Package Insert: Information for the User

Kisplyx 4 mg Hard Capsules

Kisplyx 10 mg Hard Capsules

Lenvatinib

Read this package insert carefully before you start taking this medicine, because it contains important information for you.

• Keep this package insert, as you may need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• This medicine has been prescribed for you only, and you must not give it to others even if they have the same symptoms as you, as it may harm them.
• If you experience any side effects, consult your doctor, pharmacist, or nurse, even if they are not listed in this package insert. See section 4.

What is Kisplyx

Kisplyx is a medication that contains the active ingredient 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 (called vascular endothelial growth factor (VEGF) targeted therapies) have not helped to stop the disease.

How Kisplyx works

Kisplyx blocks the action of proteins called receptor tyrosine kinases (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.

Do not take Kisplyx:

• if you are allergic to lenvatinib or any of the other components of this medication (listed in section 6);
• if you are breastfeeding your child (see the section below on Contraception, pregnancy, and breastfeeding).

Warnings and precautions

Consult your doctor before starting to take Kisplyx if:

• you have high blood pressure;
• you are a fertile woman (see the section “Contraception, pregnancy, and breastfeeding” below);
• you have a history of heart problems or stroke;
• you have liver or kidney problems;
• you have recently undergone surgery or radiation therapy;
• you are scheduled to undergo surgery. Your doctor may consider suspending Kisplyx if you undergo major surgery, as Kisplyx may affect wound healing. Treatment with Kisplyx can be resumed once wound healing is deemed adequate.
• you are over 75 years old;
• you are not of Caucasian or Asian descent;
• you weigh less than 60 kg;
• you have a history of abnormal passageways (known as fistula) between different organs of the body or between an organ and the skin.
• you have or have had an aneurysm (enlargement and weakening of the wall of a blood vessel) or a tear in the wall of a blood vessel.
• you have or have had jaw pain, tooth pain, or mandibular pain, inflammation, or stomatitis, numbness, or heaviness in the mandible, or loosening of a tooth. You may be advised to undergo a dental examination before starting Kisplyx, as osteonecrosis of the mandible has been reported in patients treated with Kisplyx. If you need to undergo invasive dental treatment or dental surgery, inform your dentist that you are being treated with Kisplyx, particularly if you are also receiving or have received bisphosphonate injections (used to treat or prevent bone disorders);
• if you are receiving or have received some medications used to treat osteoporosis (bone-resorbing inhibitors) or medications used to treat cancer that alter blood vessel formation (angiogenesis inhibitors), as the risk of bone damage may be increased.

Before starting to take Kisplyx, your doctor may perform some blood tests, for example, to check your blood pressure and renal or hepatic function, and to see if you have low sodium levels and high thyroid-stimulating hormone levels in your blood. Your doctor will discuss the results of these tests with you and decide if you can be given Kisplyx. You may need to receive additional treatment with other medications, reduce the dose of Kisplyx, or take extra precautions due to an increased risk of adverse effects.

In case of doubt, consult your doctor before taking Kisplyx.

Children and adolescents

Kisplyx is not currently recommended for use in children and adolescents under 18 years of age.

Other medications and Kisplyx

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take any other medication. This includes herbal medications and over-the-counter medications.

Contraception, pregnancy, and breastfeeding

If you are pregnant or breastfeeding, or think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medication.

• Use highly effective contraceptive methods while taking this medication and for at least one month after completing treatment.
• Do not take Kisplyx if you are planning to become pregnant during treatment, as it may severely harm your baby.
• If you become pregnant while receiving treatment with Kisplyx, inform your doctor immediately. Your doctor will help you decide whether to continue treatment.

• Do not breastfeed while taking Kisplyx, as the medication passes into breast milk and may severely harm your breastfeeding baby.

Driving and operating machinery

Kisplyx may cause side effects that may affect your ability to drive or operate machinery. Avoid driving or operating machinery if you feel dizzy or tired.

Follow exactly the administration instructions of this medication indicated by your doctor.

In case of doubt, consult your doctor or pharmacist again.

How much to take

• The recommended daily dose of Kisplyx is 20mg once a day (two 10mg capsules) in combination with pembrolizumab (200mg every 3weeks or 400mg every 6weeks) administered as an intravenous infusion for 30minutes.
• The recommended daily dose of Kisplyxis normally 18mg once a day (one 10mg capsule and two 4mg capsules) in combination with a 5mg tablet of everolimus once a day.
• If you have severe liver or kidney problems, the recommended daily dose of Kisplyxis 10mg once a day (one 10mg capsule) in combination with a 5mg tablet of everolimus once a day. If you are receiving lenvatinib combined 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.

Medication intake

• You can take the capsules with or without food.
• Do not break the capsules to avoid exposure to their 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 administered orally or through a feeding tube. If administered through a feeding tube, the liquid mixture must be prepared with water. If the liquid mixture is not used at the time of preparation, it must be stored in a covered container and refrigerated at a temperature between 2°C and 8°C for a maximum of 24hours. Once removed from the refrigerator, shake the liquid mixture for 30seconds. If not used within 24hours from preparation, the liquid mixture must be discarded.
  Preparation and administration of the liquid mixture:
• • Place the corresponding capsules for the prescribed dose (up to 5capsules) whole in a small container (approximately 20ml in capacity) or in an oral syringe (20ml). Do not break or crush the capsules.
  • Add 3ml of liquid to the container or oral syringe. Wait 10minutes until the capsule coating (outer coating) dissolves. Then, remove or shake the mixture for 3minutes until the capsules have completely dissolved.
  • • If the liquid mixture is prepared in an oral syringe, cover the syringe, pull back the plunger, and use a second syringe or a calibrated dropper to add the liquid to the first syringe. Replace the plunger before shaking it.
  • Drink the liquid from the container or use an oral syringe to administer it directly to the mouth or through a feeding tube.
  • Then, add 2ml more of liquid to the container or oral syringe with a second syringe or with the dropper, remove or shake the liquid mixture, and administer it. Repeat this step at least twice until no visible residue remains to ensure that all the medication is administered.
• Take the capsules approximately at the same time every day.

For how long should you take Kisplyx

You will generally continue to take this medication as long as you continue to receive clinical benefits.

If you take more Kisplyx than you should

If you take more Kisplyx than you should, consult your doctor or pharmacist immediately. Bring the medication packaging with you.

If you forgot to take Kisplyx

Do not take a double dose (two doses at the same time) to compensate for the missed doses.

The schedule you should follow if you forget to take a dose will depend on how much time is left 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 the next dose at the usual time.

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

Like all medicines, this medicine can cause side effects, although not everyone will experience them. The following side effects may occur with this medicine.

Inform your doctor immediately if you experience any of the following side effects,

you may need urgent medical attention:

• Numbness or weakness in one side of the body, severe headache, seizures, confusion, difficulty speaking, changes in vision or dizziness; these may be signs of a stroke, brain hemorrhage, or severe increase in blood pressure in the brain.
• Chest pain or pressure, arm, back, neck, or jaw pain, difficulty breathing, rapid or irregular heartbeat, cough, blue lips or fingers, feeling extremely tired; these effects may be signs of a heart problem, blood clot in the lung, or air leak from the lung into the chest that prevents the lung from inflating.
• Severe stomach pain; this may be due to a hole in the intestinal wall or a fistula (a hole in the intestine that connects to another part of the body or skin through a tube-like structure).
• Black, sticky, or bloody stools, or coughing up blood; these may be signs of internal bleeding.
• Diarrhea, feeling unwell; these are very common side 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 side effects.
• Mouth, tooth, or jaw pain, inflammation, or stomatitis, numbness or heaviness in the jaw, or loose teeth. These may be signs of jaw bone damage (osteonecrosis).

Inform your doctor immediately if you experience any of the side effects mentioned below.

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

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

• Low platelet count in the blood that can cause bruising and difficulty healing wounds.
• Decreased white blood cell count.
• Thyroid hormone deficiency ([hypothyroidism] fatigue, weight gain, constipation, feeling cold, dry skin) and changes in blood test results for thyroid-stimulating hormone (high levels).
• Changes in blood test results for potassium (low levels) and calcium (low levels).
• Changes in blood test results for magnesium (low levels) and cholesterol (high levels).
• Weight loss or decreased appetite.
• Difficulty sleeping.
• Dizziness.
• Headache.
• Bleeding (more frequently nosebleeds, but also other types of bleeding such as blood in the urine, bruises, gum bleeding, or intestinal wall bleeding).
• High or low 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 (erythromelalgia).
• Skin rash.
• Hair loss.
• Back pain.
• Muscle or joint pain.
• High levels of protein in the urine and urinary tract infections (increased frequency of urination and pain while urinating).
• Changes in kidney function test results and kidney failure.
• Feeling extremely tired or weak.
• Swelling of the legs.

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

• Fluid loss (dehydration).
• Signs of stroke, such as numbness or weakness in 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 other organs, which may include chest pain or pressure, arm, back, neck, or jaw pain, difficulty breathing, rapid or irregular heartbeat, cough, blue lips or fingers, and feeling extremely tired.
• Anal fistula (a small channel that forms between the anus and the skin around it).
• Feeling bloated and having gas in the intestines.
• Liver failure.
• Drowsiness, confusion, lack of concentration, loss of consciousness that may be signs of liver failure.
• Gallbladder inflammation.
• Dry, thickened, and itchy skin.
• Discomfort.
• Hole (perforation) in the stomach or intestine.

Rare(may affect up to1 in 100people):

• Infection or painful irritation near the anus.
• Severe chest pain and difficulty breathing, caused by air leaking from the lung into the chest that prevents the lung from inflating.
• Pancreatitis.
• Colitis.
• Liver damage.
• Jaw bone damage (osteonecrosis).
• Wound healing problems.
• Adrenal gland hormone reduction.

Unknown frequency(the following side effects have been reported since the commercialization ofKisplyx, but the frequency with which they occur is unknown):

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

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

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

• Low platelet count in the blood that can cause bruising and difficulty healing wounds.
• Decreased white blood cell count.
• Thyroid hormone deficiency ([hypothyroidism] fatigue, weight gain, constipation, feeling cold, dry skin) and changes in blood test results for thyroid-stimulating hormone (high levels).
• Changes in blood test results for potassium (low levels) and calcium (low levels).
• Changes in blood test results for magnesium (low levels) and cholesterol (high levels).
• Weight loss or decreased appetite.
• Difficulty sleeping.
• Dizziness.
• Headache.
• Bleeding (more frequently nosebleeds, but also other types of bleeding such as blood in the urine, bruises, gum bleeding, or intestinal wall bleeding).
• 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 (erythromelalgia).
• Skin rash.
• Back pain.
• Muscle or joint pain.
• High levels of protein in the urine.
• Changes in kidney function test results and kidney failure.
• Feeling extremely tired or weak.
• Swelling of the legs.

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

• Urinary tract infections (increased frequency of urination and pain while urinating).
• Fluid loss (dehydration).
• Dizziness.
• Palpitations.
• Heart problems or blood clots in the lungs (difficulty breathing, chest pain) or other organs, which may include chest pain or pressure, arm, back, neck, or jaw pain, difficulty breathing, rapid or irregular heartbeat, cough, blue lips or fingers, and feeling extremely tired.
• Low blood pressure.
• Pancreatitis.
• Colitis.
• Feeling bloated and having gas in the intestines.
• Gallbladder inflammation.

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

• Discomfort.
• Adrenal gland hormone reduction.
• Hole (perforation) in the stomach or intestine.

Rare(may affect up to1 in 100people):

• Infection or painful irritation near the anus.
• Signs of stroke, such as numbness or weakness in one side of the body, severe headache, seizures, confusion, difficulty speaking, changes in vision or dizziness.
• Transient ischemic attack.
• Pancreatitis.
• Anal fistula (a small channel that forms between the anus and the skin around it).
• Colitis.
• Liver failure or signs of liver damage, such as yellow skin or eyes (jaundice), drowsiness, confusion, and lack of concentration.
• Jaw bone damage (osteonecrosis).
• Dry, thickened, and itchy skin.
• Wound healing problems.
• Other types of fistulas (abnormal channel between different organs of the body or skin and others located below, such as the throat or trachea). Symptoms depend on where the fistula is located. Consult your doctor if you experience any new or unusual symptoms, such as difficulty swallowing.
• Adrenal gland hormone reduction.

Unknown frequency(the following side effects have been reported since the commercialization ofKisplyx, but the frequency with which they occur is unknown):

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

Reporting of side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through theSistema Español de Farmacovigilancia de Medicamentos de uso Humano:https://www.notificaram.es.By reporting side effects, you can contribute to providing more information on the safety of this medicine.

• Keep this medication out of the sight and reach of children.
• Do not use this medication after the expiration date that appears on the box and the blister pack after “CAD”. 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 it from moisture.
• Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the containers and medications that you no longer need. This will help protect the environment.

Composition of Kisplyx

• The active ingredient is lenvatinib.

• Kisplyx 4 mg hard capsules: each hard capsule contains 4 mg of lenvatinib (as mesylate).
• Kisplyx 10 mg hard capsules: each hard capsule contains 10 mg of lenvatinib (as mesylate).

• The other components are calcium carbonate, mannitol, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose with low substitution, talc. 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.

Appearance of the product and contents of the pack

• Kisplyx 4 mg hard capsule: red-yellow cap and body, 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: red-yellow cap and yellow body, approximately 14.3 mm in length, with black ink inscription “?” on the cap and “LENV 10 mg” on the body.
• Aluminium foil blisters that break on pressing in cartons 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: [email protected]

Responsible Person for Manufacture

Eisai GmbH

Edmund-Rumpler-Straße 3

60549 Frankfurt am Main

Germany

For further information about this medicinal product, please consult the representative of the marketing authorisation holder in your country:

Last update of the summary of product characteristics:

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