tiredness
Low blood pressure
Inflammation of the pancreas
Inflammation of the colon (colitis)
Feeling of bloating or excess gas
Inflammation of the gallbladder
Dry skin, skin thickening and itching
Hair loss
Feeling unwell
Decreased secretion of hormones produced by the adrenal glands
A hole (perforation) in the stomach or intestine

Uncommon (may affect up to 1 in 100 people)

Painful infection or irritation near the anus
Signs of stroke, including numbness or weakness on one side of the body, severe headache, convulsive seizure, confusion, difficulty speaking, changes in vision or dizziness
Mini-stroke (transient ischaemic attack)
Severe difficulty breathing and chest pain caused by air leaking from the lung into the chest cavity, preventing the lung from expanding
Anal fistula (a small channel forming between the anus and surrounding skin)
Liver failure or signs of liver damage, including yellowing of the skin or whites of the eyes (jaundice), drowsiness, confusion, poor concentration
Wound healing problems
Other types of fistulas (an abnormal connection between different organs in the body or from the skin to an underlying structure, such as the throat and trachea). Symptoms will depend on where the fistula is located. Inform your doctor if you experience new or unusual symptoms, such as coughing while swallowing.

Not known (the following side effects have been reported since Kisplyx was marketed,
but their frequency is unknown)

Widening and weakening of a blood vessel wall or a tear in the blood vessel wall (aneurysms and arterial dissections)

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

5. How to store Kisplyx

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton after “Exp.” and on the blister after “EXP”. The expiry date refers to the last day of that month.
Do not store above 25ºC. Store in the original blister to protect the medicine from moisture.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Kisplyx contains

The active substance is lenvatinib.
- Kisplyx 4 mg hard capsules: - each hard capsule contains 4 mg of lenvatinib (as mesilate).
- Kisplyx 10 mg hard capsules: - each hard capsule contains 10 mg of lenvatinib (as mesilate).
The other ingredients are calcium carbonate, mannitol, microcrystalline cellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, talc. The capsule shell contains hypromellose, titanium dioxide (E171), yellow iron oxide (E172) and red iron oxide (E172). The printing ink contains shellac, black iron oxide (E172), potassium hydroxide and propylene glycol.

Description of the appearance of Kisplyx and package contents

Kisplyx 4 mg hard capsule: yellowish-red body and yellowish-red cap, approximately 14.3 mm in length, printed in black ink with “Є” on the cap and “LENV 4 mg” on the body.
Kisplyx 10 mg hard capsule: yellow body and yellowish-red cap, approximately 14.3 mm in length, printed in black ink with “Є” on the cap and “LENV 10 mg” on the body.
The capsules are supplied in aluminum blister packs with push-through foil, in cardboard packages containing 30, 60 or 90 hard capsules. Not all pack sizes may be marketed.

Marketing Authorisation Holder
Eisai GmbH
Edmund-Rumpler-Straße 3
60549 Frankfurt am Main
Germany
E-mail: [email protected]

Manufacturer
Eisai GmbH
Edmund-Rumpler-Straße 3
60549 Frankfurt am Main
Germany

For further information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
Eisai SA/NV Ewopharma AG atstovybė
Tél/Tel: +32 (0) 800 158 58 Tel: + 370 5 2430444

България Luxembourg/Luxemburg
Ewopharma AG Eisai SA/NV
Teл.: + 359 2 962 12 00 Tél/Tel: +32 (0) 2 502 58 04
(Belgique/Belgien)

Česká republika Magyarország
Eisai GesmbH organizačni složka Ewopharma Hungary Ltd.
Tel.: + 420 242 485 839 Tel.: + 36 1 200 46 50

Danmark Malta
Eisai AB Cherubino LTD
Tlf: + 46 (0) 8 501 01 600 Tel.: + 356 21343270
(Sverige)

Deutschland Nederland
Eisai GmbH Eisai B.V.
Tel: + 49 (0) 69 66 58 50 Tel: + 31 (0) 900 575 3340

Eesti Norge
Ewopharma AG Eesti filiaal Eisai AB
Tel: + 372 6015540 Tlf: + 46 (0) 8 501 01 600
(Sverige)

Ελλάδα Österreich
Arriani Pharmaceutical S.A. Eisai GesmbH
Τηλ: + 30 210 668 3000 Tel: + 43 (0) 1 535 1980-0

España Polska
Eisai Farmacéutica, S.A. Ewopharma AG Sp. z o.o
Tel: + (34) 91 455 94 55 Tel: + 48 (22) 620 11 71

France Portugal
Eisai SAS Eisai Farmacêutica, Unipessoal Lda
Tél: + (33) 1 47 67 00 05 Tel: + 351 214 875 540

Hrvatska România
Ewopharma d.o.o Ewopharma AG
Tel: + 385 (0) 1 6646 563 Tel: + 40 21 260 13 44

Ireland Slovenija
Eisai GmbH Ewopharma d.o.o.
Tel: + 49 (0) 69 66 58 50 Tel: + 386 590 848 40
(Germany)

Ísland Slovenská republika
Eisai AB Eisai GesmbH organizační složka
Sími: + 46 (0) 8 501 01 600 Tel.: +420 242 485 839
(Svíþjóð) (Česká republika)

Italia Suomi/Finland
Eisai S.r.l. Eisai AB
Tel: + 39 02 5181401 Puh/Tel: + 46 (0) 8 501 01 600
(Ruotsi/Sverige)

Κύπρος Sverige
Arriani Pharmaceuticals S.A. Eisai AB
Τηλ: + 30 210 668 3000 Tel: + 46 (0) 8 501 01 600
(Ελλάδα)

Latvija United Kingdom (Northern Ireland)
Ewopharma AG Pārstāvniecība Eisai GmbH
Tel: + 371 67450497 Tel: + 49 (0) 69 66 58 50
(Germany)

More detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu.