KISPLYX 4 mg HARD CAPSULES

Introduction

Package Leaflet: Information for the User

Kisplyx 4 mg hard capsules

Kisplyx 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 further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you experience any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack:

1. What is Kisplyx and what is it used for
2. What you need to know before you take Kisplyx
3. How to take Kisplyx
4. Possible side effects
5. Storage of Kisplyx
6. Contents of the pack and other information

1. What is Kisplyx and what is it used for

What is Kisplyx

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 kidney cancer (advanced renal cell carcinoma). It is also used in combination with everolimus to treat adult patients with advanced kidney cancer when other treatments (so-called vascular endothelial growth factor (VEGF) targeted treatments) have not helped to stop the disease.

How Kisplyx works

Kisplyx blocks the action of proteins called tyrosine kinase receptors (RTK), which are involved in the development of new blood vessels that carry oxygen and nutrients to cells and help them grow. These proteins may be present in large quantities in cancer cells, and by blocking their action, Kisplyx can slow down the rate at which cancer cells multiply and the tumor grows, and help cut off the blood supply that cancer cells need.

2. What you need to know before you take Kisplyx

Do not take Kisplyx:

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

Warnings and precautions

Talk to your doctor before taking Kisplyx if:

• you have high blood pressure;
• you are a woman of childbearing age (see the section “Contraception, pregnancy and breast-feeding” below);
• you have a history of heart problems or stroke;
• you have liver or kidney problems;
• you have recently undergone surgery or radiotherapy;
• you are due to have surgery. Your doctor may consider stopping Kisplyx if you are having major surgery, as Kisplyx may affect wound healing. Treatment with Kisplyx can be restarted once it has been determined that the wound has healed properly.
• you are over 75 years old;
• you are not of white or Asian race;
• you weigh less than 60 kg;
• you have a history of abnormal connections (known as fistula) between different organs in the body or between an organ and the skin.
• you have had or have an aneurysm (enlargement and weakening of the wall of a blood vessel) or a tear in the wall of a blood vessel.
• you have had or have jaw pain, toothache or jaw swelling, inflammation or stomatitis, 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 jawbone damage (osteonecrosis) has been reported in patients treated with Kisplyx. If you need to have invasive dental treatment or dental surgery, tell your dentist that you are being treated with Kisplyx, especially if you are also receiving or have received injections of bisphosphonates (used to treat or prevent bone disorders);
• if you are taking or have taken certain medicines used to treat osteoporosis (anti-resorptive medicines) or cancer medicines that affect blood vessel formation (called angiogenesis inhibitors), as the risk of bone damage may be increased.

Before taking Kisplyx, your doctor may perform blood tests, for example to check your blood pressure and kidney or liver function, and to see if you have low salt levels and high thyroid-stimulating hormone levels in your blood. Your doctor will discuss the results of these tests with you and decide whether you can be given Kisplyx. You may need to receive additional treatment with other medicines, have your dose of Kisplyx reduced, or be closely monitored for a higher risk of side effects.

If you are in doubt, talk to your doctor before taking Kisplyx.

Children and adolescents

Kisplyx is not recommended for use 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. This includes herbal medicines and medicines that you buy without a prescription.

Contraception, pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

• Use highly effective contraceptive methods while you are taking this medicine and for at least one month after finishing treatment.
• Do not take Kisplyx if you are planning to become pregnant during treatment, as it may seriously harm your baby.
• If you become pregnant while being treated with Kisplyx, tell your doctor immediately. Your doctor will help you decide whether you should continue treatment.

• Do not breast-feed while you are taking Kisplyx, as the medicine passes into breast milk and may seriously harm your breast-fed baby.

Driving and using machines

Kisplyx may cause side effects that could affect your ability to drive or use machines. Avoid driving or using machines if you feel dizzy or tired.

3. How to take Kisplyx

Take this medicine exactly as your doctor has told you.

If you are not sure, ask your doctor or pharmacist.

How much to take

• 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 normally 18 mg once daily (one 10 mg capsule and two 4 mg capsules) in combination with one 5 mg everolimus tablet 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 everolimus tablet once daily. If you are receiving lenvatinib in combination with pembrolizumab, your doctor or pharmacist will check how much pembrolizumab you should receive.
• Your doctor may reduce your dose if you experience side effects.

Taking the medicine

• You can take the capsules with or without food.
• Do not open the capsules to avoid exposure to the contents.
• Swallow the capsules whole with water. If you cannot swallow the capsules whole, prepare a liquid mixture with water, apple juice or milk. The liquid mixture can be given by mouth or through a feeding tube. If it is given through a feeding tube, the liquid mixture must be prepared with water. If the liquid mixture is not used immediately, it must be stored in a closed container and refrigerated at a temperature between 2°C and 8°C for a maximum of 24 hours. Once removed from the refrigerator, shake the liquid mixture for 30 seconds. If it is not used within 24 hours of preparation, the liquid mixture must be discarded. Preparation and administration of the liquid mixture:
• • Place the capsules corresponding to the prescribed dose (up to 5 capsules) whole in a small container (about 20 ml capacity) or in an oral syringe (20 ml). Do not break or crush the capsules.
  • Add 3 ml of liquid to the container or oral syringe. Wait 10 minutes until the capsule coating (outer covering) has dissolved. Then stir or shake the mixture for 3 minutes until the capsules have completely dissolved.
  • • If the liquid mixture is prepared in an oral syringe, close the syringe, remove the plunger and use a second syringe or a calibrated dropper to add the liquid to the first syringe. Replace the plunger before shaking.
  • Drink the liquid from the container or use an oral syringe to administer it directly into the mouth or through a feeding tube.
  • Then add 2 ml more of liquid to the container or oral syringe with a second syringe or with the dropper, stir or shake the liquid mixture and administer it. Repeat this step at least twice until no visible remnants are left to ensure that all the medicine is administered.
• Take the capsules at approximately the same time every day.

How long to take Kisplyx

You will usually keep taking this medicine while you are still getting clinical benefits.

If you take more Kisplyx than you should

If you take more Kisplyx than you should, talk to your doctor or pharmacist immediately. Take the medicine pack with you.

If you forget to take Kisplyx

Do not take a double dose (two doses at the same time) to make up for forgotten doses.

The instructions that you should follow if you forget a dose will depend on how long it is until your next dose.

If there are 12 hours or more until your next dose, take the forgotten dose as soon as you remember. Then take the next dose at the usual time.

If there are less than 12 hours until your next dose, omit the forgotten dose. Then take the next dose at the usual time.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them. The following adverse effects may occur with this medicine.

Tell your doctor immediately if you experience any of the following adverse effects,

you may need urgent medical attention:

• Feeling of numbness or weakness on one side of the body, severe headache, epileptic seizures, confusion, difficulty speaking, changes in vision or dizziness; these may be signs of a stroke, bleeding in the brain or the effect of a severe increase in blood pressure in the brain.
• Chest pain or pressure, pain in the arms, back, neck or jaw, difficulty breathing, rapid or irregular heartbeats, cough, bluish color on the lips or fingers, feeling of extreme tiredness; these effects may be signs of a heart problem, a blood clot in the lung or air leakage from the lung to the chest that prevents the lung from inflating.
• Severe stomach pain (abdomen); this may be due to a hole in the intestinal wall or a fistula (a hole in the intestine that connects through a tube-like conduit to another part of the body or skin).
• Black, sticky or bloody stools, or coughing up blood; these may be signs of internal bleeding.
• Diarrhea, feeling unwell; these are very frequent adverse effects that can become severe if they cause dehydration, which in turn can cause kidney failure. Your doctor may give you a medicine to reduce these adverse effects.
• Mouth pain, tooth or jaw pain, inflammation or stomatitis, numbness or feeling of heaviness in the jaw or loosening of a tooth. These could be indicative of bone damage in the jaw (osteonecrosis).

Tell your doctor immediately if you suffer from any of the adverse effects mentioned below.

The following adverse effects may occur when the medicine is administered as monotherapy:

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

• Low platelet levels in the blood that can lead to bruising and difficulty healing wounds.
• Decrease in the number of white blood cells.
• Thyroid hormone deficiency ([hypothyroidism] fatigue, weight gain, constipation, feeling of cold, dry skin) and changes in blood tests of thyroid-stimulating hormone levels (high).
• Changes in blood tests of potassium (low) and calcium (low) levels.
• Changes in blood tests of magnesium (low) and cholesterol (high) levels.
• Weight loss or decreased appetite.
• Difficulty sleeping.
• Feeling of dizziness.
• Headache.
• Bleeding (most frequently nosebleeds, but also other types of bleeding such as blood in the urine, bruising, bleeding from the gums or intestinal wall).
• High blood pressure.
• Hoarseness.
• Nausea and vomiting, constipation, diarrhea, abdominal pain, indigestion.
• Dry, painful or inflamed mouth, strange taste sensation.
• Increased lipase and amylase (enzymes involved in digestion).
• Changes in liver function test results.
• Redness, pain and swelling of the skin on the hands and feet (palmar-plantar erythrodysesthesia).
• Skin rash.
• Hair loss.
• Back pain.
• Joint or muscle pain.
• High protein levels in the urine and urinary tract infections (increased frequency of urination and pain when urinating).
• Changes in kidney function test results 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, such as feeling of numbness or weakness on one side of the body, severe headache, epileptic seizures, confusion, difficulty speaking, changes in vision or dizziness.
• Heart palpitations.
• Heart problems or blood clots in the lungs (difficulty breathing, chest pain) or other organs, which may include chest pain or pressure, pain in the arms, back, neck or jaw, difficulty breathing, rapid or irregular heartbeats, cough, bluish color on the lips or fingers, and feeling of extreme tiredness.
• Anal fistula (a small channel that forms between the anus and the surrounding skin).
• Feeling of bloating and gas in the intestines.
• Liver failure.
• Drowsiness, confusion, lack of concentration, loss of consciousness that may be signs of liver failure.
• Inflammation of the gallbladder.
• Dry, thickened and itchy skin.
• Discomfort.
• Hole (perforation) in the stomach or intestine.

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

• Infection or painful irritation near the anus.
• Severe pain in the upper left part of the stomach (abdomen) that may be associated with fever, chills, nausea and vomiting.
• Transient ischemic attack.
• Severe respiratory difficulty and chest pain, caused by air leakage from the lung to the chest that prevents the lung from inflating.
• Pancreatitis.
• Colitis (inflammation of the colon).
• Liver damage.
• Bone damage in the jaw (osteonecrosis).
• Wound healing problems.
• Reduced secretion of hormones produced by the adrenal glands.

Frequency not known(the following adverse effects have been reported since the marketing of Kisplyx, but the frequency at which they occur is unknown):

• Increased and weakened blood vessel wall or tear of the blood vessel wall (aneurysms and arterial dissections).
• Other types of fistulas (abnormal conduit between different body organs or skin and others located below, such as the throat or trachea). Symptoms depend on the location of the fistula. Consult your doctor if you experience any new or unusual symptoms, such as coughing when swallowing.

The following adverse effects may occur when the medicine is administered in combination with everolimus:

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

• Low platelet levels in the blood that can lead to bruising and difficulty healing wounds.
• Decrease in the number of white blood cells.
• Thyroid hormone deficiency ([hypothyroidism] fatigue, weight gain, constipation, feeling of cold, dry skin) and changes in blood tests of thyroid-stimulating hormone levels (high).
• Changes in blood tests of potassium (low) and calcium (low) levels.
• Changes in blood tests of magnesium (low) and cholesterol (high) levels.
• Weight loss or decreased appetite.
• Difficulty sleeping.
• Headache.
• Bleeding (most frequently nosebleeds, but also other types of bleeding such as blood in the urine, bruising, bleeding from the gums or intestinal wall).
• High blood pressure.
• Hoarseness.
• Nausea and vomiting, constipation, diarrhea, abdominal pain, indigestion.
• Painful or inflamed mouth, strange taste sensation.
• Increased lipase and amylase (enzymes involved in digestion).
• Changes in liver function test results.
• Redness, pain and swelling of the skin on the hands and feet (palmar-plantar erythrodysesthesia).
• Skin rash.
• Back pain.
• Joint or muscle pain.
• High protein levels in the urine.
• Changes in kidney function test results 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 (increased frequency of urination and pain when urinating).
• Loss of body fluids (dehydration).
• Feeling of dizziness.
• Heart palpitations.
• Heart problems or blood clots in the lungs (difficulty breathing, chest pain) or other organs, which may include chest pain or pressure, pain in the arms, back, neck or jaw, difficulty breathing, rapid or irregular heartbeats, cough, bluish color on the lips or fingers, and feeling of extreme tiredness.
• Low blood pressure.
• Severe respiratory difficulty and chest pain, caused by air leakage from the lung to the chest that prevents the lung from inflating.
• Dry mouth.
• Feeling of bloating and gas in the intestines.
• Inflammation of the gallbladder.
• Hair loss.
• Discomfort.
• Hole (perforation) in the stomach or intestine.

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

• Infection or painful irritation near the anus.
• Signs of stroke, such as feeling of numbness or weakness on one side of the body, severe headache, epileptic seizures, confusion, difficulty speaking, changes in vision or dizziness.
• Transient ischemic attack.
• Inflammation of the pancreas.
• Anal fistula (a small channel that forms between the anus and the surrounding skin).
• Colitis (inflammation of the colon).
• Liver failure or signs of liver damage, such as yellowing of the skin or whites of the eyes (jaundice), drowsiness, confusion and lack of concentration.
• Bone damage in the jaw (osteonecrosis).
• Dry, thickened and itchy skin.
• Wound healing problems.
• Other types of fistulas (abnormal conduit between different body organs or skin and others located below, such as the throat or trachea). Symptoms depend on the location of the fistula. Consult your doctor if you experience any new or unusual symptoms, such as coughing when swallowing.
• Reduced secretion of hormones produced by the adrenal glands.

Frequency not known(the following adverse effects have been reported since the marketing of Kisplyx, but the frequency at which they occur is unknown):

• Increased and weakened blood vessel wall or tear of the blood vessel wall (aneurysms and arterial dissections).

The following adverse effects may occur when the medicine is administered in combination with pembrolizumab:

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

• Low platelet levels in the blood that can lead to bruising and difficulty healing wounds.
• Decrease in the number of white blood cells.
• Thyroid hormone deficiency ([hypothyroidism] fatigue, weight gain, constipation, feeling of cold, dry skin) and changes in blood tests of thyroid-stimulating hormone levels (high).
• Changes in blood tests of potassium (low) and calcium (low) levels.
• Changes in blood tests of magnesium (low) and cholesterol (high) levels.
• Weight loss or decreased appetite.
• Difficulty sleeping.
• Feeling of dizziness.
• Headache.
• Bleeding (most frequently nosebleeds, but also other types of bleeding such as blood in the urine, bruising, bleeding from the gums or intestinal wall).
• High blood pressure.
• Hoarseness.
• Nausea and vomiting, constipation, diarrhea, abdominal pain, indigestion.
• Dry, painful or inflamed mouth, strange taste sensation.
• Increased lipase and amylase (enzymes involved in digestion).
• Changes in liver function test results.
• Redness, pain and swelling of the skin on the hands and feet (palmar-plantar erythrodysesthesia).
• Skin rash.
• Back pain.
• Joint or muscle pain.
• High protein levels in the urine.
• Changes in kidney function test results 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 (increased frequency of urination and pain when urinating).
• Loss of body fluids (dehydration).
• Heart palpitations.
• Heart problems or blood clots in the lungs (difficulty breathing, chest pain) or other organs, which may include chest pain or pressure, pain in the arms, back, neck or jaw, difficulty breathing, rapid or irregular heartbeats, cough, bluish color on the lips or fingers, and feeling of extreme tiredness.
• Low blood pressure.
• Inflammation of the pancreas.
• Colitis (inflammation of the colon).
• Feeling of bloating and gas in the intestines.
• Inflammation of the gallbladder.

• Dry, thickened and itchy skin.
• Hair loss.

• Discomfort.
• Reduced secretion of hormones produced by the adrenal glands.
• Hole (perforation) in the stomach or intestine.

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

• Infection or painful irritation near the anus.
• Signs of stroke, such as feeling of numbness or weakness on one side of the body, severe headache, epileptic seizures, confusion, difficulty speaking, changes in vision or dizziness.
• Transient ischemic attack.
• Severe respiratory difficulty and chest pain, caused by air leakage from the lung to the chest that prevents the lung from inflating.
• Anal fistula (a small channel that forms between the anus and the surrounding skin).
• Liver failure or signs of liver damage, such as yellowing of the skin or whites of the eyes (jaundice), drowsiness, confusion and lack of concentration.
• Wound healing problems.
• Other types of fistulas (abnormal conduit between different body organs or skin and others located below, such as the throat or trachea). Symptoms depend on the location of the fistula. Consult your doctor if you experience any new or unusual symptoms, such as coughing when swallowing.

Frequency not known(the following adverse effects have been reported since the marketing of Kisplyx, but the frequency at which they occur is unknown):

• Increased and weakened blood vessel wall or tear of the blood vessel wall (aneurysms and arterial dissections).

Reporting of adverse effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that is not listed in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Kisplyx

• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiration date that appears on the box and blister pack after "EXP". The expiration date is the last day of the month indicated.
• Do not store above 25°C. Store in the original blister pack to protect from moisture.
• Medicines should not be disposed of through wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medicines you no longer need. This will help protect the environment.

6. Container contents and additional information

Kisplyx composition

• The active ingredient 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, hypromellose, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172). The capsule shell contains hypromellose, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172). The printing ink contains shellac, black iron oxide (E172), potassium hydroxide, propylene glycol.

Product appearance and container contents

• Kisplyx 4 mg hard capsule: cap and body of yellowish-red color, approximately 14.3 mm in length, with black ink inscription "?" on the cap and "LENV 4 mg" on the body.
• Kisplyx 10 mg hard capsule: cap of yellowish-red color and body of yellow color, approximately 14.3 mm in length, with black ink inscription "?" on the cap and "LENV 10 mg" on the body.
• Blister packs with an aluminum foil that breaks when pressed, in cardboard boxes of 30, 60 or 90 hard capsules.
• Only some pack sizes may be marketed.

Marketing authorization holder

Eisai GmbH

Edmund-Rumpler-Straße 3

60549 Frankfurt am Main

Germany

Email: medinfo_de@eisai.net

Manufacturer

Eisai GmbH

Edmund-Rumpler-Straße 3

60549 Frankfurt am Main

Germany

You can request more information about this medicinal product by contacting the local representative of the marketing authorization holder:

Date of last revision of this prospectus:

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