Lenalidomide

Lenalidomide comes as a capsule to take by mouth. When lenalidomide is used to treat myelodysplastic syndrome, it is usually taken with or without food once daily. When lenalidomide is used to treat multiple myeloma or mantle cell lymphoma, it is usually taken with or without food once daily for the first 21 days of a 28-day cycle. When lenalidomide is used to treat multiple myeloma after HSCT, it is usually taken with or without food once daily for 28 days of a 28-day cycle. The 28-day cycle regimen may be repeated as recommended by your doctor based on your body's response to this medication. Take lenalidomide at around the same time of day every day that you take it. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take lenalidomide exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the capsules whole with plenty of water; do not break, chew, or open them. Handle the capsules as little as possible. If you touch a broken lenalidomide capsule or the medicine in the capsule, wash that area of your body with soap and water. If the medicine in the capsule gets into your mouth, nose, or eyes, wash it away with plenty of water.

Your doctor may need to interrupt your treatment or reduce your dose if you experience certain side effects. Be sure to tell your doctor how you are feeling during your treatment with lenalidomide.

If it has been less than 12 hours since you were scheduled to take the dose, take the missed dose as soon as you remember it. If it has been more than 12 hours, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Return any medication that is outdated or no longer needed to your doctor, the pharmacy that gave you the medication, or the manufacturer.

It is important to keep all medication out of sight and reach of children as many containers (such as weekly pill minders and those for eye drops, creams, patches, and inhalers) are not child-resistant and young children can open them easily. To protect young children from poisoning, always lock safety caps and immediately place the medication in a safe location – one that is up and away and out of their sight and reach. http://www.upandaway.org

>10%

Thrombocytopenia (62%)

Neutropenia (59%)

Diarrhea (48%)

Pruritus (42%)

Nausea (35%)

Rash (35%)

Fatigue (31%)

Constipation (24%)

Arthralgia (22%)

Back pain (21%)

Peripheral edema (21%)

Pyrexia (21%)

Dizziness (20%)

Headache (20%)

Cough (19%)

Muscle cramp (18%)

Dyspnea (17%)

URTI (15%)

Anemia (12%)

Pneumonia (12%)

UTI (11%)

1-10% (critical AEs)

Tumor flare reaction - MCL (10%)

Abdominal pain (8%)

Leukopenia (8%)

Myalgia (8%)

Pain (7%)

Bronchitis (6%)

Rhinitis (6%)

Febrile neutropenia (5%)

Peripheral neuropathy (5%)

Postmarketing Reports

Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS)

Immune system disorders: Angioedema, acute graft-versus-host disease (following allogeneic hematopoietic transplant)

Neoplasms benign, malignant and unspecified (including cysts and polyps): Tumor lysis syndrome, tumor flare reaction

Respiratory, thoracic and mediastinal disorders: Pneumonitis

Hepatobiliary disorders: Hepatic failure (including fatality), toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, mixed cytolytic/cholestatic hepatitis, transient abnormal liver laboratory tests

Infections and infestations: Viral reactivation (such as hepatitis B virus and herpes zoster)

Cardiac disorder: Cardiac failure

Ear and labyrinth disorders: Vertigo

Infections and infestations: Respiratory tract infection, sinusitis, nasopharyngitis, oral herpes

Nervous system disorders: Dysgeusia, headache, neuropathy peripheral, lethargy

Psychiatric disorders: Insomnia

Blood and lymphatic system disorders: Neutropenia

Cardiac Disorder: Myocardial infarction (including acute MI), supraventricular tachycardia

Respiratory, thoracic, and mediastinal disorders: Chronic obstructive pulmonary disease, pulmonary embolism

Endocrine disorders: Hypothyroidism, hyperthyroidism

Pregnancy

Contraindicated during pregnancy (see Contraindications and Black Box Warnings)

Based on the mechanism of action and findings from animal studies, lenalidomide can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy

Thalidomide analogue; thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), bone hypoplasticity, absence of bones, external ear abnormalities (including anotia, microtia, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects

Mortality at or shortly after birth has been reported in ~40% of infants

Contraception

• Females
  • Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control simultaneously: one highly effective form of contraception (eg, tubal ligation, IUD, hormonal [birth control pills, injections, hormonal patches, vaginal rings, or implants]), or partner’s vasectomy, and 1 additional effective contraceptive method (eg, male latex or synthetic condom, diaphragm, or cervical cap)
  • Contraception must begin 4 weeks prior to initiating treatment, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of therapy
  • Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy
  • Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed
• Males
  • Present in the semen of males; therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking lenalidomide and for up to 4 weeks after discontinuing, even if they have undergone a successful vasectomy
  • Male patients taking lenalidomide must not donate sperm

Pregnancy registry

• There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to lenalidomide during pregnancy as well as female partners of male patients who are exposed
• This registry is also used to understand the root cause for the pregnancy
• Report any suspected fetal exposure to lenalidomide to the FDA via the MedWatch program at 1-800-FDA-1088 and also to the manufacturer at 1-888-423-5436

Lactation

Unknown if distributed into human breast milk

Because of the potential for adverse reactions in breastfed infants from lenalidomide, advise women not to breastfeed during treatment

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

REVLIMID®
(rev-li-mid)
(lenalidomide) Capsules

What is the most important information I should know about REVLIMID?

Before you begin taking REVLIMID, you must read and agree to all of the instructions in the REVLIMID REMS® program. Before prescribing REVLIMID, your healthcare provider will explain the REVLIMIDREMS program to you and have you sign the Patient-Physician Agreement Form.

REVLIMID may cause serious side effects including:

• Possible birth defects (deformed babies) or death of an unborn baby. Females who are pregnant or who plan to become pregnant must not take REVLIMID.

REVLIMID is similar to the medicine thalidomide. We know thalidomide can cause severe lifethreatening birth defects. REVLIMID has not been tested in pregnant females. REVLIMID has harmed unborn animals in animal testing.

Females must not get pregnant:

• For at least 4 weeks before starting REVLIMID
• While taking REVLIMID
• During any breaks (interruptions) in your treatment with REVLIMID
• For at least 4 weeks after stopping REVLIMID

Females who can become pregnant:

• Will have pregnancy tests weekly for 4 weeks, then every 4 weeks if your menstrual cycle is regular, or every 2 weeks if your menstrual cycle is irregular.
• If you miss your period or have unusual bleeding, you will need to have a pregnancy test and receive counseling.
• Must agree to use two acceptable forms of birth control at the same time, for at least 4 weeks before, while taking, during any breaks (interruptions) in your treatment, and for at least 4 weeks after stopping REVLIMID.
• Talk with your healthcare provider to find out about options for acceptable forms of birth control that you may use to prevent pregnancy before, during, and after treatment with REVLIMID.
• If you had unprotected sex or if you think your birth control has failed, stop taking REVLIMID immediately and call your healthcare provider right away.

If you become pregnant while taking REVLIMID, stop taking it right away and call your healthcare provider. If your healthcare provider is not available, you can call Celgene Customer Care Center at 1-888-423-5436. Healthcare providers and patients should report all cases of pregnancy to:

• FDA MedWatch at 1-800-FDA-1088, and
• Celgene Corporation at 1-888-423-5436

There is a pregnancy exposure registry that monitors the outcomes of females who take REVLIMID during pregnancy, or if their male partner takes REVLIMID and they are exposed during pregnancy. You can enroll in this registry by calling Celgene Corporation at the phone number listed above. REVLIMID can pass into human semen:

• Males, including those who have had a vasectomy, must always use a latex or synthetic condom during any sexual contact with a pregnant female or a female that can become pregnant while taking REVLIMID, during any breaks (interruptions) in your treatment with REVLIMID, and for up to 4 weeks after stopping REVLIMID.
• Do not have unprotected sexual contact with a female who is or could become pregnant. Tell your healthcare provider if you do have unprotected sexual contact with a female who is or could become pregnant.
• Do not donate sperm while taking REVLIMID, during any breaks (interruptions) in your treatment, and for 4 weeks after stopping REVLIMID. If a female becomes pregnant with your sperm, the baby may be exposed to REVLIMID and may be born with birth defects.

Men, if your female partner becomes pregnant, you should call your healthcare provider right away.

• Low white blood cells (neutropenia) and low platelets (thrombocytopenia). REVLIMID causes low white blood cells and low platelets in most people. You may need a blood transfusion or certain medicines if your blood counts drop too low. Your healthcare provider should check your blood counts often especially during the first several months of treatment with REVLIMID, and then at least monthly. Tell your healthcare provider if you develop any bleeding or bruising, during treatment with REVLIMID.
• Blood clots. Blood clots in the arteries, veins, and lungs happen more often in people who take REVLIMID. This risk is even higher for people with multiple myeloma who take the medicine dexamethasone with REVLIMID. Heart attacks and strokes also happen more often in people who take REVLIMID with dexamethasone. To reduce this increased risk, most people who take REVLIMID will also take a blood thinner medicine.
  Before taking REVLIMID, tell your healthcare provider:
  • If you have had a blood clot in the past
  • If you have high blood pressure, smoke, or if you have been told you have a high level of fat in your blood (hyperlipidemia)
  • About all the medicines you take. Certain other medicines can also increase your risk for blood clots
    Call your healthcare provider or get medical help right away if you get any of the following during treatment with REVLIMID:
    • Signs or symptoms of a blood clot in the lung, arm, or leg may include: shortness of breath, chest pain, or arm or leg swelling
    • Signs or symptoms of a heart attack may include: chest pain that may spread to the arms, neck, jaw, back, or stomach area (abdomen), feeling sweaty, shortness of breath, feeling sick or vomiting
    • Signs or symptoms of stroke may include: sudden numbness or weakness, especially on one side of the body, severe headache or confusion, or problems with vision, speech, or balance

What is REVLIMID?

REVLIMID is a prescription medicine, used to treat people with:

• multiple myeloma (MM)
  • in combination with the medicine dexamethasone, or
  • as maintenance treatment after autologous hematopoietic stem cell transplantation (a type of stem cell transplant that uses your own stem cells)
• a condition called myelodysplastic syndromes (MDS). REVLIMID is for the type of MDS with a chromosome problem where part of chromosome 5 is missing. This type of MDS is known as deletion 5q MDS. People with this type of MDS may have low red blood cell counts that require treatment with blood transfusions.
• mantle cell lymphoma (MCL) when the disease comes back or becomes worse after treatment with two prior medicines, one of which included bortezomib. MCL is a cancer of a type of white blood cell called lymphocytes that are in the lymph nodes.

REVLIMID should not be used to treat people who have chronic lymphocytic leukemia (CLL) unless they are participants in a controlled clinical trial.

It is not known if REVLIMID is safe and effective in children.

Who should not take REVLIMID?

Do not take REVLIMID if you:

• are pregnant, plan to become pregnant, or become pregnant during treatment with REVLIMID. See “What is the most important information I should know about REVLIMID?”
• are allergic to lenalidomide or any of the ingredients in REVLIMID. See the end of this Medication Guide for a complete list of ingredients in REVLIMID.

What should I tell my healthcare provider before taking REVLIMID?

Before you take REVLIMID, tell your healthcare provider about all of your medical conditions, including if you:

• have liver problems
• have kidney problems or receive kidney dialysis treatment
• have thyroid problems
• have had a serious skin rash with thalidomide treatment. You should not take REVLIMID.
• are lactose intolerant. REVLIMID contains lactose.
• are breastfeeding. Do not breastfeed during treatment with REVLIMID. It is not known if REVLIMID passes into your breast milk and can harm your baby.

Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements. REVLIMID and other medicines may affect each other, causing serious side effects. Talk with your healthcare provider before taking any new medicines.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist.

How should I take REVLIMID?

• Take REVLIMID exactly as prescribed and follow all the instructions of the REVLIMID REMS program
• Swallow REVLIMID capsules whole with water 1 time a day. Do not open, break, or chew your capsules.
• REVLIMID may be taken with or without food.
• Take REVLIMID at about the same time each day.
• Do not open or break REVLIMID capsules or handle them any more than needed.
  • If powder from the REVLIMID capsule comes in contact with your skin, wash the skin right away with soap and water.
  • If powder from the REVLIMID capsule comes in contact with the inside of your eyes, nose, or mouth, flush well with water.
• If you miss a dose of REVLIMID and it has been less than 12 hours since your regular time, take it as soon as you remember. If it has been more than 12 hours, just skip your missed dose. Do not take 2 doses at the same time.
• If you take too much REVLIMID, call your healthcare provider right away.

What should I avoid while taking REVLIMID?

• See “What is the most important information I should know about REVLIMID?”
• Females: Do not get pregnant and do not breastfeed while taking REVLIMID.
• Males: Do not donate sperm.
• Do not share REVLIMID with other people. It may cause birth defects and other serious problems.
• Do not donate blood while you take REVLIMID, during any breaks (interruptions) in your treatment, and for 4 weeks after stopping REVLIMID. If someone who is pregnant gets your donated blood, her baby may be exposed to REVLIMID and may be born with birth defects.

What are the possible side effects of REVLIMID?

REVLIMID can cause serious side effects, including:

• See “What is the most important information I should know about REVLIMID?”
• Increased risk of death in people who have chronic lymphocytic leukemia (CLL). People with CLL who take REVLIMID have an increased risk of death compared with people who take the medicine chlorambucil. REVLIMID may cause you to have serious heart problems that can lead to death, including atrial fibrillation, heart attack, or heart failure. You should not take REVLIMID if you have CLL unless you are participating in a controlled clinical trial.
• Risk of new cancers (malignancies). An increase in new (second) cancers has happened in patients who received REVLIMID and melphalan, or a blood stem cell transplant, including certain blood cancers, such as acute myelogenous leukemia (AML), and myelodysplastic syndrome (MDS) and certain other types of cancers of the skin and other organs. Talk with your healthcare provider about your risk of developing new cancers if you take REVLIMID. Your healthcare provider will check you for new cancers during your treatment with REVLIMID.
• Severe liver problems, including liver failure and death. Your healthcare provider should do blood tests to check your liver function during your treatment with REVLIMID. Tell your healthcare provider right away if you develop any of the following symptoms of liver problems:
  • yellowing of your skin or the white part of your eyes (jaundice)
  • dark or brown (tea-colored) urine
  • pain on the upper right side of your stomach area (abdomen)
  • bleeding or bruising more easily than normal
  • feeling very tired
• Severe skin reactions including severe allergic reactions can happen with REVLIMID and may cause death. Call your healthcare provider right away if you develop any of these signs or symptoms of a severe allergic reaction or severe skin reaction during treatment with REVLIMID:
  • swelling of your face, eyes, lips, tongue, throat
  • trouble swallowing
  • trouble breathing
  • skin rash, hives, or peeling of your skin
  • blisters
  • rash with fever and or swollen glands
• Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure and sometimes death. Your healthcare provider may do blood tests to check you for TLS.
• Worsening of your tumor (tumor flare reaction). Tell your healthcare provider if you get any of these symptoms of tumor flare reaction while taking REVLIMID: tender swollen lymph nodes, low grade fever, pain, or rash.

Your healthcare provider may tell you to decrease your dose, temporarily stop or permanently stop taking REVLIMID if you develop certain serious side effects during treatment with REVLIMID.

• Thyroid problems. Your healthcare provider may check your thyroid function before you start taking REVLIMID and during treatment with REVLIMID.
• Risk of Early Death in MCL. In people who have Mantle Cell Lymphoma (MCL), there may be a risk of dying sooner (early death) when taking REVLIMID. Talk with your healthcare provider about any concerns and possible risk factors.

The most common side effects of REVLIMID include:

• diarrhea
• rash
• nausea
• constipation
• tiredness
• fever
• itching
• swelling of the limbs and skin
• cough

These are not all the possible side effects of REVLIMID.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800- FDA-1088.

How should I store REVLIMID?

• Store REVLIMID at room temperature between 68°F to 77°F (20°C to 25°C).
• Return any unused REVLIMID to Celgene or your healthcare provider.

Keep REVLIMID and all medicines out of the reach of children.

General information about the safe and effective use of REVLIMID

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take REVLIMID for conditions for which it was not prescribed. Do not give REVLIMID to other people, even if they have the same symptoms you have. It may harm them and may cause birth defects.

If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about REVLIMID that is written for health professionals.

What are the ingredients in REVLIMID?

Active ingredient: lenalidomide

Inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

The 5 mg and 25 mg capsule shell contains gelatin, titanium dioxide and black ink.

The 2.5 and 10 mg capsule shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink.

The 15 mg capsule shell contains gelatin, FD&C blue #2, titanium dioxide and black ink.

The 20 mg capsule shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

It is not known if lenalidomide crosses into human milk. Because many medications can cross into human milk and because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using lenalidomide.

Biologic response modifier; thalidomide analog with immunomodulatory, antineoplastic, and antiangiogenic activity.1 a b c d e 30

Take lenalidomide exactly as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Also, do not stop taking lenalidomide without first checking with your doctor.

It is very important that you understand the rules of the Revlimid® REMS program. Read the patient Medication Guide. Ask your doctor or pharmacist if you have any questions. You might be asked to sign a form to show that you understand the information.

Swallow the capsule whole with water. Do not break, chew, or open it. If you accidentally open the capsule and have contact with the powder, wash your skin with soap and clear water. If the medicine gets into your eyes, nose, or mouth, rinse them with water.

Take lenalidomide at the same time each day. This means take it at the same time and take it consistently, either with or without food.

Dosing

The dose of lenalidomide will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of lenalidomide. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (capsules):
  • For anemia in patients with myelodysplastic syndrome:
    • Adults—At first, 10 milligrams (mg) once a day. Your doctor may adjust your dose as needed.
    • Children—Use and dose must be determined by your doctor.
  • For mantle cell lymphoma:
    • Adults—At first, 25 milligrams (mg) once a day. lenalidomide is taken on Days 1 to 21 of repeated 28-day cycles. Your doctor may adjust your dose as needed.
    • Children—Use and dose must be determined by your doctor.
  • For multiple myeloma in combination with dexamethasone:
    • Adults—At first, 25 milligrams (mg) once a day. lenalidomide is taken on Days 1 to 21 of repeated 28-day cycles. Your doctor may adjust your dose as needed.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of lenalidomide, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you miss a dose of lenalidomide and it is less than 12 hours since your regular time, take it as soon as you can and take your next dose at the normal time. If you miss a dose and it is more than 12 hours since your regular time, skip the missed dose and take your next dose at the normal time.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

(le na LID oh mide)

Chronic lymphocytic leukemia, relapsed or refractory

Data from a phase II study in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), supports the use of lenalidomide (in combination with cyclic rituximab) in the treatment of patients with CLL [Badoux 2013]. Additional trials may be necessary to further define the role of lenalidomide in the treatment of this condition.

Diffuse large B-cell lymphoma, relapsed or refractory

Data from a phase II, single-arm, multicenter study in patients with relapsed or refractory aggressive non-Hodgkin lymphoma, supports the use of lenalidomide in the treatment of patients with this condition [Wiernik 2008]. Additional trials may be necessary to further define the role of lenalidomide in the treatment of this condition.

Myelodysplastic syndrome (MDS) without deletion 5q

Data from a phase II, multicenter study in patients with MDS, supports the use of lenalidomide in the treatment of patients with MDS without deletion 5q [Raza 2008]. Additional trials may be necessary to further define the role of lenalidomide in the treatment of this condition.

Multiple myeloma, newly diagnosed

Data from two phase II trials in patients with newly diagnosed multiple myeloma support the use of lenalidomide (in combination with bortezomib and dexamethasone) in the treatment of this condition [Kumar 2012], [Richardson 2010]. In addition, data from a small phase I/II trial supports the use of lenalidomide (in combination with carfilzomib and dexamethasone) for the treatment of newly diagnosed multiple myeloma [Jakubowiak 2012].

Systemic light chain amyloidosis

Data from two phase II studies in patients with systemic light chain amyloidosis, supports the use of lenalidomide in the treatment of patients with this condition [Nair 2012], [Sanchorawala 2007]. Additional trials may be necessary to further define the role of lenalidomide in the treatment of this condition.

Note: Maintain appropriate number of treatment days per cycle based on indication and/or protocol. Further individualize (increase or decrease dose) based on tolerance.

Recommended initial dose adjustment in the manufacturer's labeling:

MCL and multiple myeloma (combination therapy with dexamethasone):

CrCl >60 mL/minute: No dosage adjustment necessary.

CrCl 30 to 60 mL/minute: 10 mg once daily (for multiple myeloma, may increase to 15 mg once daily after 2 cycles if nonresponsive but tolerating treatment)

CrCl <30 mL/minute (nondialysis dependent): 15 mg every 48 hours

ESRD: CrCl <30 mL/minute and dialysis dependent: 5 mg once daily (administer after dialysis on dialysis days)

MDS and multiple myeloma (maintenance treatment after autologous stem cell transplant):

CrCl >60 mL/minute: No dosage adjustment necessary.

CrCl 30 to 60 mL/minute: 5 mg once daily

CrCl <30 mL/minute (nondialysis dependent): 2.5 mg once daily

ESRD: CrCl <30 mL/minute and dialysis dependent: 2.5 mg once daily (administer after dialysis on dialysis days)

Dialysis removal: Approximately 30% removed during a 4-hour hemodialysis session

The International Myeloma Working Group (IMWG) recommendations (Dimopoulos 2016b):

The IMWG recommends use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (preferred) or the Modification of Diet in Renal Disease (MDRD) formula to evaluate renal function estimation in multiple myeloma patients with a stable serum creatinine.

Combination therapy with dexamethasone:

CrCl ≥60 mL/minute: 25 mg once daily (no dosage adjustment necessary).

CrCl 30 to 59 mL/minute: 10 mg once daily (may increase to 15 mg once daily in the absence of toxicity).

CrCl 15 to 29 mL/minute: 15 mg once every other day; may adjust to 10 mg once daily.

CrCl <15 mL/minute: 5 mg once daily.

ESRD on dialysis: 5 mg once daily.

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C and 30°C (59°F and 86°F).

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Hematologic toxicity (neutropenia and thrombocytopenia) occurs in a majority of patients (grade 3/4: 80% in patients with del 5q myelodysplastic syndrome) and may require dose reductions and/or delays; the use of blood product support and/or growth factors may be needed. CBC should be monitored weekly for the first 8 weeks and at least monthly thereafter in patients being treated for del 5q myelodysplastic syndromes. In patients being treated for multiple myeloma, monitor CBC weekly for the first 2 cycles, every 2 weeks during cycle 3, and monthly thereafter. In patients receiving lenalidomide for mantle cell lymphoma (MCL), monitor CBC weekly for the first cycle, every 2 weeks during cycles 2 to 4, and monthly thereafter. Monitor for signs of infection, bleeding, or bruising; may require dosage adjustment.

• CNS effects: May cause dizziness or fatigue; caution patients about performing tasks which require mental alertness (eg, operating machinery or driving).

• Dermatologic reactions: Angioedema, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported; may be fatal. Consider interrupting or discontinuing treatment with grade 2 or 3 skin rash; discontinue and do not reinitiate treatment with angioedema, grade 4 rash, exfoliative or bullous rash, or for suspected SJS or TEN. Patients with a history of grade 4 rash with thalidomide should not receive lenalidomide.

• Hepatotoxicity: Hepatic failure, including fatalities, has occurred in patients treated with combination lenalidomide and dexamethasone therapy; may have hepatocellular, cholestatic, or mixed characteristics. Risk factors may include preexisting viral liver disease, elevated liver enzymes at baseline, and concomitant medications. Monitor closely; interrupt therapy in patients with abnormal hepatic function tests. May consider resuming treatment at a lower dose upon return to baseline.

• Secondary malignancy: Second primary malignancies (SPMs), including hematologic (primarily AML and MDS) and solid tumor malignancies, and non-melanoma skin cancers, have been reported with lenalidomide when used for the treatment of MDS and multiple myeloma; the incidence may be higher when lenalidomide is used in combination with an alkylating agent. Monitor for development of secondary malignancies.

• Thromboembolic events: [US Boxed Warning]: Lenalidomide has been associated with a significant increase in risk for arterial and venous thromboembolic events in multiple myeloma patients treated with lenalidomide and dexamethasone combination therapy. Deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction, and stroke have occurred; monitor for signs and symptoms of thromboembolism (shortness of breath, chest pain, or arm or leg swelling) and instruct patients to seek prompt medical attention with development of these symptoms. Thromboprophylaxis is recommended; the choice of regimen should be based on an assessment of the patient's underlying risk factors. Erythropoietin-stimulating agents (ESAs) and estrogens may contribute to thromboembolic risk; use with caution. Patients with a prior history of arterial thromboembolic events may be at greater risk; minimize modifiable factors such as hyperlipidemia, hypertension, and smoking. Anticoagulant prophylaxis should be individualized and selected based on the thromboembolism risk of the combination treatment regimen, using the safest and easiest to administer (Palumbo 2008).

• Thyroid disorders: Both hypothyroidism and hyperthyroidism have been reported with lenalidomide use; monitor thyroid function prior to therapy initiation and periodically throughout treatment.

• Tumor flare: Observed in studies of lenalidomide for the treatment of chronic lymphocytic leukemia (CLL) and lymphoma; clinical presentation includes low grade fever, pain, rash, and tender lymph node swelling. In patients with mantle cell lymphoma (MCL), tumor flare may mimic disease progression; monitor closely. In clinical trials, the majority of tumor flare events occurred in the first cycle of therapy. Treatment with corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or analgesics may be considered; therapy interruption may be necessary as well.

• Tumor lysis syndrome: Patients with a high tumor burden may be at risk for tumor lysis syndrome; monitor closely; institute appropriate management for hyperuricemia. Tumor lysis syndrome (with fatalities) has been reported with lenalidomide.

Disease-related concerns:

• Heart failure: In a scientific statement from the American Heart Association, lenalidomide has been determined to be an agent that may either cause direct myocardial toxicity or exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]).

• Renal impairment: Use with caution in patients with renal impairment; may experience an increased rate of toxicities due to reduced clearance and increased half-life. Initial dosage adjustments are recommended for moderate to severe and dialysis-dependent renal impairment.

• Stem cell mobilization: Lenalidomide use (≥4 cycles) may decrease the number of CD34+ cells collected for autologous stem cell transplant. Transplant eligible patients receiving lenalidomide should be referred to an appropriate transplant center in order to optimize the timing of stem cell collection. Cyclophosphamide in combination with G-CSF or G-CSF in combination with a CXC chemokine receptor 4 inhibitor (eg, plerixafor) may be considered when CD34+ cell collection is impaired.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Certain adverse reactions (DVT, pulmonary embolism, atrial fibrillation, renal failure) are more likely in elderly patients. Monitor renal function closely, and select dose accordingly.

• Pediatric: If used in patients between 12 to 18 years of age, the parent or legal guardian must agree to ensure compliance with the Revlimid REMS program.

• Pregnancy: [US Boxed Warning]: Do not use lenalidomide in pregnant women. Lenalidomide is an analogue of thalidomide (a human teratogen) and could potentially cause severe birth defects or embryo-fetal death; use is contraindicated during pregnancy and pregnancy must be avoided while taking lenalidomide. Obtain 2 negative pregnancy tests prior to initiation of treatment; 2 forms of contraception (or abstain from heterosexual intercourse) must be used at least 4 weeks prior to, during and for 4 weeks after lenalidomide treatment (and during treatment interruptions). In order to decrease the risk of embryo-fetal exposure, lenalidomide is available only through a restricted distribution program (Revlimid REMS). Males taking lenalidomide (even those vasectomized) must use a latex or synthetic condom during any sexual contact with women of childbearing potential and for up to 28 days following discontinuation of therapy. Males taking lenalidomide must not donate sperm.

Other warnings/precautions:

• Appropriate use: In a clinical trial comparing lenalidomide versus chlorambucil single agent therapy in patients >65 years of age with chronic lymphocytic leukemia patients (not an FDA-approved indication), increased mortality was observed in the lenalidomide treatment arm. Atrial fibrillation, cardiac failure, and MI were observed more frequently in lenalidomide-treated patients; lenalidomide (alone or in combination) is not currently recommended for first-line treatment of CLL.

• REMS program: Due to the embryo-fetal risk, lenalidomide is only available through a restricted program under the Revlimid REMS program. Prescribers and pharmacies must be certified with the program to prescribe or dispense lenalidomide. Lenalidomide should only be prescribed to patients (male and female) who can understand and comply with the conditions of the Revlimid REMS program.

• Blood donation: Patients should be advised not to donate blood during therapy and for 1 month following completion of therapy.

• Lactose intolerance: Product may contain lactose; avoid use in patients with Lapp lactase deficiency, glucose-galactose malabsorption, or glucose intolerance.

[US Boxed Warning]: Do not use lenalidomide in pregnant women. Lenalidomide is an analogue of thalidomide (a human teratogen) and could potentially cause severe birth defects or embryo-fetal death; use is contraindicated during pregnancy and pregnancy must be avoided while taking lenalidomide. Obtain 2 negative pregnancy tests prior to initiation of treatment; 2 forms of contraception (or abstain from heterosexual intercourse) must be used at least 4 weeks prior to, during, and for 4 weeks after lenalidomide treatment (and during treatment interruptions). In order to decrease the risk of embryo-fetal exposure, lenalidomide is available only through a restricted distribution program (Revlimid REMS).

Women of childbearing potential should be treated only if they are able to comply with the conditions of the Revlimid REMS program. Women of reproductive potential must avoid pregnancy beginning 4 weeks prior to therapy, during therapy, during therapy interruptions, and for ≥4 weeks after therapy is discontinued. Two forms of effective/reliable contraception (eg, tubal ligation, IUD, hormonal birth control methods, male latex or synthetic condom, diaphragm, or cervical cap) or total abstinence from heterosexual intercourse must be used by females who are not infertile or who have not had a hysterectomy. A negative pregnancy test (sensitivity of at least 50 milliunits/mL) 10 to 14 days prior to therapy, within 24 hours prior to beginning therapy, weekly during the first 4 weeks, and every 4 weeks (every 2 weeks for women with irregular menstrual cycles) thereafter is required for women of childbearing potential. Lenalidomide must be immediately discontinued for a missed period, abnormal pregnancy test or abnormal menstrual bleeding; refer patient to a reproductive toxicity specialist if pregnancy occurs during treatment.

Lenalidomide is also present in the semen of males. Males (including those vasectomized) should use a latex or synthetic condom during any sexual contact with women of childbearing age during treatment, during treatment interruptions, and for 4 weeks after discontinuation. Male patients should not donate sperm during, and for 4 weeks after treatment, and during therapy interruptions.

A pregnancy exposure registry has been created to monitor outcomes in females exposed to lenalidomide during pregnancy and female partners of male patients and to understand the root cause for the pregnancy. The pregnancy exposure registry may be contacted at 1-888-423-5436. The parent or legal guardian for patients between 12 and 18 years of age must agree to ensure compliance with the required guidelines. Any suspected fetal exposure should be reported to the FDA via the MedWatch program (1-800-FDA-1088) and to Celgene Corporation (1-888-423-5436).

Applies to lenalidomide: oral capsule

Hematologic

Very common (10% or more): Neutropenia (79%), thrombocytopenia (72.3%), anemia (43.8%), leukopenia (31.7%), lymphopenia (17.9%), neutropenic infection (17.9%), febrile neutropenia (17.4%)
Common (1% to 10%): Pancytopenia, autoimmune hemolytic anemia
Uncommon (0.1% to 1%): Hypercoagulation
Frequency not reported: Warm type hemolytic anemia, splenic infarction, bone marrow depression, coagulopathy, hemolysis, refractory anemia, decreased hemoglobin, acquired hemophilia[Ref]

Gastrointestinal

Very common (10% or more): Diarrhea (54.5%), constipation (40.5%), nausea (26.1%), gastroenteritis (22.5%), abdominal pain (20.5%), vomiting (12.2%), dyspepsia (10.7%)
Common (1% to 10%): Upper abdominal pain, dry mouth, gastrointestinal hemorrhage, glossodynia, loose stools, toothache
Uncommon (0.1% to 1%): Cecitis
Frequency not reported: Clostridium difficile colitis, ischemic colitis, intestinal perforation, rectal hemorrhage, colonic polyp, diverticulitis, dysphagia, gastritis, gastroenteritis, gastroesophageal reflux disease, obstructive inguinal hernia, irritable bowel syndrome, melena, pancreatitis, perirectal abscess, small intestinal obstruction, upper gastrointestinal hemorrhage, oral infection, pelvic pain[Ref]

Respiratory

Very common (10% or more): Bronchitis (47.4%), nasopharyngitis (34.8%), cough (28%), upper respiratory tract infection (26.8%), dyspnea (23.5%), pneumonia (17.5%), pharyngitis (15.5%), rhinitis (15%), epistaxis (14.9%), sinusitis (14%), oropharyngeal pain (10%)
Common (1% to 10%): Respiratory tract infection, lung infection, lower respiratory tract infection, bacterial lower respiratory tract infection, exertional dyspnea, rhinorrhea, pulmonary embolism, respiratory distress, hoarseness, pleural effusion, hypoxia
Frequency not reported: Chronic obstructive pulmonary disease, pulmonary edema, lobar pneumonia, respiratory failure, interstitial lung disease, lung infiltration, wheezing
Postmarketing reports: Pneumonitis[Ref]

Other

Very common (10% or more): Fatigue (43.9%), asthenia (29.7%), pyrexia (27.5%), peripheral edema (26.3%), influenza (13.3%), edema (10.1%)
Common (1% to 10%): Non-cardiac chest pain, sepsis, Staphylococcal sepsis, fall, infection, bacteremia, herpes zoster, lethargy, malaise, pain, rigors, general physical health deterioration, chills, deafness (including hypoacusis), tinnitus
Frequency not reported: Disease progression, abnormal gait, intermittent pyrexia, nodule, sudden death, central line infection, clostridial infection, ear infection, Enterobacter sepsis, fungal infection, Klebsiella sepsis, localized infection, Pseudomonas infection, septic shock, transfusion reaction, overdose, post procedural hemorrhage, road traffic accident
Postmarketing reports: Viral reactivation[Ref]

Dermatologic

Very common (10% or more): Pruritus (41.9%), rash (35.8%), dry skin (14.2%), hyperhidrosis (10.2%)
Common (1% to 10%): Cellulitis, hirsutism, exanthema, skin hyperpigmentation, contusion, night sweats, ecchymosis, erythema, urticarial, eczema
Uncommon (0.1% to 1%): Photosensitivity reaction
Frequency not reported: Acute febrile neutrophilic dermatosis
Postmarketing reports: Stevens-Johnson Syndrome, toxic epidermal necrolysis, leukocytoclastic vasculitis[Ref]

Musculoskeletal

Very common (10% or more): Muscle cramp (33.4%), muscle spasms (33.4%), back pain (32%), arthralgia (21.6%), bone pain (16.4%), pain in extremity (14.8%), musculoskeletal pain (12.6%), musculoskeletal chest pain (11.3%)
Common (1% to 10%): Muscular weakness, neck pain, myalgia, peripheral swelling
Uncommon (0.1% to 1%): Joint swelling
Rare (less than 0.1%): Rhabdomyolysis
Frequency not reported: Femur fracture, cervical vertebral fracture, femoral neck fracture, fractured pelvis, hip fracture, rib fracture, spinal cord compression, spinal compression fracture, connective tissue pain/discomfort, arthritis, gouty arthritis, chondrocalcinosis pyrophosphate[Ref]

Psychiatric

Very common (10% or more): Insomnia (27.6%), depression (10.9%), anxiety (10.2%)
Common (1% to 10%): Mood swings, hallucination, loss of libido, erectile dysfunction, confusional state, altered mood[Ref]

Nervous system

Very common (10% or more): Dizziness (23.2%), tremor (21.2%), headache (19.6%), dysgeusia (15.3%), peripheral neuropathy (15.2%), paresthesia (13.3%), hypoesthesia (10.2%)
Common (1% to 10%): Neuropathy, syncope, cerebrovascular accident, cerebral ischemia, ataxia, impaired balance, vertigo
Uncommon (0.1% to 1%): Intracranial hemorrhage, transient ischemic attack
Frequency not reported: Vertigo, aphasia, cerebellar infarction, cerebral infarction, depressed level of consciousness, dysarthria, migraine, subarachnoid hemorrhage[Ref]

Metabolic

Very common (10% or more): Decreased appetite (23.1%), decreased weight (19.5%), hypokalemia (17.1%), anorexia (15.6%), hypocalcemia (10.7%)
Common (1% to 10%): Dehydration, gout, hypophosphatemia, hyponatremia, hypomagnesemia, increased c-reactive protein, iron overload
Frequency not reported: Hypernatremia[Ref]

Ocular

Very common (10% or more): Blurred vision (17.3%), cataracts (13.7%)
Common (1% to 10%): Subcapsular cataract, unilateral cataract, blindness, ocular hypertension, reduced visual acuity[Ref]

Hepatic

Very common (10% or more): Hyperbilirubinemia (15.2%)
Common (1% to 10%): Increased ALT, increased AST, abnormal liver function tests
Frequency not reported: Cholecystitis, hepatic failure, kidney infection
Postmarketing reports: Toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, mixed cytolytic/cholestatic hepatitis, cholestasis[Ref]

Genitourinary

Very common (10% or more): Urinary tract infection (14.3%)
Common (1% to 10%): Dysuria, hyperuricemia, hematuria, urinary retention, urinary incontinence
Frequency not reported: Urosepsis[Ref]

Endocrine

Very common (10% or more): Hyperglycemia (11.7%)
Common (1% to 10%): Diabetes mellitus, acquired hypothyroidism
Frequency not reported: Basedow's disease, hypoglycemia
Postmarketing reports: Hypothyroidism, hyperthyroidism[Ref]

Cardiovascular

Very common (10% or more): Deep vein thrombosis (10.3%)
Common (1% to 10%): Hypertension, hypotension, atrial fibrillation, myocardial infarction, tachycardia, congestive cardiac failure, bradycardia, hematoma, angina pectoris, palpitations, vasculitis
Uncommon (0.1% to 1%): Arrhythmia, QT prolongation, atrial flutter, ventricular extrasystoles, ischemia, peripheral ischemia, intracranial venous sinus thrombosis
Frequency not reported: Supraventricular tachycardia/arrhythmia, cardiac arrest, cardio-respiratory arrest, cardiomyopathy, myocardial ischemia, cardiac failure, cardiogenic shock, ventricular dysfunction, increased troponin, aortic disorder, ischemia, superficial thrombophlebitis, thrombosis[Ref]

Oncologic

Very common (10% or more): Tumor flare (10%)
Common (1% to 10%): Squamous cell carcinoma, basal cell carcinoma, myelodysplastic syndrome
Frequency not reported: Acute leukemia, acute myeloid leukemia, bronchoalveolar carcinoma, metastatic lung cancer, lymphoma, metastatic prostate cancer, tumor lysis syndrome[Ref]

Renal

Very common (10% or more): Renal failure (10%)
Uncommon (0.1% to 1%): Renal tubular necrosis, acquired Fanconi syndrome
Frequency not reported: Increased blood creatinine, azotemia, ureteric calculus, renal mass[Ref]

Hypersensitivity

Frequency not reported: Hypersensitivity
Postmarketing reports: Angioedema, acute graft-versus-host disease (following allogeneic hematopoietic transplant)[Ref]

Some side effects of lenalidomide may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

25 mg orally once a day on Days 1 to 21 of repeated 28-day cycles.
Duration of Therapy: Until disease progression or unacceptable toxicity; treatment is continued, modified, or discontinued based upon clinical and laboratory findings.

Use: Treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after 2 prior therapies, one of which included bortezomib.

-IMPAIRED HEPATIC FUNCTION: There are no dose adjustments provided in the manufacturer product information; however, it has been observed that mild hepatic impairment does not influence drug clearance. Data not available for moderate to severe hepatic impairment.
-IF ABNORMAL LIVER FUNCTION TEST RESULTS/ELEVATED LIVER ENZYMES ARE REPORTED: Interrupt treatment; consider resuming treatment at a lower dose once parameters have returned to baseline.

This drug is a structural analog of thalidomide, a known human teratogen that causes embryo-fetal death and a high frequency of life-threatening human birth defects. Mortality at or shortly after birth has been reported in about 40% of infants. Animal studies revealed this drug crossed the placenta and caused maternal and developmental toxicity as well as teratogenicity (e.g., thalidomide-type limb abnormalities) in offspring. Limb malformations were seen at all doses tested. However, no adverse effects on fertility have been observed. In the U.S., any suspected fetal exposure to this drug should be reported to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436. In Australia, consult the manufacturer product information for details about the i-access(R) Program conditions for pregnancy prevention. In the United Kingdom, consult the manufacturer product information for details about the Pregnancy Prevention Programme. AU TGA pregnancy category X: Drugs which have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy. US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D and X are being phased out.

Based on the mechanism of action and findings from animal studies indicating this drug can cause embryo-fetal harm, use of this drug is contraindicated during pregnancy. AU TGA pregnancy category: X US FDA pregnancy category: Not Assigned Comments: -Direct all patients not to donate blood during treatment and for 1 to 4 weeks after treatment completion because their blood might be given to a pregnant female whose fetus should not be exposed to this drug. FEMALES OF REPRODUCTIVE POTENTIAL: -Obtain 2 negative pregnancy tests prior to treatment initiation; consult the manufacturer product information for pregnancy testing instructions. -Instruct patients to avoid pregnancy through continuous abstinence from heterosexual sexual intercourse or by using 1 to 2 forms of effective contraception for at least 4 weeks before therapy, during therapy, during dose interruptions, and for 4 weeks after completing therapy. -Educate patients on suitable methods of effective contraception (e.g., medroxyprogesterone acetate depot, tubal sterilization, ovulation inhibitory progesterone-only pills); advise against use of combined oral contraceptive pills (due to the increased risk of venous thromboembolism, which continues 4 to 6 weeks after discontinuing this type of contraception) and copper-releasing intrauterine devices (due to potential risk of infection at the time of insertion and menstrual blood loss, which may compromise patients with neutropenia or thrombocytopenia). -Advise patients to immediately discontinue this drug if pregnancy occurs during treatment or during the first week after treatment discontinuation, and refer them to a physician experienced in reproductive toxicity/teratology for further evaluation and consultation. MALES: -Due to the presence of this drug in the semen of male patients, instruct these patients not to donate any sperm and to always use a latex or synthetic condom during any sexual contact with females of reproductive potential during treatment, during dose interruptions, and for 7 to 28 days after treatment discontinuation (even if they have undergone a successful vasectomy).