Revlimid

Dosage Form: capsule
FULL PRESCRIBING INFORMATION

WARNING: FETAL RISK, HEMATOLOGIC TOXICITY, and DEEP VEIN THROMBOSIS AND PULMONARY EMBOLISM

Do not use Revlimid during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or death to a developing baby. In women of childbearing potential, obtain 2 negative pregnancy tests before starting Revlimid® treatment. Women of childbearing potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after Revlimid treatment [see Warnings and Precautions (5.1), and Medication Guide (17)]. To avoid fetal exposure to lenalidomide, Revlimid is only available under a restricted distribution program called “RevAssist®” (5.2).

Information about the RevAssist program is available at www.Revlimid.com or by calling the manufacturer’s toll-free number 1-888-423-5436.

Hematologic Toxicity (Neutropenia and Thrombocytopenia)

Revlimid can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see Dosage and Administration (2.2)].

Deep Vein Thrombosis and Pulmonary Embolism

Revlimid has demonstrated an increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma who were treated with Revlimid and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with Revlimid may lessen the potential for venous thromboembolic events. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.

FULL PRESCRIBING INFORMATION

Indications and Usage for Revlimid

Multiple Myeloma

Revlimid in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM) 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 a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.

Revlimid Dosage and Administration

 Revlimid should be taken orally at about the same time each day, either with or without food. Revlimid capsules should be swallowed whole with water. The capsules should not be opened, broken, or chewed.

Multiple Myeloma

 The recommended starting dose of Revlimid is 25 mg once daily on Days 1-21 of repeated 28-day cycles. The recommended dose of dexamethasone is 40 mg once daily on Days 1-4, 9-12, and 17-20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg once daily orally on Days 1-4 every 28 days. Treatment is continued or modified based upon clinical and laboratory findings.

Dose Adjustments for Hematologic Toxicities During Multiple Myeloma Treatment

Dose modification guidelines, as summarized below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to lenalidomide.

Platelet counts

Thrombocytopenia in MM

When Platelets	Recommended Course
Fall to <30,000/mcL	Interrupt Revlimid treatment, follow CBC weekly
Return to ≥30,000/mcL	Restart Revlimid at 15 mg daily
For each subsequent drop <30,000/mcL	Interrupt Revlimid treatment
Return to ≥30,000/mcL	Resume Revlimid at 5 mg less than the previous dose. Do not dose below 5 mg daily

Absolute Neutrophil counts (ANC)

Neutropenia in MM

When Neutrophils	Recommended Course
Fall to <1000/mcL	Interrupt Revlimid treatment, add G-CSF, follow CBC weekly
Return to ≥1,000/mcL and neutropenia is the only toxicity	Resume Revlimid at 25 mg daily
Return to ≥1,000/mcL and if other toxicity	Resume Revlimid at 15 mg daily
For each subsequent drop <1,000/mcL	Interrupt Revlimid treatment
Return to ≥1,000/mcL	Resume Revlimid at 5 mg less than the previous dose. Do not dose below 5 mg daily

Other Grade 3 / 4 Toxicities in MM

For other Grade 3/4 toxicities judged to be related to Revlimid, hold treatment and restart at next lower dose level when toxicity has resolved to ≤ Grade 2.

Starting Dose Adjustment for Renal Impairment in MM

Since REVLIMD is primarily excreted unchanged by the kidney, adjustments to the starting dose of Revlimid are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to nonmalignant conditions, Revlimid starting dose adjustment is recommended for patients with CLcr < 60 mL/min. Non-dialysis patients with creatinine clearances less than 11 mL/min and dialysis patients with creatinine clearances less than 7 mL/min have not been studied. The recommendations for initial starting doses for patients with multiple myeloma (MM) are as follows:

Table 1: Starting Dose Adjustment for Renal Impairment in Multiple Myeloma (Days 1 – 21 of each 28 day cycle)

Category	Renal Function (Cockcroft-Gault)	Dose
Moderate Renal Impairment	CLcr 30-60 mL/min	10 mg Every 24 hours
Severe Renal Impairment	CLcr < 30 mL/min (not requiring dialysis)	15 mg Every 48 hours
End Stage Renal Disease	CLcr < 30 mL/min (requiring dialysis)	5 mg Once daily. On dialysis days, administer the dose following dialysis.

After initiation of Revlimid therapy, subsequent Revlimid dose modification should be based on individual patient treatment tolerance, as described elsewhere in this section.

Myelodysplastic Syndromes

 The recommended starting dose of Revlimid is 10 mg daily. Treatment is continued or modified based upon clinical and laboratory findings.

Dose Adjustments for Hematologic Toxicities During MDS Treatment

Patients who are dosed initially at 10 mg and who experience thrombocytopenia should have their dosage adjusted as follows:

Platelet counts

If thrombocytopenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS

If baseline ≥100,000/mcL
When Platelets	Recommended Course
Fall to <50,000/mcL	Interrupt Revlimid treatment
Return to ≥50,000/mcL	Resume Revlimid at 5 mg daily
If baseline <100,000/mcL
When Platelets	Recommended Course
Fall to 50% of the baseline value	Interrupt Revlimid treatment
If baseline ≥60,000/mcL and returns to ≥50,000/mcL	Resume Revlimid at 5 mg daily
If baseline <60,000/mcL and returns to ≥30,000/mcL	Resume Revlimid at 5 mg daily

If thrombocytopenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS

When Platelets	Recommended Course
<30,000/mcL or <50,000/mcL with platelet transfusions	Interrupt Revlimid treatment
Return to ≥30,000/mcL (without hemostatic failure)	Resume Revlimid at 5 mg daily

Patients who experience thrombocytopenia at 5 mg daily should have their dosage adjusted as follows:

If thrombocytopenia develops during treatment at 5 mg daily in MDS

When Platelets	Recommended Course
<30,000/mcL or <50,000/mcL with platelet transfusions	Interrupt Revlimid treatment
Return to ≥30,000/mcL (without hemostatic failure)	Resume Revlimid at 2.5 mg every other day

Patients who are dosed initially at 10 mg and experience neutropenia should have their dosage adjusted as follows:

Absolute Neutrophil counts (ANC)

If neutropenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS

If baseline ANC ≥1,000/mcL
When Neutrophils	Recommended Course
Fall to <750/mcL	Interrupt Revlimid treatment
Return to ≥1,000/mcL	Resume Revlimid at 5 mg daily
If baseline ANC <1,000/mcL
When Neutrophils	Recommended Course
Fall to <500/mcL	Interrupt Revlimid treatment
Return to ≥500/mcL	Resume Revlimid at 5 mg daily

If neutropenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS

When Neutrophils	Recommended Course
<500/mcL for ≥7 days or <500/mcL associated with fever (≥38.5°C)	Interrupt Revlimid treatment
Return to ≥500/mcL	Resume Revlimid at 5 mg daily

Patients who experience neutropenia at 5 mg daily should have their dosage adjusted as follows:

If neutropenia develops during treatment at 5 mg daily in MDS

When Neutrophils	Recommended Course
<500/mcL for ≥7 days or <500/mcL associated with fever (≥38.5°C)	Interrupt Revlimid treatment
Return to ≥500/mcL	Resume Revlimid at 2.5 mg every other day

Other Grade 3 / 4 Toxicities in MDS

For other Grade 3/4 toxicities judged to be related to Revlimid, hold treatment and restart at next lower dose level when toxicity has resolved to ≤ Grade 2.

Starting Dose Adjustment for Renal Impairment in MDS:

Since Revlimid is primarily excreted unchanged by the kidney, adjustments to the starting dose of Revlimid are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to nonmalignant conditions, Revlimid starting dose adjustment is recommended for patients with CLcr < 60 mL/min. Non-dialysis patients with creatinine clearances less than 11 mL/min and dialysis patients with creatinine clearances less than 7 mL/min have not been studied. The recommendations for initial starting doses for patients with myelodysplastic syndromes (MDS) are as follows:

Table 2: Starting Dose Adjustment for Renal Impairment in Myelodysplastic Syndromes (Days 1 – 28 of each 28 day cycle)

Category	Renal Function (Cockcroft-Gault)	Dose
Moderate Renal Impairment	CLcr 30-60 mL/min	5 mg Every 24 hours
Severe Renal Impairment	CLcr < 30 mL/min (not requiring dialysis)	2.5 mg Every 24 hours
End Stage Renal Disease	CLcr < 30 mL/min (requiring dialysis)	2.5 mg once daily. On dialysis days, administer the dose following dialysis.

After initiation of Revlimid therapy, subsequent Revlimid dose modification should be based on individual patient treatment tolerance, as described elsewhere in this section.

Dosage Forms and Strengths

 Revlimid 2.5 mg, 5 mg, 10 mg, 15 mg and 25 mg capsules will be supplied through the RevAssist program

Revlimid is available in the following capsule strengths:

2.5 mg: White and blue-green opaque hard capsules imprinted “REV” on one half and “2.5 mg” on the other half in black ink

5 mg: White opaque capsules imprinted “REV” on one half and “5 mg” on the other half in black ink

10 mg: Blue/green and pale yellow opaque capsules imprinted “REV” on one half and “10 mg” on the other half in black ink

15 mg: Powder blue and white opaque capsules imprinted “REV” on one half and “15 mg” on the other half in black ink

25 mg: White opaque capsules imprinted “REV” on one half and “25 mg” on the other half in black ink

Contraindications

Pregnancy

Revlimid may cause fetal harm when administered to a pregnant woman. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in pregnant women and women capable of becoming pregnant [see Boxed Warning]. Females of childbearing potential may be treated with lenalidomide provided adequate precautions are taken to avoid pregnancy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, including at least one highly effective method (e.g., hormonal contraception, tubal ligation, IUD or partner’s vasectomy) and one additional effective method (e.g., latex condom, diaphragm, or cervical cap), beginning 4 weeks prior to initiating treatment with Revlimid, during therapy, during dose interruptions , and continuing for 4 weeks following discontinuation of Revlimid therapy. If hormonal or IUD contraception is medically contraindicated, two other effective or highly effective methods may be used.

Females of childbearing potential being treated with Revlimid must have pregnancy testing (sensitivity of at least 50 mIU/mL). The first test should be performed within 10-14 days and the second test within 24 hours prior to beginning Revlimid therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles. Pregnancy testing and counseling must be performed if a patient misses her period or if there is any abnormality in menstrual bleeding. If pregnancy occurs, Revlimid must be immediately discontinued. Under these conditions, the patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.

. Allergic Reactions

Revlimid is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see Warnings and precautions (5.5)}.

Warnings and Precautions

Fetal Risk

Revlimid is a thalidomide analogue. Thalidomide is a known human teratogen that causes life-threatening human birth defects. An embryofetal development study in non-human primates indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy. If Revlimid is used during pregnancy, it may cause birth defects or death to a developing baby. Females of childbearing potential must be advised to avoid pregnancy while on Revlimid. Two effective contraceptive methods should be used during therapy, during dose interruptions and for at least 4 weeks after completing therapy.

There are no adequate and well-controlled studies in pregnant females.

Reproductive Risk and Special Prescribing Requirements (RevAssist Program)

 Because of this potential toxicity and to avoid fetal exposure, Revlimid is only available under a special restricted distribution program called "RevAssist". Prescribers and pharmacists registered with the program can prescribe and dispense the product to patients who are registered and meet all the conditions of the RevAssist program.

Please see the following information for prescribers, female patients, and male patients about this restricted distribution program.

RevAssist Program Description

Prescribers

Revlimid can be prescribed only by licensed prescribers who are registered in the RevAssist program and understand the potential risk of teratogenicity if lenalidomide is used during pregnancy.

Effective contraception must be used by female patients of childbearing potential for at least 4 weeks before beginning Revlimid therapy, during therapy, during dose interruptions and for 4 weeks following discontinuation of Revlimid therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or because the patient has been postmenopausal naturally for at least 24 consecutive months. Females of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed. Sexually mature females who have not undergone a hysterectomy, have not had a bilateral oophorectomy or who have not been postmenopausal naturally for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be females of childbearing potential. Two reliable forms of contraception must be used simultaneously unless continuous abstinence from heterosexual sexual contact is the chosen method.

Females of childbearing potential must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL). The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing Revlimid. A prescription for Revlimid for a female of childbearing potential must not be issued by the prescriber until negative pregnancy tests have been verified by the prescriber.

Male Patients: Clinical data has demonstrated the presence of lenalidomide in human semen. Male patients taking Revlimid should not donate sperm.

Males receiving Revlimid must always use a latex condom during any sexual contact with females of childbearing potential even if they have undergone a successful vasectomy.

Once treatment has started and during dose interruptions, pregnancy testing for females of childbearing potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her pregnancy test or in her menstrual bleeding. Revlimid treatment must be discontinued during this evaluation.

Pregnancy test results should be verified by the prescriber and the pharmacist prior to dispensing any prescription.

If pregnancy does occur during treatment, Revlimid must be discontinued immediately.

Any suspected fetal exposure to Revlimid must be reported to the FDA via the MedWatch number at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. The patient should be referred to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling.

Female Patients

Revlimid may be used in females of childbearing potential only when the PATIENT MEETS ALL OF THE FOLLOWING CONDITIONS (i.e., she is unable to become pregnant while on Revlimid therapy):

• she is capable of complying with the mandatory contraceptive measures, pregnancy testing, patient registration, and patient survey as described in the RevAssist program.


• she has received and understands both oral and written warnings of the potential risks of taking Revlimid during pregnancy and of exposing a fetus to the drug.


• she has received both oral and written warnings of the risk of possible contraception failure and of the need to use two reliable forms of contraception simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, patch or implants) or partner’s vasectomy and one additional effective contraceptive method - latex condom, diaphragm or cervical cap, unless continuous abstinence from heterosexual sexual contact is the chosen method. Sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months), or had a bilateral oophorectomy are considered to be females of childbearing potential.


• she acknowledges, in writing, her understanding of these warnings and of the need for using two reliable methods of contraception for 4 weeks prior to beginning Revlimid therapy, during therapy, during dose interruptions and for 4 weeks after discontinuation of therapy.


• she has had two negative pregnancy tests with a sensitivity of at least 50 mIU/mL, within 10-14 days and 24 hours prior to beginning therapy.


• if the patient is between 12 and 18 years of age, her parent or legal guardian must have read the educational materials and agreed to ensure compliance with the above.

Male Patients

Revlimid may be used in sexually active males when the PATIENT MEETS ALL OF THE FOLLOWING CONDITIONS:

• he is capable of complying with the mandatory contraceptive measures that are appropriate for men, patient registration, and patient survey as described in the RevAssist program.


• he has received and understands both oral and written warnings of the potential risks of taking Revlimid and exposing a fetus to the drug.


• he has received both oral and written warnings of the risk of possible contraception failure and that it is known that lenalidomide is present in semen. He has been instructed that he must always use a latex condom during any sexual contact with females of childbearing potential, even if he has undergone a successful vasectomy. Females of childbearing potential are considered to be sexually mature females who have not undergone a hysterectomy, have not had a bilateral oophorectomy or who have not been postmenopausal for at least 24 consecutive months (i.e., who have had menses at any time in the preceding 24 consecutive months).


• he acknowledges, in writing, his understanding of these warnings and of the need to use a latex condom during any sexual contact with females of childbearing potential, even if he has undergone a successful vasectomy.


• if the patient is between 12 and 18 years of age, his parent or legal guardian must have read the educational materials and agreed to ensure compliance with the above.

Hematologic Toxicity

Revlimid can cause significant neutropenia and thrombocytopenia. Patients taking Revlimid for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter. Patients taking Revlimid for MM should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter. Patients may require dose interruption and/or dose reduction [see Dosage and Administration (2.1)].

Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days [see Boxed Warning and Dosage and Administration (2.2)].

In the pooled multiple myeloma studies Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of Revlimid and dexamethasone than in patients treated with dexamethasone alone [see Adverse Reactions (6.1)].

Deep Vein Thrombosis and Pulmonary Embolism

Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with multiple myeloma treated with lenalidomide combination therapy [see Boxed Warning] and patients with MDS treated with lenalidomide monotherapy. A significantly increased risk of DVT and PE was observed in patients with multiple myeloma who were treated with Revlimid and dexamethasone therapy in a clinical trial [see Boxed Warning]. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with Revlimid may lessen the potential for venous thromboembolic events. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.

Allergic Reactions

 Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive Revlimid. Revlimid interruption or discontinuation should be considered for Grade 2-3 skin rash. Revlimid must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions.

Revlimid capsules contain lactose. Risk-benefit of Revlimid treatment should be evaluated in patients with lactose intolerance.

Tumor Lysis Syndrome

Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Tumor Flare Reaction

Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. Treatment of CLL or lymphoma with lenalidomide outside of a well-monitored clinical trial is discouraged.

Hepatotoxicity

 Cases of transient liver laboratory abnormalities (predominantly transaminases) were reported in patients treated with lenalidomide. Treatment with lenalidomide should be interrupted and restarted once the levels return to baseline. Successful re-challenge without recurrence of liver laboratory elevation was reported in some patients.

6. ADVERSE REACTIONS

The following adverse reactions are described in detail in other labeling sections:

• Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings and Precautions (5.3)]


• Deep vein thrombosis and pulmonary embolism [see Boxed Warnings, Warnings and Precautions (5.4)]


• Allergic Reactions [see Warnings and Precautions (5.5)]


• Tumor lysis syndrome [see Warnings and Precautions (5.6)]


• Tumor flare reactions [see Warnings and Precautions (5.7)]


• Hepatotoxicity [see Warnings and Precautions (5.8)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience in Multiple Myeloma

Data were evaluated from 703 patients in two studies who received at least one dose of Revlimid/dexamethasone (353 patients) or placebo/dexamethasone (350 patients).

In the Revlimid/dexamethasone treatment group, 269 patients (76%) underwent at least one dose interruption with or without a dose reduction of Revlimid compared to 199 patients (57%) in the placebo/dexamethasone treatment group. Of these patients who had one dose interruption with or without a dose reduction, 50% in the Revlimid/dexamethasone treatment group underwent at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse events and Grade 3/4 adverse events were more frequent in patients who received the combination of Revlimid/dexamethasone compared to placebo/dexamethasone.

Tables 3, 4, and 5 summarize the adverse reactions reported for Revlimid/dexamethasone and placebo/dexamethasone groups.

Table 3: Adverse Reactions Reported in ≥5% of Patients and with a ≥2% Difference in Proportion of Patients Between the Revlimid/dexamethasone and Placebo/dexamethasone Groups

System Organ Class/ Preferred Term	Revlimid/Dex* (n=353) n (%)	Placebo/Dex * (n=350) n (%)
Blood and lymphatic system disorders
Neutropenia %	149 (42.2)	22 (6.3)
Anemia @	111 (31.4)	83 (23.7)
Thrombocytopenia @	76 (21.5)	37 (10.6)
Leukopenia	28 (7.9)	4 (1.1)
Lymphopenia	19 (5.4)	5 (1.4)
General disorders and administration site conditions
Fatigue	155 (43.9)	146 (41.7)
Pyrexia	97 (27.5)	82 (23.4)
Peripheral edema	93 (26.3)	74 (21.1)
Chest Pain	29 ( 8.2)	20 (5.7)
Lethargy	24 ( 6.8)	8 (2.3)
Gastrointestinal disorders
Constipation	143 (40.5)	74 (21.1)
Diarrhea@	136 (38.5)	96 (27.4)
Nausea @	92 (26.1)	75 (21.4)
Vomiting @	43 (12.2)	33 (9.4)
Abdominal Pain @	35 (9.9)	22 (6.3)
Dry Mouth	25 (7.1)	13 (3.7)
Musculoskeletal and connective tissue disorders
Muscle cramp	118 (33.4)	74 (21.1)
Back pain	91 (25.8)	65 (18.6)
Bone Pain	48 (13.6)	39 (11.1)
Pain in Limb	42 (11.9)	32 (9.1)
Nervous system disorders
Dizziness	82 (23.2)	59 (16.9)
Tremor	75 (21.2)	26 (7.4)
Dysgeusia	54 (15.3)	34 (9.7)
Hypoaesthesia	36 (10.2)	25 (7.1)
Neuropathy a	23 (6.5)	13 (3.7)
Respiratory, Thoracic and Mediastinal Disorders
Dyspnea	83 (23.5)	60 (17.1)
Nasopharyngitis	62 (17.6)	31 (8.9)
Pharyngitis	48 (13.6)	33 (9.4)
Bronchitis	40 (11.3)	30 (8.6)
Infectionsb and infestations
Upper respiratory tract infection	87 (24.6)	55 (15.7)
Pneumonia @	48 (13.6)	29 (8.3)
Urinary Tract Infection	30 (8.5)	19 (5.4)
Sinusitis	26 (7.4)	16 (4.6)
Skin and subcutaneous system disorders
Rash c	75 (21.2)	33 (9.4)
Sweating Increased	35 (9.9)	25 (7.1)
Dry Skin	33 (9.3)	14 (4.0)
Pruritus	27 (7.6)	18 (5.1)
Metabolism and nutrition disorders
Anorexia	55 (15.6)	34 (9.7)
Hypokalemia	48 (13.6)	21 (6.0)
Hypocalcemia	31 (8.8)	10 (2.9)
Appetite Decreased	24 (6.8)	14 (4.0)
Dehydration	23 (6.5)	15 (4.3)
Hypomagnesaemia	24 (6.8)	10 (2.9)
Investigations
Weight Decreased	69 (19.5)	52 (14.9)
Eye disorders
Blurred vision	61 (17.3)	40 (11.4)
Vascular disorders
Deep vein thrombosis %	33 (9.3)	15 (4.3)
Hypertension	28 (7.9)	20 (5.7)
Hypotension	25 (7.1)	15 (4.3)

Table 4: Grade 3/4 Adverse Reactions Reported in ≥2% Patients and With a ≥1% Difference in Proportion of Patients Between the Revlimid/dexamethasone and Placebo/dexamethasone groups

System Organ Class/ Preferred Term	Revlimid/Dex# (n=353) n (%)	Placebo/Dex# (n=350) n (%)
Blood and lymphatic system disorders
Neutropenia %	118 (33.4)	12 (3.4)
Thrombocytopenia @	43 (12.2)	22 (6.3)
Anemia @	35 (9.9)	20 (5.7)
Leukopenia	14 (4.0)	1 (0.3)
Lymphopenia	10 (2.8)	4 (1.1)
Febrile Neutropenia %	8 (2.3)	0 (0.0)
General disorders and administration site conditions
Fatigue	23 (6.5)	17 (4.9)
Vascular disorders
Deep vein thrombosis %	29 (8.2)	12 (3.4)
Infectionsb and infestations
Pneumonia @	30 (8.5)	19 (5.4)
Urinary Tract Infection	5 (1.4)	1 (0.3)
Metabolism and nutrition disorders
Hypokalemia	17 (4.8)	5 (1.4)
Hypocalcemia	13 (3.7)	6 (1.7)
Hypophosphatemia	9 (2.5)	0 (0.0)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism@	14 (4.0)	3 (0.9)
Respiratory Distress @	4 (1.1)	0 (0.0)
Musculoskeletal and connective tissue disorders
Muscle weakness	20 (5.7)	10 (2.9)
Gastrointestinal disorders
Diarrhea @	11 (3.1)	4 (1.1)
Constipation	7 (2.0)	1 (0.3)
Nausea @	6 (1.7)	2 (0.6)
Cardiac disorders
Atrial fibrillation @	13 (3.7)	4 (1.1)
Tachycardia	6 (1.7)	1 (0.3)
Cardiac Failure Congestive @	5 (1.4)	1 (0.3)
Nervous System disorders
Syncope	10 (2.8)	3 (0.9)
Dizziness	7 (2.0)	3 (0.9)
Eye Disorders
Cataract	6 (1.7)	1 (0.3)
Cataract Unilateral	5 (1.4)	0 (0.0)
Psychiatric Disorder
Depression	10 (2.8)	6 (1.7)

Table 5: Serious Adverse Events Reported in ≥1% Patients and With a ≥1% Difference in Proportion of Patients Between the Revlimid/dexamethasone and Placebo/dexamethasone Groups

For all tables above: n – Number of Patients * - All Treatment Emergent AEs with ≥5% of Patients in Revlimid/ Dex and at Least 2% Difference in Proportion between the Two Arms - (Safety population) # - All Treatment Emergent Grades 3 and 4 AEs with ≥1% Patients in Revlimid/ Dex and at Least 1% Difference in Proportion between the Two Arms - (Safety population) & - All Treatment Emergent Serious AEs with ≥1% Patients in Revlimid/ Dex and at Least 1% Difference in Proportion between the Two Arms - (Safety population) @ - ADRs with Death as an outcome % - ADRs which were considered to be life threatening (if the outcome of the event was death, it is included with death cases) a - All PTs under the MedDRA SMQ of Neuropathy of a peripheral sensory nature will be considered listed b - All PTs under SOC of Infections except for rare infections of Public Health interest will be considered listed c- All PTs under HLT of Rash will be considered listed Dex=dexamethasone Median duration of exposure among patients treated with Revlimid/dexamethasone was 44 weeks while median duration of exposure among patients treated with placebo/dexamethasone was 23 weeks. This should be taken into consideration when comparing frequency of adverse events between two treatment groups Revlimid/dexamethasone vs. placebo/dexamethasone.
System Organ Class/ Preferred Term	Revlimid/Dex& (n=353) n (%)	Placebo/Dex& (n=350) n (%)
Blood and lymphatic system disorders
Febrile Neutropenia%	6 (1.7)	0 (0.0)
Vascular disorders
Deep vein thrombosis%	26 (7.4)	11 (3.1)
Infectionsb and infestations
Pneumonia @	33 (9.3)	21 (6.0)
Respiratory, thoracic, and mediastinal disorders
Pulmonary embolism@	13 (3.7)	3 (0.9)
Cardiac disorders
Atrial fibrillation @	11 (3.1)	2 (0.6)
Cardiac Failure Congestive @	5 (1.4)	0 (0.0)
Nervous system disorders
Cerebrovascular accident @	7 (2.0)	3 (0.9)
Gastrointestinal disorders
Diarrhea @	6 (1.7)	2 (0.6)
Musculoskeletal and connective tissue disorders
Bone Pain	4 (1.1)	0 (0.0)