Consumer medicine information

Lenvima

Lenvatinib

BRAND INFORMATION

Brand name

Lenvima

Active ingredient

Lenvatinib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lenvima.

SUMMARY CMI

LENVIMA®

Consumer Medicine Information (CMI) summary

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

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

1. WHY AM I USING LENVIMA?

LENVIMA contains the active ingredient Lenvatinib (as lenvatinib mesilate). LENVIMA is used to treat patients with thyroid cancer, advanced kidney cancer (advanced renal cell carcinoma), liver cancer or endometrial cancer.

For more information, see Section 1. Why am I using LENVIMA? in the full CMI.

2. WHAT SHOULD I KNOW BEFORE I USE LENVIMA?

Do not use if you have ever had an allergic reaction to LENVIMA or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use LENVIMA? in the full CMI.

3. WHAT IF I AM TAKING OTHER MEDICINES?

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

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

4. HOW DO I USE LENVIMA?

  • The recommended dose of LENVIMA changes depending on which cancer LEVIMA is being used to treat. Your doctor will tell you the correct dose

More instructions can be found in Section 4. How do I use LENVIMA? in the full CMI.

5. WHAT SHOULD I KNOW WHILE USING LENVIMA?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking LENVIMA.
  • Keep all of your doctor's appointments so that your progress can be checked.
Things you should not do
  • Do not stop using this medicine suddenly or change the dose without checking with your doctor.
  • Do not take LENVIMA to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
Driving or using machines
  • Do not drive or operating machinery until you know how LENVIMA affects you
Drinking alcohol
  • Avoid alcohol while taking LENVIMA as it may make these effects worse.
Looking after your medicine
  • Keep your medicine out of the reach of children.
  • Keep your medicine in the original container in a cool dry place where the temperature stays below 30°C.

For more information, see Section 5. What should I know while using LENVIMA? in the full CMI.

6. ARE THERE ANY SIDE EFFECTS?

Tell your doctor straight away if you notice any of the following side effects; you may need urgent medical attention:

  • Are feeling numb or weak on one side of your body, severe headache, seizure or fit, confusion, difficulty talking, vision changes or feeling dizzy
  • Have chest pain or pressure, pain in your arms, back, neck, jaw, being short of breath, rapid or irregular heart rate, coughing, bluish colour to the lips or fingers, feeling very tired
  • Have severe pain in your belly (abdomen)
  • Have black, tarry, or bloody stools, or coughing up of blood
  • Have yellow skin or yellowing of the whites of the eyes (jaundice) or drowsiness, confusion, poor concentration
  • Have diarrhoea, feeling and being sick
  • Have pain in the mouth, teeth and/or jaw.

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

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

LENVIMA®

Active ingredient(s): lenvatinib (as lenvatinib mesilate)

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using LENVIMA?

LENVIMA contains the active ingredient Lenvatinib (as Lenvatinib mesilate). LENVIMA is a tyrosine kinase Inhibitor (TKI).

LENVIMA blocks the action of proteins called receptor tyrosine kinases (RTKs), which are involved in the development of new blood vessels that supply oxygen and nutrients to cells and help them to grow. These proteins can be present in high amounts in cancer cells, and by blocking their action LENVIMA may slow the rate at which the cancer cells multiply and the tumour grows and by helping to cut off the blood supply that the cancer needs.

LENVIMA is used to treat thyroid cancer in adults when radioactive iodine treatment has not helped to stop your disease.

It is also used in combination to treat patients with advanced kidney cancer (advanced renal cell carcinoma):

  • LENVIMA may be used with the medicine pembrolizumab as your first treatment when your kidney cancer has spread or cannot be removed by surgery.
  • LENVIMA may be used with the medicine everolimus after one course of treatment with another anti-cancer medicine.

It is also used to treat liver cancer (hepatocellular carcinoma).

It is also used (along with another medicine called pembrolizumab) to treat a kind of uterine cancer called endometrial carcinoma, if laboratory tests show the cancer is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) and other treatments have not helped stop the disease.

2. What should I know before I use LENVIMA?

Before taking LENVIMA, your doctor may carry out some blood tests, for example to check your blood pressure and your liver or kidney function and to see if you have low levels of salt and high levels of thyroid stimulating hormone in your blood. Your doctor will discuss the results of these tests with you and decide whether you can be given LENVIMA. You may need to have additional treatment with other medicines, to take a lower dose of LENVIMA, or to take extra care due to an increased risk of side effects.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Warnings

Do not use LENVIMA if:

  • you are allergic to Lenvatinib (as Lenvatinib mesilate), or any of the ingredients listed at the end of this leaflet.
  • you are breast-feeding.
  • Always check the ingredients to make sure you can use this medicine.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Check with your doctor if you:

  • Have high blood pressure
  • are a woman able to become pregnant
  • Have a history of heart problems or stroke
  • Are over 75 years of age
  • Have had recent surgery or radiotherapy
  • Have liver or kidney problems
  • have had recent surgery or radiotherapy
  • take any medicines for any other condition
  • need to have a surgical procedure. Your doctor may consider stopping LENVIMA if you will be undergoing a major surgical procedure as LENVIMA may affect wound healing. LENVIMA may be restarted once adequate wound healing is established.
  • have or have had pain in the mouth, teeth and/or jaw, swelling or sores inside 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 LENVIMA as bone damage in the jaw (osteonecrosis) has been reported in patients treated with LENVIMA. If you need to undergo an invasive dental treatment or dental surgery, tell your dentist that you are being treated with LENVIMA, particularly when you are also receiving or have received injections of bisphosphonates (used to treat or prevent bone disorders).
  • are receiving or have received some medicines used to treat osteoporosis (antiresorptive medicines) or cancer medicines which alter formation of blood vessels (so called angiogenesis inhibitors), as the risk of bone damage in the jaw may be increased.
  • belong to an ethnic group other than white or Asian
  • weigh less than 60 kg
  • have a history of abnormal passageways (known as a fistula) between different organs in the body or from an organ to the skin
  • If you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in a blood vessel wall.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

LENVIMA is not recommended in pregnancy.

You must use a highly effective method of contraception to avoid becoming pregnant while you are taking LENVIMA. You should continue doing this for one month after stopping treatment.

Do not breast-feed if you are taking LENVIMA. This is because the medicine may pass into breast milk and may seriously harm your breastfed baby.

Children and Teenagers

Do not give this medicine to anyone under the age of 18 years. LENVIMA is not recommended for use in children and teenagers. The effects of LENVIMA in people younger than 18 years old are not known.

Safety and effectiveness in children younger than 18 years have not been established.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

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

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

4. How do I use LENVIMA?

How much to take / use

Thyroid Cancer

  • If you have thyroid cancer, the recommended dose for this medicine is 24 mg once a day (taken as 2 x 10 mg capsules and 1 x 4 mg capsule).
  • If you have severe liver or kidney problems your doctor may prescribe a lower dose of 14 mg once a day (taken as 1 x 10 mg capsule and 1 x 4 mg capsule).

Kidney Cancer

  • If you have advanced kidney cancer and you have been prescribed Lenvima in combination with pembrolizumab, the recommended daily dose for Lenvima is 20 mg once a day (two 10-mg capsules) in combination with pembrolizumab. Your doctor will also give you an intravenous infusion of pembrolizumab for about 30 minutes every three weeks or every six weeks depending on the dose you are given.
  • If you have advanced kidney cancer and you have been prescribed Lenvima in combination with everolimus, the recommended dose for Lenvima is 18 mg once a day (taken as 1 x 10 mg capsule and 2 x 4 mg capsules) in combination with one 5 mg tablet of everolimus once a day.
  • If you have severe liver or kidney problems your doctor may prescribe a lower dose of 10 mg once a day (taken as 1 x 10 mg capsule). Your doctor will check to see how much pembrolizumab or everolimus you should receive.

Liver Cancer

  • It you have liver cancer. the recommended dose for this medicine is usually 12 mg if your body weight is equal to or more than 60 kg (3 capsules of 4 mg) and 8 mg if your body weight is less than 60 kg ( 2 capsules of 4 mg) once a day.

Endometrial carcinoma

  • If you have endometrial carcinoma, the recommended dose for this medicine is 20 mg once a day (taken as 2 x 10 mg capsules). Your doctor will also give you an intravenous infusion of pembrolizumab for about 30 minutes every three weeks or every six weeks depending on the dose you are given.
  • If you have severe liver or kidney problems your doctor may prescribe a lower dose of 10 mg once a day (taken as 1 x 10 mg capsule). Your doctor will check to see how much pembrolizumab you should receive.

Your doctor may have prescribed a different dose.

Your doctor may decrease your dose if you have problems with side effects.

Follow the instructions provided and use LENVIMA until your doctor tells you to stop.

Ask your doctor or pharmacist if you are unsure of the correct dose for you. They will tell you exactly how much to take.

Follow the instructions they give you.

If you take the wrong dose, LENVIMA may not work as well and your problem may not improve.

When to take LENVIMA

  • LENVIMA should be taken at about the same time each day.
  • Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How to take LENVIMA

Swallow the capsules whole with a full glass of water. If unable to swallow the capsule whole, then place the capsule in a glass of about 25 mL of water or apple juice without breaking or crushing the capsules.

Do not mix more than one medicine in the glass at the same time.

Let the capsules disintegrate for about 10 minutes and then gently stir for at least 3 minutes to dissolve the capsule shells. Then swallow the suspension. After drinking, add the same amount of water or apple juice to the glass and gently swirl it around and swallow the mixture.

The person preparing the suspension should thoroughly wash their hands before and after the suspension is prepared and the dose taken.

You can take LENVIMA with or without food.

Do not chew, crush or split the capsules. To ensure you get the entire dose, the capsules should be swallowed whole without chewing or crushing.

Caregivers should not open capsules to avoid exposure to the contents of the capsule.

If you forget to use LENVIMA

LENVIMA should be used regularly at the same time each day.

If it is 12 hours or more until your next dose, take the missed dose as soon as you remember. Then take the next dose at the normal time. If it is less than 12 hours until your next dose, skip the missed dose. Then take your next dose at the normal time.

Do not take a double dose to make up for the dose that you missed.

This may increase the chance of you getting an unwanted side effect.

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

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you use too much LENVIMA

If you think that you have used too much LENVIMA, you may need urgent medical attention.

You should immediately:

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

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

5. What should I know while using LENVIMA?

Things you should do

Call your doctor straight away if you:

  • If you do not feel well while you are taking LENVIMA.
  • If you become pregnant while taking LENVIMA. Do not stop treatment without first discussing it with your doctor.

Remind any doctor, dentist or pharmacist you visit that you are using LENVIMA.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking LENVIMA. It may affect other medicines used during surgery.

If you are about to have any blood tests, tell your doctor that you are taking LENVIMA. It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked.

Things you should not do

  • Do not stop using this medicine suddenly.
  • Do not take LENVIMA to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not stop taking your medicine or lower the dosage without checking with your doctor.

Patients starting LENVIMA should be carefully observed especially when starting treatment and if the dose is increased.

Driving or using machines

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

LENVIMA may cause side effects that can affect your ability to drive or use machines.

LENVIMA may make you feel dizzy or sleepy, particularly at the beginning of treatment. If this happens to you, do not drive or use any tools or machines.

Drinking alcohol

Tell your doctor if you drink alcohol.

Avoid alcohol while taking LENVIMA as it may make these effects worse.

Looking after your medicine

  • Keep your medicine in the original container.
  • If you take it out of its original container it may not keep well
  • Keep your medicine in a cool dry place where the temperature stays below 30°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If the medicine has expired or the packing is damaged, return it to your pharmacist for disposal.

When to discard your medicine

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Your doctor may do blood tests to check for side effects.

Other side effects not listed here may occur in some people.

Serious side effects

When you take LENVIMA, you may have some serious side effects. These side effects can sometimes become life-threatening and can lead to death. These side effects may happen anytime during treatment or even after your treatment has ended. You may experience more than one side effect at the same time.

If you have any of the following symptoms, call or see your doctor right away.

Serious side effectsWhat to do
Signs and symptoms of a stroke or mini-stroke, bleeding on your brain or the effect on your brain of a severe increase in blood pressure:
  • feeling numb or weak on one side of your body,
  • severe headache
  • seizure or fit
  • confusion
  • difficulty talking
  • vision changes
  • feeling dizzy
Signs and symptoms of a heart problem or a blood clot in your lungs or a leak of air from your lung into your chest so your lung cannot inflate:
  • chest pain or pressure, pain in your arms, back, neck, jaw
  • being short of breath
  • rapid or irregular heart rate
  • coughing
  • bluish colour to the lips or fingers
  • feeling very tired
Signs and symptoms of a hole in the wall of your gut or a fistula (a hole your gut which links through a tube-like passage to another part of your body or skin):
  • have severe pain in your belly (abdomen)
  • other types of fistulae (an abnormal connection between different organs in the body or from the skin to an underlying structure such as throat and windpipe). Symptoms would depend on where the fistula is located. Talk to your doctor if you experience any new or unsual symptoms such as coughing when swallowing
Signs and symptoms of bleeding inside your body:
  • have black, tarry, or bloody stools
  • coughing up of blood
  • severe pain in the back, chest or abdomen associated with tearing in the wall of the aorta and internal bleeding
Signs and symptoms of liver problems including liver failure:
  • yellow skin or yellowing of the whites of the eyes (jaundice)
  • drowsiness, confusion, poor concentration, loss of consciousness
Signs and symptoms of bone damage in the jaw (osteonecrosis):
  • pain in the mouth, teeth and/or jaw
  • swelling or sores inside the mouth
  • numbness or a feeling of heaviness in the jaw
  • loosening of a tooth
Very common side effects that can become serious if they cause you to become dehydrated, which can lead to kidney failure. Your doctor can give you medicine to reduce these side effects:
  • diarrhoea
  • feeling and being sick
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Less serious side effects

The following side effects have been reported in clinical trials:

Less serious side effectsWhat to do
Hormone related:
  • underactive thyroid (tiredness, weight gain, constipation, feeling cold, dry skin)
Gastrointestinal related:
  • feeling sick and being sick, constipation, diarrhoea, stomach pain, indigestion
  • dry, sore or inflamed mouth, odd taste sensation
  • feeling bloated or gas in the bowel
  • inflammation of the pancreas causing severe pain in the upper left part of the belly (abdomen) which may be associated with fever, chills, nausea and vomiting
  • anal fistula (a small channel that forms between the anus and surrounding skin)
General disorders:
  • feeling very tired or weak
  • swelling of the legs
  • feeling unwell
Muscle or bone related:
  • swelling and inflammation of the joints, and stiff muscles, bones and joints
  • pain – muscle, joint, back
Nervous system related:
  • feeling dizzy
  • headache
Blood test related:
  • changes in blood test results for magnesium (low), potassium levels (low and high), calcium levels (low), cholesterol (high) and thyroid stimulating hormone (high), high lipase and amylase levels (enzymes involved in digestion), high creatinine levels (blood test results for kidney function). decreases in the number of white blood cells
  • changes in blood test results for liver function
  • changes in blood test results for kidney function (high blood urea levels)
Metabolism related:
  • loss of appetite or weight loss
  • loss of body fluids (dehydration)
Psychiatric related:
  • trouble sleeping
  • feeling sleepy (drowsiness or somnolence)
Liver or gallbladder related:
  • liver damage
  • inflammation of the gallbladder
Infection related:
  • urinary infections (increased frequency in urination and difficult or painful passing of urine)
  • painful infection or irritation near the anus
Kidney or bladder related:
  • reduced kidney function or failure
  • increased protein in the urine
Breathing or respiratory system related:
  • cough or hoarse voice
Skin related:
  • rash
  • redness, soreness and swelling of the skin on the hands and feet (hand-foot syndrome)
  • dry skin, thickening and itching of skin
  • hair loss
  • wound healing problems
Heart or circulatory system related:
  • high or low blood pressure
  • heart palpitations
  • bleeding (most commonly nose bleeds, but may include bleeding from other sites such as blood in the urine, bruising, bleeding from the gums or gut wall)
  • bruising – signs of low level of platelets in the blood
  • Bulging and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections)
Speak to your doctor if you have any of these less serious side effects and they worry you.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What LENVIMA contains

Active ingredient
(main ingredient)		lenvatinib (as lenvatinib mesilate)
Other ingredients
(inactive ingredients)

Calcium carbonate

Mannitol

Cellulose – microcrystalline

Hydroxypropylcellulose, Low-substituted hydroxypropylcellulose

Talc – purified

Hypromellose

Titanium dioxide

Iron oxide yellow

Iron oxide red

Shellac

Iron oxide black

Potassium hydroxide

Propylene glycol

Potential allergensnone

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

What LENVIMA looks like

4 mg hard capsule: A yellowish-red body and yellowish-red cap, approximately 14.3 mm in length, marked in black ink with “Є” on the cap, and “LENV 4 mg” on the body.

10 mg hard capsule: A yellow body and yellowish-red cap, approximately 14.3 mm in length, marked in black ink with “Є” on the cap, and “LENV 10 mg” on the body.

Australian Register Numbers:

AUST R 233425: LENVIMA lenvatinib 4mg hard capsule blister pack

AUST R 233426: LENVIMA lenvatinib 10mg hard capsule blister pack

Who distributes LENVIMA

Eisai Australia Pty Ltd
Level 2, 437 St Kilda Road
Melbourne, VIC, 3004
[email protected]

This leaflet was prepared in April 2022.

Published by MIMS June 2022

BRAND INFORMATION

Brand name

Lenvima

Active ingredient

Lenvatinib

Schedule

S4

 

1 Name of Medicine

Lenvatinib as lenvatinib mesilate.

2 Qualitative and Quantitative Composition

Each Lenvima 4 mg hard capsule contains 4 mg lenvatinib (as mesilate).
Each Lenvima 10 mg hard capsule contains 10 mg lenvatinib (as mesilate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Hard capsule.
Lenvima 4 mg hard capsule: A yellowish-red body and yellowish-red cap, approximately 14.3 mm in length, marked in black ink with [lunate epsilon symbol] on the cap, and "LENV 4 mg" on the body.
Lenvima 10 mg hard capsule: A yellow body and yellowish-red cap, approximately 14.3 mm in length, marked in black ink with [lunate epsilon symbol] on the cap, and "LENV 10 mg" on the body.

4 Clinical Particulars

4.1 Therapeutic Indications

Endometrial carcinoma.

Lenvima, in combination with pembrolizumab, is indicated for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

Differentiated thyroid cancer (DTC).

Lenvima is indicated for the treatment of patients with progressive, locally advanced or metastatic, radioactive iodine (RAI) refractory differentiated thyroid cancer (DTC).

Renal cell carcinoma (RCC).

Lenvima, in combination with pembrolizumab, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).
Lenvima, in combination with everolimus, is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) whose disease has progressed following one prior vascular endothelial growth factor targeted therapy.

Hepatocellular carcinoma (HCC).

Lenvima is indicated for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC).

4.2 Dose and Method of Administration

Lenvima treatment should be supervised by a health care professional experienced in the use of anticancer therapies.

Starting dose in RAI - refractory differentiated thyroid cancer (DTC).

The recommended dose of Lenvima is 24 mg orally once daily.
Treatment should continue as long as there is clinical benefit or until unacceptable toxicity occurs.

Starting dose in advanced renal cell carcinoma.

First-line treatment of patients with advanced RCC.

The recommended dosage of Lenvima is 20 mg orally once daily in combination with pembrolizumab either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes until disease progression or until unacceptable toxicity.
Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information.

Previously treated RCC.

The recommended dose of Lenvima is 18 mg orally once daily in combination with 5 mg everolimus orally once daily. Treatment should continue as long as there is clinical benefit or until unacceptable toxicity occurs.

Starting dose in hepatocellular carcinoma.

The recommended dose of Lenvima is based on actual body weight:
8 mg orally once daily for patients with a body weight of < 60 kg; or
12 mg orally once daily for patients with a body weight of ≥ 60 kg.
Treatment should continue as long as there is clinical benefit or until unacceptable toxicity occurs.

Starting dose in endometrial carcinoma.

The recommended dose of Lenvima is 20 mg orally once daily, in combination with pembrolizumab either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. Treatment should continue as long as there is clinical benefit or until unacceptable toxicity occurs. Refer to the pembrolizumab product information for recommended pembrolizumab dosing information.

Dose adjustment during therapy.

Management of adverse reactions may require dose interruption, adjustment, or discontinuation of Lenvima. For toxicities thought to be related to Lenvima, general advice about dose management is included in Table 1, and recommendations for dose reduction increments are in Table 2.
When administering Lenvima in combination with pembrolizumab, interrupt one or both drugs, dose reduce or discontinue Lenvima as appropriate. Withhold or discontinue pembrolizumab in accordance with the instructions in the pembrolizumab product information. No dose reductions are recommended for pembrolizumab.
When administering Lenvima in combination with everolimus, for toxicities thought to be related to both drugs, Lenvima should be interrupted or reduced prior to reducing everolimus. For toxicities thought to be related only to everolimus, everolimus treatment should be interrupted, reduced to alternate day dosing, or discontinued (see the everolimus PI for advice on specific adverse reactions).
Medical management of nausea, vomiting and diarrhoea should be optimised to reduce the risk of dehydration and renal failure (see Section 4.4 Special Warnings and Precautions for Use, Renal failure and impairment) prior to any Lenvima therapy interruption or dose reduction.

Special populations.

Dose adjustment in severe hepatic impairment.

A reduced starting dose of Lenvima is recommended for patients with DTC, RCC or endometrial carcinoma who have severe hepatic impairment (Child-Pugh C):
14 mg orally once daily for DTC;
10 mg orally once daily for RCC;
10 mg orally once daily for endometrial carcinoma.
The available data do not allow for a dosing recommendation for patients with HCC and moderate hepatic impairment (Child-Pugh B). The available data do not allow for a dosing recommendation for patients with HCC and severe hepatic impairment (Child-Pugh C), and use in this population is not recommended.

Dose adjustment in renal impairment.

A reduced starting dose of Lenvima is recommended for patients with DTC, RCC or endometrial carcinoma who have severe renal impairment (CrCL < 30 mL/min):
14 mg orally once daily for DTC;
10 mg orally once daily for RCC;
10 mg orally once daily for endometrial carcinoma.
Lenvima has not been studied in patients with end stage renal disease, and use in this population is not recommended.
The available data do not allow for a dosing recommendation for patients with HCC and severe renal impairment, and use in this population is not recommended.

Paediatric population.

Lenvima should not be used in children younger than 2 years of age because of safety concerns identified in animal studies. The safety and efficacy of Lenvima in children aged 2 to < 18 years have not yet been established (see Section 5.1 Pharmacodynamic Properties, Clinical trials). No data are available.

Method of administration.

Lenvima should be taken at about the same time each day, with or without food. The capsules should be swallowed whole with water.
Alternatively, if unable to swallow the capsule whole place the capsule, without breaking or crushing, in a glass of approximately 25 mL of water or apple juice. The capsules must be left to disintegrate in the liquid for at least 10 minutes and then gently stirred for at least 3 minutes to dissolve the capsules shells. The suspension is to be swallowed. After drinking, the same amount of water or apple juice (25 mL) must be added to the glass and swirled a few times. The additional liquid must be swallowed. Do not mix more than one medicine in the glass at the same time.
The person preparing the suspension should ensure their hands are thoroughly washed on completion of preparation and taking of the medication.
If a patient misses a dose, and it cannot be taken within 12 hours, then that dose should be skipped and the next dose should be taken at the usual time of administration.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Gastrointestinal toxicity: diarrhoea and dehydration.

Diarrhoea has been reported frequently in patients treated with Lenvima usually occurring early in the course of treatment (see Section 4.8 Adverse Effects (Undesirable Effects), Selected adverse reactions in DTC, RCC and HCC). Prompt medical management of diarrhoea should be instituted in order to prevent dehydration. Lenvima should be discontinued in the event of persistent Grade 4 diarrhoea despite medical management (see Section 4.2 Dose and Method of Administration).
Gastrointestinal toxicity (including events of diarrhoea, nausea and vomiting) should be actively managed in order to reduce the risk of development of renal impairment or renal failure. Serious adverse events of both hypokalaemia and hyperkalaemia have occurred and renal function and electrolytes should be monitored closely. (See Section 4.4 Special Warnings and Precautions for Use, Renal failure and impairment).

Renal failure and impairment.

Patients with baseline renal function < 60 mL/minute experienced more adverse events, including fatal and serious adverse events and Grade 3 or 4 events, than those with normal renal function and were more likely to require a treatment interruption, dose reduction or discontinuation of treatment. The recommended starting dose is lower for patients with renal impairment (see Section 4.2 Dose and Method of Administration) and it is also recommended these patients be monitored closely during treatment. There is no clinical trial experience of patients with severe renal impairment.
Renal impairment (including renal failure) has been reported in patients treated with Lenvima (see Section 4.8 Adverse Effects (Undesirable Effects), Selected adverse reactions in DTC, RCC and HCC). The primary risk factors identified were pre-existing renal impairment and dehydration and/or hypovolemia due to gastrointestinal toxicity. (See Section 4.4 Special Warnings and Precautions for Use, Gastrointestinal toxicity: diarrhoea and dehydration). Caution should be taken in patients receiving agents acting on the renin-angiotensin aldosterone system given a potentially higher risk for acute renal failure with the combination treatment. Dose interruptions, adjustments, or discontinuation may be necessary (see Section 4.2 Dose and Method of Administration).
If patients have severe renal impairment, the initial dose of Lenvima should be adjusted (see Section 4.2 Dose and Method of Administration).

Aneurysms and artery dissections.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating Lenvima, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Hypertension.

Hypertension has been reported in patients treated with Lenvima, usually occurring early in the course of treatment (see Section 4.8 Adverse Effects (Undesirable Effects), Selected adverse reactions in DTC, RCC and HCC).
Blood pressure (BP) should be well controlled prior to treatment with Lenvima and, if patients are known to be hypertensive they should be on a stable dose of an antihypertensive therapy for at least 1 week prior to treatment with Lenvima. The early detection and effective management of hypertension are important to minimise the need for Lenvima dose interruptions and reductions. Serious complications of poorly controlled hypertension, including aortic dissection, have been reported. Antihypertensives should be started as soon as elevated BP is confirmed. Blood pressure should be monitored after 1 week of treatment with Lenvima, then every 2 weeks for the first 2 months, and monthly thereafter. The choice of antihypertensive treatment should be individualised to the patient's clinical circumstances and follow standard medical practice. For previously normotensive subjects, monotherapy with one of the classes of antihypertensives should be started when elevated BP is observed. For those patients already on antihypertensive medication, the dose of the current agent may be increased, if appropriate, or one or more agents of a different class of antihypertensive should be added. When necessary, manage hypertension as recommended in Table 3.

Proteinuria.

Proteinuria has been reported in patients treated with Lenvima, usually occurring early in the course of the treatment (see Section 4.8 Adverse Effects (Undesirable Effects), Selected adverse reactions in DTC, RCC and HCC). Monitor urine protein regularly. If urine dipstick proteinuria ≥ 2+ is detected, dose interruptions, adjustments, or discontinuation may be necessary (see Section 4.2 Dose and Method of Administration). Lenvima should be discontinued in the event of nephrotic syndrome.

Cardiac dysfunction.

Cardiac failure (< 1%) and decreased left ventricular ejection fraction have been reported in patients treated with Lenvima (see Section 4.8 Adverse Effects (Undesirable Effects), Selected adverse reactions in DTC, RCC and HCC).
Patients should be monitored for clinical symptoms or signs of cardiac decompensation, as dose interruptions, adjustments, or discontinuation may be necessary (see Section 4.2 Dose and Method of Administration).
Lenvima has not been studied in patients who have had cardiac failure within the previous 6 months and therefore should be used with caution in such patients.

Posterior reversible encephalopathy syndrome (PRES)/ reversible posterior leucoencephalopathy syndrome (RPLS).

Posterior reversible encephalopathy syndrome (PRES, also known as RPLS) has been reported in patients treated with Lenvima (observed in < 1% of patients; see Section 4.8 Adverse Effects (Undesirable Effects), Selected adverse reactions in DTC, RCC and HCC). PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, altered mental function, blindness, and other visual or neurological disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of PRES. Appropriate measures should be taken to control blood pressure (see Section 4.4 Special Warnings and Precautions for Use, Hypertension). In patients with signs or symptoms of PRES, dose interruptions, adjustments, or discontinuation may be necessary (see Section 4.2 Dose and Method of Administration).

Hepatotoxicity.

In DTC and RCC, liver-related adverse reactions most commonly reported in patients treated with Lenvima included increases in alanine aminotransferase (ALT), increases in aspartate aminotransferase (AST), and increases in blood bilirubin (see Section 4.8 Adverse Effects (Undesirable Effects), Selected adverse reactions in DTC, RCC and HCC). Hepatic failure and acute hepatitis (observed in < 1% of patients) have been reported in patients with DTC and RCC treated with Lenvima. The hepatic failure events were generally reported in patients with progressive metastatic liver disease.
Liver-related adverse reactions including hepatic encephalopathy and hepatic failure (including fatal reactions) were reported at a higher frequency in Lenvima treated HCC patients (see Section 4.8 Adverse Effects (Undesirable Effects)) compared to DTC and RCC patients. Patients with worse hepatic impairment and/or greater liver tumour burden at baseline had a higher risk of developing hepatic encephalopathy and hepatic failure. Hepatic encephalopathy also occurred more frequently in patients aged 75 years and older. Approximately half of the events of hepatic failure were reported in patients with disease progression.
Liver function tests should be monitored before initiation of treatment, then every 2 weeks for the first 2 months and monthly thereafter during treatment. Patients with HCC should be monitored for worsening liver function including hepatic encephalopathy. In the case of hepatotoxicity, dose interruptions, adjustments, or discontinuation may be necessary (see Section 4.2 Dose and Method of Administration).
If patients have any degree of liver impairment they need to be monitored closely for liver related adverse reactions. For DTC and RCC patients with severe hepatic impairment, the initial dose of Lenvima should be adjusted. The available data do not allow for a dosing recommendation for patients with HCC and moderate hepatic impairment (Child-Pugh B). Lenvima has not been studied in patients with HCC and severe hepatic impairment (Child-Pugh C) and therefore the use of Lenvima in these patients is not recommended.

Arterial thromboembolic events.

Arterial thromboembolic events (cerebrovascular accident, transient ischaemic attack, and myocardial infarction) have been reported in patients treated with Lenvima (see Section 4.8 Adverse Effects (Undesirable Effects), Selected adverse reactions in DTC, RCC and HCC). Lenvima has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months and therefore should be used with caution in such patients. A treatment decision should be made based upon an assessment of the individual patient's benefit/risk. Lenvima should be discontinued following an arterial thrombotic event (see Section 4.2 Dose and Method of Administration).

Haemorrhagic events and thrombocytopenia.

Serious haemorrhagic events have been reported in patients treated with Lenvima. The most frequently reported haemorrhagic event was mild epistaxis. Serious events of thrombocytopenia have also been reported in patients treated with Lenvima and thrombocytopenia may increase risk of developing haemorrhagic events (see Section 4.8 Adverse Effects (Undesirable Effects), Selected adverse reactions in DTC, RCC and HCC).
Serious tumour related bleeds have been reported, including fatal haemorrhagic events in Lenvima treated patients and there have been reports of haemorrhage associated with thrombocytopenia.
The degree of tumour invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe haemorrhage associated with tumour shrinkage/necrosis following Lenvima therapy. In the case of haemorrhagic events/ thrombocytopenia, dose interruptions, adjustments, or discontinuation may be necessary (see Section 4.2 Dose and Method of Administration).

Wound healing complications.

No formal studies of the effect of Lenvima on wound healing have been conducted. Impaired wound healing has been reported in patients receiving Lenvima. Temporary interruption of Lenvima should be considered in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of Lenvima following a major surgical procedure. Therefore, the decision to resume Lenvima following a major surgical procedure should be based on clinical judgment of adequate wound healing.

Gastrointestinal perforation and fistula formation.

Gastrointestinal perforation or fistulae have been reported in patients treated with Lenvima (see Section 4.8 Adverse Effects (Undesirable Effects), Selected adverse reactions in DTC, RCC and HCC). In most cases, gastrointestinal perforation and fistulae occurred in patients with risk factors such as prior surgery or radiotherapy. In the case of a gastrointestinal perforation or fistula, dose interruptions, adjustments, or discontinuation may be necessary (see Section 4.2 Dose and Method of Administration).

Non-gastrointestinal fistula.

Patients may be at increased risk for the development of fistulae when treated with Lenvima. Cases of fistula formation or enlargement that involve other areas of the body than stomach or intestines were observed in clinical trials and in post-marketing experience (e.g. tracheal, tracheo-oesophageal, oesophageal, cutaneous, female genital tract fistulae). In addition, pneumothorax has been reported with and without clear evidence of a bronchopleural fistula. Some reports of gastrointestinal perforation, fistula and pneumothorax occurred in association with tumour regression or necrosis. Prior surgery and radiotherapy may be contributing risk factors. Lenvima should not be started in patients with fistulae to avoid worsening and Lenvima should be permanently discontinued in patients with oesophageal or tracheobronchial tract involvement and any Grade 4 fistula (see Section 4.2 Dose and Method of Administration); limited information is available on the use of dose interruption or reduction in management of other events, but worsening was observed in some cases and caution should be taken. Lenvima may adversely affect the wound healing process as do other agents of the same class.

QT interval prolongation.

QT/QTc interval prolongation has been reported at a higher incidence in patients treated with Lenvima than in patients treated with placebo (see Section 4.8 Adverse Effects (Undesirable Effects), Selected adverse reactions in DTC, RCC and HCC). The median time to onset of QTc prolongation was 16.1 weeks in the DTC study, 31.1 weeks in the HCC study for patients on Lenvima monotherapy and 30 weeks in the RCC study for combination patients. Electrocardiograms should be monitored in patients on an ongoing basis with a special attention for those with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, and those taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Lenvima should be withheld in the event of development of QT interval prolongation greater than 500 ms. Lenvima should be resumed at a reduced dose when QTc prolongation is resolved to < 480 ms or baseline (see Section 4.2 Dose and Method of Administration).
Electrolyte disturbances such as hypokalaemia, hypocalcaemia, or hypomagnesaemia increase the risk of QT prolongation; therefore electrolyte abnormalities should be monitored and corrected in all patients before starting treatment. Periodic monitoring of ECG and electrolytes (magnesium, potassium and calcium) should be considered during treatment. Blood calcium levels should be monitored at least monthly and calcium should be replaced as necessary during Lenvima treatment. Lenvima dose should be interrupted or dose adjusted as necessary depending on severity, presence of ECG changes, and persistence of hypocalcaemia.

Impairment of thyroid stimulating hormone suppression/thyroid dysfunction.

Lenvima impairs exogenous thyroid suppression (see Section 4.8 Adverse Effects (Undesirable Effects)).
Hypothyroidism has been reported as very common in patients treated with Lenvima in the RCC trial (see Section 4.8 Adverse Effects (Undesirable Effects), Selected adverse reactions in DTC, RCC and HCC).
Thyroid function should be monitored before initiation of treatment, and periodically at least monthly throughout treatment with Lenvima. Hypothyroidism should be treated according to standard medical practice to maintain euthyroid state.

Osteonecrosis of the jaw (ONJ).

Events of osteonecrosis of the jaw (ONJ) have been observed with Lenvima (see Section 4.8). Invasive dental procedures are an identified risk factor for the development of ONJ. An oral dental examination and appropriate preventive dentistry should be considered prior to initiation of Lenvima. Patients should be advised regarding periodic dental examinations and oral hygiene practice during Lenvima therapy. Avoid invasive dental procedures during Lenvima treatment, if possible. Use caution in patients receiving agents associated with ONJ, such as bisphosphonates and denosumab.

Special populations.

Limited data are available for patients of ethnic origin other than Caucasian or Asian, and in patients aged ≥ 75 years. Lenvima should be used with caution in such patients, given the reduced tolerability of Lenvima in Asian patients (see Section 4.8 Adverse Effects (Undesirable Effects), Other special populations).
There are no data on the use of Lenvima immediately following sorafenib or other anticancer treatments and there may be a potential risk for additive toxicities unless there is an adequate washout period between treatments. The minimal washout period in clinical trials was of 4 weeks.

Patients with poor ECOG performance status.

Patients with an ECOG performance status of 2 or higher were excluded from the RCC, HCC and endometrial carcinoma studies (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Patients with an ECOG performance 3 or higher were excluded from the DTC studies (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Benefit-risk in these patients has not been evaluated.

Patients with hypertension.

Blood pressure should be well controlled prior to treatment with Lenvima, and should be regularly monitored during treatment (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration, Dose adjustment in severe hepatic impairment; Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic impairment.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration, Dosage adjustment in renal impairment; Section 5.2 Pharmacokinetic Properties, Special populations, Renal impairment.

Use in the elderly.

Limited data are available in patients aged ≥ 75 years. Lenvima should be used with caution in such patients, given the reduced tolerability of Lenvima in elderly patients (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects), Other special populations).

Paediatric use.

Clinical data are not yet available in this population.
Mortality was the dose-limiting toxicity in juvenile rats in which dosing was initiated on postnatal day (PND) 7 or PND21. Mortality occurred at lower doses in neonatal rats (dosing initiated on PND7), or after a shorter duration of treatment in juvenile rats (dosing initiated on PND21). The exposure (as AUC) to lenvatinib in juvenile rats was lower compared to adults, suggesting increased susceptibility to the toxic effects of lenvatinib in young animals. Growth retardation, secondary delay of physical development, and lesions attributable to pharmacologic effects (incisors, femur [epiphyseal growth plate], kidneys, adrenals, and duodenum) were also observed in juvenile rats.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effect of other medicinal products on Lenvima.

CYP3A, P-gp, and BCRP inhibitors or inducers.

Lenvima may be administered regardless of co-administration with CYP3A, P-gp, and BCRP inhibitors. In healthy subjects, ketoconazole (400 mg for 18 days) increased lenvatinib (administered as a single dose on Day 5) AUC0-inf and AUC0-t approximately 15% while Cmax increased 19%. This is supported by a population PK analysis which found CYP3A4 inhibitors decreased Cl/F by 7.8%.
Lenvima may be co-administered without dose adjustment with CYP3A and P-gp inducers, based on a study in which healthy subjects were administered repeated doses of rifampicin (600 mg for 21 days) and a single dose of lenvatinib (24 mg, Day 15). AUC0-inf and AUC0-t decreased approximately 18% while Cmax did not change. The effect of CYP3A induction alone was estimated by comparing the PK parameters for lenvatinib following single and multiple doses of rifampicin. Lenvatinib AUC and Cmax were predicted to decrease by 30% and 15%, respectively, after strong induction in the absence of acute P-gp inhibition. This is supported by a population PK analysis which found CYP3A4 inducers increased Cl/F by 30%.

Gastric pH altering agents.

In a population pharmacokinetic analysis of patients receiving Lenvima up to 24 mg once daily, agents which increase gastric pH (H2-receptor blockers, proton pump inhibitors, antacids) did not have a significant effect on lenvatinib exposure.

Other chemotherapeutic agents.

Concomitant administration of lenvatinib, carboplatin, and paclitaxel had no significant impact on the pharmacokinetics of any of these 3 substances.

Effect of Lenvima on other medicinal products.

Cytochrome P450 or UGT enzyme substrates.

Lenvatinib is considered neither a strong inhibitor nor an inducer of cytochrome P450 or uridine 5'-diphosphoglucuronosyl transferase (UGT) enzymes.

P-gp and BCRP substrates.

Lenvatinib showed minimal inhibitory activities toward P-gp-mediated and BCRP-mediated transport activities. Similarly, no induction of P-gp mRNA expression was observed.

OAT, OCT, OATP, BSEP, MATE and aldehyde oxidase substrates.

Lenvatinib showed inhibitory effects on organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)1, OCT2, organic anion transporting polypeptide (OATP)1B1, and bile salt export pump (BSEP), but minimal or no inhibitory effect on OATP1B3 and multidrug and toxin extrusion 2 (MATE2)-K. Lenvatinib weakly inhibits MATE1. In human liver cytosol, lenvatinib did not inhibit aldehyde oxidase activity.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Effects in humans are unknown. However, testicular and ovarian toxicity has been observed in rats, dogs, and monkeys.
No specific studies with lenvatinib have been conducted in animals to evaluate the effect on fertility. However, testicular and ovarian changes were observed in repeated-dose toxicity studies in animals at exposures 11 to 15 times (rat) or 0.6 to 7 times (monkey) the anticipated clinical exposure (based on AUC) at the maximum tolerated human dose. These findings were reversible at the end of a 4-week recovery period.
(Category D)
There is limited information on the use of Lenvima in pregnant women. Lenvatinib was embryotoxic and teratogenic when administered to rats and rabbits during organogenesis at exposures below the clinical exposure (based on body surface area) at the maximum recommended human dose. Fetal anomalies included parietal oedema, cryptophthalmia, abnormal tail (rats), retroesophageal subclavian artery, fused ribs, and vertebral abnormalities (rabbits). These embryofetal findings are probably related to the pharmacologic activity of lenvatinib as an antiangiogenic agent.
Lenvima should not be used during pregnancy unless clearly necessary and after a careful consideration of the needs of the mother and the risk to the foetus.

Women of childbearing potential.

Women of childbearing potential should avoid becoming pregnant and use highly effective contraception while on treatment with Lenvima and for at least one month after finishing treatment. It is currently unknown whether Lenvima may reduce the effectiveness of hormonal contraceptives, and therefore women using oral hormonal contraceptives should add a barrier method.
 It is not known whether lenvatinib is excreted in human milk. Lenvatinib and its metabolites are excreted in rat milk and neonatal rats were more sensitive to the toxicity of lenvatinib compared to adults (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use). Therefore, a risk to newborns or infants cannot be excluded and Lenvima should not be used during breastfeeding.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Lenvima may cause side effects such as fatigue and dizziness. Patients who experience these symptoms should use caution when driving or operating machines.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

Radioactive iodine refractory differentiated thyroid cancer. The safety of Lenvima was evaluated in 392 patients from the Phase 3 SELECT trial with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) randomised to receive Lenvima 24 mg once daily (n = 261) or placebo (n = 131) (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In the SELECT study, the most common adverse reactions observed in Lenvima-treated patients (greater than or equal to 30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhoea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysaesthesia (PPE) syndrome, abdominal pain, and dysphonia. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%).
Adverse reactions led to dose reductions in 68% of patients receiving Lenvima and 5% of patients receiving placebo; 18% of patients discontinued Lenvima and 5% discontinued placebo for adverse reactions. The most common adverse reactions (at least 10%) resulting in dose reductions of Lenvima were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhoea (10%); the most common adverse reactions (at least 1%) resulting in discontinuation of Lenvima were hypertension (1%) and asthenia (1%).
Table 4 presents the incidence rates of treatment-emergent adverse events observed in the double blind phase of the DTC study. All adverse events occurring with a treatment difference of at least 5% over placebo are included in the table. Clinically significant events (CSEs) that were observed more frequently than placebo are also included based on an assessment of the known pharmacology of Lenvima and class effects.
Renal cell carcinoma.

First-line treatment of renal cell carcinoma in combination with pembrolizumab (CLEAR).

The safety of Lenvima was evaluated in CLEAR, a study in which patients with advanced renal cell carcinoma (RCC) were randomised (1:1:1) to Lenvima 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks (n=352), Lenvima 18 mg orally once daily in combination with everolimus 5 mg orally once daily (n=355), or sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks (n=340) [see Clinical studies (14.2)]. All patients on the Lenvima plus pembrolizumab arm were started on Lenvima 20 mg orally once daily. The median time to first dose reduction for Lenvima was 1.9 months. The median average daily dose for Lenvima was 14 mg. The median duration of study treatment was 17.0 months (range: 0.07 to 39.13 months). Pembrolizumab was continued for a maximum of 24 months; however, treatment with Lenvima could be continued beyond 24 months.
Fatal adverse reactions occurred in 4.3% of patients receiving Lenvima and pembrolizumab, including arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm, sepsis and subarachnoid haemorrhage.
Serious adverse reactions occurred in 51% of patients receiving Lenvima and pembrolizumab. Serious adverse reactions in ≥ 2% of patients were haemorrhagic events (5%), diarrhoea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%).
Discontinuation of Lenvima, pembrolizumab, or both due to an adverse reaction (Grade 14) occurred in 36% of patients; 24% Lenvima, and 12% both drugs. The most common adverse reactions (≥ 2%) leading to discontinuation of Lenvima, pembrolizumab, or both were pneumonitis (3%), myocardial infarction (3%), rash (3%), and diarrhoea (2%). Refer to the pembrolizumab prescribing information for pembrolizumab discontinuation information.
Dose interruptions of Lenvima, pembrolizumab, or both due to an adverse reaction occurred in 78% of patients; Lenvima was interrupted in 73%, and both drugs in 39% of patients. Lenvima was dose reduced in 69% of patients. The most common adverse reactions (≥ 5%) resulting in dose reduction or interruption of Lenvima were diarrhoea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), PPE (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), and vomiting (6%), increased ALT (5%), and increased amylase (5%). Refer to the pembrolizumab prescribing information for pembrolizumab interruption information.
Table 5 presents the adverse reactions in ≥ 20% of patients in the Lenvima with pembrolizumab arm.
Table 6 presents laboratory abnormalities occurring in ≥ 20% of patients (All grades) or ≥ 3% (Grades 3-4) of patients with Lenvima in combination with pembrolizumab.

Previously treated renal cell caracinoma in combination with everolimus (Study 205).

The most common adverse reactions observed in the Lenvima in combination with everolimus-treated group (> 30%) were, in order of decreasing frequency, diarrhoea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral oedema, cough, abdominal pain, dyspnoea, rash, weight decreased, haemorrhagic events, and proteinuria. The most common serious adverse reactions (≥ 5%) were renal failure (11%), dehydration (10%), anaemia (6%), thrombocytopenia (5%), diarrhoea (5%), vomiting (5%), and dyspnoea (5%).
Adverse reactions led to dose reductions or interruption in 89% of patients receiving Lenvima + everolimus and 54% in patients receiving everolimus. The most common adverse reactions (≥ 5%) resulting in dose reductions in the Lenvima + everolimus-treated group were diarrhoea (21%), fatigue (8%), thrombocytopaenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%).
Treatment discontinuation due to an adverse reaction occurred in 29% of patients in the Lenvima + everolimus-treated group and 12% of patients in the everolimus-treated group.
Table 7 presents the adverse reactions in > 15% of patients in the Lenvima + everolimus arm.
In Table 8, Grade 3-4 laboratory abnormalities occurring in ≥ 3% of patients in the Lenvima with everolimus arm are presented.
Hepatocellular carcinoma. The safety of Lenvima was evaluated in REFLECT, which randomised (1:1) patients with unresectable hepatocellular carcinoma (HCC) to Lenvima (n = 476) or sorafenib (n = 475) (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The dose of Lenvima was 12 mg orally once daily for patients with a baseline body weight of ≥ 60 kg and 8 mg orally once daily for patients with a baseline body weight of < 60 kg. The dose of sorafenib was 400 mg orally twice daily. Duration of treatment was ≥ 6 months in 49% and 32% of patients in the Lenvima and sorafenib groups, respectively. Among the 476 patients who received Lenvima in REFLECT, the median age was 63 years, 85% were men, 28% were White and 70% were Asian.
The most common adverse reactions observed in the Lenvima-treated patients (≥ 20%) were, in order of decreasing frequency, hypertension, fatigue, diarrhoea, decreased appetite, arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysaesthesia syndrome, proteinuria, dysphonia, haemorrhagic events, hypothyroidism, and nausea. The most common serious adverse reactions (≥ 2%) in Lenvima-treated patients were hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite (2%).
Adverse reactions led to dose reduction or interruption in 62% of patients receiving Lenvima. The most common adverse reactions (≥ 5%) resulting in dose reduction or interruption of Lenvima were fatigue (9%), decreased appetite (8%), diarrhoea (8%), proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysaesthesia syndrome (5%).
Treatment discontinuation due to adverse reactions occurred in 20% of patients in the Lenvima-treated group. The most common adverse reactions (≥ 1%) resulting in discontinuation of Lenvima were fatigue (1%), hepatic encephalopathy (2%), hyperbilirubinemia (1%), and hepatic failure (1%).
Table 9 summarises the adverse reactions that occurred in ≥ 10% of patients receiving Lenvima in REFLECT. REFLECT was not designed to demonstrate a statistically significant reduction in adverse reaction rates for Lenvima, as compared to sorafenib, for any specified adverse reaction listed in Table 9.
Table 10, Grade 3-4 laboratory abnormalities occurring in ≥ 2% of patients in the Lenvima arm in REFLECT (HCC) are presented.
Endometrial carcinoma. The safety of Lenvima in combination with pembrolizumab was investigated in Study 309, a multicentre, open-label, randomised (1:1), active-controlled trial in patients with advanced endometrial carcinoma previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings (see Section 5.1, Clinical trials, Endometrial carcinoma (EC)). Patients with endometrial carcinoma that are not MSI-H or dMMR received Lenvima 20 mg orally once daily with pembrolizumab 200 mg intravenously every 3 weeks (n=342); or received doxorubicin or paclitaxel (n= 325).
For patients with not MSI-H or dMMR status, the median duration of study treatment was 7.2 months (range 1 day to 26.8 months) and the median duration of exposure to Lenvima was 6.7 months (range: 1 day to 26.8 months).
Fatal adverse reactions among these patients occurred in 4.7% of those treated with Lenvima and pembrolizumab, including 2 cases of pneumonia, and 1 case of the following: acute kidney injury, acute myocardial infarction, colitis, decreased appetite, intestinal perforation, lower gastrointestinal haemorrhage, malignant gastrointestinal obstruction, multiple organ dysfunction syndrome, myelodysplastic syndrome, pulmonary embolism, and right ventricular dysfunction.
Serious adverse reactions occurred in 50% of these patients receiving Lenvima and pembrolizumab. Serious adverse reactions with frequency ≥ 3% were hypertension (4.4%), and urinary tract infection (3.2%).
Discontinuation of Lenvima due to an adverse reaction occurred in 26% of these patients. The most common (≥ 1%) adverse reactions leading to discontinuation of Lenvima were hypertension (2%), asthenia (1.8%), diarrhoea (1.2%), decreased appetite (1.2%), proteinuria (1.2%), and vomiting (1.2%).
Dose reductions of Lenvima due to adverse reactions occurred in 67% of patients. The most common (≥ 5%) adverse reactions resulting in dose reduction of Lenvima were hypertension (18%), diarrhoea (11%), palmar-plantar erythrodysesthesia syndrome (9%), proteinuria (7%), fatigue (7%), decreased appetite (6%), asthenia (5%), and weight decreased (5%).
Dose interruptions of Lenvima due to an adverse reaction occurred in 58% of these patients. The most common (≥ 2%) adverse reactions leading to interruption of Lenvima were hypertension (11%), diarrhoea (11%), proteinuria (6%), decreased appetite (5%), vomiting (5%), increased alanine aminotransferase (3.5%), fatigue (3.5%), nausea (3.5%), abdominal pain (2.9%), weight decreased (2.6%), urinary tract infection (2.6%), increased aspartate aminotransferase (2.3%), asthenia (2.3%), and palmar-plantar erythrodysesthesia (2%).
Table 11 and Table 12 summarise adverse reactions and laboratory abnormalities, respectively, in patients receiving Lenvima in combination with pembrolizumab in Study 309.

Post-marketing adverse drug reactions.

The following adverse reactions have been identified during postapproval use of Lenvima. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal disorders.

Amylase increased, lipase increased, pancreatitis.

Hepatobiliary disorders.

Cholecystitis.

General disorders and administration site conditions.

Impaired healing.

Musculoskeletal and connective tissue disorders.

Osteonecrosis of the jaw.

Renal and urinary disorders.

Nephrotic syndrome.

Respiratory, thoracic and mediastinal disorders.

Pneumothorax.

Vascular disorders.

Aortic dissection, cases of aneurysms and artery dissections, sometimes fatal, have been reported with VEGF pathway inhibitors.

Selected adverse reactions in DTC, RCC and HCC.

Hypertension.

In the pivotal DTC Phase 3 SELECT trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), hypertension (including hypertension, hypertensive crisis, blood pressure diastolic increased, and blood pressure increased) was reported in 72.8% of Lenvima-treated patients and 16.0% of patients in the placebo treated group. The median time to onset in Lenvima-treated patients was 16 days. Events of Grade 3 or higher (including 1 event of Grade 4) occurred in 44.4% of Lenvima-treated patients compared with 3.8% of placebo-treated patients. The majority of cases recovered or resolved following dose interruption or reduction, which occurred in 13.0% and 13.4% of patients, respectively. In 1.1% of patients, hypertension led to permanent treatment discontinuation.
In the Phase 3 HCC trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), hypertension (including hypertension, blood pressure increased, blood pressure diastolic increased and orthostatic hypertension) was reported in 44.5% of Lenvima-treated patients compared with 30.9% of patients in the sorafenib-treated group and Grade 3 hypertension occurred in 23.5% (14.5% in the sorafenib-treated group). The median time to onset was 26 days. The majority of cases recovered following dose interruption or reduction, which occurred in 3.6% and 3.4% of patients respectively. One subject (0.2%) discontinued Lenvima due to hypertension.

Proteinuria.

In the pivotal DTC Phase 3 SELECT trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), proteinuria was reported in 33.7% of Lenvima treated patients and 3.1% of patients in the placebo-treated group. The median time to onset was 6.7 weeks. Grade 3 events occurred in 10.7% of Lenvima-treated patients and no placebo-treated patients. The majority of cases had an outcome of recovered or resolved following dose interruption or reduction, which occurred in 16.9% and 10.7% of patients, respectively. Proteinuria led to permanent treatment discontinuation in 0.8% of patients.
In the Phase 3 HCC trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), proteinuria was reported in 26.3% of Lenvima-treated patients compared with 12.2% of patients in the sorafenib-treated group and Grade 3 reactions occurred in 5.9% (1.7% in the sorafenib-treated group). The median time to onset was 6.1 weeks. The majority of cases recovered following dose interruption or reduction, which occurred in 6.9% and 2.5% of patients respectively. Proteinuria led to permanent treatment discontinuation in 0.6% of patients.

Renal failure and impairment.

In the pivotal DTC Phase 3 SELECT trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), 5.0% of patients developed renal failure and 1.9% developed renal impairment, (3.1% of patients had a Grade ≥ 3 event of renal failure or impairment). In the placebo group 0.8% of patients developed renal failure or impairment (0.8% were Grade ≥ 3).
In the Phase 3 HCC trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), 7.1% of Lenvima-treated patients developed a renal failure/impairment event compared with 4.0% in the sorafenib-treated group. Grade 3 or greater reactions occurred in 1.9% of Lenvima-treated patients and in 1.3% of sorafenib-treated patients.

Cardiac dysfunction.

In the pivotal DTC Phase 3 SELECT trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), decreased ejection fraction/cardiac failure was reported in 6.5% of patients (1.5% were Grade ≥ 3) in the Lenvima treated group, and 2.3% in the placebo group (none were Grade ≥ 3).
In the Phase 3 HCC trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), cardiac dysfunction (including congestive cardiac failure, cardiogenic shock, and cardiopulmonary failure) was reported in 0.6% of patients in the Lenvima-treated group compared with 0.2% of patients in the sorafenib-treated group. 0.4% in the Lenvima-treated group experienced events of Grade ≥ 3 compared to none in the sorafenib-treated group. There were no events of decreased ejection fraction in the Lenvima arm.

Posterior reversible encephalopathy syndrome (PRES)/ reversible posterior leucoencephalopathy syndrome (RPLS).

In the pivotal DTC Phase 3 SELECT trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), there was 1 event of PRES (Grade 2) in the Lenvima-treated group and no reports in the placebo group.
In the Phase 3 HCC trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), there was 1 event of PRES (Grade 2) in the Lenvima treated group and no events in the sorafenib-treated group.
Amongst 1,823 patients treated with Lenvima monotherapy in clinical trials, there were 5 cases (0.3%) of PRES (0.2% were Grade 3 or 4), all of which resolved after treatment and/or dose interruption, or permanent discontinuation.

Hepatotoxicity.

In the pivotal DTC Phase 3 SELECT trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), the most commonly reported liver-related adverse reactions were hypoalbuminaemia (9.6% Lenvima vs. 1.5% placebo) and elevations of liver enzyme levels, including increases in alanine aminotransferase (7.7% Lenvima vs. 0 placebo), aspartate aminotransferase (6.9% Lenvima vs. 1.5% placebo), and blood bilirubin (1.9% Lenvima vs. 0 placebo). The median time to onset of liver events in Lenvima-treated patients was 12.1 weeks. Liver-related events of Grade 3 or higher (including 1 Grade 5 event of hepatic failure) occurred in 5.4% of Lenvima-treated patients compared with 0.8% in placebo-treated patients. Liver-related events led to dose interruptions and reductions in 4.6% and 2.7% of patients, respectively, and to permanent discontinuation in 0.4%.
In the Phase 3 HCC trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials) hepatotoxicity events were reported in 47.7% of Lenvima-treated patients compared to 41.7% of sorafenib-treated patients. The most commonly reported hepatotoxicity adverse reactions in the Lenvima-treated patients were blood bilirubin increased (14.9%), aspartate aminotransferase increased (13.7%), alanine aminotransferase increased (11.1%), hypoalbuminaemia (9.2%), hepatic encephalopathy (8.0%), gamma-glutamyltransferase increased (7.8%) and blood alkaline phosphatase increased (6.7%). The median time to onset of hepatotoxicity adverse reactions was 6.4 weeks.
Hepatotoxicity reactions of ≥ Grade 3 occurred in 26.1% of Lenvima-treated patients and 23.4% of sorafenib-treated patients. In Lenvima-treated patients, hepatic failure (HF) (including fatal events) occurred in 3.2% of patients (all were ≥ Grade 3). Hepatic encephalopathy (HE) (including fatal events) occurred in 8.0% of patients (4.8% were ≥ Grade 3). Hepatotoxicity adverse reactions led to dose interruptions and reductions in 12.2% and 7.4% of Lenvima-treated patients respectively, and to permanent discontinuation in 5.5%. The events of HF and HE were reported at a higher frequency in Lenvima-treated HCC patients (3.6% and 8.0% for HF and HE, respectively) in comparison to sorafenib-treated HCC patients (2.5% and 1.9% for HF and HE, respectively).
Across clinical studies in which 1327 patients received Lenvima monotherapy in indications other than HCC, hepatic failure (including fatal events) was reported in 4 patients (0.3%), liver injury in 2 patients (0.2%), acute hepatitis in 2 patients (0.2%), and hepatocellular injury in 1 patient (0.1%).

Arterial thromboembolisms.

In the pivotal DTC Phase 3 SELECT trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), arterial thromboembolic events were reported in 5.4% of Lenvima-treated patients and 2.3% of patients in the placebo group.
In the Phase 3 HCC trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), arterial thromboembolic events were reported in 2.3% of patients treated with Lenvima as compared to 1.7% in sorafenib-treated patients.
Amongst 1,823 patients treated with Lenvima monotherapy in clinical trials, there were 10 cases (0.5%) of arterial thromboembolisms (5 cases of myocardial infarction and 5 cases of cerebrovascular accident) with a fatal outcome.

Haemorrhagic events and thrombocytopenia.

In the pivotal DTC Phase 3 SELECT trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), haemorrhagic events were reported in 34.9% of Lenvima-treated patients versus 18.3% of placebo-treated patients. Events that occurred at an incidence of ≥ 0.75% above placebo were: epistaxis (11.9%), haematuria (6.5%), contusion (4.6%), gingival bleeding (2.3%), haematochezia (2.3%), rectal haemorrhage (1.5%), haematoma (1.1%), haemorrhoidal haemorrhage (1.1%), laryngeal haemorrhage (1.1%), petechiae (1.1%), and intracranial tumour haemorrhage (0.8%). When adjusted to account for the 4-fold greater duration of exposure in the Lenvima versus the placebo arm, the following reactions occurred less frequently on Lenvima than placebo: haemoptysis (0.05 episodes/subject-year on Lenvima vs. 0.21 episodes/subject-year on placebo) and pulmonary haemorrhage (0.02 episodes/subject year on Lenvima vs. 0.09 episodes/subject-year on placebo).
The median time to first onset in Lenvima-treated patients was 10.1 weeks. No differences between Lenvima and placebo-treated patients were observed in the incidences of serious adverse events (3.4% vs. 3.8%), events leading to premature discontinuation (1.1% vs. 1.5%), or events leading to dose interruption (3.4% vs. 3.8%) or reduction (0.4% vs. 0).
Thrombocytopenia or platelet count decreased was reported in 15.3% of Lenvima-treated patients (1.9% were Grade ≥ 3) versus 2.3% in the placebo arm (none were Grade ≥ 3). There were no Grade 4 TEAEs. The incidence of serious thrombocytopenia was 0.8%. Most reactions resolved following supportive treatment, although 5.0% of patients had events of thrombocytopenia that required dose interruption, and 1.9% required dose reduction. No patients discontinued treatment as a result of thrombocytopenia.
Thrombocytopenia or platelet count decreased was reported in 14.5% of patients in the Lenvima plus everolimus-treated group (4.8% were Grade ≥ 3) and 10.0% of patients in the everolimus-treated group (none were Grade ≥ 3). There was one Grade 4 TEAE. The incidence of serious thrombocytopenia was 4.8%. Dose reduction or interruption due to thrombocytopenia occurred in 9.7% of patients and 3.2% of patients discontinued treatment due to thrombocytopenia.
In the Phase 3 HCC trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), haemorrhage was reported in 24.6% of Lenvima-treated patients as compared to 16.0% of sorafenib-treated patients. 5.0% of Lenvima-treated patients experienced Grade ≥ 3 events as compared to 4.6% of sorafenib-treated patients. Grade 3 reactions occurred in 3.4%, Grade 4 reactions in 0.2% and 7 patients (1.5%) had a grade 5 reaction including cerebral haemorrhage, upper gastrointestinal haemorrhage, intestinal haemorrhage and tumour haemorrhage. The median time to first onset was 11.9 weeks. A haemorrhage event led to dose interruption or reduction in 3.2% and 0.8% patients respectively and to treatment discontinuation in 1.7% of patients.
Thrombocytopenia or platelet count decreased was reported in 25.0% of Lenvima-treated patients as compared to 18.1% of sorafenib-treated patients. Of the Lenvima-treated patients, 7.4% experienced Grade ≥ 3 reactions compared to 4.6% of sorafenib-treated patients. There was one Grade 4 TEAE and no serious events. Dose reduction or interruption due to thrombocytopenia or platelet count decreased occurred in 1.3% and 4.6% of patients respectively and there were no discontinuations.
Amongst 1,823 patients treated with Lenvima monotherapy in clinical trials, 30% of patients experienced haemorrhagic events (3.9% were Grade ≥ 3), 4 patients (0.2%) had a Grade 4 haemorrhage and 15 patients (0.8%) had a Grade 5 reaction including arterial haemorrhage, cerebral haemorrhage, haemorrhagic stroke, intracranial haemorrhage, intracranial tumour haemorrhage, intestinal haemorrhage, haematemesis, melaena, haemoptysis, upper gastrointestinal haemorrhage, and tumour haemorrhage.

Hypocalcaemia.

In the pivotal DTC Phase 3 SELECT trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), hypocalcaemia was reported in 12.6% of Lenvima treated patients vs. no events in the placebo arm. The median time to first onset in Lenvima-treated patients was 11.1 weeks. Events of Grade 3 or 4 severity occurred in 5.0% of Lenvima-treated vs 0 placebo-treated patients. Most events resolved following supportive treatment, without dose interruption or reduction, which occurred in 1.5% and 1.1% of patients, respectively; 1 patient with Grade 4 hypocalcaemia discontinued treatment permanently.
In the Phase 3 HCC trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), was reported in 1.1% of patients compared with 1.7% of sorafenib-treated patients. 0.4% of patients treated with Lenvima experienced Grade ≥ 3 reactions and this figure was 0.2% in sorafenib-treated patients. Lenvima dose interruption due to hypocalcaemia occurred in one subject (0.2%) and there were no dose reductions or discontinuations.

Gastrointestinal perforation and fistula formation.

In the pivotal DTC Phase 3 SELECT trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), events of gastrointestinal perforation or fistula were reported in 1.9% of Lenvima treated patients and 0.8% of patients in the placebo group.
In the Phase 3 HCC trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), events of gastrointestinal perforation or fistula were reported in 1.9% of Lenvima-treated patients and in 1.1% of sorafenib-treated patients.

Non-gastrointestinal fistulae (see Section 4.4 Special Warnings and Precautions for Use).

Lenvima use has been associated with cases of fistulae including reactions resulting in death. Reports of fistulae that involve areas of the body other than stomach or intestines were observed across various indications. Reactions were reported at various time points during treatment ranging from two weeks to greater than 1 year from initiation of Lenvima, with a median latency of about 3 months.

QT interval prolongation.

In the pivotal DTC Phase 3 SELECT trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), QT/QTc interval prolongation was reported in 8.8% of Lenvima treated patients and 1.5% of patients in the placebo group. The incidence of QT interval prolongation of greater than 500 ms was 2% in the Lenvima-treated patients compared to no reports in the placebo group.
In the Phase 3 HCC trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), QT/QTc interval prolongation was reported in 6.9% of Lenvima-treated patients and 5.1% of sorafenib-treated patients. The incidence of QTcF interval prolongation of greater than 500 ms was 2.4%.

Blood thyroid stimulating hormone increased (see Section 4.4 Special Warnings and Precautions for Use, Impairment of thyroid stimulating hormone suppression/thyroid dysfunction).

In the pivotal DTC Phase 3 SELECT trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), 88% of all patients had a baseline TSH level less than or equal to 0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level above 0.5 mU/L was observed postbaseline in 57% of Lenvima-treated patients as compared with 14% of placebo-treated patients.
In the RCC study (see Section 5.1 Pharmacodynamic Properties, Clinical trials) Phase 1b plus Phase 2 population, hypothyroidism occurred in 24% of patients in the Lenvima plus everolimus-treated group and 2% of patients in the everolimus-treated group. All events of hypothyroidism in the Lenvima plus everolimus-treated group were of Grade 1 or 2. In patients with a normal TSH at baseline, an elevation of TSH level was observed postbaseline in 60.5% of Lenvima plus everolimus-treated patients as compared with none in patients receiving everolimus alone.
In the Phase 3 HCC trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), 10.4% of patients had a baseline TSH level over the upper limit of normal. Elevation of TSH above the upper limit of normal was observed postbaseline in 69.6% of Lenvima-treated patients. On the sorafenib arm, 9.9% of patients had a baseline TSH level over the upper limit of normal and postbaseline, was observed to be above the upper limit of normal in 32.2% of patients.

Dyslipidaemia.

In the pivotal DTC Phase 3 SELECT trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), hypercholesterolaemia or blood cholesterol increased were reported in 5.0% of Lenvima treated patients (0.4% were Grade ≥ 3) vs. no events in the placebo arm. Hypertriglyceridaemia or blood triglycerides increased were reported in 2.7% of Lenvima treated patients (0.8% were Grade ≥ 3) vs. no events in the placebo arm. Most events resolved following supportive treatment, without dose interruption or reduction, which occurred in 0.4% and 0.4% of patients, respectively. No patients discontinued treatment as a result of dyslipidaemia.
In the HCC Phase 3 study (see Section 5.1 Pharmacodynamic Properties, Clinical trials), there were no events of hypercholesterolaemia on the Lenvima arm vs. a frequency of 1.3% reported in sorafenib-treated patients. Events of blood cholesterol increased were reported in 1.5% of Lenvima treated patients (there were no Grade ≥ 3 events) and in 0.2% of sorafenib-treated patients. Hyperlipidaemia was reported in 0.6% of Lenvima treated patients (no Grade ≥ 3 event) and none were reported in sorafenib-treated patients. Hypertriglyceridaemia was reported in one patient (0.2%, Grade 3 event) on the Lenvima arm with no events in the sorafenib arm. No dose interruptions /reductions or discontinuations occurred as a result of these events.

Diarrhoea.

In the pivotal DTC Phase 3 SELECT trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), diarrhoea was reported in 67.4% of patients in the Lenvima-treated group (9.2% were Grade ≥ 3) and in 16.8% of patients in the placebo group (none were Grade ≥ 3).
In the Phase 3 HCC trial (see Section 5.1 Pharmacodynamic Properties, Clinical trials), diarrhoea was reported in 38.7% of patients treated with Lenvima compared with 46.3% of patients treated with sorafenib. There was an equal frequency (4.2%) of Grade ≥ 3 events in both treatment arms.

Other special populations.

Elderly.

In DTC, patients of age ≥ 75 years were more likely to experience Grade 3 or 4 hypertension, proteinuria, decreased appetite, and dehydration.
In CLEAR, patients of age ≥ 75 years had a higher (≥ 10% difference) incidence of proteinuria than patients of age < 65 years.
In HCC, patients of age ≥ 75 years were more likely to experience hypertension, proteinuria, decreased appetite, asthenia, dehydration, dizziness and hepatic encephalopathy. Arterial thromboembolic events also occurred at an increased incidence in this age group.

Sex.

In DTC, females had a higher incidence of hypertension (including Grade 3 or 4 hypertension), proteinuria, and PPE, while males had a higher incidence of decreased ejection fraction and gastrointestinal perforation and fistula formation.
In HCC, females had a higher incidence of hypertension, fatigue and ECG QT prolongation. Hepatic failure events were observed in male patients only.
In CLEAR, males had a higher (≥ 10% difference) incidence than females of diarrhoea.

Race.

In DTC, Asian patients had a higher incidence than Caucasian patients of oedema peripheral, hypertension, fatigue, PPE, proteinuria, thrombocytopenia, and blood thyroid stimulating hormone increased. Japanese patients had a higher incidence of Grade 3 or 4 hypertension, decreased appetite, fatigue, and thrombocytopenia compared with non-Japanese subjects.
In CLEAR, Asian patients had a higher (≥ 10% difference) incidence than Caucasian patients of palmar-plantar erythrodysaesthesia syndrome, proteinuria and hypothyroidism (including blood thyroid hormone increased) while Caucasian patients had a higher incidence of fatigue, nausea, arthralgia, vomiting, and asthenia.
In HCC, Asian patients had a higher incidence than Caucasian patients of proteinuria and PPE syndrome, while Caucasian patients had a higher incidence of fatigue, hepatic encephalopathy and acute kidney injury.

Baseline hypertension.

In DTC, patients with baseline hypertension had a higher incidence of Grade 3 or 4 hypertension, proteinuria, diarrhoea, and dehydration, and experienced more serious events of dehydration, hypotension, pulmonary embolism, malignant pleural effusion, atrial fibrillation, and GI symptoms (abdominal pain, diarrhoea, vomiting).
In CLEAR, patients with baseline hypertension had a higher incidence of proteinuria than patients without baseline hypertension.

Hepatic impairment.

In DTC, patients with baseline hepatic impairment had a higher incidence of hypertension and PPE, and a higher incidence of Grade 3 or 4 hypertension, asthenia, fatigue, and hypocalcaemia compared with patients with normal hepatic function. There are limited data on patients with hepatic impairment in RCC and endometrial carcinoma.
In HCC, patients with a baseline Child Pugh (CP) score of 6 compared to a baseline CP score of 5 had a higher incidence of decreased appetite, fatigue, proteinuria, hepatic encephalopathy and hepatic failure. Hepatotoxicity events and haemorrhage events also occurred at a higher incidence in CP score 6 patients compared to CP score 5 patients.
Limited data are available for the combination of Lenvima with pembrolizumab in patients with hepatic impairment. The combination should be used in patients with severe hepatic impairment only if the anticipated benefit exceeds the risk (see Section 4.8).

Renal impairment.

In DTC, patients with baseline renal impairment had a higher incidence of Grade 3 or 4 hypertension, proteinuria, fatigue, stomatitis, oedema peripheral, thrombocytopenia, dehydration, prolonged electrocardiogram QT, hypothyroidism, hyponatraemia, blood thyroid stimulating hormone increased and pneumonia compared with subjects with normal renal function. These patients also had a higher incidence of renal events and a trend towards a higher incidence of liver events.
See Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use.
In HCC, patients with baseline renal impairment had a higher incidence of fatigue, hypothyroidism, dehydration, diarrhoea, decreased appetite, proteinuria and hepatic encephalopathy. These patients also had a higher incidence of renal reactions and arterial thromboembolic events.

Patients with body weight < 60 kg.

In DTC, patients with low body weight (< 60 kg) had a higher incidence of PPE, proteinuria, Grade 3 or 4 hypocalcaemia and hyponatraemia, and a trend towards a higher incidence of Grade 3 or 4 decreased appetite. There are limited data on patients with body weight < 60 kg in RCC.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).
There have been reports of overdose with Lenvima including a single administration of 144 mg, 6 times the recommended daily dose. These cases were associated with adverse reactions consistent with the known safety profile of Lenvima, or were without adverse reactions. Death due to multiorgan dysfunction occurred in a patient who received a single dose of Lenvima 120 mg orally. There is no specific antidote for overdose with Lenvima, due to the high plasma protein binding, lenvatinib is not expected to be dialyzable. In case of suspected overdose, Lenvima should be withheld and appropriate supportive care given as required.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Lenvatinib is a multiple receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, the platelet derived growth factor (PDGF) receptor PDGFRα, KIT, and RET.
In addition, lenvatinib inhibited the proliferation of human hepatocellular carcinoma (HCC) cell lines dependent on FGFR signaling in vitro and caused a concurrent inhibition of FGF receptor substrate 2α (FRS2α) phosphorylation.
In syngeneic mouse tumour models, lenvatinib decreased tumour-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumour activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone.
The combination of lenvatinib and everolimus showed increased antiangiogenic and antitumour activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signalling in vitro and tumour volume in mouse xenograft models of human renal cell cancer greater than each drug alone.

Pharmacodynamic effects.

Cardiac electrophysiology.

A single 32-mg dose of lenvatinib did not prolong the QT/QTc interval based on results from a thorough QT study in healthy volunteers; however, QT/QTc interval prolongation has been reported at a higher incidence in patients treated with Lenvima than in patients treated with placebo (see Section 4.8 Adverse Effects (Undesirable Effects), Selected adverse reactions in DTC, RCC and HCC).

Clinical trials.

Radioactive iodine refractory differentiated thyroid cancer. The SELECT study was a multicentre, randomised, double-blind, placebo-controlled trial that was conducted in 392 patients with radioactive iodine refractory differentiated thyroid cancer with independent, centrally reviewed, radiographic evidence of disease progression within 12 months (+1 month window) prior to enrolment. Radioiodine-refractory status was defined as one or more measurable lesions either with a lack of iodine uptake or with progression in spite of radioactive-iodine (RAI) therapy, or having a cumulative activity of RAI of > 600 mCi or 22 GBq with the last dose at least 6 months prior to study entry.
Randomisation was stratified by geographic region (Europe, North America, and Other), prior VEGF/VEGFR-targeted therapy (patients may have received 0 or 1 prior VEGF/VEGFR-targeted therapy), and age (≤ 65 years or > 65 years). The main efficacy outcome measure was progression-free survival (PFS) as determined by blinded independent radiologic review using Response Evaluation Criteria in Solid Tumours (RECIST) 1.1.
Secondary efficacy outcome measures included overall response rate and overall survival (OS). Patients in the placebo arm could opt to receive Lenvima treatment at the time of confirmed disease progression.
Eligible patients with measurable disease according to RECIST 1.1 were randomised 2:1 to receive Lenvima 24 mg once daily (n = 261) or placebo (n = 131). Baseline demographics and disease characteristics were well balanced for both treatment groups. Of the 392 patients randomised, 76.3% were naïve to prior VEGF/VEGFR-targeted therapies, 49.0% were female, 49.7% were European, and the median age was 63 years. Histologically, 66.1% had a confirmed diagnosis of papillary thyroid cancer and 33.9% had follicular thyroid cancer which included Hurthle cell 14.8% and clear cell 3.8%. Metastases were present in 99% of the patients: lungs in 89.3%, lymph nodes in 51.5%, bone in 38.8%, liver in 18.1%, pleura in 16.3%, and brain in 4.1%. The majority of patients (54%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 0; 42.1% had a status of 1; 3.9% had a status above 1. The median cumulative RAI activity administered prior to study entry was 350 mCi (12.95 GBq).
A statistically significant prolongation in PFS was demonstrated in Lenvima-treated patients compared with those receiving placebo (p < 0.0001). The positive effect on PFS was similar in the subgroups that received 0 or 1 prior VEGF/VEGFR-targeted therapy (see Table 13 and Figure 1). In addition, the positive effect on PFS was seen across the subgroups of age, sex, race, histological subtype, and geographic region. Following independent review confirmation of disease progression, 109 (83.2%) patients randomised to placebo crossed over to receive open-label Lenvima.
There was no statistically significant difference in overall survival in the treatment arm compared to the placebo group at the primary analysis (HR (95% CI): 0.73 (0.59, 1.07)).
However, the SELECT study was not powered to demonstrate an improvement in OS, and the high rate of crossover of patients in the placebo arm to the treatment arm after confirmed disease progression made demonstration of a statistically significant difference in OS difficult.
The median time to first dose reduction was 2.8 months. The median time to objective response was 2.0 (95% CI: 1.9, 3.5) months; however, of the patients who experienced a complete or partial response to Lenvima, 70.4% were observed to develop the response on or within 30 days of being on the 24-mg dose.
The study did not measure quality of life (QoL). The effect of treatment on QoL can therefore not be assessed and QoL may not be improved with Lenvima treatment.
Renal cell carcinoma.

First-line treatment of patients with RCC in combination with pembrolizumab (CLEAR).

The efficacy of Lenvima in combination with pembrolizumab was investigated in CLEAR (NCT02811861), a multicenter, open-label, randomised trial that enrolled 1069 patients with advanced RCC in the first-line setting. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Randomisation was stratified by geographic region (North America and Western Europe versus "Rest of the World") and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups (favorable, intermediate and poor risk).
Patients were randomised to Lenvima 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every 3 weeks (n=355), or Lenvima 18 mg orally once daily in combination with everolimus 5 mg orally once daily (n=357), or sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks (n=357). Treatment continued until unacceptable toxicity or disease progression as determined by the investigator and confirmed by independent radiologic review committee (IRC) using RECIST 1.1.
Administration of Lenvima with pembrolizumab was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. Pembrolizumab dosing was continued for a maximum of 24 months; however, treatment with Lenvima could be continued beyond 24 months. Assessment of tumor status was performed at baseline and then every 8 weeks.
The overall study population characteristics were: median age of 62 years (range: 29 to 88 years); 42% age 65 or older, 75% male; 74% White, 21% Asian, 1% Black, and 2% other races; 18% and 82% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; patient distribution by IMDC (International Metastatic RCC Database Consortium) risk categories was 33% favorable, 56% intermediate, and 10% poor, and MSKCC risk categories was 27% favorable, 64% intermediate and 9% poor. Common sites of metastases in patients were lung (68%), lymph node (45%), and bone (25%).
The primary efficacy outcome measure was PFS based on RECIST 1.1 per IRC. Key secondary efficacy outcome measures included OS and ORR. LENVIMA in combination with pembrolizumab demonstrated statistically significant improvements in PFS, OS, and ORR compared with sunitinib. At a median overall survival follow-up time of 26.6 months, efficacy results for CLEAR are summarised in Table 14, Figure 2 and Figure 3. Consistent results were observed across pre-specified subgroups, MSKCC prognostic groups, and PD-L1 tumor expression status.

Previously treated RCC in combination with everolimus (Study 205).

A multicentre, randomised, open-label, trial was conducted to determine the safety and efficacy of Lenvima administered alone or in combination with everolimus in subjects with unresectable advanced or metastatic Renal Cell Carcinoma (RCC). The study consisted of a Phase 1b dose finding and a Phase 2 portion. The Phase 1b portion included 11 patients who received the combination of 18 mg of Lenvima plus 5 mg of everolimus. The Phase 2 portion enrolled a total of 153 patients with unresectable advanced or metastatic RCC, who had previously received 1 prior VEGF-targeted treatment, 1:1:1 to Lenvima 18 mg plus everolimus 5 mg, Lenvima 24 mg monotherapy, or everolimus 10 mg monotherapy. All medications were administered orally once daily. Patients were required to have histological confirmation of predominant clear cell RCC, and ECOG Performance Status of 0 or 1. Patients were stratified by haemoglobin level (≤ 13 g/dL vs. > 13 g/dL for males and ≤ 11.5 g/dL vs > 11.5 g/dL for females) and corrected serum calcium (≥ 10 mg/dL vs. < 10 mg/dL).
Of the 101 patients randomly allocated to the Lenvima plus everolimus arm and everolimus monotherapy, 72% were male, the median age was 60 years, 31% were 65 years or older, and 96% were Caucasian. All patients were classified as having Stage IV RCC. All patients had a baseline ECOG PS of either 0 (54%) or 1 (46%) with similar distribution across the 2 treatment arms. Memorial Sloan Kettering Cancer Centre (MSKCC) favourable, intermediate, and poor risk categories were observed respectively, in 24%, 37%, and 39% of patients in the Lenvima plus everolimus arm, and 24%, 38%, and 38% of patients in the everolimus arm.
The primary efficacy outcome measure was investigator assessed PFS evaluated according to RECIST 1.1. Efficacy results are summarised in Table 15, Figure 4 and Figure 5. The treatment effect of the combination on PFS was supported by a retrospective independent blinded review of radiographs with an observed hazard ratio (HR) of 0.43 (95% CI: 0.24, 0.75) compared with the everolimus arm.
Hepatocellular carcinoma. A multicentre, open-label study was conducted in 954 patients with unresectable hepatocellular carcinoma who were randomised to Lenvima or sorafenib. The starting dose of Lenvima, given once daily, was based on baseline body weight: 12 mg for patients with a body weight ≥ 60 kg and 8 mg for patients with a body weight < 60 kg. The dose of sorafenib was 400 mg given orally twice daily.
Patients were required to have a histologically or cytologically confirmed diagnosis of unresectable HCC, or a clinically confirmed diagnosis of HCC according to the American Association for the Study of Liver Diseases criteria, including cirrhosis of any etiology, or with chronic hepatitis B or C infection. Patients could have BCLC stage B or C disease, and could only have Child Pugh category A liver dysfunction (i.e. a score of 5-6). Patients had at least 1 measurable target hepatic or nonhepatic lesion according to mRECIST, and adequate liver, bone marrow, blood coagulation, renal, and pancreatic function. Patients were stratified by region, presence or absence of macroscopic portal vein invasion (MPVI) or extrahepatic spread (EHS) or both, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1, and BW (< 60 kg or ≥ 60 kg). The majority of patients in both treatment arms had an ECOG PS of 0 at Baseline (63%), Child-Pugh score of 5 (76%), and weighed ≥ 60 kg (69%). The median age was 62 years, 84% were male, 16% were female, 69% were Asian, 1% were black, and 29% were white. Approximately 80% of patients in Study 304 had BCLC stage C disease at study entry. This percentage was similar between the treatment arms (Lenvima 374/478, 78.2%; sorafenib 384/476, 80.7%).
Lenvima was non-inferior for Overall Survival (OS) to sorafenib. Median OS was 13.6 months compared to 12.3 months for sorafenib with HR = 0.92 [95% CI of (0.79, 1.06)].
Based on investigator assessment evaluated according to mRECIST, Lenvima treatment resulted in statistically significant (P < 0.00001) and clinically meaningful improvement over sorafenib in the secondary endpoints of PFS and ORR. Lenvima treatment significantly prolonged TTP compared to sorafenib, with a median TTP that was more than twice as long as that of sorafenib. Retrospective independent review of imaging corroborated the secondary endpoints of PFS, TTP and ORR. These efficacy results are summarised in Table 16, Figure 6, Figure 7 and Figure 8.

Assessment on quality of life (QoL) in patients with HCC.

Three QoL questionnaires were administered EORTC QLQ-C30, EORTC QLQ-HCC18 and the EQ-5D-3L.
Compared to patients treated with Lenvima, those treated with sorafenib experienced greater risks of more rapid time to clinically meaningful worsening of symptoms and function for the domain of Diarrhoea (nominal p < 0.0001) from the EORTC QLQ-C30.
Endometrial carcinoma (EC). The efficacy of Lenvima in combination with pembrolizumab was investigated in Study 309, a multicentre, open-label, randomised, active-controlled trial that enrolled 827 patients with advanced endometrial carcinoma who had been previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings. Patients with endometrial sarcoma, including carcinosarcoma, or patients who had active autoimmune disease or a medical condition that required immunosuppression were ineligible. Patients with endometrial carcinoma that were not MSI-H or dMMR were stratified by ECOG performance status, geographic region, and history of pelvic radiation.
Patients were randomised (1:1) to one of the following treatment arms:
Lenvima 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every 3 weeks.
Investigator's choice consisting of either doxorubicin 60 mg/m2 every 3 weeks, or paclitaxel 80 mg/m2 given weekly, 3 weeks on/1 week off.
Treatment with Lenvima and pembrolizumab continued until RECIST v1.1-defined progression of disease as verified by BICR, unacceptable toxicity, or for pembrolizumab, a maximum of 24 months. Treatment was permitted beyond RECIST v1.1-defined disease progression if the treating investigator considered the patient to be deriving clinical benefit and the treatment was tolerated. Assessment of tumour status was performed every 8 weeks. The primary efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures included ORR and DOR, as assessed by BICR.
Among the 697 not MSI-H or dMMR patients, 346 patients were randomised to Lenvima in combination with pembrolizumab, and 351 patients were randomised to investigator's choice of doxorubicin (n=254) or paclitaxel (n=97). The population characteristics of these patients were: median age of 65 years (range: 30 to 86), 52% age 65 or older; 62% White, 22% Asian, and 3% Black; 60% ECOG PS of 0 and 40% ECOG PS of 1. The histologic subtypes were endometrioid carcinoma (55%), serous (30%), clear cell carcinoma (7%), mixed (4%), and other (3%). All 697 of these patients received prior systemic therapy for endometrial carcinoma: 67% had one, 30% had two, and 3% had three or more prior systemic therapies. Thirty-seven percent of patients received only prior neoadjuvant or adjuvant therapy.
Efficacy results are summarised in Table 17 and Figure 9 and Figure 10.

5.2 Pharmacokinetic Properties

Absorption.

Lenvatinib is rapidly absorbed after oral administration with Tmax typically observed from 1 to 4 hours post-dose. Food does not affect the extent of absorption, but slows the rate of absorption. When administered with food to healthy subjects, peak plasma concentrations are delayed by 2 hours.
A high degree of inter-individual variability in average exposure at steady state was observed, with a 6-fold range when used as monotherapy at the 24 mg dose, and 7-fold range when Lenvima 18 mg dose is administered in combination with 5 mg everolimus. In HCC subjects, the inter-individual variability in average exposure at steady state was 6-fold and 5-fold range when used as monotherapy at 8 mg and 12 mg doses, respectively.

Distribution.

In vitro binding of lenvatinib to human plasma proteins was high and ranged from 98% to 99% (0.3 - 30 microgram/mL, mesilate). This binding was mainly to albumin with minor binding to α1-acid glycoprotein and γ-globulin. A similar plasma protein binding (97% to 99%) with no dependencies on lenvatinib concentrations (0.2 to 1.2 microgram/mL) was observed in plasma from hepatically impaired, renally impaired, and matching healthy subjects.
In vitro, the lenvatinib blood-to-plasma concentration ratio ranged from 0.589 to 0.608 (0.1 - 10 microgram/mL, mesilate). In vitro studies indicate that lenvatinib is a substrate for P-gp and BCRP. Lenvatinib is not a substrate for OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, MATE1, MATE2-K or the BSEP.
In patients, the median apparent volume of distribution (Vz/F) of the first dose ranged from 50.5 L to 92 L and was generally consistent across the dose groups from 3.2 mg to 32 mg. The analogous median apparent volume of distribution at steady-state (Vz/Fss) was also generally consistent and ranged from 43.2 L to 121 L.

Metabolism.

In vitro, cytochrome P450 3A4 was the predominant (> 80%) cytochrome isoform involved in the P450-mediated metabolism of lenvatinib. In vivo, inducers and inhibitors of CYP3A4 had a minimal effect on lenvatinib exposure (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Patients should avoid strong inducers of CYP3A4 and exercise caution with mild or moderate inhibitors or inducers when using everolimus (see everolimus product information) in combination with Lenvima.
In human liver microsomes, the demethylated form of lenvatinib (M2) was identified as the main metabolite. M2' and M3', the major metabolites in human faeces, were formed from M2 and lenvatinib, respectively, by aldehyde oxidase.
In plasma samples collected up to 24 hours after administration, lenvatinib constituted 97% of the radioactivity in plasma radiochromatograms while the M2 metabolite accounted for an additional 2.5%. Based on AUC(0-inf), lenvatinib accounted for 60% and 64% of the total radioactivity in plasma and blood, respectively.
Data from a human mass balance/excretion study indicate lenvatinib is extensively metabolised in humans. The main metabolic pathways in humans were identified as oxidation by aldehyde oxidase, demethylation via CYP3A4, glutathione conjugation with elimination of the O-aryl group (chlorbenzyl moiety), and combinations of these pathways followed by further biotransformations (e.g. glucuronidation, hydrolysis of the glutathione moiety, degradation of the cysteine moiety, and intramolecular rearrangement of the cysteinylglycine and cysteine conjugates with subsequent dimerisation). These in vivo metabolic routes align with the data provided in the in vitro studies using human biomaterials.

Excretion.

Plasma concentrations decline bi-exponentially following Cmax. The mean terminal exponential half-life of lenvatinib is approximately 28 hours.
Following administration of radiolabelled lenvatinib to 6 patients with solid tumours, approximately two-thirds and one-fourth of the radiolabel were eliminated in the faeces and urine, respectively. The M2 metabolite was the predominant analyte in excreta (~5% of the dose) with lenvatinib the second most prominent (~2.5%).

Linearity/non-linearity.

Dose proportionality and accumulation.

In patients with solid tumours administered single and multiple doses of lenvatinib once daily, exposure to lenvatinib (Cmax and AUC) increased in direct proportion to the administered dose over the range of 3.2 to 32 mg once-daily (QD).
Lenvatinib displays minimal accumulation at steady state. Over this range, the median accumulation index (Rac) ranged from 0.96 (20 mg) to 1.54 (6.4 mg). In patients with HCC, the mean accumulation ratio was 1.49 in those with higher Child-Pugh scores (7-8) receiving 8 mg lenvatinib.

Special populations.

Hepatic impairment.

The pharmacokinetics of lenvatinib following a single 10-mg dose were evaluated in 6 subjects each with mild or moderate hepatic impairment (Child-Pugh A and Child-Pugh B, respectively). A 5-mg dose was evaluated in 6 subjects with severe hepatic impairment (Child-Pugh C). Eight healthy, demographically matched subjects served as controls and received a 10-mg dose. The median half-life was comparable in subjects with mild, moderate, and severe hepatic impairment as well as those with normal hepatic function and ranged from 26 hours to 31 hours. The percentage of the dose of lenvatinib excreted in urine was low in all cohorts (< 2.16% across treatment cohorts).
Lenvatinib exposure, based on dose-adjusted AUC0-t,unbound and AUC0-inf,unbound, was approximately 65%, 122%, and 273% of normal for subjects with mild, moderate, and severe hepatic impairment, respectively. Based on the analogous AUC0-t and AUC0-inf data, lenvatinib exposure was 119%, 107%, and 180% of normal for subjects with mild, moderate, and severe hepatic impairment, respectively (see Section 4.2 Dose and Method of Administration).

Renal impairment.

The pharmacokinetics of lenvatinib following a single 24 mg dose were evaluated in 6 subjects each with mild, moderate, or severe renal impairment, and compared with 8 healthy, demographically matched subjects. Subjects with end-stage renal disease were not studied. The percentage of unbound lenvatinib was similar between subjects with normal renal function (8% ± 3%, mean ± SD) and those with severely impaired renal function (9% ± 2%). AUC0-inf,unbound estimates for subjects with mild, moderate, or severe renal impairment were 54%, 129%, and 184%, respectively, compared with normal subjects. Additionally, a linear equation was fit to the creatinine clearance vs. AUC0-inf,unbound data and exposure was predicted. Subjects with severe renal impairment were predicted to have a 2.4-fold increase in exposure. Therefore dosage needs to be reduced in DTC, RCC and endometrial carcinoma patients with severe renal impairment (see Section 4.2 Dose and Method of Administration). No dosage recommendations are available for HCC patients with severe renal impairment (see Section 4.2 Dose and Method of Administration). Use in HCC patients with severe renal impairment is not recommended.

Age, sex, weight, race.

Based on a population pharmacokinetic analysis of patients receiving up to 24 mg Lenvima once daily, including HCC patients weighing < 60 kg and ≥ 60 kg receiving 8 mg and 12 mg, respectively, weight showed a statistically significant effect. The final PK model for lenvatinib included body-weight effect as an allometric constant on both clearance (CL/F) and volume parameters, whereby parameters increased with increasing body weight. The decrease in CL/F in subjects with low body weight resulted in an increase in lenvatinib exposure (AUC) whereby subjects weighing < 60 kg had approximately 35% higher exposure to lenvatinib than subjects weighing ≥ 60 kg when receiving the same dose. Based on the individual lenvatinib AUC at steady state for subjects with HCC, the median value and range of AUC are comparable between the group of starting dose of 8 mg for body weight < 60 kg and 12 mg for body weight ≥ 60 kg, which supports the starting doses of 8 mg and 12 mg for body weight < 60 kg and ≥ 60 kg, respectively, in HCC patients.
After accounting for body weight, neither age, sex, or race (Japanese vs. other, Chinese vs other, white vs. other) influenced lenvatinib PK.

Paediatric population.

Paediatric patients have not been studied.

Genomic assessment of lenvatinib pharmacokinetic parameters.

Because of lenvatinib's extensive metabolism, the effect of selected drug-metabolising enzyme phenotypes on lenvatinib clearance was investigated using data derived from the Affymetrix drug-metabolising enzyme and transporter (DMET Plus) microarray genotyping platform. None of the phenotypes for CYP3A5, CYP1A2, CYP2A6, or CYP2C19 had a significant impact on lenvatinib clearance.

5.3 Preclinical Safety Data

In the repeated-dose toxicity studies (up to 39 weeks), lenvatinib caused toxicologic changes in various organs and tissues related to the expected pharmacologic effects of lenvatinib including glomerulopathy, testicular hypocellularity, ovarian follicular atresia, gastrointestinal changes, bone changes, changes to the adrenals (rats and dogs), and arterial (arterial fibrinoid necrosis, medial degeneration, or haemorrhage) lesions in rats, dogs, and cynomolgus monkeys. Elevated transaminase levels asociated with signs of hepatotoxicity, were also observed in rats, dogs and monkeys. Reversibility of the toxicologic changes was observed at the end of a 4-week recovery period in all animal species investigated.

Genotoxicity.

Lenvatinib was not mutagenic in the in vitro Ames and mouse lymphoma tests and not clastogenic in an in vivo micronucleus assay in rats. These studies indicate a low genotoxic potential for Lenvima.

Carcinogenicity.

Carcinogenicity studies have not been conducted with Lenvima.

Reproductive and developmental toxicity.

No specific studies with lenvatinib have been conducted in animals to evaluate the effect on fertility. However, testicular (hypocellularity of the seminiferous epithelium) and ovarian changes (follicular atresia) were observed in repeated-dose toxicity studies in animals at exposures 11 to 15 times (rat) or 0.6 to 7 times (monkey) the anticipated clinical exposure (based on AUC) at the maximum tolerated human dose. These findings were reversible at the end of a 4-week recovery period.
Administration of lenvatinib during organogenesis resulted in embryolethality and teratogenicity in rats (foetal external and skeletal anomalies) at exposures below the clinical exposure (based on AUC) at the maximum tolerated human dose, and rabbits (foetal external, visceral or skeletal anomalies) based on body surface area; mg/m2 at the maximum tolerated human dose. These findings indicate that lenvatinib has a teratogenic potential, likely related to the pharmacologic activity of lenvatinib as an antiangiogenic agent. Lenvatinib and its metabolites are excreted in rat milk.

Juvenile animal toxicity studies.

Mortality was the dose-limiting toxicity in juvenile rats in which dosing was initiated on postnatal day (PND) 7 or PND21 and was observed at exposures that were respectively 125- or 12-fold lower compared with the exposure at which mortality was observed in adult rats, suggesting an increasing sensitivity to toxicity with decreasing age. Therefore, mortality may be attributed to complications related to primary duodenal lesions with possible contribution from additional toxicities in immature target organs.
The toxicity of lenvatinib was more prominent in younger rats (dosing initiated on PND7) compared with those with dosing initiated on PND21 and mortality and some toxicities were observed earlier in the juvenile rats at 10 mg/kg compared with adult rats administered the same dose level. Growth retardation, secondary delay of physical development, and lesions attributable to pharmacologic effects (incisors, femur [epiphyseal growth plate], kidneys, adrenals, and duodenum) were also observed in juvenile rats.

6 Pharmaceutical Particulars

6.1 List of Excipients

The capsules contain the excipients calcium carbonate, mannitol, microcrystalline cellulose, hydroxypropylcellulose, and purified talc. The capsule shell contains the excipients hypromellose, titanium dioxide, iron oxide yellow and iron oxide red. The printing ink on the capsules contains the excipients shellac, iron oxide black, potassium hydroxide and propylene glycol.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Lenvima 4 mg hard capsules are available in polyamide/aluminium/PVC/aluminium blisters of 30 capsules.
Lenvima 10 mg hard capsules are available in polyamide/aluminium/PVC/aluminium blisters of 30 capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Lenvatinib mesilate is a white powder and is sparingly soluble in acetic acid and slightly soluble in water, N,N-dimethylformamide, methanol, N-methylpyrrolidone, and pyridine. It is very slightly soluble in 1,3-dimethyl-2-imidazolidinone and practically insoluble in acetonitrile, dehydrated ethanol, 1-propanol, 2-propanol, 1-octanol and isopropyl acetate. In aqueous solutions, lenvatinib mesilate is very slightly soluble in 0.1 mol/L HCl and practically insoluble in Britton-Robinson buffer, pH 3-11.

Chemical structure.

Lenvatinib is a multiple receptor tyrosine kinase (RTK) inhibitor.
Chemical Name: 4-[3-chloro-4-(N'-cyclopropylureido) phenoxy]-7-methoxyquinoline-6- carboxamide methanesulfonate.
The empirical formula of lenvatinib is C21H19ClN4O4.CH4O3S.

CAS number.

CAS: 857890-39-2.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription only medicine.

Summary Table of Changes