Active ingredients: Lenalidomide
Revlimid 2.5 mg hard capsules
Revlimid 5 mg hard capsules
Revlimid 7.5 mg hard capsules
Revlimid 10 mg hard capsules
Revlimid 15 mg hard capsules
Revlimid 20 mg hard capsules
Revlimid 25 mg hard capsules
Why is Revlimid used? What is it for?
Revlimid contains the active substance "lenalidomide". This medicine belongs to a group of medicines which affect the functioning of the immune system.
Revlimid is used in adults for:
- Multiple myeloma
- Myelodysplastic syndromes
- Mantle cell lymphoma
Multiple myeloma and Revlimid
Multiple myeloma is a type of cancer that affects a certain type of white blood cell, called plasma cells. These cells collect in the bone marrow and divide uncontrollably. This can damage the bones and kidneys.
Multiple myeloma is typically incurable. However, the signs and symptoms can be greatly reduced or disappear for some time. This result is called "response".
In the treatment of multiple myeloma, Revlimid is used in combination with other medicines.
Revlimid in patients with newly diagnosed multiple myeloma
Revlimid is only used in newly diagnosed patients when they cannot have a bone marrow transplant.
If you are 75 years of age or older or have moderate to severe kidney problems, your doctor will check you carefully before starting treatment.
There are two types of treatment in newly diagnosed patients:
- Revlimid together with an anti-inflammatory medicine called 'dexamethasone'.
- Revlimid together with a chemotherapy medicine called 'melphalan' and an immunosuppressive medicine called 'prednisone'. You will take these other medicines at the start of treatment and then continue to take Revlimid alone.
Revlimid in patients with multiple myeloma who have had at least one other type of treatment before
- Revlimid is taken together with an anti-inflammatory medicine called 'dexamethasone'.
Revlimid can stop the signs and symptoms of multiple myeloma from getting worse. It has also been shown to delay the return of multiple myeloma after treatment.
Myelodysplastic syndromes and Revlimid
Myelodysplastic syndromes (MDS) are a collection of many different diseases of the blood and bone marrow. Blood cells become abnormal and don't function properly. Patients can have a variety of signs and symptoms, including a low red blood cell count (anemia), a need for blood transfusions, and a risk of infection.
Revlimid on its own is used to treat adult patients diagnosed with myelodysplastic syndromes who have all of the following conditions:
- if you need regular blood transfusions to treat low levels of red blood cells ("transfusion-dependent anemia")
- if you have a "bone marrow cell abnormality called" isolated 5q deletion cytogenetic abnormality. "This means that your body does not produce enough healthy blood cells
- if other treatments used previously are unsuitable or not effective enough.
Revlimid can increase the number of healthy red blood cells produced by the body by reducing the number of abnormal cells:
- This can reduce the number of blood transfusions needed. No transfusion may be needed.
Mantle cell lymphoma and Revlimid
Mantle cell lymphoma is a cancer of the lymphatic tissue (part of the immune system), which affects a type of white blood cell called B lymphocytes. In mantle cell lymphoma, B lymphocytes grow out of control and accumulate in the lymph tissue, bone marrow, or blood. .
Revlimid is used on its own to treat adult patients diagnosed with previously untreated mantle cell lymphoma.
How Revlimid works
Revlimid acts on the body's immune system and directly on the tumor in several ways:
- stopping the development of cancer cells
- stopping the growth of blood vessels that carry blood to the tumor cells
- by stimulating part of the immune system to attack cancer cells.
Contraindications When Revlimid should not be used
Do not take Revlimid
- If you are pregnant or think you may be pregnant, or if you are planning to become pregnant, as Revlimid is expected to be harmful to an unborn baby (see section 2, "Warnings and precautions" and "Pregnancy and breast-feeding").
- If there is a possibility that you may become pregnant unless you take all necessary measures to avoid pregnancy (see section 2 "Warnings and precautions" and "Pregnancy and breast-feeding"). If there is a chance that you may become pregnant, your doctor will note and confirm with each prescription that the necessary measures to avoid pregnancy have been taken.
- If you are allergic to lenalidomide or any of the other ingredients of this medicine (listed in section 6). If you think you are allergic, ask your doctor for advice.
If any of these apply to you, do not take Revlimid. If in doubt, consult your doctor.
Precautions for use What you need to know before taking Revlimid
Tell your doctor before starting treatment if:
- you have had episodes of blood clots in the past as the risk of blood clots in the veins and arteries increases during treatment
- have any signs of infection, such as cough or fever
- you have kidney problems - your doctor may change the dose of Revlimid
- have had a heart attack, have had a blood clot, or if you smoke, have high blood pressure or high cholesterol levels
- has a high tumor burden throughout the body, including in the bone marrow. This could lead to a disease in which tumors break down and cause unusual levels of chemicals in the blood, which can lead to kidney failure (this disease occurs called "tumor lysis syndrome")
- have had an allergic reaction during treatment with thalidomide, such as rash, itching, swelling, dizziness or difficulty in breathing
If any of these apply to you, tell your doctor before starting treatment.
If you have myelodysplastic syndromes, you are more likely to develop a more advanced disease called acute myeloid leukemia (AML). Furthermore, the role of Revlimid on the likelihood of developing AML is not known. Your doctor may ask you for some tests to check for signs that could more accurately predict the likelihood of developing AML during treatment with Revlimid.
Analysis and controls
You will have regular blood tests before and during treatment with Revlimid, as Revlimid can cause a reduction in the blood cells that defend you against infections (white blood cells) and those that help blood to clot (platelets). Your doctor will ask you to have a blood test:
- before treatment
- every week for the first 8 weeks of treatment (for patients with mantle cell lymphoma, this will happen every 2 weeks in cycles 3 and 4 and then at the start of each cycle)
- at least once a month thereafter.
Your doctor may check for changes in your skin, such as red spots or rashes.
Your doctor may decide to adjust the dose of Revlimid or stop treatment depending on the results of the blood tests and your general condition. If you are a newly diagnosed patient, your doctor may also evaluate treatment based on your age and any other conditions that may already be present.
Blood donation
You must not donate blood during lenalidomide therapy and for one week after stopping treatment.
Children and adolescents
Revlimid is not recommended for use in children and adolescents below 18 years of age.
Interactions Which drugs or foods may change the effect of Revlimid
Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines, including non-prescription and herbal medicines. This is because Revlimid can affect the way some other medicines work, and some other medicines can affect the way Revlimid works. .
In particular, tell your doctor or nurse if you are taking any of the following medicines:
- some medicines used to prevent pregnancy, such as oral contraceptives, as they may no longer be effective
- some medicines used for heart problems, such as digoxin
- some medicines used to thin the blood, such as warfarin
Warnings It is important to know that:
Pregnancy, breastfeeding and contraception - information for women and men
Pregnancy
For women taking Revlimid
- You should not take Revlimid if you are pregnant, as this medicine is expected to be harmful to an unborn baby.
- You should not become pregnant while being treated with Revlimid. If there is a possibility of pregnancy, you must use effective methods of contraception (see section "Contraception").
- If you become pregnant while taking Revlimid, you must stop treatment immediately and inform your doctor.
For men taking Revlimid
- If your partner becomes pregnant while you are taking Revlimid, tell your doctor immediately. It is also recommended that your partner contact your doctor.
- In addition, you must use effective methods of contraception (see "Contraception" section).
Feeding time
You should not breastfeed while taking Revlimid, as it is not known whether this medicine passes into breast milk.
Contraception
For women taking Revlimid
Before starting treatment, you should ask your doctor if there is a possibility for you to become pregnant, even if you think it is unlikely.
If there is a possibility that you will become pregnant
- you will have to undergo pregnancy tests under the supervision of your doctor (before each treatment, every 4 weeks during treatment and 4 weeks after the end of treatment) except in cases where it has been confirmed that the fallopian tubes have been cut and closed, to prevent the eggs from reaching the uterus (sterilization by tying the tubes)
- you must use effective methods of contraception for 4 weeks before starting treatment, during treatment and up to 4 weeks after stopping treatment. Your doctor will advise you on suitable methods of contraception.
For men taking Revlimid
Revlimid passes into human semen. If there is a possibility that your partner is pregnant or becoming pregnant and she is not using effective contraceptive methods, you should use condoms during treatment and for one week after the end of treatment, even if you have had a vasectomy. .
Driving and using machines
Do not drive or operate machinery if you feel dizzy, tired, sleepy, dizzy or have blurred vision.
Revlimid contains lactose
Revlimid contains lactose. If you have been told by your doctor that you have an "intolerance to some sugars, contact your doctor before taking Revlimid.
Dose, Method and Time of Administration How to use Revlimid: Posology
Revlimid should be administered by healthcare professionals experienced in the treatment of multiple myeloma or myelodysplastic syndromes and mantle cell lymphoma.
- When used to treat multiple myeloma, Revlimid is taken in combination with other medicines (see section 1 'What' Revlimid is and what it is used for ').
- When used for the treatment of myelodysplastic syndromes and mantle cell lymphoma, Revlimid is taken alone.
Always take Revlimid alone or Revlimid in combination with other medicines, always following the doctor's instructions exactly. If in doubt, consult your doctor or pharmacist.
If you are taking Revlimid in combination with other medicines, please consult the package leaflets of those medicines for more information on their use and effects.
Treatment cycle
- Revlimid and the medicines you need to take in combination with Revlimid are taken over a few days over a period of 4 weeks (28 days).
- Each 28-day period is called a "treatment cycle".
- Depending on the day of your period, you will take one or more of the medicines. However, in some days you will not take any medicines.
- Once each 28-day cycle is complete, a new "cycle" must begin over the next 28 days.
Revlimid dose to take
Before starting treatment, your doctor will tell you:
- the dose of Revlimid to take
- the dose of other medicines to be taken in combination with Revlimid, if prescribed
- on which days of the treatment cycle to take each medicine.
Doctors may observe changes on the skin, such as red spots or rashes.
Your doctor may also decide to change the dose of Revlimid or the other medicines during treatment, based on the results of the blood tests and your general condition (see section 2, "What you need to know before you take Revlimid").
How and when to take Revlimid
- The capsules should be swallowed whole, preferably with water.
- Do not break, open or chew the capsules.
- The capsules can be taken with or without food.
- You should take Revlimid on the appointed days at approximately the same time.
To remove the capsule from the blister, press only on one side of the capsule, pushing it through the aluminum foil. Do not press on the center of the capsule, otherwise it may break.
Duration of treatment with Revlimid
Revlimid is taken in treatment cycles, each lasting 28 days (see 'Treatment cycle' above). You must continue the courses of treatment until your doctor tells you to stop the treatment.
If you forget to take Revlimid
If you forget to take Revlimid at the usual time e
- less than 12 hours have passed: take your capsule immediately
- more than 12 hours have passed: do not take the forgotten capsule, but take the next capsule the next day at the usual time.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Revlimid
If you have taken more Revlimid than you were told to, tell your doctor immediately.
Side Effects What are the side effects of Revlimid
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Serious side effects which may affect more than 1 in 10 people
Revlimid can reduce the number of white blood cells that fight infections and blood cells that promote blood clotting (platelets), which can lead to bleeding disorders, eg. nosebleed and bruising. Revlimid can also cause blood clots in the veins (thrombosis).
Therefore you should seek immediate medical attention if you experience any of the following side effects:
- fever, chills, sore throat, cough, mouth ulcers or any other symptoms of infection (including within the bloodstream (sepsis))
- bleeding or bruising in the absence of wounds
- pain in the chest or legs
- shortness of breath.
If you experience any of the side effects listed above, please tell your doctor immediately.
Other side effects are listed below
It is important to note that a small number of patients may develop other types of cancer and it is possible that this risk may increase with treatment with Revlimid; therefore, your doctor must carefully weigh the benefit and risk when prescribing Revlimid for you.
Very common side effects may affect more than 1 in 10 people:
- Decrease in the number of red blood cells (anemia), which can cause tiredness and weakness
- Constipation, diarrhea, nausea, red skin, rash, vomiting, muscle cramps, muscle aches, bone pain, joint pain, fatigue, generalized swelling, including swelling of the arms and legs
- Fever and flu symptoms, including fever, muscle pain, headache, earache and chills
- Numbness, tingling or burning sensation on the skin, pain in the hands or feet, dizziness, tremor, change in taste
- Chest pain that radiates to the arms, neck, jaw, back or stomach, with a sensation of sweating and shortness of breath, nausea or vomiting, which may be symptoms of a heart attack (myocardial infarction)
- Reduction of appetite
- Low levels of potassium in the blood
- Leg pain (which may be a symptom of thrombosis), chest pain or shortness of breath (which may be symptoms of blood clots in the lungs, called pulmonary embolism)
- Infections of any kind
- Infection of the lungs and upper respiratory tract, shortness of breath
- Blurred vision
- Blurred vision (cataracts)
- Kidney problems
- Changes in a protein in the blood that can cause swelling of the arteries (vasculitis)
- Increases in blood sugar (diabetes)
- Headache
- Dry skin
- Stomach pain
- Change in mood, difficulty sleeping
Common side effects may affect up to 1 in 10 people:
- Infection of the sinuses surrounding the nose
- Bleeding from the gums, stomach or intestines
- Increased pain, tumor size, redness around the tumor
- Increase or decrease in blood pressure, slow, rapid or irregular heartbeat
- Darkening of the skin
- Rashes, skin cracking, peeling or peeling
- Hives, itching, increased sweating, dehydration
- Sore mouth with ulcers, dry mouth, difficulty swallowing
- Stomach ache
- Urine production far more or less than usual (which may be a symptom of kidney failure), blood in the urine
- Shortness of breath, especially when lying down (which could be a symptom of heart failure)
- Difficulty getting an erection
- Stroke, fainting
- Muscle weakness
- Swelling of the joints
- Changes in thyroid hormone in the blood, low levels of calcium, phosphate or magnesium in the blood
- Depression
- Deafness
- Abnormal liver function tests
- Balance disorders, movement difficulties
- Ringing in the ears (tinnitus)
- Iron overload
- Thirst
- Confusion
- Toothache
- Weight loss.
Uncommon side effects may affect up to 1 in 100 people:
- Hemorrhage inside the skull
- Circulatory problems
- Loss of vision
- Loss of sex drive (libido)
- Abundant urine flow with pain and weakness in the bones, which could be symptoms of a kidney disorder (Fanconi syndrome)
- Stomach pain, bloating or diarrhea, which may be symptoms of inflammation of the large intestine (called colitis or typhlitis)
- Production of much more or less urine than usual, which may be a symptom of a type of kidney problem (called renal tubular necrosis
- Skin discolouration, sensitivity to sunlight
- Some types of skin cancers
- Hives, rash, swelling of the eyes, mouth or face, difficulty in breathing or itching, which may be symptoms of an allergic reaction.
Rare side effects may affect up to 1 in 1,000 people:
- Severe allergic reaction, which may start as a rash in one area but spread with extensive skin loss throughout the body (Stevens-Johnson syndrome and / or toxic epidermal necrolysis).
- Tumor lysis syndrome - metabolic complications that can occur during tumor treatment and sometimes even without treatment. These complications are caused by the breakdown products of dying cancer cells and may include the following complications: changes in haematological parameters; high values of potassium, phosphorus and uric acid; and low calcium values which consequently lead to changes in kidney function, heart rate, convulsions and sometimes death.
Frequency not known: frequency cannot be estimated from the available data:
- Sudden or mild but worsening pain in the upper abdomen and / or back that persists for a few days, possibly with nausea, vomiting, fever and a rapid pulse. These symptoms may be due to inflammation of the pancreas.
- Wheezing, shortness of breath, or dry cough, which could be symptoms caused by inflammation of the lung tissue.
- Yellowish discoloration of the skin, mucous membranes or eyes (jaundice), light colored stools, dark colored urine, itchy skin, rash, pain or swelling of the abdomen. These could be symptoms of liver damage (liver disease ).
- Rare cases of muscle breakdown (pain, weakness or swelling of the muscles), which can cause kidney problems (rhabdomyolysis), have been observed, some of which when Revlimid is given with a statin (a type of cholesterol-lowering drug).
- A disease that affects the skin and is caused by inflammation of small blood vessels, with pain in the joints and fever (leukocytoclastic vasculitis).
- Deterioration of the stomach or bowel wall, which can lead to very serious infections.Tell your doctor if you have severe abdominal pain, fever, nausea, vomiting, blood in your stool or changes in bowel habits.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
- Keep this medicine out of the sight and reach of children.
- Do not use this medicine after the expiry date which is stated on the blister and carton after "EXP". The expiry date refers to the last day of that month.
- This medicine does not require any special storage conditions.
- Do not use this medicine if you notice packs that are damaged or show signs of tampering.
- Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Deadline "> Other information
What Revlimid contains
Revlimid 2.5 mg hard capsules:
- The active ingredient is lenalidomide. Each capsule contains 2.5 mg of lenalidomide.
- The other ingredients are:
- capsule content: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate
- capsule shell: gelatin, titanium dioxide (E171), indigo carmine (E132) and yellow iron oxide (E172)
- lettering ink: shellac, propylene glycol, potassium hydroxide and black iron oxide (E172).
Revlimid 5 mg hard capsules:
- The active ingredient is lenalidomide. Each capsule contains 5 mg of lenalidomide.
- The other ingredients are:
- capsule content: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate
- capsule shell: gelatin and titanium dioxide (E171)
- lettering ink: shellac, propylene glycol, potassium hydroxide and black iron oxide (E172).
Revlimid 7.5 mg hard capsules:
- The active ingredient is lenalidomide. Each capsule contains 7.5 mg of lenalidomide.
- The other ingredients are:
- capsule content: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate
- capsule shell: gelatin, titanium dioxide (E171), yellow iron oxide (E172)
- lettering ink: shellac, propylene glycol, potassium hydroxide and black iron oxide (E172).
Revlimid 10 mg hard capsules:
- The active ingredient is lenalidomide. Each capsule contains 10 mg of lenalidomide.
- The other ingredients are:
- capsule content: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate
- capsule preparation: gelatin, titanium dioxide (E171), indigo carmine (E132) and yellow iron oxide (E172)
- lettering ink: shellac, propylene glycol, potassium hydroxide and black iron oxide (E172).
Revlimid 15 mg hard capsules:
- The active ingredient is lenalidomide. Each capsule contains 15 mg of lenalidomide.
- The other ingredients are:
- capsule content: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate
- capsule shell: gelatin, titanium dioxide (E171) and indigo carmine (E132)
- lettering ink: shellac, propylene glycol, potassium hydroxide and black iron oxide (E172).
Revlimid 20 mg hard capsules:
- The active ingredient is lenalidomide. Each capsule contains 20 mg of lenalidomide.
- The other ingredients are:
- capsule content: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate
- capsule shell: gelatin, titanium dioxide (E171), indigo carmine (E132) and yellow iron oxide (E172)
- lettering ink: shellac, propylene glycol, potassium hydroxide and black iron oxide (E172).
Revlimid 25 mg hard capsules:
- The active ingredient is lenalidomide. Each capsule contains 25 mg of lenalidomide.
- The other ingredients are:
- capsule content: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and magnesium stearate
- capsule shell: gelatin and titanium dioxide (E171)
- lettering ink: shellac, propylene glycol, potassium hydroxide and black iron oxide (E172).
What Revlimid looks like and contents of the pack
Revlimid 2.5 mg hard capsules are blue-green / white, marked "REV 2.5 mg".
The capsules are supplied in packs, each containing one or three blisters. Each blister contains seven capsules, for a total of 7 or 21 capsules per pack.
Revlimid 5 mg hard capsules are white, marked "REV 5 mg".
The capsules are supplied in packs, each containing one or three blisters. Each blister contains seven capsules, for a total of 7 or 21 capsules per pack.
Revlimid 7.5 mg hard capsules are pale yellow / white, marked "REV 7.5 mg".
The capsules are supplied in packs, each containing three blisters. Each blister contains seven capsules, for a total of 21 capsules per pack.
Revlimid 10 mg hard capsules are blue-green / light yellow, marked "REV 10 mg".
The capsules are supplied in packs, each containing three blisters. Each blister contains seven capsules, for a total of 21 capsules per pack.
Revlimid 15 mg hard capsules are light blue / white, marked "REV 15 mg".
The capsules are supplied in packs, each containing three blisters. Each blister contains seven capsules, for a total of 21 capsules per pack.
Revlimid 20 mg hard capsules are blue-green / light blue, marked "REV 20 mg".
The capsules are supplied in packs, each containing three blisters. Each blister contains seven capsules, for a total of 21 capsules per pack.
Revlimid 25 mg hard capsules are white, marked "REV 25 mg".
The capsules are supplied in packs, each containing three blisters. Each blister contains seven capsules, for a total of 21 capsules per pack.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT -
REVLIMID 10 MG HARD CAPSULES
▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -
Each capsule contains 10 mg of lenalidomide.
Excipients with known effects:
Each capsule contains 294 mg of anhydrous lactose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM -
Hard capsule.
Blue-green / light yellow capsules, size 0.21.7 mm, marked "REV 10 mg".
04.0 CLINICAL INFORMATION -
04.1 Therapeutic indications -
Multiple myeloma
Revlimid is indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for transplant (see section 4.2).
Revlimid, in combination with dexamethasone, is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
Myelodysplastic syndromes
Revlimid is indicated for the treatment of patients with transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes (MDS) associated with isolated 5q deletion cytogenetic abnormality, when other treatment options are insufficient or inadequate.
Mantle cell lymphoma
Revlimid is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (see sections 4.4 and 5.1).
04.2 Posology and method of administration -
Treatment with Revlimid should be supervised by a physician experienced in the use of cancer therapies (see section 4.4, karyotype).
Dosage
Newly diagnosed multiple myeloma
Lenalidomide in combination with dexamethasone until disease progression, in non-patients eligible for transplantation
Treatment with lenalidomide should not be initiated if the absolute neutrophil count (Absolute
Neutrophil Count, ANC) is
Recommended dose
The recommended starting dose of lenalidomide is 25 mg orally once daily on days 1-21 of repeated 28-day cycles. The recommended dose of dexamethasone is 40 mg orally once daily on days 1, 8, 15, and 22 of repeated 28-day cycles. Patients can continue lenalidomide and dexamethasone therapy until disease progression or intolerance develops.
The dosage can be continued or modified based on clinical and laboratory findings (see section 4.4). For patients ≥ 75 years of age, the starting dose of dexamethasone is 20 mg / day on days 1, 8, 15 and 22 of each 28-day treatment cycle. The recommended dose of lenalidomide for patients with moderate renal impairment is 10 mg once daily.
Recommended dose adjustments during treatment and upon resumption of treatment
As summarized in the tables below, dose adjustments are recommended for the management of Grade 3 or 4 thrombocytopenia and neutropenia, or for the management of any other Grade 3 or 4 toxicities believed to be related to lenalidomide.
• Levels of dose reduction
• Thrombocytopenia
a If dose-limiting toxicity occurs (Dose Limiting Toxicity, DLT)> Day 15 of a cycle, lenalidomide dosing will be stopped for at least the remainder of the current 28 day cycle.
• Neutropenia
In case of neutropenia, the physician should consider the use of growth factors in patient management.
If the lenalidomide dose has been reduced due to haematological DLT, the lenalidomide dose may be reintroduced at the next higher dose level (up to the starting dose), at the discretion of the treating physician, if continued lenalidomide therapy / dexamethasone produced improved bone marrow function (absence of DLT for at least 2 consecutive cycles and ANC ≥ 1,500 / mcl, with a platelet count ≥ 100,000 / mcl, at the start of a new cycle at the current dose).
Lenalidomide in combination with melphalan and prednisone, followed by maintenance monotherapy, in patients not eligible for transplantation
Lenalidomide treatment should not be initiated if the ANC is
Recommended dose
The recommended starting dose is lenalidomide 10 mg / day orally on days 1-21 of repeated 28-day cycles for up to 9 cycles, melphalan 0.18 mg / kg orally on days 1-4 of repeated cycles of 28 days, prednisone 2 mg / kg orally on days 1-4 of repeated 28-day cycles. Patients completing 9 cycles or unable to complete combination therapy due to intolerance should be treated with lenalidomide monotherapy, 10 mg / day orally, on days 1-21 of repeated cycles. 28 days until disease progression. The dosage can be continued or modified based on clinical and laboratory findings (see section 4.4).
Recommended dose adjustments during treatment and upon resumption of treatment
As summarized in the tables below, dose adjustments are recommended for the treatment of Grade 3 or 4 thrombocytopenia or neutropenia, or for the management of any other Grade 3 or 4 toxicity thought to be related to lenalidomide.
• Levels of dose reduction
If neutropenia is the only toxicity at any dosage, add granulocyte colony stimulating factor (G-CSF) and maintain the lenalidomide dosage..
• Thrombocytopenia
• Neutropenia
a If subject has not received G-CSF therapy, initiate G-CSF therapy. On Day 1 of the next cycle, continue GCSF as needed and maintain the melphalan dose if neutropenia was the only DLT. Otherwise, reduce one dose level at the start of the next cycle.
In case of neutropenia, the use of growth factors in patient management should be considered.
Multiple myeloma with at least one previous therapy
Recommended dose
The recommended starting dose is 25 mg lenalidomide orally once daily on days 1-21 of repeated 28-day cycles. The recommended dose of dexamethasone is 40 mg orally once daily on days 1-4, 9-12 and 17-20 of each 28-day cycle for the first 4 cycles of therapy and 40 mg once daily thereafter. day on days 1-4 every 28 days.
The dosage can be continued or modified based on clinical and laboratory findings (see section 4.4). Physicians should carefully evaluate the dosage of dexamethasone to use, taking into consideration the patient's condition and disease status.
Treatment with lenalidomide should not be initiated if the ANC is bone marrow by plasma cells, if the platelet count is
Recommended dose adjustments during treatment and upon resumption of treatment
As summarized in the tables below, dose adjustments are recommended for the treatment of grade 3 or 4 neutropenia or thrombocytopenia, or for the management of any grade 3 or 4 toxicity thought to be related to lenalidomide.
• Levels of dose reduction
• Thrombocytopenia
• Neutropenia
In case of neutropenia, the use of growth factors in patient management should be considered.
Myelodysplastic syndromes
Lenalidomide treatment should not be initiated if the ANC is
Recommended dose
The recommended starting dose is 10 mg lenalidomide orally once daily on days 1-21 of repeated 28-day cycles. The dosage can be continued or modified based on clinical and laboratory findings (see section 4.4).
Recommended dose adjustments during treatment and upon resumption of treatment
As summarized in the tables below, dose adjustments are recommended for the treatment of grade 3 or 4 neutropenia or thrombocytopenia, or for the management of any grade 3 or 4 toxicity thought to be related to lenalidomide.
• Levels of dose reduction
For patients starting with a 10 mg dose and experiencing thrombocytopenia or neutropenia:
• Thrombocytopenia
• Neutropenia
Suspension of lenalidomide
Patients who do not have at least a mild erythroid response within 4 months of starting therapy, demonstrated by a reduction of at least 50% in transfusion requirements or, if not receiving transfusions, by a 1 g / dl increase in hemoglobin , should stop lenalidomide treatment.
Mantle cell lymphoma
Recommended dose
The recommended starting dose is 25 mg lenalidomide orally once daily on days 1-21 of repeated 28-day cycles.
The assay is continued or modified based on clinical and laboratory findings (see section 4.4).
Recommended dose adjustments during treatment and upon resumption of treatment
As summarized in the tables below, dose adjustments are recommended for the treatment of Grade 3 or 4 neutropenia or thrombocytopenia, or for the management of any Grade 3 or 4 toxicity thought to be related to lenalidomide.
• Levels of dose reduction
1 - In countries where the 2.5 mg capsule is available.
• Thrombocytopenia
• Neutropenia
• Tumor flare reaction
Treatment with lenalidomide can be continued in patients with Tumor Flare Reaction, Grade 1 or 2 severance pay, without interruption or modification, at the discretion of the physician. In patients with Grade 3 or 4 TFR, lenalidomide treatment should be withheld until TFR is reduced to ≤ Grade 1; For symptom management, patients can be treated according to grade 1 and 2 TFR guidelines (see section 4.4).
All patients
For other Grade 3 or 4 toxic effects believed to be related to lenalidomide, treatment should be discontinued and resumed at the next lower dose only when toxicity has decreased to ≤ Grade 2 at the physician's discretion.
Discontinuation or discontinuation of lenalidomide should be considered in case of grade 2 or 3 skin rash. Stevens-Johnson (SSJ) or toxic epidermal necrolysis (NET), and should not be resumed after discontinuation due to these reactions.
Special populations
Pediatric population
Revlimid should not be used in children and adolescents from birth to 18 years of age due to safety concerns (see section 4.4).
Elderly patients
Currently available pharmacokinetic data are described in section 5.2. Lenalidomide has been used in clinical studies in patients with multiple myeloma up to 91 years of age, in patients with myelodysplastic syndromes up to 95 years of age and in patients with mantle cell lymphoma up to 88 years of age (see section 5.1 ).
In newly diagnosed multiple myeloma patients 75 years of age and older treated with lenalidomide, there was a higher incidence of serious adverse reactions and adverse reactions leading to treatment discontinuation (see section 4.4). Newly diagnosed multiple myeloma patients 75 years of age or older should be carefully evaluated before considering treatment (see section 4.4).
• Newly diagnosed multiple myeloma
For patients over 75 years of age treated with lenalidomide in combination with dexamethasone, the starting dose of dexamethasone is 20 mg / day on days 1, 8, 15 and 22 of each 28-day treatment cycle.
No dose adjustments are proposed for patients over 75 years of age treated with lenalidomide in combination with melphalan and prednisone.
In clinical trials of newly diagnosed multiple myeloma in transplant-ineligible patients, lenalidomide combination therapy was less tolerated in patients over 75 years of age than in the younger population. Among these patients, the percentage who discontinued treatment due to intolerance (grade 3 or 4 adverse events and serious adverse events) was higher than in patients aged
• Multiple myeloma previously treated with at least one therapy
The percentage of patients with multiple myeloma aged 65 years or older was not significantly different between the lenalidomide / dexamethasone and placebo / dexamethasone groups. In general, no differences in safety and efficacy were observed between these patients and younger patients, although a greater predisposition of older patients cannot be ruled out.
• Myelodysplastic syndromes
For patients with myelodysplastic syndromes treated with lenalidomide, no overall difference in safety and efficacy was observed between patients over 65 years of age and younger patients.
• Mantle cell lymphoma
For patients with mantle cell lymphoma treated with lenalidomide, no overall difference in safety and efficacy was observed between patients aged 65 years and over and patients aged below 65 years.
As elderly patients are more likely to have impaired renal function, particular care should be taken in dose selection and renal function monitoring should be performed as a precaution.
Patients with renal insufficiency
Lenalidomide is substantially excreted via the kidneys; in patients with higher degrees of renal insufficiency the tolerability of the treatment may be altered (see section 4.4). Particular care should be taken in choosing the dosage and monitoring of renal function is advisable.
No dose adjustment is required in patients with mild renal insufficiency and multiple myeloma, myelodysplastic syndromes or mantle cell lymphoma. In patients with moderate or severe renal insufficiency or end-stage renal disease, at initiation of therapy and throughout the duration of treatment, the following dose adjustments are recommended. There is no phase III clinical trial experience in patients with End Stage Renal Disease (ESRD) (CLcr dialysis).
• Multiple myeloma
1 The dose can be increased to 15 mg once daily after 2 cycles if the patient does not respond to treatment but tolerates the medicine.
2 In countries where the 7.5 mg capsule is available.
• Myelodysplastic syndromes
* Recommended dose reduction levels during treatment and upon resumption of treatment, to manage grade 3 or 4 neutropenia or thrombocytopenia, or other grade 3 or 4 toxicity deemed related to lenalidomide, as described above.
• Mantle cell lymphoma
1 The dose can be increased to 15 mg once daily after 2 cycles if the patient does not respond to treatment but tolerates the medicine.
2 In countries where the 7.5 mg capsule is available.
Following initiation of lenalidomide therapy, subsequent dose modification of lenalidomide in patients with impaired renal function should be based on the tolerability of the treatment for the individual patient, as described above.
Patients with hepatic impairment
Lenalidomide has not been formally studied in patients with hepatic impairment and there are no specific dosage recommendations.
Method of administration
Oral use.
Revlimid capsules should be taken on the designated days, around the same time. The capsules must not be opened, broken or chewed. The capsules should be swallowed whole, preferably with water, with or without food. The patient can take a missed dose if less than 12 hours have passed since the scheduled time of taking it. If, on the other hand, more than 12 hours have passed, the patient should not take the missed dose, but wait for the usual time of the following day to take the next dose.
It is recommended to apply pressure to only one side of the capsule to remove it from the blister, thus reducing the risk of deforming or breaking it.
04.3 Contraindications -
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Pregnant women.
• Women of childbearing potential, unless all conditions of the Pregnancy Prevention Program are met (see sections 4.4 and 4.6).
04.4 Special warnings and appropriate precautions for use -
Precautions in case of pregnancy
Lenalidomide is structurally related to thalidomide, an active substance with a known teratogenic effect in humans, which causes severe life-threatening birth defects. Lenalidomide induced malformations in monkeys similar to those described for thalidomide (see sections 4.6 and 5.3). a teratogenic effect of lenalidomide is expected in humans during pregnancy.
The conditions of the Pregnancy Prevention Program must be met for all patients, unless there is firm evidence that the patient is unable to conceive.
Criteria for establishing that a woman is not of childbearing potential
A female patient or the partner of a male patient is considered capable of conceiving unless she meets at least one of the following criteria:
• Age ≥ 50 years and natural amenorrhea * for ≥ 1 year
• Premature ovarian failure confirmed by a gynecologist
• Previous bilateral salpingo-oophorectomy or hysterectomy
• XY genotype, Turner syndrome, uterine agenesis.
* Amenorrhea following anticancer therapy or during breastfeeding does not rule out potential fertility.
Orientation
Lenalidomide is contraindicated for women of childbearing potential unless all of the following conditions are met:
• The patient is aware that a teratogenic risk for the fetus is expected
• The patient is aware of the need to use effective contraceptive methods, without interruption, 4 weeks before starting treatment, for the entire duration of treatment and up to 4 weeks after the end of treatment.
• Even in the presence of amenorrhea, a patient of childbearing potential must follow all recommendations for effective contraception
• The patient must be able to comply with effective contraceptive measures
• The patient is informed and aware of the potential consequences of pregnancy and the need to seek immediate medical attention if there is a risk of pregnancy
• The patient is aware of the need to start treatment as soon as lenalidomide is dispensed following a negative pregnancy test
• The patient is aware of the need and agrees to undergo pregnancy tests every 4 weeks, except in cases of confirmed sterilization by tubal ligation
• The patient acknowledges that she is aware of the risks and necessary precautions associated with the use of lenalidomide
For male patients taking lenalidomide, pharmacokinetic studies have shown that, during treatment, lenalidomide is present at extremely low levels in semen and is undetectable in the semen of healthy subjects 3 days after stopping the substance ( see paragraph 5.2). As a precaution, all male patients taking lenalidomide must meet the following conditions:
• Be aware of the expected teratogenic risk of having sexual activity with a woman who is pregnant or of childbearing potential
• Be aware of the need to use condoms in case of sexual activity with a pregnant or potentially fertile woman who does not use effective contraception (even if the man has had a vasectomy) during treatment and for 1 week after dose suspension and / or treatment discontinuation.
• Be aware that if the partner becomes pregnant while the patient is taking Revlimid or shortly after stopping Revlimid treatment, they should inform the doctor immediately and refer the partner to a specialist or teratologist who can evaluate the situation and give an opinion.
In the case of women of childbearing potential, the doctor must ensure that:
• The patient meets the requirements of the Pregnancy Prevention Program, including confirmation that she has an adequate level of understanding
• The patient has accepted the conditions mentioned above
Contraception
Women of childbearing potential should use effective contraception for 4 weeks prior to therapy, during therapy and up to 4 weeks after lenalidomide therapy, and also in the event of dose interruption, unless the patient undertakes to observe an "absolute and continuous abstinence, confirmed month by month. If effective contraceptive therapy has not already been started, the patient should be referred to a specialist doctor in order to establish an effective contraceptive method.
Below are examples of contraceptive methods considered adequate:
• Plant
• Levonorgestrel-releasing intrauterine system (IUS)
• Medroxyprogesterone acetate depot
• Tubal sterilization
• Sexual intercourse only with a vasectomised male partner; vasectomy must be confirmed by two negative semen analyzes
• Progestogen-only pills to inhibit ovulation (eg desogestrel)
Due to the increased risk of venous thromboembolism in patients with multiple myeloma taking lenalidomide in combination regimens, and to a lesser extent in patients with myelodysplastic syndromes and mantle cell lymphoma taking lenalidomide alone, the use of oral contraceptives is not recommended. combined type (see also section 4.5). If the patient is currently taking a combined oral contraceptive, she should replace the method of birth control with one of the above. The risk of venous thromboembolism remains for 4-6 weeks after discontinuation of the combined oral contraceptive. The efficacy of contraceptive steroids may be reduced during concomitant treatment with dexamethasone (see section 4.5).
Levonorgestrel-releasing intrauterine implants and systems are associated with an increased risk of infection upon insertion, as well as irregular vaginal bleeding. Antibiotic prophylaxis should be considered, particularly in patients with neutropenia.
Copper-releasing intrauterine devices are generally not recommended due to the potential risk of infection from the time of insertion and due to menstrual blood loss, which can adversely affect patients with neutropenia or thrombocytopenia.
Pregnancy test
In accordance with local practice, in patients of childbearing potential, pregnancy tests with a minimum sensitivity of 25 mIU / ml should be performed under medical supervision, as described below. This obligation is also valid for patients of childbearing potential who practice absolute and continuous abstinence. Ideally, the pregnancy test, prescription and dispensing of the medicine should occur on the same day. Lenalidomide should be dispensed to patients of childbearing potential within 7 days of the prescription date.
Before starting the treatment
Once the patient has been using effective contraception for at least 4 weeks, a medically supervised pregnancy test should be performed during the consultation in which lenalidomide is prescribed, or in the 3 days prior to the visit to the doctor. The test must ensure that the patient is not pregnant before starting treatment with lenalidomide.
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, except in cases of confirmed tubal sterilization. These pregnancy tests should be performed on the same day as the doctor's prescription or in the 3 days prior to the doctor's visit.
Male patients
During treatment, lenalidomide is present at extremely low levels in semen and is undetectable in the semen of healthy subjects 3 days after drug discontinuation (see section 5.2). As a precaution and taking into account special patient populations with a prolonged elimination time, such as patients with renal impairment, all male patients taking lenalidomide should use condoms for the entire duration of treatment, while discontinuing treatment. dose and up to one week after stopping therapy, if your partner is pregnant or of childbearing potential and is not using effective contraception (even if the man has had a vasectomy).
Additional precautions for use
Patients should be instructed never to give this medicine to other people and to return unused capsules to the pharmacist at the end of treatment.
Patients should not donate blood during lenalidomide therapy and for at least one week after stopping treatment.
Educational material, prescription and dispensing restrictions
To help patients avoid fetal exposure to lenalidomide, the Marketing Authorization Holder will provide educational materials to medical personnel to reinforce the warnings on the expected teratogenicity of lenalidomide, to advise on contraception before initiation of therapy and to provide guidance on the need for a pregnancy test. The physician must inform male and female patients about the teratogenic risk and strict pregnancy prevention measures, as specified in the Pregnancy Prevention Program, and provide patients with the appropriate educational booklet, patient card and / or equivalent instrument, in compliance with the measures implemented at national level. A national distribution control system has been implemented in collaboration with each National Competent Authority. This system provides for the use of a patient card and / or equivalent instrument, for the control of the prescription and dispensing, and the collection of detailed data relating to the indication, in order to carefully control the use off-label of the medicine within the national territory. Ideally, the pregnancy test, the issuing of the prescription and the dispensing of the medicine should take place on the same day. Lenalidomide should be dispensed to patients of childbearing potential within 7 days from the date of prescription and after the " negative outcome of the pregnancy test performed under medical supervision.
Additional special warnings and precautions for use
Cardiovascular Disorders
Myocardial infarction
Cases of myocardial infarction have been observed in patients who received lenalidomide, particularly in those with known risk factors, and within the first 12 months when given in combination with dexamethasone. Patients with known risk factors, including those with prior thrombosis, should be monitored closely and action should be taken to attempt to minimize all modifiable risk factors (e.g. smoking, hypertension and hyperlipidaemia).
Venous and arterial thromboembolic events
In patients with multiple myeloma, the combination of lenalidomide and dexamethasone is associated with an increased risk of venous thromboembolism (mainly deep vein thrombosis and pulmonary embolism) and arterial thromboembolism (mainly events of myocardial infarction and cerebrovascular event). Venous thromboembolism has been observed to a lesser extent with lenalidomide in combination with melphalan and prednisone in newly diagnosed multiple myeloma and as monotherapy in myelodysplastic syndromes See sections 4.5 and 4.8.
In patients with myelodysplastic syndromes and mantle cell lymphoma, treatment with lenalidomide alone has also been associated with a risk of venous thromboembolism (mainly deep vein thrombosis and pulmonary embolism), but to a lesser extent than in patients with multiple myeloma - see sections 4.5 and 4.8.
Therefore, patients with known risk factors for thromboembolism - including a previous thrombosis - should be monitored closely. Action should be taken to attempt to minimize all modifiable risk factors (e.g. smoking, hypertension and hyperlipidaemia). In these patients, concomitant administration of erythropoietic agents or a previous history of thromboembolic events may also increase the risk of thrombosis. It is therefore recommended, in patients with multiple myeloma taking lenalidomide and dexamethasone, that erythropoietic agents or other agents that may increase the risk of thrombosis, such as eg. hormone replacement therapy. If the hemoglobin concentration increases beyond 12 g / dl the use of erythropoietic agents should be discontinued.
Patients and physicians should be aware of the need to pay attention to the signs and symptoms of thromboembolism. Patients should seek medical attention if symptoms such as shortness of breath, chest pain, swelling of the lower or upper limbs occur. For prophylactic purposes, the intake of antithrombotic drugs should be recommended, especially in patients with additional thrombotic risk factors. The decision to adopt prophylactic antithrombotic measures should be made after careful consideration of the risk factors for each individual patient.
If the patient experiences any thromboembolic event, treatment should be discontinued and standard anticoagulant therapy initiated. Once the patient has been stabilized on anticoagulation and all complications of the thromboembolic event have resolved, lenalidomide treatment can be resumed at the original dose following a benefit-risk assessment. The patient should continue anticoagulation therapy during the treatment. treatment with lenalidomide.
Neutropenia and thrombocytopenia
The main dose-limiting toxicities of lenalidomide include neutropenia and thrombocytopenia. In order to monitor the possible occurrence of cytopenia, a complete blood cell count, including white blood cell count including differential, platelet count, hemoglobin and hematocrit, at baseline, once a week, should be performed during the first 8 weeks of treatment. with lenalidomide, and once a month thereafter. In patients with mantle cell lymphoma, the monitoring schedule should be every 2 weeks in cycles 3 and 4 and at the start of each cycle thereafter. A dose reduction may be necessary (see section 4.2). In case of neutropenia, the physician should consider using growth factors in patient management. Patients should be advised to report febrile episodes immediately. Caution is advised in concomitant administration of lenalidomide with other myelosuppressive agents.
• Newly diagnosed multiple myeloma in patients treated with lenalidomide in combination with low dose dexamethasone
Grade 4 neutropenia was observed to a lesser extent in the lenalidomide in combination with low-dose dexamethasone treatment arms compared to the comparator arm (8.5% in Rd [continuous treatment] and Rd18 [treatment for 18 cycles of four weeks], compared with 15% in the melphalan / prednisone / thalidomide arm, see section 4.8). Episodes of grade 4 febrile neutropenia were consistent with the comparator arm (0.6% in patients treated with lenalidomide / dexamethasone Rd and Rd18, compared with 0.7% in patients in the melphalan / prednisone / thalidomide arm, see section 4.8 ). Patients should be advised to report febrile episodes immediately and dose reduction may be required (see section 4.2).
Grade 3 or 4 thrombocytopenia was observed to a lesser extent in the Rd and Rd18 arms than in the comparator arm (8.1% vs 11.1%, respectively). Patients and physicians should observe the signs and symptoms of bleeding, including petechiae and epistaxis, especially in patients undergoing concomitant treatment that could induce bleeding (see section 4.8, Bleeding disorders).
• Newly diagnosed multiple myeloma in patients treated with lenalidomide in combination with melphalan and prednisone
In clinical studies in patients with newly diagnosed multiple myeloma, the combination of lenalidomide with melphalan and prednisone is associated with a higher incidence of grade 4 neutropenia (34.1% in patients in the melphalan, prednisone and lenalidomide arm followed by lenalidomide [MPR + R] and melphalan, prednisone and lenalidomide followed by placebo [MPR + p], compared with 7.8% of patients treated with MPp + p; see section 4.8). Grade 4 febrile neutropenia episodes were observed not frequently (1.7% in patients treated with MPR + R / MPR + p, compared to 0.0% in patients treated with MPp + p; see section 4.8).
In patients with multiple myeloma, the combination of lenalidomide with melphalan and prednisone is associated with a higher incidence of grade 3 and grade 4 thrombocytopenia (40.4% in patients treated with MMR + R / MMR + p, compared to 13.7% in patients treated with MPp + p; see section 4.8) Patients and physicians should be alert for signs and symptoms of bleeding, including petechiae and epistaxis, especially in patients treated concomitantly with medicinal products that increase predisposition to bleeding (see section 4.8, Bleeding disorders).
• Multiple myeloma with at least one previous therapy
In patients with multiple myeloma receiving at least one prior therapy, the combination of lenalidomide and dexamethasone is associated with a higher incidence of grade 4 neutropenia (5.1% of patients treated with lenalidomide / dexamethasone compared to 0.6% of patients treated with placebo / dexamethasone; see section 4.8). Episodes of febrile neutropenia grade 4 were observed infrequently (in 0.6% of patients treated with lenalidomide / dexamethasone compared to 0.0% of patients treated with placebo / dexamethasone; see section 4.8) Patients should be advised to report febrile episodes immediately. Dose reduction may be necessary (see section 4.2). In case of neutropenia, physicians should consider using growth factors in patient management.
In patients with multiple myeloma, the combination of lenalidomide and dexamethasone is associated with a higher incidence of grade 3 and grade 4 thrombocytopenia (9.9% and 1.4%, respectively, the higher incidence of grade 3 thrombocytopenia). 3 and Grade 4 (9.9% and 1.4% of patients treated with lenalidomide / dexamethasone respectively compared to 2.3% and 0.0% of patients treated with placebo / dexamethasone; see section 4.8) Patients and physicians should monitor for signs and symptoms of bleeding, including petechiae and epistaxis, especially in patients concomitantly treated with medicinal products that may induce bleeding (see section 4.8, Bleeding disorders).
• Myelodysplastic syndromes
In patients with myelodysplastic syndromes, lenalidomide treatment is associated with a higher incidence of grade 3 and 4 neutropenia and thrombocytopenia than in placebo-treated patients (see section 4.8).
• Mantle cell lymphoma
In patients with mantle cell lymphoma, lenalidomide treatment is associated with a higher incidence of grade 3 and 4 neutropenia than in patients in the control arm (see section 4.8).
Infection with or without neutropenia
Multiple myeloma patients are prone to developing infections, including pneumonia. A higher rate of infections was observed during treatment with lenalidomide in combination with dexamethasone than with MPT. Grade ≥ 3 infections occurred in the context of neutropenia in less than one third of patients. Patients with known risk factors for infections should be monitored closely. All patients should be advised to consult their physician immediately at the first sign of infection (e.g. cough, fever, etc.), to allow for prompt intervention to reduce severity.
Kidney failure
Lenalidomide is substantially excreted via the kidneys. Therefore, in patients with renal insufficiency particular care should be taken in the choice of dose and monitoring of renal function is advisable (see section 4.2).
Disorders of the thyroid gland
Cases of hypothyroidism and hyperthyroidism have been observed. Before starting treatment, optimal control of comorbidities affecting thyroid function is recommended. It is recommended that thyroid function be monitored at baseline and during treatment.
Peripheral neuropathy
Lenalidomide is structurally related to thalidomide, which is known to cause 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.
Tumor Flare Reaction and Tumor Lysis Syndrome
Since lenalidomide exhibits anti-neoplastic activity, complications of tumor lysis syndrome (Tumor Lysis Syndrome, TLS). TLS and the Tumor Flare Reaction (TFR) were commonly observed in patients with chronic lymphocytic leukemia (CLL) and uncommonly observed in patients with lymphomas treated with lenalidomide. Cases of TLS with fatal outcome have been reported during treatment with lenalidomide. Patients at risk of TLS and TFR are those with high tumor burden before treatment. Caution should be exercised when initiating lenalidomide treatment in these patients. It is recommended that such patients be carefully monitored, especially during the first cycle or dose escalation, and that appropriate precautions be taken. There have been rare reports of TLS in patients with MM treated with lenalidomide, while no cases have been reported in patients with MDS treated with lenalidomide.
Tumor mass
• Mantle cell lymphoma
Lenalidomide is not recommended for the treatment of patients with high tumor burden if alternative treatment options are available.
Early death
In Study MCL-002 there was an overall evident increase in early deaths (within 20 weeks). Patients with high baseline tumor burden have a higher risk of early death: there were 16/81 (20%) early deaths in the lenalidomide arm and 2/28 (7%) early deaths in the control arm. By 52 weeks the corresponding figures were 32/81 (40%) and 6/28 (21%) (see section 5.1).
Adverse events
In Study MCL-002 during treatment cycle 1, 11/81 (14%) patients with high tumor burden were withdrawn from lenalidomide therapy, compared with 1/28 (4%) in the control group. The main reason for discontinuing treatment for patients with high tumor burden during treatment cycle 1 in the lenalidomide arm was due to adverse events, 7/11 (64%).
Patients with high tumor burden should therefore be carefully monitored for adverse reactions (see section 4.8), including any signs of Tumor Flare Reaction (TFR). For dose adjustments in case of TFR, see section 4.2.
An elevated tumor mass was defined as at least one lesion ≥ 5 cm in diameter or 3 lesions ≥ 3 cm.
Tumor Flare Reaction
• Mantle cell lymphoma
Careful monitoring and evaluation for TFR is recommended. Patients with elevated MIPI (Mantel Cell Lymphoma International Prognostic Index) at diagnosis or disease characterized by large tumor masses (at least one lesion that is ≥ 7 cm in the longest diameter) at baseline may be at risk for TFR. There Tumor Flare Reaction can simulate disease progression (PD). Patients in studies MCL-002 and MCL-001 who experienced grade 1 and 2 TFR were treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), and / or narcotic analgesics for the management of symptoms of TFR. The decision to adopt therapeutic measures for TFR must be made after a "careful clinical evaluation of the individual patient (see section 4.2).
Allergic reactions
Cases of allergic / hypersensitivity reactions have been reported in patients treated with lenalidomide (see section 4.8). It is recommended to carefully monitor patients who have had previous allergic reactions to thalidomide as a possible cross-reaction between lenalidomide and thalidomide has been reported in the literature.
Severe skin reactions
Cases of SSJ and NET have been reported. Treatment with lenalidomide should be discontinued in the event of an exfoliative or bullous rash, or if SSJ or NET is suspected, and should not be resumed after discontinuation due to these reactions. Interruption or discontinuation of lenalidomide should be considered for other forms of skin reactions depending on their severity. Patients with a previous history of severe rash associated with thalidomide treatment should not receive lenalidomide.
Lactose intolerance
Revlimid capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Unused capsules
Patients should be advised never to give this medicine to other people and to return unused capsules to the pharmacist at the end of treatment.
Second primary tumors
An increase in second primary tumors (Second Primary Malignancy, SPM) in myeloma patients previously treated with lenalidomide / dexamethasone (3.98 per 100 person-years) versus controls (1.38 per 100 person-years). Non-invasive SPMs consist of basal cell or squamous cell carcinomas.
Most invasive SPMs were solid tumors.
In clinical trials in newly diagnosed multiple myeloma patients ineligible for transplantation, a 4.9-fold increase in the incidence rate of haematological PMS (cases of AML, MDS) was observed in patients treated with lenalidomide in combination with melphalan and prednisone to progression (1.75 per 100 person-years), compared with melphalan in combination with prednisone (0.36 per 100 per person-years).
A 2.12-fold increase in the incidence rate of solid SPMs was observed in patients treated with lenalidomide (9 cycles) in combination with melphalan and prednisone (1.57 per 100 person-years), compared to melphalan in combination with prednisone (0.74 per 100 per person-years).
In patients treated with lenalidomide in combination with dexamethasone until progression or for 18 months, the incidence rate of haematological PMS (0.16 per 100 person-years) was not increased compared to thalidomide in combination with melphalan and prednisone (0.79 per 100 person-years).
A 1.3-fold increase in the incidence rate of solid PMS was observed in patients treated with lenalidomide in combination with dexamethasone until progression or for 18 months (1.58 per 100 person-years) compared to thalidomide in combination with melphalan and prednisone (1.19 per 100 person-years).
In clinical trials in newly diagnosed multiple myeloma patients eligible for transplantation, an increased incidence rate of haematological PMS has been observed in patients treated with lenalidomide immediately following high-dose melphalan and autologous stem cell transplantation (Autologous Stem Cell Transplant, ASCT), compared to placebo-treated patients (1.27 to 1.56 and 0.46 to 0.53 per 100 person-years, respectively). Cases of malignant B cell tumors (including Hodgkin's lymphoma) observed in clinical trials were in patients treated with lenalidomide in the post-ASCT setting.
The risk of haematological PMS should be considered before initiating treatment with Revlimid in combination with melphalan or in the period immediately following high-dose melphalan and ASCT. Physicians should carefully evaluate patients before and during treatment, using standard cancer screening for PMS, and institute treatment as directed.
Progression to acute myeloid leukemia (AML) in myelodysplastic syndrome (MDS) at risk low or intermediate-1
• Karyotype
Baseline variables including complex cytogenetic abnormalities are associated with progression to AML in transfusion-dependent subjects with isolated 5q deletion abnormality. In a combined analysis of two clinical studies conducted with Revlimid in low- or intermediate-1 risk MDS, subjects with complex cytogenetic abnormalities had the highest cumulative risk of progression to AML estimated at 2 years (38.6%). Estimated 2-year progression rate to AML in patients with isolated 5q deletion abnormality was 13.8%, compared with 17.3% for patients with isolated 5q deletion abnormality and one "additional cytogenetic abnormality.
Consequently, the benefit / risk balance of Revlimid is not known when MDS is associated with isolated 5q deletion abnormality and complex cytogenetic abnormalities.
• TP53 status
A TP53 mutation is present in 20-25% of MDS patients with low-risk 5q isolated deletion anomaly and is associated with a higher risk of progression to AML. In a "post-hoc analysis of a clinical study (MDS-004) conducted with Revlimid in low- or intermediate-1 risk MDS, the estimated 2-year progression rate to AML was 27.5% in patients with positive IHC-p53 (1% cut-off of strong nuclear staining, using immunohistochemical evaluation of p53 protein as surrogate for TP53 mutation status) and 3.6% in patients with IHC-p53 negative (p = 0.0038) (see section 4.8).
Progression to other malignancies in mantle cell lymphoma
In mantle cell lymphoma, AML, malignant B cell tumors, and non-melanoma skin cancer (NMSC) are potential risks.
Liver disorders
Cases of hepatic failure, including with fatal outcome, have been observed in patients treated with lenalidomide in combination therapy: 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, risk factors may be pre-existing viral liver disease, elevated baseline liver enzymes and possibly treatment with antibiotics.
Abnormalities in liver function tests were commonly observed and were generally asymptomatic and reversible on discontinuation of treatment. Once parameters have returned to baseline values, resumption of treatment at a lower dose may be considered.
Lenalidomide is excreted via the kidney. It is important to adjust the dose in patients with renal insufficiency in order to avoid reaching plasma levels which could increase the risk of more important haematological adverse reactions or hepatotoxicity. Monitoring of liver function is recommended, particularly in case of previous or concomitant viral liver infection or when lenalidomide is administered in combination with medicinal products known to be associated with hepatic dysfunction.
Patients with newly diagnosed multiple myeloma
There was a higher rate of intolerance (grade 3 or 4 adverse events, serious adverse events, treatment discontinuation) in patients aged> 75 years, ISS stage (International Staging System) III, performance status (PS) ≤ 2 assessed according to ECOG criteria (Eastern Cooperative Oncology Group) or CLcr
Cataract
Cataracts have been observed more frequently in patients treated with lenalidomide in combination with dexamethasone, particularly when used for a prolonged period. It is recommended to periodically monitor the visual ability.
04.5 Interactions with other medicinal products and other forms of interaction -
Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution in patients with multiple myeloma taking lenalidomide and dexamethasone (see sections 4.4 and 4.8). taking lenalidomide and dexamethasone (see sections 4.4 and 4.8).
Oral contraceptives
No interaction studies have been conducted with oral contraceptives. Lenalidomide is not an enzyme inducer. In a studio in vitro conducted with human hepatocytes, lenalidomide, tested at various concentrations, did not induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4 / 5. Therefore, if lenalidomide is administered alone, induction leading to reduced efficacy of medicinal products, including hormonal contraceptives, is not expected. However, dexamethasone is known to be a weak to moderate inducer of CYP3A4 and likely to affect other enzymes and transport proteins. It is not excluded that the efficacy of oral contraceptives may be reduced during treatment.
Effective measures must be taken to avoid pregnancy (see sections 4.4 and 4.6).
Warfarin
Concomitant administration of 10 mg repeated doses 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 effects on warfarin are unknown. Close monitoring of warfarin concentration is advised during treatment.
Digoxin
Concomitant administration of 10 mg / day of lenalidomide increased the plasma concentration of digoxin by 14% (0.5 mg, single dose) with a CI (confidence interval) of 90% [0.52% -28.2% ]. It is not known whether the effect would differ in the therapeutic situation (higher doses of lenalidomide and concomitant treatment with dexamethasone). Therefore, monitoring of digoxin concentration is recommended during treatment with lenalidomide.
Statins
When statins are administered with lenalidomide, there is an increased risk of rhabdomyolysis, which may simply be additive. Enhanced clinical and laboratory monitoring is warranted, particularly during the first weeks of treatment.
Dexamethasone
Coadministration of single or multiple doses of dexamethasone (40 mg / day) has no clinically relevant effect on the multiple dose pharmacokinetics of lenalidomide (25 mg / day).
Interactions with P-glycoprotein (P-gp) inhibitors
In vitro, Lenalidomide is a substrate of P-gp, but is not a P-gp inhibitor. Co-administration of multiple doses of the potent P-gp inhibitor, quinidine (600 mg, twice daily) or the moderate-acting P-gp inhibitor / substrate temsirolimus (25 mg), has no clinically relevant effect on Pharmacokinetics of lenalidomide (25 mg) Concomitant administration of lenalidomide does not alter the pharmacokinetics of temsirolimus.
04.6 Pregnancy and breastfeeding -
Women of childbearing potential / Contraception in men and women
Women of childbearing potential must use effective contraception. If pregnancy occurs during treatment with lenalidomide, therapy should be discontinued and the patient should go to a specialist or experienced in teratology who can assess the situation and give an opinion. If the partner of a male patient taking lenalidomide is pregnant, the partner should be advised to go to a specialist doctor or doctor with experience in teratology who can assess the situation and give an opinion.
During treatment, lenalidomide is present at extremely low levels in semen and is undetectable in the semen of healthy subjects 3 days after drug discontinuation (see section 5.2). As a precaution and taking into account special patient populations with a prolonged elimination time, such as patients with renal impairment, all male patients taking lenalidomide should use condoms for the entire duration of treatment, during dose suspension and up to one week after stopping therapy if your partner is pregnant or of childbearing potential and does not use any contraceptive methods.
Pregnancy
Lenalidomide is structurally related to thalidomide, an active substance with a known teratogenic effect in humans, which causes severe life-threatening birth defects.
Lenalidomide induced malformations in monkeys similar to those described for thalidomide (see section 5.3). Therefore, a teratogenic effect of lenalidomide is expected, and lenalidomide is contraindicated during pregnancy (see section 4.3).
Feeding time
As it is not known whether lenalidomide is excreted in human breast milk, it is recommended that breastfeeding be discontinued during lenalidomide therapy.
Fertility
A fertility study conducted in rats with doses of lenalidomide up to 500 mg / kg (approximately 200 to 500 times the doses of 25 mg and 10 mg, respectively, used in humans and calculated based on body surface area) , showed no adverse effects on fertility or maternal toxicity.
04.7 Effects on ability to drive and use machines -
Lenalidomide has a mild or moderate effect on the ability to drive and use machines. Fatigue, dizziness, somnolence, dizziness and blurred vision have been reported during treatment with lenalidomide. Caution is therefore recommended when driving vehicles or using machines.
04.8 Undesirable effects -
Summary of the safety profile
Newly diagnosed multiple myeloma in patients treated with lenalidomide in combination with low-dose dexamethasone
The most frequently observed (≥ 5%) serious adverse reactions with lenalidomide in combination with low dose dexamethasone (Rd and Rd18), compared to melphalan, prednisone and thalidomide (MPT), were:
• Pneumonia (9.8%)
• Renal failure (including acute) (6.3%)
Adverse reactions observed more frequently with Rd or Rd18 than with MPT were: diarrhea (45.5%), fatigue (32.8%), back pain (32.0%), asthenia (28.2%), insomnia (27.6%), rash (24.3%), decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%) and muscle spasms (20.5%) .
Newly diagnosed multiple myeloma patients treated with lenalidomide in combination with melphalan and prednisone
The most frequently observed serious adverse reactions (≥ 5%) with melphalan, prednisone and lenalidomide followed by maintenance therapy with lenalidomide (MPR + R) or melphalan, prednisone and lenalidomide followed by placebo (MPR + p), compared to melphalan, prednisone and placebo followed by placebo (MPp + p), were:
• Febrile neutropenia (6.0%)
• Anemia (5.3%)
The adverse reactions observed more frequently with MPR + R or MPR + p than with MPp + p were: neutropenia (83.3%), anemia (70.7%), thrombocytopenia (70.0%), leukopenia (38, 8%), constipation (34.0%), diarrhea (33.3%), rash (28.9%), pyrexia (27.0%), peripheral edema (25.0%), cough (24.0 %), decreased appetite (23.7%) and asthenia (22.0%).
Multiple myeloma with at least one previous therapy
In two Phase III placebo-controlled studies, 353 patients with multiple myeloma were exposed to combined lenalidomide / dexamethasone treatment and 351 to combined placebo / dexamethasone treatment.
The most serious adverse reactions observed more frequently with the lenalidomide / dexamethasone combination than with the placebo / dexamethasone combination were:
• Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see section 4.4)
• Grade 4 neutropenia (see section 4.4).
The adverse reactions that occurred more frequently with lenalidomide and dexamethasone, compared to placebo and dexamethasone, when combining multiple myeloma clinical trials (MM-009 and MM-010), were fatigue (43.9%), neutropenia, ( 42.2%), constipation (40.5%), diarrhea (38.5%), muscle cramps (33.4%), anemia (31.4%), thrombocytopenia (21.5%) and rash (21 ,2%).
Myelodysplastic syndromes
The overall safety profile of Revlimid in patients with myelodysplastic syndromes is based on data from a total of 286 patients included in a Phase II and a Phase III study (see section 5.1). In Phase II, all 148 patients were on lenalidomide treatment. In the Phase III study, 69 patients were treated with lenalidomide 5 mg, 69 patients were treated with lenalidomide 10 mg, and 67 patients received placebo during the double-blind phase of the study.
Most adverse reactions tended to occur during the first 16 weeks of lenalidomide therapy.
Serious adverse reactions include:
• Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see section 4.4)
• Grade 3 or 4 neutropenia, febrile neutropenia and grade 3 or 4 thrombocytopenia (see section 4.4).
The most commonly observed adverse reactions that occurred more frequently in the lenalidomide groups than in the control (placebo) arm in the Phase III study were neutropenia, (76.8%), thrombocytopenia (46.4%). , diarrhea (34.8%), constipation (19.6%), nausea (19.6%), itching (25.4%), rash (18.1%), fatigue (18.1%) and spasms muscle (16.7%).
Mantle cell lymphoma
The overall safety profile of Revlimid in patients with mantle cell lymphoma is based on data from 254 patients included in a randomized, controlled Phase II study, MCL-002 (see section 5.1).
In addition, the adverse drug reactions (ADRs) observed in the supporting study MCL-001 were included in Table 3.
The most frequently observed serious adverse reactions in Study MCL-002 (with a difference of at least 2 percentage points) in the lenalidomide arm versus the control arm were:
• Neutropenia (3.6%)
• Pulmonary embolism (3.6%)
• Diarrhea (3.6%)
The most commonly observed adverse reactions occurring more frequently in the lenalidomide arm than in the control arm in Study MCL-002 were neutropenia, (50.9%), anemia (28.7%), diarrhea (22 , 8%), fatigue (21.0%), constipation (17.4%), pyrexia (16.8%) and rash (including allergic dermatitis) (16.2%).
In Study MCL-002 there was an overall evident increase in early deaths (within 20 weeks). Patients with high baseline tumor burden have a higher risk of early death: 16/81 (20%) early deaths in the lenalidomide arm and 2/28 (7%) early deaths in the control arm. By 52 weeks the corresponding figures were 32/81 (39.5%) and 6/28 (21%) (see section 5.1).
During treatment cycle 1, 11/81 (14%) patients with high tumor burden were withdrawn from lenalidomide therapy, compared with 1/28 (4%) in the control group. The main reason for discontinuing treatment for patients with high tumor burden during treatment cycle 1 in the lenalidomide arm was due to adverse events, 7/11 (64%).
An elevated tumor mass was defined as at least one lesion ≥ 5 cm in diameter or 3 lesions ≥ 3 cm.
Summary list of adverse reactions
Summary table for combination therapy
Adverse reactions observed in patients treated for multiple myeloma are listed below by system organ class and frequency. Within each frequency class, adverse reactions are listed in order of decreasing severity. Frequencies are defined as follows: very common (≥ 1/10); common (≥ 1/100,
The following table was compiled based on data collected during multiple myeloma studies with combination therapy. The data were not updated taking into account the longer duration of treatment in the lenalidomide-containing arms continued until disease progression, compared to the comparator arms in the pivotal multiple myeloma studies (see section 5.1).
Adverse reactions were placed in the appropriate category in the table below, according to the highest incidence observed in any of the pivotal clinical studies.
Table 1: Adverse reactions reported in clinical trials in multiple myeloma patients treated with lenalidomide in combination with dexamethasone, or with melphalan and prednisone
^ See section 4.8 Description of selected adverse reactions
* Squamous cell skin cancer was observed in clinical trials in myeloma patients previously treated with lenalidomide / dexamethasone compared to controls
** Squamous cell skin cancer was observed in a clinical study in newly diagnosed myeloma patients with lenalidomide / dexamethasone compared to controls
Summary table for monotherapy
Adverse reactions observed in patients treated for myelodysplastic syndromes and mantle cell lymphoma are listed below by system organ class and frequency.
Within each frequency class, adverse reactions are listed in order of decreasing severity. Frequency is defined as: very common (≥ 1/10); common (≥ 1/100,
The following tables have been compiled based on data collected during the main studies in monotherapy for myelodysplastic syndromes and mantle cell lymphoma.
Adverse reactions were placed in the appropriate category in the following tables, according to the highest incidence observed in any of the pivotal clinical studies.
Table 2: Adverse reactions reported in clinical trials in patients with myelodysplastic syndromes treated with lenalidomide
^ See section 4.8 Description of selected adverse reactions
♦ Adverse events observed as serious in myelodysplastic syndromes clinical trials.
≈ Mood alteration was observed as a common serious adverse event in the Phase III myelodysplastic syndromes study; was not reported as a grade 3 or 4 adverse event.
Algorithm applied for SmPC entry: All adverse drug reactions (ADRs) captured by the Phase III study algorithm are included in the European SmPC. For these ADRs, an additional control of the frequency of ADRs acquired by the Phase II study algorithm was performed and, if the frequency of ADRs in the Phase II study was higher than that recorded in the Phase III study, the event is was included in the European CPR at the frequency observed in the Phase II study.
Algorithm applied for myelodysplastic syndromes:
• Phase III study in myelodysplastic syndromes (double-blind safety population, difference between lenalidomide 5/10 mg and placebo for initial dosing regimen with occurrence in at least 2 subjects))
o All adverse events occurring during treatment in ≥ 5% of subjects treated with lenalidomide and a difference of at least 2% in the percentage between lenalidomide and placebo
o All Grade 3 or 4 adverse events occurring during treatment in 1% of subjects treated with lenalidomide and a difference of at least 1% in the percentage between lenalidomide and placebo
o All serious adverse events occurring during treatment in 1% of subjects treated with lenalidomide and a difference of at least 1% in the percentage between lenalidomide and placebo
• Phase II study on myelodysplastic syndromes
o All adverse events occurring during treatment in ≥ 5% of subjects treated with lenalidomide o All grade 3 or 4 adverse events occurring during treatment in 1% of subjects treated with lenalidomide o All serious adverse events occurring during treatment in 1% of subjects treated with lenalidomide
Table 3: Adverse reactions reported in clinical trials in patients with mantle cell lymphoma treated with lenalidomide
^ See section 4.8 Description of selected adverse reactions
♦ Adverse events observed as serious in mantle cell lymphoma clinical trials.
Algorithm applied for mantle cell lymphoma:
• Phase II controlled study in mantle cell lymphoma
o All adverse events occurring during treatment in ≥ 5% of subjects in the lenalidomide arm and a difference of at least 2% in the percentage between lenalidomide and control arm
o All Grade 3 or 4 adverse events occurring during treatment in ≥ 1% of subjects in the lenalidomide arm and a difference of at least 1.0% in the percentage between lenalidomide and control arm
o All serious adverse events occurring during treatment in ≥ 1% of subjects in the lenalidomide arm and a difference of at least 1.0% in the percentage between lenalidomide and control arm
• Phase II single-arm study in mantle cell lymphoma
o All adverse events occurring during treatment in ≥ 5% of subjects
o All Grade 3 or 4 adverse events occurring during treatment reported in 2 or more subjects
Summary table of post-marketing adverse reactions
In addition to the aforementioned adverse reactions identified from the pivotal clinical studies, the following table has been compiled based on data collected from post-marketing.
Table 4: Adverse reactions reported in post-marketing use in patients treated with lenalidomide
^ See section 4.8 Description of selected adverse reactions
Description of selected adverse reactions
Teratogenicity
Lenalidomide is structurally related to thalidomide, an active substance with a known teratogenic effect in humans, which causes severe life-threatening birth defects. Lenalidomide induced malformations in monkeys similar to those described for thalidomide (see sections 4.6 and 5.3). a teratogenic effect of lenalidomide is expected in humans during pregnancy.
Neutropenia and thrombocytopenia
• Newly diagnosed multiple myeloma patients treated with lenalidomide in combination with low dose dexamethasone
In patients with newly diagnosed multiple myeloma, the combination of lenalidomide with low-dose dexamethasone is associated with a reduced incidence of grade 4 neutropenia (8.5% in Rd and Rd18, compared to 15% in MPT). Febrile neutropenia Grade 4 was observed infrequently (0.6%, compared with 0.7% in MPT).
In patients with newly diagnosed multiple myeloma, the combination of lenalidomide with low-dose dexamethasone is associated with a reduced incidence of grade 3 and 4 thrombocytopenia (8.1% in Rd and Rd18, compared to 11% in MPT).
• Newly diagnosed multiple myeloma patients treated with lenalidomide in combination with melphalan and prednisone
In patients with newly diagnosed multiple myeloma, the combination of lenalidomide with melphalan and prednisone is associated with a higher incidence of grade 4 neutropenia (34.1% in MMR + R / MPR + p, compared with 7.8% in MPp + p) A higher incidence of febrile grade 4 neutropenia was observed (1.7% in MPR + R / MPR + p, compared to 0.0% in MPp + p).
In patients with newly diagnosed multiple myeloma, the combination of lenalidomide with melphalan and prednisone is associated with a higher incidence of grade 3 and grade 4 thrombocytopenia (40.4% in patients treated with MMR + R / MMR + p , compared with 13.7% in patients treated with MPp + p).
• Multiple myeloma with at least one previous therapy
In patients with multiple myeloma, the combination of lenalidomide and dexamethasone is associated with a higher incidence of grade 4 neutropenia (5.1% of lenalidomide / dexamethasone treated patients versus 0.6% of placebo / dexamethasone treated patients Episodes of grade 4 febrile neutropenia were observed infrequently (in 0.6% of patients treated with lenalidomide / dexamethasone versus 0.0% of patients treated with placebo / dexamethasone).
In patients with multiple myeloma, the combination of lenalidomide and dexamethasone is associated with a higher incidence of grade 3 and grade 4 thrombocytopenia (in 9.9% and 1.4% of patients treated with lenalidomide / dexamethasone, respectively. compared with 2.3% and 0.0% of patients treated with placebo / dexamethasone).
• Myelodysplastic syndromes
In patients with myelodysplastic syndromes, lenalidomide is associated with a higher incidence of grade 3 or 4 neutropenia (74.6% of lenalidomide-treated patients versus 14.9% of placebo-treated patients in the Phase III study). Grade 3 or 4 febrile neutropenia episodes were observed in 2.2% of patients treated with lenalidomide compared to 0.0% of patients treated with placebo. Lenalidomide is associated with a higher incidence of grade 3 or 4 thrombocytopenia (37% in lenalidomide-treated patients versus 1.5% in placebo-treated patients in the Phase III study).
• Mantle cell lymphoma
In patients with mantle cell lymphoma, lenalidomide is associated with a higher incidence of grade 3 or 4 neutropenia (43.7% of patients treated with lenalidomide compared with 33.7% of patients in the control arm in the Phase III study). Grade 3 or 4 febrile neutropenia episodes were observed in 6.0% of patients treated with lenalidomide compared with 2.4% of patients in the control arm.
Venous thromboembolism
An increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) is associated with the use of lenalidomide and dexamethasone in patients with multiple myeloma and, to a lesser extent, in patients treated with melphalan and prednisone or as monotherapy in patients with syndromes. myelodysplastic and mantle cell lymphoma treated with lenalidomide (see section 4.5) In these patients, concomitant administration of erythropoietic agents or a previous history of DVT may also increase the risk of thrombosis.
Myocardial infarction
Cases of myocardial infarction have been observed in patients receiving lenalidomide, particularly in those with known risk factors.
Bleeding disorders
Bleeding disorders are listed under different classifications based on the organ involved: pathologies of the blood and lymphatic system; pathologies of the nervous system (intracranial haemorrhage); respiratory, thoracic and mediastinal pathologies (epistaxis); gastrointestinal pathologies (gingival bleeding, haemorrhoidal haemorrhage, rectal haemorrhage ); kidney and urinary pathologies (hematuria); trauma, poisoning and procedural complications (contusion); vascular pathologies (ecchymosis).
Allergic reactions
Cases of allergic / hypersensitivity reactions have been reported. A possible cross reaction between lenalidomide and thalidomide has been reported in the literature.
Severe skin reactions
Cases of SSJ and NTE have been reported. Patients with a previous history of severe rash associated with thalidomide treatment should not receive lenalidomide.
Second primary tumors
* In clinical trials in myeloma patients previously treated with lenalidomide / dexamethasone versus controls, consisting mainly of basal cell or squamous cell skin cancers.
Acute myeloid leukemia
• Multiple myeloma
In clinical trials in newly diagnosed multiple myeloma, cases of AML have been observed in patients treated with lenalidomide in combination with melphalan, or shortly after high dose melphalan and ASCT (see section 4.4). This increase was not observed in clinical trials in newly diagnosed multiple myeloma patients treated with lenalidomide in combination with low dose dexamethasone, compared to thalidomide in combination with melphalan and prednisone.
• Myelodysplastic syndromes
Baseline variables including complex cytogenetic abnormalities and TP53 mutation are associated with progression to AML in transfusion-dependent subjects with isolated 5q deletion abnormality (see section 4.4). The cumulative risk of progression to AML estimated at 2 years was 13.8% in patients with isolated 5q deletion abnormality, compared to 17.3% for patients with isolated 5q deletion abnormality and one "additional cytogenetic abnormality. , and 38.6% in patients with complex karyotype.
In a "post-hoc analysis of a clinical study conducted with Revlimid in myelodysplastic syndromes, the estimated 2-year progression rate to AML was 27.5% in IHC-p53-positive patients and 3.6% in IHC-p53-positive patients. IHC-p53-negative (p = 0.0038). In IHC-p53-positive patients, a lower rate of progression to AML was observed among those who achieved transfusion independence response (11.1%) , compared to non-responders (34.8%).
Liver disorders
The following post-marketing adverse reactions have been observed (frequency not known): acute hepatic failure and cholestasis (both life-threatening), toxic hepatitis, cytolytic hepatitis, mixed cytolytic / cholestatic hepatitis.
Rhabdomyolysis
Rare cases of rhabdomyolysis have been observed, some of them when lenalidomide was administered with a statin.
Disorders of the thyroid gland
Cases of hypothyroidism and hyperthyroidism have been observed (see section 4.4 Thyroid disorders).
Tumor Flare Reaction and Tumor Lysis Syndrome
In Study MCL-002, approximately 10% of patients treated with lenalidomide experienced TFR, compared with 0% in the control arm. Most events occurred in cycle 1, all were judged to be treatment related, and most reports were Grade 1 or 2. Patients with high MIPI at diagnosis and disease characterized by large tumor masses (at least one lesion that is ≥ 7 cm in longest diameter) at baseline may be at risk for TFR. In study MCL-002, TLS was reported for one patient in each of the two treatment arms. In the MCL-001 support study, approximately 10% of subjects experienced TFR; all reports were Grade 1 or 2 in severity and all were judged to be treatment related. Most events occurred in cycle 1. There were no reports of TLS in study MCL-001 (see section 4.4).
Gastrointestinal disorders
Gastrointestinal perforations, which may lead to septic complications and may be associated with a fatal outcome, have been observed during lenalidomide treatment.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. in "Annex V.
04.9 Overdose -
There is no specific experience in the management of lenalidomide overdose in patients, although in dose-setting studies some patients were exposed to doses up to 150 mg and, in single dose studies, some patients were exposed to doses up to 400. mg. In these studies, dose-limiting toxicity was essentially haematological in nature. In the event of an overdose, supportive therapy is recommended.
05.0 PHARMACOLOGICAL PROPERTIES -
05.1 "Pharmacodynamic properties -
Pharmacotherapeutic group: other immunosuppressants.
ATC code: L04 AX04.
Mechanism of action
The mechanism of action of lenalidomide includes anti-neoplastic, anti-angiogenic, pro-erythropoietic and immunomodulatory properties. Specifically, lenalidomide inhibits the proliferation of specific haematopoietic tumor cells (including cancer plasma cells of the MM and those with chromosome 5 deletion). , enhances cell-mediated immunity from T lymphocytes and natural killer (NK) cells and increases the number of NKT cells; inhibits angiogenesis by blocking the migration and adhesion of endothelial cells and the formation of microvessels; increases the production of fetal hemoglobin by CD34 + hematopoietic stem cells, and inhibits the production of proinflammatory cytokines (eg TNF-α and IL-6) by monocytes.
In MDS with isolated 5q deletion anomaly, lenalidomide has been shown to selectively inhibit the abnormal clone, increasing the apoptosis of Del (5q) cells.
Lenalidomide binds directly to cereblon, a component of a cullin-RING E3 ubiquitin ligase enzyme complex, which includes the deoxyribonucleic acid (DNA) damage binding protein 1 (DDB1,DNA Damage-Binding Protein-1), cullin 4 (CUL4) and culling regulator 1 (Roc1). In the presence of lenalidomide, cereblon binds to substrate proteins Aiolos and Ikaros, which are lymphoid transcription factors, causing their ubiquitination and subsequent degradation, with consequent cytotoxic and immunomodulatory effects.
Clinical efficacy and safety
Lenalidomide has been evaluated in two Phase III studies in newly diagnosed multiple myeloma and in two Phase III studies in relapsed refractory multiple myeloma, as described below.
Me And L or m a newly diagnosed multiple
Lenalidomide in combination with dexamethasone in patients not eligible for stem cell transplantation
The efficacy and safety of lenalidomide were evaluated in a multicentre, randomized, open-label, three-arm Phase III study (MM-020) in patients who were 65 years of age or older or, if aged under the age of 65, who were ineligible for stem cell transplantation due to patient decision or unavailability of stem cell transplantation for cost or other reasons. The study (MM-020) compared lenalidomide and dexamethasone (Rd) administered for 2 different treatment durations (eg until disease progression [Rd arm] or up to eighteen 28-day cycles [72 weeks, Rd18 arm]) with melphalan, prednisone and thalidomide (MPT) for up to twelve 42-day (72-week) cycles. Patients were randomized (1: 1: 1) to one of 3 treatment arms. At randomization, patients were stratified by age (≤ 75 years vs> 75 years), stage (ISS stages I and II vs stage III), and country.
Patients in the Rd and Rd18 arms received lenalidomide 25 mg once daily on Days 1 to 21 of 28-day cycles, according to the protocol arm. Dexamethasone 40 mg was administered once daily on Days 1, 8, 15, and 22 of each 28-day treatment cycle. The starting dose and regimen for Rd and Rd18 were adjusted for age and renal function (see section 4.2). Patients> 75 years old received a dexamethasone dose of 20 mg once daily on Days 1, 8, 15 and 22 of each 28-day treatment cycle All patients underwent anticoagulant prophylaxis (low molecular weight heparin, warfarin, heparin, low dose aspirin) during the study.
The primary efficacy endpoint in the study was progression-free survival (Progression Free Survival, PFS). In total, 1623 patients were enrolled in the study: 535 patients randomized to Rd, 541 patients randomized to Rd18, and 547 patients randomized to MPT. Patient demographic and disease-related characteristics at baseline were well balanced across all 3 arms.Overall, study subjects had advanced disease: of the total study population, 41% were in ISS stage III, 9% had severe renal impairment (creatinine clearance [CLcr]
In an updated analysis of PFS, PFS2, and overall survival (OS) using the cut-off date of March 3, 2014, where the median follow-up time for all surviving subjects was 45.5 months, the results of the study are presented in Table 5.
Table 5: Summary of overall efficacy data
AMT = anti-myeloma therapy; CI = confidence interval; CR = complete response; d = low dose dexamethasone; HR = hazard ratio; IMWG = International Myeloma Working Group; IRAC = Independent Response Adjudication Committee; M = melphalan; max = maximum; min = minimum; NS = not estimable; OS = overall survival; P = prednisone; PFS = progression-free survival; PR = partial response; R = lenalidomide; Rd = Rd administered until documented disease progression; Rd18 = Rd administered for ≥ 18 cycles; SE = standard error; T = thalidomide; VGPR = optimal partial response; vs = versus.
a The median is based on the Kaplan-Meier estimate.
b 95% CI about the median.
c Based on the Cox proportional hazards model comparing the hazard functions associated with the indicated treatment arms.
d The p-value is based on the unstratified log rank test of the differences in Kaplan-Meier curves between the indicated treatment arms.
e Exploratory endpoint (PFS2)
f The median is the univariate statistic with no truncation correction.
g Improved assessment of the adjudicated response during the treatment phase of the study (for the definitions of each response category Data cut-off date = 24 May 2013).
h Cut-off date = 24 May 2013
Lenalidomide in combination with melphalan and prednisone, followed by maintenance monotherapy, in patients not eligible for transplantation
The safety and efficacy of lenalidomide (MPR) were evaluated in a multicentre, randomized, double-blind, 3-arm Phase III study (MM-015) in patients 65 years of age and older and with serum creatinine. 75 years) and stage (ISS stages I and II vs stage III).
This study examined the use of MMR combination therapy (melphalan 0.18 mg / kg orally on days 1-4 of repeated 28-day cycles; prednisone 2 mg / kg orally on days 1-4 of repeated 28-day cycles; and lenalidomide 10 mg / day orally on days 1-21 of repeated 28-day cycles), for induction therapy, up to a maximum of 9 cycles. Patients who had completed 9 cycles, or who were unable to complete the 9 cycles due to intolerance, switched to maintenance monotherapy, started with lenalidomide 10 mg orally on days 1-21 of repeated 28-day cycles, until disease progression
The primary efficacy endpoint in the study was progression-free survival (PFS). In total, 459 patients were enrolled in the study: 152 patients randomized to MMR + R, 153 patients randomized to MMR + p and 154 patients randomized to MPp + p. Patient demographic and disease-related characteristics at baseline were well balanced in all 3 arms; in particular, approximately 50% of patients enrolled in each arm had the following characteristics: ISS stage III and creatinine clearance
In an "analysis of PFS, PFS2 and OS using the cut-off date of April 2013, for which the median follow-up time for all surviving subjects was 62.4 months, the study results are presented in Table 6. .
Table 6: Summary of overall efficacy data
CI = confidence interval; CR = complete response; HR = hazard ratio; M = melphalan; NS = not estimable; OS = overall survival; p = placebo; P = prednisone;
PD = progressive disease; PR = partial response; R = lenalidomide; SD = stable disease; VGPR = optimal partial response.
a The median is based on the Kaplan-Meier estimate.
¤ PFS2 (an exploratory endpoint) was defined for all patients (ITT) as the time from randomization to initiation of third-line anti-myeloma therapy or death from any cause, for all randomized patients
Supportive studies in newly diagnosed multiple myeloma
An open-label, randomized, multicenter Phase III study (ECOG E4A03) was conducted in 445 patients with newly diagnosed multiple myeloma; 222 patients were randomized to the lenalidomide / low dose dexamethasone arm and 223 were randomized to the lenalidomide / standard dose dexamethasone arm. Patients randomized to the lenalidomide / standard dose dexamethasone arm received lenalidomide 25 mg / day on days 1 to 21, every 28 days, plus dexamethasone 40 mg / day on days 1 to 4, 9 to 12 and 17 at 20, every 28 days, for the first four cycles. Patients randomized to the lenalidomide / low-dose dexamethasone arm received lenalidomide 25 mg / day on days 1 to 21, every 28 days, plus low-dose dexamethasone 40 mg / day on days 1, 8, 15, and 22, each 28 days. In the lenalidomide / low dose dexamethasone group, 20 patients (9.1%) experienced at least one dose interruption compared with 65 patients (29.3%) in the lenalidomide / standard dose dexamethasone arm.
In a post-hoc analysis, the lowest mortality was observed in the lenalidomide / low dose dexamethasone arm 6.8% (15/220), compared to the lenalidomide / standard dose dexamethasone arm 19.3% (43/223 ), in the newly diagnosed multiple myeloma patient population, with a median follow-up of 72.3 weeks.
However, with extended follow-up, the difference in overall survival in favor of low-dose lenalidomide / dexamethasone tends to decrease.
Multiple myeloma with at least one previous therapy
The efficacy and safety of lenalidomide were evaluated in two Phase III multicentre, randomized, double-blind, placebo-controlled, parallel group (MM-009 and MM-010) studies of lenalidomide in combination with dexamethasone versus Dexamethasone monotherapy in previously treated patients with multiple myeloma. Of the 353 patients included in studies MM-009 and MM-010 treated with lenalidomide / dexamethasone, 45.6% were 65 years of age or older. Of the 704 patients evaluated in studies MM-009 and MM-010, 44.6% were 65 years of age or older.
In both studies, patients in the lenalidomide / dexamethasone (len / des) group received lenalidomide 25 mg orally once daily on days 1 to 21 and an identical looking placebo capsule once daily. days 22 to 28 of each 28-day cycle Patients in the placebo / dexamethasone (placebo / des) group took 1 capsule of placebo on days 1 to 28 of each 28-day cycle. Patients in both 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. After the first 4 courses of therapy, the dexamethasone dose was reduced to 40 mg orally once daily on days 1 to 4 of each 28-day cycle. In both studies, treatment was to continue until to disease progression Dosage adjustments were allowed in both studies based on clinical and laboratory findings.
The primary efficacy endpoint in both studies was time to disease progression (TTP, time to progression). A total of 353 patients were evaluated in study MM-009: 177 in the lenalidomide / dexamethasone group and 176 in the placebo / dexamethasone group. A total of 351 patients were evaluated in study MM-010: 176 in the lenalidomide / dexamethasone group and 175 in the placebo / dexamethasone group.
In both studies, the lenalidomide / dexamethasone and placebo / dexamethasone groups had comparable initial demographic and disease-related characteristics. Both patient populations had a median age of 63 years, with a comparable ratio between male and female patients.Eastern Cooperative Oncology Group), both the number and type of previous therapies were comparable in both groups.
Analyzes interim pre-scheduled for both studies showed that the lenalidomide / dexamethasone combination therapy showed a statistically significant improvement (p
An extended follow-up efficacy analysis was conducted for a median of 130.7 weeks. Table 7 shows the results of the follow-up efficacy analyzes - joint studies MM-009 and MM-010.
In this pooled extended follow-up analysis, the median TTP was 60.1 weeks (95% CI: 44.3, 73.1) in patients treated with lenalidomide / dexamethasone (N = 353) compared to the median of 20 , 1 week (95% CI: 17.7, 20.3) in patients treated with placebo / dexamethasone (N = 351). Median progression-free survival was 48.1 weeks (95% CI: 36.4, 62.1) in patients treated with lenalidomide / dexamethasone compared with a median time of 20.0 weeks (95% CI: 16, 1, 20.1) in patients treated with placebo / dexamethasone. Median duration of treatment was 44.0 weeks (min: 0.1, max: 254.9) for lenalidomide / dexamethasone and 23.1 weeks (min: 0.3, max: 238.1) for placebo / dexamethasone. In both studies, the complete response rates (CR, complete response), partial response (PR, partial response) and overall response (CR + PR) in the lenalidomide / dexamethasone group remained significantly higher than in the dexamethasone / placebo group. Median overall survival in the extended follow-up analysis of the joint studies is 164.3 weeks (95% CI: 145.1, 192.6) in patients treated with lenalidomide / dexamethasone compared with 136.4 weeks (95% CI: 113.1, 161.7) in patients treated with placebo / dexamethasone. Despite the fact that 170 of the 351 patients randomized to placebo / dexamethasone treatment received lenalidomide therapy after disease progression or after blindness, the pooled overall survival analysis demonstrated a statistically significant survival advantage for the lenalidomide / dexamethasone group compared to the placebo / dexamethasone group (hazard ratio = 0.833, 95% CI = [0.687, 1.009], p = 0.045).
Table 7: Summary of the results of the efficacy analyzes at the cut-off date for extended follow-up - Joint studies MM-009 and MM-010 (respective cut-off dates: 23 July 2008 and 2 March 2008)
a: Two-sided univariate analysis comparing survival curves between treatment groups. b: Two-tailed chi-square test with continuity correction.
Myelodysplastic syndromes
The efficacy and safety of lenalidomide were evaluated in patients with transfusion-dependent anemia due to low or intermediate-1 risk myelodysplastic syndromes associated with 5q deletion cytogenetic abnormality, with or without other cytogenetic abnormalities, in two main studies. : a Phase III, multicenter, randomized, double-blind, placebo-controlled, 3-arm, two-dose oral lenalidomide (10 mg and 5 mg) versus placebo study (MDS-004); and a Phase II, multicentre, single arm, open label, on lenalidomide (10 mg) (MDS-003).
The results below represent the intent-to-treat population studied in MDS-003 and MDS-004; results for the subpopulation with isolated 5q deletion are shown separately (see section 4.1 for the approved indication).
In study MDS-004, in which 205 patients were equally randomized to treatment with lenalidomide 10 mg, 5 mg or placebo, the primary efficacy analysis consisted of comparing transfusion independence response rates in the lenalidomide 10 mg arms. and 5 mg, compared to the placebo arm (double-blind phase from 16 to 52 weeks and open-label phase up to a total of 156 weeks). In patients who did not show at least a mild erythroid response after 16 weeks, treatment was stopped. patients who had evidence of at least a mild erythroid response could continue therapy until erythroid recurrence, disease progression, or unacceptable toxicity. after 16 weeks of treatment they were allowed to switch from placebo to 5 mg of lenalidomide or continue on treatment with lenalidomide at a higher dose (5 mg to 10 mg).
In study MDS-003, in which 148 patients were treated with lenalidomide at a dose of 10 mg, the primary efficacy analysis consisted of an evaluation of the efficacy of lenalidomide treatments in achieving hematopoietic improvement in subjects with myelodysplastic syndromes. low or intermediate risk-1.
Table 8: Summary of efficacy results - MDS-004 (double-blind phase) and MDS-003, intent-to-treat population
† Subjects treated with lenalidomide 10 mg on 21 of the 28-day cycle
†† Subjects treated with lenalidomide 5 mg on 28 of the 28-day cycle
* Most patients in the placebo group discontinued double-blind treatment due to lack of efficacy after 16 weeks of treatment, before entering the open-label phase
#Associated with an increase in Hgb of ≥ 1 g / dL
∞ Not reached (median was not reached)
In study MDS-004, a significantly higher proportion of patients with myelodysplastic syndromes achieved the primary endpoint of transfusion independence (> 182 days) with lenalidomide 10 mg, compared to placebo (55.1% vs. 6.0%) Among the 47 patients with cytogenetic abnormality.
Del (5q) isolated and treated with 10 mg lenalidomide, 27 patients (57.4%) achieved independence from erythrocyte transfusions.
The median time to transfusion independence in the lenalidomide 10 mg arm was 4.6 weeks. The median duration of transfusion independence was not achieved in any of the treatment arms, but is expected to exceed 2 years for treated subjects. with lenalidomide. The median increase in hemoglobin (Hgb) from baseline in the 10 mg arm was 6.4 g / dL.
Additional study endpoints included cytogenetic response (major and minor cytogenetic responses in the 10 mg arm were observed in 30.0% and 24.0% of subjects, respectively), health-related quality of life (HRQoL) assessment. and progression to acute myeloid leukemia. The results of cytogenetic response and HRQoL were consistent with the results of the primary endpoint and in favor of treatment with lenalidomide over placebo.
In study MDS-003, a high percentage of patients with myelodysplastic syndromes achieved transfusion independence (> 182 days) with lenalidomide 10 mg (58.1%). The median time to transfusion independence was 4.1 weeks. The median duration of transfusion independence was 114.4 weeks. The median increase in hemoglobin (Hgb) was 5.6 g / dl .
Major and minor cytogenetic responses were observed in 40.9% and 30.7% of subjects, respectively.
A large percentage of subjects enrolled in MDS-003 (72.9%) and MDS-004 (52.7%) had previously been treated with erythropoiesis-stimulating agents.
Mantle cell lymphoma
The efficacy and safety of lenalidomide in patients with mantle cell lymphoma were evaluated in a Phase II, multicentre, randomized, open label study versus investigator's choice of monotherapy in patients who were refractory to the last regimen or who had presented from one to three relapses (Study MCL-002).
Patients at least 18 years of age with histologically confirmed mantle cell lymphoma and measurable disease on CT were enrolled. Patients had to have received adequate prior treatment with at least one prior combination chemotherapy regimen. In addition, patients had to be ineligible for intensive chemotherapy and / or transplant at the time of study inclusion. Patients were randomized 2: 1 to lenalidomide or the control arm. Investigator's choice of treatment was decided earlier. of randomization and consisted of monotherapy with chlorambucil, cytarabine, rituximab, fludarabine or gemcitabine.
Lenalidomide was administered orally, at a dose of 25 mg once daily for the first 21 days (G1 to G21) of repeated 28-day cycles until progression or unacceptable toxicity. Patients with moderate renal impairment were to receive a lower starting dose of lenalidomide (10 mg per day) with the same schedule.
Baseline demographics were comparable between the lenalidomide and control arms. Both patient populations had a median age of 68.5 years, with a comparable ratio of male to female patients. Both ECOG performance status and number of prior therapies were comparable in both groups.
The primary efficacy endpoint in MCL-002 was progression-free survival (PFS).
Efficacy results for the Intent-to-Treat (ITT) population were evaluated by the Independent Review Commission (Independent Review Committee, IRC) and are presented in the table below.
Table 9: Summary of efficacy results - MCL-002 study, intent-to-treat population
CI = confidence interval; CRR = complete response rate; CR = complete response; CRu = complete response not confirmed; DMC = data monitoring committee; ITT = intent-to-treat; HR = hazard ratio; KM = Kaplan-Meier; MIPI = Mantle Cell Lymphoma International Prognostic Index; NP = not relevant; ORR = overall response rate; PD = progressive disease; PFS = progression-free survival; PR = partial response; SCT = stem cell transplant; SD = stable disease; SE = standard error.
a The median is based on the KM estimate.
b The range was calculated as 95% CI with respect to the median survival time.
e The mean and median are the univariate statistics with no truncation correction.
d Stratification variables included time from diagnosis to first dose (
e Sequential testing was based on a weighted average of the log rank test statistic, using the unstratified log rank test for sample size increase and the unstratified log rank test from the primary analysis. The weights are based on the events observed at the date of the third meeting of the RCD and are based on the difference between the events observed and the events expected at the time of the primary analysis.
The associated sequential HR and the corresponding 95% CI are presented.
In study MCL-002 in the ITT population, there was an overall evident increase in deaths within 20 weeks in the lenalidomide arm, 22/170 (13%), compared with 6/84 (7%) in the control arm. In patients with high tumor burden, the corresponding figures were 16/81 (20%) and 2/28 (7%) (see section 4.4).
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Revlimid in all subsets of the pediatric population for multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma (see section 4.2 for information on " pediatric use).
05.2 "Pharmacokinetic properties -
Lenalidomide has an asymmetric carbon atom; therefore its molecule exists in the optically active forms S (-) and R (+). Lenalidomide is produced as a racemic mixture. Lenalidomide is generally more soluble in organic solvents, but exhibits the highest solubility in 0.1N HCl solution.
Absorption
Lenalidomide is rapidly absorbed after oral administration in healthy volunteers, under fasted conditions, reaching maximum plasma concentrations between 0.5 and 2 hours after dosing. In both patients and healthy volunteers the maximum concentration (Cmax) and l " area under the concentration-time curve (AUC) increase proportionally with increasing dose. Repeated doses do not cause significant drug accumulation. In plasma, the relative concentration of the S- and R- enantiomers of lenalidomide is approximately 56% and 44%, respectively.
Co-administration of a high-calorie, high-fat meal in healthy volunteers reduces the extent of absorption, resulting in an approximately 20% decrease in the area below the AUC and a 50% decrease in plasma Cmax. However, in the pivotal multiple myeloma and myelodysplastic syndromes registration studies where the safety and efficacy of lenalidomide were established, the medicine was administered without consideration of food intake. Therefore, lenalidomide can be administered with or without food.
Population pharmacokinetic analyzes indicate that the absorption rate of oral lenalidomide is similar among patients with multiple myeloma, patients with myelodysplastic syndromes and patients with mantle cell lymphoma.
Distribution
In vitro, 14C-labeled lenalidomide is poorly bound to plasma proteins, with a mean value of 23% and 29%, respectively, in patients with multiple myeloma and healthy volunteers.
Lenalidomide is present in semen (
Biotransformation and elimination
The results of human metabolism studies conducted in vitro indicate that lenalidomide is not metabolised by cytochrome P450 enzymes, suggesting that administration of lenalidomide together with medicinal products that inhibit cytochrome P450 enzymes is unlikely to produce metabolic drug interactions in humans. in vitro indicate that lenalidomide has no inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A or UGT1A1. Therefore, lenalidomide is unlikely to cause clinically relevant drug interactions when administered concomitantly with substrates of these enzymes.
Education in vitro indicate that lenalidomide is not a substrate of human breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2 or MRP3, organic anion transporters (OAT) OAT1 and OAT3, polypeptide organic anion transporter (OATP) OATP1B1, organic cation transporter (OCT) OCT1 and OCT2, drug and toxin extrusion protein (MATE) MATE1 and new organic cation transporter (OCTN) OCTN1 and OCTN2.
Education in vitro indicate that lenalidomide has no inhibitory effect on the human bile salt export pump (BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3 and OCT2.
Most of lenalidomide is eliminated by urinary excretion. The contribution of renal excretion to total clearance in subjects with normal renal function was 90%, while 4% of lenalidomide was eliminated in faeces.
Lenalidomide is poorly metabolised, so 82% of the dose is excreted unchanged in the urine. Hydroxy-lenalidomide and N-acetyl-lenalidomide account for 4.59% and 1.83% of the excreted dose, respectively. Renal clearance of lenalidomide exceeds the glomerular filtration rate, therefore at least to some extent it is actively secreted.
At doses of 5 to 25 mg / day, the plasma half-life is approximately 3 hours in healthy volunteers and ranges from 3 to 5 hours in patients with multiple myeloma, myelodysplastic syndromes or mantle cell lymphoma.
Elderly patients
No specific clinical studies have been conducted to evaluate the pharmacokinetics of lenalidomide in elderly patients. Population pharmacokinetic analyzes included patients aged 39 to 85 years and indicated that age does not affect the clearance (plasma concentration) of lenalidomide. As elderly patients are more likely to have decreased renal function, it is recommended that Caution should be exercised in dose selection and monitoring of renal function is advised as a precaution.
Kidney failure
The pharmacokinetics of lenalidomide were studied in subjects with renal insufficiency caused by non-malignant diseases. In this study, two methods were used for the classification of renal function: urinary creatinine clearance measured over 24 hours and creatinine clearance estimated with the Cockcroft-Gault formula. The results indicate that, as renal function decreases ( half-life of lenalidomide increased from approximately 3.5 hours in subjects with creatinine clearance> 50 ml / min to more than 9 hours in subjects with impaired renal function
Hepatic insufficiency
The population pharmacokinetic analyzes included patients with mild hepatic insufficiency (N = 16, total bilirubin> 1 to ≤ 1.5 x ULN (Upper Limit of Normal) or AST> ULN) and indicate that "mild hepatic insufficiency does not affect clearance (plasma concentration) of lenalidomide No data are available in patients with moderate to severe hepatic impairment.
Other intrinsic factors
Population pharmacokinetic analyzes indicate that body weight (33-135 kg), gender, race and type of haematological malignancy (MM, MDS or MCL) have no clinically relevant effect on lenalidomide clearance in adult patients.
05.3 Preclinical safety data -
An embryo-fetal development study was conducted in monkeys treated with lenalidomide at doses ranging from 0.5 to 4 mg / kg / day. The results of this study indicated that lenalidomide causes external malformations including non-patent anal orifice and malformations of the upper and lower extremities (parts of the extremities that are curved, shortened, malformed, malrotated and / or absent, oligo and / or polydactyly) in the offspring. of female monkeys who received the drug during gestation.
Different visceral effects have also been observed in individual fetuses (discolouration, red foci in various organs, small colorless mass above the atrioventricular valve, small gallbladder, malformed diaphragm).
Lenalidomide shows a potential risk of acute toxicity; in rodents, minimal lethal doses following oral administration were> 2,000 mg / kg / day. Repeated oral administration of 75, 150 and 300 mg / kg / day for up to 26 weeks resulted in a reversible treatment-related increase in renal pelvic mineralization in rats, mainly females, at all dose levels. The level of no observable adverse effects (NOAEL, no observed adverse effect level) was considered to be less than 75 mg / kg / day, and is approximately 25 times greater than the daily human exposure based on AUC values. In monkeys, repeated oral administration of 4 and 6 mg / kg / day for periods up to 20 weeks produced significant mortality and toxicity (marked weight loss, reduced white blood cell, red blood cell and platelet counts, haemorrhages in several organs, inflammation of the gastrointestinal tract, atrophy of the lymphatic tissue and bone marrow). Also in monkeys, repeated oral administration of 1 and 2 mg / kg / day, for periods up to 1 year, produced reversible changes in bone marrow cellularity, a slight reduction in the myelo-erythroid cell ratio and thymic atrophy. A slight decrease in white blood cell count was observed to 1 mg / kg / day, which corresponds to approximately the same dose in humans, based on AUC comparison.
Mutagenicity studies conducted in vitro (bacterial mutation, human lymphocytes, murine lymphoma, transformation into Syrian hamster embryonic cells) and in vivo (rat micronucleus test) did not reveal any drug-related effects either at the gene level or at the chromosome level. Carcinogenicity studies have not been conducted with lenalidomide.
Developmental toxicity has previously been studied in rabbits. In these studies, rabbits were given orally 3, 10 and 20 mg / kg / day of lenalidomide. The absence of the intermediate lobe of the lung was observed at the dose of 10 and 20 mg / kg / day, with a correlation with the dose, and ectopic kidney at the dose of 20 mg / kg / day. Although these conditions were observed at a dose of 20 mg / kg / day. dosages toxic to the mother, they may be attributable to a direct effect At doses of 10 and 20 mg / kg / day, changes in soft tissue and skeleton have also been observed in fetuses.
06.0 PHARMACEUTICAL INFORMATION -
06.1 Excipients -
Capsule contents
Anhydrous lactose
Microcrystalline cellulose
Croscarmellose sodium
Magnesium stearate
Capsule shell
Jelly
Titanium dioxide (E171)
Indigo carmine (E132)
Yellow iron oxide (E172)
Ink of the wording
Shellac
Propylene glycol
Black iron oxide (E172)
Potassium hydroxide
06.2 Incompatibility "-
Not relevant.
06.3 Period of validity "-
3 years.
06.4 Special precautions for storage -
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package -
Polyvinyl chloride (PVC) / polychlorotrifluoroethylene (PCTFE) / aluminum foil blister containing 7 hard capsules.
Pack of 21 capsules.
06.6 Instructions for use and handling -
Unused medicine and wastes derived from this medicine must be disposed of in accordance with local regulations.
07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -
Celgene Europe Limited
1 Longwalk Road
Stockley Park
Uxbridge
UB11 1DB
UK
08.0 MARKETING AUTHORIZATION NUMBER -
EU / 1/07/391/002
038016022
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -
Date of first authorization: 14 June 2007
Date of most recent renewal: June 14, 2012
10.0 DATE OF REVISION OF THE TEXT -
D.CCE September 2016
11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY -
12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL -
