Consumer medicine information

Lenalidomide Sandoz

Lenalidomide

BRAND INFORMATION

Brand name

Lenalidomide Sandoz

Active ingredient

Lenalidomide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lenalidomide Sandoz.

SUMMARY CMI

Lenalidomide Sandoz®

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.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using Lenalidomide Sandoz?

Lenalidomide Sandoz contains the active ingredient lenalidomide. Lenalidomide Sandoz is used to treat patients with multiple myeloma or a type of myelodysplatic syndrome (MDS) where part of chromosome 5 is missing, and adult patients who have been diagnosed with or previously treated for Mantle Cell Lymphoma.

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

2. What should I know before I use Lenalidomide Sandoz?

Do not use if you have ever had an allergic reaction to lenalidomide 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 Lenalidomide Sandoz? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Lenalidomide Sandoz 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 Lenalidomide Sandoz?

  • Lenalidomide Sandoz should be taken either one hour before or two hours after eating food.
  • Swallow the capsules whole, preferably with water, once a day as directed by your doctor.

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

5. What should I know while using Lenalidomide Sandoz?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Lenalidomide Sandoz.
  • Keep all of your doctor's appointments so that your progress can be checked.
Things you should not do
  • Do not stop taking Lenalidomide Sandoz (unless you suspect that you are pregnant) or change the dose without first checking with your doctor. Do not become pregnant whilst taking Lenalidomide Sandoz.
  • Do not donate blood during treatment or treatment interruption, or for at least 1 week after stopping treatment.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how Lenalidomide Sandoz affects you.
Looking after your medicine
  • Keep your capsules in a cool dry place where the temperature stays below 25°C.
  • Keep your capsules in the original package until it is time to take them.

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

6. Are there any side effects?

Tell your doctor as soon as possible if you notice any of the following more serious side effects: Heart palpitations or fast heart beat, chest pains, dizziness or fainting, shortness of breath, weakness, or reduced ability to exercise; Bleeding (including nosebleeds) or bruising more easily than normal; Tiredness, headaches, shortness of breath, dizziness and looking pale; Numbness, tingling, pins and needles or weakness of the arms and legs; Blurred vision or difficulty seeing; Passing large amounts of urine, excessive thirst, and having a dry mouth and skin; Abnormal eye movements, convulsions, mood changes or irregular heart rhythms; Tender swollen lymph nodes, low-grade fever, pain, or rash.

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.

WARNING: Lenalidomide Sandoz (lenalidomide) is structurally related to 'thalidomide', which is known to cause severe life-threatening human birth defects (deformed babies) and death to an unborn baby if taken during pregnancy. If Lenalidomide Sandoz is taken during pregnancy, it may cause birth defects or death to an unborn baby. Do not take Lenalidomide Sandoz if you are pregnant or think that you are pregnant.



FULL CMI

Lenalidomide Sandoz®

Active ingredient(s): lenalidomide

Consumer Medicine Information (CMI)

This leaflet provides important information about using Lenalidomide Sandoz. 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 Lenalidomide Sandoz.

Where to find information in this leaflet:

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

1. Why am I using Lenalidomide Sandoz?

Lenalidomide Sandoz contains the active ingredient lenalidomide. Lenalidomide Sandoz belongs to a group of medicines called immunomodulating agents that work by acting on the cells involved in the body's immune system. The immune system is part of the body's defence which helps to fight illness and infection.

Treatment of Multiple Myeloma

Multiple myeloma (MM) is a cancer of the bone marrow. Lenalidomide Sandoz is used to treat patients with Multiple Myeloma.

Treatment of Myelodysplastic Syndromes

Lenalidomide Sandoz is also used to treat patients who have conditions called myelodysplastic syndromes (MDS) in whom the bone marrow does not produce enough mature blood cells. This causes a lack of healthy blood cells in the body. There are different types of MDS.

Lenalidomide Sandoz is approved to treat a type of MDS where part of chromosome 5 is missing. This type of MDS is known as deletion 5q MDS (or 5q minus). Patients with this type of MDS often have low red blood cell counts that require treatment with blood transfusions. It is hoped that the use of Lenalidomide Sandoz will reduce the need for blood transfusions.

Treatment of Mantle Cell Lymphoma

Lenalidomide Sandoz is used to treat adult patients who have been diagnosed with and previously treated for Mantle Cell Lymphoma (MCL).

MCL is a cancer of the lymph tissue (part of the immune system), affecting a type of white blood cell called 'B-lymphocytes'. MCL is a disease where B-cells grow in an uncontrolled way and accumulate in the lymph tissue, bone marrow or blood.

Ask your doctor if you have any questions about how Lenalidomide Sandoz works, or why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

This medicine is not addictive.

Lenalidomide Sandoz will only be prescribed to you by a doctor who has experience in medicines to treat cancers of the blood.

2. What should I know before I use Lenalidomide Sandoz?

Please read the Consumer Medicine Information leaflets of any medicinal products to be taken in combination with Lenalidomide Sandoz before starting treatment with Lenalidomide Sandoz.

Warnings

Do not use Lenalidomide Sandoz if:

  • you are allergic to lenalidomide, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • you are pregnant, or think that you are pregnant.
    Lenalidomide Sandoz may cause birth defects (deformed babies), and may affect your developing baby if you take it during pregnancy.
  • you are able to become pregnant, unless you are willing to follow the required pregnancy prevention measures (outlined in Program - see section The MyCheckPoint Pregnancy Prevention Program). If you are not sure whether you should start taking this medicine, talk to your doctor.
  • you have the rare hereditary problems of glucose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption.

Check with your doctor if you:

  • have any other medical conditions, including:
    - heart attack, blood clots, high blood pressure or high cholesterol
    - frequent bleeding or bruising
    - frequent infections
    - hepatitis B virus infection
    - peripheral neuropathy (numbness, tingling, weakness, abnormal coordination or pain in your hands and feet)
    - thyroid problems
    - abnormal kidney function
    - liver problems e.g. liver infections
    - allergic reactions to thalidomide or lenalidomide.
  • take any medicines for any other condition

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

Follow your doctor's instructions carefully.

You will have been given specific instructions by your doctor particularly on the potential effects of lenalidomide on unborn babies.

If you have not fully understood these instructions, ask your doctor again before taking Lenalidomide Sandoz.

Your doctor will have enrolled you in the MyCheckPoint Pregnancy Prevention Program to ensure that lenalidomide is used safely.

The MyCheckPoint Pregnancy Prevention Program

Lenalidomide Sandoz (lenalidomide) is structurally related to 'thalidomide', which is known to cause severe life threatening human birth defects (deformed babies) and can cause death to an unborn baby if taken during pregnancy. If Lenalidomide Sandoz is taken during pregnancy, it may cause birth defects or death to an unborn baby.

To avoid exposure to unborn babies, Lenalidomide Sandoz is available only under a special distribution program. This program is designed to ensure that this medicine is always prescribed and taken in the recommended way.

Importantly, only patients who are formally enrolled in this program and agree to fully comply with all the requirements of this program can receive Lenalidomide Sandoz.

Some of the requirements of the Program are outlined in the following sections. Your doctor will discuss all the details with you.

1. For Women taking Lenalidomide Sandoz

Before starting this treatment, your doctor will discuss your potential to become pregnant, even if you think this is unlikely e.g. if your periods have stopped.

If you are able to become pregnant:

  • Your doctor will discuss the potential risk to unborn babies if Lenalidomide Sandoz is taken during pregnancy.
  • You will be required to have pregnancy tests before treatment, every 4 weeks during treatment, and 4 weeks after stopping treatment.
  • You should start your Lenalidomide Sandoz treatment as soon as you get it from the pharmacy following a negative pregnancy test.
  • Use reliable means of contraception for at least 4 weeks before starting Lenalidomide Sandoz treatment, during treatment and treatment interruption, and for at least 4 weeks after Lenalidomide Sandoz treatment has stopped.

Your doctor will tell you what method of contraception to use.

Effective methods of contraception include the following:

  • Implant
  • Levonorgestrel-releasing intrauterine system (IUS)
  • Medroxyprogesterone acetate depot
  • Tubal sterilisation
  • Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two negative semen analyses
  • Ovulation inhibitory progesterone-only pills (i.e. desogestrel).

Combined oral contraceptive pills are not recommended as they can increase the risk of blood clots blocking blood vessels in patients with MM being treated with this medicine.

You must stop taking Lenalidomide Sandoz and inform your doctor straight away if:

  • You miss or think you have missed a period, or you have unusual menstrual bleeding, or suspect you are pregnant.
  • You have heterosexual intercourse without using reliable means of contraception.

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

It is not known if Lenalidomide Sandoz is excreted in human milk. Therefore, you should discuss with your doctor whether to discontinue breast-feeding while you are receiving this medicine.

2. For Men taking Lenalidomide Sandoz

Before starting this treatment, discuss with your doctor if your partner is able to become pregnant.

If your partner is able to become pregnant, use barrier methods of contraception (e.g. condoms) even if you are vasectomised, during Lenalidomide Sandoz treatment, during treatment interruption, and for at least 7 days after treatment has stopped.

Tell your doctor immediately if your partner becomes pregnant whilst you are taking this medicine.

Do not donate semen during treatment or during treatment interruption, or for 7 days after stopping treatment.

3. For All Patients taking Lenalidomide Sandoz

Do not donate blood during Lenalidomide Sandoz treatment or during treatment interruption, and for at least 1 week after stopping treatment.

Your doctor will ask you to have regular blood tests during treatment with Lenalidomide Sandoz.

Your doctor may adjust your dose of Lenalidomide Sandoz or stop your treatment based on the results of your blood tests and on your general condition.

If you are older than 65 years, in addition to these blood tests, your doctor may also check your kidney function with other tests.

It is important to note that a small number of patients with MM may develop additional types of cancer (regardless of their type of therapy).

At this stage, it cannot be excluded that this risk may be slightly increased with Lenalidomide Sandoz treatment. Therefore, your doctor will carefully evaluate the benefit and risk when you are prescribed this medicine.

Use in Children

Do not give this medicine to a child or adolescent under the age of 18 years.

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 and Lenalidomide Sandoz may interfere with each other. These include:

  • medicines used to prevent pregnancy, such as oral contraceptives
  • medicines used to treat symptoms of menopause e.g. hormone replacement therapy
  • medicines used for heart problems e.g. digoxin
  • medicines used to thin the blood e.g. warfarin.

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

4. How do I use Lenalidomide Sandoz?

Follow all directions given to you by your doctor carefully.

They may differ from the information contained in this leaflet.

How much to take

Your doctor will tell you how much Lenalidomide Sandoz to take and for how long you will need to take it.

  • For treatment of newly diagnosed multiple myeloma (NDMM) in combination with bortezomib and dexamethasone, the usual starting dose of Lenalidomide Sandoz is 25 mg once daily.
  • Your doctor will tell you if you are to take Lenalidomide Sandoz for 14 continuous days of a 21-Day cycle or for 21 continuous days of a 28-Day cycle.
  • Your doctor will also tell you the duration and the quantity of the other medicines to be taken in combination with Lenalidomide Sandoz. After the initial treatment of about 24 weeks, you may have a stem cell transplant or your doctor may ask you to take 25 mg of Lenalidomide Sandoz once daily for 21 days of a 28-Day cycle continuously.
  • For the treatment of NDMM after a stem cell transplant, the usual starting dose is 10 mg once daily continuously (28 days of a 28-Day cycle).
  • For the treatment of MM in combination with dexamethasone (either NDMM in patients not eligible for stem cell transplantation or MM in patients whose disease has progressed after one therapy), the usual starting dose is 25 mg once a day for 21 days of a 28-Day cycle.
  • For the treatment of MDS, the recommended starting dose is 10 mg once a day for 21 days of a 28-Day cycle.
  • For the treatment for MCL, the usual starting dose is 25 mg once a day for 21 days of a 28-Day cycle.

Your doctor will monitor your progress, and may adjust your dose of Lenalidomide Sandoz or stop your treatment based on the results of your blood tests and on your general condition.

  • Follow the instructions provided and use Lenalidomide Sandoz until your doctor tells you to stop

When to take Lenalidomide Sandoz

  • Lenalidomide Sandoz should be taken either one hour before or two hours after eating food.

How to take Lenalidomide Sandoz

  • Swallow the capsules whole, preferably with water, once a day as directed by your doctor.
  • Do not open, break or chew the capsules.
  • If powder from inside the capsules leaks out and contacts the skin, wash the skin immediately and thoroughly with soap and water. If lenalidomide contacts the mucous membranes e.g. the eyes, flush thoroughly with water.

How to long to take Lenalidomide Sandoz

  • Continue taking Lenalidomide Sandoz as instructed by your doctor, until your doctor tells you to stop.
  • Your doctor will keep a close check on you to make sure you continue to benefit from Lenalidomide Sandoz.

If you forget to take Lenalidomide Sandoz

Lenalidomide Sandoz should be used regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember, and then go back to taking your medicine as you would normally.

If it is less than 12 hours before your next dose, skip the dose you missed and take your next dose when you are meant to.

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

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

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

If you use too much Lenalidomide Sandoz

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

You should immediately:

  • phone the Australian Poisons Information Centre
    (by calling 13 11 26), or the New Zealand National Poisons Information Centre (by calling 0800 POISONS
    or 0800 764 766    ), 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 Lenalidomide Sandoz?

Things you should do

Female Patients:

Call your doctor straight away if you:

  • become pregnant or suspect that you may be pregnant. You should also immediately stop taking Lenalidomide Sandoz in this case.

All Patients:

  • Keep all of your doctor's appointments so that your progress can be checked.
  • Your doctor will do some blood tests regularly and will check your general condition to make sure the medicine is working and to prevent unwanted side effects.
  • Remind any doctor, dentist or pharmacist you visit that you are using Lenalidomide Sandoz.

Things you should not do

Female Patients:

  • Do not become pregnant whilst taking Lenalidomide Sandoz.
  • Do not have sexual intercourse without using effective means of contraception described to you by your doctor.

Male Patients:

  • Do not donate sperm during treatment or treatment interruption, or for at least 1 week after stopping treatment.
    Lenalidomide Sandoz can pass into human semen.
  • Do not have sexual intercourse without using effective means of contraception described to you by your doctor.

All Patients:

  • Do not donate blood during treatment or treatment interruption, or for at least 1 week after stopping treatment.
    In Australia, patients with some types of cancer are permanently excluded from donating blood.
  • Do not stop taking Lenalidomide Sandoz (unless you suspect that you are pregnant) or change the dose without first checking with your doctor.
  • Do not let yourself run out of medicine over the weekend or on holidays.
  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not take this medicine to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. In that case, return it to your pharmacist.

Driving or using machines

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

Lenalidomide Sandoz may cause dizziness, tiredness or blurred vision in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Looking after your medicine

  • Keep your capsules in a cool dry place where the temperature stays below 25°C.
  • Keep your capsules in the original package until it is time to take them.

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.

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.

Less serious side effects

Less serious side effectsWhat to do
  • Diarrhoea; constipation; feeling sick (also called nausea); vomiting; stomach pain; indigestion; dehydration; dry mouth; sore mouth: mouth ulcers: difficulty in speaking toothache; increase or decrease in weight; increase or decrease in appetite; loss of taste.
  • Itchiness; rash; redness of the skin; dry skin; bruising; excessive sweating.
  • Dizziness; fainting; headache; shaking or tremors; unusual weakness; night sweats; reduced sense of touch.
  • Difficulty sleeping; depression; anxiety; feeling of confusion.
  • Back pain; muscle spasms; muscle and/or joint pain; swollen joints; bone pain; muscular weakness; pain in the extremities; feeling tired; fall.
  • Swelling of hands, ankles or feet.
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • Heart palpitations or fast heart beat, chest pains, dizziness or fainting, shortness of breath, weakness, or reduced ability to exercise.
    These could be symptoms of atrial fibrillation (irregular heart beat) or tachycardia (fast heart beat).
  • Bleeding (including nosebleeds) or bruising more easily than normal.
    Lenalidomide Sandoz can reduce the number of platelets, which are responsible for making the blood clot properly. Your doctor may monitor your blood cell numbers during treatment with Lenalidomide Sandoz.
  • Tiredness, headaches, shortness of breath, dizziness and looking pale.
    Lenalidomide Sandoz can reduce the number of red blood cells that carry oxygen around the body.
  • Numbness, tingling, pins and needles or weakness of the arms and legs.
    This may be due to nerve damage.
  • Blurred vision or difficulty seeing.
    This could be due to a cataract in your eye(s).
  • Passing large amounts of urine, excessive thirst, and having a dry mouth and skin.
    These could be symptoms of high blood sugar or diabetes.
  • Abnormal eye movements, convulsions, mood changes or irregular heart rhythms.
    These could be due to low levels of minerals such as potassium, calcium, magnesium or sodium.
  • Tender swollen lymph nodes, low-grade fever, pain, or rash.
    This could be due to worsening of your tumour (for patients with MCL).
Tell your doctor as soon as possible if you experience any of the following symptoms.

Very serious side effects

Very Serious side effectsWhat to do
  • Shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, mouth, tongue or other parts of the body; rash, itching or hives on the skin.
    These could be symptoms of an allergic reaction.
  • Severe blisters and bleeding in the lips, eyes, mouth, nose and genitals; painful red area on the skin that spreads quickly; peeling of the skin. You may have a high temperature, chills and muscle ache at the same time.
    These could be due to rare but severe skin reactions such as Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis and Drug Reaction with Eosinophilia and Systemic Symptoms.
  • Blurred vision; severe headache; weakness or numbness in the face, arm or leg; trouble speaking or understanding; loss of balance.
    This may be due to a stroke which could be a result of blood clots in the blood vessels of your brain.
  • Sudden pain in your chest or difficulty in breathing.
    This may be due to a heart attack or blood clots in the artery leading to your lungs. These blood clots can happen during treatment, or after treatment has stopped.
  • Chest pain, severe weakness, rapid or irregular heartbeat, and/or sudden, severe shortness of breath and coughing up pink, foamy mucus.
    This could be due to heart failure, a condition where the heart muscle cannot pump blood strongly enough to supply blood throughout the body.
  • Pain or swelling in your legs, especially in your lower leg or calves.
    This may be due to blood clots in the veins of your leg. These can happen during treatment, or after treatment has stopped.
  • Fever; severe chills; decreased urination; rapid pulse; rapid breathing; confusion; nausea; vomiting; diarrhoea; pain or burning when you urinate; hacking cough; phlegm; sore mouth or throat; flu-like symptoms; feeling of tension in the nose, cheeks and behind your eyes; or mouth ulcers
    These could symptoms of sepsis (blood infection) or other serious infections such as pneumonia.
  • Passing little or no urine; drowsiness; nausea; vomiting; or breathlessness.
    These could be symptoms of kidney disease.
  • Abdominal pain, dark urine, fever, joint pain, loss of appetite, nausea and vomiting, yellowing of the skin and/or eyes.
    These are symptoms of liver failure, which in some cases, may be due to Hepatitis B virus infection. Some cases of Hepatitis B virus infection may not result in symptoms initially.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these very serious side effect.

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

Other side effects not listed here may occur in some people. Some side effects (for example, changes in thyroid function, or blood pressure) can only be found when your doctor does tests from time to time to check your progress.

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 or to Medsafe at www.medsafe.govt.nz/safety/report-a-problem.asp. 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 Lenalidomide Sandoz contains

Active ingredient
(main ingredient)		lenalidomide
Other ingredients
(inactive ingredients)

lactose, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, gelatin, titanium dioxide, indigo carmine (E132) (2.5 mg, 10 mg, 15 mg, 20 mg capsules), iron oxide yellow (E172) (2.5 mg, 7.5 mg, 10 mg, 20 mg capsules), iron oxide black (E172), propylene glycol, potassium hydroxide

Evaporated solvents not included in CMI.

Potential allergenslactose

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

What Lenalidomide Sandoz looks like

Lenalidomide Sandoz 2.5 mg capsules – opaque white body and opaque green cap with “L9NL” and “2.5” printed. (Aust R 410017)

Lenalidomide Sandoz 5 mg capsules – opaque white body and opaque white cap with "L8NL" and “5” printed. (Aust R 348791)

Lenalidomide Sandoz 7.5 mg capsules – opaque white body and opaque yellow cap with “L9NL” and “7.5” printed. (Aust R 410030)

Lenalidomide Sandoz 10 mg capsules – opaque yellow body and opaque green cap with “L9NL” and “10” printed. (Aust R 348792)

Lenalidomide Sandoz 15 mg capsules – opaque white body and opaque blue cap with “L9NL” and “15” printed. (Aust R 348793)

Lenalidomide Sandoz 20 mg capsules – opaque blue body and opaque green cap with “L9NL” and “20” printed. (Aust R 410031)

Lenalidomide Sandoz 25 mg capsules – opaque white body and opaque white cap with “L9NL” and “25” printed. (Aust R 348790)

The capsules are provided in packs of 14, 21 or 28 capsules.

Some strengths and pack sizes of Lenalidomide Sandoz may not be available as not all strengths and pack sizes are being distributed.

Who distributes Lenalidomide Sandoz

Lenalidomide Sandoz is supplied in Australia by:

Sandoz Pty Ltd
100 Pacific Highway
North Sydney, NSW 2060
Australia

Tel 1800 726 369

Lenalidomide Sandoz is supplied in New Zealand by:

Sandoz New Zealand Limited
12 Madden Street
Auckland 1010
New Zealand

Tel: 0800 726 369

This leaflet was prepared in March 2024.

® Registered trademark. The trademarks mentioned in this material are the property of their respective owners.

Published by MIMS April 2024

BRAND INFORMATION

Brand name

Lenalidomide Sandoz

Active ingredient

Lenalidomide

Schedule

S4

 

1 Name of Medicine

Lenalidomide.

2 Qualitative and Quantitative Composition

Each 2.5 mg capsule contains 2.5 mg lenalidomide and 33.2 mg of lactose.
Each 5 mg capsule contains 5 mg lenalidomide and 66.4 mg of lactose.
Each 7.5 mg capsule contains 7.5 mg lenalidomide and 99.7 mg of lactose.
Each 10 mg capsule contains 10 mg lenalidomide and 132.9 mg of lactose.
Each 15 mg capsule contains 15 mg lenalidomide and 199.3 mg of lactose.
Each 20 mg capsule contains 20 mg lenalidomide and 265.8 mg of lactose.
Each 25 mg capsule contains 25 mg lenalidomide and 332.2 mg of lactose.

Excipients with known effect.

Contains sugars (as lactose).
For the full list of excipients, see Section 6.1 List of Excipients.

Description.

Lenalidomide is an off-white to pale-yellow solid, with a melting point between 265°C and 270°C. Lenalidomide is generally more soluble in organic solvents but exhibits the greatest solubility in 0.1 N HCl buffer. The solubility of lenalidomide in water and at pH 1.21 is < 1.5 mg/mL and 18 mg/mL, respectively.
Lenalidomide has an asymmetric carbon atom and can therefore exist as the optically active forms S(-) and R(+). Lenalidomide is produced as a racemic mixture with a net optical rotation of zero.

3 Pharmaceutical Form

Lenalidomide Sandoz (lenalidomide) 2.5 mg capsules.

Opaque white body and opaque green cap with "L9NL" and "2.5" printed radial on body. Capsule size: 4.

Lenalidomide Sandoz (lenalidomide) 5 mg capsules.

Opaque white body and opaque white cap with "L9NL" and "5" printed radial on body. Capsule size: 2.

Lenalidomide Sandoz (lenalidomide) 7.5 mg capsules.

Opaque white body and opaque yellow cap with "L9NL" and "7.5" printed radial on body. Capsule size: 2.

Lenalidomide Sandoz (lenalidomide) 10 mg capsules.

Opaque yellow body and opaque green cap with "L9NL" and "10" printed radial on body. Capsule size: 0.

Lenalidomide Sandoz (lenalidomide) 15 mg capsules.

Opaque white body and opaque blue cap with "L9NL" and "15" printed radial on body. Capsule size: 0.

Lenalidomide Sandoz (lenalidomide) 20 mg capsules.

Opaque blue body and opaque green cap with "L9NL" and "20" printed radial on body. Capsule size: 0.

Lenalidomide Sandoz (lenalidomide) 25 mg capsules.

Opaque white body and opaque white cap with "L9NL" and "25" printed radial on body. Capsule size: 0.

4 Clinical Particulars

4.1 Therapeutic Indications

Multiple myeloma (MM).

Lenalidomide Sandoz is indicated for the treatment of multiple myeloma.

Myelodysplastic syndromes (MDS).

Lenalidomide Sandoz is indicated for treatment of patients with transfusion-dependent anaemia due to low- or intermediate-1 risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.

Mantle cell lymphoma (MCL).

Lenalidomide Sandoz is indicated for the treatment of patients with relapsed and/or refractory mantle cell lymphoma.

4.2 Dose and Method of Administration

To be used as recommended in this product information and product information documents for other products approved for combination therapy with Lenalidomide Sandoz.
Treatment must be initiated and monitored under the supervision of a registered specialist physician experienced in the management of haematological and oncological malignancies.
Lenalidomide Sandoz capsules should be administered orally at about the same time each day. The capsules should not be opened, broken or chewed. The capsules should be swallowed whole, preferably with water and either one hour before or two hours after food.
If less than 12 hours have elapsed since missing a dose, the patient can take the dose. If more than 12 hours have elapsed since missing a dose at the normal time, the patient should not take the dose, but take the next dose at the normal time on the following day.
When Lenalidomide Sandoz is given in combination with other medicinal products, the corresponding product information documents must be consulted for specific dosage instructions prior to initiation of treatment.

Dosage.

Multiple myeloma.

Newly diagnosed multiple myeloma - Lenalidomide Sandoz in combination with bortezomib and dexamethasone. Lenalidomide Sandoz in combination with bortezomib and dexamethasone may be used as initial therapy for patients who are ineligible for autologous stem cell transplantation or as an induction regimen prior to autologous hematopoietic stem cell transplantation.
Lenalidomide Sandoz treatment in combination with bortezomib and dexamethasone must not be started if the Absolute Neutrophil Count (ANC) is < 1 x 109/L and platelet count < 50 x 109/L.
During the initial period when Lenalidomide Sandoz is used in combination with bortezomib and dexamethasone, complete blood count should be assessed every 7 days (weekly) for the first cycle, then prior to the start of each subsequent cycle. With continued use of Lenalidomide Sandoz in combination with dexamethasone, monitor monthly (every 4 weeks). Dose interruptions and/or dose reductions may be required.
Dosing is continued or modified based upon clinical and laboratory findings. Therapy may continue until disease progression or intolerance.
Patients who are ineligible for autologous stem cell transplantation (TNE).

Recommended starting dose (initial therapy).

Up to eight 21-day treatment cycles (24 weeks of initial treatment) are recommended (see Table 1).

Recommended continued treatment: Lenalidomide Sandoz in combination with dexamethasone until progression.

See Table 2.
Patients who are eligible for autologous stem cell transplantation (TE).

Recommended starting dose (induction regimen).

Up to eight 21-day or six 28-day treatment cycles (24 weeks of initial treatment) are recommended (see Table 3).

Continued treatment: Autologous stem cell transplant.

For patients who proceed to autologous stem cell transplant, hematopoietic stem cell mobilization should occur within 4 cycles of initial therapy.
Newly diagnosed multiple myeloma transplant ineligible - Lenalidomide Sandoz in combination with dexamethasone. Lenalidomide Sandoz treatment in combination with dexamethasone must not be started if ANC < 1.5 x 109/L, and platelet count < 50 x 109/L.
For NDMM patients, CBC should be assessed every 7 days (weekly) for the first 2 cycles, every 2 weeks (days 1 and 15) of cycle 3, and every 28 days (4 weeks) thereafter.
Patients should continue Lenalidomide Sandoz and dexamethasone therapy until disease progression or intolerance. Dosing is continued or modified based upon clinical and laboratory findings. See Table 4.
Recommended dose adjustments for NDMM patients ineligible for transplant receiving Lenalidomide Sandoz in combination with dexamethasone are found in Section 4.2 Dose and Method of Administration, Dose adjustments.
Newly diagnosed multiple myeloma post transplant maintenance - Lenalidomide Sandoz monotherapy. Lenalidomide Sandoz maintenance therapy should be initiated after adequate haematologic recovery following ASCT. Lenalidomide Sandoz treatment must not be started if the ANC is < 1 x 109/L, and/or platelet counts are < 75 x 109/L. Patients should continue Lenalidomide Sandoz therapy until disease progression or intolerance. Dosing is continued or modified based upon clinical and laboratory findings. See Table 5.
Recommended dose adjustments for NDMM post-transplant patients receiving Lenalidomide Sandoz maintenance are found in Section 4.2 Dose and Method of Administration, Dose adjustments.
Previously treated multiple myeloma - Lenalidomide Sandoz in combination with dexamethasone. Lenalidomide Sandoz treatment must not be started if the ANC < 1.0 x 109/L, and/or platelet counts < 75 x 109/L or, dependent on bone marrow infiltration by plasma cells, platelet counts < 30 x 109/L.
For patients with previously treated MM, CBC (including white blood cell count with differential count, platelet count), haemoglobin, and haematocrit should be performed at baseline, every 2 weeks for the first 12 weeks of Lenalidomide Sandoz treatment, and monthly thereafter to monitor for cytopenias.
Treatment should be continued until disease progression or unacceptable toxicity. Dosing is continued or modified based upon clinical and laboratory findings. See Table 6.
Recommended dose adjustments for previously treated MM patients are found in Section 4.2 Dose and Method of Administration, Dose adjustments.

Myelodysplastic syndromes - Lenalidomide Sandoz monotherapy.

Lenalidomide Sandoz treatment must not be started if the ANC < 0.5 x 109/L, and/or platelet counts < 50 x 109/L.
For patients on therapy for the approved MDS indication, CBC should be monitored weekly for the first 8 weeks of therapy and at least monthly thereafter.
Dosing is continued or modified based upon clinical and laboratory findings. See Table 7.
Recommended dose adjustments for MDS patients are found in Section 4.2 Dose and Method of Administration, Dose adjustments.

Previously treated mantle cell lymphoma - Lenalidomide Sandoz monotherapy.

For MCL patients treated with Lenalidomide Sandoz, CBC monitoring is recommended weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then at the start of each cycle thereafter.
Treatment should be continued until disease progression or unacceptable toxicity. Dosing is continued or modified based upon clinical and laboratory findings. See Table 8.
Recommended dose adjustments for MCL patients are found in Section 4.2 Dose and Method of Administration, Dose adjustments.

Recommended starting dose for renal impairment - all indications.

Lenalidomide is substantially excreted by the kidney. For patients with impaired renal function, care should be taken in dose selection. Monitoring of renal function is advised in patients with renal impairment. The following starting doses of Lenalidomide Sandoz are recommended for patients with impaired renal function, or end stage renal disease (see Table 9).
After initiation of Lenalidomide Sandoz therapy, subsequent Lenalidomide Sandoz dose modifications should be based on individual patient treatment tolerance. Patients with impaired renal function should be monitored for signs and symptoms of neutropenia or thrombocytopenia as per the recommendations in Section 4.4 Special Warnings and Precautions for Use.

Dose adjustments.

Dose adjustments, as summarised below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia, or other Grade 3 or 4 toxicities judged to be related to lenalidomide.
For dose adjustments due to toxicity with either bortezomib or dexamethasone, refer to the respective Product Information document. The recommended dose adjustments for Lenalidomide Sandoz are provided below.

Thrombocytopenia and/or neutropenia.

Multiple myeloma.

Newly diagnosed multiple myeloma - Lenalidomide Sandoz in combination with bortezomib and dexamethasone.

See Tables 10 and 11.

Newly diagnosed multiple myeloma transplant ineligible - Lenalidomide Sandoz in combination with dexamethasone.

See Tables 12 and 13.
If the dose of Lenalidomide Sandoz was reduced for a haematologic dose-limiting toxicity (DLT), the dose of Lenalidomide Sandoz may be re-increased to the next higher dose level (up to the starting dose) at the discretion of the treating physician if continued Lenalidomide Sandoz/dexamethasone therapy resulted in improved bone marrow function (no DLT for at least 2 consecutive cycles and an ANC ≥ 1.5 x 109/L with a platelet count ≥ 100 x 109/L at the beginning of a new cycle at the current dose level).

Newly diagnosed multiple myeloma post transplant maintenance - Lenalidomide Sandoz.

See Tables 14 and 15.

Previously treated multiple myeloma - Lenalidomide Sandoz in combination with dexamethasone.

See Tables 16 and 17.
Myelodysplastic syndromes-Lenalidomide Sandoz monotherapy.

Dose reduction guidance.

For patients with MDS, dose reduction guidelines are divided into 2 sets - for within the first 4 weeks of treatment, and after the first 4 weeks of treatment. See Tables 18 and 19.
Previously treated mantle cell lymphoma - Lenalidomide Sandoz monotherapy. See Table 20.

Recommended dose adjustments - all indications.

See Table 21.

4.3 Contraindications

Women who are pregnant.
Women of childbearing potential unless all of the conditions of the MyCheckPoint Pregnancy Prevention Program are met [see Section 4.4 Special Warnings and Precautions for Use, Pregnancy warning].
Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings and Precautions for Use

When Lenalidomide Sandoz is given in combination with other medicinal products, the corresponding product information documents must be consulted prior to initiation of treatment.

Pregnancy warning.

Do not use Lenalidomide Sandoz during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death.
To avoid embryo-fetal exposure to lenalidomide, Lenalidomide Sandoz is only available through the MyCheckPoint Pregnancy Prevention Program.

The MyCheckPoint pregnancy prevention program conditions for pregnancy prevention.

Lenalidomide Sandoz is available under a restricted distribution program (MyCheckPoint Pregnancy Prevention Program). Only physicians and pharmacists registered with this program can prescribe and dispense the product. In addition, Lenalidomide Sandoz must only be dispensed to patients who are registered and meet all the conditions of the program.
Females of non-childbearing potential. A female patient or a female partner of a male patient is considered to have childbearing potential unless she meets at least one of the following criteria:
Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year*.
Premature ovarian failure confirmed by a specialist gynaecologist.
Previous bilateral salpingo-oophorectomy, or hysterectomy.
XY genotype, Turner syndrome, uterine agenesis.
*Amenorrhoea following cancer therapy does not rule out childbearing potential.
Female patients of non-childbearing potential are only required to comply with the general conditions listed within the MyCheckPoint Pregnancy Prevention Program.
Females of childbearing potential. Female patients of childbearing potential must comply with the following requirements on counselling, contraception and pregnancy testing.
If pregnancy occurs in a female patient treated with Lenalidomide Sandoz, treatment must be stopped and the patient should be referred to a physician specialised or experienced in teratology for evaluation and advice. Similarly, if pregnancy occurs in a partner of a male patient taking Lenalidomide Sandoz, the female partner should be referred to a physician specialised or experienced in teratology for evaluation and advice.

Counselling.

For female patients of childbearing potential, Lenalidomide Sandoz is contraindicated unless all of the following are met:
She understands the potential teratogenic risk to the unborn child.
She understands and agrees to comply with the need for effective contraception, without interruption, 4 weeks before starting treatment, throughout the entire duration of treatment, and 4 weeks after the end of treatment.
Even if a female of childbearing potential has amenorrhea, she must follow all the advice on effective contraception.
She should be capable of complying with effective contraceptive measures.
She is informed and understands the potential consequences of pregnancy and the need to rapidly consult her physician if there is a risk of pregnancy.
She understands the need to commence the treatment as soon as Lenalidomide Sandoz is dispensed following a negative pregnancy test.
She understands the need and accepts to undergo medically supervised pregnancy testing every 4 weeks.
She acknowledges that she understands the hazards and necessary precautions associated with the use of Lenalidomide Sandoz.

Contraception.

Female patients of childbearing potential must use one effective method of contraception for 4 weeks before therapy, during therapy, and until 4 weeks after Lenalidomide Sandoz therapy, even in case of dose interruption, unless the patient commits to absolute and continuous abstinence confirmed on a monthly basis. If not established on effective contraception, the patient must be referred to an appropriately trained health care professional for contraceptive advice in order that contraception can be initiated (see Table 22).

Pregnancy testing.

Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be performed for females of childbearing potential as outlined below.
This requirement includes females of childbearing potential who practice absolute and continuous abstinence. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same day. For females of childbearing potential, dispensing of Lenalidomide Sandoz must occur within a maximum of 7 days of the negative pregnancy test.
Prior to starting treatment: a medically supervised pregnancy test should be performed when Lenalidomide Sandoz is prescribed. The test should occur either at the time of consultation, or in the 3 days prior to the visit to the prescriber and at a point where the patient has been using effective contraception for at least 4 weeks. The test should ensure the patient is not pregnant when she starts treatment with Lenalidomide Sandoz. This requirement includes females of childbearing potential who practice absolute and continuous abstinence.
Follow-up and end of treatment: a medically supervised pregnancy test should be repeated every 4 weeks, including 4 weeks after the end of treatment. These pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber. This requirement includes females of childbearing potential who practice absolute and continuous abstinence.
Male patients. Male patients must comply with the following requirements on counselling and contraception as clinical data has demonstrated the presence of lenalidomide in human semen.

Counselling and contraception.

He understands the potential teratogenic risk if engaged in sexual activity with a female of childbearing potential.
He understands and complies with the need for the use of a condom (if engaged in sexual activity with a female of childbearing potential) throughout treatment duration, during dose interruption, and for at least 7 days after cessation of treatment if his partner is of childbearing potential and has no contraception.
He understands that if his partner becomes pregnant whilst he is taking Lenalidomide Sandoz or during the 1st week after he discontinues taking Lenalidomide Sandoz, he should inform his treating physician immediately.
He understands that he must not donate sperm during therapy (including during dose interruptions) or for at least 7 days following discontinuation of Lenalidomide Sandoz.
Prescribers. Ensure that female patients of childbearing potential comply with the conditions of the MyCheckPoint Pregnancy Prevention Program, including confirmation that the patients have an adequate level of understanding of the program requirements.
Provide full patient information about the potential teratogenic risk and the strict pregnancy prevention measures as specified in the MyCheckPoint Pregnancy Prevention Program to female patients of childbearing potential and, as appropriate, to male patients.
Ensure that all patients acknowledge and agreed to comply with the aforementioned conditions of the MyCheckPoint Pregnancy Prevention Program.
General conditions. All patients should be instructed never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of treatment.
All patients should not donate blood during therapy (including during dose interruptions), or for 1 week following discontinuation of Lenalidomide Sandoz. In Australia, patients with a history of cancers that involve the haematopoietic system directly e.g. myeloma and lymphoma, are permanently excluded from donating blood.

Myocardial infarction.

Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with known risk factors. Patients with known risk factors (including prior thrombosis) should be closely monitored, and action should be taken to try to minimise all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

Venous and arterial thromboembolism.

In patients with MM, the combination of lenalidomide/dex is associated with an increased risk of venous thromboembolism [VTE (predominantly DVT and PE)].
In patients with MM, MDS or MCL, treatment with lenalidomide monotherapy was associated with a lower risk of VTE (predominantly DVT and PE) than in MM patients treated with lenalidomide in combination therapy.
In patients with MM, the combination of lenalidomide/dex is associated with an increased risk of arterial thromboembolism [ATE (predominantly myocardial infarction and cerebrovascular event)]. The risk of ATE is lower in MM patients treated with lenalidomide monotherapy than in MM patients treated with lenalidomide in combination therapy.
Patients with known risk factors for thromboembolism (including prior thrombosis) should be closely monitored, and action should be taken to try to minimise all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia). Concomitant administration of erythropoietic agents or previous history of DVT may also increase thrombotic risk in these patients. Therefore, erythropoietic agents, or other agents that may increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution in MM patients receiving lenalidomide/dex. A haemoglobin concentration above 120 g/L should lead to discontinuation of erythropoietic agents.
Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or leg swelling. Prophylactic antithrombotic medicines, such as low molecular weight heparins or warfarin, should be recommended, especially in patients with additional thrombotic risk factors. The decision to take antithrombotic prophylactic measures should be made after careful assessment of an individual patient's underlying risk factors.
If a patient experiences any thromboembolic events, treatment must be discontinued and standard anticoagulation therapy started. Once the patient has been stabilised on the anticoagulation treatment and any complications of the thromboembolic event have been managed, Lenalidomide Sandoz treatment may be restarted at the original dose dependent upon a benefit-risk assessment. The patient should continue anticoagulation therapy during the course of Lenalidomide Sandoz treatment.

Pulmonary hypertension.

Cases of pulmonary hypertension, some fatal, have been reported in patients treated with lenalidomide. Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during lenalidomide therapy.

Neutropenia and thrombocytopenia.

The major dose-limiting toxicities of lenalidomide include neutropenia and thrombocytopenia. Patients with neutropenia should be monitored for signs of infection. Patients should be advised to promptly report febrile episodes. Patients and physicians are advised to be observant for signs and symptoms of bleeding, including petechiae and epistaxis, especially with use of concomitant medication that may increase risk of bleeding. Therefore, co-administration of Lenalidomide Sandoz with other myelosuppressive agents should be undertaken with caution. Appropriate management should be instituted if such toxicity is observed.
Patients taking Lenalidomide Sandoz should have their complete blood counts (CBC) assessed periodically as described below. A dose interruption and/or dose reduction may be required.

Newly diagnosed multiple myeloma - Lenalidomide Sandoz in combination with bortezomib and dexamethasone.

Complete blood count assessed every 7 days (weekly) for the first cycle, then prior to the start of each subsequent cycle if Lenalidomide Sandoz is used in combination with bortezomib and dexamethasone. With continued use of Lenalidomide Sandoz in combination with dexamethasone, monitor monthly (every 4 weeks). Dose interruptions and/or dose reductions may be required.

Newly diagnosed multiple myeloma - transplant ineligible - Lenalidomide Sandoz in combination with dexamethasone.

For NDMM patients, CBC should be assessed every 7 days (weekly) for the first 2 cycles, every 2 weeks (days 1 and 15) of cycle 3, and every 28 days (4 weeks) thereafter.

Previously treated multiple myeloma - Lenalidomide Sandoz in combination with dexamethasone.

The combination of lenalidomide/dex in previously treated MM patients is associated with a higher incidence of Grade 4 neutropenia (4.8% in lenalidomide/dex-treated patients compared with 0.6% in placebo/dex-treated patients. Grade 4 febrile neutropenia episodes were observed infrequently [0.6% in lenalidomide/dex-treated patients compared to 0.0% in placebo/dex-treated patients; see Section 4.8 Adverse Effects (Undesirable Effects)]. A dose reduction may be required. In case of neutropenia, the physician should consider the use of growth factors in patient management.
The combination of lenalidomide/dex in previously treated MM patients is associated with a higher incidence of Grade 3 and Grade 4 thrombocytopenia [10.8% and 1.4%, respectively, in lenalidomide/dex-treated patients compared to 5.4% and 0.9% in placebo/dex-treated patients; see Section 4.8 Adverse Effects (Undesirable Effects)].
For patients with previously treated MM, CBC (including white blood cell count with differential count), platelet count, haemoglobin, and haematocrit should be performed at baseline, every 2 weeks for the first 12 weeks of Lenalidomide Sandoz treatment and monthly thereafter to monitor for cytopenias.

Myelodysplastic syndromes - Lenalidomide Sandoz monotherapy.

In clinical studies of patients with del 5q MDS, lenalidomide as monotherapy was associated with significant neutropenia and thrombocytopenia. Grade 3 or 4 haematologic toxicity was seen in 80% of patients. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days).
Patients on therapy for del 5q MDS should have their CBC monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require the use of blood product support and/or growth factors.

Previously treated mantle cell lymphoma - Lenalidomide Sandoz monotherapy.

For MCL patients treated with Lenalidomide Sandoz, CBC monitoring is recommended weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then at the start of each cycle thereafter. A dose interruption and/or dose reduction may be required.

Peripheral neuropathy.

Lenalidomide is structurally related to thalidomide, which is known to induce severe peripheral neuropathy. There was no increase in peripheral neuropathy observed with long-term use of lenalidomide for the treatment of newly diagnosed multiple myeloma.
The combination of lenalidomide with intravenous bortezomib and dexamethasone in multiple myeloma patients was associated with a higher frequency of peripheral neuropathy. The frequency was lower when bortezomib was administered subcutaneously. For additional information, see Section 4.8 Adverse Effects (Undesirable Effects).

Tumour lysis syndrome (TLS) and tumour flare reaction (TFR).

Cases of TLS and TFR, including fatal cases have been reported; see Section 4.8 Adverse Effects (Undesirable Effects). TLS and TFR have commonly been observed in patients with chronic lymphocytic leukaemia (CLL), and uncommonly in patients with lymphomas, who were treated with lenalidomide. There have been reports of TLS in patients with Multiple Myeloma (MM) and Myelodysplastic Syndromes (MDS) treated with lenalidomide. Fatal instances of TLS have been reported during treatment with lenalidomide. Patients at risk of TLS and TFR are those with high tumour burden prior to treatment. Caution should be practiced when introducing these patients to lenalidomide. These patients should be monitored closely, especially during the first cycle or dose-escalation, and appropriate precautions taken.
There were no reports of TLS in study MCL-001. In study MCL-002, TLS was reported for one patient in each treatment arm.
In study MCL-001, approximately 10% of subjects experienced TFR; all reports were Grade 1 or 2 in severity and all were assessed as treatment-related. The majority of the events occurred in cycle 1. In study MCL-002, approximately 10% of lenalidomide-treated patients experienced TFR compared to 0% in the control arm. The majority of the events occurred in cycle 1, all were assessed as treatment-related, and the majority of the reports were Grade 1 or 2.
Careful monitoring and evaluation for TFR is recommended. Tumour flare may mimic progression of disease. Lenalidomide Sandoz may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician's discretion. Patients in studies MCL-001 and MCL-002 that experienced Grade 1 and 2 TFR were treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. The decision to take therapeutic measures for TFR should be made after careful clinical assessment of the individual patient. In patients with Grade 3 or 4 TFR, withhold treatment with Lenalidomide Sandoz until TFR resolves to ≤ Grade 1 and patients may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR.

Allergic reactions and serious skin reactions.

Rare cases of angioedema, anaphylaxis and serious dermatological reactions including Stevens-Johnson syndrome toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported from post-marketing experience. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These events have the potential to be fatal.
Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive Lenalidomide Sandoz. Lenalidomide Sandoz interruption or discontinuation should be considered for Grade 2-3 skin rash.
Lenalidomide Sandoz must be discontinued for angioedema, anaphylaxis, Grade 4 rash, exfoliative or bullous rash, or if Stevens-Johnson syndrome, toxic epidermal necrolysis or DRESS is suspected. Lenalidomide Sandoz should not be resumed following the discontinuation for these reactions.

Atrial fibrillation.

In the two pivotal randomised controlled trials in previously treated (relapsed/refractory) MM patients, atrial fibrillation occurred in 14 (4.0%) subjects treated with lenalidomide/dex compared to 4 (1.1%) subjects treated with placebo/dex (unadjusted for the longer on-study observation time for patients receiving lenalidomide). Careful review of these cases revealed the presence of multiple risk factors for atrial fibrillation (e.g. infections, hypertension, congestive heart failure, electrolyte imbalance), and a causal relationship to lenalidomide treatment has not yet been determined.

Use in patients with impaired thyroid function.

Cases of hypothyroidism and hyperthyroidism have been reported. Optimal control of co-morbid conditions that can affect thyroid function is recommended before start of treatment. Baseline and ongoing monitoring of thyroid function is recommended.

Use in patients with lactose intolerance.

Lenalidomide Sandoz capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Lenalidomide Sandoz.

Use in hepatic impairment.

Hepatic failure, including fatal cases, has been reported in patients treated with lenalidomide/dex. This includes reports of acute hepatic failure, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis. The mechanisms of severe drug-induced hepatotoxicity remain unknown although, in some cases, pre-existing viral liver disease, elevated baseline liver enzymes, and possibly treatment with antibiotics might be risk factors.
Abnormal liver function tests have been commonly reported and were generally asymptomatic and reversible upon dosing interruption. Monitoring of liver function is recommended, particularly when there is a history of or concurrent viral liver infection, or when lenalidomide is combined with medications known to be associated with liver dysfunction. If abnormal liver function test results are reported, treatment with Lenalidomide Sandoz should be interrupted. Once parameters have returned to baseline, treatment at a lower dose may be considered.

Use in renal impairment.

Lenalidomide is excreted by the kidneys. It is important to dose adjust patients with renal impairment in order to avoid plasma levels which may increase the risk for higher haematological side effects or hepatotoxicity.

Use in the elderly.

Population pharmacokinetic analyses included patients with ages ranging from 39 to 85 years old and show that age does not influence the disposition of lenalidomide. No dose adjustments are needed for Lenalidomide Sandoz.
For NDMM patients > 75 years of age and ineligible for ASCT, a reduced starting dose of dexamethasone is recommended.
Lenalidomide has been used in clinical trials in previously treated MM patients up to 86 years of age. The percentage of patients aged 65 or over was not significantly different between the lenalidomide/dex and placebo/dex groups. No overall difference in effectiveness was observed between these patients and younger patients. However, overall serious adverse events (AEs), in particular the serious vascular events [including deep vein thrombosis (DVT) and pulmonary embolism (PE)] and serious cardiovascular events (including atrial fibrillation), were all more frequent in lenalidomide-treated patients 65 years and over.
Lenalidomide has also been used in MDS clinical trials in patients up to 95 years of age. Of the 395 patients in the MDS clinical trials who received 10 mg lenalidomide, 72.2% were aged 65 and over. No overall difference in safety was observed between these patients and younger patients, but greater pre-disposition of older individuals to drug-related toxicities cannot be ruled out.
Lenalidomide is known to be substantially excreted by the kidney. The risk of ADRs may be greater in patients with impaired renal function. Elderly patients are more likely to have decreased renal function, so care should be taken in dose selection for such patients. Renal function should therefore be monitored.

Paediatric use.

There is no experience in treating children and adolescents with lenalidomide. Therefore, Lenalidomide Sandoz should not be used in the paediatric age group (0-18 years).

Second primary malignancies (SPM).

In clinical trials in NDMM patients ineligible for ASCT, a 4.9-fold increase in incidence rate of haematologic second primary malignancies (SPM) (cases of AML and MDS) has been observed in patients receiving lenalidomide in combination with melphalan and prednisone (MPR+R) until progression (1.75 per 100 person-years) compared with melphalan in combination with prednisone (MPp+p) (0.36 per 100 person-years). A 2.12-fold increase in incidence rate of solid tumour SPM has been observed in patients receiving MPR+R (9 cycles) (1.57 per 100 person-years) compared with MPp+p (0.74 per 100 person-years).
In NDMM patients receiving lenalidomide in combination with dexamethasone (lenalidomide/dex) until progression or for 18 months, the haematologic SPM incidence rate (0.16 per 100 person-years) was not increased as compared to thalidomide in combination with melphalan and prednisone (MPT) (0.79 per 100 person-years). A 1.3-fold increase in incidence rate of solid tumour SPM has been observed in patients receiving lenalidomide/dex until progression or for 18 months (1.58 per 100 person-years) compared to MPT (1.19 per 100 person-years).
In clinical trials of NDMM patients eligible for ASCT, an increased incidence rate of haematologic SPM (most notably AML, MDS and B-cell malignancies [including Hodgkin's lymphoma] has been observed in patients receiving lenalidomide maintenance immediately following high-dose melphalan/ASCT (1.31 per 100 person-years) compared with patients who received placebo (0.58 per 100 person-years). The incidence rate of solid tumour SPMs was 1.36 per 100 person-years for the lenalidomide arms and 1.05 per 100 person-years for the placebo arms.
Based on a low number of cases, a numerical imbalance in SPM (comprising mainly of basal cell and squamous cell skin cancers) has been observed in clinical trials in previously treated MM patients with lenalidomide/dex (3.98 per 100 patient-years) compared with placebo/dex (1.38 per 100 patient-years).
Subjects who received lenalidomide-containing therapy until disease progression did not show a higher incidence of invasive SPM than subjects treated in the fixed duration lenalidomide-containing arms. These results suggest that duration of lenalidomide treatment is not associated with an increased risk for the occurrence of invasive SPM.
Both the benefit achieved with lenalidomide and the risk of SPMs should be considered and discussed with patients, before initiating treatment with the product. Physicians should also carefully evaluate patients before and during treatment using standard cancer screening for occurrence of SPMs and institute treatment as appropriate.

Increased mortality in chronic lymphocytic leukaemia (CLL).

In a prospective randomized (1:1) clinical trial in the first line treatment of patients with CLL, single agent lenalidomide therapy was associated with an increased risk of death as compared to single agent chlorambucil. lenalidomide is not recommended for use in CLL outside of controlled clinical trials.

Progressive multifocal leukoencephalopathy.

Cases of progressive multifocal leukoencephalopathy (PML), including fatal cases, have been reported with lenalidomide in combination with immunosuppressive therapy including dexamethasone. PML was reported several months to several years after starting the treatment with lenalidomide. Physicians should consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioural signs or symptoms and appropriate diagnostic measures for PML are recommended. If PML is suspected, further lenalidomide dosing must be suspended until PML has been excluded. If PML is confirmed, lenalidomide must be permanently discontinued.

Solid organ transplant.

Cases of solid organ transplant (SOT) rejection have been reported in the post-market setting with the use of lenalidomide and, in some cases, have resulted in a fatal outcome. Onset may be acute, occurring within 1 to 3 cycles of lenalidomide treatment. The incidence rate of SOT rejection cannot be reliably estimated due to the limitation of post-marketing safety data and that patients with SOT were generally excluded from Celgene-sponsored lenalidomide clinical trials. The benefit of treatment with lenalidomide versus the risk of possible SOT rejection should be considered in patients with a history of SOT before initiating lenalidomide therapy. Clinical and laboratory signs of SOT rejection should be closely monitored and lenalidomide therapy should be discontinued in the event of SOT rejection.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Hepatic disorders.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution in MM patients receiving lenalidomide/dex.
In vitro, lenalidomide does not inhibit UGT1A1-mediated bilirubin glucuronidation in human liver microsomes derived from donors representing genotypes UGT1A1*1/*1, UGT1A1*1/*28, and UGT1A1*28/*28.
The major dose-limiting toxicities of lenalidomide include neutropenia and thrombocytopenia. Therefore, co-administration of Lenalidomide Sandoz with other myelosuppressive agents should be undertaken with caution.

Oral contraceptives.

No interaction study has been performed with oral contraceptives. Lenalidomide is not an enzyme inducer (see below). Dexamethasone is known to be a weak to moderate inducer of CYP3A4 and is likely to also affect other enzymes as well as transporters. It may not be excluded that the efficacy of oral contraceptives may be reduced during treatment. Effective measures to avoid pregnancy must be taken.
Lenalidomide is not a substrate, inhibitor or inducer of cytochrome P450 enzymes in vitro. Hence, co-administration of cytochrome P450 substrates (including hormonal contraceptives), inhibitors or inducers with lenalidomide is not likely to result in clinically relevant drug-drug interactions.
However, it is noteworthy that there is an increased risk of VTE in patients treated with lenalidomide in combination with dexamethasone for MM and to a lesser extent in patients treated with lenalidomide monotherapy for MM, MDS or MCL. Since there is an increased risk of VTE in patients taking combined oral contraceptive pills or hormone replacement therapy, physicians should discuss the benefit/risk of contraceptive methods or hormone replacement with their patients. Effective measures to avoid pregnancy must be taken.

Dexamethasone.

In patients with MM, co-administration of single or multiple doses of dexamethasone (40 mg/day) had no significant effect on the multiple dose pharmacokinetics of lenalidomide (25 mg/day).

Warfarin.

Co-administration of multiple doses of 10 mg of lenalidomide had no effect on the single dose pharmacokinetics of R- and S-warfarin. Co-administration of a single 25 mg dose of warfarin had no effect on the pharmacokinetics of lenalidomide. However, it is not known whether there is an interaction during clinical use (concomitant treatment with dexamethasone). Dexamethasone is a weak to moderate enzyme inducer and its effect on warfarin is unknown. Close monitoring of warfarin concentration is advised during the treatment.

Digoxin.

Concomitant administration with lenalidomide 10 mg/day increased the plasma exposure of digoxin (0.5 mg, single dose) by 14% [90% CI: 0.52%-28.2%]. It is not known whether the effect will be different in the therapeutic situation (higher lenalidomide doses and concomitant treatment with dexamethasone).
Therefore, monitoring of the digoxin concentration is advised during lenalidomide treatment. In the same study, the co-administration of digoxin (a P-glycoprotein substrate) did not significantly affect the pharmacokinetics of lenalidomide.

Human efflux transporters.

Lenalidomide is a weak substrate but not an inhibitor of P-glycoprotein (P-gp). Co-administration of multiple doses of P-gp inhibitor, quinidine (600 mg, twice daily) had no effect on the single dose pharmacokinetics of lenalidomide (25 mg). Single dose co-administration of lenalidomide (25 mg) and P-gp inhibitor/substrate, temsirolimus (25 mg), does not affect the pharmacokinetics of either drug.
Lenalidomide is not an inhibitor of bile salt export pump (BSEP), MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2.

Renal drug interactions.

Renal drug-drug interaction studies have not been performed. The renal clearance of lenalidomide is slightly greater than the glomerular filtration rate, suggesting that active secretion contributes to a minor extent (≤ 25%) of renal clearance. Hence, the inhibition of the active secretion of lenalidomide will most likely not result in a clinically relevant drug-drug interaction.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

A fertility and early embryonic development study in male and female rats, with administration of lenalidomide up to 500 mg/kg/day, produced no parental toxicity and no adverse effects on fertility or early embryonic development. The systemic exposure in rats at 500 mg/kg was > 70-fold higher than the human exposure at 25 mg/day, based on AUC.
(Category X)
For lenalidomide, no clinical data on exposed pregnancies are available. Because lenalidomide is a structural analogue of thalidomide (a known human teratogen that causes severe, life-threatening birth defects), and has shown teratogenic effects in animal studies, lenalidomide must not be used in pregnant women. Females of childbearing potential must use effective means of contraception.
Embryo foetal development studies were conducted in monkeys and rabbits. In monkeys, lenalidomide was teratogenic at systemic exposures (based on plasma AUC) well below that anticipated clinically, and a NOEL for the teratogenic effects could not be established in the study.
In rabbits treated with 3, 10 and 20 mg/kg/day orally, maternal and developmental toxicity was noted at ≥ 10 mg/kg/day. The toxicity was characterised by slightly reduced foetal body weights, increased incidences of post-implantation loss, and gross external findings in the foetuses associated with maternal toxicity of lenalidomide. Increased incidences of soft tissue and skeletal variations in the foetuses were also observed at 10 and 20 mg/kg/day. The NOEL for developmental toxicity of lenalidomide in rabbits was identified as 3 mg/kg/day, which is associated with a plasma AUC value equivalent to that anticipated clinically at the 25 mg/day dose in humans.
 It is not known whether lenalidomide is excreted in human milk. Because of the potential for adverse drug reactions (ADRs) in nursing infants from lenalidomide, a decision should be made whether to discontinue nursing or to discontinue the medicine, taking into account the importance of the medicine to the mother.

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. Lenalidomide may have minor or moderate influence on the ability to drive and use machines. Fatigue, dizziness, somnolence, vertigo and blurred vision have been reported with the use of lenalidomide. Therefore, caution is recommended when driving or operating machines.

4.8 Adverse Effects (Undesirable Effects)

Tabulated summary of adverse events.

Multiple myeloma (MM).

Newly diagnosed multiple myeloma - lenalidomide in combination with bortezomib and dexamethasone.

The most frequent adverse events with the lenalidomide, bortezomib and dexamethasone combination across the 3 studies were in the system organ classes of nervous system disorders, blood and lymphatic system disorders and gastrointestinal disorders. Compared with lenalidomide and dexamethasone, the combination of lenalidomide, bortezomib and dexamethasone was associated with increased incidences of treatment-emergent serious adverse events (40.1% Rbd vs. 28.5% Rd) and discontinuations due to treatment emergent AEs (22.9% Rbd vs. 9.4% Rd). Increases in the incidence of Grade 3/ 4 adverse events in the Rbd arm versus the Rd arm were most notable for peripheral sensory and motor neuropathy, thrombocytopenia, hypotension, diarrhoea, syncope, hypokalaemia and dehydration. See Table 23.

Newly diagnosed multiple myeloma transplant ineligible - lenalidomide in combination with dexamethasone.

In the large phase III, controlled study (MM-020), data were evaluated from 1072 patients who received at least one dose of lenalidomide with low-dose dexamethasone, either given continuously (Rd) or for 18 cycles (Rd18). Median treatment duration was notably longer in the continuous Rd arm (80.1 weeks) when compared to the Rd18 arm (72 weeks) and the MPT arm (67.1 weeks), as the continuous Rd arm sustained treatment until disease progression, while treatments in arms Rd18 and MPT were both capped at 72 weeks. The median average daily dose of lenalidomide was 21.8 mg in the continuous Rd arm and 24.4 mg in the Rd18 arm.
In general, the most frequently reported adverse events (AEs) were comparable in arm Rd until progression and arm Rd18, and included diarrhoea, anaemia, constipation, peripheral oedema, neutropenia, fatigue, back pain, nausea, asthenia, insomnia, decreased appetite and muscle spasms. The most frequently reported Grade 3 or 4 events included neutropenia, anaemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalaemia, rash, cataract, lymphopenia, dyspnoea, DVT, hyperglycaemia, and leukopenia. No particular AE led to discontinuation of any study drug in more than 2% of subjects in either arm. Over time, the Rd regimen was generally better tolerated than MPT. Subjects in arm MPT discontinued treatment sooner and more frequently prior to disease progression than subjects receiving Rd. Subjects in arm MPT also more frequently experienced AEs leading to study drug discontinuation. Extended treatment in the Rd arm beyond 18 months generally resulted in a limited increase in most AEs compared with Rd18 or MPT.
For the Rd regimen, 66.4% of patients experienced at least one AE leading to lenalidomide interruption, 60.0% experienced at least one AE leading to dexamethasone interruption, and 69.2% experienced at least one AE leading to lenalidomide or dexamethasone interruption, compared to 77.4% in the MPT arm for thalidomide or melphalan or prednisone interruption.
A list of the treatment-emergent adverse events (TEAEs) that occurred at a frequency of greater than or equal to 10% in any arm for study MM-020 is provided, see Table 25.

Newly diagnosed multiple myeloma post transplant maintenance - lenalidomide monotherapy.

The safety of lenalidomide was assessed in two phase 3 multicenter, randomised, double-blind, 2-arm, parallel group, placebo-controlled studies: CALGB 100104 and IFM 2005-02. The AEs from study CALGB 100104 included events reported post-high dose melphalan/ASCT as well as events from the maintenance treatment period. In study IFM 2005-02, the AEs were from the maintenance treatment period only.
In study CALGB 100104, the overall frequencies of TEAEs, Grade 3 or 4 TEAEs, serious TEAEs (SAEs), and TEAEs leading to discontinuation of study drug were higher in the subjects administered lenalidomide (96.0%, 79.5%, 28.1%, and 28.1%, respectively) compared to subjects administered placebo (85.1%, 55.2%, 12.2%, and 2.7%, respectively). Of note, the treatment duration in the CALGB lenalidomide arm was longer than in the CALGB placebo arm (mean maintenance treatment duration: 30.3 months versus 13.2 months, respectively; total person-years of maintenance therapy: 565 versus 243, respectively), resulting in a longer AE observation period in the lenalidomide arm compared with the placebo arm.
In study IFM 2005-02, the frequency of overall TEAEs in subjects administered lenalidomide (99.3%) was similar compared to placebo subjects (97.1%). For Grade 3 or 4 TEAEs, SAEs, and TEAEs leading to discontinuation of study drug, the overall frequencies of AEs were higher in the lenalidomide arm (75.1%, 44.7%, and 27.6%, respectively) compared with the placebo arm (32.1%, 22.9%, and 10.0%, respectively).
A list of the TEAEs that occurred at a frequency of greater than or equal to 10% in any arm for studies CALGB 100104 (post-transplant and maintenance period) and IFM 2005-02 (maintenance period only) is provided in Table 24.
The following SAEs were also noted in both studies - lung infection, infection, urinary tract infection, herpes zoster and myelodysplastic syndrome.

Previously treated multiple myeloma - lenalidomide in combination with dexamethasone.

In two phase III placebo-controlled studies (MM-009 and MM-010), 353 patients with previously treated MM were exposed to the lenalidomide/dex combination and 351 to the placebo/dex combination. The median duration of exposure to study treatment was significantly longer (44.0 weeks) in the lenalidomide/dex group as compared to placebo/dex (23.1 weeks). The difference was accounted for by a lower rate of discontinuation from study treatment due to lower progression of disease in patients exposed to lenalidomide/dex (39.7%) than in placebo/dex patients (70.4%).
The most serious AEs were: venous thromboembolism (DVT and PE) and Grade 4 neutropenia (see Section 4.4 Special Warnings and Precautions for Use).
Table 25 collectively shows the TEAEs that occurred at a frequency of ≥ 10% in any of the lenalidomide/dex study arms for studies in subjects with previously treated MM (Studies MM-009 and MM-010) and the study in NDMM subjects ineligible for ASCT (study MM-020).
Myelodysplastic syndromes - lenalidomide monotherapy. Data from the placebo-controlled MDS-004 study demonstrate that lenalidomide is also well tolerated in subjects with low- or intermediate-1-risk MDS with a deletion 5q cytogenetic abnormality with or without other cytogenetic abnormalities. The most frequently reported AEs were related to blood and lymphatic system disorders, skin and subcutaneous tissue disorders, gastrointestinal disorders, and general disorders and administrative site conditions.
In study MDS-004, neutropenia in 76.8% (106/138) of subjects and thrombocytopenia in 46.4% (64/138) of subjects were the most frequently reported AEs. The next most common AEs observed were diarrhoea (34.8%), constipation (19.6%) and nausea (19.6%); pruritus (25.4%) and rash (18.1%); fatigue (18.1%) and oedema peripheral (15.2%); and muscle spasms (16.7%). Table 26 summarises the AEs that were reported in ≥ 10% of the lenalidomide-treated patients in study MDS-004.
The safety results (N=148) from the phase 2 open-label study MDS-003 are consistent with the findings from MDS-004. Neutropenia (66.2%) and thrombocytopenia (64.9%) were the most frequently reported AEs, followed by diarrhoea (60.1%), pruritus (44.6%), fatigue (42.6%), rash (37.8%) and arthralgia (31.8%).
The most serious Grade 3 and Grade 4 AEs from the MDS-004 study (N=138, 5 mg and 10 mg doses combined) were neutropenia (5.8%), thrombocytopenia (5.8%), venous thromboembolism [DVT (3.6%)] and PE (2.9%), and altered mood (0.7%). The frequency of these events in the open-label MDS-003 study (N=148) were neutropenia (64.9%), thrombocytopenia (54.7%) and venous thromboembolism [DVT (4.7%) and PE (3.4%)].
In the 10 mg group from study MDS-004, the dose of lenalidomide was reduced or interrupted at least once due to an AE in 44 (62.3%) patients, which occurred a mean of 50.1 days into the study and lasted a mean of 26.8 days. Twenty-four (34.8%) subjects had a second dose reduction or interruption. In study MDS-003, the dose of lenalidomide was reduced or interrupted at least once due to an AE in 127 (85.8%) patients, which occurred a mean of 75.2 days into the study and lasted a mean of 30.4 days. Eighty-two (55.4%) subjects had a second dose reduction or interruption. The mean interval between the first and second dose reduction/interruption was 198.2 days. The second dose reduction/interruption due to an AE lasted a mean of 44.5 days.
Previously treated mantle cell lymphoma - lenalidomide monotherapy. The overall safety profile of lenalidomide in patients with previously treated MCL is based on data from 254 patients from a phase II, randomised, controlled study (MCL-002) and 134 patients from a phase II, single arm study (MCL-001).
Table 27 summarises the most common AEs i.e. that were reported in ≥ 10% of the lenalidomide-treated subjects in studies MCL-001 and MCL-002.

Tabulated list of adverse reactions [multiple myeloma (MM), myelodysplastic syndromes (MDS), and mantle cell lymphoma (MCL)].

The ADRs observed in MM patients treated with lenalidomide in combination with bortezomib and dexamethasone, lenalidomide in combination with dexamethasone or lenalidomide monotherapy post-ASCT, MDS patients treated with at least one dose of 10 mg lenalidomide, and in MCL patients are tabulated by system organ class and frequency (Table 28). Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100, < 1/10); and uncommon (≥ 1/1,000, < 1/100).
Table 28 is derived from data gathered during the main clinical trials in MM, MDS and MCL. The data were not adjusted according to differences in duration of treatment across the MM studies.
ADRs have been included under the appropriate category in Table 28 according to the highest frequency observed in the lenalidomide arm of any of the main clinical trials.

Post-marketing experience.

The following AEs have been identified during post-marketing use of lenalidomide. Because these reactions are reported voluntarily, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Skin and subcutaneous tissue disorders1.

Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS.

Neoplasms benign, malignant and unspecified (including cysts and polyps).

Tumour lysis syndrome, tumour flare reaction.

Respiratory, thoracic and mediastinal disorders.

Pneumonitis, pulmonary hypertension.

Cardiac disorders.

Myocardial infarction.

Endocrine disorders.

Hyperthyroidism, hypothyroidism.

Hepatobiliary disorders.

Transient abnormal liver laboratory tests, hepatic failure, acute hepatic failure, hepatitis toxic, cytolytic hepatitis, cholestatic hepatitis, mixed cytolytic/cholestatic hepatitis.

Infections and infestations.

Viral reactivation (such as hepatitis B virus or herpes zoster), progressive multifocal leukoencephalopathy (also see Section 4.4 Special Warnings and Precautions for Use).

Immune system disorders1.

Allergic conditions (angioedema, anaphylaxis, urticaria), acute graft-versus-host disease (following allogenic hematopoietic transplant), solid organ transplant rejection.

Musculoskeletal and connective tissue disorders.

Cases of rhabdomyolysis have been observed, some of them when lenalidomide is administered with a statin.
1 All PTs under MedDRA SMQ of severe cutaneous ADRs and HLT rash, and All PTs under HLGT angioedema and urticaria will be considered listed.
Hepatic disorders. Cases of transient liver laboratory abnormalities (predominantly transaminases) were reported in patients treated with lenalidomide. For such patients, treatment with lenalidomide should be interrupted and restarted once the levels return to baseline. Successful re-challenge with lenalidomide, without recurrence of elevated liver laboratory results, was reported in some patients.
Thyroid function. Cases of hypothyroidism and hyperthyroidism have been reported. Optimal control of co-morbid conditions is recommended before start of treatment. Baseline and ongoing monitoring of thyroid function is recommended.
Rhabdomyolysis. Cases of rhabdomyolysis have been reported. Some cases have been when lenalidomide is administered with a statin. This risk may be simply additive.

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

There is no specific experience in the management of lenalidomide overdose in patients with MM, MDS, or MCL. In dose-ranging studies, healthy subjects were exposed to up to 200 mg (administered 100 mg twice daily) and in single-dose studies, some subjects were exposed to up to 400 mg. Pruritus, urticaria, rash, and elevated liver transaminases were the primary reported adverse events. No clinically significant changes in ECGs, blood pressure, or pulse rate were observed.
While no haematologic events were associated with an overdose, such events may be expected since in clinical trials, the dose-limiting toxicity was essentially haematological. In the event of overdose, supportive care is advised. For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Immunomodulating agent.

Mechanism of action.

Lenalidomide has a pleiotropic mechanism of action including immunomodulatory, anti-neoplastic, anti-angiogenic, and pro-erythropoietic properties. Specifically, lenalidomide inhibits proliferation of certain haematopoietic tumour cells (including multiple myeloma [MM] plasma tumour cells and those with deletions of chromosome 5), enhances T cell and natural killer (NK) cell-mediated immunity and increases the number of NK T cells, inhibits production of pro-inflammatory cytokines (e.g. TNF-α and IL-6) by monocytes, inhibits angiogenesis by blocking the migration and adhesion of endothelial cells and the formation of microvessels, and augments foetal haemoglobin production by CD34+ haematopoietic stem cells.

Cardiac electrophysiology.

A QTc study was conducted to evaluate the effects of lenalidomide on QT interval at single doses of 10 mg and 50 mg. A single dose of lenalidomide up to 50 mg is not associated with prolongation of the QT interval in healthy male subjects. This indicates that lenalidomide is not expected to result in clinically significant prolongation of the QT interval in patients at the approved therapeutic doses.

Clinical trials.

Transplant ineligible newly diagnosed multiple myeloma - lenalidomide in combination with bortezomib and dexamethasone - study SWOG-S0777.

The SWOG S0777 study is a phase 3, randomized, active-controlled, open-label, multicentre 2-arm clinical study of 523 patients to compare the efficacy and safety of lenalidomide, bortezomib, and dexamethasone (Rbd) to that of lenalidomide and dexamethasone (Rd) in newly diagnosed multiple myeloma patients who were not intended for immediate stem cell transplant. Patients in the Rbd arm were treated with lenalidomide at 25 mg/day orally on days 1-14, intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, and dexamethasone 20 mg/day orally on days 1, 2, 4, 5, 8, 9, 11 and 12, up to eight 21-day repeated cycles. Patients in the Rd arm were treated with lenalidomide at 25 mg/day orally on days 1-21, and dexamethasone 40 mg/day orally on days 1, 8, 15, and 22, up to six 28-day repeated cycles. After initial treatment (24 weeks for each treatment arm), Rd was continued until disease progression for all patients in repeated 28-day cycles with lenalidomide 25 mg orally on days 1-21 and dexamethasone 40 mg on days 1, 8, 15, and 22. Treatment was to be continued until disease progression.
Table 29 provides a summary of the subject disposition of the 'Intent To Treat' population.
The primary efficacy endpoint in the study was progression free survival (PFS). The demographics and disease-related baseline characteristics of the patients were similar across the two treatment groups and reflected a broad NDMM patient population. In total 523 patients were enrolled into the study, with 263 patients randomised to Rbd and 260 patients randomised to Rd, 162 (30.9%) subjects were stratified as "no intent to transplant at disease progression", 81 subjects in the Rbd arm and 81 subjects in the Rd arm.
The results of PFS, as assessed by The Independent Response Adjudication Committee (IRAC), at the time of the primary analysis, using a cut-off of 05 November 2015 (50.6 months follow up) showed a 24% reduction in risk of disease progression or death favoring Rbd (HR = 0.76; 95% CI 0.61, 0.94; p = 0.010). The median overall PFS was 42.5 months (95% CI 34.0, 54.8) in the Rbd arm versus 29.9 months (95% CI 25.6, 38.2) in the Rd arm. The benefit was observed regardless of eligibility for stem cell transplant.
The results for the study, using a cut-off of 01 December 2016, where the median follow-up time for surviving subjects was 69.0 months, are presented in Table 30. The benefit favouring Rbd was observed regardless of eligibility for stem cell transplant.

Transplant eligible newly diagnosed multiple myeloma - lenalidomide in combination with bortezomib and dexamethasone - studies PETHEMA GEM2012 and IFM 2009.

The efficacy and safety of lenalidomide in combination with bortezomib and dexamethasone (Rbd) in this patient group was assessed in two phase 3 multicentre studies: PETHEMA GEM2012 and IFM 2009.
The PETHEMA GEM2012 study was a phase 3, randomized, controlled, open-label, multicentre study that compared 2 pre-transplant conditioning regimens (busulfan-melphalan and MEL200) in patients who had received Rbd (lenalidomide, bortezomib and dexamethasone) as initial therapy. Patients received lenalidomide 25 mg/day orally on days 1-21, bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, and dexamethasone 40 mg/day orally on days 1-4, 9-12 of repeated 28-day cycles. Following initial treatment, patients received either a busulfan-melphalan or MEL200 conditioning regimen (1:1 randomization) and ASCT. Patients also received two additional 4-week cycles of Rbd following ASCT. In total 458 patients were enrolled into the study. This study is ongoing and the primary efficacy endpoint of PFS has not been reached yet. The primary efficacy results from the most recent analysis i.e. as of the 31 Mar 2017 data cutoff date, 102 (22.3%) PD or death events have occurred (both arms combined), which is approximately one third of the 294 total events needed for the final analysis of PFS. Rbd was given as six 4-week cycles (24 weeks).
The IFM 2009 study was a phase 3, randomized, controlled, open-label, multicenter study that compared Rbd with and without ASCT as initial treatment for patients with previously untreated multiple myeloma who are eligible for transplant. Patients received lenalidomide 25 mg/day orally on days 1-14, intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, and dexamethasone 20 mg/day orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of repeated 21-day cycles. Rbd was given as eight 3-week cycles (24 weeks) without immediate ASCT (arm A) or three 3-week cycles (9 weeks) before ASCT (arm B). Patients in arm B also received and two additional 3-week cycles of Rbd following ASCT. In total 700 patients were enrolled into the study. Using the EMA censoring rules median PFS was 43.9 months (95%CI 41.1, NE) in the Rbd + auto-HSCT arm and 34.8 (95%CI 31.5, 37.7) in the Rbd arm. There was a statistically significant 33% reduction of risk of disease progression for subjects treated with Rbd + auto-HSCT compared with Rbd (HR = 0.67; 95% CI: 0.55, 0.82; p = 0.00010).
A summary of myeloma response rates for the treatment arms utilizing up to 24 weeks of Rbd initial treatment (i.e. six 28-day cycles or eight 21-day cycles) for the PETHEMA GEM2012 and IFM 2009 studies, using a cut-off of 31 March 2017 and the 01 December 2016 data respectively, are presented in Table 31.

Newly diagnosed multiple myeloma ineligible for transplant - lenalidomide and dexamethasone.

Study MM-020 was a phase III, multicenter, randomised, open-label, 3-arm study to compare the efficacy and safety of lenalidomide and low-dose dexamethasone (Rd) given for 2 different durations of time (i.e. [arm A: continuous Rd, until progressive disease] or [arm B: Rd18, for up to eighteen 28-day cycles {72 weeks}]), to arm C (melphalan, prednisone and thalidomide [MPT] for a maximum of twelve 42-day cycles [72 weeks]). A total of 1623 subjects with newly diagnosed multiple myeloma (NDMM) (ineligible for autologous stem cell transplantation [ASCT]) were enrolled and randomised in a 1:1:1 ratio to arm A (n = 535), arm B (n = 541), or arm C (n = 547).
Patients in the continuous Rd arm and the Rd18 arm received lenalidomide 25 mg once daily on days 1 to 21 of 28-day cycles. Dexamethasone 40 mg was dosed once daily on days 1, 8, 15, and 22 of each 28-day cycle. Initial dose and regimen for the continuous Rd and Rd18 arms were adjusted according to age and renal function. Patients > 75 years received a dexamethasone dose of 20 mg once daily on days 1, 8, 15, and 22 of each 28-day cycle. All patients received prophylactic anticoagulation (low molecular weight heparin, warfarin, heparin, or low-dose aspirin) during the study.
The primary efficacy endpoint in the study was progression-free survival (PFS). The demographics and disease-related baseline characteristics of the patients were well balanced in all 3 arms. In general, study subjects had advanced-stage disease: of the total study population, 41% had ISS stage III, and 9% had severe renal insufficiency (creatinine clearance [CLcr] < 30 mL/min). The median age was 73 in the 3 arms, with 35% of total patients > 75 years of age.
The study showed a statistically significant prolongation of PFS benefit in patients receiving continuous Rd (arm A) compared to MPT (arm C). The hazard ratio was 0.72 ([95% CI: 0.61, 0.85]; p = 0.00006), indicating a 28% decrease in the risk of disease progression for patients treated with continuous Rd compared with those treated with MPT. The median follow-up time for all surviving subjects at the interim analysis was 37.0 months. The overall response rate (≥ partial response [PR]) was higher in continuous Rd (75.1%) than in MPT (62.3%) (p < 0.00001). A greater percentage of patients achieved at least a complete response (CR) in continuous Rd than in MPT (15.1% versus 9.3%, respectively).
The preliminary analysis of the primary comparison of overall survival (OS) shows a reduction of risk of death of 22% in the continuous Rd arm compared with the MPT arm. In an updated analysis of OS where the median follow-up time for all surviving subjects was 45.5 months, a further improvement in the reduction of risk of death was noted in the continuous Rd arm compared with the MPT arm (HR 0.75; p = 0.002). The efficacy results are summarised in Table 32.
PFS2 (an exploratory endpoint) was defined for all patients as the time from randomisation to second objective progressive disease (PD), or death from any cause, whichever occurred first. PFS2 was significantly longer in the continuous Rd arm compared to arm MPT (HR 0.77 [95% CI: 0.65, 0.92]; p = 0.003). The results show a difference in patients who have started 2nd line treatment and type of therapy received: for continuous Rd, of the 43% who started 2nd line treatment, 62% received bortezomib-containing therapy vs. 12% lenalidomide therapy; for MPT, of the 57% who started 2nd line therapy, 49% received bortezomib-containing therapy vs. 34% lenalidomide therapy.

Newly diagnosed multiple myeloma post transplant maintenance - lenalidomide.

The efficacy and safety of lenalidomide maintenance therapy in NDMM patients post-ASCT were assessed in two phase III, multicenter, randomised, double-blind, 2-arm, parallel group, placebo-controlled studies: Studies CALGB 100104 and IFM 2005-02. The primary endpoint of both studies was PFS (defined from randomisation to the date of progression or death, whichever occurred first). Neither study was powered for the overall survival endpoint.
Study CALGB 100104 recruited patients aged 18-70 years with active NDMM requiring treatment and without prior progression after initial induction therapy. Induction therapy was required to have occurred within 12 months.
Within 90-100 days after high-dose chemotherapy supported by ASCT, patients were randomised 1:1 to receive either lenalidomide or placebo maintenance therapy. The maintenance dose was 10 mg/day continuously (increased up to 15 mg/day after 3 months in the absence of dose-limiting toxicity), and treatment was continued until PD or patient withdrawal for another reason.
In total, 460 patients were randomised: 231 patients to lenalidomide and 229 patients to placebo. The demographic and disease-related characteristics were balanced across both arms.
The study was unblinded (upon the recommendation of the data monitoring committee) after surpassing the threshold for a pre-planned interim analysis of PFS. After unblinding, patients in the placebo arm were allowed to cross over to receive lenalidomide before disease progression.
The results of PFS at unblinding (following a pre-planned interim analysis) using a cut off of 17 December 2009 (15.5 months median follow-up), and an updated analysis of PFS and OS using a cut off of 1 February 2016 (81.6 months median follow-up), are presented in Table 33.
Study IFM 2005-02 recruited patients aged < 65 years at diagnosis who had undergone treatment with high-dose chemotherapy supported by ASCT and had achieved at least a stable disease response at the time of haematologic recovery.
Within 6 months after ASCT, patients were randomised 1:1 to receive either lenalidomide or placebo maintenance therapy. Following 2 courses of lenalidomide consolidation (25 mg/day, days 1-21 of a 28-day cycle), the maintenance dose was 10 mg/day continuously (increased up to 15 mg/day after 3 months in the absence of dose-limiting toxicity), and treatment was continued until PD or patient withdrawal for another reason.
In total, 614 patients were randomised: 307 patients to lenalidomide and 307 patients to placebo. The demographic and disease-related characteristics were balanced across both arms.
The study was unblinded (upon the recommendation of the data monitoring committee) after surpassing the respective threshold for a pre-planned interim analysis of PFS.
The results of PFS at unblinding (following a pre-planned interim analysis) using a cut off of 7 July 2010 (31.4 months median follow-up), and an updated analysis of PFS and OS using a cut off of 1 February 2016 (96.7 months median follow-up), are presented in Table 34.
The efficacy of lenalidomide maintenance versus placebo/no maintenance as a treatment for adult NDMM patients who have undergone ASCT, as measured by overall survival (OS), was further assessed in a meta-analysis of 3 randomised controlled trials (including studies CALGB 100104, IFM 2005-02 and GIMEMA). A total of 1209 patients are included in the meta-analysis. The demographic and disease characteristics were reflective of a typical transplant-eligible patient population with NDMM.
For the primary analysis using a cut-off of 1 March 2015, the observed HR was 0.74 for lenalidomide versus placebo/no maintenance ([95% CI: 0.62, 0.89]; p = 0.001) indicating a 26% reduction in the risk of death. The median OS was not reached in the lenalidomide maintenance pool and was estimated at 86.0 months ([95% CI: 79.8, 96.0]) in the placebo/no maintenance pool.
An updated OS analysis, using a cut-off of 1 February 2016 (88.8 months median follow-up), continued to show an OS advantage for lenalidomide versus placebo/no maintenance (see Table 35).

Previously treated multiple myeloma - lenalidomide in combination with dexamethasone.

The efficacy and safety of lenalidomide in MM patients who had received at least one prior treatment were evaluated in two phase III, multi-centre, randomised, double-blind, placebo-controlled, parallel-group controlled studies (MM-009 and MM-010) of lenalidomide plus high-dose dexamethasone therapy versus high-dose dexamethasone alone. Out of 353 patients in the MM-009 and MM-010 studies who received lenalidomide/dexamethasone (lenalidomide/dex), 45.6% were aged 65 or over. Of the 704 patients evaluated in the MM-009 and MM-010 studies, 44.6% were aged 65 or over.
In both studies, patients in the lenalidomide/dex group took 25 mg of lenalidomide orally once daily on days 1 to 21 and a matching placebo capsule once daily on days 22 to 28 of each 28-day cycle. Patients in the placebo/dexamethasone (placebo/dex) group took 1 placebo capsule on days 1 to 28 of each 28-day cycle. Patients in both treatment groups took 40 mg of dexamethasone orally once daily on days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the first 4 cycles of therapy. The dose of dexamethasone was reduced to 40 mg orally once daily on days 1 to 4 of each 28-day cycle after the first 4 cycles of therapy.
In both studies, treatment was to continue until disease progression. In both studies, dose adjustments were allowed based on clinical and laboratory finding.
The primary efficacy endpoint in both studies was time-to-progression (TTP). In total, 353 patients were evaluated in the MM-009 study (177 in the lenalidomide/dex group and 176 in the placebo/dex group) and, in total, 351 patients were evaluated in the MM-010 study (176 in the lenalidomide/dex group and 175 in the placebo/dex group).
In both studies, the baseline demographic and disease-related characteristics were comparable between the lenalidomide/dex and placebo/dex groups. Both patient populations presented a median age of 63 years, with a comparable male to female ratio. The ECOG performance status was comparable between both groups, as were the number and type of prior therapies.
Pre-planned interim analyses of both studies showed that lenalidomide/dex was statistically significantly superior (p < 0.00001) to dexamethasone alone for the primary efficacy endpoint, TTP. CR and overall response (OR) rates in the lenalidomide/dex arm were also significantly higher than the placebo/dex arm in both studies. An extended follow-up efficacy analysis was conducted with a median follow-up of 30.2 months. Table 36 summarises the results of the follow-up efficacy analyses.

Myelodysplastic syndromes - lenalidomide.

The efficacy and safety of lenalidomide were evaluated in low- or intermediate-1-risk MDS patients with a deletion-5q (q31-33) cytogenetic abnormality, with or without additional cytogenetic abnormalities, were evaluated in two studies: MDS-003 and MDS-004.
Study MDS-004 was a phase III, multi-centre, randomised, double-blind, placebo-controlled study in red blood cell (RBC) transfusion-dependent patients. The 52-week double-blind treatment phase included 205 patients who were randomised to receive 10 mg lenalidomide for 21 days of a 28-day cycle, 5 mg lenalidomide continuously, or placebo. The primary efficacy endpoint was transfusion independence at 182 days. The median age of patients was 68.0 years (range 36 to 86), the median duration of MDS was 2.6 years (range 0.2 to 29.2) and 76.1% of patients were females. The study enrolled patients with absolute neutrophil counts (ANC) ≥ 0.5 x 109/L, platelet counts ≥ 25 x 109/L, serum creatinine ≤ 2.0 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3.0 x upper limit of normal (ULN), and serum total bilirubin ≤ 1.5 mg/dL. An overview of the efficacy results for the Intent-to-Treat (ITT) populations from MDS-004 receiving either cyclic lenalidomide dosing at 10 mg, or placebo, is presented in Table 37.
Study MDS-003 was a phase II, multi-centre, open-label, single-arm study of 148 patients who were RBC transfusion-dependent. Dosing was primarily at a continuous dose of 10 mg once daily for 28 days, with some experience at a dose of 10 mg daily for 21 of 28 days. The primary efficacy endpoint was RBC transfusion independence of at least 2 months duration, as defined by the MDS International Working Group (IWG) criteria. The median age of patients was 71.0 years (range 37 to 95), the median duration of MDS was 2.5 years (range 0.1 to 20.7) and 65.5% of patients were females. The study enrolled patients with absolute neutrophil counts (ANC) ≥ 0.5 x 109/L, platelet counts ≥ 50 x 109/L, serum creatinine ≤ 2.5 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3.0 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2.0 mg/dL. Table 37 summarises the efficacy results for the ITT population from MDS-003.
In both MDS-003 and MDS-004, granulocyte colony-stimulating factor was permitted for patients who developed neutropenia or fever in association with neutropenia.

Previously treated mantle cell lymphoma - lenalidomide.

The efficacy and safety of lenalidomide were evaluated in subjects with relapsed/refractory mantle cell lymphoma (MCL) were evaluated in study MCL-002.
Study MCL-002 was a phase II, multicenter, randomised, open-label, controlled study to compare the efficacy and safety of single-agent lenalidomide versus single agent of investigator's choice (IC) in subjects with MCL who were refractory to their last regimen or had between 1 and 3 relapses. Patients were randomised 2:1 to the lenalidomide or the control arm. The IC treatment (control arm) was selected before randomisation and consisted of monotherapy with either chlorambucil, cytarabine, rituximab, fludarabine, or gemcitabine.
Lenalidomide was administered orally 25 mg once daily for the first 21 days (Day 1 to 21) of repeating 28-day cycles until progression or unacceptable toxicity. Patients with moderate renal insufficiency were to receive a lower starting dose of lenalidomide 10 mg daily on the same schedule.
The primary efficacy endpoint in study MCL-002 was PFS defined as the time from randomisation to the first observation of disease progression or death due to any cause. OS was a secondary endpoint.
Lenalidomide significantly reduced the PFS risk by 39% compared to the control arm (HR 0.61 [95% CI: 0.44, 0.84]; p = 0.004). There was a significant improvement in median PFS for lenalidomide (37.6 weeks [8.7 months]) compared to control (22.7 weeks [5.2 months]).
The key efficacy results from study MCL-002 are presented in Table 38.

5.2 Pharmacokinetic Properties

Absorption.

In healthy volunteers, lenalidomide is rapidly absorbed following oral administration with maximum plasma concentrations occurring between 0.6 and 1.5 hours post-dose. The maximum concentration (Cmax) and area-under-the-concentration versus time curve (AUC) increase proportionately with increases in dose. Multiple dosing does not cause marked drug accumulation. In plasma, the relative exposures of the S- and R-enantiomers of lenalidomide are approximately 56% and 44%, respectively. The absolute bioavailability of lenalidomide has not been determined.
Co-administration with a high-fat and high-calorie meal in healthy volunteers reduces the extent of absorption, resulting in an approximately 20% decrease in AUC and 50% decrease in the Cmax in plasma.
The pharmacokinetics of lenalidomide were very similar in subjects with myelodysplastic syndromes (MDS) compared to subjects with MM. In patients with low- or intermediate-1-risk MDS, a single 10 mg oral dose of lenalidomide was rapidly absorbed with a median time to maximum concentration (tmax) of around 1 hour post-dose. The mean terminal half-life (t1/2) was approximately 4 hours. Following multiple dosing of 10 mg per day for 14 days, there was no accumulation of lenalidomide in plasma, with the mean plasma exposure (Cmax and AUC) and renal clearance at the steady-state comparable to those observed with a single dose. The plasma concentrations 1 hour after dosing were relatively stable for 280 days.

Distribution.

In vitro (14C)-lenalidomide binding to plasma proteins was low with mean plasma protein binding at 22.7% and 29.2% in MM patients and healthy volunteers, respectively.

Metabolism and excretion.

In vitro studies indicate that lenalidomide has no inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A.
A majority of lenalidomide is eliminated unchanged through urinary excretion. The contribution of renal excretion to total clearance in subjects with normal renal function was 65 - 85%. The t1/2 of elimination has been observed to increase with dose, from approximately 3 hours at 5 mg up to approximately 9 hours at doses of 400 mg (the higher dose is believed to provide a better estimate of t1/2). Steady-state levels are achieved by Day 4.
Following a single oral administration of [14C]-lenalidomide (25 mg) to healthy volunteers, approximately 90% and 4% of the radioactive dose is eliminated in urine and faeces, respectively. Approximately 82% of the radioactive dose is excreted as lenalidomide, almost exclusively via the urinary route. Hydroxy-lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose, respectively.
The renal clearance of lenalidomide exceeds the glomerular filtration rate and therefore is at least actively secreted to some extent.
Pharmacokinetic analyses in patients with impaired renal function indicate that as renal function decreases (< 50 mL/min), the total drug clearance decreases proportionally resulting in an increase in AUC. The t1/2 of lenalidomide increased from approximately 3.5 hours in subjects with creatinine clearance > 50 mL/min to more than 9 hours in subjects with reduced renal function (< 50 mL/min). However, renal impairment did not alter the oral absorption of lenalidomide. The Cmax was similar between healthy subjects and patients with renal impairment. Recommended dose adjustments in patients with impaired renal function are described in Section 4.2 Dose and Method of Administration, Dose adjustments.
Pharmacokinetic analyses based on MM studies indicate that lenalidomide is rapidly absorbed at all dose levels, with maximum plasma concentrations occurring between 0.5 and 4.0 hours post-dose both on days 1 and 28. The Cmax and AUC values increase proportionally with dose following single and multiple doses in MM patients. Exposure in MM patients is slightly higher based on Cmax and AUC values as compared to healthy male volunteers since the clearance/bioavailable fraction of a drug (CL/F) in MM patients is lower (approximately 200 mL/min compared to 300 mL/min) than it is in healthy volunteers. This is consistent with the compromised renal function in the MM patients, possibly as a consequence of their age (average patient age of 58 vs. 29 for healthy volunteers) and their disease.

5.3 Preclinical Safety Data

Genotoxicity.

In vitro (mutation in bacteria, chromosomal aberration in human lymphocytes, mutation in mouse lymphoma cells, and Syrian hamster embryo cell transformation) and in vivo (rat micronucleus) genotoxicity studies revealed no drug-related effects at either the gene or chromosomal level.

Carcinogenicity.

Carcinogenicity studies with lenalidomide have not been conducted.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lenalidomide Sandoz capsules contain the following excipients: lactose; microcrystalline cellulose; croscarmellose sodium; and magnesium stearate.
The capsule shells contain gelatin, titanium dioxide (E171), black ink, and the following colourants: 2.5 mg, 10 mg, 20 mg (indigo carmine [E132], and iron oxide yellow [E172]); 7.5 mg (iron oxide yellow [E172]) and 15 mg (indigo carmine [E132]).
The black printing ink used on the capsules contains shellac, iron oxide black [E172], propylene glycol and potassium hydroxide. Evaporated solvents not included.

6.2 Incompatibilities

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

6.3 Shelf Life

3 years.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Capsules are supplied in PA/Al/PVC/Al blister packs.

Lenalidomide Sandoz 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and 20 mg.

Pack size of 14, 21 and 28 capsules. However, not all strengths and pack sizes are being distributed in Australia.

Lenalidomide Sandoz 25 mg.

Pack size of 14 and 21 capsules. However, not all strengths and pack sizes are being distributed in Australia.

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

Molecular formula: C13H13N3O3.
Molecular weight: 259.25 g/mol.
ATC code: L04 AX04.
Chemical name: 3-(4'-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione.

CAS number.

191732-72-6.

Chemical structure.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes