Drug Safety-related Labeling Changes (SrLC)

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REVLIMID (NDA-021880)

(LENALIDOMIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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05/24/2022 (SUPPL-65)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Embryo-Fetal Toxicity

Additions underlined

Males

Lenalidomide 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 REVLIMID and for up to 4 weeks after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm and for up to 4 weeks after discontinuing REVLIMID [see Use in Specific Populations (8.3)].

5.11 Tumor Flare Reaction

Additions underlined

Tumor flare reaction (TFR), including fatal reactions, have occurred during investigational use of REVLIMID for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials.

Monitoring and evaluation for TFR is recommended in patients with MCL, FL, or MZL. 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. In the AUGMENT trial in FL or MZL patients, TFR was reported in 19/176 (10.8%) of patients in REVLIMID with rituximab arm; one patient in the REVLIMID/rituximab arm experienced a Grade 3 TFR. In the MAGNIFY trial, 9/222 (4.1%) of patients experienced TFR; all reports were Grade 1 or 2 in severity and 1 event was considered as serious. In a separate MCL phase 2 trial, one case of TFR resulted in a fatal outcome.

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

Additions underlined

Males

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

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions underlined

REVLIMID can pass into human semen:

    • Do not donate sperm while taking REVLIMID, during any breaks (interruptions) in your treatment, and for up to 4 weeks after stopping REVLIMID. If a female becomes pregnant with your sperm, the baby may be exposed to REVLIMID and may be born with birth defects.

      What should I avoid while taking REVLIMID?

  • Males: Do not donate sperm while taking REVLIMID, during any breaks (interruptions) in your treatment, and for up to 4 weeks after stopping REVLIMID.

    What are the possible side effects of REVLIMID?

    REVLIMID can cause serious side effects, including:

  • Worsening of your tumor (tumor flare reaction) can happen with REVLIMID and may cause death. Tell your healthcare provider if you get any of these symptoms of tumor flare reaction during treatment with REVLIMID: tender swollen lymph nodes, low grade fever, pain, or rash.

PATIENT COUNSELING INFORMATION

Additions underlined

Embryo-Fetal Toxicity

Advise patients that REVLIMID is contraindicated in pregnancy [see Boxed Warning and Contraindications (4.1)]. REVLIMID is a thalidomide analogue and can cause serious birth defects or death to a developing baby [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

  • Advise male patients taking REVLIMID that they must not donate sperm and for up to 4 weeks after discontinuation of REVLIMID [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3)].

10/30/2019 (SUPPL-60)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.9 Severe Cutaneous Reactions

(additions underlined)

These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. Consider REVLIMID interruption or discontinuation for Grade 2-3 skin rash. Permanently discontinue REVLIMID for Grade 4 rash, exfoliative or bullous rash, or for other severe cutaneous reactions such as SJS, TEN or DRESS.

5.15Hypersensitivity

(new subsection added)

Hypersensitivity, including angioedema, anaphylaxis, and anaphylactic reactions to REVLIMID has been reported. Permanently discontinue REVLIMID for angioedema and anaphylax.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

 

Severe Cutaneous Reactions

Inform patients of the potential risk for severe skin reactions such as SJS, TEN, and DRESS and report any signs and symptoms associated with these reactions to their healthcare provider for evaluation. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID.

Hypersensitivity

Inform patients of the potential for severe hypersensitivity reactions such as angioedema and anaphylaxis to REVLIMID. Instruct patients to contact their healthcare provider right away for signs and symptoms of these reactions. Advise patients to seek emergency medical attention for signs or symptoms of severe hypersensitivity reactions.

05/28/2019 (SUPPL-57)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Hematologic Toxicity

Addition of the following:

Monitor complete blood counts (CBC) in patients taking REVLIMID for FL or MZL weekly for the first 3 weeks of Cycle 1 (28 days), every 2 weeks during Cycles 2- 4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction. In the AUGMENT and MAGNIFY trials, Grade 3 or 4 neutropenia was reported in 50% and 33%, respectively, of patients in the REVLIMID/rituximab arm. Grade 3 or 4 thrombocytopenia was reported in 2% and 8%, respectively, of patients in the REVLIMID/rituximab arm.

5.4 Venous and Arterial Thromboembolism

Addition of the following:

In the AUGMENT trial, the incidence of VTE (including DVT and PE) in FL or MZL patients was 3.4% in the REVLIMID/rituximab arm. In the AUGMENT trial, the incidence of ATE (including MI) in FL or MZL patients was 0.6% in the REVLIMID/rituximab arm

5.6 Second Primary Malignancies

Addition of the following:

In the AUGMENT trial with FL or MZL patients receiving REVLIMID/rituximab therapy, hematologic plus solid tumor SPMs, notably AML, have been observed. In the AUGMENT trial, hematologic SPM of AML occurred in 0.6% of patients with FL or MZL receiving REVLIMID/rituximab therapy. The incidence of hematologic plus solid tumor SPMs (excluding nonmelanoma skin cancers) was 1.7% in the REVLIMID/rituximab arm with a median follow-up of 29.8 months (range 0.5 to 51.3 months). Monitor patients for the development of second primary malignancies. Take into account both the potential benefit of REVLIMID and the risk of second primary malignancies when considering treatment with REVLIMID.

5.10 Tumor Lysis Syndrome

Additions and/or revisions underlined:

Monitor patients at risk closely and take appropriate preventive approaches. In the AUGMENT trial in FL or MZL patients, TLS occurred in 2 patients (1.1%) in the REVLIMID/rituximab arm. TLS occurred in 1 patient (0.5%) in the MAGNIFY trial during the REVLIMID/rituximab induction period; the event was a serious, Grade 3 adverse reaction.

5.11 Tumor Flare Reaction

Additions and/or revisions underlined:

Monitoring and evaluation for TFR is recommended in patients with MCL, FL, or MZL. 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. In the AUGMENT trial in FL or MZL patients, TFR was reported in 19/176 (10.8%) of patients in REVLIMID with rituximab arm; one patient in the REVLIMID/rituximabarm experienced a Grade 3 TFR. In the MAGNIFY trial, 9/222 (4.1%) of patients experienced TFR; all reports were Grade 1 or 2 in severity and 1 event was considered as serious.

6 Adverse Reactions

Addition of the term ‘clinically significant’ in referring to the adverse reactions described in detail in other sections.

Addition of the ‘with MM’ following in Proportion of Patients in the following Table Titles:

Table 4

Table 5

Table 6

Table 7

Table 8

‘Reactions’ replaces events in Table 9

Additions and/or revisions underlined:

Table 10: Most Frequently Observed Grade 3 and 4 Adverse Reactions1

Regardless of Relationship to Study Drug Treatment in the del 5q MDS Clinical Study

Newly added information following Table 11:

Follicular Lymphoma or Marginal Zone Lymphoma

The safety of REVLIMID/ rituximab was evaluated in 398 patients with either previously treated follicular lymphoma or marginal zone lymphoma in two clinical trials; AUGMENT (N=176) and MAGNIFY (N=222) [see Clinical Studies (14.4)]. Subjects were 18 years or older in age, had an ECOG PS less than or equal to 2, ANC greater than or equal to 1,000 cells/mm3 and platelets greater than or equal to  75,000/mm3 (unless secondary to bone marrow involvement by lymphoma), hemoglobin greater than or equal to 8g/dL, AST and ALT less than or equal to  3x ULN (unless documented liver involvement with lymphoma, and creatinine clearance of greater than or equal to  30mL/min. Subjects with active HIV, hepatitis B or C were not eligible.

In the AUGMENT trial, patients received REVLIMID 20 mg daily by mouth on days 1 – 21 of each 28 day cycle with rituximab 375 mg/m2 weekly (days 1, 8, 15 and 22 in cycle 1) then on day 1 of cycles 2-5 (n=176) or placebo with rituximab 375 mg/m2 weekly (days 1, 8, 15 and 22 in cycle 1) then on day 1 of cycles 2-5 (n=180) for up to 12 cycles. In the MAGNIFY trial, patients received REVLIMID 20 mg by mouth daily, days 1-21 of each 28-day cycle with rituximab 375 mg/m2 weekly (days 1, 8, 15 and 22 in cycle 1) then on day 1 of cycles 3, 7, 9 and 11 in the induction phase of the trial (n=222). In the AUGMENT trial, 88.1% of patients completed at least 6 cycles of REVLIMID/rituximab, and 71% of patients completed 12 cycles. In the ongoing MAGNIFY trial as of May 1, 2017, 62.2% of patients completed at least 6 cycles of REVLIMID/rituximab, and 30.6% of patients completed 12 cycles.

Across both clinical trials (AUGMENT and MAGNIFY), patients had a median age of 64.5 years (26 to 91); 49% were male; and 81% were White.

Fatal adverse reactions occurred in 6 patients (1.5%) receiving REVLIMID/rituximab. Fatal adverse reactions (1 each) included cardio-respiratory arrest, arrhythmia, cardiopulmonary failure, multiple organ dysfunction syndrome, sepsis, and acute kidney injury. Serious adverse reactions occurred in 26% of patients receiving REVLIMID/rituximab on AUGMENT and 29% on MAGNIFY. The most frequent serious adverse reaction that occurred in greater than or equal to 2.5% of patients in the REVLIMID/rituximab arm was febrile neutropenia (3%). Permanent discontinuation of REVLIMID or rituximab due to an adverse reaction occurred in 14.6% of patients in the REVLIMID/rituximab arm. The most common adverse reaction (in at least 1%) requiring permanent discontinuation of REVLIMID or rituximab was neutropenia (4.8%).

The most common adverse reactions occurring in at least 20% of subjects were; neutropenia (48%), fatigue (37%), diarrhea (32%), constipation (27%), nausea (21%), and cough (20%).

Table 12: All Grade Adverse Reactions (greater than or equal to 5%) or Grade 3/4 Adverse Reactions (greater than or equal to 1%) in Patients with FL and MZL with a Difference Between Arms of >1% When Compared to Control Arm in AUGMENT Trial For table data, please refer to the label for complete information.

8 Use in Specific Populations

8.5 Geriatric Use

Addition of the following:

FL or MZL in Combination: Overall, 48% (282/590) of patients were 65 years of age or older, while 14% (82/590) of patients were over 75 years of age. The overall frequency of adverse reactions was similar in patients 65 years of age or older and younger patients for both studies pooled (98%). Grade 3 or 4 adverse reactions were higher in the REVLIMID arm (more than 5% higher) in the patients 65 years of age or older versus younger patients (71% versus 59%). The frequency of Grade 3 or 4 adverse reactions were higher in the REVLIMID arm (more than 5% higher) in the patients 65 years of age or older versus younger patients in the Blood and Lymphatic System Disorders (47% versus 40%) and Infections and Infestations (16% versus 11%). Serious adverse reactions were higher in the REVLIMID arm (more than 5% higher) in the patients 65 years of age or older versus younger patients (37% versus 18%). The frequency of serious adverse reactions were higher in the REVLIMID arm (more than 5% higher) in the patients 65 years of age or older versus younger patients in Infections and Infestations (15% versus 6%).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

The most common side effects of REVLIMID include:

Additions and/or revisions underlined:

  • tiredness or weakness 

  • swelling of your arms, hands, legs, feet and skin

  • muscle cramps or spasms

  • shortness of breath

  • cough, sore throat, and other symptoms of a cold

  • upper respiratory tract infection or bronchitis

  • inflammation of the stomach and intestine (stomach flu)

  • nose bleed

  • shaking or trembling

  • joint aches

  • pain in your back or stomach-area (abdomen)

Other

REMS modifications

01/22/2019 (SUPPL-56)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone

(Subsection title has been revised; additions and/or revisions are underlined)

In two randomized clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or blocking antibody is indicated, resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

6 Adverse Reactions

6 ADVERSE REACTIONS

(Additions and/or revisions are underlined)

 ….

  • Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone.

 Table 9

(Table has been revised; please refer to label)

 

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

 

The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID. 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

 

Endocrine disorders: Hypothyroidism, hyperthyroidism

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

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

Infections and infestations: Viral reactivation (such as hepatitis B virus and herpes zoster), progressive multifocal leukoencephalopathy (PML)

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

Respiratory, thoracic and mediastinal disorders: Pneumonitis

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

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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.

8.2 Lactation

(Additions and/or revisions are underlined)

 

Risk Summary

 

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

 

12/29/2017 (SUPPL-55)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone

(Subsection title has been revised; additions and/or revisions are underlined)

In two randomized clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone, a use for which no PD-1 or blocking antibody is indicated, resulted in increased mortality. Treatment of patients with MM with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

6 Adverse Reactions

(Additions and/or revisions are underlined)

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

  • Increased Mortality in Patients with MM When Pembrolizumab Is Added to a Thalidomide Analogue and Dexamethasone

11/30/2017 (SUPPL-52)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.7 Increased Mortality in MM When Pembrolizumab Is Added to Dexamethasone and a Thalidomide Analogue

(Newly added subsection)

No PD-1 or PD-L1 blocking antibodies are approved for the treatment of MM. In two randomized clinical trials in patients with MM, the addition of pembrolizumab to a thalidomide analogue plus dexamethasone resulted in increased mortality. In Study KN183 (NCT02576977), patients with relapsed or refractory MM were randomized to receive pomalidomide and dexamethasone with (n=125) or without (n=124) pembrolizumab. The hazard ratio for overall survival (OS) was 1.61 (95% CI: 0.91, 2.85), increasing the relative risk of death by more than 50% in the experimental arm containing pembrolizumab. Causes of death in the experimental arm, excluding disease progression, included: myocarditis, Stevens-Johnson syndrome, myocardial infarction, pericardial hemorrhage, cardiac failure, respiratory tract infection, neutropenic sepsis, sepsis, multiple organ dysfunction, and respiratory failure. In Study KN185 (NCT02579863), patients with NDMM were randomized to receive lenalidomide and dexamethasone with (n=151) or without (n=150) pembrolizumab. The hazard ratio for OS was 2.06 (95% CI: 0.93, 4.55), increasing the relative risk of death by more than 100% in the experimental arm containing pembrolizumab. Causes of death in the experimental arm, excluding disease progression, included: intestinal ischemia, cardio-respiratory arrest, suicide, pulmonary embolism, cardiac arrest, pneumonia, sudden death, myocarditis, large intestine perforation, and cardiac failure.

The addition of a PD-1 or PD-L1 blocking antibody to a thalidomide analogue is not recommended for the treatment of patients with MM outside of controlled clinical trials.

6 Adverse Reactions

6 ADVERSE REACTIONS

(Additions and/or revisions are underlined)

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

    • Increased Mortality in MM When Pembrolizumab Is Added to Dexamethasone and a Thalidomide Analogue

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Increased Mortality in MM Patients When Pembrolizumab Was Added to Dexamethasone and a Thalidomide Analogue Regimen

Inform patients of potential for increased risk of death in people with MM when a PD-1 blocking antibody was added to a dexamethasone and thalidomide analogue treatment regimen.

MEDICATION GUIDE

(Additions and/or revisions are underlined)

What are the possible side effects of REVLIMID?

REVLIMID can cause serious side effects, including:

  • Increased risk of death in people with MM when used with pembrolizumab. An increased risk of death has been observed in people with MM when pembrolizumab was added to dexamethasone and REVLIMID. The use of these drugs together for treating MM is not recommended outside of controlled clinical trials.

11/30/2017 (SUPPL-53)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID. 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.

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

09/15/2017 (SUPPL-51)

Approved Drug Label (PDF)

4 Contraindications

4.2 Severe Hypersensitivity Reactions

Above subsection title replaces previous subsection title Allergic Reactions

Additions and/or revisions underlined:

REVLIMID is contraindicated in patients who have demonstrated severe hypersensitivity …

5 Warnings and Precautions

Additions and/or revisions underlined:

5.8 Severe Cutaneous Reactions Including Hypersensivity Reactions

Angioedema and severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. These events can be fatal … REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS, TEN or DRESS is suspected and should not be resumed following discontinuation for these reactions.

Addition of the following subsection:

5.13 Early Mortality in Patients with MCL

In another MCL study, there was an increase in early deaths (within 20 weeks), 12.9% in the REVLIMID arm versus 7.1% in the control arm. On exploratory multivariate analysis, risk factors for early deaths include high tumor burden, MIPI score at diagnosis, and high WBC at baseline (greater than or equal to 10 x 109/L).

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions are underlined:

The following adverse reactions which have occurred in other indications including another MCL study and not described above have been reported (1%-10%) in patients treated with REVLIMID monotherapy for mantle cell lymphoma.

Cardiac disorder: Cardiac failure

Ear and labyrinth disorders: Vertigo

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

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

Psychiatric disorders: Insomnia

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

Blood and lymphatic system disorders:  Neutropenia

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

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

6.2 Postmarketing Experience

Additions and/or revisions are underlined:

… 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, drug reaction with eosinophilia and systemic symptoms (DRESS)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

What should I tell my healthcare provider before taking REVLIMID?

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

Addition and/or revisions underlined:

  • have had a serious skin rash with thalidomide treatment. You should not take REVLIMID.

  • Severe skin reactions including severe allergic reactions can happen with REVLIMID and may cause death. Call your healthcare provider right away if you develop any of these signs or symptoms of a severe allergic reaction or severe skin reaction during treatment with REVLIMID:

  • Rash with fever and or swollen glands

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

  • Thyroid problems …

  • Risk of Early Death in MCL.  In people who have Mantle Cell Lymphoma (MCL), there may be a risk of dying sooner (early death) when taking REVLIMID. Talk with your healthcare provider about any concerns and possible risk factors.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Severe Cutaneous Reactions Including Hypersensitivity Reactions

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

Newly added information:

Early Mortality in Patients with MCL

Inform patients with MCL of the potential for early death.

02/22/2017 (SUPPL-49)

Approved Drug Label (PDF)

4 Contraindications

4.1 Pregnancy

(Additions and/or revisions are underlined)

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.

5 Warnings and Precautions

5.1 Embryo-Fetal Toxicity

(Additions and/or revisions are underlined)

Males

Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 4 weeks after discontinuing REVLIMID, even if they have undergone a successful vasectomy.

Blood Donation

Patients must not donate blood during treatment with REVLIMID and for 4 weeks following discontinuation of the drug…

5.12 Thyroid Disorders

(Newly added subsection)

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

5.3 Hematologic Toxicity

(Additions and/or revisions are underlined)

Patients taking REVLIMID in combination with dexamethasone or as REVLIMID maintenance therapy for MM should have their complete blood counts (CBC) assessed… 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.

5.4 Venous and Arterial Thromboembolism

(Additions and/or revisions are underlined)

Venous thromboembolic events (VTE [DVT and PE]) and arterial thromboembolic events (ATE, myocardial infarction and stroke) are increased in patients treated with REVLIMID.

 

…The median time to first thrombosis event was 4.3 months in the combined Rd Continuous and Rd18 Arms.

5.6 Second Primary Malignancies

(Additions and/or revisions are underlined)

In clinical trials in patients with MM receiving REVLIMID, an increase of hematologic plus solid tumor second primary malignancies (SPM) 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 REVLIMID in combination with oral melphalan compared with 1.3% of patients receiving melphalan 5without REVLIMID. The frequency of AML and MDS cases in patients with NDMM treated with REVLIMID in combination with dexamethasone without melphalan was 0.4%.

In patients receiving REVLIMID 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 REVLIMID 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.

6 Adverse Reactions

(Additions and/or revisions are underlined)

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

  • Hematologic Toxicity

  • Thyroid Disorders

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Newly Diagnosed MM – REVLIMID Combination Therapy:

 

Table 4: All Adverse Reactions in Greater than or Equal to 5.0% and Grade 3/4 Adverse Reactions in Greater than or Equal to 1.0% of Patients in the Rd Continuous or Rd18 Arms(asterisk) (Additions and/or revisions have been made to the footnote of this table; please refer to label)

 

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

Data were evaluated from 1018 patients in two randomized trials who received at least one dose of REVLIMID 10 mg daily as maintenance therapy after auto-HSCT until progressive disease or unacceptable toxicity, The mean treatment duration for REVLIMID 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 REVLIMID arm were still on treatment and none of the patients in the Maintenance Study 2 REVLIMID 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 REVLIMID 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 REVLIMID arm) included neutropenia, thrombocytopenia, and leukopenia. The serious adverse reactions lung infection and neutropenia (more than 4.5%) occurred in the REVLIMID arm.

For REVLIMID, 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 REVLIMID were hematologic events (17.7%, data available in Maintenance Study 2 only). The most common adverse reactions leading to discontinuation of REVLIMID 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 REVLIMID and placebo maintenance treatment arms.

Table 5: All Adverse Reactions in Greater than or Equal to 5.0% and Grade 3/4 Adverse Reactions in Greater than or Equal to 1.0% of Patients in the REVLIMID Vs Placebo Arms(asterisk)

(Table has been added; please refer to label)

 

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

Table 6: Adverse Reactions Reported in Greater than or Equal to 5% of Patients and with a Greater than or Equal to 2% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups

Table 7: Grade 3/4 Adverse Reactions Reported in Greater than or Equal to 2% Patients and With a Greater than or Equal to 1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone groups

Table 8: Serious Adverse Reactions Reported in Greater than or Equal to 1% Patients and With a Greater than or Equal to 1% Difference in Proportion of Patients Between the REVLIMID/dexamethasone and Placebo/dexamethasone Groups

 

Venous and Arterial Thromboembolism

VTE and ATE are increased in patients treated with REVLIMID.

 

Table 9: Summary of Adverse Events Reported in Greater than or Equal to 5% of the REVLIMID Treated Patients in del 5q MDS Clinical Study (Additions and/or revisions have been made to the footnote of this table; please refer to label)

Table 10: Most Frequently Observed Grade 3 and 4 Adverse Events [1] Regardless of Relationship to Study Drug Treatment (Additions and/or revisions have been made to the footnote of this table; please refer to label)

 

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

 

Table 11 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with REVLIMID…

Table 11: Incidence of Adverse Reactions (?10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma (Additions and/or revisions have been made to the footnote of this table; please refer to label)

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

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

7.3 Warfarin

(Additions and/or revisions are underlined)

Co-administration of multiple doses of REVLIMID (10 mg/day) with a single dose of warfarin (25 mg) had no effect on the pharmacokinetics of lenalidomide or R- and S-warfarin.

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in females exposed to REVLIMID during pregnancy as well as female partners of male patients who are exposed to REVLIMID. This registry is also used to understand the root cause for the pregnancy. Report any suspected fetal exposure to REVLIMID 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, REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy

REVLIMID is a thalidomide analogue

…Lenalidomide crossed the placenta after administration to pregnant rabbits and pregnant rats…

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

Following daily oral administration of lenalidomide from Gestation Day 7 through Gestation Day 20 in pregnant rabbits, fetal plasma lenalidomide concentrations were approximately 20-40% of the maternal Cmax.   Following a single oral dose to pregnant rats, lenalidomide 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 lenalidomide crossed the placenta.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

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

8.3 Females and Males of Reproductive Potential

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Pregnancy Testing

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

 

Contraception

Males

…Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 4 weeks after discontinuing REVLIMID, even if they have undergone a successful vasectomy…

8.5 Geriatric Use

(Additions and/or revisions are underlined)

MM In Combination:

…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)…

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 REVLIMID 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 REVLIMID 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 REVLIMID 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.

8.6 Renal Impairment

(Additions and/or revisions are underlined)

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

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

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

 

Embryo-Fetal Toxicity

  • 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 REVLIMID and for up to 4 weeks after discontinuing REVLIMID, even if they have undergone a successful vasectomy.

  • All patients must be instructed to not donate blood while taking REVLIMID, during dose interruptions and for 4 weeks following discontinuation of REVLIMID

REVLIMID REMS program

Pregnancy Exposure Registry

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

 

Dosing Instructions

Inform patients how to take REVLIMID

  • REVLIMID should be taken once daily at about the same time each day,

  • REVLIMID may be taken either with or without food.

MEDICATION GUIDE

(Additions and/or revisions are underlined)

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

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

REVLIMID may cause serious side effects including:

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

    Females who can become pregnant:

    • Will have pregnancy tests weekly for 4 weeks, then every 4 weeks if your menstrual cycle is regular, or every 2 weeks if your menstrual cycle is irregular.

    • If you miss your period or have unusual bleeding, you will need to have a pregnancy test and receive counseling.

    • Must agree to use two acceptable forms of birth control at the same time, for at least 4 weeks before, while taking, during any breaks (interruptions) in your treatment, and for at least 4 weeks after stopping REVLIMID.

    • Talk with your healthcare provider to find out about options for acceptable forms of birth control that you may use to prevent pregnancy before, during, and after treatment with REVLIMID.

    • If you had unprotected sex or if you think your birth control has failed, stop taking REVLIMID immediately and call your healthcare provider right away.

If you become pregnant while taking REVLIMID, stop taking it right away and call your healthcare provider. If your healthcare provider is not available, you can call Celgene Customer Care Center at 1-888-423-5436

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

REVLIMID can pass into human semen:

    • Males, including those who have had a vasectomy, must always use a latex or synthetic condom during any sexual contact with a pregnant female or a female that can become pregnant while taking REVLIMID, during any breaks (interruptions) in your treatment with REVLIMID, and for up to 4 weeks after stopping REVLIMID.

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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