Mydolen

When are you taking this medicine? Empty stomach Before food After food With a meal

Mydolen uses

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Drug interactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• References
• How supplied/storage and handling
• Patient counseling information
• Mydolen reviews

1 INDICATIONS AND USAGE

Mydolen is a thalidomide analogue indicated for the treatment of patients with:

• Multiple myeloma, in combination with dexamethasone (1.1).
• MM, as maintenance following autologous hematopoietic stem cell transplantation (auto-HSCT) (1.1).
• Transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities (1.2).
• Mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib (1.3).

Limitations of Use:

• Mydolen is not indicated and is not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials (1.4).

1.1 Multiple Myeloma

Mydolen in combination with dexamethasone is indicated for the treatment of patients with multiple myeloma (MM).

Mydolen is indicated as maintenance therapy in patients with MM following autologous hematopoietic stem cell transplantation (auto-HSCT).

1.2 Myelodysplastic Syndromes

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

1.3 Mantle Cell Lymphoma

Mydolen is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

1.4 Limitations of Use

Mydolen is not indicated and is not recommended for the treatment of patients with CLL outside of controlled clinical trials .

2 DOSAGE AND ADMINISTRATION

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

• MM combination therapy: 25 mg once daily orally on Days 1-21 of repeated 28-day cycles. Refer to section 14.1 for dexamethasone dosing.
• MM maintenance therapy following auto-HSCT: 10 mg once daily continuously on Days 1-28 of repeated 28-day cycles (2.1).
• MDS: 10 mg once daily (2.2).
• MCL: 25 mg once daily orally on Days 1-21 of repeated 28-day cycles (2.3).
• Continue or modify dosing based on clinical and laboratory findings (2.1, 2.2, 2.3).
• Renal impairment: Adjust starting dose based on the creatinine clearance value (2.4).

2.1 Multiple Myeloma

Mydolen Combination Therapy

The recommended starting dose of Mydolen is 25 mg orally once daily on Days 1-21 of repeated 28-day cycles in combination with dexamethasone. Refer to Section 14.1 for specific dexamethasone dosing. For patients > 75 years old, the starting dose of dexamethasone may be reduced . Treatment should be continued until disease progression or unacceptable toxicity.

In patients who are not eligible for auto-HSCT, treatment should continue until disease progression or unacceptable toxicity. For patients who are auto-HSCT-eligible, hematopoietic stem cell mobilization should occur within 4 cycles of a REVLIMID-containing therapy .

Dose Adjustments for Hematologic Toxicities During MM Treatment

Dose modification guidelines, as summarized in Table 1 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to Mydolen.

Table 1: Dose Adjustments for Hematologic Toxicities for MM

Platelet counts

Thrombocytopenia in MM

When Platelets	Recommended Course Days 1-21 of repeated 28-day cycle
Fall to <30,000/mcL	Interrupt Mydolen treatment, follow CBC weekly
Return to ≥30,000/mcL	Resume Mydolen at next lower dose. Do not dose below 2.5 mg daily
For each subsequent drop <30,000/mcL	Interrupt Mydolen treatment
Return to ≥30,000/mcL	Resume Mydolen at next lower dose. Do not dose below 2.5 mg daily

Absolute Neutrophil counts (ANC)

Neutropenia in MM

When Neutrophils	Recommended Course Days 1-21 of repeated 28-day cycle
Fall to <1000/mcL	Interrupt Mydolen treatment, follow CBC weekly
Return to ≥1,000/mcL and neutropenia is the only toxicity	Resume Mydolen at 25 mg daily or initial starting dose
Return to ≥1,000/mcL and if other toxicity	Resume Mydolen at next lower dose. Do not dose below 2.5 mg daily
For each subsequent drop <1,000/mcL	Interrupt Mydolen treatment
Return to ≥1,000/mcL	Resume Mydolen at next lower dose. Do not dose below 2.5 mg daily

Mydolen Maintenance Therapy Following Auto-HSCT

Following auto-HSCT, initiate Mydolen maintenance therapy after adequate hematologic recovery (ANC ≥ 1000/mcL and/or platelet counts ≥75,000/mcL). The recommended starting dose of Mydolen is 10 mg once daily continuously (Days 1-28 of repeated 28-day cycles) until disease progression or unacceptable toxicity. After 3 cycles of maintenance therapy, the dose can be increased to 15 mg once daily if tolerated.

Dose Adjustments for Hematologic Toxicities During MM Treatment

Dose modification guidelines, as summarized in Table 2 below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to Mydolen.

Table 2: Dose Adjustments for Hematologic Toxicities for MM

Platelet counts

Thrombocytopenia in MM

When Platelets	Recommended Course
Fall to <30,000/mcL	Interrupt Mydolen treatment, follow CBC weekly
Return to ≥30,000/mcL	Resume Mydolen at next lower dose, continuously for Days 1-28 of repeated 28-day cycle
If at the 5 mg daily dose, For a subsequent drop <30,000/mcL	Interrupt Mydolen treatment. Do not dose below 5 mg daily for Day 1 to 21 of 28 day cycle
Return to ≥30,000/mcL	Resume Mydolen at 5 mg daily for Days 1 to 21of 28-day cycle. Do not dose below 5 mg daily for Day 1 to 21 of 28 day cycle

Absolute Neutrophil counts (ANC)

Neutropenia in MM

When Neutrophils	Recommended Course
Fall to <500/mcL	Interrupt Mydolen treatment, follow CBC weekly
Return to ≥500/mcL	Resume Mydolen at next lower dose, continuously for Days 1-28 of repeated 28-day cycle
If at 5 mg daily dose, For a subsequent drop <500/mcL	Interrupt Mydolen treatment. Do not dose below 5 mg daily for Days 1 to 21 of 28-day cycle
Return to >500/mcL	Resume Mydolen at 5 mg daily for Days 1 to 21 of 28-day cycle. Do not dose below 5 mg daily for Days 1 to 21 of 28-day cycle

Other Toxicities in MM

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

Starting Dose Adjustment for Renal Impairment in MM

.

2.2 Myelodysplastic Syndromes

The recommended starting dose of Mydolen 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 Mydolen treatment
Return to ≥50,000/mcL	Resume Mydolen at 5 mg daily
If baseline <100,000/mcL
When Platelets	Recommended Course
Fall to 50% of the baseline value	Interrupt Mydolen treatment
If baseline ≥60,000/mcL and returns to ≥50,000/mcL	Resume Mydolen at 5 mg daily
If baseline <60,000/mcL and returns to ≥30,000/mcL	Resume Mydolen 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 Mydolen treatment
Return to ≥30,000/mcL	Resume Mydolen 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 Mydolen treatment
Return to ≥30,000/mcL (without hemostatic failure)	Resume Mydolen at 2.5 mg daily

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 Mydolen treatment
Return to ≥1,000/mcL	Resume Mydolen at 5 mg daily
If baseline ANC <1,000/mcL
When Neutrophils	Recommended Course
Fall to <500/mcL	Interrupt Mydolen treatment
Return to ≥500/mcL	Resume Mydolen 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 Mydolen treatment
Return to ≥500/mcL	Resume Mydolen 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 Mydolen treatment
Return to ≥500/mcL	Resume Mydolen at 2.5 mg daily

Other Grade 3 / 4 Toxicities in MDS

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

Starting Dose Adjustment for Renal Impairment in MDS

.

2.3 Mantle Cell Lymphoma

The recommended starting dose of Mydolen is 25 mg/day orally on Days 1-21 of repeated 28-day cycles for relapsed or refractory mantle cell lymphoma. Treatment should be continued until disease progression or unacceptable toxicity.

Treatment is continued, modified or discontinued based upon clinical and laboratory findings.

Dose Adjustments for Hematologic Toxicities During MCL Treatment

Dose modification guidelines as summarized below are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicities considered to be related to Mydolen.

Platelet counts

Thrombocytopenia during treatment in MCL

When Platelets	Recommended Course
Fall to <50,000/mcL	Interrupt Mydolen treatment and follow CBC weekly
Return to ≥50,000/mcL	Resume Mydolen at 5 mg less than the previous dose. Do not dose below 5 mg daily

Absolute Neutrophil counts (ANC)

Neutropenia during treatment in MCL

When Neutrophils	Recommended Course
Fall to <1000/mcL for at least 7 days OR Falls to < 1,000/mcL with an associated temperature ≥ 38.5°C OR Falls to < 500 /mcL	Interrupt Mydolen treatment and follow CBC weekly
Return to ≥1,000/mcL	Resume Mydolen at 5 mg less than the previous dose. Do not dose below 5 mg daily

Other Grade 3 / 4 Toxicities in MCL

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

Starting Dose Adjustment for Renal Impairment in MCL

.

2.4 Starting Dose for Renal Impairment

The recommendations for starting doses for patients with renal impairment are shown in the following table .

Renal Function (Cockcroft-Gault)	Dose in Mydolen Combination Therapy for MM and for MCL	Dose in Mydolen Maintenance Therapy Following Auto-HSCT for MM and for MDS
CLcr 30 to 60 mL/min	10 mg once daily	5 mg once daily
CLcr < 30 mL/min (not requiring dialysis)	15 mg every other day	2.5 mg once daily
CLcr < 30 mL/min (requiring dialysis)	5 mg once daily. On dialysis days, administer the dose following dialysis.	2.5 mg once daily. On dialysis days, administer the dose following dialysis.

Mydolen Combination Therapy for MM: For CLcr of 30 to 60 mL/min, consider escalating the dose to 15 mg after 2 cycles if the patient tolerates the 10 mg dose of Mydolen without dose-limiting toxicity.

Mydolen Maintenance Therapy Following Auto-HSCT for MM and for MCL and MDS: Base subsequent Mydolen dose increase or decrease on individual patient treatment tolerance .

3 DOSAGE FORMS AND STRENGTHS

Mydolen 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg and 25 mg capsules will be supplied through the Mydolen REMS program.

Mydolen 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

20 mg: Powder blue and blue-green opaque hard capsules imprinted “REV” on one half and “20 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

• Capsules: 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg (3).

4 CONTRAINDICATIONS

• Pregnancy.
• Demonstrated hypersensitivity to Mydolen (4.2, 5.8).

4.1 Pregnancy

Mydolen can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with Mydolen 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, Mydolen is contraindicated in females who are pregnant . If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus .

4.2 Allergic Reactions

Mydolen is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to Mydolen .

5 WARNINGS AND PRECAUTIONS

• Increased mortality: serious and fatal cardiac adverse reactions occurred in patients with CLL treated with Mydolen.
• Second Primary Malignancies (SPM): Higher incidences of SPM were observed in controlled trials of patients with MM receiving Mydolen (5.6).
• Hepatotoxicity: Hepatic failure including fatalities; monitor liver function. Stop Mydolen and evaluate if hepatotoxicity is suspected (5.7).
• Allergic Reactions, including fatalities: Hypersensitivity, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis; discontinue Mydolen if reactions are suspected. Do not resume Mydolen if these reactions are verified (5.8).
• Tumor lysis syndrome (TLS) including fatalities: Monitor patients at risk of TLS (i.e., those with high tumor burden) and take appropriate precautions (5.9).
• Tumor flare reaction: Serious tumor flare reactions have occurred during investigational use of Mydolen for chronic lymphocytic leukemia and lymphoma (5.10, 6.3).
• Impaired Stem Cell mobilization: A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with Mydolen has been reported. Consider early referral to transplant center (5.11).

5.1 Embryo-Fetal Toxicity

Mydolen is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes life-threatening human birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. An embryo-fetal development study in monkeys indicates that Mydolen 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.

Mydolen is only available through the Mydolen REMS program .

Females of Reproductive Potential

Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning Mydolen therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy.

Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with Mydolen, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of Mydolen therapy.

Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing Mydolen therapy and then weekly during the first month, then monthly thereafter in females with regular menstrual cycles or every 2 weeks in females with irregular menstrual cycles .

Males

Mydolen is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking Mydolen and for up to 4 weeks after discontinuing Mydolen, even if they have undergone a successful vasectomy. Male patients taking Mydolen must not donate sperm .

Blood Donation

Patients must not donate blood during treatment with Mydolen and for 4 weeks following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to Mydolen.

5.2 Mydolen REMS Program

Because of the embryo-fetal risk [see Warnings and Precautions ], Mydolen is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the Mydolen REMS program .

Required components of the Mydolen REMS program include the following:

• Prescribers must be certified with the Mydolen REMS program by enrolling and complying with the REMS requirements.
• Patients must sign a Patient-Physician agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements and males must comply with contraception requirements .
• Pharmacies must be certified with the Mydolen REMS program, must only dispense to patients who are authorized to receive Mydolen and comply with REMS requirements.

Further information about the Mydolen REMS program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436.

5.3 Hematologic Toxicity

Mydolen can cause significant neutropenia and thrombocytopenia. Monitor patients with neutropenia for signs of infection. Advise patients to observe for bleeding or bruising, especially with use of concomitant medication that may increase risk of bleeding. Patients taking Mydolen should have their complete blood counts assessed periodically as described below .

Patients taking Mydolen in combination with dexamethasone or as Mydolen maintenance therapy for MM should have their complete blood counts (CBC) assessed every 7 days (weekly) for the first 2 cycles, on Days 1 and 15 of Cycle 3, and every 28 days (4 weeks) thereafter. A dose interruption and/or dose reduction may be required . In the MM maintenance therapy trials, Grade 3 or 4 neutropenia was reported in up to 59% of REVLIMID-treated patients and Grade 3 or 4 thrombocytopenia in up to 38% of REVLIMID-treated patients .

Patients taking Mydolen for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter. 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) .

Patients taking Mydolen for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients.

5.4 Venous and Arterial Thromboembolism

Venous thromboembolic events and arterial thromboembolic events (ATE, myocardial infarction and stroke) are increased in patients treated with Mydolen.

A significantly increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with MM after at least one prior therapy who were treated with Mydolen and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group (3.1% and 0.9%) in clinical trials with varying use of anticoagulant therapies. In the newly diagnosed multiple myeloma (NDMM) study in which nearly all patients received antithrombotic prophylaxis, DVT was reported as a serious adverse reaction (3.6%, 2.0%, and 1.7%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms (3.8%, 2.8%, and 3.7%, respectively) .

Myocardial infarction (1.7%) and stroke (CVA) (2.3%) are increased in patients with MM after at least one prior therapy who were treated with Mydolen and dexamethasone therapy compared to patients treated with placebo and dexamethasone (0.6%, and 0.9%) in clinical trials. In the NDMM study, myocardial infarction (including acute) was reported as a serious adverse reaction (2.3%, 0.6%, and 1.1%) in the Rd Continuous, Rd18, and MPT Arms, respectively. The frequency of serious adverse reactions of CVA was similar between the Rd Continuous, Rd18, and MPT Arms (0.8%, 0.6 %, and 0.6%, respectively) .

Patients with known risk factors, including prior thrombosis, may be at greater risk and actions should be taken to try to minimize all modifiable factors (e.g. hyperlipidemia, hypertension, smoking).

In controlled clinical trials that did not use concomitant thromboprophylaxis, 21.5% overall thrombotic events (Standardized MedDRA Query Embolic and Thrombotic events) occurred in patients with refractory and relapsed MM who were treated with Mydolen and dexamethasone compared to 8.3% thrombosis in patients treated with placebo and dexamethasone. The median time to first thrombosis event was 2.8 months. In the NDMM study in which nearly all patients received antithrombotic prophylaxis, the overall frequency of thrombotic events was 17.4% in patients in the combined Rd Continuous and Rd18 Arms, and was 11.6% in the MPT Arm. The median time to first thrombosis event was 4.3 months in the combined Rd Continuous and Rd18 Arms.

Thromboprophylaxis is recommended. The regimen of thromboprophylaxis should be based on an assessment of the patient’s underlying risks. Instruct patients to report immediately any signs and symptoms suggestive of thrombotic events. ESAs and estrogens may further increase the risk of thrombosis and their use should be based on a benefit-risk decision in patients receiving Mydolen .

5.5 Increased Mortality in Patients with CLL

In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent Mydolen therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the Mydolen treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08 – 3.41], consistent with a 92% increase in the risk of death. The trial was halted for safety in July 2013.

Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the Mydolen treatment arm. Mydolen is not indicated and not recommended for use in CLL outside of controlled clinical trials.

5.6 Second Primary Malignancies

In clinical trials in patients with MM receiving Mydolen, an increase of hematologic plus solid tumor second primary malignancies notably AML and MDS have been observed. An increase in hematologic SPM including AML and MDS occurred in 5.3% of patients with NDMM receiving Mydolen in combination with oral melphalan compared with 1.3% of patients receiving melphalan without Mydolen. The frequency of AML and MDS cases in patients with NDMM treated with Mydolen in combination with dexamethasone without melphalan was 0.4%.

In patients receiving Mydolen maintenance therapy following high dose intravenous melphalan and auto-HSCT, hematologic SPM occurred in 7.5% of patients compared to 3.3% in patients receiving placebo. The incidence of hematologic plus solid tumor (excluding squamous cell carcinoma and basal cell carcinoma) SPM was 14.9%, compared to 8.8% in patients receiving placebo with a median follow-up of 91.5 months. Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.9% of patients receiving Mydolen maintenance, compared to 2.6% in the placebo arm.

In patients with relapsed or refractory MM treated with REVLIMID/dexamethasone, the incidence of hematologic plus solid tumor (excluding squamous cell carcinoma and basal cell carcinoma) SPM was 2.3% versus 0.6% in the dexamethasone alone arm. Non-melanoma skin cancer SPM, including squamous cell carcinoma and basal cell carcinoma, occurred in 3.1% of patients receiving REVLIMID/dexamethasone, compared to 0.6% in the dexamethasone alone arm.

Patients who received REVLIMID-containing therapy until disease progression did not show a higher incidence of invasive SPM than patients treated in the fixed duration REVLIMID-containing arms. Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of Mydolen and the risk of second primary malignancies when considering treatment with Mydolen.

5.7 Hepatotoxicity

Hepatic failure, including fatal cases, has occurred in patients treated with Mydolen in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with MM and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop Mydolen upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered.

5.8 Allergic Reactions

Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome 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 Mydolen. Mydolen interruption or discontinuation should be considered for Grade 2-3 skin rash. Mydolen 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.

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

5.9 Tumor Lysis Syndrome

Fatal instances of tumor lysis syndrome have been reported during treatment with Mydolen. 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.

5.10 Tumor Flare Reaction

Tumor flare reaction has occurred during investigational use of Mydolen for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. Mydolen is not indicated and not recommended for use in CLL outside of controlled clinical trials.

Monitoring and evaluation for tumor flare reaction is recommended in patients with MCL. Tumor flare reaction may mimic progression of disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Mydolen may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with Mydolen until TFR resolves to ≤ Grade 1. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR.

5.11 Impaired Stem Cell Mobilization

A decrease in the number of CD34+ cells collected after treatment (> 4 cycles) with Mydolen has been reported. In patients who are auto-HSCT candidates, referral to a transplant center should occur early in treatment to optimize the timing of the stem cell collection. In patients who received more than 4 cycles of a REVLIMID-containing treatment or for whom inadequate numbers of CD 34+ cells have been collected with G-CSF alone, G-CSF with cyclophosphamide or the combination of G-CSF with a CXCR4 inhibitor may be considered.

5.12 Thyroid Disorders

Both hypothyroidism and hyperthyroidism have been reported . Measure thyroid function before start of Mydolen treatment and during therapy.

6 ADVERSE REACTIONS

The following adverse reactions are described in detail in other sections of the prescribing information:

• Embryo-Fetal Toxicity
• Hematologic Toxicity
• Venous and Arterial Thromboembolism
• Increased Mortality in Patients with CLL
• Second Primary Malignancies
• Hepatotoxicity
• Allergic Reactions
• Tumor Lysis Syndrome
• Tumor Flare Reactions
• Impaired Stem Cell Mobilization
• Thyroid Disorders

• MM: Most common adverse reactions (≥20%) include diarrhea, fatigue, anemia, constipation, neutropenia, leukopenia, peripheral edema, insomnia, muscle cramp/spasms, abdominal pain, back pain, nausea, asthenia, pyrexia, upper respiratory tract infection, bronchitis, nasopharyngitis, gastroenteritis, cough, rash, dyspnea, dizziness, decreased appetite, thrombocytopenia, and tremor (6.1).
• MDS: Most common adverse reactions (>15%) include thrombocytopenia, neutropenia, diarrhea, pruritus, rash, fatigue, constipation, nausea, nasopharyngitis, arthralgia, pyrexia, back pain, peripheral edema, cough, dizziness, headache, muscle cramp, dyspnea, pharyngitis, and epistaxis (6.1).
• MCL: Most common adverse reactions (≥15%) include neutropenia, thrombocytopenia, fatigue, diarrhea, anemia, nausea, cough, pyrexia, rash, dyspnea, pruritus, constipation, peripheral edema and leukopenia (6.1).

To report SUSPECTED ADVERSE REACTIONS contact Celgene Corporation at 1-888-423-5436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

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.

Newly Diagnosed MM – Mydolen Combination Therapy:

Data were evaluated from 1613 patients in a large phase 3 study who received at least one dose of Mydolen with low dose dexamethasone (Rd) given for 2 different durations of time (i.e., until progressive disease [Arm Rd Continuous; N=532] or for up to eighteen 28-day cycles [72 weeks, Arm Rd18; N=540] or who received melphalan, prednisone and thalidomide (Arm MPT; N=541) for a maximum of twelve 42-day cycles (72 weeks). The median treatment duration in the Rd Continuous arm was 80.2 weeks (range 0.7 to 246.7) or 18.4 months (range 0.16 to 56.7).

In general, the most frequently reported adverse reactions were comparable in Arm Rd Continuous and Arm Rd18, and included diarrhea, anemia, constipation, peripheral edema, neutropenia, fatigue, back pain, nausea, asthenia, and insomnia. The most frequently reported Grade 3 or 4 reactions included neutropenia, anemia, thrombocytopenia, pneumonia, asthenia, fatigue, back pain, hypokalemia, rash, cataract, lymphopenia, dyspnea, DVT, hyperglycemia, and leukopenia. The highest frequency of infections occurred in Arm Rd Continuous (75%) compared to Arm MPT (56%). There were more grade 3 and 4 and serious adverse reactions of infection in Arm Rd Continuous than either Arm MPT or Rd18.

In the Rd Continuous arm, the most common adverse reactions leading to dose interruption of Mydolen were infection events (28.8%); overall, the median time to the first dose interruption of Mydolen was 7 weeks. The most common adverse reactions leading to dose reduction of Mydolen in the Rd Continuous arm were hematologic events (10.7%); overall, the median time to the first dose reduction of Mydolen was 16 weeks. In the Rd Continuous arm, the most common adverse reactions leading to discontinuation of Mydolen were infection events (3.4%).

In both Rd arms, the frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment, except for cataracts. The frequency of onset of cataracts increased over time with 0.7% during the first 6 months and up to 9.6% by the 2nd year of treatment with Rd Continuous.

Table 4 summarizes the adverse reactions reported for the Rd Continuous, Rd18, and MPT treatment arms.

Note: A subject with multiple occurrences of an adverse reaction is counted only once under the applicable Body System/Adverse Reaction. a All treatment-emergent adverse reactions in at least 5.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 2.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. b All grade 3 or 4 treatment-emergent adverse reactions in at least 1.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 1.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. c Serious treatment-emergent adverse reactions in at least 1.0% of subjects in the Rd Continuous or Rd18 Arms and at least a 1.0% higher frequency (%) in either the Rd Continuous or Rd18 Arms compared to the MPT Arm. d Preferred terms for the blood and lymphatic system disorders body system were included by medical judgment as known adverse reactions for Rd Continuous/Rd18, and have also been reported as serious. e Footnote “a” not applicable f Footnote “b” not applicable. Mydolen - adverse reactions in which at least one resulted in a fatal outcome % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases) * Adverse reactions include in combined adverse reaction terms: Abdominal Pain: Abdominal pain, abdominal pain upper, abdominal pain lower, gastrointestinal pain Pneumonias: Pneumonia, lobar pneumonia, pneumonia pneumococcal, bronchopneumonia, pneumocystis jiroveci pneumonia, pneumonia legionella, pneumonia staphylococcal, pneumonia klebsiella, atypical pneumonia, pneumonia bacterial, pneumonia escherichia, pneumonia streptococcal, pneumonia viral Sepsis: Sepsis, septic shock, urosepsis, escherichia sepsis, neutropenic sepsis, pneumococcal sepsis, staphylococcal sepsis, bacterial sepsis, meningococcal sepsis, enterococcal sepsis, klebsiella sepsis, pseudomonal sepsis Rash: Rash, rash pruritic, rash erythematous, rash maculo-papular, rash generalised, rash papular, exfoliative rash, rash follicular, rash macular, drug rash with eosinophilia and systemic symptoms, erythema multiforme, rash pustular Deep Vein Thrombosis: Deep vein thrombosis, venous thrombosis limb, venous thrombosis
Body System Adverse Reaction	All Adverse Reactionsa			Grade 3/4 Adverse Reactionsb
	Rd Continuous (N = 532)	Rd18 (N = 540)	MPT (N = 541)	Rd Continuous (N = 532)	Rd18 (N = 540)	MPT (N = 541)
General disorders and administration site conditions
Fatigue%	173 (32.5)	177 (32.8)	154 (28.5)	39 (7.3)	46 (8.5)	31 (5.7)
Asthenia	150 (28.2)	123 (22.8)	124 (22.9)	41 (7.7)	33 (6.1)	32 (5.9)
Pyrexiac	114 (21.4)	102 (18.9)	76 (14.0)	13 (2.4)	7 (1.3)	7 (1.3)
Non-cardiac chest pain f	29 (5.5)	31 (5.7)	18 (3.3)	<1%	<1%	<1%
Gastrointestinal disorders
Diarrhea	242 (45.5)	208 (38.5)	89 (16.5)	21 (3.9)	18 (3.3)	8 (1.5)
Abdominal pain% f	109 (20.5)	78 (14.4)	60 (11.1)	7 (1.3)	9 (1.7)	<1%
Dyspepsia f	57 (10.7)	28 (5.2)	36 (6.7)	<1%	<1%	0 (0.0)
Musculoskeletal and connective tissue disorders
Back painc	170 (32.0)	145 (26.9)	116 (21.4)	37 (7.0)	34 (6.3)	28 (5.2)
Muscle spasms f	109 (20.5)	102 (18.9)	61 (11.3)	<1%	<1%	<1%
Arthralgia f	101 (19.0)	71 (13.1)	66 (12.2)	9 (1.7)	8 (1.5)	8 (1.5)
Bone pain f	87 (16.4)	77 (14.3)	62 (11.5)	16 (3.0)	15 (2.8)	14 (2.6)
Pain in extremity f	79 (14.8)	66 (12.2)	61 (11.3)	8 (1.5)	8 (1.5)	7 (1.3)
Musculoskeletal pain f	67 (12.6)	59 (10.9)	36 (6.7)	<1%	<1%	<1%
Musculoskeletal chest pain f	60 (11.3)	51 (9.4)	39 (7.2)	6 (1.1)	<1%	<1%
Muscular weakness f	43 (8.1)	35 (6.5)	29 (5.4)	<1%	8 (1.5)	<1%
Neck pain f	40 (7.5)	19 (3.5)	10 (1.8)	<1%	<1%	<1%
Infections and infestations
Bronchitis c	90 (16.9)	59 (10.9)	43 (7.9)	9 (1.7)	6 (1.1)	3 (0.6)
Nasopharyngitis f	80 (15.0)	54 (10.0)	33 (6.1)	0 (0.0)	0 (0.0)	0 (0.0)
Urinary tract infection f	76 (14.3)	63 (11.7)	41 (7.6)	8 (1.5)	8 (1.5)	<1%
Upper respiratory tract infection c % f	69 (13.0)	53 (9.8)	31 (5.7)	<1%	8 (1.5)	<1%
Pneumonia c Mydolen	93 (17.5)	87 (16.1)	56 (10.4)	60 (11.3)	57 (10.5)	41 (7.6)
Respiratory tract infection %	35 (6.6)	25 (4.6)	21 (3.9)	7 (1.3)	4 (0.7)	1 (0.2)
Influenza f	33 (6.2)	23 (4.3)	15 (2.8)	<1%	<1%	0 (0.0)
Gastroenteritis f	32 (6.0)	17 (3.1)	13 (2.4)	0 (0.0)	<1%	<1%
Lower respiratory tract infection	29 (5.5)	14 (2.6)	16 (3.0)	10 (1.9)	3 (0.6)	3 (0.6)
Rhinitis f	29 (5.5)	24 (4.4)	14 (2.6)	0 (0.0)	0 (0.0)	0 (0.0)
Cellulitisc	<5%	<5%	<5%	8 (1.5)	3 (0.6)	2 (0.4)
Sepsis c Mydolen	33 (6.2)	26 (4.8)	18 (3.3)	26 (4.9)	20 (3.7)	13 (2.4)
Nervous system disorders
Headache f	75 (14.1)	52 (9.6)	56 (10.4)	<1%	<1%	<1%
Dysgeusia f	39 (7.3)	45 (8.3)	22 (4.1)	<1%	0 (0.0)	<1%
Blood and lymphatic system disordersd
Anemia	233 (43.8)	193 (35.7)	229 (42.3)	97 (18.2)	85 (15.7)	102 (18.9)
Neutropenia	186 (35.0)	178 (33.0)	328 (60.6)	148 (27.8)	143 (26.5)	243 (44.9)
Thrombocytopenia	104 (19.5)	100 (18.5)	135 (25.0)	44 (8.3)	43 (8.0)	60 (11.1)
Febrile neutropenia	7 (1.3)	17 (3.1)	15 (2.8)	6 (1.1)	16 (3.0)	14 (2.6)
Pancytopenia	5 (0.9)	6 (1.1)	7 (1.3)	1 (0.2)	3 (0.6)	5 (0.9)
Respiratory, thoracic and mediastinal disorders
Cough f	121 (22.7)	94 (17.4)	68 (12.6)	<1%	<1%	<1%
Dyspneac,e	117 (22.0)	89 (16.5)	113 (20.9)	30 (5.6)	22 (4.1)	18 (3.3)
Epistaxis f	32 (6.0)	31 (5.7)	17 (3.1)	<1%	<1%	0 (0.0)
Oropharyngeal pain f	30 (5.6)	22 (4.1)	14 (2.6)	0 (0.0)	0 (0.0)	0 (0.0)
Dyspnea exertional e	27 (5.1)	29 (5.4)	<5%	6 (1.1)	2 (0.4)	0 (0.0)
Metabolism and nutrition disorders
Decreased appetite	123 (23.1)	115 (21.3)	72 (13.3)	14 (2.6)	7 (1.3)	5 (0.9)
Hypokalemia %	91 (17.1)	62 (11.5)	38 (7.0)	35 (6.6)	20 (3.7)	11 (2.0)
Hyperglycemia	62 (11.7)	52 (9.6)	19 (3.5)	28 (5.3)	23 (4.3)	9 (1.7)
Hypocalcemia	57 (10.7)	56 (10.4)	31 (5.7)	23 (4.3)	19 (3.5)	8 (1.5)
Dehydration %	25 (4.7)	29 (5.4)	17 (3.1)	8 (1.5)	13 (2.4)	9 (1.7)
Gout e	<5%	<5%	<5%	8 (1.5)	0 (0.0)	0 (0.0)
Diabetes mellitus % e	<5%	<5%	<5%	8 (1.5)	4 (0.7)	2 (0.4)
Hypophosphatemia e	<5%	<5%	<5%	7 (1.3)	3 (0.6)	1 (0.2)
Hyponatremia % e	<5%	<5%	<5%	7 (1.3)	13 (2.4)	6 (1.1)
Skin and subcutaneous tissue disorders
Rash	139 (26.1)	151 (28.0)	105 (19.4)	39 (7.3)	38 (7.0)	33 (6.1)
Pruritus f	47 (8.8)	49 (9.1)	24 (4.4)	<1%	<1%	<1%
Psychiatric disorders
Insomnia	147 (27.6)	127 (23.5)	53 (9.8)	4 (0.8)	6 (1.1)	0 (0.0)
Depression	58 (10.9)	46 (8.5)	30 (5.5)	10 (1.9)	4 (0.7)	1 (0.2)
Vascular disorders
Deep vein thrombosisc%	55 (10.3)	39 (7.2)	22 (4.1)	30 (5.6)	20 (3.7)	15 (2.8)
Hypotensionc%	51 (9.6)	35 (6.5)	36 (6.7)	11 (2.1)	8 (1.5)	6 (1.1)
Injury, Poisoning, and Procedural Complications
Fall f	43 (8.1)	25 (4.6)	25 (4.6)	<1%	6 (1.1)	6 (1.1)
Contusion f	33 (6.2)	24 (4.4)	15 (2.8)	<1%	<1%	0 (0.0)
Eye disorders
Cataract	73 (13.7)	31 (5.7)	5 (0.9)	31 (5.8)	14 (2.6)	3 (0.6)
Cataract subcapsular e	<5%	<5%	<5%	7 (1.3)	0 (0.0)	0 (0.0)
Investigations
Weight decreased	72 (13.5)	78 (14.4)	48 (8.9)	11 (2.1)	4 (0.7)	4 (0.7)
Cardiac disorders
Atrial fibrillationc	37 (7.0)	25 (4.6)	25 (4.6)	13 (2.4)	9 (1.7)	6 (1.1)
Myocardial infarction (including acute) c,e	<5%	<5%	<5%	10 (1.9)	3 (0.6)	5 (0.9)
Renal and Urinary disorders
Renal failure (including acute)c Mydolen, f	49 (9.2)	54 (10.0)	37 (6.8)	28 (5.3)	33 (6.1)	29 (5.4)
Neoplasms benign, malignant and unspecified (Incl cysts and polyps)
Squamous cell carcinoma c e	<5%	<5%	<5%	8 (1.5)	4 (0.7)	0 (0.0)
Basal cell carcinomac e,f	<5%	<5%	<5%	<1%	<1%	0 (0.0)

Newly Diagnosed MM - Mydolen Maintenance Therapy Following Auto-HSCT:

Data were evaluated from 1018 patients in two randomized trials who received at least one dose of Mydolen 10 mg daily as maintenance therapy after auto-HSCT until progressive disease or unacceptable toxicity, The mean treatment duration for Mydolen treatment was 30.3 months for Maintenance Study 1 and 24.0 months for Maintenance Study 2 (overall range across both studies from 0.1 to 108 months). As of the cut-off date of 1 Mar 2015, 48 patients (21%) in the Maintenance Study 1 Mydolen arm were still on treatment and none of the patients in the Maintenance Study 2 Mydolen arm were still on treatment at the same cut-off date

The adverse reactions listed from Maintenance Study 1 included events reported post-transplant (completion of high-dose melphalan /auto-HSCT), and the maintenance treatment period. In Maintenance Study 2, the adverse reactions were from the maintenance treatment period only. In general, the most frequently reported adverse reactions (more than 20% in the Mydolen arm) across both studies were neutropenia, thrombocytopenia, leukopenia, anemia, upper respiratory tract infection, bronchitis, nasopharyngitis, cough, gastroenteritis, diarrhea, rash, fatigue, asthenia, muscle spasm and pyrexia. The most frequently reported Grade 3 or 4 reactions (more than 20% in the Mydolen arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions lung infection and neutropenia (more than 4.5%) occurred in the Mydolen arm.

For Mydolen, the most common adverse reactions leading to dose interruption were hematologic events (29.7%, data available in Maintenance Study 2 only). The most common adverse reaction leading to dose reduction of Mydolen were hematologic events (17.7%, data available in Maintenance Study 2 only). The most common adverse reactions leading to discontinuation of Mydolen were thrombocytopenia (2.7%) in Maintenance Study 1 and neutropenia (2.4%) in Maintenance Study 2.

The frequencies of onset of adverse reactions were generally highest in the first 6 months of treatment and then the frequencies decreased over time or remained stable throughout treatment.

Table 5 summarizes the adverse reactions reported for the Mydolen and placebo maintenance treatment arms.

Note: AEs are coded to body system /adverse reaction using MedDRA v15.1. A subject with multiple occurrences of an AE is counted only once in each AE category. a All treatment-emergent AEs in at least 5% of patients in the Mydolen Maintenance group and at least 2% higher frequency (%) than the Placebo Maintenance group. b All grade 3 or 4 treatment-emergent AEs in at least 1% of patients in the Mydolen Maintenance group and at least 1% higher frequency (%) than the Placebo Maintenance group. c All serious treatment-emergent AEs in at least 1% of patients in the Mydolen Maintenance group and at least 1% higher frequency (%) than the Placebo Maintenance group. d Footnote “a” not applicable for either study e Footnote “b” not applicable for either study Mydolen -ADRs where at least one resulted in a fatal outcome % - ADRs where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases) # - All adverse reactions under Body System of Infections and Infestation except for rare infections of Public Health interest will be considered listed * Adverse Reactions for combined ADR terms (based on relevant TEAE PTs included in Maintenance Studies 1 and 2 [per MedDRA v 15.1]): Pneumonias Bronchopneumonia,. Lobar pneumonia, Pneumocystis jiroveci pneumonia, Pneumonia, Pneumonia klebsiella, Pneumonia legionella, Pneumonia mycoplasmal, Pneumonia pneumococcal, Pneumonia streptococcal, Pneumonia viral, Lung disorder, Pneumonitis Sepsis: Bacterial sepsis, Pneumococcal sepsis, Sepsis, Septic shock, Staphylococcal sepsis Peripheral neuropathy: Neuropathy peripheral, Peripheral motor neuropathy, Peripheral sensory neuropathy, Polyneuropathy Deep vein thrombosis: Deep vein thrombosis, Thrombosis, Venous thrombosis
Body System Adverse Reaction	Maintenance Study 1				Maintenance Study 2
	All Adverse Reactions [a]		Grade 3/4 Adverse Reactions [b]		All Adverse Reactions [a]		Grade 3/4 Adverse Reactions [b]
	Mydolen (N=224) n (%)	Placebo (N=221) n (%)	Mydolen (N=224) n (%)	Placebo (N=221) n (%)	Mydolen (N=293) n (%)	Placebo (N=280) n (%)	Mydolen (N=293) n (%)	Placebo (N=280) n (%)
Blood and lymphatic system disorders
Neutropenia c %	177 ( 79.0)	94 ( 42.5)	133 ( 59.4)	73 ( 33.0)	178 ( 60.8)	33 ( 11.8)	158 ( 53.9)	21 ( 7.5)
Thrombocytopenia c %	162 ( 72.3)	101 ( 45.7)	84 ( 37.5)	67 ( 30.3)	69 ( 23.5)	29 ( 10.4)	38 ( 13.0)	8 ( 2.9)
Leukopenia c	51 ( 22.8)	25 ( 11.3)	45 ( 20.1)	22 ( 10.0)	93 ( 31.7)	21 ( 7.5)	71 ( 24.2)	5 ( 1.8)
Anemia	47 ( 21.0)	27 ( 12.2)	23 ( 10.3)	18 ( 8.1)	26 ( 8.9)	15 ( 5.4)	11 ( 3.8)	3 ( 1.1)
Lymphopenia	40 ( 17.9)	29 ( 13.1)	37 ( 16.5)	26 ( 11.8)	13 ( 4.4)	3 ( 1.1)	11 ( 3.8)	2 ( 0.7)
Pancytopenia c d %	1 ( 0.4)	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)	12 ( 4.1)	1 ( 0.4)	7 ( 2.4)	1 ( 0.4)
Febrile neutropenia c	39 ( 17.4)	34 ( 15.4)	39 ( 17.4)	34 ( 15.4)	7 ( 2.4)	1 ( 0.4)	5 ( 1.7)	1 ( 0.4)
Infections and infestations#
Upper respiratory tract infection e	60 ( 26.8)	35 ( 15.8)	7 ( 3.1)	9 ( 4.1)	32 ( 10.9)	18 ( 6.4)	1 ( 0.3)	0 ( 0.0)
Neutropenic infection	40 ( 17.9)	19 ( 8.6)	27 ( 12.1)	14 ( 6.3)	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)
Pneumonias* c %	31 ( 13.8)	15 ( 6.8)	23 ( 10.3)	7 ( 3.2)	50 ( 17.1)	13 ( 4.6)	27 ( 9.2)	5 ( 1.8)
Bronchitis c	10 ( 4.5)	9 ( 4.1)	1 ( 0.4)	5 ( 2.3)	139 ( 47.4)	104 ( 37.1)	4 ( 1.4)	1 ( 0.4)
Nasopharyngitis e	5 ( 2.2)	2 ( 0.9)	0 ( 0.0)	0 ( 0.0)	102 ( 34.8)	84 ( 30.0)	1 ( 0.3)	0 ( 0.0)
Gastroenteritis c	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)	66 ( 22.5)	55 ( 19.6)	6 ( 2.0)	0 ( 0.0)
Rhinitis e	2 ( 0.9)	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)	44 ( 15.0)	19 ( 6.8)	0 ( 0.0)	0 ( 0.0)
Sinusitis e	8 ( 3.6)	3 ( 1.4)	0 ( 0.0)	0 ( 0.0)	41 ( 14.0)	26 ( 9.3)	0 ( 0.0)	1 ( 0.4)
Influenza c	8 ( 3.6)	5 ( 2.3)	2 ( 0.9)	1 ( 0.5)	39 ( 13.3)	19 ( 6.8)	3 ( 1.0)	0 ( 0.0)
Lung infection c	21 ( 9.4)	2 ( 0.9)	19 ( 8.5)	2 ( 0.9)	9 ( 3.1)	4 ( 1.4)	1 ( 0.3)	0 ( 0.0)
Lower respiratory tract infection e	13 ( 5.8)	5 ( 2.3)	6 ( 2.7)	4 ( 1.8)	4 ( 1.4)	4 ( 1.4)	0 ( 0.0)	2 ( 0.7)
Infection c	12 ( 5.4)	6 ( 2.7)	9 ( 4.0)	5 ( 2.3)	17 ( 5.8)	5 ( 1.8)	0 ( 0.0)	0 ( 0.0)
Urinary tract infection c d e	9 ( 4.0)	5 ( 2.3)	4 ( 1.8)	4 ( 1.8)	22 ( 7.5)	17 ( 6.1)	1 ( 0.3)	0 ( 0.0)
Lower respiratory tract infection bacterial d	6 ( 2.7)	1 ( 0.5)	4 ( 1.8)	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)
Bacteremia d	5 ( 2.2)	0 ( 0.0)	4 ( 1.8)	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)
Herpes zoster c d	11 ( 4.9)	10 ( 4.5)	3 ( 1.3)	2 ( 0.9)	29 ( 9.9)	25 ( 8.9)	6 ( 2.0)	2 ( 0.7)
Sepsis* c d Mydolen	2 ( 0.9)	1 ( 0.5)	0 ( 0.0)	0 ( 0.0)	6 ( 2.0)	1 ( 0.4)	4 ( 1.4)	1 ( 0.4)
Gastrointestinal disorders
Diarrhea	122 ( 54.5)	83 ( 37.6)	22 ( 9.8)	17 ( 7.7)	114 ( 38.9)	34 ( 12.1)	7 ( 2.4)	0 ( 0.0)
Nausea e	33 ( 14.7)	22 ( 10.0)	16 ( 7.1)	10 ( 4.5)	31 ( 10.6)	28 ( 10.0)	0 ( 0.0)	0 ( 0.0)
Vomiting	17 ( 7.6)	12 ( 5.4)	8 ( 3.6)	5 ( 2.3)	16 ( 5.5)	15 ( 5.4)	1 ( 0.3)	0 ( 0.0)
Constipation e	12 ( 5.4)	8 ( 3.6)	0 ( 0.0)	0 ( 0.0)	37 ( 12.6)	25 ( 8.9)	2 ( 0.7)	0 ( 0.0)
Abdominal pain e	8 ( 3.6)	7 ( 3.2)	1 ( 0.4)	4 ( 1.8)	31 ( 10.6)	15 ( 5.4)	1 ( 0.3)	1 ( 0.4)
Abdominal pain upper e	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)	20 ( 6.8)	12 ( 4.3)	1 ( 0.3)	0 ( 0.0)
General disorders and administration site conditions
Asthenia	0 ( 0.0)	1 ( 0.5)	0 ( 0.0)	0 ( 0.0)	87 ( 29.7)	53 ( 18.9)	10 ( 3.4)	2 ( 0.7)
Fatigue	51 ( 22.8)	30 ( 13.6)	21 ( 9.4)	9 ( 4.1)	31 ( 10.6)	15 ( 5.4)	3 ( 1.0)	0 ( 0.0)
Pyrexia e	17 ( 7.6)	10 ( 4.5)	2 ( 0.9)	2 ( 0.9)	60 ( 20.5)	26 ( 9.3)	1 ( 0.3)	0 ( 0.0)
Skin and subcutaneous tissue disorders
Dry skin e	9 ( 4.0)	4 ( 1.8)	0 ( 0.0)	0 ( 0.0)	31 ( 10.6)	21 ( 7.5)	0 ( 0.0)	0 ( 0.0)
Rash	71 ( 31.7)	48 ( 21.7)	11 ( 4.9)	5 ( 2.3)	22 ( 7.5)	17 ( 6.1)	3 ( 1.0)	0 ( 0.0)
Pruritus	9 ( 4.0)	4 ( 1.8)	3 ( 1.3)	0 ( 0.0)	21 ( 7.2)	25 ( 8.9)	2 ( 0.7)	0 ( 0.0)
Nervous system disorders
Paresthesia e	2 ( 0.9)	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)	39 ( 13.3)	30 ( 10.7)	1 ( 0.3)	0 ( 0.0)
Peripheral neuropathy* e	34 ( 15.2)	30 ( 13.6)	8 ( 3.6)	8 ( 3.6)	29 ( 9.9)	15 ( 5.4)	4 ( 1.4)	2 ( 0.7)
Headache d	11 ( 4.9)	8 ( 3.6)	5 ( 2.2)	1 ( 0.5)	25 ( 8.5)	21 ( 7.5)	0 ( 0.0)	0 ( 0.0)
Investigations
Alanine aminotransferase increased	16 ( 7.1)	3 ( 1.4)	8 ( 3.6)	0 ( 0.0)	5 ( 1.7)	5 ( 1.8)	0 ( 0.0)	1 ( 0.4)
Aspartate aminotransferase increased d	13 ( 5.8)	5 ( 2.3)	6 ( 2.7)	0 ( 0.0)	2 ( 0.7)	5 ( 1.8)	0 ( 0.0)	0 ( 0.0)
Metabolism and nutrition disorders
Hypokalemia	24 ( 10.7)	13 ( 5.9)	16 ( 7.1)	12 ( 5.4)	12 ( 4.1)	1 ( 0.4)	2 ( 0.7)	0 ( 0.0)
Dehydration	9 ( 4.0 )	5 ( 2.3)	7 ( 3.1)	3 ( 1.4)	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)
Hypophosphatemia d	16 ( 7.1)	15 ( 6.8)	13 ( 5.8)	14 ( 6.3)	0 ( 0.0)	1 ( 0.4)	0 ( 0.0)	0 ( 0.0)
Musculoskeletal and connective tissue disorders
Muscle spasms e	0 ( 0.0)	1 ( 0.5)	0 ( 0.0)	0 ( 0.0)	98 ( 33.4)	43 ( 15.4)	1 ( 0.3)	0 ( 0.0)
Myalgia e	7 ( 3.1)	8 ( 3.6)	3 ( 1.3)	5 ( 2.3)	19 ( 6.5)	12 ( 4.3)	2 ( 0.7)	1 ( 0.4)
Musculoskeletal paine	1 ( 0.4)	1 ( 0.5)	0 ( 0.0)	0 ( 0.0)	19 ( 6.5)	11 ( 3.9)	0 ( 0.0)	0 ( 0.0)
Hepatobiliary disorders
Hyperbilirubinemia e	34 ( 15.2)	19 ( 8.6)	4 ( 1.8)	2 ( 0.9)	4 ( 1.4)	1 ( 0.4)	2 ( 0.7)	0 ( 0.0)
Respiratory, thoracic and mediastinal disorders
Cough e	23 ( 10.3)	12 ( 5.4)	3 ( 1.3)	1 ( 0.5)	80 ( 27.3)	56 ( 20.0)	0 ( 0.0)	0 ( 0.0)
Dyspnea c e	15 ( 6.7)	9 ( 4.1)	8 ( 3.6)	4 ( 1.8)	17 ( 5.8)	9 ( 3.2)	2 ( 0.7)	0 ( 0.0)
Rhinorrhea e	0 ( 0.0)	3 ( 1.4)	0 ( 0.0)	0 ( 0.0)	15 ( 5.1)	6 ( 2.1)	0 ( 0.0)	0 ( 0.0)
Pulmonary embolism c d e	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)	0 ( 0.0)	3 ( 1.0)	0 ( 0.0)	2 ( 0.7)	0 ( 0.0)
Vascular disorders
Deep vein thrombosis*c d %	8 ( 3.6)	2 ( 0.9)	5 ( 2.2)	2 ( 0.9)	7 ( 2.4)	1 ( 0.4)	4 ( 1.4)	1 ( 0.4)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myelodysplastic syndrome c d e	5 ( 2.2)	0 ( 0.0)	2 ( 0.9)	0 ( 0.0)	3 ( 1.0)	0 ( 0.0)	1 ( 0.3)	0 ( 0.0)

After At Least One Prior Therapy for MM:

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%) had at least one dose interruption with or without a dose reduction of Mydolen 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 had at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group. Most adverse reactions and Grade 3/4 adverse reactions were more frequent in patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone.

Tables 6, 7, and 8 summarize the adverse reactions reported for REVLIMID/dexamethasone and placebo/dexamethasone groups.

Body System Adverse Reaction	REVLIMID/Dex* (N=353) n (%)	Placebo/Dex * (N=350) n (%)
Blood and lymphatic system disorders
Neutropenia%	149 (42.2)	22 (6.3)
AnemiaMydolen	111 (31.4)	83 (23.7)
ThrombocytopeniaMydolen	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)
DiarrheaMydolen	136 (38.5)	96 (27.4)
NauseaMydolen	92 (26.1)	75 (21.4)
VomitingMydolen	43 (12.2)	33 (9.4)
Abdominal PainMydolen	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)
Neuropathya	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)
PneumoniaMydolen	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
Rashc	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)
Hypomagnesemia	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)

Body System Adverse Reaction	REVLIMID/Dex# (N=353) n (%)	Placebo/Dex# (N=350) n (%)
Blood and lymphatic system disorders
Neutropenia%	118 (33.4)	12 (3.4)
ThrombocytopeniaMydolen	43 (12.2)	22 (6.3)
AnemiaMydolen	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)
Infections and infestations
PneumoniaMydolen	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 embolismMydolen	14 (4.0)	3 (0.9)
Respiratory DistressMydolen	4 (1.1)	0 (0.0)
Musculoskeletal and connective tissue disorders
Muscle weakness	20 (5.7)	10 (2.9)
Gastrointestinal disorders
DiarrheaMydolen	11 (3.1)	4 (1.1)
Constipation	7 (2.0)	1 (0.3)
NauseaMydolen	6 (1.7)	2 (0.6)
Cardiac disorders
Atrial fibrillationMydolen	13 (3.7)	4 (1.1)
Tachycardia	6 (1.7)	1 (0.3)
Cardiac Failure CongestiveMydolen	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)

For Tables 6, 7 and 8 above: Mydolen - adverse reactions in which at least one resulted in a fatal outcome % - adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases) 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 reactions between two treatment groups REVLIMID/dexamethasone vs. placebo/dexamethasone.
Body System Adverse Reaction	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)
Infections and infestations
PneumoniaMydolen	33 (9.3)	21 (6.0)
Respiratory, thoracic, and mediastinal disorders
Pulmonary embolismMydolen	13 (3.7)	3 (0.9)
Cardiac disorders
Atrial fibrillationMydolen	11 (3.1)	2 (0.6)
Cardiac Failure CongestiveMydolen	5 (1.4)	0 (0.0)
Nervous system disorders
Cerebrovascular accidentMydolen	7 (2.0)	3 (0.9)
Gastrointestinal disorders
Diarrhea Mydolen	6 (1.7)	2 (0.6)
Musculoskeletal and connective tissue disorders
Bone Pain	4 (1.1)	0 (0.0)

Venous and Arterial Thromboembolism [see Boxed Warning, Warnings and Precautions (5.4)]

VTE and ATE are increased in patients treated with Mydolen.

Deep vein thrombosis (DVT) was reported as a serious (7.4%) or severe (8.2%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 3.1 % and 3.4% in the placebo/dexamethasone group, respectively in the 2 studies in patients with at least 1 prior therapy with discontinuations due to DVT adverse reactions reported at comparable rates between groups. In the NDMM study, DVT was reported as an adverse reaction (all grades: 10.3%, 7.2%, 4.1%), as a serious adverse reaction (3.6%, 2.0%, 1.7%), and as a Grade 3/4 adverse reaction (5.6%, 3.7%, 2.8%) in the Rd Continuous, Rd18, and MPT Arms, respectively. Discontinuations and dose reductions due to DVT adverse reactions were reported at comparable rates between the Rd Continuous and Rd18 Arms (both <1%). Interruption of Mydolen treatment due to DVT adverse reactions was reported at comparable rates between the Rd Continuous (2.3%) and Rd18 (1.5%) arms. Pulmonary embolism (PE) was reported as a serious adverse drug reaction (3.7%) or Grade 3/4 (4.0%) at a higher rate in the REVLIMID/dexamethasone group compared to 0.9% (serious or grade 3/4) in the placebo/dexamethasone group in the 2 studies in patients with, at least 1 prior therapy, with discontinuations due to PE adverse reactions reported at comparable rates between groups. In the NDMM study, the frequency of adverse reactions of PE was similar between the Rd Continuous, Rd18, and MPT Arms for adverse reactions (all grades: 3.9%, 3.3%, and 4.3%, respectively), serious adverse reactions (3.8%, 2.8%, and 3.7%, respectively), and grade 3/4 adverse reactions (3.8%, 3.0%, and 3.7%, respectively).

Myocardial infarction was reported as a serious (1.7%) or severe (1.7%) adverse drug reaction at a higher rate in the REVLIMID/dexamethasone group compared to 0.6 % and 0.6% respectively in the placebo/dexamethasone group. Discontinuation due to MI (including acute) adverse reactions was 0.8% in REVLIMID/dexamethasone group and none in the placebo/dexamethasone group. In the NDMM study, myocardial infarction (including acute) was reported as an adverse reaction (all grades: 2.4%, 0.6%, and 1.1%), as a serious adverse reaction, (2.3%, 0.6%, and 1.1%), or as a severe adverse reaction (1.9%, 0.6%, and 0.9%) in the Rd Continuous, Rd18, and MPT Arms, respectively.

Stroke (CVA) was reported as a serious (2.3%) or severe (2.0%) adverse drug reaction in the REVLIMID/dexamethasone group compared to 0.9% and 0.9% respectively in the placebo/dexamethasone group. Discontinuation due to stroke (CVA) was 1.4% in REVLIMID/ dexamethasone group and 0.3% in the placebo/dexamethasone group. In the NDMM study, CVA was reported as an adverse reaction (all grades: 0.8%, 0.6%, and 0.6%), as a serious adverse reaction (0.8%, 0.6 %, and 0.6%), or as a severe adverse reaction (0.6%, 0.6%, 0.2%) in the Rd Continuous, Rd18, and MPT arms respectively.

Other Adverse Reactions: After At Least One Prior Therapy for MM

In these 2 studies, the following adverse drug reactions (ADRs) not described above that occurred at ≥1% rate and of at least twice of the placebo percentage rate were reported:

Blood and lymphatic system disorders: pancytopenia, autoimmune hemolytic anemia

Cardiac disorders: bradycardia, myocardial infarction, angina pectoris

Endocrine disorders: hirsutism

Eye disorders: blindness, ocular hypertension

Gastrointestinal disorders: gastrointestinal hemorrhage, glossodynia

General disorders and administration site conditions: malaise

Investigations: liver function tests abnormal, alanine aminotransferase increased

Nervous system disorders: cerebral ischemia

Psychiatric disorders: mood swings, hallucination, loss of libido

Reproductive system and breast disorders: erectile dysfunction

Respiratory, thoracic and mediastinal disorders: cough, hoarseness

Skin and subcutaneous tissue disorders: exanthem, skin hyperpigmentation

Myelodysplastic Syndromes:

A total of 148 patients received at least 1 dose of 10 mg Mydolen in the del 5q MDS clinical study. At least one adverse event was reported in all of the 148 patients who were treated with the 10 mg starting dose of Mydolen. The most frequently reported adverse events were related to blood and lymphatic system disorders, skin and subcutaneous tissue disorders, gastrointestinal disorders, and general disorders and administrative site conditions.

Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse events. The next most common adverse events observed were diarrhea (48.6%; 72/148), pruritus (41.9%; 62/148), rash (35.8%; 53/148) and fatigue (31.1%; 46/148). Table 9 summarizes the adverse events that were reported in ≥ 5% of the Mydolen treated patients in the del 5q MDS clinical study. Table 10 summarizes the most frequently observed Grade 3 and Grade 4 adverse reactions regardless of relationship to treatment with Mydolen. In the single-arm studies conducted, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease.

[a] Body System and adverse events are coded using the MedDRA dictionary. Body System and adverse events are listed in descending order of frequency for the Overall column. A patient with multiple occurrences of an AE is counted only once in the AE category.
	10 mg Overall
Body System
Adverse Event [a]	(N=148)
Patients with at least one adverse event	148 (100.0)
Blood and Lymphatic System Disorders Thrombocytopenia Neutropenia Anemia Leukopenia Febrile Neutropenia	91 (61.5) 87 (58.8) 17 (11.5) 12 (8.1) 8 (5.4)
Skin and Subcutaneous Tissue Disorders Pruritus Rash Dry Skin Contusion Night Sweats Sweating Increased Ecchymosis Erythema	62 (41.9) 53 (35.8) 21 (14.2) 12 (8.1) 12 (8.1) 10 (6.8) 8 (5.4) 8 (5.4)
Gastrointestinal Disorders Diarrhea Constipation Nausea Abdominal Pain Vomiting Abdominal Pain Upper Dry Mouth Loose Stools	72 (48.6) 35 (23.6) 35 (23.6) 18 (12.2) 15 (10.1) 12 (8.1) 10 (6.8) 9 (6.1)
Respiratory, Thoracic and Mediastinal Disorders Nasopharyngitis Cough Dyspnea Pharyngitis Epistaxis Dyspnea Exertional Rhinitis Bronchitis	34 (23.0) 29 (19.6) 25 (16.9) 23 (15.5) 22 (14.9) 10 (6.8) 10 (6.8) 9 (6.1)
General Disorders and Administration Site Conditions Fatigue Pyrexia Edema Peripheral Asthenia Edema Pain Rigors Chest Pain	46 (31.1) 31 (20.9) 30 (20.3) 22 (14.9) 15 (10.1) 10 (6.8) 9 (6.1) 8 (5.4)
Musculoskeletal and Connective Tissue Disorders Arthralgia Back Pain Muscle Cramp Pain in Limb Myalgia Peripheral Swelling	32 (21.6) 31 (20.9) 27 (18.2) 16 (10.8) 13 (8.8) 12 (8.1)
Nervous System Disorders Dizziness Headache Hypoesthesia Dysgeusia Peripheral Neuropathy	29 (19.6) 29 (19.6) 10 (6.8) 9 (6.1) 8 (5.4)
Infections and Infestations Upper Respiratory Tract Infection Pneumonia Urinary Tract Infection Sinusitis Cellulitis	22 (14.9) 17 (11.5) 16 (10.8) 12 (8.1) 8 (5.4)
Metabolism and Nutrition Disorders Hypokalemia Anorexia Hypomagnesemia	16 (10.8) 15 (10.1) 9 (6.1)
Investigations Alanine Aminotransferase Increased	12 (8.1)
Psychiatric Disorders Insomnia Depression	15 (10.1) 8 (5.4)
Renal and Urinary Disorders Dysuria	10 (6.8)
Vascular Disorders Hypertension	9 ( 6.1)
Endocrine Disorders Acquired Hypothyroidism	10 (6.8)
Cardiac Disorders Palpitations	8 (5.4)

[1] Adverse events with frequency ≥1% in the 10 mg Overall group. Grade 3 and 4 are based on National Cancer Institute Common Toxicity Criteria version 2. [2]Adverse events are coded using the MedDRA dictionary. A patient with multiple occurrences of an AE is counted only once in the adverse event category.
Adverse Events[2]	10 mg (N=148)
Patients with at least one Grade 3/4 AE	131 (88.5)
Neutropenia	79 (53.4)
Thrombocytopenia	74 (50.0)
Pneumonia	11 (7.4)
Rash	10 (6.8)
Anemia	9 (6.1)
Leukopenia	8 (5.4)
Fatigue	7 (4.7)
Dyspnea	7 (4.7)
Back Pain	7 (4.7)
Febrile Neutropenia	6 (4.1)
Nausea	6 (4.1)
Diarrhea	5 (3.4)
Pyrexia	5 (3.4)
Sepsis	4 (2.7)
Dizziness	4 (2.7)
Granulocytopenia	3 (2.0)
Chest Pain	3 (2.0)
Pulmonary Embolism	3 (2.0)
Respiratory Distress	3 (2.0)
Pruritus	3 (2.0)
Pancytopenia	3 (2.0)
Muscle Cramp	3 (2.0)
Respiratory Tract Infection	2 (1.4)
Upper Respiratory Tract Infection	2 (1.4)
Asthenia	2 (1.4)
Multi-organ Failure	2 (1.4)
Epistaxis	2 (1.4)
Hypoxia	2 (1.4)
Pleural Effusion	2 (1.4)
Pneumonitis	2 (1.4)
Pulmonary Hypertension	2 (1.4)
Vomiting	2 (1.4)
Sweating Increased	2 (1.4)
Arthralgia	2 (1.4)
Pain in Limb	2 (1.4)
Headache	2 (1.4)
Syncope	2 (1.4)

In other clinical studies of Mydolen in MDS patients, the following serious adverse events (regardless of relationship to study drug treatment) not described in Table 9 or 10 were reported:

Blood and lymphatic system disorders: warm type hemolytic anemia, splenic infarction, bone marrow depression, coagulopathy, hemolysis, hemolytic anemia, refractory anemia

Cardiac disorders: cardiac failure congestive, atrial fibrillation, angina pectoris, cardiac arrest, cardiac failure, cardio-respiratory arrest, cardiomyopathy, myocardial infarction, myocardial ischemia, atrial fibrillation aggravated, bradycardia, cardiogenic shock, pulmonary edema, supraventricular arrhythmia, tachyarrhythmia, ventricular dysfunction

Ear and labyrinth disorders: vertigo

Endocrine disorders: Basedow’s disease

Gastrointestinal disorders: gastrointestinal hemorrhage, colitis ischemic, intestinal perforation, rectal hemorrhage, colonic polyp, diverticulitis, dysphagia, gastritis, gastroenteritis, gastroesophageal reflux disease, obstructive inguinal hernia, irritable bowel syndrome, melena, pancreatitis due to biliary obstruction, pancreatitis, perirectal abscess, small intestinal obstruction, upper gastrointestinal hemorrhage

General disorders and administration site conditions: disease progression, fall, gait abnormal, intermittent pyrexia, nodule, rigors, sudden death

Hepatobiliary disorders: hyperbilirubinemia, cholecystitis, acute cholecystitis, hepatic failure

Immune system disorders: hypersensitivity

Infections and infestations: infection bacteremia, central line infection, clostridial infection, ear infection, Enterobacter sepsis, fungal infection, herpes viral infection NOS, influenza, kidney infection, Klebsiella sepsis, lobar pneumonia, localized infection, oral infection, Pseudomonas infection, septic shock, sinusitis acute, sinusitis, Staphylococcal infection, urosepsis

Injury, poisoning and procedural complications: femur fracture, transfusion reaction, cervical vertebral fracture, femoral neck fracture, fractured pelvis, hip fracture, overdose, post procedural hemorrhage, rib fracture, road traffic accident, spinal compression fracture

Investigations: blood creatinine increased, hemoglobin decreased, liver function tests abnormal, troponin I increased

Metabolism and nutrition disorders: dehydration, gout, hypernatremia, hypoglycemia

Musculoskeletal and connective tissue disorders: arthritis, arthritis aggravated, gouty arthritis, neck pain, chondrocalcinosis pyrophosphate

Neoplasms benign, malignant and unspecified: acute leukemia, acute myeloid leukemia, bronchoalveolar carcinoma, lung cancer metastatic, lymphoma, prostate cancer metastatic

Nervous system disorders: cerebrovascular accident, aphasia, cerebellar infarction, cerebral infarction, depressed level of consciousness, dysarthria, migraine, spinal cord compression, subarachnoid hemorrhage, transient ischemic attack

Psychiatric disorders: confusional state

Renal and urinary disorders: renal failure, hematuria, renal failure acute, azotemia, calculus ureteric, renal mass

Reproductive system and breast disorders: pelvic pain

Respiratory, thoracic and mediastinal disorders: bronchitis, chronic obstructive airways disease exacerbated, respiratory failure, dyspnea exacerbated, interstitial lung disease, lung infiltration, wheezing

Skin and subcutaneous tissue disorders: acute febrile neutrophilic dermatosis

Vascular system disorders: deep vein thrombosis, hypotension, aortic disorder, ischemia, thrombophlebitis superficial, thrombosis

Mantle Cell Lymphoma:

In the MCL trial, a total of 134 patients received at least 1 dose of Mydolen. Their median age was 67 (range 43-83) years, 128/134 (96%) were Caucasian, 108/134 (81%) were males and 82/134 (61%) had duration of MCL for at least 3 years.

Table 11 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with Mydolen. Across the 134 patients treated in this study, median duration of treatment was 95 days (1-1002 days). Seventy-eight patients (58%) received 3 or more cycles of therapy, 53 patients (40%) received 6 or more cycles, and 26 patients (19%) received 12 or more cycles. Seventy-six patients (57%) underwent at least one dose interruption due to adverse events, and 51 patients (38%) underwent at least one dose reduction due to adverse events. Twenty-six patients (19%) discontinued treatment due to adverse events.

1-MCL trial AEs – All treatment emergent AEs with ≥10% of subjects 2-MCL trial Grade 3/4 AEs – All treatment-emergent Grade 3/4 AEs in 2 or more subjects $-MCL trial Serious AEs – All treatment-emergent SAEs in 2 or more subjects Mydolen - AEs where at least one resulted in a fatal outcome % - AEs where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases) #- All adverse reactions under Body System of Infections except for rare infections of Public Health interest will be considered listed +-All adverse reactions under HLT of Rash will be considered listed
Body System Adverse Reaction	All AEs1 (N=134)	Grade 3/4 AEs2 (N=134)
	n (%)	n (%)
General disorders and administration site conditions
Fatigue	45 (34)	9 (7)
Pyrexia$	31 (23)	3 (2)
Edema peripheral	21 (16)	0
Asthenia$	19 (14)	4 (3)
General physical health deterioration	3 (2)	2 (1)
Gastrointestinal disorders
Diarrhea$	42 (31)	8 (6)
Nausea$	40 (30)	1 (<1)
Constipation	21 (16)	1 (<1)
Vomiting$	16 (12)	1 (<1)
Abdominal pain$	13 (10)	5 (4)
Musculoskeletal and connective tissue disorders
Back pain	18 (13)	2 (1)
Muscle spasms	17 (13)	1 (<1)
Arthralgia	11 (8)	2 (1)
Muscular weakness$	8 (6)	2 (1)
Respiratory, thoracic and mediastinal disorders
Cough	38 (28)	1 (<1)
Dyspnea$	24 (18)	8 (6)
Pleural Effusion	10 (7)	2 (1)
Hypoxia	3 (2)	2 (1)
Pulmonary embolism	3 (2)	2 (1)
Respiratory distress$	2 (1)	2 (1)
Oropharyngeal pain	13 (10)	0
Infections and infestations
PneumoniaMydolen $	19 (14)	12 (9)
Upper respiratory tract infection	17 (13)	0
Cellulitis$	3 (2)	2 (1)
Bacteremia$	2 (1)	2 (1)
Staphylococcal sepsis$	2 (1)	2 (1)
Urinary tract infection$	5 (4)	2 (1)
Skin and subcutaneous tissue disorders
Rash+	30 (22)	2 (1)
Pruritus	23 (17)	1 (<1)
Blood and lymphatic system disorders
Neutropenia	65 (49)	58 (43)
Thrombocytopenia% $	48 (36)	37 (28)
Anemia$	41 (31)	15 (11)
Leukopenia$	20 (15)	9 (7)
Lymphopenia	10 (7)	5 (4)
Febrile neutropenia$	8 (6)	8 (6)
Metabolism and nutrition disorders
Decreased appetite	19 (14)	1 (<1)
Hypokalemia	17 (13)	3 (2)
Dehydration$	10 (7)	4 (3)
Hypocalcemia	4 (3)	2 (1)
Hyponatremia	3 (2)	3 (2)
Renal and urinary disorders
Renal failure$	5 (4)	2 (1)
Vascular disorders
HypotensionMydolen $	9 (7)	4 (3)
Deep vein thrombosis$	5 (4)	5 (4)
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Tumor flare	13 (10)	0
Squamous cell carcinoma of skin$	4 (3)	4 (3)
Investigations
Weight decreased	17 (13)	0

The following adverse events which have occurred in other indications and not described above have been reported (5%-10%) in patients treated with Mydolen monotherapy for mantle cell lymphoma.

General disorders and administration site conditions: Chills

Musculoskeletal and connective tissue disorders: Pain in extremity

Nervous system disorders: Dysgeusia, headache, neuropathy peripheral

Infections and infestations: Respiratory tract infection, sinusitis, nasopharyngitis

Skin and subcutaneous tissue disorders: Dry skin, night sweats

The following serious adverse events not described above and reported in 2 or more patients treated with Mydolen monotherapy for mantle cell lymphoma.

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

Infections and infestations: Clostridium difficile colitis, sepsis

Neoplasms benign, malignant and unspecified (including cysts and polyps): Basal cell carcinoma

Cardiac disorder: Supraventricular tachycardia

6.2 Postmarketing Experience

The following adverse drug reactions have been identified from the worldwide post-marketing experience with Mydolen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure

Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome, toxic epidermal necrolysis

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

Neoplasms benign, malignant and unspecified (incl 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)

Endocrine disorders: Hypothyroidism, hyperthyroidism

7 DRUG INTERACTIONS

• Digoxin: Periodic monitoring of digoxin plasma levels is recommended due to increased C_max and AUC with concomitant Mydolen therapy.
• Patients taking concomitant therapies such as erythropoietin stimulating agents or estrogen containing therapies may have an increased risk of thrombosis (7.2).

7.1 Digoxin

When digoxin was co-administered with multiple doses of Mydolen (10 mg/day) the digoxin C_max and AUC_inf were increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of Mydolen.

7.2 Concomitant Therapies That May Increase the Risk of Thrombosis

Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution after making a benefit-risk assessment in patients receiving Mydolen .

7.3 Warfarin

Co-administration of multiple doses of Mydolen (10 mg/day) with a single dose of warfarin (25 mg) had no effect on the pharmacokinetics of Mydolen or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant Mydolen administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in patients with MM taking concomitant warfarin.

8 USE IN SPECIFIC POPULATIONS

• Lactation: Advise women not to breastfeed..
• Renal Impairment: Adjust the starting dose of Mydolen for patients based on creatinine clearance value (2.4).

8.1 Pregnancy

Pregnancy Exposure Registry

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

Risk Summary

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

Mydolen is a 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), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants.

Mydolen caused thalidomide-type limb defects in monkey offspring. Mydolen crossed the placenta after administration to pregnant rabbits and pregnant rats . If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential risk to a fetus.

If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to Mydolen to the FDA via the MedWatch program at 1-800-FDA-1088 and also to Celgene Corporation at 1-888-423-5436.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

Data

Animal data

In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral Mydolen during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats.

In a pre- and post-natal development study in rats, animals received Mydolen from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with Mydolen at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for Mydolen.

Following daily oral administration of Mydolen from Gestation Day 7 through Gestation Day 20 in pregnant rabbits, fetal plasma Mydolen concentrations were approximately 20-40% of the maternal C_max. Following a single oral dose to pregnant rats, Mydolen was detected in fetal plasma and tissues; concentrations of radioactivity in fetal tissues were generally lower than those in maternal tissues. These data indicated that Mydolen crossed the placenta.

8.2 Lactation

Risk Summary

There is no information regarding the presence of Mydolen in human milk, the effects of Mydolen on the breastfed infant, or the effects of Mydolen on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants from Mydolen, advise women not to breastfeed during treatment with Mydolen.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Mydolen can cause fetal harm when administered during pregnancy . Verify the pregnancy status of females of reproductive potential prior to initiating Mydolen therapy and during therapy. Advise females of reproductive potential that they must avoid pregnancy 4 weeks before therapy, while taking Mydolen, during dose interruptions and for at least 4 weeks after completing therapy.

Females of reproductive potential must have 2 negative pregnancy tests before initiating Mydolen. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing Mydolen. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive 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 menstrual bleeding. Mydolen treatment must be discontinued during this evaluation.

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 – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partner’s vasectomy, and 1 additional effective contraceptive method – male latex or synthetic condom, diaphragm, or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with Mydolen, during therapy, during dose interruptions, and continuing for 4 weeks following discontinuation of Mydolen 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

Mydolen is present in the semen of males who take Mydolen. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking Mydolen and for up to 4 weeks after discontinuing Mydolen, even if they have undergone a successful vasectomy. Male patients taking Mydolen must not donate sperm.

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use

MM In Combination: Overall, of the 1613 patients in the NDMM study who received study treatment, 94% were 65 years of age or older, while 35% (561/1613) were over 75 years of age. The percentage of patients over age 75 was similar between study arms (Rd Continuous: 33%; Rd18: 34%; MPT: 33%). Overall, across all treatment arms, the frequency in most of the AE categories (eg, all AEs, grade 3/4 AEs, serious AEs) was higher in older (> 75 years of age) than in younger (≤ 75 years of age) subjects. Grade 3 or 4 AEs in the General Disorders and Administration Site Conditions body system were consistently reported at a higher frequency (with a difference of at least 5%) in older subjects than in younger subjects across all treatment arms. Grade 3 or 4 TEAEs in the Infections and Infestations, Cardiac Disorders (including cardiac failure and congestive cardiac failure), Skin and Subcutaneous Tissue Disorders, and Renal and Urinary Disorders (including renal failure) body systems were also reported slightly, but consistently, more frequently (<5% difference), in older subjects than in younger subjects across all treatment arms. For other body systems (e.g., Blood and Lymphatic System Disorders, Infections and Infestations, Cardiac Disorders, Vascular Disorders), there was a less consistent trend for increased frequency of grade 3/4 AEs in older vs younger subjects across all treatment arms Serious AEs were generally reported at a higher frequency in the older subjects than in the younger subjects across all treatment arms.

MM Maintenance Therapy: Overall, 10% (106/1018) of patients were 65 years of age or older, while no patients were over 75 years of age. Grade 3 or 4 AEs were higher in the Mydolen arm (more than 5% higher) in the patients 65 years of age or older versus younger patients. The frequency of Grade 3 or 4 AEs in the Blood and Lymphatic System Disorders were higher in the Mydolen arm (more than 5% higher) in the patients 65 years of age or older versus younger patients. There were not a sufficient number of patients 65 years of age or older in Mydolen maintenance studies who experienced either a serious AE, or discontinued therapy due to an AE to determine whether elderly patients respond relative to safety differently from younger patients.

MM After At Least One Prior Therapy: Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received REVLIMID/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of Mydolen. No differences in efficacy were observed between patients over 65 years of age and younger patients.

Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse events (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse events than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients.

Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse events was similar in patients over 65 years of age and in younger patients (98% vs. 100%). The overall incidence of grade 3 and 4 adverse events was also similar in these 2 patient groups (79% vs. 78%, respectively). The frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients.

Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function.

8.6 Renal Impairment

Adjust the starting dose of Mydolen based on the creatinine clearance value and for patients on dialysis .

10 OVERDOSAGE

There is no specific experience in the management of Mydolen overdose in patients with MM, MDS, or MCL. In dose-ranging studies in healthy subjects, some were exposed to up to 200 mg (administered 100 mg BID) and in single-dose studies, some subjects were exposed to up to 400 mg. Pruritus, urticaria, rash, and elevated liver transaminases were the primary reported AEs. In clinical trials, the dose-limiting toxicity was neutropenia and thrombocytopenia.

11 DESCRIPTION

Mydolen, a thalidomide analogue, is an immunomodulatory agent with antiangiogenic and antineoplastic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure:

3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione

The empirical formula for Mydolen is C₁₃H₁₃N₃O₃, and the gram molecular weight is 259.3.

Mydolen is an off-white to pale-yellow solid powder. It is soluble in organic solvent/water mixtures, and buffered aqueous solvents. Mydolen is more soluble in organic solvents and low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 0.4 to 0.5 mg/ml. Mydolen has an asymmetric carbon atom and can exist as the optically active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of zero.

Mydolen is available in 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg and 25 mg capsules for oral administration. Each capsule contains Mydolen as the active ingredient and the following 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 mg 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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Mydolen is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Cellular activities of Mydolen are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. In vitro, in the presence of drug, substrate proteins are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects. Mydolen inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including MM, mantle cell lymphoma, and del (5q) myelodysplastic syndromes in vitro. Mydolen causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including MM. Immunomodulatory properties of Mydolen include increased number and activation of T cells and natural killer (NK) cells leading to direct and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) via increased secretion of interleukin-2 and interferon-gamma, increased numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes. In MM cells, the combination of Mydolen and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis.

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of Mydolen on the QTc interval was evaluated in 60 healthy male subjects in a thorough QT study. At a dose two times the maximum recommended dose, Mydolen did not prolong the QTc interval. The largest upper bound of the two-sided 90% CI for the mean differences between Mydolen and placebo was below 10 ms.

12.3 Pharmacokinetics

Absorption

Mydolen is rapidly absorbed following oral administration. Following single and multiple doses of Mydolen in patients with MM or MDS, the maximum plasma concentrations occurred between 0.5 and 6 hours post-dose. The single and multiple dose pharmacokinetic disposition of Mydolen is linear with AUC and C_max values increasing proportionally with dose. Multiple doses of Mydolen at the recommended dosage does not result in drug accumulation.

Administration of a single 25 mg dose of Mydolen with a high-fat meal in healthy subjects reduces the extent of absorption, with an approximate 20% decrease in AUC and 50% decrease in C_max. In the trials where the efficacy and safety were established for Mydolen, the drug was administered without regard to food intake. Mydolen can be administered with or without food.

The oral absorption rate of Mydolen in patients with MCL is similar to that observed in patients with MM or MDS.

Distribution

In vitro [¹⁴C]-lenalidomide binding to plasma proteins is approximately 30%.

Mydolen is present in semen at 2 hours (1379 ng/ejaculate) and 24 hours (35 ng/ejaculate) after the administration of Mydolen 25 mg daily.

Elimination

The mean half-life of Mydolen is 3 hours in healthy subjects and 3 to 5 hours in patients with MM, MDS or MCL

Metabolism

Mydolen undergoes limited metabolism. Unchanged Mydolen is the predominant circulating component in humans. Two identified metabolites are 5-hydroxy-lenalidomide and N-acetyl-lenalidomide; each constitutes less than 5% of parent levels in circulation.

Excretion

Elimination is primarily renal. Following a single oral administration of [¹⁴C]-lenalidomide 25 mg to healthy subjects, approximately 90% and 4% of the radioactive dose was eliminated within ten days in urine and feces, respectively. Approximately 82% of the radioactive dose was excreted as Mydolen in the urine within 24 hours. Hydroxy-lenalidomide and N-acetyl-lenalidomide represented 4.6% and 1.8% of the excreted dose, respectively. The renal clearance of Mydolen exceeds the glomerular filtration rate.

Specific Populations

Renal Impairment: Eight subjects with mild renal impairment (creatinine clearance (CLcr) 50 to 79 mL/min calculated using Cockcroft-Gault), 9 subjects with moderate renal impairment (CLcr 30 to 49 mL/min), 4 subjects with severe renal impairment (CLcr < 30 mL/min), and 6 patients with end stage renal disease (ESRD) requiring dialysis were administered a single 25 mg dose of Mydolen. Three healthy subjects of similar age with normal renal function (CLcr > 80 mL/min) were also administered a single 25 mg dose of Mydolen. As CLcr decreased, half-life increased and drug clearance decreased linearly. Patients with moderate and severe impairment had a 3-fold increase in half-life and a 66% to 75% decrease in drug clearance compared to healthy subjects. Patients on hemodialysis (n=6) had an approximate 4.5-fold increase in half-life and an 80% decrease in drug clearance compared to healthy subjects. Approximately 30% of the drug in body was removed during a 4-hour hemodialysis session.

Adjust the starting dose of Mydolen in patients with renal impairment based on the CLcr value .

Hepatic Impairment: Mild hepatic impairment (defined as total bilirubin > 1 to 1.5 times upper limit normal (ULN) or any aspartate transaminase greater than ULN) did not influence the disposition of Mydolen. No pharmacokinetic data is available for patients with moderate to severe hepatic impairment.

Other Intrinsic Factors: Age (39 to 85 years), body weight (33 to 135 kg), sex, race, and type of hematological malignancies (MM, MDS or MCL) did not have a clinically relevant effect on Mydolen clearance in adult patients.

Drug Interactions

Co-administration of a single dose or multiple doses of dexamethasone (40 mg) had no clinically relevant effect on the multiple dose pharmacokinetics of Mydolen (25 mg).

Co-administration of Mydolen (25 mg) after multiple doses of a P-gp inhibitor such as quinidine (600 mg twice daily) did not significantly increase the Cmax or AUC of Mydolen.

Co-administration of the P-gp inhibitor and substrate temsirolimus (25 mg),with Mydolen (25 mg) did not significantly alter the pharmacokinetics of Mydolen, temsirolimus, or sirolimus (metabolite of temsirolimus).

In vitro studies demonstrated that Mydolen is a substrate of P-glycoprotein (P-gp). Mydolen 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, organic anion transporting polypeptide 1B1 (OATP1B1), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2. Mydolen is not an inhibitor of P-gp, bile salt export pump (BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2. Mydolen does not inhibit or induce CYP450 isoenzymes. Also, Mydolen does not inhibit bilirubin glucuronidation formation in human liver microsomes with UGT1A1 genotyped as UGT1A1*1/*1, UGT1A1*1/*28, and UGT1A1*28/*28.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with Mydolen have not been conducted.

Mydolen was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Mydolen did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats.

A fertility and early embryonic development study in rats, with administration of Mydolen up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility.

14 CLINICAL STUDIES

14.1 Multiple Myeloma

Randomized, Open-Label Clinical Trial in Patients with Newly Diagnosed MM:

A randomized multicenter, open-label, 3-arm trial of 1,623 patients, was conducted to compare the efficacy and safety of Mydolen and low-dose dexamethasone given for 2 different durations of time to that of melphalan, prednisone and thalidomide (MPT) in newly diagnosed MM patients who were not a candidate for stem cell transplant. In the first arm of the study, Rd was given continuously until progressive disease [Arm Rd Continuous]. In the second arm, Rd was given for up to eighteen 28-day cycles [72 weeks, Arm Rd18]). In the third arm, melphalan, prednisone and thalidomide (MPT) was given for a maximum of twelve 42-day cycles (72 weeks). For the purposes of this study, a patient who was < 65 years of age was not a candidate for SCT if the patient refused to undergo SCT therapy or the patient did not have access to SCT due to cost or other reasons. Patients were stratified at randomization by age (≤75 versus >75 years), stage (ISS Stages I and II versus Stage III), and country.

Patients in the Rd Continuous and Rd18 arms received Mydolen 25 mg once daily on Days 1 to 21 of 28-day cycles. Dexamethasone was dosed 40 mg once daily on Days 1, 8, 15, and 22 of each 28-day cycle. For patients over > 75 years old, the starting dose of dexamethasone was 20 mg orally once daily on days 1,8,15, and 22 of repeated 28-day cycles. Initial dose and regimens for Rd Continuous and Rd18 were adjusted according to age and renal function. All patients received prophylactic anticoagulation with the most commonly used being aspirin.

The demographics and disease-related baseline characteristics of the patients were balanced among the 3 arms. In general, study subjects had advanced-stage disease. Of the total study population, the median age was 73 in the 3 arms with 35% of total patients > 75 years of age; 59% had ISS Stage I/II; 41% had ISS stage III; 9% had severe renal impairment (creatinine clearance [CLcr] < 30 mL/min); 23% had moderate renal impairment (CLcr > 30 to 50 mL/min; 44% had mild renal impairment (CLcr > 50 to 80 mL/min). For ECOG Performance Status, 29% were Grade 0, 49% Grade 1, 21% Grade 2, 0.4% ≥ Grade 3.

The primary efficacy endpoint, progression-free survival (PFS), was defined as the time from randomization to the first documentation of disease progression as determined by Independent Response Adjudication Committee (IRAC), based on International Myeloma Working Group [IMWG] criteria or death due to any cause, whichever occurred first during the study until the end of the PFS follow-up phase. For the efficacy analysis of all endpoints, the primary comparison was between Rd Continuous and MPT arms. The efficacy results are summarized in the table below. PFS was significantly longer with Rd Continuous than MPT: HR 0.72 (95% CI: 0.61-0.85 p <0.0001). A lower percentage of subjects in the Rd Continuous arm compared with the MPT arm had PFS events (52% versus 61%, respectively). The improvement in median PFS time in the Rd Continuous arm compared with the MPT arm was 4.3 months. The myeloma response rate was higher with Rd Continuous compared with MPT (75.1% versus 62.3%); with a complete response in 15.1% of Rd Continuous arm patients versus 9.3% in the MPT arm. The median time to first response was 1.8 months in the Rd Continuous arm versus 2.8 months in the MPT arm.

For the interim OS analysis with 03 March 2014 data cutoff, the median follow-up time for all surviving patients is 45.5 months, with 697 death events, representing 78% of prespecified events required for the planned final OS analysis (697/896 of the final OS events). The observed OS HR was 0.75 for Rd Continuous versus MPT (95% CI = 0.62, 0.90).

CR = complete response; d = low-dose dexamethasone; HR = hazard ratio; IRAC = Independent Response Adjudication Committee; M = melphalan; NE = not estimable; OS = overall survival; P = prednisone; PFS = progression-free survival; PR = partial response; R = Mydolen; Rd Continuous = Rd given until documentation of progressive disease; Rd18 = Rd given for ≤ 18 cycles; T = thalidomide; VGPR = very good partial response; vs = versus. a The median is based on the Kaplan-Meier estimate. b The 95% Confidence Interval (CI) about the median. c Based on 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 Kaplan-Meier curve differences between the indicated treatment arms. e Best assessment of response during the treatment phase of the study f Including patients with no response assessment data or whose only assessment was “response not evaluable.” g Data cutoff date = 24 May 2013. h Data cutoff date = 3 March 2014.
	Rd Continuous (N = 535)	Rd18 (N = 541)	MPT (N = 547)
PFS - IRAC (months)g
Number of PFS events	278 (52.0)	348 (64.3)	334 (61.1)
Mediana PFS time, months (95% CI)b	25.5 (20.7, 29.4)	20.7 (19.4, 22.0)	21.2 (19.3, 23.2)
HR [95% CI]c; p-valued
Rd Continuous vs MPT	0.72 (0.61, 0.85); <0.0001
Rd Continuous vs Rd18	0.70 (0.60, 0.82)
Rd18 vs MPT	1.03 (0.89, 1.20)
Overall Survival (months)h
Number of Death events	208 (38.9)	228 (42.1)	261 (47.7)
Mediana OS time, months (95% CI)b	58.9 (56.0, NE)f	56.7 (50.1, NE)	48.5 (44.2, 52.0 )
HR [95% CI]c
Rd Continuous vs MPT	0.75 (0.62, 0.90)
Rd Continuous vs Rd18	0.91 (0.75, 1.09)
Rd18 vs MPT	0.83 (0.69, 0.99)
Response Ratee - IRAC, n (%)g
CR	81 (15.1)	77 (14.2)	51 (9.3)
VGPR	152 (28.4)	154 (28.5)	103 (18.8)
PR	169 (31.6)	166 (30.7)	187 (34.2)
Overall response: CR, VGPR, or PR	402 (75.1)	397 (73.4)	341 (62.3)

Kaplan-Meier Curves of Progression-free Survival Based on IRAC Assessment (ITT Population)

Between Arms Rd Continuous, Rd18 and MPT

Cutoff date: 24 May 2013

CI = confidence interval; d = low-dose dexamethasone; HR = hazard ratio; IRAC = Independent Response Adjudication Committee;

M = melphalan; P = prednisone; R = Mydolen; Rd Continuous = Rd given until documentation of progressive disease; Rd18 = Rd given for ≤ 18 cycles; T = thalidomide.

Kaplan-Meier Curves of Overall Survival (ITT Population)

Between Arms Rd Continuous, Rd18 and MPT

Cutoff date: 03 Mar 2014

CI = confidence interval; d = low-dose dexamethasone; HR = hazard ratio; M = melphalan; P = prednisone; R = Mydolen; Rd

Continuous = Rd given until documentation of progressive disease; Rd18 = Rd given for ≤18 cycles; T = thalidomide.

Randomized, Placebo-Controlled Clinical Trials - Maintenance Following Auto-HSCT:

Two multicenter, randomized, double-blind, parallel group, placebo-controlled studies were conducted to evaluate the efficacy and safety of Mydolen maintenance therapy in the treatment of MM patients after auto-HSCT. In Maintenance Study 1, patients between 18 and 70 years of age who had undergone induction therapy followed by auto-HSCT were eligible. Induction therapy must have occurred within 12 months. Within 90-100 days after auto-HSCT, patients with at least a stable disease response were randomized 1:1 to receive either Mydolen or placebo maintenance. In Maintenance Study 2, patients aged < 65 years at diagnosis who had undergone induction therapy followed by auto-HSCT and had achieved at least a stable disease response at the time of hematologic recovery were eligible. Within 6 months after auto-HSCT, patients were randomized 1:1 to receive either Mydolen or placebo maintenance. Patients eligible for both trials had to have CLcr ≥30 mL/minute.

In both studies, the Mydolen maintenance dose was 10 mg once daily on days 1-28 of repeated 28-day cycles, could be increased to 15 mg once daily after 3 months in the absence of dose-limiting toxicity, and treatment was to be continued until disease progression or patient withdrawal for another reason. The dose was reduced, or treatment was temporarily interrupted or stopped, as needed to manage toxicity. A dose increase to 15 mg once daily occurred in 135 patients (58%) in Maintenance Study 1, and in 185 patients (60%) in Maintenance Study 2.

The demographics and disease-related baseline characteristics of the patients were similar across the two studies and reflected a typical MM population after auto-HSCT.

Data cutoff date = 1 March 2015.
	Maintenance Study 1		Maintenance Study 2
	Mydolen N = 231	Placebo N = 229	Mydolen N = 307	Placebo N = 307
Age (years)
Median	58.0	58.0	57.5	58.1
(Min, max)	(29.0, 71.0)	(39.0, 71.0)	(22.7, 68.3)	(32.3, 67.0)
Sex, n (%)
Male	121 (52)	129 (56)	169 (55)	181 (59)
Female	110 (48)	100 (44)	138 (45)	126 (41)
ISS Stage at Diagnosis, n (%)
Stage I or II	120 (52)	131 (57)	232 (76)	250 (81)
Stage I	62 (27)	85 (37)	128 (42)	143 (47)
Stage II	58 (25)	46 (20)	104 (34)	107 (35)
Stage III	39 (17)	35 (15)	66 (21)	46 (15)
Missing	72 (31)	63 (28)	9 (3)	11 (4)
CrCl at Post-auto-HSCT, n (%)
< 50 mL/min	23 (10)	16 (7)	10 (3)	9 (3)
≥ 50 mL/min	201 (87)	204 (89)	178 (58)	200 (65)
Missing	7 (3)	9 (4)	119 (39)	98 (32)

The major efficacy endpoint of both studies was PFS defined from randomization to the date of progression or death, whichever occurred first; the individual studies were not powered for an overall survival endpoint. Both studies were unblinded upon the recommendations of their respective data monitoring committees and after surpassing the respective thresholds for preplanned interim analyses of PFS. After unblinding, patients continued to be followed as before. Patients in the placebo arm of Maintenance Study 1 were allowed to cross over to receive Mydolen before disease progression (76 patients [33%] crossed over to Mydolen); patients in Maintenance Study 2 were not recommended to cross over. The efficacy results are summarized in the following table. In both studies, the primary analysis of PFS at unblinding was significantly longer with Mydolen compared to placebo: Maintenance Study 1 HR 0.38 (95% CI: 0.27-0.54 p <0.001) and Maintenance Study 2 HR 0.50 (95% CI: 0.39-0.64 p <0.001). For both studies, PFS was updated with a cutoff date of 1 March 2015 as shown in the table and the following Kaplan Meier graphs. With longer follow-up (median 72.4 and 86.0 months, respectively), the updated PFS analyses for both studies continue to show a PFS advantage for Mydolen compared to placebo: Maintenance Study 1 HR 0.38 (95% CI: 0.28-0.50) with median PFS of 68.6 months and Maintenance Study 2 HR 0.53 (95% CI: 0.44-0.64) with median PFS of 46.3 months.

Descriptive analysis of OS data with a cutoff date of 1 February 2016 are provided in Table 14. Median follow-up time was 81.6 and 96.7 months for Maintenance Study 1 and Maintenance Study 2, respectively. Median OS was 111.0 and 84.2 months for Mydolen and placebo, respectively, for Maintenance Study 1, and 105.9 and 88.1 months, for Mydolen and placebo, respectively, for Maintenance Study 2.

Date of Unblinding in Maintenance Study 1 and 2 = 17 December 2009 and 7 July 2010, respectively Auto-HSCT = autologous hematopoietic stem cell transplantation; CI = confidence interval; ITT = intent to treat; NE = not estimable; PFS = progression-free survival PFS at time of unblinding for Maintenance Study 2 was based on assessment by an Independent Review Committee. All other PFS analyses were based on assessment by investigator. Note: The median is based on Kaplan-Meier estimate, with 95% CIs about the median overall PFS time. Hazard ratio is based on a proportional hazards model stratified by stratification factors comparing the hazard functions associated with treatment arms (lenalidomide:placebo).
	Maintenance Study 1		Maintenance Study 2
	Mydolen N = 231	Placebo N = 229	Mydolen N = 307	Placebo N = 307
PFS at Unblinding
PFS Events n (%)
	46 (20)	98 (43)	103 (34)	160 (52)
Median in months [95% CI]	33.9 [NE, NE]	19.0 [16.2, 25.6]	41.2 [38.3, NE]	23.0 [21.2, 28.0]
Hazard Ratio [95% CI]	0.38 [0.27, 0.54]		0.50 [0.39, 0.64]
Log-rank Test p-value	<0.001		<0.001
PFS at Updated Analysis 1 March 2015 (Studies 1 and 2)
PFS Events n (%)	97 (42)	116 (51)	191 (62)	248 (81)
Median in months [95% CI]	68.6 [52.8, NE]	22.5 [18.8, 30.0]	46.3 [40.1, 56.6]	23.8 [21.0, 27.3]
Hazard Ratio [95% CI]	0.38 [0.28, 0.50]		0.53 [0.44, 0.64]
OS at Updated Analysis 1 Feb 2016 (Studies 1 and 2)
OS Events n (%)	82 (35)	114 (50)	143 (47)	160 (52)
Median in months [95% CI]	111.0 [101.8, NE]	84.2 [71.0, 102.7]	105.9 [88.8, NE]	88.1 [80.7, 108.4]
Hazard Ratio [95% CI]	0.59 [0.44, 0.78]		0.90 [0.72, 1.13]

Kaplan-Meier Curves of Progression-free Survival From Randomization (ITT Post-Auto-HSCT Population)

in Maintenance Study 1 Between Mydolen and Placebo Arms (Updated Cutoff Date 1 March 2015)

Auto-HSCT = autologous hematopoietic stem cell transplantation; CI = confidence interval; HR = hazard ratio; ITT = intent to treat; KM = Kaplan-Meier; PFS = progression-free survival; vs = versus

Kaplan-Meier Curves of Progression-free Survival From Randomization (ITT Post-Auto-HSCT Population)

in Maintenance Study 2 Between Mydolen and Placebo Arms (Updated Cutoff Date 1 March 2015)

Auto-HSCT = autologous hematopoietic stem cell transplantation; CI = confidence interval; HR = hazard ratio; ITT = intent to treat; KM = Kaplan-Meier; NE = not estimable; PFS = progression-free survival; vs = versus

Randomized, Open-Label Clinical Studies in Patients with MM After At Least One Prior Therapy

Two randomized studies (Studies 1 and 2) were conducted to evaluate the efficacy and safety of Mydolen. These multicenter, multinational, double-blind, placebo-controlled studies compared Mydolen plus oral pulse high-dose dexamethasone therapy to dexamethasone therapy alone in patients with MM who had received at least one prior treatment. These studies enrolled patients with absolute neutrophil counts (ANC) ≥ 1000/mm³, platelet counts ≥ 75,000/mm³, serum creatinine ≤ 2.5 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2 mg/dL.

In both studies, patients in the REVLIMID/dexamethasone group took 25 mg of Mydolen orally once daily on Days 1 to 21 and a matching placebo capsule once daily on Days 22 to 28 of each 28-day cycle. Patients in the placebo/dexamethasone group took 1 placebo capsule on Days 1 to 28 of each 28-day cycle. Patients in both treatment groups took 40 mg of dexamethasone orally once daily on Days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the first 4 cycles of therapy.

The dose of dexamethasone was reduced to 40 mg orally once daily on Days 1 to 4 of each 28-day cycle after the first 4 cycles of therapy. In both studies, treatment was to continue until disease progression.

In both studies, dose adjustments were allowed based on clinical and laboratory findings. Sequential dose reductions to 15 mg daily, 10 mg daily and 5 mg daily were allowed for toxicity [see Dosage and Administration (2.1)].

Table 15 summarizes the baseline patient and disease characteristics in the two studies. In both studies, baseline demographic and disease-related characteristics were comparable between the REVLIMID/dexamethasone and placebo/dexamethasone groups.

	Study 1		Study 2
	REVLIMID/Dex N=177	Placebo/Dex N=176	REVLIMID/Dex N=176	Placebo/Dex N=175
Patient Characteristics
Age (years) Median Min, Max	64 36, 86	62 37, 85	63 33, 84	64 40, 82
Sex Male Female	106 (60%) 71 (40%)	104 (59%) 72 (41%)	104 (59%) 72 (41%)	103 (59%) 72 (41%)
Race/Ethnicity White Other	141(80%) 36 (20%)	148 (84%) 28 (16%)	172 (98%) 4 (2%)	175(100%) 0 (0%)
ECOG Performance Status 0-1	157 (89%)	168 (95%)	150 (85%)	144 (82%)
Disease Characteristics
Multiple Myeloma Stage (Durie- Salmon) I II III	3% 32% 64%	3% 31% 66%	6% 28% 65%	5% 33% 63%
B2-microglobulin (mg/L) ≤ 2.5 mg/L >2.5 mg/L	52 (29%) 125 (71%)	51 (29%) 125 (71%)	51 (29%) 125 (71%)	48 (27%) 127 (73%)
Number of Prior Therapies
1 ≥ 2	38% 62%	38% 62%	32% 68%	33% 67%
Types of Prior Therapies
Stem Cell Transplantation	62%	61%	55%	54%
Thalidomide	42%	46%	30%	38%
Dexamethasone	81%	71%	66%	69%
Bortezomib	11%	11%	5%	4%
Melphalan	33%	31%	56%	52%
Doxorubicin	55%	51%	56%	57%

The primary efficacy endpoint in both studies was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive disease.

Preplanned interim analyses of both studies showed that the combination of REVLIMID/dexamethasone was significantly superior to dexamethasone alone for TTP. The studies were unblinded to allow patients in the placebo/dexamethasone group to receive treatment with the REVLIMID/dexamethasone combination. For both studies, the extended follow-up survival data with crossovers were analyzed. In study 1, the median survival time was 39.4 months (95%CI: 32.9, 47.4) in REVLIMID/dexamethasone group and 31.6 months (95%CI: 24.1, 40.9) in placebo/dexamethasone group, with a hazard ratio of 0.79 (95% CI: 0.61-1.03). In study 2, the median survival time was 37.5 months (95%CI: 29.9, 46.6) in REVLIMID/dexamethasone group and 30.8 months (95%CI: 23.5, 40.3) in placebo/dexamethasone group, with a hazard ratio of 0.86 (95% CI: 0.65-1.14).

	Study 1		Study 2
	REVLIMID/Dex N=177	Placebo/Dex N=176	REVLIMID/Dex N=176	Placebo/Dex N=175
TTP
Events n (%)	73 (41)	120 (68)	68 (39)	130 (74)
Median TTP in months [95% CI]	13.9 [9.5, 18.5]	4.7 [3.7, 4.9]	12.1 [9.5, NE]	4.7 [3.8, 4.8]
Hazard Ratio [95% CI]	0.285 [0.210, 0.386]		0.324 [0.240, 0.438]
Log-rank Test p-value 3	<0.001		<0.001
Response
Complete Response (CR) n (%)	23 (13)	1 (1)	27 (15)	7 (4)
Partial Response (RR/PR) n (%)	84 (48)	33 (19)	77 (44)	34 (19)
Overall Response n (%)	107 (61)	34 (19)	104 (59)	41 (23)
p-value	<0.001		<0.001
Odds Ratio [95% CI]	6.38 [3.95, 10.32]		4.72 [2.98, 7.49]

Kaplan-Meier Estimate of Time to Progression - Study 1

Kaplan-Meier Estimate of Time to Progression - Study 2

14.2 Myelodysplastic Syndromes (MDS) with a Deletion 5q Cytogenetic Abnormality

The efficacy and safety of Mydolen were evaluated in patients with transfusion-dependent anemia in low- or intermediate-1- risk MDS with a 5q (q31-33) cytogenetic abnormality in isolation or with additional cytogenetic abnormalities, at a dose of 10 mg once daily or 10 mg once daily for 21 days every 28 days in an open-label, single-arm, multi-center study. The major study was not designed nor powered to prospectively compare the efficacy of the 2 dosing regimens. Sequential dose reductions to 5 mg daily and 5 mg every other day, as well as dose delays, were allowed for toxicity [Dosage and Administration (2.2)].

This major study enrolled 148 patients who had RBC transfusion dependent anemia. RBC transfusion dependence was defined as having received ≥ 2 units of RBCs within 8 weeks prior to study treatment. The study enrolled patients with absolute neutrophil counts (ANC) ≥ 500/mm³, platelet counts ≥ 50,000/mm³, serum creatinine ≤ 2.5 mg/dL, serum SGOT/AST or SGPT/ALT ≤ 3 x upper limit of normal (ULN), and serum direct bilirubin ≤ 2 mg/dL. Granulocyte colony-stimulating factor was permitted for patients who developed neutropenia or fever in association with neutropenia. Baseline patient and disease-related characteristics are summarized in Table 17.

[a] IPSS Risk Category: Low (combined score = 0), Intermediate-1 (combined score = 0.5 to 1.0), Intermediate-2 (combined score = 1.5 to 2.0), High (combined score ≥ 2.5); Combined score = (Marrow blast score + Karyotype score + Cytopenia score) [b] French-American-British (FAB) classification of MDS.
	Overall (N=148)
Age (years)
Median	71.0
Min, Max	37.0, 95.0
Gender	n	(%)
Male	51	(34.5)
Female	97	(65.5)
Race	n	(%)
White	143	(96.6)
Other	5	(3.4)
Duration of MDS (years)
Median	2.5
Min, Max	0.1, 20.7
Del 5 (q31-33) Cytogenetic Abnormality	n	(%)
Yes	148	(100.0)
Other cytogenetic abnormalities	37	(25.2)
IPSS Score [a]	n	(%)
Low (0)	55	(37.2)
Intermediate-1 (0.5-1.0)	65	(43.9)
Intermediate-2 (1.5-2.0)	6	(4.1)
High (≥2.5)	2	(1.4)
Missing	20	(13.5)
FAB Classification [b] from central review	n	(%)
RA	77	(52.0)
RARS	16	(10.8)
RAEB	30	(20.3)
CMML	3	(2.0)

The frequency of RBC transfusion independence was assessed using criteria modified from the International Working Group (IWG) response criteria for MDS. RBC transfusion independence was defined as the absence of any RBC transfusion during any consecutive “rolling” 56 days (8 weeks) during the treatment period.

Transfusion independence was seen in 99/148 (67%) patients (95% CI [59, 74]). The median duration from the date when RBC transfusion independence was first declared (i.e., the last day of the 56-day RBC transfusion-free period) to the date when an additional transfusion was received after the 56-day transfusion-free period among the 99 responders was 44 weeks (range of 0 to >67 weeks). Ninety percent of patients who achieved a transfusion benefit did so by completion of three months in the study.

RBC transfusion independence rates were unaffected by age or gender.

The dose of Mydolen was reduced or interrupted at least once due to an adverse event in 118 (79.7%) of the 148 patients; the median time to the first dose reduction or interruption was 21 days (mean, 35.1 days; range, 2-253 days), and the median duration of the first dose interruption was 22 days (mean, 28.5 days; range, 2-265 days). A second dose reduction or interruption due to adverse events was required in 50 (33.8%) of the 148 patients. The median interval between the first and second dose reduction or interruption was 51 days (mean, 59.7 days; range, 15-205 days) and the median duration of the second dose interruption was 21 days (mean, 26 days; range, 2-148 days).

14.3 Mantle Cell Lymphoma

A multicenter, single-arm, open-label trial of single-agent Mydolen was conducted to evaluate the safety and efficacy of Mydolen in patients with mantle cell lymphoma who have relapsed after or were refractory to bortezomib or a bortezomib-containing regimen. Patients with a creatinine clearance ≥60 mL/min were given Mydolen at a dose of 25 mg once daily for 21 days every 28 days. Patients with a creatinine clearance ≥30 mL/min and <60 mL/min were given Mydolen at a dose of 10 mg once daily for 21 days every 28 days. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent.

The trial included patients who were at least 18 years of age with biopsy-proven MCL with measurable disease by CT scan. Patients were required to have received prior treatment with an anthracycline or mitoxantrone, cyclophosphamide, rituximab, and bortezomib, alone or in combination. Patients were required to have documented refractory disease (defined as without any response of PR or better during treatment with bortezomib or a bortezomib-containing regimen), or relapsed disease (defined as progression within one year after treatment with bortezomib or a bortezomib-containing regimen). At enrollment patients were to have an absolute neutrophil counts (ANC) ≥1500/ mm³, platelet counts ≥ 60,000/mm³, serum SGOT/AST or SGPT/ALT ≤3x upper limit of normal (ULN) unless there was documented evidence of liver involvement by lymphoma, serum total bilirubin ≤1.5 x ULN except in cases of Gilbert’s syndrome or documented liver involvement by lymphoma, and calculated creatinine clearance (Cockcroft-Gault formula) ≥30 mL/min.

The median age was 67 years (43-83), 81% were male and 96% were Caucasian. The table below summarizes the baseline disease-related characteristics and prior anti-lymphoma therapy in the Mantle Cell Lymphoma trial.

a) ECOG = Eastern Cooperative Oncology Group b) MIPI = MCL International Prognostic Index c) High tumor burden is defined as at least one lesion that is ≥5 cm in diameter or 3 lesions that are ≥3 cm in diameter d) Bulky disease is defined as at least one lesion that is ≥7cm in the longest diameter
Baseline Disease Characteristics and Prior Anti - Lymphoma Treatment	Total Patients (N=134)
ECOG Performance Statusa n (%) 0 1 2 3	43 (32) 73 (54) 17 (13) 1 (<1)
Advanced MCL Stage, n (%) III IV	27 (20) 97 (72)
High or Intermediate MIPI Score b, n (%)	90 (67)
High Tumor Burdenc, n (%)	77 (57)
Bulky Diseased, n (%)	44 (33)
Extranodal Disease, n (%)	101 (75)
Number of Prior Systemic Anti-Lymphoma Therapies, n (%) Median (range) 1 2 3 ≥ 4	4 (2, 10) 0 (0) 29 (22) 34 (25) 71 (53)
Number of Subjects Who Received Prior Regimen Containing, n (%): Anthracycline/mitoxantrone Cyclophosphamide Rituximab Bortezomib	133 (99) 133 (99) 134 (100) 134 (100)
Refractory to Prior Bortezomib, n (%)	81 (60)
Refractory to Last Prior Therapy, n (%)	74 (55)
Prior Autologous Bone Marrow or Stem Cell Transplant, n (%)	39 (29)

The efficacy endpoints in the MCL trial were overall response rate (ORR) and duration of response (DOR). Response was determined based on review of radiographic scans by an independent review committee according to a modified version of the International Workshop Lymphoma Response Criteria (Cheson, 1999). The DOR is defined as the time from the initial response (at least PR) to documented disease progression. The efficacy results for the MCL population were based on all evaluable patients who received at least one dose of study drug and are presented in Table 19. The median time to response was 2.2 months (range 1.8 to 13 months).

Response Analyses (N = 133)	N (%)	95% CI
Overall Response Rate (IWRC) (CR + CRu +PR) Complete Response (CR + CRu) CR CRu Partial Response (PR)	34 (26) 9 (7) 1 (1) 8 (6) 25 (19)	(18.4, 33.9) (3.1, 12.5)
Duration of Response (months)	Median	95% CI
Duration of Overall Response (CR + CRu + PR) (N = 34)	16.6	(7.7, 26.7)

15 REFERENCES

1. OSHA Hazardous Drugs. OSHA [Accessed on 29 January 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

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

2.5 mg bottles of 28

2.5 mg bottles of 100 (NDC 59572-402-00)

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

5 mg bottles of 28 (NDC 59572-405-28)

5 mg bottles of 100 (NDC 59572-405-00)

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

10 mg bottles of 28 (NDC 59572-410-28)

10 mg bottles of 100 (NDC 59572-410-00)

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

15 mg bottles of 21 (NDC 59572-415-21)

15 mg bottles of 100 (NDC 59572-415-00)

Powder blue and blue-green opaque hard capsules imprinted “REV” on one half and “20 mg” on the other half in black ink.

20 mg bottles of 21 (NDC 59572-420-21)

20 mg bottles of 100 (NDC 59572-420-00)

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

25 mg bottles of 21 (NDC 59572-425-21)

25 mg bottles of 100 (NDC 59572-425-00)

16.2 Storage

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

16.3 Handling and Disposal

Care should be exercised in the handling of Mydolen. Mydolen capsules should not be opened or broken. If powder from Mydolen contacts the skin, wash the skin immediately and thoroughly with soap and water. If Mydolen contacts the mucous membranes, flush thoroughly with water.

Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published.¹

Dispense no more than a 28-day supply.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved Patient labeling (Medication Guide)

Embryo-Fetal Toxicity

Advise patients that Mydolen is contraindicated in pregnancy . Mydolen is a thalidomide analog and can cause serious birth defects or death to a developing baby .

• Advise females of reproductive potential that they must avoid pregnancy while taking Mydolen and for at least 4 weeks after completing therapy.
• Initiate Mydolen treatment in females of reproductive potential only following a negative pregnancy test.
• Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use 2 different forms of contraception including at least 1 highly effective form, simultaneously during Mydolen therapy, during dose interruption and for 4 weeks after she has completely finished taking Mydolen. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap.
• Instruct patient to immediately stop taking Mydolen and contact her healthcare provider if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant.
• Advise patient that if her healthcare provider is not available, she should call Celgene Customer Care Center at 1-888-423-5436 .
• Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking Mydolen and for up to 4 weeks after discontinuing Mydolen, even if they have undergone a successful vasectomy.
• Advise male patients taking Mydolen that they must not donate sperm .
• All patients must be instructed to not donate blood while taking Mydolen, during dose interruptions and for 4 weeks following discontinuation of Mydolen .

Mydolen REMS program

Because of the risk of embryo-fetal toxicity, Mydolen is only available through a restricted program called the Mydolen REMS program .

• Patients must sign a Patient-Physician agreement form and comply with the requirements to receive Mydolen. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements .
• Mydolen is available only from pharmacies that are certified in Mydolen REMS program. Provide patients with the telephone number and website for information on how to obtain the product.

Pregnancy Exposure Registry

Inform females there is a Pregnancy Exposure Registry that monitors pregnancy outcomes in females exposed to Mydolen during pregnancy and that they can contact the Pregnancy Exposure Registry by calling 1-888-423-5436 .

Hematologic Toxicity

Inform patients that Mydolen is associated with significant neutropenia and thrombocytopenia .

Venous and Arterial Thromboembolism

Inform patients of the risk of thrombosis including DVT, PE, MI, and stroke and to report immediately any signs and symptoms suggestive of these events for evaluation .

Increased Mortality in Patients with CLL

Inform patients that Mydolen had increased mortality in patients with CLL and serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure .

Second Primary Malignancies

Inform patients of the potential risk of developing second primary malignancies during treatment with Mydolen .

Hepatotoxicity

Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare provider for evaluation .

Allergic Reactions

Inform patients of the potential for allergic reactions including hypersensitivity, angioedema, Stevens-Johnson Syndrome, or toxic epidermal necrolysis if they had such a reaction to THALOMID and report symptoms associated with these events to their healthcare provider for evaluation .

Tumor Lysis Syndrome

Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation .

Tumor Flare Reaction

Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation .

Dosing Instructions

Inform patients how to take Mydolen

• Mydolen should be taken once daily at about the same time each day,
• Mydolen may be taken either with or without food.
• The capsules should not be opened, broken, or chewed. Mydolen should be swallowed whole with water.
• Instruct patients that if they miss a dose of Mydolen, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take Mydolen at the usual time. Warn patients to not take 2 doses to make up for the one that they missed.

Manufactured for: Celgene Corporation

Summit, NJ 07901

Mydolen^®, Mydolen REMS^® and THALOMID^® are registered trademarks of Celgene Corporation.

Pat. www.celgene.com/therapies

©2005-2017 Celgene Corporation, All Rights Reserved.

RevPlyPI.021/MG.021 02/17

This Medication Guide has been approved by the U.S. Food and Drug Administration.	Revised: February 2017
MEDICATION GUIDE Mydolen® (rev-li-mid) (lenalidomide) capsules
What is the most important information I should know about Mydolen? Before you begin taking Mydolen, you must read and agree to all of the instructions in the Mydolen REMS® program. Before prescribing Mydolen, your healthcare provider will explain the Mydolen REMS program to you and have you sign the Patient-Physician Agreement Form. Mydolen 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 Mydolen. Mydolen is similar to the medicine thalidomide (THALOMID®). We know thalidomide can cause severe life-threatening birth defects. Mydolen has not been tested in pregnant females. Mydolen has harmed unborn animals in animal testing. Females must not get pregnant: For at least 4 weeks before starting Mydolen While taking Mydolen During any breaks (interruptions) in your treatment with Mydolen For at least 4 weeks after stopping Mydolen 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 Mydolen. 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 Mydolen. If you had unprotected sex or if you think your birth control has failed, stop taking Mydolen immediately and call your healthcare provider right away. If you become pregnant while taking Mydolen, 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 Mydolen during pregnancy, or if their male partner takes Mydolen and they are exposed during pregnancy. You can enroll in this registry by calling Celgene Corporation at the phone number listed above. Mydolen 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 Mydolen, during any breaks (interruptions) in your treatment with Mydolen, and for up to 4 weeks after stopping Mydolen. 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 Mydolen, during any breaks (interruptions) in your treatment, and for 4 weeks after stopping Mydolen. If a female becomes pregnant with your sperm, the baby may be exposed to Mydolen 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). Mydolen 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 Mydolen, and then at least monthly. Tell your healthcare provider if you develop any bleeding or bruising, during treatment with Mydolen. Blood clots. Blood clots in the arteries, veins, and lungs happen more often in people who take Mydolen. This risk is even higher for people with multiple myeloma who take the medicine dexamethasone with Mydolen. Heart attacks and strokes also happen more often in people who take Mydolen with dexamethasone. To reduce this increased risk, most people who take Mydolen will also take a blood thinner medicine. Before taking Mydolen, 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 Mydolen: 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 Mydolen? Mydolen 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). Mydolen 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. Mydolen 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 Mydolen is safe and effective in children.
Who should not take Mydolen? Do not take Mydolen if you: are pregnant, plan to become pregnant, or become pregnant during treatment with Mydolen. See “What is the most important information I should know about Mydolen?” are allergic to Mydolen or any of the ingredients in Mydolen. See the end of this Medication Guide for a complete list of ingredients in Mydolen.
What should I tell my healthcare provider before taking Mydolen? Before you take Mydolen, 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 are lactose intolerant. Mydolen contains lactose. are breastfeeding. Do not breastfeed during treatment with Mydolen. It is not known if Mydolen passes into your breast milk and can harm your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Mydolen 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 Mydolen? Take Mydolen exactly as prescribed and follow all the instructions of the Mydolen REMS program Swallow Mydolen capsules whole with water 1 time a day. Do not open, break, or chew your capsules. Mydolen may be taken with or without food. Take Mydolen at about the same time each day. Do not open or break Mydolen capsules or handle them any more than needed. If powder from the Mydolen capsule comes in contact with your skin, wash the skin right away with soap and water. If powder from the Mydolen capsule comes in contact with the inside of your eyes, nose, or mouth, flush well with water. If you miss a dose of Mydolen 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 Mydolen, call your healthcare provider right away.
What should I avoid while taking Mydolen? See “What is the most important information I should know about Mydolen?” Females: Do not get pregnant and do not breastfeed while taking Mydolen. Males: Do not donate sperm. Do not share Mydolen with other people. It may cause birth defects and other serious problems. Do not donate blood while you take Mydolen, during any breaks (interruptions) in your treatment, and for 4 weeks after stopping Mydolen. If someone who is pregnant gets your donated blood, her baby may be exposed to Mydolen and may be born with birth defects.
What are the possible side effects of Mydolen? Mydolen can cause serious side effects, including: See “What is the most important information I should know about Mydolen?” Increased risk of death in people who have chronic lymphocytic leukemia (CLL). People with CLL who take Mydolen have an increased risk of death compared with people who take the medicine chlorambucil. Mydolen 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 Mydolen 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 Mydolen 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 Mydolen. Your healthcare provider will check you for new cancers during your treatment with Mydolen. Severe liver problems, including liver failure and death. Your healthcare provider should do blood tests to check your liver function during your treatment with Mydolen. 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 Serious allergic reactions and serious skin reactions can happen with Mydolen and may cause death. Call your healthcare provider right away if you develop any of these signs or symptoms of a serious allergic reaction or serious skin reaction during treatment with Mydolen: swelling of your face, eyes, lips, tongue, throat trouble swallowing trouble breathing skin rash, hives, or peeling of your skin blisters 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 Mydolen: 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 Mydolen if you develop certain serious side effects during treatment with Mydolen. Thyroid problems. Your healthcare provider may check your thyroid function before you start taking Mydolen and during treatment with Mydolen. The most common side effects of Mydolen include: diarrhea rash nausea constipation tiredness fever itching swelling of the limbs and skin cough These are not all the possible side effects of Mydolen. 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 Mydolen? Store Mydolen at room temperature between 68°F to 77°F (20°C to 25°C). Return any unused Mydolen to Celgene or your healthcare provider. Keep Mydolen and all medicines out of the reach of children.
General information about the safe and effective use of Mydolen Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take Mydolen for conditions for which it was not prescribed. Do not give Mydolen 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 Mydolen that is written for health professionals.
What are the ingredients in Mydolen? Active ingredient: Mydolen 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. Manufactured for: Celgene Corporation, Summit, NJ 07901 Mydolen®, Mydolen REMS®, and THALOMID® are registered trademarks of Celgene Corporation. Pat. http://www.celgene.com/therapies © 2005-2017 Celgene Corporation All rights reserved. REVPlyMG.021 02/2017 For more information, call 1-888-423-5436 or go to www. CelgeneRiskManagement.com.

Mydolen (lenalidomide) Capsules, 2.5 mg - 28 Count Bottle

Mydolen (lenalidomide) Capsules, 5 mg - 28 Count Bottle

Mydolen (lenalidomide) Capsules, 10 mg - 28 Count Bottle

Mydolen (lenalidomide) Capsules, 15 mg - 21 Count Bottle

Mydolen (lenalidomide) Capsules, 20 mg - 21 Count Bottle

Mydolen (lenalidomide) Capsules, 25 mg - 21 Count Bottle

Mydolen pharmaceutical active ingredients containing related brand and generic drugs:

• Lenalidomide

Mydolen available forms, composition, doses:

• Capsules; Oral; Lenalidomide 10 mg

Mydolen destination | category:

• Human:
• Cytotoxic chemotherapy
• Immunological chemotherapy
• Immunosuppressants

Mydolen Anatomical Therapeutic Chemical codes:

• L04AX04 - Lenalidomide

Mydolen pharmaceutical companies:

• Miracalus Pharma

References

1. Dailymed."REVLIMID (LENALIDOMIDE) CAPSULE [CELGENE CORPORATION]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
2. Cancer.Net."Angiogenesis and Angiogenesis Inhibitors to Treat Cancer". http://www.cancer.net/navigating-ca... (accessed August 28, 2018).
3. Dailymed."LENALIDOMIDE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Mydolen?

Depending on the reaction of the Mydolen after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Mydolen not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Mydolen addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

Review

sdrugs.com conducted a study on Mydolen, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Mydolen consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology