REVLIMID ® 10 MG

דבכנ ת/חקור ,ה/אפור

לע ךעידוהל החמש םרפואינ לש הרושיא היוותה תפסות

רישכתל :םי

Revlimid 2.5 mg Hard Capsule

דימילבר

2.5

ג"מ

החישק היילבט

Revlimid 5 mg Hard Capsule

דימילבר

5

ג"מ החישק היילבט

Revlimid 7.5 mg Hard Capsule

דימילבר

7.5

ג"מ החישק היילבט

Revlimid 10 mg Hard Capsule

דימילבר

10

ג"מ החישק היילבט

Revlimid 15 mg Hard Capsule

דימילבר

15

ג"מ החישק היילבט

Revlimid 20 mg Hard Capsule

דימילבר

20

ג"מ החישק היילבט

Revlimid 25 mg Hard Capsule

דימילבר

25

ג"מ החישק היילבט

םירמוחה

םיליעפה

:םתומכו

Revlimid 2.5 mg: each hard capsule contains 2.5 mg Lenalidomide.

Revlimid 5 mg: each hard capsule contains 5 mg Lenalidomide.

Revlimid 7.5 mg: each hard capsule contains 7.5 mg Lenalidomide.

Revlimid 10 mg: each hard capsule contains 10 mg Lenalidomide.

Revlimid 15 mg: each hard capsule contains 15 mg Lenalidomide.

Revlimid 20 mg: each hard capsule contains 20 mg Lenalidomide.

Revlimid 25 mg: each hard capsule contains 25 mg Lenalidomide.

:השדחה היוותהה חסונ

Multiple Myeloma

Revlimid is indicated for:

The maintenance treatment of adult patients with newly diagnosed multiple myeloma (MM) who

have undergone autologous stem cell transplantation.

Previously untreated multiple myeloma in adult patients who are not eligible for transplant.

In combination with dexamethasone treatment of multiple myeloma patients who have received

at least one prior therapy.

Myelodysplastic Syndromes

REVLIMID is indicated for patients with transfusion-dependent anemia due to low- or intermediate-

1-risk

myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or

without additional cytogenetic abnormalities.

Revlimid 7.5 mg is not indicated for treatment in MDS.

Mantle Cell Lymphoma

REVLIMID is indicated for the treatment of adult patients with relapsed and/or refractory mantle

cell lymphoma (MCL).

ףסונב .הרמחה םניאש םיפסונ םייוניש ןולעב .הרמחה םיווהמה םייונישה םיניוצמ וז העדוהב

טסקט ,יתחת וקב ןמוסמ ףסוותהש טסקט .הצוח וקב ןמוסמ רסוהש

םינוכדעה םיירקיעה :םיאבה םיפיעסב ושענ אפורל ןולעב

5.

WARNINGS AND PRECAUTIONS

…….

5.2 Reproductive Risk and Special Prescribing Requirements (Revlimid RMP-PPP)

…….

Prescriptions for women of childbearing potential can be for a maximum duration of 4 weeks, and prescriptions

for all other patients can be for a maximum duration of 12 weeks.

5.3 Other warnings and precautions of use

Hematologic Toxicity

REVLIMID can cause significant neutropenia and thrombocytopenia. REVLIMID 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

REVLIMID should have their complete blood counts assessed periodically as described below [see Dosage and

Administration (2.1, 2.2, 2.3)]. Patients should be advised to promptly report febrile episodes and dose reductions may

be required. Patients and physicians are advised to be observant for signs and symptoms of bleeding, including

petechiae and epistaxes, especially in patients receiving concomitant medicinal products susceptible to induce

bleeding.

Patients taking REVLIMID in combination with dexamethasone or as REVLIMID 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 [see

Dosage and Administration (2.1)]. 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

[see Adverse Reactions (6.1)].

…….

myelomaPatients taking REVLIMID 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.

Neutropenia and thrombocytopenia

NDMM

Newly diagnosed multiple myeloma in: patients who have undergone ASCT treated with lenalidomide maintenance

The adverse reactions from CALGB 100104 included events reported post-high dose melphalan and ASCT

(HDM/ASCT) as well as events from the maintenance treatment period. A second analysis identified events that

occurred after the start of maintenance treatment. In IFM 2005-02, the adverse reactions were from the maintenance

treatment period only.

Overall, grade 4 neutropenia was observed at a higher frequency in the lenalidomide maintenance arms compared to

the placebo maintenance arms in the 2 studies evaluating lenalidomide maintenance in NDMM patients who have

undergone ASCT (32.1% vs 26.7% [16.1% vs 1.8% after the start of maintenance treatment] in CALGB 100104 and

16.4% vs 0.7% in IFM 2005-02, respectively). Treatment-emergent AEs of neutropenia leading to lenalidomide

discontinuation were reported in 2.2% of patients in CALGB 100104 and 2.4% of patients in IFM 2005-02,

respectively. Grade 4 febrile neutropenia was reported at similar frequencies in the lenalidomide maintenance arms

compared to placebo maintenance arms in both studies (0.4% vs 0.5% [0.4% vs 0.5% after the start of maintenance

treatment] in CALGB 100104 and 0.3% vs 0% in IFM 2005-02, respectively). Patients should be advised to promptly

report febrile episodes, a treatment interruption and/or dose reductions may be required (see section 4.2).

Grade 3 or 4 thrombocytopenia was observed at a higher frequency in the lenalidomide maintenance arms compared

to the placebo maintenance arms in studies evaluating lenalidomide maintenance in NDMM patients who have

undergone ASCT (37.5% vs 30.3% [17.9% vs 4.1% after the start of maintenance treatment] in CALGB 100104 and

13.0% vs 2.9% in IFM 2005-02, respectively). Patients and physicians are advised to be observant for signs and

symptoms of bleeding, including petechiae and epistaxes, especially in patients receiving concomitant medicinal

products susceptible to induce bleeding (see section 4.8, Haemorrhagic disorders).

…….

Myelodysplastic Syndromes patients

Patients taking REVLIMID 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) [see Boxed Warning and Dosage and Administration (2.2)].

…….

Infection with or without Neutropenia

Patients with multiple myeloma are prone to develop infections including pneumonia. A higher rate of infections was

observed with lenalidomide in combination with dexamethasone than with MPT. in patients with NDMM who are not

eligible for transplant, and with lenalidomide maintenance compared to placebo in patients with NDMM who had

undergone ASCT.

…….

1.1

5.4 Venous and Arterial Thromboembolism

Venous thromboembolic events (deep

In patients with multiple myeloma, the combination of lenalidomide with dexamethasone is associated with an

increased risk of venous thromboembolism (predominantly deep vein thrombosis and pulmonary embolism) and

arterial was seen to a lesser extent with lenalidomide in combination with melphalan and prednisone.

In patients with multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma, treatment with lenalidomide

monotherapy was associated with a lower risk of venous thromboembolism (predominantly deep vein thrombosis are

increasedand pulmonary embolism) than in patients with multiple myeloma treated with REVLIMID. A

significantlylenalidomide in combination therapy

In patients with multiple myeloma, the combination of lenalidomide with dexamethasone is associated with an

increased risk of DVT (7.4%) and of PE (3.7%) occurred in patients with multiple myeloma who were treated with

REVLIMID and dexamethasone therapy compared to patients treated in the placebo and dexamethasone group (3.1%

arterial thromboembolism (predominantly myocardial infarction and 0.9%) in a clinical trials with varying use of

anticoagulant therapies. [see Boxed Warning and Adverse Reactions (6.1)].

Venous thromboembolism cerebrovascular event) and was seen to a lesser extent with lenalidomide in combination

with melphalan and prednisone. The risk of ATE is lower in newly diagnosed patients with multiple myeloma

andtreated with lenalidomide monotherapy than in patients with multiple myeloma treated with lenalidomide in

myelodysplastic syndromes.

…….

Consequently, patients with known risk factors for thromboembolism – including prior thrombosis – should be closely

monitored. Action should be taken to try to minimize all modifiable risk factors (e.g. smoking, hypertension, and

hyperlipidaemia). Concomitant administration of erythropoietic agents or previous history of thromboembolic events

may also increase thrombotic risk in these patients. Therefore, erythropoietic agents, or other agents that may

increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution in multiple

myeloma patients receiving lenalidomide with dexamethasone. A haemoglobin concentration above 12 g/dl should

lead to discontinuation of erythropoietic agents.

Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients

should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or

leg swelling. Prophylactic antithrombotic medicines should be recommended, especially in patients with additional

thrombotic risk factors. The decision to take antithrombotic prophylactic measures should be made after careful

assessment of an individual patient’s underlying risk factors.

If the patient experiences any thromboembolic events, treatment must be discontinued and standard anticoagulation

therapy started. Once the patient has been stabilised on the anticoagulation treatment and any complications of the

thromboembolic event have been managed, the lenalidomide treatment may be restarted at the original dose

dependent upon a benefit risk assessment. The patient should continue anticoagulation therapy during the course of

lenalidomide treatment.

…….

5.6 Second Primary Malignancies

An increase of second primary malignancies (SPM) has been observed in clinical trials in previously treated myeloma

patients receiving lenalidomide/dexamethasone (3.98 per 100 person-years) compared to controls (1.38 per 100

person-years). Non-invasive SPM comprise basal cell or squamous cell skin cancers. Most of the invasive SPMs were

solid tumour malignancies.

…….

The increased risk of secondary primary malignancies associated with lenalidomide is relevant also in the context of

NDMM after stem cell transplantation. Though this risk is not yet fully characterized, it should be kept in mind when

considering and using Revlimid in this setting.

The incidence rate of hematologic malignancies, most notably AML, MDS and B-cell malignancies (including

Hodgkin’s lymphoma), was 1.31 per 100 person-years for the lenalidomide arms and 0.58 per 100 person-years for

the placebo arms (1.02 per 100 person-years for patients exposed to lenalidomide after ASCT and 0.60 per 100

person-years for patients not-exposed to lenalidomide after ASCT). The incidence rate of solid tumour SPMs was 1.36

per 100 person-years for the lenalidomide arms and 1.05 per 100 person-years for the placebo arms (1.26 per 100

person-years for patients exposed to lenalidomide after ASCT and 0.60 per 100 person-years for patients not-exposed

to lenalidomide after ASCT).

The risk of occurrence of hematologic SPM must be taken into account before initiating treatment with lenalidomide

either in combination with melphalan or immediately following high-dose melphalan and ASCT. Physicians should

carefully evaluate patients before and during treatment using standard cancer screening for occurrence of SPM and

institute treatment as indicated.

…….

5.8 Allergic Reactionsand severe skin reactions

…….

Severe cutaneous reactions including SJS, and TEN and DRESS have been reported with the use of lenalidomide.

Patients should be advised of the signs and symptoms of these reactions by their prescribers and should be told to

seek medical attention immediately if they develop these symptoms. Lenalidomide must be discontinued for exfoliative

or bullous rash, or if SJS, TEN or DRESS is suspected, and should not be resumed following discontinuation for these

reactions. Interruption or discontinuation of lenalidomide should be considered for other forms of skin reaction

depending on severity. Patients with a history of severe rash associated with thalidomide treatment should not receive

lenalidomide.

…….

Peripheral neuropathy

Lenalidomide is structurally related to thalidomide, which is known to induce severe peripheral neuropathy. There was

no increase in peripheral neuropathy observed with long term use of lenalidomide for the treatment of newly

diagnosed multiple myeloma.

…….

6.1 Clinical Trials Experience in Multiple Myeloma

…….

Tabulated summary for monotherapy in MM

…….

Table 1. ADRs reported in clinical trials in patients with multiple myeloma treated with lenalidomide

maintenance therapy

System Organ Class/Preferred

Term

All ADRs/Frequency

Grade 3-4 ADRs/Frequency

Infections and Infestations

Very Common

Pneumonias

◊, a

, Upper respiratory

tract infection, Neutropenic infection,

Bronchitis

, Influenza

Gastroenteritis

, Sinusitis,

Nasopharyngitis, Rhinitis

Common

Infection

, Urinary tract infection

Lower respiratory tract infection, Lung

infection

Very Common

Pneumonias

◊, a

, Neutropenic infection

Common

Sepsis

◊, b

, Bacteraemia, Lung

infection

, Lower respiratory tract

infection bacterial, Bronchitis

Influenza

, Gastroenteritis

, Herpes

zoster

, Infection

Neoplasms Benign, Malignant and

Unspecified (incl cysts and

polyps)

Common

Myelodysplastic syndrome

Blood and Lymphatic System

Disorders

Very Common

Neutropenia

, Febrile neutropenia

Thrombocytopenia

, Anemia,

Leucopenia

, Lymphopenia

Very Common

Neutropenia

, Febrile neutropenia

Thrombocytopenia

, Anemia,

Leucopenia

, Lymphopenia

Common

Pancytopenia

Metabolism and Nutrition

Disorders

Very Common

Hypokalaemia

Common

Hypokalaemia, Dehydration

Nervous System Disorders

Very Common

Paraesthesia

Common

Common

Headache

System Organ Class/Preferred

Term

All ADRs/Frequency

Grade 3-4 ADRs/Frequency

Peripheral neuropathy

Vascular Disorders

Common

Pulmonary embolism

Common

Deep vein thrombosis

,◊,d

Respiratory, Thoracic and

Mediastinal Disorders

Very Common

Cough

Common

Dyspnoea

, Rhinorrhoea

Common

Dyspnoea

Gastrointestinal Disorders

Very Common

Diarrhoea, Constipation, Abdominal

pain, Nausea

Common

Vomiting, Abdominal pain upper

Common

Diarrhoea, Vomiting, Nausea

Hepatobiliary Disorders

Very Common

Abnormal liver function tests

Common

Abnormal liver function tests

Skin and Subcutaneous Tissue

Disorders

Very Common

Rash, Dry skin

Common

Rash, Pruritus

Musculoskeletal and Connective

Tissue Disorders

Very Common

Muscle spasms

Common

Myalgia, Musculoskeletal pain

General Disorders and

Administration Site Conditions

Very Common

Fatigue, Asthenia, Pyrexia

Common

Fatigue, Asthenia

Adverse reactions reported as serious in clinical trials in patients with NDMM who had undergone ASCT

Applies to serious adverse drug reactions only

“Pneumonias” combined AE term includes the following PTs: Bronchopneumonia, Lobar pneumonia, Pneumocystis

jiroveci pneumonia, Pneumonia, Pneumonia klebsiella, Pneumonia legionella, Pneumonia mycoplasmal, Pneumonia

pneumococcal, Pneumonia streptococcal, Pneumonia viral, Lung disorder, Pneumonitis

“Sepsis” combined AE term includes the following PTs: Bacterial sepsis, Pneumococcal sepsis, Septic shock,

Staphylococcal sepsis

“Peripheral neuropathy” combined AE term includes the following preferred terms (PTs): Neuropathy peripheral,

Peripheral sensory neuropathy, Polyneuropathy

“Deep vein thrombosis” combined AE term includes the following PTs: Deep vein thrombosis, Thrombosis, Venous

thrombosis

Tabulated summary for combination therapy in MM

…….

Table 12: ADRs reported in clinical studies in patients with multiple myeloma treated with lenalidomide in

combination with dexamethasone, or with melphalan and prednisone

System Organ

Class

/ Preferred Term

All ADRs/Frequency

Grade 3−4 ADRs/Frequency

Infections

and Infestations

Very Common

Pneumonia

, Upper respiratory tract infection

Bacterial, viral and fungal infections (including

opportunistic infections)

, Nasopharyngitis,

Pharyngitis, Bronchitis

Common

Sepsis

, Sinusitis

Common

Pneumonia

, Bacterial, viral and

fungal infections (including

opportunistic infections

Cellulitis

, Sepsis

, Bronchitis

Metabolism and

Nutrition Disorders

Very Common

Hypokalaemia

, Hyperglycaemia,

Hypocalcaemia

, Decreased appetite, Weight

decreased

Common

Hypomagnesaemia, Hyperuricaemia,

Dehydration

, Hypercalcaemia

Common

Hypokalaemia

, Hyperglycaemia

Hypocalcaemia, Diabetes

mellitus

, Hypophosphataemia,

Hyponatraemia

, Hyperuricaemia,

Gout, Decreased appetite,

Weight decreased

System Organ

Class

/ Preferred Term

All ADRs/Frequency

Grade 3−4 ADRs/Frequency

Musculoskeletal

and Connective

Tissue Disorders

Very Common

Muscle spasms, Bone pain

Musculoskeletal and connective tissue pain and

discomfort (including back pain

),, Arthralgia

Common

Muscular weakness, Joint swelling, Myalgia

Common

Muscular weakness, Bone pain

Musculoskeletal and connective

tissue pain and discomfort

(including back pain

Uncommon

Joint swelling

◊ Adverse reactions reported as serious in clinical trials in patients with multiple myeloma treated with lenalidomide in

combination with dexamethasone, or with melphalan and prednisone

+ Applies to serious adverse drug reactions only

* Squamous skin cancer was reported in clinical trials in previously treated myeloma patients with

lenalidomide/dexamethasone compared to controls

** Squamous cell carcinoma of skin was reported in a clinical trial in newly diagnosed myeloma patients with

lenalidomide/dexamethasone compared to controls

…….

6.3 Clinical Trials Experience in Mantle Cell Lymphoma

…….

Table 5:

ADRs reported in clinical trials in patients with mantle cell lymphoma treated with lenalidomide

System Organ

Class

/ Preferred Term

All ADRs/Frequency

Grade 3−4 ADRs/Frequency

Cardiac

Disorders

Common

Acute mMyocardial infarction (including

acute)

, Cardiac failure

Adverse events reported as serious in mantle cell lymphoma clinical trials

…….

Table 56: ADRs reported in post-marketing use in patients treated with lenalidomide

System Organ Class

/ Preferred Term

All ADRs/Frequency

Grade 3−4 ADRs/Frequency

Immune System

Disorders

Not Known

Solid organ transplant rejection

Skin and

Subcutaneous Tissue

Disorders

Uncommon

Angioedema

Rare

Stevens-Johnson Syndrome, Toxic

epidermal necrolysis

Not Known

Leukocytoclastic vasculitis, Drug

Reaction with Eosinophilia and

Systemic Symptoms

…….

7.

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category X [see Boxed Warnings and Contraindications (4.1)] 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.

…….

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

…….

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 Nursing mothers Lactation

It is not known whether this drug is excreted in human milk.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 nursing infants from lenalidomide, a decision should be made

whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

advice women not to breastfeed during treatment with REVLIMID.

8.3 Females and males of reproductive potential

Pregnancy Testing

REVLIMID can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. 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.

Females of reproductive potential must have 2 negative pregnancy tests before initiating REVLIMID. The first test

should be performed within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID. 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. REVLIMID 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 REVLIMID, during therapy, during dose

interruptions, and continuing for 4 weeks following discontinuation of REVLIMID

therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to

hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if

needed.

1.1

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.

1.2

8.4 Pediatric use

Revlimid should not be used in children and adolescents from birth to less than 18 years because of safety concerns.

Safety and effectiveness have not been established in pediatric patients.

8.45 Geriatric use

REVLIMID has been usedMM in multiple myeloma (MM) clinical trials in combination: Overall, of the 1613 patients up

to 91 years of age. in the NDMM study

Newly diagnosed multiple myeloma

In patients with newly diagnosed multiple myeloma aged 75 years and older who received lenalidomide, there was a

higher incidence of serious adverse reactions and adverse reactions that led to study treatment discontinuation

Patients with newly diagnosed multiple myeloma aged, 94% (1521 /1613) were 65 years of age or older, while 35%

(561/1613) were over 75 years of age. The percentage of patients over age 75 years and older should be carefully

assessed beforewas similar between study arms (Rd Continuous: 33%; Rd18: 34%; MPT: 33%). Overall, across all

treatment is considered.

In clinical trials of newly diagnosed multiple myelomaarms, the frequency in transplant non eligible patients,

lenalidomide combined therapymost of the AE categories (eg, all AEs, grade 3/4 AEs, serious AEs) was less tolerated

higher in patients older (> 75 years of age) than in younger (≤ 75 years of age compared to the younger population.

These patients discontinued at a higher rate due to intolerance () subjects. Grade 3 or 4 adverse events and serious

adverse events), when compared to patients < 75years.AEs in the General Disorders and Administration Site

Conditions body system were consistently reported at a higher

Multiple myeloma withfrequency (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 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.

MM after at least one prior therapy:

…….

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.

…….

אפורל ןולעה ב"צמ יפכ

רשואש

לע

ידי

דרשמ

תואירבה

.ילארשיה

ןולעה

אפורל

דרשמל חלשנ

תואירבה

ךרוצל

תאלעה

תופורתה רגאמל

רתאבש

דרשמ

תואירבה

ולבקל ןתינו

ספדומ

לע

ידי

היינפ

םרפואינ :םושירה לעבל

מ"עב

חולישה 'חר

.ד.ת ,

7063

חתפ

,הווקת

:לט

03-9373737

,הכרבב

ךלוו זוע

ו היצלוגר להנמ הנוממ חקור

םרפואינ

קיפיטנייס

מ"עב

FULL PRESCRIBING INFORMATION

NAME OF THE MEDICINAL PRODUCT

Revlimid 2.5 mg, hard capsules

Revlimid 5 mg, hard capsules

Revlimid 7.5 mg, hard capsules

Revlimid 10 mg, hard capsules

Revlimid 15 mg, hard capsules

Revlimid 20 mg, hard capsules

Revlimid 25 mg, hard capsules

QUALITATIVE AND QUANTITATIVE COMPOSITION

Revlimid 2.5 mg hard capsules

Each capsule contains 2.5 mg of lenalidomide.

Excipient(s) with known effect

Each capsule contains 73.5 mg of lactose (as anhydrous lactose).

Revlimid 5 mg hard capsules

Each capsule contains 5 mg of lenalidomide.

Excipient(s) with known effect

Each capsule contains 147 mg of lactose (as anhydrous lactose).

Revlimid 7.5 mg hard capsules

Each capsule contains 7.5 mg of lenalidomide.

Excipient(s) with known effect

Each capsule contains 144.5 mg of lactose (as anhydrous lactose).

Revlimid 10 mg hard capsules

Each capsule contains 10 mg of lenalidomide.

Excipient(s) with known effect

Each capsule contains 294 mg of lactose (as anhydrous lactose).

Revlimid 15 mg hard capsules

Each capsule contains 15 mg of lenalidomide.

Excipient(s) with known effect

Each capsule contains 289 mg of lactose (as anhydrous lactose).

Revlimid 20 mg hard capsules

Each capsule contains 20 mg of lenalidomide.

Excipient(s) with known effect

Each capsule contains 244.5 mg of lactose (as anhydrous lactose).

Revlimid 25 mg hard capsules

Each capsule contains 25 mg of lenalidomide.

Excipient(s) with known effect

Each capsule contains 200 mg of lactose (as anhydrous lactose).

PHARMACEUTICAL FORM

Please refer to section 3.

Because of the embryo-fetal risk, the marketing of Revlimid is subject to a risk management plan

(RMP), including the following:

Prescribers guide. Prescribers must be certified with the REVLIMID RMP program by

enrolling and complying with the RMP requirements.

Patients brochure. patient must sign a Patient-Physician agreement form and comply with the

RMP requirements. In particular, female patients of reproductive potential who are not pregnant

must comply with the pregnancy testing and contraception and males must comply with

contraception requirements.

Pharmacies must be certified with the REVLIMID RMP program, must only dispense to

patients who are authorized to receive REVLIMID and comply with RMP requirements.

Please ensure you are familiar with this important information and explain to the patient the need

to review the brochures before starting treatment.

WARNING: EMBRYO FETAL TOXICITY, HEMATOLOGIC TOXICITY, and

VENOUS and ARTERIAL THROMBOEMBOLISM

Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused

limb abnormalities in a developmental monkey study. Thalidomide is a known human

teratogen that causes severe life-threatening human birth defects. If lenalidomide is used

during pregnancy, it may cause birth defects or death to a developing baby. In women of

childbearing potential, obtain a negative pregnancy test before starting REVLIMID

treatment. Women of childbearing potential must use 2 reliable forms of contraception

simultaneously or continuously abstain from heterosexual sex 4 weeks before starting

treatment, during (including dose interruptions) and for 4 weeks following discontinuation

of REVLIMID treatment [see Warnings and Precautions (5.1 )]].

Hematologic Toxicity (Neutropenia and Thrombocytopenia

REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of

patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during

the major study. Thirty-four percent of patients had to have a second dose delay/reduction.

Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study.

Patients on therapy for del 5q myelodysplastic syndromes should have their complete

blood counts monitored weekly for the first 8 weeks of therapy and at least monthly

thereafter. Patients may require dose interruption and/or reduction. Patients may require

use of blood product support and/or growth factors [see Dosage and Administration (2.2)].

Venous and Arterial Thromboembolism

REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT)

and pulmonary embolism (PE), as well as risk of myocardial infarction, and stroke in

patients with multiple myeloma who were treated with REVLIMID and dexamethasone

therapy. Monitor for and advise patients about signs and symptoms of thromboembolism.

Advise patients to seek immediate medical care if they develop symptoms such as shortness

of breath, chest pain, or arm or leg swelling. Thromboprophylasix is recommended and

the choice of regimen should be based on an assessment of an individual patient’s

underlying risk factors [see Warnings and Precautions (5.4)].

1.

INDICATIONS AND USAGE

1.1

Multiple Myeloma

Revlimid is indicated for:

The maintenance treatment of adult patients with newly diagnosed multiple myeloma (MM) who have

undergone autologous stem cell transplantation.

previously untreated multiple myeloma in adult patients who are not eligible for transplant.

in combination with dexamethasone treatment of multiple myeloma patients who have

received at least one prior therapy.

1.2

Myelodysplastic Syndromes

REVLIMID is indicated for patients with transfusion-dependent anemia due to low- or

intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic

abnormality with or without additional cytogenetic abnormalities.

Revlimid 7.5 mg is not indicated for treatment in MDS.

1.3

Mantle Cell Lymphoma

REVLIMID is indicated for the treatment of adult patients with relapsed and/or refractory mantle

cell lymphoma (MCL).

2.

DOSAGE AND ADMINISTRATION

REVLIMID should be taken orally at about the same time each day, either with or without food.

REVLIMID hard capsules should be swallowed whole with water. The hard capsules should not

be opened, broken, or chewed.

2.1 Newly Diagnosed Multiple Myeloma

(NDMM)

Lenalidomide maintenance in patients who have undergone autologous stem cell transplantation

(ASCT)

Lenalidomide maintenance should be initiated after adequate haematologic recovery following

ASCT in patients without evidence of progression. Lenalidomide must not be started if the

Absolute Neutrophil Count (ANC) is < 1.0 x 10

/L, and/or platelet counts are < 75 x 10

Recommended dose

The recommended starting dose is lenalidomide 10 mg orally once daily continuously (on days 1

to 28 of repeated 28-day cycles) given until disease progression or intolerance. After 3 cycles of

lenalidomide maintenance, the dose can be increased to 15 mg orally once daily if tolerated.

Dose reduction steps

Starting dose (10 mg)

If dose increased (15 mg)

Dose level -1

5 mg

10 mg

Dose level -2

5 mg (days 1-21 every 28 days)

5 mg

Dose level -3

Not applicable

5 mg (days 1-21 every 28 days)

Do not dose below 5 mg (days 1-21 every 28 days)

After 3 cycles of lenalidomide maintenance, the dose can be increased to 15 mg orally once daily if tolerated.

Thrombocytopenia

When platelets

Recommended course

Fall to < 30 x 10

Interrupt lenalidomide treatment

Return to ≥ 30 x 10

Resume lenalidomide at dose level -1 once

daily

For each subsequent drop below 30 x 10

Interrupt lenalidomide treatment

Return to ≥ 30 x 10

Resume lenalidomide at next lower dose

level once daily

Neutropenia

When neutrophils

Recommended course

Fall to < 0.5 x 10

Interrupt lenalidomide treatment

Return to ≥ 0.5 x 10

Resume lenalidomide at dose level -1 once

daily

For each subsequent drop below < 0.5 x 10

Interrupt lenalidomide treatment

Return to ≥ 0.5 x 10

Resume lenalidomide at next lower dose

level once daily

At the physician’s discretion, if neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and

maintain the dose level of lenalidomide.

Lenalidomide in combination with dexamethasone until disease progression in

patients who are

not eligible for transplant

Lenalidomide treatment must not be started if the ANC is < 1.0 x 10

/L, and/or platelet counts are

< 50 x 10

Recommended dose

The recommended starting dose of lenalidomide is 25 mg orally once daily on days 1-21 of

repeated 28-day cycles. The recommended dose of dexamethasone is 40 mg orally once daily on

days 1, 8, 15 and 22 of repeated 28-day cycles. Patients may continue lenalidomide and

dexamethasone therapy until disease progression or intolerance.

Dosing is continued or modified based upon clinical and laboratory findings. For patients ≥75

years of age, the starting dose of dexamethasone is 20 mg/day on days 1, 8, 15 and 22 of each 28-

day treatment cycle. The recommended dose of lenalidomide for patients suffering from

moderate renal impairment is 10 mg once daily.

Recommended dose adjustments during treatment and restart of treatment:

Dose adjustments, as summarised below, are recommended to manage grade 3 or 4

thrombocytopenia, neutropenia, or other grade 3 or 4 toxicity judged to be related to

lenalidomide.

Dose reduction steps

Lenalidomide

Dexamethasone

Starting dose

25 mg

40 mg

Dose level -1

20 mg

20 mg

Dose level -2

15 mg

12 mg

Dose level -3

10 mg

8 mg

Dose level- 4

5 mg

4 mg

Dose level -5

2.5 mg

Thrombocytopenia

When platelets

Recommended course

Fall to < 25 x 10

Stop lenalidomide dosing for

remainder of cycleª

Return to ≥ 50 x 10

Decrease by one dose level when

dosing resumed at next cycle

If Dose Limiting Toxicity (DLT) occurs on > day15 of a cycle, lenalidomide dosing will be interrupted for at least the remainder of the current

28-day cycle.

Neutropenia

When neutrophils

Recommended course

First fall to < 0.5 x 10

Interrupt lenalidomide treatment

Return to ≥ 1 x 10

/L when neutropenia is

the only observed toxicity

Resume lenalidomide at Starting dose

once daily

Return to ≥ 0.5 x 10

/L when dose-

dependent haematological toxicities other

than neutropenia are observed

Resume lenalidomide at Dose level -1

once daily

For each subsequent drop below

< 0.5 x 10

Interrupt lenalidomide treatment

Return to ≥ 0.5 x 10

Resume lenalidomide at next lower

dose level once daily.

In case of neutropenia, the use of growth factors in patient management should be considered.

If the dose of lenalidomide was reduced for a hematologic DLT, the dose of lenalidomide may

be re-introduced to the next higher dose level (up to the starting dose) at the discretion of the

treating physician if continued lenalidomide / dexamethasone therapy resulted in improved bone

marrow function (no DLT for at least 2 consecutive cycles and an ANC ≥1,5 x 10

/L with a

platelet count ≥ 100,

x 10

/L at the beginning of a new cycle at the current dose level).

Lenalidomide in combination with melphalan and prednisone followed by maintenance

monotherapy in patients who are

not eligible for transplant

Lenalidomide treatment must not be started if the ANC is < 1.5 x 10

/L, and/or platelet counts

are < 75 x 10

Recommended dose

The recommended starting dose is lenalidomide

mg/day orally on days 1-21 of repeated

28-day cycles for up to 9 cycles, melphalan 0.18 mg/kg orally on days 1-4 of repeated 28

cycles, prednisone 2 mg/kg orally on days 1-4 of repeated 28-day cycles. Patients who

complete

cycles or who are unable to complete the combination therapy due

intolerance

are treated with lenalidomide alone, 10 mg/day orally on days 1-21 of repeated

28-day

cycles

given until disease

progression.

Dosing is continued or modified based upon clinical and

laboratory findings.

Recommended dose adjustments during treatment and restart of treatment:

Dose adjustments, as summarised below, are recommended to manage grade 3 or 4

thrombocytopenia, neutropenia, or other grade 3 or 4 toxicity judged to be related to

lenalidomide.

Dose reduction steps

Lenalidomide

Melphalan

Prednisone

Starting dose

10 mgª

0.18 mg/kg

2 mg/kg

Dose level -1

7.5 mg

0.14 mg/kg

1 mg/kg

Dose level -2

5 mg

0.10 mg/kg

0.5 mg/kg

Dose level -3

2.5 mg

0.25 mg/kg

If neutropenia is the only toxicity at any dose level, add granulocyte colony stimulating factor (G-CSF) and maintain the dose level of

lenalidomide

Thrombocytopenia

When platelets

Recommended course

First fall to < 25 x 10

Interrupt lenalidomide treatment

Return to ≥ 25 x 10

Resume lenalidomide and melphalan

at Dose level -1

For each subsequent drop below

30 x 10

Interrupt lenalidomide treatment

Return to ≥ 30 x 10

Resume lenalidomide at next lower

dose level (Dose level -2 or -3) once

daily.

Neutropenia

When neutrophils

Recommended course

First fall to < 0.5 x 10

/Lª

Interrupt lenalidomide treatment

Return to ≥ 0.5 x 10

/L when neutropenia

is the only observed toxicity

Resume lenalidomide at Starting dose

once daily

Return to ≥ 0.5 x 10

/L when dose-

dependent haematological toxicities other

than neutropenia are observed

Resume lenalidomide at Dose level -1

once daily

For each subsequent drop below

< 0.5 x 10

Interrupt lenalidomide treatment

Return to ≥ 0.5 x 10

Resume lenalidomide at next lower

dose level once daily.

ªIf the subject has not been receiving G-CSF therapy, initiate G-CSF therapy. On Day 1 of next cycle, continue G-CSF as needed and maintain

dose of melphalan if neutropenia was the only DLT. Otherwise, decrease by one dose level at start of next cycle.

In case of neutropenia, the use of growth factors in patient management should be considered.

For patients older than 75 years of age treated with lenalidomide in combination with

dexamethasone, the starting dose of dexamethasone is 20 mg/day on days 1, 8, 15 and 22 of each

28-day treatment cycle.

No dose adjustment is proposed for patients older than 75 years treated with lenalidomide in

combination with melphalan and prednisone.

2.2

Multiple Myeloma with at least one prior therapy

The recommended starting dose of REVLIMID is 25 mg once daily on days 1-21 of repeated 28-

day cycles. The recommended dose of dexamethasone is 40 mg once daily on days 1-4, 9-12,

and 17-20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg once daily orally

on days 1-4 every 28 days. Treatment is continued or modified based upon clinical and

laboratory findings.

Prescribing physicians should carefully evaluate which dose of dexamethasone to use, taking

into account the condition and disease status of the patient.

Lenalidomide treatment must not be started if the ANC < 1,000/mcL, and/or platelet counts <

75,000/ mcL or, dependent on bone marrow infiltration by plasma cells, platelet counts <

30,000/mcL.

Dose Adjustments for Hematologic Toxicities During Multiple Myeloma Treatment

Dose modification guidelines, as summarized below, are recommended to manage Grade 3 or 4

neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to

REVLIMID.

Platelet counts

Thrombocytopenia in MM

When Platelets

Recommended Course

Fall to <30,000/mcL

Interrupt REVLIMID

treatment, follow CBC weekly

Return to ≥30,000/mcL

Restart REVLIMID at 15 mg

daily

For each subsequent drop <30,000/mcL

Interrupt REVLIMID

treatment

Return to ≥30,000/mcL

Resume REVLIMID at 5 mg

less than the previous dose. Do

not dose below 5 mg daily

Absolute Neutrophil counts (ANC)

Neutropenia in MM

When Neutrophils

Recommended Course

Fall to <1000/mcL

Interrupt REVLIMID

treatment, add G-CSF, follow

CBC weekly

Return to ≥1,000/mcL and neutropenia is the only

toxicity

Resume REVLIMID at 25

mg daily

Return to ≥1,000/mcL and if other toxicity

Resume REVLIMID at 15

mg daily

For each subsequent drop <1,000/mcL

Interrupt REVLIMID

treatment

Return to ≥1,000/mcL

Resume REVLIMID at 5 mg

less than the previous dose.

Do not dose below 5 mg daily

In case of neutropenia, the physician should consider the use of growth factors in patient

management.

Starting Dose Adjustment for Renal Impairment in MM:

See Section 2.5

2.3

Myelodysplastic Syndromes

The recommended starting dose of REVLIMID is 10 mg daily. Treatment is continued or

modified based upon clinical and laboratory findings.

Dose Adjustments for Hematologic Toxicities During MDS Treatment

Patients who are dosed initially at 10 mg and who experience thrombocytopenia should have

their dosage adjusted as follows:

Platelet counts

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

MDS

If baseline ≥100,000/mcL

When Platelets

Recommended Course

Fall to <50,000/mcL

Interrupt REVLIMID treatment

Return to ≥50,000/mcL

Resume REVLIMID at 5 mg daily

If baseline <100,000/mcL

When Platelets

Recommended Course

Fall to 50% of the baseline value

Interrupt REVLIMID treatment

If baseline ≥60,000/mcL and

returns to ≥50,000/mcL

Resume REVLIMID at 5 mg daily

If baseline <60,000/mcL and

returns to ≥30,000/mcL

Resume REVLIMID at 5 mg daily

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

When Platelets

Recommended Course

<30,000/mcL or <50,000/mcL

with platelet transfusions

Interrupt REVLIMID treatment

Return to ≥30,000/mcL

(without hemostatic failure)

Resume REVLIMID at 5 mg daily

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

follows:

If thrombocytopenia develops during treatment at 5 mg daily in MDS

When Platelets

Recommended Course

<30,000/mcL or <50,000/mcL

with platelet transfusions

Interrupt REVLIMID treatment

Return to ≥30,000/mcL

(without hemostatic failure)

Resume REVLIMID at 2.5 mg

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 REVLIMID treatment

Return to ≥1,000/mcL

Resume REVLIMID at 5 mg

daily

If baseline ANC <1,000/mcL

When Neutrophils

Recommended Course

Fall to <500/mcL

Interrupt REVLIMID treatment

Return to ≥500/mcL

Resume REVLIMID at 5 mg

daily

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

When Neutrophils

Recommended Course

<500/mcL for ≥7 days or <500/mcL

associated with fever (≥38.5°C)

Interrupt REVLIMID treatment

Return to ≥500/mcL

Resume REVLIMID at 5 mg

daily

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

If neutropenia develops during treatment at 5 mg daily in MDS

When Neutrophils

Recommended Course

<500/mcL for ≥7 days or <500/mcL

associated with fever (≥38.5°C)

Interrupt REVLIMID

treatment

Return to ≥500/mcL

Resume REVLIMID at 2.5

mg daily

Discontinuation of lenalidomide

Patients without at least a minor erythroid response within 4 months of therapy initiation,

demonstrated by at least a 50% reduction in transfusion requirements or, if not transfused, a

1g/dl rise in haemoglobin, should discontinue lenalidomide treatment.

Starting Dose Adjustment for Renal Impairment in MDS:

See Section 2.5

2.4

Mantle Cell Lymphoma

The recommended starting dose of REVLIMID is 25 mg/day orally on days 1-21 of repeated

28-day cycles.

Dosing is continued or modified based upon clinical and laboratory findings.

Dose reduction steps

Starting dose

25 mg once daily on days 1-21, every 28 days

Dose Level -1

20 mg once daily on days 1-21, every 28 days

Dose Level -2

15 mg once daily on days 1-21, every 28 days

Dose Level -3

10 mg once daily on days 1-21, every 28 days

Dose Level -4

5 mg once daily on days 1-21, every 28 days

Dose Level -5

2.5 mg once daily on days 1-21, every 28 days

5 mg every other day on days 1-21, every 28 days

Thrombocytopenia

When Platelets

Recommended Course

Fall to <50 x 10

Interrupt REVLIMID

treatment and conduct

Complete Blood Count (CBC)

at least every 7 days

Return to ≥ 60 x 10

Resume lenalidomide at next

lower level (Dose Level -1)

For each subsequent drop below 50 x 10

Return to ≥60 x 10

Interrupt REVLIMID

treatment and conduct the

CBC at least every 7 days

Resume REVLIMID at next

lower level (Dose Level -2, -3,

-4 or -5). Do not dose below

Dose Level -5

Neutropenia

When Neutrophils

Recommended Course

Fall to <1 x 10

for at least 7 days

Falls to <1 x 10

/L with an associated fever (body

temperature ≥ 38.5°C)

Falls to <0.5 x 10

Interrupt REVLIMID

treatment and conduct the

CBC at least every 7 days

Return to ≥1 x 10

Resume REVLIMID at next

lower dose level (Dose Level

– 1)

For each subsequent drop below 1 x 10

/L for at least

7 days or drop to < 1 x 10

/L with associated fever

(body temperature ≥ 38.5°C) or drop to < 0.5 x 10

Returns to ≥1 x 10

Interrupt REVLIMID

treatment

Resume REVLIMID at next

lower dose level (Dose Level

-2, -3, -4, -5). Do not dose

below Dose Level -5

Tumour flare reaction

REVLIMID may be continued in patients with Grade 1 or 2 tumour flare reaction (TFR) without

interruption or modification, at the physician’s discretion. In patients with Grade 3 or 4 TFR,

withhold treatment with REVLIMID until TFR resolves to ≤ Grade 1 and patients may be treated

for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR.

Starting Dose Adjustment for Renal Impairment in MCL:

See Section 2.5.

2.5 Starting Dose for Renal Impairment in MM, MDS or MCL

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

following table.

Starting Dose Adjustments for Patients with Renal Impairment

Renal Function

(Cockcroft-Gault)

Dose in

Revlimid

combination

therapy for

MM and for

MCL

Dose in Revlimid

maintenance therapy

following auto-HSCT

for MM and for MDS

CLcr 30to 60 mL/min

10 mg once

daily

5 mg once daily

CLcr < 30 mL/min

(not requiring

dialysis)

7.5 mg

once daily

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.

REVLIMID Maintenance Therapy Following Auto-HSCT for MM and for MCL and

MDS:

Base subsequent REVLIMID dose increase or decrease on individual patient treatment

tolerance [see Dosage and Administration (2.1- 2.3)].

All patients

For other grade 3 or 4 toxicities judged to be related to lenalidomide, treatment should be

stopped and only restarted at next lower dose level when toxicity has resolved to ≤ grade 2

depending on the physician’s discretion.

Lenalidomide interruption or discontinuation should be considered for grade 2 or 3 skin rash.

Lenalidomide must be discontinued for angioedema, grade 4 rash, exfoliative or bullous rash, or

if Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) or Drug Reaction with

Eosinophilia and Systemic Symptoms (DRESS) is suspected, and should not be resumed

following discontinuation from these reactions.

3.

DOSAGE FORMS AND STRENGTHS

REVLIMID 2.5 mg, 5 mg, 7.5mg, 10 mg, 15 mg, 20 mg and 25 mg hard capsules will be

supplied through the Revlimid RMP-PPP.

REVLIMID is available in the following hard 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 hard capsules imprinted “REV” on one half and “5 mg” on the other half

in black ink

7.5mg: Pale yellow/white hard capsules marked “REV 7.5 mg”

10 mg: Blue/green and pale yellow opaque hard capsules imprinted “REV” on one half and “10

mg” on the other half in black ink

15 mg: Powder blue and white opaque hard 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 hard capsules imprinted “REV” on one half and “25 mg” on the other half

in black ink

4.

CONTRAINDICATIONS

4.1 Pregnancy

REVLIMID can cause fetal harm when administered to a pregnant female. Limb abnormalities

were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis.

This effect was seen at all doses tested. Due to the results of this developmental monkey study,

and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide

is contraindicated in pregnant women and women capable of becoming pregnant [

see Boxed

Warning

.

Females of childbearing potential may be treated with lenalidomide provided adequate

precautions are taken to avoid pregnancy.

If hormonal or IUD contraception is medically contraindicated, two other effective or highly

effective methods may be used.

Females of childbearing potential being treated with REVLIMID must have pregnancy testing

(sensitivity of at least 25 mIU/mL). The test should be performed prior to beginning therapy within

3 days prior to prescribing REVLIMID and then monthly thereafter (including dose interruptions).

Pregnancy

testing

should

be

performed

also

4

weeks

following

discontinuation

of

REVLIMID therapy.

Pregnancy testing and counseling must be performed if a patient misses her period or if there is

any abnormality in menstrual bleeding. If pregnancy occurs, REVLIMID must be immediately

discontinued. Under these conditions, the patient should be referred to an obstetrician/gynecologist

experienced in reproductive toxicity for further evaluation and counseling.

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 hazard to the fetus [

see Warnings and Precautions (5.1,

5.2), Use in Special Populations (8.1), (8.5)

4.2

Allergic Reactions

REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g.,

angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [

see

Warnings and Precautions (5.8)

.

5.

WARNINGS AND PRECAUTIONS

5.1 Embryo-Fetal Toxicity

REVLIMID

thalidomide

analogue

contraindicated

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 lenalidomide produced malformations in the offspring of female monkeys

who received the drug during pregnancy, similar to birth defects observed in humans following

exposure to thalidomide during pregnancy.

If REVLIMID is used during pregnancy, it may cause birth defects or death to a developing baby.

Females of childbearing potential must be advised to avoid pregnancy while on REVLIMID. Two

reliable forms of contraception should be used simultaneously during therapy, during dose

interruptions and for at least 4 weeks following discontinuation of therapy.

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

REVLIMID can be prescribed only in agreement with RMP limitations.

5.2

Reproductive Risk and

Special Prescribing Requirements (Revlimid RMP-PPP)

Revlimid can be prescribed and dispensed only if following the Revlimid Risk Management

Program. All patients must follow the Revlimid Risk Minimization Program in order to receive

Revlimid (refer to black box warning section)

Female Patients:

Two effective contraception methods must be used by female patients of childbearing potential for

at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions

and for 4 weeks following discontinuation of REVLIMID therapy unless continuous abstinence

from heterosexual sexual contact is the chosen method. Reliable contraception is indicated even

where there has been a history of infertility, unless due to hysterectomy, a bilateral oophorectomy,

because the patient has been postmenopausal naturally for at least 24 consecutive months or in any

other case indicated in Revlimid RMP. Females of childbearing potential should be referred to a

qualified provider of contraceptive methods, if needed. Sexually mature females who have not

undergone

hysterectomy,

have

bilateral

oophorectomy,

have

been

postmenopausal naturally for at least 24 consecutive months (i.e., who have had menses at some

time in the preceding 24 consecutive months) or in any other case indicated in the Revlimid RMP,

are considered to be females of childbearing potential.

Cessation of menses due to anti-cancer therapy, do not exclude the potential to become

pregnant.

Two reliable forms of contraception must be used simultaneously unless continuous abstinence

from heterosexual sexual contact is the chosen method.

Females of childbearing potential must have a negative pregnancy test (sensitivity of at least 25

mIU/mL) before starting the therapy, and then monthly thereafter (including dose interruptions

and including 4 weeks following discontinuation of REVLIMID therapy). The test should be

performed within 3 days prior to prescribing REVLIMID. A prescription for REVLIMID for a

female of childbearing potential must not be issued by the prescriber until a negative pregnancy

test has been verified by the prescriber.

Pregnancy testing and counseling should be performed if a patient misses her period or if there is

any abnormality in her pregnancy test or in her menstrual bleeding. REVLIMID therapy must be

discontinued during this evaluation.

Pregnancy test results should be verified by the prescriber prior to dispensing

any

prescription.

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

Any suspected fetal exposure to REVLIMID must be reported to the attending physician and

Neopharm.

patient

should

referred

obstetrician/gynecologist

experienced

reproductive toxicity for further evaluation and counseling.

Do not breastfeed during therapy (including dose interruptions).

Patients should not donate blood while taking REVLIMID, during any breaks (discontinuations)

in your therapy, and for 4 weeks following discontinuation of REVLIMID therapy.

Male Patients:

Clinical data has demonstrated the presence of lenalidomide in human semen. Therefore, males

receiving REVLIMID must always use a latex/ polyurethane condom during any sexual contact

with females of childbearing potential, even if they have undergone a successful vasectomy. In the

case of a male patient with an allergy to latex or polyurethane, at least one highly effective form

of contraception should be used by any female sexual partner. Contraception should be started in

this partner at least 4 weeks prior to the start of a sexual relationship with the patient, and continued

throughout

REVLIMID

therapy

including

dose

interruptions

weeks

following

discontinuation of therapy.

Patients should not donate blood and semen or sperm while taking REVLIMID, during any breaks

(discontinuations) in your therapy, and for 4 weeks following discontinuation of REVLIMID

therapy.

Once treatment has started and during dose interruptions

, pregnancy testing for females of

childbearing potential should be performed every 4 weeks.

Pregnancy testing should be performed also 4 weeks following discontinuation of

REVLIMID therapy

Prescriptions for women of childbearing potential can be for a maximum duration of 4 weeks,

and prescriptions for all other patients can be for a maximum duration of 12 weeks.

5.3 Other warnings and precautions of use

Hematologic Toxicity

REVLIMID 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

REVLIMID should have their complete blood counts assessed periodically as described below

[see Dosage and Administration (2.1, 2.2, 2.3)]. Patients should be advised to promptly report

febrile episodes and dose reductions may be required. Patients and physicians are advised to be

observant for signs and symptoms of bleeding, including petechiae and epistaxes, especially in

patients receiving concomitant medicinal products susceptible to induce bleeding.

Patients taking REVLIMID in combination with dexamethasone or as REVLIMID 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 [see Dosage and Administration (2.1)].

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 [see Adverse Reactions (6.1)].

Patients taking REVLIMID for MDS should have their complete blood counts monitored weekly

for the first 8 weeks and at least monthly thereafter.

Patients taking REVLIMID for 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.

Neutropenia and thrombocytopenia

NDMM

Newly diagnosed multiple myeloma: patients who have undergone ASCT treated with

lenalidomide maintenance

The adverse reactions from CALGB 100104 included events reported post-high dose melphalan

and ASCT (HDM/ASCT) as well as events from the maintenance treatment period. A second

analysis identified events that occurred after the start of maintenance treatment. In IFM 2005-02,

the adverse reactions were from the maintenance treatment period only.

Overall, grade 4 neutropenia was observed at a higher frequency in the lenalidomide

maintenance arms compared to the placebo maintenance arms in the 2 studies evaluating

lenalidomide maintenance in NDMM patients who have undergone ASCT (32.1% vs 26.7%

[16.1% vs 1.8% after the start of maintenance treatment] in CALGB 100104 and 16.4% vs 0.7%

in IFM 2005-02, respectively). Treatment-emergent AEs of neutropenia leading to lenalidomide

discontinuation were reported in 2.2% of patients in CALGB 100104 and 2.4% of patients in

IFM 2005-02, respectively. Grade 4 febrile neutropenia was reported at similar frequencies in the

lenalidomide maintenance arms compared to placebo maintenance arms in both studies (0.4% vs

0.5% [0.4% vs 0.5% after the start of maintenance treatment] in CALGB 100104 and 0.3% vs

0% in IFM 2005-02, respectively). Patients should be advised to promptly report febrile

episodes, a treatment interruption and/or dose reductions may be required (see section 4.2).

Grade 3 or 4 thrombocytopenia was observed at a higher frequency in the lenalidomide

maintenance arms compared to the placebo maintenance arms in studies evaluating lenalidomide

maintenance in NDMM patients who have undergone ASCT (37.5% vs 30.3% [17.9% vs 4.1%

after the start of maintenance treatment] in CALGB 100104 and 13.0% vs 2.9% in IFM 2005-02,

respectively). Patients and physicians are advised to be observant for signs and symptoms of

bleeding, including petechiae and epistaxes, especially in patients receiving concomitant

medicinal products susceptible to induce bleeding (see section 4.8, Haemorrhagic disorders).

Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with

lenalidomide in combination with low dose dexamethasone

Grade 4 neutropenia was observed in the lenalidomide arms in combination with low dose

dexamethasone to a lesser extent than in the comparator arm (8.5% in the Rd [continuous

treatment] and Rd18 [treatment for 18 four-week cycles] compared with 15% in the

melphalan/prednisone/thalidomide arm). Grade 4 febrile neutropenia episodes were consistent

with the comparator arm (0.6 % in the Rd and Rd18 lenalidomide/dexamethasone-treated

patients compared with 0.7% in the melphalan/prednisone/thalidomide arm.

Grade 3 or 4 thrombocytopenia was observed to a lesser extent in the Rd and Rd18 arms than in

the comparator arm (8.1% vs 11.1%, respectively).

Newly diagnosed multiple myeloma: patients who are not eligible for transplant treated with

lenalidomide in combination with melphalan and prednisone

The combination of lenalidomide with melphalan and prednisone in clinical trials of newly

diagnosed multiple myeloma patients is associated with a higher incidence of grade 4

neutropenia (34.1% in melphalan, prednisone and lenalidomide arm followed by lenalidomide

(MPR+R) and melphalan, prednisone and lenalidomide followed by placebo (MPR+p) treated

patients compared with 7.8% in MPp+p-treated patients;). Grade 4 febrile neutropenia episodes

were observed infrequently (1.7% in MPR+R/MPR+p treated patients compared to 0.0 % in

MPp+p treated patients;).

The combination of lenalidomide with melphalan and prednisone in multiple myeloma patients is

associated with a higher incidence of grade 3 and grade 4 thrombocytopenia (40.4% in

MPR+R/MPR+p treated patients, compared with 13.7% in MPp+p-treated patients).

Multiple myeloma: patients with at least one prior therapy

In the pooled MM trials Grade 3 and 4 hematologic toxicities were more frequent in patients

treated with the combination of REVLIMID and dexamethasone than in patients treated with

dexamethasone alone [

see Adverse Reactions (6.1)

Myelodysplastic Syndromes patients

Patients taking REVLIMID 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) [see Boxed Warning and Dosage and Administration (2.2)].

Mantle cell lymphoma patients

Lenalidomide treatment in mantle cell lymphoma patients is associated with a higher incidence

of grade 3 and 4 neutropenia compared with patients on the control arm.

Tumour flare reaction and tumour lysis syndrome

Because lenalidomide has anti-neoplastic activity the complications of tumour lysis syndrome

(TLS) may occur. TLS and tumour flare reaction (TFR) have uncommonly been observed in

patients with lymphomas, who were treated with lenalidomide. Fatal instances of TLS have been

reported during treatment with lenalidomide. The patients at risk of TLS and TFR are those with

high tumour burden prior to treatment. Caution should be practiced when introducing these

patients to lenalidomide. These patients should be monitored closely, especially during the first

cycle or dose-escalation, and appropriate precautions taken. There have been rare reports of TLS

in patients with MM treated with lenalidomide, and no reports in patients with MDS treated with

lenalidomide.

Tumour burden

Mantle cell lymphoma

Lenalidomide is not recommended for the treatment of patients with high tumour burden if

alternative treatment options are available.

Early death

In study MCL-002 there was overall an apparent increase in early (within 20 weeks) deaths.

Patients with high tumour burden at baseline are at increased risk of early death, there were

16/81 (20%) early deaths in the lenalidomide arm and 2/28 (7%) early deaths in the control arm.

Within 52 weeks corresponding figures were 32/81 (40%) and 6/28 (21%) (See section 5.1).

Adverse events

In study MCL-002, during treatment cycle 1, 11/81 (14%) patients with high tumour burden

were withdrawn from therapy in the lenalidomide arm vs. 1/28 (4%) in the control group. The

main reason for treatment withdrawal for patients with high tumour burden during treatment

cycle 1 in the lenalidomide arm was adverse events, 7/11 (64%).

Patients with high tumour burden should therefore be closely monitored for adverse reactions

(see Section 4.8) including signs of tumour flare reaction (TFR). Please refer to section 4.2 for

dose adjustments for TFR.

High tumour burden was defined as at least one lesion ≥5 cm in diameter or 3 lesions ≥3 cm.

Tumour flare reaction

Mantle cell lymphoma

Careful monitoring and evaluation for TFR is recommended. Patients with high mantle cell

lymphoma International Prognostic Index (MIPI) at diagnosis or bulky disease (at least one

lesion that is ≥ 7 cm in the longest diameter) at baseline may be at risk of TFR. Tumour flare

reaction may mimic progression of disease (PD). Patients in studies MCL-002 and MCL-001 that

experienced Grade 1 and 2 TFR were treated with corticosteroids, non-steroidal anti-

inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms.

The decision to take therapeutic measures for TFR should be made after careful clinical

assessment of the individual patient (see section 4.2).

Infection with or without Neutropenia

Patients with multiple myeloma are prone to develop infections including pneumonia. A higher

rate of infections was observed with lenalidomide in combination with dexamethasone than with

MPT in patients with NDMM who are not eligible for transplant, and with lenalidomide

maintenance compared to placebo in patients with NDMM who had undergone ASCT.

Grade ≥ 3 infections occurred within the context of neutropenia in less than one-third of the

patients. Patients with known risk factors for infections should be closely monitored. All patients

should be advised to seek medical attention promptly at the first sign of infection (e.g., cough,

fever, etc.) thereby allowing for early management to reduce severity.

Viral reactivation

Cases of viral reactivation have been reported in patients receiving lenalidomide, including

serious cases of herpes zoster or hepatitis B virus (HBV) reactivation.

Some of the cases of viral reactivation had a fatal outcome.

Some of the cases of herpes zoster reactivation resulted in disseminated herpes zoster, meningitis

herpes zoster or ophthalmic herpes zoster requiring a temporary hold or permanent

discontinuation of the treatment with lenalidomide and adequate antiviral treatment.

Reactivation of hepatitis B has been reported rarely in patients receiving lenalidomide who have

previously been infected with the hepatitis B virus (HBV). Some of these cases have progressed

to acute hepatic failure resulting in discontinuation of lenalidomide and adequate antiviral

treatment. Hepatitis B virus status should be established before initiating treatment with

lenalidomide. For patients who test positive for HBV infection, consultation with a physician

with expertise in the treatment of hepatitis B is recommended. Caution should be exercised when

lenalidomide is used in patients previously infected with HBV, including patients who are anti-

HBc positive but HBsAg negative. These patients should be closely monitored for signs and

symptoms of active HBV infection throughout therapy.

Venous and Arterial Thromboembolism

In patients with multiple myeloma, the combination of lenalidomide with dexamethasone is

associated with an increased risk of venous thromboembolism (predominantly deep vein

thrombosis and pulmonary embolism) and was seen to a lesser extent with lenalidomide in

combination with melphalan and prednisone.

In patients with multiple myeloma, myelodysplastic syndromes and mantle cell lymphoma,

treatment with lenalidomide monotherapy was associated with a lower risk of venous

thromboembolism (predominantly deep vein thrombosis and pulmonary embolism) than in

patients with multiple myeloma treated with lenalidomide in combination therapy

In patients with multiple myeloma, the combination of lenalidomide with dexamethasone is

associated with an increased risk of arterial thromboembolism (predominantly myocardial

infarction and cerebrovascular event) and was seen to a lesser extent with lenalidomide in

combination with melphalan and prednisone. The risk of ATE is lower in patients with multiple

myeloma treated with lenalidomide monotherapy than in patients with multiple myeloma treated

with lenalidomide in combination therapy.

Consequently, patients with known risk factors for thromboembolism – including prior

thrombosis – should be closely monitored. Action should be taken to try to minimize all

modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia). Concomitant

administration of erythropoietic agents or previous history of thromboembolic events may also

increase thrombotic risk in these patients. Therefore, erythropoietic agents, or other agents that

may increase the risk of thrombosis, such as hormone replacement therapy, should be used with

caution in multiple myeloma patients receiving lenalidomide with dexamethasone. A

haemoglobin concentration above 12 g/dl should lead to discontinuation of erythropoietic agents.

Patients and physicians are advised to be observant for the signs and symptoms of

thromboembolism. Patients should be instructed to seek medical care if they develop symptoms

such as shortness of breath, chest pain, arm or leg swelling. Prophylactic antithrombotic

medicines should be recommended, especially in patients with additional thrombotic risk factors.

The decision to take antithrombotic prophylactic measures should be made after careful

assessment of an individual patient’s underlying risk factors.

If the patient experiences any thromboembolic events, treatment must be discontinued, and

standard anticoagulation therapy started. Once the patient has been stabilised on the

anticoagulation treatment and any complications of the thromboembolic event have been

managed, the lenalidomide treatment may be restarted at the original dose dependent upon a

benefit risk assessment. The patient should continue anticoagulation therapy during the course of

lenalidomide treatment.

Second Primary Malignancies

An increase of second primary malignancies (SPM) has been observed in clinical trials in

previously treated myeloma patients receiving lenalidomide/dexamethasone (3.98 per 100

person-years) compared to controls (1.38 per 100 person-years). Non-invasive SPM comprise

basal cell or squamous cell skin cancers. Most of the invasive SPMs were solid tumour

malignancies.

In clinical trials of newly diagnosed multiple myeloma patients not eligible for transplant, a 4.9-

fold increase in incidence rate of hematologic SPM (cases of AML, MDS) has been observed in

patients receiving lenalidomide in combination with melphalan and prednisone until progression

(1.75 per 100 person-years) compared with melphalan in combination with prednisone (0.36 per

100 person-years).

A 2.12-fold increase in incidence rate of solid tumor SPM has been observed in patients

receiving lenalidomide (9 cycles) in combination with melphalan and prednisone (1.57 per 100

person-years) compared with melphalan in combination with prednisone (0.74 per 100 person-

years).

In patients receiving lenalidomide in combination with dexamethasone until progression or for

18 months, the hematologic SPM incidence rate (0.16 per 100 person-years) was not increased as

compared to thalidomide in combination with melphalan and prednisone (0.79 per 100 person-

years).

A 1.3-fold increase in incidence rate of solid tumor SPM has been observed in patients receiving

lenalidomide in combination with dexamethasone until progression or for 18 months (1.58 per

100 person-years) compared to thalidomide in combination with melphalan and prednisone (1.19

per 100 person-years).

The increased risk of secondary primary malignancies associated with lenalidomide is relevant

also in the context of NDMM after stem cell transplantation. Though this risk is not yet fully

characterized, it should be kept in mind when considering and using Revlimid in this setting.

The incidence rate of hematologic malignancies, most notably AML, MDS and B-cell

malignancies (including Hodgkin’s lymphoma), was 1.31 per 100 person-years for the

lenalidomide arms and 0.58 per 100 person-years for the placebo arms (1.02 per 100 person-

years for patients exposed to lenalidomide after ASCT and 0.60 per 100 person-years for patients

not-exposed to lenalidomide after ASCT). The incidence rate of solid tumour SPMs was 1.36 per

100 person-years for the lenalidomide arms and 1.05 per 100 person-years for the placebo arms

(1.26 per 100 person-years for patients exposed to lenalidomide after ASCT and 0.60 per 100

person-years for patients not-exposed to lenalidomide after ASCT).

The risk of occurrence of hematologic SPM must be taken into account before initiating treatment

with lenalidomide either in combination with melphalan or immediately following high-dose

melphalan and ASCT. Physicians should carefully evaluate patients before and during treatment

using standard cancer screening for occurrence of SPM and institute treatment as indicated.

Hepatotoxicity

Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in

combination with dexamethasone: acute hepatic failure, toxic hepatitis, cytolytic hepatitis,

cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis have been reported. In clinical

trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed

characteristics); 2% of patients with multiple myeloma 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 possibly treatment with

antibiotics and older age might be risk factors. Monitor liver enzymes periodically. Stop

Revlimid upon elevation of liver enzymes. After return to baseline values, treatment at a lower

dose may be considered.

Lenalidomide is excreted by the kidneys. It is important to dose adjust patients with renal

impairment in order to avoid plasma levels which may increase the risk for higher

haematological side effects or hepatotoxicity. Monitoring of liver function is recommended,

particularly when there is a history of or concurrent viral liver infection or when lenalidomide is

combined with medications known to be associated with liver dysfunction.

Allergic and severe skin reactions

Severe cutaneous reactions including SJS, and TEN and DRESS have been reported with the use

of lenalidomide. Patients should be advised of the signs and symptoms of these reactions by their

prescribers and should be told to seek medical attention immediately if they develop these

symptoms. Lenalidomide must be discontinued for exfoliative or bullous rash, or if SJS, TEN or

DRESS is suspected, and should not be resumed following discontinuation for these reactions.

Interruption or discontinuation of lenalidomide should be considered for other forms of skin

reaction depending on severity. Patients with a history of severe rash associated with thalidomide

treatment should not receive lenalidomide.

REVLIMID hard capsules contain lactose. Risk-benefit of REVLIMID treatment should be

evaluated in patients with lactose intolerance.

Newly diagnosed multiple myeloma patients

There was a higher rate of intolerance (grade 3 or 4 adverse events, serious adverse events,

discontinuation) in patients with age > 75 years, ISS stage III, ECOG PS≤2 or CLcr<60 mL/min

when lenalidomide is given in combination. Patients should be carefully assessed for their ability

to tolerate lenalidomide in combination, with consideration to age, ISS stage III, ECOG PS≤2 or

CLcr<60 mL/min.

Cataract

Cataract has been reported with a higher frequency in patients receiving lenalidomide in

combination with dexamethasone particularly when used for a prolonged time. Regular

monitoring of visual ability is recommended.

Peripheral neuropathy

Lenalidomide is structurally related to thalidomide, which is known to induce severe peripheral

neuropathy. There was no increase in peripheral neuropathy observed with long term use of

lenalidomide for the treatment of newly diagnosed multiple myeloma.

6 ADVERSE REACTIONS

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

information:

Embryo-Fetal Toxicity [

see Boxed Warnings, Warnings and Precautions (5.1, 5.2)

Neutropenia and thrombocytopenia [

see Boxed Warnings, Other Warnings and

Precautions of use (5.3)

Venous and arterial thromboembolism [

see Other Warnings and Precautions of use

(5.3)]

Second Primary Malignancies [

see Other Warnings and Precautions of use (5.3)

Hepatotoxicity [

see Other

Warnings

and Precautions of use (5.3)

Allergic and severe skin reactions [

see Other Warnings and Precautions of use (5.3)

Cataract [

see Other Warnings and Precautions of use (5.3)

Peripheral Neuropathy [

see Other Warnings and Precautions of use (5.3)

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.

6.1 Clinical Trials Experience in Multiple Myeloma

Summary of the safety profile

Newly diagnosed multiple myeloma: patients who have undergone ASCT treated with

lenalidomide maintenance

A conservative approach was applied to determine the adverse reactions from CALGB 100104.

The adverse reactions described in Table 1 included events reported post-HDM/ASCT as well as

events from the maintenance treatment period. A second analysis that identified events that

occurred after the start of maintenance treatment suggests that the frequencies described in Table

1 may be higher than actually observed during the maintenance treatment period. In IFM 2005-

02, the adverse reactions were from the maintenance treatment period only.

The serious adverse reactions observed more frequently (≥5%) with lenalidomide maintenance

than placebo were:

Pneumonias (10.6%; combined term) from IFM 2005-02

Lung infection (9.4% [9.4% after the start of maintenance treatment]) from CALGB

100104

In the IFM 2005-02 study, the adverse reactions observed more frequently with lenalidomide

maintenance than placebo were neutropenia (60.8%), bronchitis (47.4%), diarrhoea (38.9%),

nasopharyngitis (34.8%), muscle spasms (33.4%), leucopenia (31.7%), asthenia (29.7%), cough

(27.3%), thrombocytopenia (23.5%), gastroenteritis (22.5%) and pyrexia (20.5%).

In the CALGB 100104 study, the adverse reactions observed more frequently with lenalidomide

maintenance than placebo were neutropenia (79.0% [71.9% after the start of maintenance

treatment]), thrombocytopenia (72.3% [61.6%]), diarrhoea (54.5% [46.4%]), rash (31.7%

[25.0%]), upper respiratory tract infection (26.8% [26.8%]), fatigue (22.8% [17.9%]), leucopenia

(22.8% [18.8%]) and anemia (21.0% [13.8%]).

Summary of the safety profile in newly diagnosed multiple myeloma:patients who are not eligible

for transplant treated with lenalidomide in combination with low dose dexamethasone:

The serious adverse reactions observed more frequently (≥5%) with lenalidomide in combination

with low dose dexamethasone (Rd and Rd18) than with melphalan, prednisone and thalidomide

(MPT) were:

Pneumonia (9.8%)

Renal failure (including acute) (6.3%)

The adverse reactions observed more frequently with Rd or Rd18 than MPT were: diarrhoea

(45.5%), fatigue (32.8%), back pain (32.0%), asthenia (28.2%), insomnia (27.6%), rash (24.3%),

decreased appetite (23.1%), cough (22.7%), pyrexia (21.4%), and muscle spasms (20.5%).

Summary of the safety profile in newly diagnosed multiple myeloma: who are not eligible for

transplant treated with lenalidomide in combination with melphalan and prednisone:

The serious adverse reactions observed more frequently (≥5%) with melphalan prednisone, and

lenalidomide followed by lenalidomide maintenance (MPR+R) or melphalan prednisone, and

lenalidomide followed by placebo (MPR+p) than melphalan, prednisone and placebo followed

by placebo (MPp+p) were:

Febrile neutropenia (6.0%)

Anemia (5.3%)

The adverse reactions observed more frequently with MPR+R or MPR+ p than MPp+p were:

neutropenia (83.3%), anemia (70.7%), thrombocytopenia (70.0%), leukopenia (38.8%),

constipation (34.0%), diarrhoea (33.3%), rash (28.9%), pyrexia (27.0%), peripheral oedema

(25.0%), cough (24.0%), decreased appetite (23.7%), and asthenia (22.0%).

Summary of the safety profile in multiple myeloma: patients with at least one prior therapy

In two Phase III placebo-controlled studies, 353 patients with multiple myeloma were exposed to

the lenalidomide/dexamethasone combination and 351 to the placebo/dexamethasone

combination.

The most serious adverse reactions observed more frequently in lenalidomide/dexamethasone

than placebo/dexamethasone combination were:

Venous thromboembolism (deep vein thrombosis, pulmonary embolism)

Grade 4 neutropenia.

The observed adverse reactions which occurred more frequently with lenalidomide and

dexamethasone than placebo and dexamethasone in pooled multiple myeloma clinical trials

(MM-009 and MM-010) were fatigue (43.9%), neutropenia (42.2%), constipation (40.5%),

diarrhoea (38.5%), muscle cramp (33.4%), anemia (31.4%), thrombocytopenia (21.5%), and rash

(21.2%).

Tabulated summary of adverse reactions

The adverse reactions observed in patients treated for multiple myeloma are listed below by

system organ class and frequency. Within each frequency grouping, adverse reactions are

presented in order of decreasing seriousness. Frequencies are defined as: very common (≥ 1/10);

common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000);

very rare (< 1/10,000), not known (cannot be estimated from the available data).

Adverse reactions have been included under the appropriate category in the table below

according to the highest frequency observed in any of the main clinical trials.

Tabulated summary for monotherapy in MM

The following table is derived from data gathered during NDMM studies in patients who have

undergone ASCT treated with lenalidomide maintenance. The data were not adjusted according

to the longer duration of treatment in the lenalidomide-containing arms continued until disease

progression versus the placebo arms in the pivotal multiple myeloma studies (see section 5.1).

Table 1. ADRs reported in clinical trials in patients with multiple myeloma treated with

lenalidomide maintenance therapy

System Organ Class/Preferred

Term

All ADRs/Frequency

Grade 3-4 ADRs/Frequency

Infections and Infestations

Very Common

Pneumonias

◊, a

, Upper

respiratory tract infection,

Neutropenic infection,

Bronchitis

, Influenza

Gastroenteritis

, Sinusitis,

Nasopharyngitis, Rhinitis

Common

Infection

, Urinary tract

infection

*, Lower respiratory

tract infection, Lung infection

Very Common

Pneumonias

◊, a

, Neutropenic

infection

Common

Sepsis

◊, b

, Bacteraemia, Lung

infection

, Lower respiratory

tract infection bacterial,

Bronchitis

, Influenza

Gastroenteritis

, Herpes zoster

Infection

Neoplasms Benign, Malignant

and Unspecified (incl cysts

and polyps)

Common

Myelodysplastic syndrome

Blood and Lymphatic System

Disorders

Very Common

Neutropenia

, Febrile

neutropenia

Thrombocytopenia

Anemia

Leucopenia

, Lymphopenia

Very Common

Neutropenia

, Febrile

neutropenia

Thrombocytopenia

nemia

Leucopenia

, Lymphopenia

Common

Pancytopenia

Metabolism and Nutrition

Disorders

Very Common

Hypokalaemia

Common

Hypokalaemia, Dehydration

Nervous System Disorders

Very Common

Paraesthesia

Common

Peripheral neuropathy

Common

Headache

Vascular Disorders

Common

Pulmonary embolism

Common

Deep vein thrombosis

,◊,d

Respiratory, Thoracic and

Mediastinal Disorders

Very Common

Cough

Common

Dyspnoea

, Rhinorrhoea

Common

Dyspnoea

Gastrointestinal Disorders

Very Common

Diarrhoea, Constipation,

Abdominal pain, Nausea

Common

Vomiting, Abdominal pain

upper

Common

Diarrhoea, Vomiting, Nausea

Hepatobiliary Disorders

Very Common

Abnormal liver function tests

Common

Abnormal liver function tests

Skin and Subcutaneous Tissue

Disorders

Very Common

Rash, Dry skin

Common

Rash, Pruritus

Musculoskeletal and

Connective Tissue Disorders

Very Common

Muscle spasms

System Organ Class/Preferred

Term

All ADRs/Frequency

Grade 3-4 ADRs/Frequency

Common

Myalgia, Musculoskeletal pain

General Disorders and

Administration Site

Conditions

Very Common

Fatigue, Asthenia, Pyrexia

Common

Fatigue, Asthenia

Adverse reactions reported as serious in clinical trials in patients with NDMM who had undergone ASCT

Applies to serious adverse drug reactions only

“Pneumonias” combined AE term includes the following PTs: Bronchopneumonia, Lobar pneumonia, Pneumocystis jiroveci pneumonia,

Pneumonia, Pneumonia klebsiella, Pneumonia legionella, Pneumonia mycoplasmal, Pneumonia pneumococcal, Pneumonia streptococcal,

Pneumonia viral, Lung disorder, Pneumonitis

“Sepsis” combined AE term includes the following PTs: Bacterial sepsis, Pneumococcal sepsis, Septic shock, Staphylococcal sepsis

“Peripheral neuropathy” combined AE term includes the following preferred terms (PTs): Neuropathy peripheral, Peripheral sensory

neuropathy, Polyneuropathy

“Deep vein thrombosis” combined AE term includes the following PTs: Deep vein thrombosis, Thrombosis, Venous thrombosis

Tabulated summary for combination therapy in MM

The following table is derived from data gathered during the multiple myeloma studies with

combination therapy. The data were not adjusted according to the greater duration of treatment in

the lenalidomide/dexamethasone versus the placebo/dexamethasone arms in the pivotal multiple

myeloma studies.

Table 2:

ADRs reported in clinical studies in patients with multiple myeloma treated with

lenalidomide in combination with dexamethasone, or with melphalan and

prednisone

System Organ

Class

/ Preferred Term

All ADRs/Frequency

Grade 3−4 ADRs/Frequency

Infections

and Infestations

Very Common

Pneumonia

, Upper respiratory tract

infection

, Bacterial, viral and fungal

infections (including opportunistic

infections)

, Nasopharyngitis, Pharyngitis,

Bronchitis

Common

Sepsis

, Sinusitis

Common

Pneumonia

, Bacterial, viral

and fungal infections

(including opportunistic

infections

), Cellulitis

Sepsis

, Bronchitis

Neoplasms

Benign,

Malignant and

Unspecified (incl

cysts and polyps)

Uncommon

Basal cell carcinoma

Squamous skin cancer

◊,

Common

Acute myeloid leukaemia

Myelodysplastic syndrome

Squamous cell carcinoma of

skin

◊,

Uncommon

T-cell type acute leukaemia

Basal cell carcinoma

, Tumour

lysis syndrome

System Organ

Class

/ Preferred Term

All ADRs/Frequency

Grade 3−4 ADRs/Frequency

Blood and

Lymphatic

System Disorders

Very Common

Neutropenia

, Thrombocytopenia

Anaemia

, Haemorrhagic disorder,

Leucopenias

Common

Febrile neutropenia

, Pancytopenia

Uncommon

Haemolysis, Autoimmune haemolytic

anaemia, Haemolytic anaemia

Very Common

Neutropenia

Thrombocytopenia

Anaemia

, Leucopenias

Common

Febrile neutropenia

Pancytopenia

, Haemolytic

anaemia

Uncommon

Hypercoagulation,

Coagulopathy

Immune System

Disorders

Uncommon

Hypersensitivity

Endocrine

Disorders

Common

Hypothyroidism

Metabolism and

Nutrition

Disorders

Very Common

Hypokalaemia

, Hyperglycaemia,

Hypocalcaemia

, Decreased appetite, Weight

decreased

Common

Hypomagnesaemia, Hyperuricaemia,

Dehydration

, Hypercalcaemia

Common

Hypokalaemia

Hyperglycaemia

Hypocalcaemia, Diabetes

mellitus

Hypophosphataemia,

Hyponatraemia

Hyperuricaemia, Gout,

Decreased appetite, Weight

decreased

Psychiatric

Disorders

Very Common

Depression, Insomnia

Uncommon

Loss of libido

Common

Depression, Insomnia

Nervous System

Disorders

Very Common

Peripheral neuropathies (excluding motor

neuropathy), Dizziness, Tremor, Dysgeusia,

Headache

Common

Ataxia, Balance impaired

Common

Cerebrovascular accident

Dizziness, Syncope

Uncommon

Intracranial haemorrhage,

Transient ischaemic attack,

Cerebral ischemia

Eye Disorders

Very Common

Cataracts, Blurred vision

Common

Reduced visual acuity

Common

Cataract

Uncommon

Blindness

Ear and

Labyrinth

Disorders

Common

Deafness (Including Hypoacusis), Tinnitus

System Organ

Class

/ Preferred Term

All ADRs/Frequency

Grade 3−4 ADRs/Frequency

Cardiac

Disorders

Common

Atrial fibrillation

, Bradycardia

Uncommon

Arrhythmia, QT prolongation, Atrial flutter,

Ventricular extrasystoles

Common

Myocardial infarction

(including acute)

, Atrial

fibrillation

, Congestive

cardiac failure

, Tachycardia,

Cardiac failure

, Myocardial

ischemia

Vascular

Disorders

Very Common

Venous thromboembolic events,

predominantly deep vein thrombosis and

pulmonary embolism

Common

Hypotension

, Hypertension, Ecchymosis

Very Common

Venous thromboembolic

events, predominantly deep

vein thrombosis and

pulmonary embolism

Common

Vasculitis

Uncommon

Ischemia, Peripheral ischemia,

Intracranial venous sinus

thrombosis

Respiratory,

Thoracic

and Mediastinal

Disorders

Very Common

Dyspnoea

, Epistaxis

Common

Respiratory distress

Dyspnoea

Gastrointestinal

Disorders

Very Common

Diarrhoea

, Constipation

, Abdominal pain

Nausea, Vomiting, Dyspepsia

Common

Gastrointestinal haemorrhage (including

rectal haemorrhage, haemorrhoidal

haemorrhage, peptic ulcer haemorrhage and

gingival bleeding), Dry mouth, Stomatitis,

Dysphagia

Uncommon

Colitis, Caecitis

Common

Diarrhoea

, Constipation

Abdominal pain

, Nausea,

Vomiting

Hepatobiliary

Disorders

Common

Abnormal liver function tests

Uncommon

Hepatic failure

Common

Cholestasis

, Abnormal liver

function tests

Uncommon

Hepatic failure

Skin and

Subcutaneous

Tissue Disorders

Very Common

Rashes, Pruritus

Common

Urticaria, Hyperhidrosis, Dry skin, Skin

hyperpigmentation, Eczema, Erythema

Uncommon

Skin discolouration, Photosensitivity

reaction

Common

Rashes

System Organ

Class

/ Preferred Term

All ADRs/Frequency

Grade 3−4 ADRs/Frequency

Musculoskeletal

and Connective

Tissue Disorders

Very Common

Muscle spasms, Bone pain

Musculoskeletal and connective tissue pain

and discomfort (including back pain

Arthralgia

Common

Muscular weakness, Joint swelling

, Myalgia

Common

Muscular weakness, Bone

pain

, Musculoskeletal and

connective tissue pain and

discomfort (including back

pain

Uncommon

Joint swelling

Renal and

Urinary

Disorders

Very Common

Renal failure (including acute)

Common

Haematuria, Urinary retention,

Urinary incontinence

Uncommon

Acquired Fanconi syndrome

Uncommon

Renal tubular necrosis

Reproductive

System and

Breast Disorders

Common

Erectile dysfunction

General

Disorders

and

Administration

Site Conditions

Very Common

Fatigue

, Oedema (including peripheral

oedema), Pyrexia

, Asthenia, Influenza like

illness syndrome (including pyrexia, cough,

myalgia, musculoskeletal pain, headache and

rigors)

Common

Chest pain, Lethargy

Common

Fatigue

, Pyrexia

, Asthenia

Investigations

Common

C-reactive protein increased

Injury, Poisoning

and Procedural

Complications

Common

Fall, Contusion

◊ Adverse reactions reported as serious in clinical trials in patients with multiple myeloma treated with lenalidomide in combination with

dexamethasone, or with melphalan and prednisone

+ Applies to serious adverse drug reactions only

* Squamous skin cancer was reported in clinical trials in previously treated myeloma patients with lenalidomide/dexamethasone compared to

controls

** Squamous cell carcinoma of skin was reported in a clinical trial in newly diagnosed myeloma patients with lenalidomide/dexamethasone

compared to controls

Other Adverse Reactions After At Least One Prior Therapy for Multiple Myeloma

In these studies, the following adverse drug reactions (ADRs) not described in other MM tables

(or the postmarketing experience table) that occurred at ≥1% rate and of at least twice of the

placebo percentage rate were reported:

Blood and lymphatic system disorders:

autoimmune hemolytic anemia

Cardiac disorders:

angina pectoris

Endocrine disorders:

hirsutism

Eye disorders:

blindness, ocular hypertension,

Gastrointestinal disorders:

glossodynia

General disorders and administration site conditions:

malaise

Investigations:

liver function tests abnormal, alanine aminotransferase increased

Psychiatric disorders:

mood swings, hallucination

Respiratory, thoracic and mediastinal disorders:

hoarseness

Skin and subcutaneous tissue disorders:

exanthem

6.2 Clinical Trials Experience in Myelodysplastic Syndromes

A total of 148 patients received at least 1 dose of 10 mg REVLIMID 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 REVLIMID. 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 3

summarizes the adverse events that were reported in ≥ 5% of the REVLIMID treated patients in

the del 5q MDS clinical study. Table 3 summarizes the most frequently observed Grade 3 and

Grade 4 adverse reactions regardless of relationship to treatment with REVLIMID. 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.

Table 3: Summary of Adverse Events Reported in ≥5% of the

REVLIMID Treated Patients in del 5q MDS Clinical Study

10 mg Overall

System organ class/Preferred term

[a]

(N=148)

Patients with at least one adverse event

(100.0)

Blood and Lymphatic System Disorders

Thrombocytopenia

(61.5)

Neutropenia

(58.8)

Anemia

(11.5)

Leukopenia

(8.1)

Febrile Neutropenia

(5.4)

Skin and Subcutaneous Tissue Disorders

Pruritus

62 (41.9)

Rash

(35.8)

Dry Skin

(14.2)

Contusion

(8.1)

Night Sweats

(8.1)

Sweating Increased

(6.8)

Ecchymosis

(5.4)

Erythema

(5.4)

Gastrointestinal Disorders

Diarrhea

(48.6)

Constipation

(23.6)

Nausea

(23.6)

Abdominal Pain

(12.2)

Vomiting

(10.1)

Abdominal Pain Upper

(8.1)

Dry Mouth

(6.8)

Loose Stools

(6.1)

Respiratory, Thoracic and Mediastinal Disorders

Nasopharyngitis

(23.0)

Cough

(19.6)

Dyspnea

(16.9)

Pharyngitis

(15.5)

Epistaxis

(14.9)

Dyspnea Exertional

(6.8)

Rhinitis

(6.8)

Bronchitis

(6.1)

General Disorders and Administration Site Conditions

Fatigue

(31.1)

Pyrexia

(20.9)

Edema Peripheral

(20.3)

Asthenia

(14.9)

Edema

(10.1)

Pain

(6.8)

Rigors

(6.1)

Chest Pain

(5.4)

Musculoskeletal and Connective Tissue Disorders

Arthralgia

(21.6)

Back Pain

(20.9)

Muscle Cramp

(18.2)

Pain in Limb

(10.8)

Myalgia

(8.8)

Peripheral Swelling

(8.1)

Nervous System Disorders

Dizziness

(19.6)

Headache

(19.6)

Hypoesthesia

(6.8)

Dysgeusia

(6.1)

Peripheral Neuropathy

(5.4)

Infections and Infestations

Upper Respiratory Tract Infection

(14.9)

Pneumonia

(11.5)

Urinary Tract Infection

(10.8)

Sinusitis

(8.1)

Cellulitis

(5.4)

Metabolism and Nutrition Disorders

Hypokalemia

(10.8)

Anorexia

(10.1)

Hypomagnesemia

(6.1)

Investigations

Alanine Aminotransferase Increased

(8.1)

Psychiatric Disorders

Insomnia

(10.1)

Depression

(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)

System organ classes and preferred terms are coded using the MedDRA

dictionary. System organ classes

and preferred terms 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.

Table 4: Most Frequently Observed Grade 3 and 4 Adverse Events [1]

Regardless of Relationship to Study Drug Treatment

10 mg

Preferred term

[2]

(N=148)

Patients with at least one Grade 3/4 AE

(88.5)

Neutropenia

(53.4)

Thrombocytopenia

(50.0)

Pneumonia

(7.4)

Rash

(6.8)

Anemia

(6.1)

Leukopenia

(5.4)

Fatigue

(4.7)

Dyspnea

(4.7)

Back Pain

(4.7)

Febrile Neutropenia

(4.1)

Nausea

(4.1)

Diarrhea

(3.4)

Pyrexia

(3.4)

Sepsis

(2.7)

Dizziness

(2.7)

Granulocytopenia

(2.0)

Chest Pain

(2.0)

Pulmonary Embolism

(2.0)

Respiratory Distress

(2.0)

Pruritus

(2.0)

Pancytopenia

(2.0)

Muscle Cramp

(2.0)

Respiratory Tract Infection

(1.4)

Upper Respiratory Tract Infection

(1.4)

Asthenia

(1.4)

Multi-organ Failure

(1.4)

Epistaxis

(1.4)

Hypoxia

(1.4)

Pleural Effusion

(1.4)

Pneumonitis

(1.4)

Pulmonary Hypertension

(1.4)

Vomiting

(1.4)

Sweating Increased

(1.4)

Arthralgia

(1.4)

Pain in Limb

(1.4)

Headache

(1.4)

Syncope

(1.4)

[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] Preferred Terms are coded using the MedDRA dictionary. A patient with multiple occurrences of an AE is

counted only once in the Preferred Term category.

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 6 or 7 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

6.3 Clinical Trials Experience in Mantle Cell Lymphoma

The overall safety profile of Revlimid in patients with mantle cell lymphoma is based on data

from 254 patients from a Phase II randomised controlled study MCL-002.

Additionally, ADRs from supportive study MCL-001 have been included in table 4.

The serious adverse reactions observed more frequently in Study MCL-002 (with a difference of

at least 2 percentage points) in the lenalidomide arm compared with the control arm were

Neutropenia (3.6%)

Pulmonary embolism (3.6%)

Diarrhoea (3.6%)

The most frequently observed adverse reactions which occurred more frequently in the

lenalidomide arm compared with the control arm in Study MCL-002 were neutropenia (50.9%),

anemia

(28.7%), diarrhoea (22.8%), fatigue (21.0%), constipation (17.4%), pyrexia (16.8%), and

rash (including dermatitis allergic) (16.2%).

In study MCL-002 there was overall an apparent increase in early (within 20 weeks) deaths.

Patients with high tumour burden at baseline are at increased risk of early death, 16/81 (20%) early

deaths in the lenalidomide arm and 2/28 (7%) early deaths in the control arm. Within 52 weeks

corresponding figures were 32/81 (39.5%) and 6/28 (21%).

During treatment cycle 1, 11/81 (14%) patients with high tumour burden were withdrawn from

therapy in the lenalidomide arm vs. 1/28 (4%) in the control group. The main reason for treatment

withdrawal for patients with high tumour burden during treatment cycle 1 in the lenalidomide arm

was adverse events, 7/11 (64%). High tumour burden was defined as at least one lesion ≥5 cm in

diameter or 3 lesions ≥3 cm.

Table 5:

ADRs reported in clinical trials in patients with mantle cell lymphoma treated

with lenalidomide

System Organ

Class

/ Preferred

Term

All ADRs/Frequency

Grade 3−4 ADRs/Frequency

Infections and

Infestations

Very Common

Bacterial, viral and fungal

infections (including opportunistic

infections)

, Nasopharyngitis,

Pneumonia

Common

Sinusitis

Common

Bacterial, viral and fungal infections

(including opportunistic infections)

Pneumonia

Neoplasms

Benign,

Malignant and

Unspecified

(incl cysts and

polyps)

Common

Tumour flare reaction

Common

Tumour flare reaction, Squamous skin

cancer

◊,

Basal cell carcinoma

Blood and

Lymphatic

System

Disorders

Very Common

Thrombocytopenia, Neutropenia

Leucopenias

, Anemia

Common

Febrile neutropenia

Very Common

Thrombocytopenia, Neutropenia

Anemia

Common

Febrile neutropenia

, Leucopenias

Metabolism

and Nutrition

Disorders

Very

Common

Decreased appetite, Weight

decreased, Hypokalaemia

Common

Dehydration

Common

Dehydration

, Hyponatraemia,

Hypocalcaemia

Psychiatric

Disorders

Common

Insomnia

Nervous

System

Disorders

Common

Dysgeuesia, Headache, neuropathy

peripheral

Common

Peripheral sensory neuropathy,

Lethargy

Ear and

Labyrinth

Disorders

Common

Vertigo

Cardiac

Disorders

Common

Myocardial infarction (including

acute)

, Cardiac failure

Vascular

Disorders

Common

Hypotension

Common

Deep vein thrombosis

, pulmonary

embolism

, Hypotension

Respiratory,

Thoracic and

Mediastinal

Disorders

Very

Common

Dyspnoea

Common

Dyspnoea

System Organ

Class

/ Preferred

Term

All ADRs/Frequency

Grade 3−4 ADRs/Frequency

Gastrointestina

l Disorders

Very

Common

Diarrhoea

, Nausea

, Vomiting

Constipation

Common

Abdominal pain

Common

Diarrhoea

, Abdominal pain

Constipation

Skin and

Subcutaneous

Tissue

Disorders

Very

Common

Rashes (including dermatitis

allergic), Pruritus

Common

Night sweats, Dry skin

Common

Rashes

Musculoskeleta

l and

Connective

Tissue

Disorders

Very

Common

Muscle spasms, Back pain

Common

Arthralgia, Pain in extremity,

Muscular weakness

Common

Back pain, Muscular weakness

Arthralgia, Pain in extremity

Renal and

Urinary

Disorders

Common

Renal failure

General

Disorders and

Administration

Site Conditions

Very

Common

Fatigue, Asthenia

, Peripheral

oedema, Influenza like illness

syndrome (including pyrexia

cough)

Common

Chills

Common

Pyrexia

, Asthenia

, Fatigue

Adverse events reported as serious in mantle cell lymphoma clinical trials

Algorithm applied for mantle cell lymphoma:

Mantle cell lymphoma controlled Phase II study

All treatment-emergent adverse events with ≥ 5% of subjects in lenalidomide arm and at least 2% difference

in proportion between lenalidomide and control arm

All treatment-emergent grade 3 or 4 adverse events in ≥1% of subjects in lenalidomide arm and at least 1.0%

difference in proportion between lenalidomide and control arm

All Serious treatment-emergent adverse events in ≥1% of subjects in lenalidomide arm and at least 1.0%

difference in proportion between lenalidomide and control arm

Mantle cell lymphoma single arm Phase II study

All treatment-emergent adverse events with ≥ 5% of subjects

All grade 3 or 4 treatment-emergent adverse events reported in 2 or more subjects

All Serious treatment-emergent adverse events reported in 2 or more subjects

Tabulated summary of post-marketing adverse reactions

In addition to the above adverse reactions identified from the pivotal clinical trials, the following

table is derived from data gathered from post-marketing data.

Table 6: ADRs reported in post-marketing use in patients treated with lenalidomide

System Organ Class/

Preferred Term

All ADRs/Frequency

Grade 3−4

ADRs/Frequency

Infections and

Infestations

Not Known

Viral infections, including herpes

zoster and hepatitis B virus

reactivation

Not Known

Viral infections, including

herpes zoster and hepatitis B

virus reactivation

Neoplasms Benign,

Malignant and

Unspecified (incl

cysts and polyps)

Rare

Tumour lysis syndrome

Blood and

Lymphatic System

Disorders

Not Known

Acquired haemophilia

Immune System

Disorders

Not Known

Solid organ transplant rejection

Endocrine Disorders

Common

Hyperthyroidism

Respiratory,

Thoracic and

Mediastinal

Disorders

Not Known

Interstitial pneumonitis

Gastrointestinal

Disorders

Not Known

Pancreatitis, Gastrointestinal

perforation (including

diverticular, intestinal and

large intestine perforations)

Hepatobiliary

Disorders

Not Known

Acute hepatic failure, Hepatitis toxic,

Cytolytic hepatitis, Cholestatic

hepatitis, Mixed cytolytic/cholestatic

hepatitis

Not Known

Acute hepatic failure,

Hepatitis toxic^

Skin and

Subcutaneous Tissue

Disorders

Uncommon

Angioedema

Rare

Stevens-Johnson Syndrome,

Toxic epidermal necrolysis

Not Known

Leukocytoclastic vasculitis,

Drug Reaction with

Eosinophilia and Systemic

Symptoms

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal

product. Any suspected adverse events should be reported to the Ministry of Health

according to the National Regulation by using an online form

/https://sideeffects.health.gov.il and additionally emailed to the Registration Holder’s

Patient Safety Unit at: drugsafety@neopharmgroup.com

7.

DRUG INTERACTIONS

7.1 Digoxin

When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin

and AUC

0-∞

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 REVLIMID.

7.2

Warfarin

Co-administration of multiple dose REVLIMID (10 mg) with single dose warfarin (25 mg) had

no effect on the pharmacokinetics of total lenalidomide 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 REVLIMID administration. It is not known whether

there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is

recommended in multiple myeloma patients taking concomitant warfarin.

7.3 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 REVLIMID [

see Warnings and Precautions (5.4)

8.

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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.

Risk Summary

Based on the mechanism of action [see Clinical Pharmacology (12.1)] and findings from animal

studies [see Data], REVLIMID can cause embryo-fetal harm when administered to a pregnant

female and is contraindicated during pregnancy [see Boxed Warning, Contraindications (4.1),

and Use in Specific Populations (5.1)].

REVLIMID 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.

Lenalidomide caused thalidomide-type limb defects in monkey offspring. 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 hazard 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. Any suspected fetal exposure to REVLIMID must be reported

to the attending physician and Neopharm.

The estimated background risk of major birth defects and miscarriage for the indicated

population is unknown.

Data

Animal data

embryo-fetal

developmental

toxicity

study

monkeys,

teratogenicity,

including

thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral

lenalidomide 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.

pre-

post-natal

development

study

rats,

animals

received

lenalidomide

from

organogenesis through lactation. The study revealed a few adverse effects on the offspring of

female rats treated with lenalidomide 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 lenalidomide.

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

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

nursing infants from lenalidomide advice women not to breastfeed during treatment with

REVLIMID.

8.3 Females and males of reproductive potential

Pregnancy Testing

REVLIMID can cause fetal harm when administered during pregnancy [see Use in Specific

Populations (8.1)]. 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.

Females of reproductive potential must have 2 negative pregnancy tests before initiating

REVLIMID. The first test should be performed within 10-14 days, and the second test within 24

hours prior to prescribing REVLIMID. 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. REVLIMID 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 REVLIMID, during therapy,

during dose interruptions, and continuing for 4 weeks following discontinuation of REVLIMID

therapy. Reliable contraception is indicated even where there has been a history of infertility,

unless due to hysterectomy. Females of reproductive potential should be referred to a qualified

provider of contraceptive methods, if needed.

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.

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% (1521 /1613) 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 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.

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 REVLIMID. 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.

Because elderly patients are more likely to have decreased renal function, care should be taken in

dose selection and it would be prudent to monitor renal function.

8.6 Renal Impairment

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

on dialysis [

see Dosage and Administration (2.4)

.

9.

OVERDOSAGE

There is no specific experience in the management of lenalidomide overdose in patients;

although in dose-ranging studies, some patients were exposed to up to 150 mg and in single-dose

studies, some patients were exposed to up to 400 mg.

In studies, the dose-limiting toxicity was essentially hematological. In the event of overdose,

supportive care is advised.

10.

DESCRIPTION

REVLIMID, a thalidomide analogue, is an immunomodulatory agent with antiangiogenic and

antineoplastic properties. The chemical name is 3-(4-amino-1-oxo 1,3-dihydro-2

H

-isoindol-2-yl)

piperidine-2,6-dione and it has the following chemical structure:

3-(4-amino-1-oxo 1,3-dihydro-2

H

-isoindol-2-yl) piperidine-2,6-dione

The empirical formula for lenalidomide is C

and the gram molecular weight is 259.3.

Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic solvent/water

mixtures, and buffered aqueous solvents. Lenalidomide 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. Lenalidomide 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.

REVLIMID is available in 2.5 mg, 5 mg, 7.5mg, 10 mg, 15 mg, 20 mg and 25 mg hard capsules

for oral administration. Each hard capsule contains lenalidomide as the active ingredient and the

following inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose

sodium, and magnesium stearate. The 5 mg and 25 mg hard capsule shell contains gelatin,

titanium dioxide and black ink. The 2.5 mg and 10 mg hard capsule shell contains gelatin, FD&C

blue #2, yellow iron oxide, titanium dioxide and black ink. The 15 mg hard capsule shell

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

contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink.

11.

CLINICAL PHARMACOLOGY

11.1 Mechanism of Action

Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and

antineoplastic properties. Lenalidomide inhibits proliferation and induces apoptosis of certain

hematopoietic tumor cells including multiple myeloma, mantle cell lymphoma, and del (5q)

myelodysplastic syndromes

in vitro

. Lenalidomide causes a delay in tumor growth in some

in vivo

nonclinical hematopoietic tumor models including multiple myeloma.

Immunomodulatory

properties of lenalidomide include activation of T cells and natural killer (NK) cells, increased

numbers of NKT cells, and inhibition of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by

monocytes. In multiple myeloma cells, the combination of lenalidomide and dexamethasone

synergizes the inhibition of cell proliferation and the induction of apoptosis.

Lenalidomide binds directly to cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme

complex that includes deoxyribonucleic acid (DNA) damage-binding protein 1(DDB1), cullin 4

(CUL4), and regulator of cullins 1 (Roc1). In the presence of lenalidomide, cereblon binds

substrate proteins Aiolos and Ikaros which are lymphoid transcriptional factors, leading to their

ubiquitination and subsequent degradation resulting in cytoxic and immunomodulatory effects.

11.2 Pharmacodynamics

The effect of lenalidomide on the QTc interval was evaluated in 60 healthy male subjects in a

randomised, thorough QT study with placebo and positive controls. At a dose two times the

maximum recommended dose, lenalidomide does not prolong the QTc interval to any clinically

relevant extent. The largest upper bound of the 2-sided 90% CI for the mean differences between

lenalidomide and placebo was below 10 ms.

11.3 Pharmacokinetics

Absorption

Lenalidomide is rapidly absorbed following oral administration. Following single and multiple

doses of REVLIMID 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 lenalidomide is linear with AUC and C

values increasing proportionally with

dose. Multiple dosing at the recommended dose-regimen does not result in medicinal product

accumulation.

Systemic exposure (AUC) of lenalidomide in MM and MDS patients with normal or mild renal

function (CLcr

60 mL/min) is approximately 60% higher as compared to young healthy male

subjects.

Administration of a single 25 mg dose of REVLIMID 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

. In the trials where the efficacy and safety were established for REVLIMID, the

medicinal product was administered without regard to food intake. REVLIMID can be

administered with or without food.

Population pharmacokinetic analyses show that the oral absorption rate of lenalidomide in

patients with MCL is similar to that observed in patients with MM or MDS.

Distribution

In vitro (

C)-lenalidomide binding to plasma proteins is approximately 30%.

Lenalidomide is present in semen at 2 hours (1379 ng/ejaculate) and 24 hours (35 ng/ejaculate)

after the administration of REVLIMID 25 mg daily.

Elimination

Metabolism

Lenalidomide undergoes limited metabolism. Unchanged lenalidomide is the predominant

circulating component in humans. Two identified metabolites are 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 [

C]-lenalidomide (25

mg) to healthy subjects, approximately 90% and 4% of the radioactive dose is eliminated within

ten days in urine and feces, respectively. Approximately 82% of the radioactive dose is excreted

as lenalidomide in the urine within 24 hours. Hydroxy-lenalidomide and N-acetyl-lenalidomide

represent 4.59% and 1.83% of the excreted dose, respectively. The renal clearance of

lenalidomide 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

REVLIMID. Three healthy subjects of similar age with normal renal function (CLcr > 80 mL/min)

were also administered a single 25 mg dose of REVLIMID. 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 REVLIMID in patients with renal impairment based on the CLcr

value [see Dosage and Administration (2.4)].

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 lenalidomide. 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

lenalidomide 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 REVLIMID (25 mg). Co-administration

of REVLIMID (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 lenalidomide. Co-administration of the

P-gp inhibitor and substrate temsirolimus (25 mg),with REVLIMID (25 mg) did not significantly

alter the pharmacokinetics of lenalidomide, temsirolimus, or sirolimus (metabolite of

temsirolimus). In vitro studies demonstrated that REVLIMID is a substrate of P-glycoprotein (P-

gp). REVLIMID 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. Lenalidomide is

not an inhibitor of P-gp, bile salt export pump (BSEP), BCRP, MRP2, OAT1, OAT3, OATP1B1,

OATP1B3, or OCT2. Lenalidomide does not inhibit or induce CYP450 isoenzymes. Also,

lenalidomide does not inhibit bilirubin glucuronidation formation in human liver microsomes

with UGT1A1 genotyped as UGT1A1*1/*1, UGT1A1*1/*28, and UGT1A1*28/*28

12. NONCLINICAL TOXICOLOGY

12.1 Carcinogenesis

Mutagenesis, Impairment of Fertility

Carcinogenicity studies with lenalidomide have not been conducted.

Lenalidomide 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. Lenalidomide 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 lenalidomide

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.

12.

2 Reproductive and Developmental Toxicity

Lenalidomide had an embryocidal effect in rabbits at a dose of 50 mg/kg (approximately 120

times the human dose of 10 mg based on body surface area).

In an embryofetal developmental toxicity study in monkeys, teratogenicity, including

thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral

lenalidomide during organogenesis at doses approximately 0.17 times the maximum

recommended human dose (MRHD) of 25 mg, based on body surface area.

A pre- and post-natal development study in rats revealed few adverse effects on the offspring of

female rats treated with lenalidomide 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.

13. CLINICAL STUDIES

13.1 Newly diagnosed multiple myeloma

Lenalidomide efficacy and safety have been evaluated in five phase III studies in newly

diagnosed multiple myeloma.

Newly diagnosed multiple myeloma

Lenalidomide maintenance in patients who have undergone ASCT

The efficacy and safety of lenalidomide maintenance was assessed in two phase 3 multicenter,

randomized, double-blind 2-arm, parallel group, placebo-controlled studies: CALGB 100104 and

IFM 2005-002.

CALGB 100104

Patients between 18 and 70 years of age with active MM requiring treatment and without prior

progression after initial therapy were eligible.

Patients were randomised 1:1 within 90-100 days after ASCT to receive either lenalidomide or

placebo maintenance. The maintenance dose was 10 mg once daily on days 1-28 of repeated 28-

day cycles (increased up to 15 mg once daily after 3 months in the absence of dose-limiting

toxicity), and treatment was continued until disease progression.

primary

efficacy

endpoint

study

progression

free

survival

(PFS)

from

randomisation to the date of progression or death, whichever occurred first; the study was not

powered for the overall survival endpoint. In total 460 patients were randomised: 231 patients to

Lenalidomide and 229 patients to placebo. The demographic and disease-related characteristics

were balanced across both arms.

The study was unblinded upon the recommendations of the data monitoring committee after

surpassing the threshold for a preplanned interim analysis of PFS. After unblinding, patients in the

placebo arm were allowed to cross over to receive lenalidomide before disease progression.

The results of PFS at unblinding, following a preplanned interim analysis, using a cut-off of 17

December 2009 (15.5 months follow up) showed a 62% reduction in risk of disease progression

or death favoring lenalidomide (HR = 0.38; 95% CI 0.27, 0.54; p <0.001). The median overall PFS

was 33.9 months (95% CI NE, NE) in the lenalidomide arm versus 19.0 months (95% CI 16.2,

25.6) in the placebo arm.

The PFS benefit was observed both in the subgroup of patients with CR and in the subgroup of

patients who had not achieved a CR.

Table 7: Summary of overall efficacy data

Lenalidomide

(N = 231)

Placebo

(N = 229)

Investigator-assessed PFS

Median

PFS time, months (95% CI)

56.9

(41.9, 71.7)

29,4

(20.7, 35.5)

HR [95% CI]

; p-valued

0.61

(0.48, 0.76); <0.001

PFS2

e

Median

PFS2 time, months (95% CI)b

80.2

(63.3, 101.8)

52.8

(41.3, 64.0)

HR [95% CI]c ; p-valued

0.61

(0.48, 0.78); <0.001

Overall survival

Median

OS time, months (95% CI)

111.0

(101.8, NE)

84.2

(71.0, 102.7)

8-year survival rate, % (SE)

60.9 (3.78)

44.6 (3.98)

HR [95% CI]

; p-value

0.61

(0.46, 0.81); <0.001

Follow-up

Median

(min, max), months: all surviving patients

81.9

(0.0, 119.8)

81.0

(4.1, 119.5)

CI = confidence interval; HR = hazard ratio; max = maximum; min = minimum; NE = not estimable; OS = overall survival; PFS = progression-

free survival;

The median is based on the Kaplan-Meier estimate.

The 95% CI about the median.

Based on Cox proportional hazards model comparing the hazard functions associated with the indicated treatment arms.

The p-value is based on the unstratified log-rank test of Kaplan-Meier curve differences between the indicated treatment arms.

Exploratory endpoint (PFS2). Lenalidomide received by subjects in the placebo arm who crossed over prior to PD upon study unblinding was

not considered as a second-line therapy.

Median follow-up post-ASCT for all surviving subjects.

Data cuts:

17 Dec 2009 and 01 Feb 2016

IFM 2005-02

Patients aged < 65 years at diagnosis who had undergone ASCT and had achieved at least a stable

disease response at the time of hematologic recovery were eligible. Patients were randomised 1:1

to receive either lenalidomide or placebo maintenance (10 mg once daily on days 1-28 of repeated

28-day cycles increased up to 15 mg once daily after 3 months in the absence of dose-limiting

toxicity) following 2 courses of lenalidomide consolidation (25 mg/day, days 1-21 of a 28-day

cycle). Treatment was to be continued until disease progression.

The primary endpoint was PFS defined from randomisation to the date of progression or death,

whichever occurred first; the study was not powered for the overall survival endpoint. In total 614

patients were randomised: 307 patients to lenalidomide and 307 patients to placebo.

The study was unblinded upon the recommendations of the data monitoring committee after

surpassing the threshold for a preplanned interim analysis of PFS. After unblinding, patients

receiving placebo were not crossed over to lenalidomide therapy prior to progressive disease. The

lenalidomide arm was discontinued, as a proactive safety measure, after observing an imbalance

of SPMs (see Section 4.4).

The results of PFS at unblinding, following a preplanned interim analysis, using a cut-off of 7 July

2010 (31.4 months follow up) showed a 48% reduction in risk of disease progression or death

favoring lenalidomide (HR = 0.52; 95% CI 0.41, 0.66; p <0.001). The median overall PFS was

40.1 months (95% CI 35.7, 42.4) in the lenalidomide arm versus 22.8 months (95% CI 20.7, 27.4)

in the placebo arm.

The PFS benefit was less in the subgroup of patients with CR than in the subgroup of patients who

had not achieved a CR.

The updated PFS, using a cut-off of 1 February 2016 (96.7 months follow up) continues to show

a PFS advantage: HR = 0.57 (95% CI 0.47, 0.68; p < 0.001). The median overall PFS was 44.4

months (39.6, 52.0) in the lenalidomide arm versus 23.8 months (95% CI 21.2, 27.3) in the placebo

arm. For PFS2, the observed HR was 0.80 (95% CI 0.66, 0.98; p = 0.026) for lenalidomide versus

placebo. The median overall PFS2 was 69.9 months (95% CI 58.1, 80.0) in the lenalidomide arm

versus 58.4 months (95% CI 51.1, 65.0) in the placebo arm. For OS, the observed HR was 0.90:

(95% CI 0.72, 1.13; p = 0.355) for lenalidomide versus placebo. The median overall survival time

was 105.9 months (95% CI 88.8, NE) in the lenalidomide arm versus 88.1 months (95% CI 80.7,

108.4) in the placebo arm.

Lenalidomide in combination with dexamethasone in patients

who are not candidates for stem

cell transplantation:

The safety and efficacy of lenalidomide was assessed in a Phase III, multicenter, randomised, open-

label, 3-arm study (MM-020) of

patients who were

at least 65 years of age or older or, if younger

than 65 years of age, were not candidates for stem cell transplantation because they declined to

undergo stem cell transplantation or stem cell transplantation is not available to the patient due to

cost or other reason. The study (MM-020) compared lenalidomide and dexamethasone (Rd) given

for 2 different durations of time (i.e., until progressive disease [Arm Rd] or for up to eighteen 28-

day cycles [72 weeks, Arm Rd18]) to that of melphalan, prednisone and thalidomide (MPT) for a

maximum of twelve 42-day cycles (72 weeks). Patients

were randomised (1:1:1) to 1 of 3

treatment arms. Patients were stratified at randomisation by age (≤75 versus >75 years), stage (ISS

Stages I and II versus Stage III), and country.

Patients in the Rd and Rd18 arms took lenalidomide 25 mg once daily on days 1 to 21 of 28-day

cycles according to protocol arm. Dexamethasone 40 mg was dosed once daily on days 1, 8, 15,

and 22 of each 28-day cycle. Initial dose and regimen for Rd and Rd18 were adjusted according

to age and renal function. Patients >75 years received a dexamethasone dose of 20 mg once daily

on days 1, 8, 15, and 22 of each 28-day cycle. All patients received prophylactic anticoagulation

(low molecular weight heparin, warfarin, heparin, low-dose aspirin) during the study.

The primary efficacy endpoint in the study was progression free survival (PFS). In total 1623

patients were enrolled into the study, with 535 patients randomised to Rd, 541 patients

randomised to Rd18 and 547 patients randomised to MPT. The demographics and disease-

related baseline characteristics of the patients were well balanced in all 3 arms. In general, study

subjects had advanced-stage disease: of the total study population, 41% had ISS stage III, 9%

had severe renal insufficiency (creatinine clearance [CLcr] < 30 mL/min). The median age was

73 in the 3 arms.

In an updated analysis of PFS, PFS2, OS and DR where the median follow up time for all

surviving subjects was 45.5 months, the results of the study are presented in Table 8:

Table 8: Summary of overall efficacy data

Rd

(N = 541)

Rd18

(N = 540)

MPT

(N = 542)

Investigator-assessed PFS

(months)

Median

PFS time, months (95% CI)

26.0 (20.7,

29.7)

21.0 (19.7,

22.4)

21.9 (19.8,

23.9)

HR [95% CI]

; p-value

Rd vs MPT

0.69 (0.59, 0.80); <0.001

Rd vs Rd18

0.71 (0.61, 0.83); <0.001

Rd18 vs MPT

0.99 (0.86, 1.14); <0.001

PFS2

e

(months)

Median

PFS time, months (95% CI)

42.9 (38.1,

47.4)

40.0 (36.2, 44.2) 35.0 (30.4, 37.8)

HR [95% CI]

; p-value

Rd vs MPT

0.74 (0.63, 0.86); <0.001

Rd vs Rd18

0.92 (0.78, 1.08); 0.316

Rd18 vs MPT

0.80 (0.69, 0.93); 0.004

Overall survival (months)

Median

OS time, months (95% CI)

58.9 (56.0, NE)

56.7 (50.1, NE)

48.5 (44.2,

52.0)

HR [95% CI]

; p-value

Rd vs MPT

0.75 (0.62, 0.90); 0.002

Rd vs Rd18

0.91 (0.75, 1.09); 0.305

Rd18 vs MPT

0.83 (0.69, 0.99); 0.034

Follow-up (months)

Median

(min, max): all patients

40.8 (0.0, 65.9)

40.1 (0.4, 65.7)

38.7 (0.0, 64.2)

Myeloma response

n (%)

81 (15.1)

77 (14.2)

51 (9.3)

VGPR

152 (28.4)

154 (28.5)

103 (18.8)

169 (31.6)

166 (30.7)

187 (34.2)

Overall response: CR, VGPR, or PR

402 (75.1)

397 (73.4)

341 (62.3)

Duration of response

(months)

Median

(95% CI)

35.0 (27.9,

43.4)

22.1 (20.3,

24.0)

22.3 (20.2,

24.9)

AMT = antimyeloma therapy; CI = confidence interval; CR = complete response; d = low-dose dexamethasone; HR = hazard ratio;

IMWG = International Myeloma Working Group; IRAC = Independent Response Adjudication Committee; M = melphalan; max = maximum;

min = minimum; NE = not estimable; OS = overall survival; P = prednisone; PFS = progression-free survival; PR = partial response;

R = lenalidomide; Rd = Rd given until documentation of progressive disease; Rd18 = Rd given for

18 cycles; SE = standard error;

T = thalidomide; VGPR = very good partial response; vs = versus.

The median is based on the Kaplan-Meier estimate.

The 95% CI about the median.

Based on Cox proportional hazards model comparing the hazard functions associated with the indicated treatment arms.

The p-value is based on the unstratified log-rank test of Kaplan-Meier curve differences between the indicated treatment arms.

Exploratory endpoint (PFS2)

The median is the univariate statistic without adjusting for censoring.

Best assessment of adjudicated response during the treatment phase of the study (for definitions of each response category, Data cutoff date =

24 May 2013).

data cut 24 May 2014

Lenalidomide in combination with melphalan and prednisone followed by maintenance

therapy in patients

not eligible for transplant

The safety and efficacy of lenalidomide was assessed in a Phase III multicenter, randomised

double blind 3 arm study (MM-015) of patients who were 65 years or older and had a serum

creatinine < 2.5 mg/dL. The study compared lenalidomide in combination with melphalan and

prednisone

(MPR)

with

without

lenalidomide

maintenance

monotherapy

until

disease

progression, to that of melphalan and prednisone for a maximum of 9 cycles. Patients were

randomised in a 1:1:1 ratio to one of 3 treatment arms. Patients were stratified at randomisation

by age (

75 vs. > 75 years) and stage (ISS; Stages I and II vs. stage III).

This study investigated the use of combination therapy of MPR (melphalan 0.18 mg/kg orally on

days 1-4 of repeated 28-day cycles; prednisone 2 mg/kg orally on days 1-4 of repeated 28-day

cycles; and lenalidomide 10 mg/day orally on days 1-21 of repeated 28-day cycles) for induction

therapy, up to 9 cycles. Patients who completed 9 cycles or who were unable to complete 9 cycles

due to intolerance proceeded to maintenance monotherapy starting with lenalidomide 10 mg orally

on days 1-21 of repeated 28-day cycles until disease progression.

The primary efficacy endpoint in the study was progression free survival (PFS). In total 459

patients were enrolled into the study, with 152 patients randomised to MPR+R, 153 patients

randomised to MPR+p and 154 patients randomised to MPp+p. The demographics and disease-

related baseline characteristics of the patients were well balanced in all 3 arms; notably,

approximately 50% of the patients enrolled in each arm had the following characteristics; ISS

Stage III, and creatinine clearance < 60 mL/min. The median age was 71 in the MPR+R and

MPR+p arms and 72 in the MPp+p arm.

In an analysis of PFS, PFS2, OS using a cut off of April 2013 where the median follow up time

for all surviving subjects was 62.4 months, the results of the study are presented in Table 9:

Table 9: Summary of overall efficacy data

MPR+R

(N = 152)

MPR+p

(N = 153)

MPp +p

(N = 154)

Investigator-assessed PFS

(months)

Median

PFS time, months (95% CI)

27.4 (21.3,

35.0)

14.3 (13.2,

15.7)

13.1 (12.0,

14.8)

HR [95% CI]; p-value

MPR+R vs MPp+p

0.37 (0.27, 0.50); <0.001

MPR+R vs MPR+p

0.47 (0.35, 0.65); <0.001

MPR+p vs MPp +p

0.78 (0.60, 1.01); 0.059

PFS2

(months)

Median

PFS time, months (95% CI)

39.7 (29.2,

48.4)

27.8 (23.1, 33.1) 28.8 (24.3, 33.8)

HR [95% CI]; p-value

MPR+R vs MPp+p

0.70 (0.54, 0.92); 0.009

MPR+R

(N = 152)

MPR+p

(N = 153)

MPp +p

(N = 154)

MPR+R vs MPR+p

0.77 (0.59, 1.02); 0.065

MPR+p vs MPp +p

0.92 (0.71, 1.19); 0.051

Overall survival (months)

Median

OS time, months (95% CI)

55.9 (49.1,

67.5)

51.9 (43.1,

60.6)

53.9 (47.3,

64.2)

HR [95% CI]; p-value

MPR+R vs MPp+p

0.95 (0.70, 1.29); 0.736

MPR+R vs MPR+p

0.88 (0.65, 1.20); 0.43

MPR+p vs MPp +p

1.07 (0.79, 1.45); 0.67

Follow-up (months)

Median (min, max): all patients

48.4 (0.8, 73.8)

46.3 (0.5, 71.9)

50.4 (0.5, 73.3)

Investigator-assessed Myeloma

response n (%)

30 (19.7)

17 (11.1)

9 (5.8)

90 (59.2)

99 ( 64.7)

75 (48.7)

Stable Disease (SD)

24 (15.8)

31 (20.3)

63 (40.9)

Response Not Evaluable (NE)

8 (5.3)

4 (2.6)

7 (4.5)

Investigator-assessed Duration of

response (CR+PR)

(months)

Median

(95% CI)

26.5 (19.4,

35.8)

12.4 (11.2,

13.9)

12.0 (9.4, 14.5)

CI = confidence interval; CR = complete response; HR = Hazard Rate; M = melphalan; NE = not estimable; OS = overall survival; p = placebo; P

= prednisone;

PD = progressive disease; PR = partial response; R = lenalidomide; SD = stable disease; VGPR = very good partial response.

ª The median is based on the Kaplan-Meier estimate

PFS2 (an exploratory endpoint) was defined for all patients (ITT) as time from randomisation to start of 3rd line antimyeloma therapy (AMT) or

death for all randomised patients

Supportive newly diagnosed multiple myeloma studies

An open-label, randomised, multicenter, Phase III study (ECOG E4A03) was conducted in 445

patients

with

newly

diagnosed

multiple

myeloma;

patients

were

randomised

lenalidomide/low

dose

dexamethasone

arm,

were

randomized

lenalidomide/standard dose dexamethasone arm. Patients randomised to the lenalidomide/standard

dose dexamethasone arm received lenalidomide 25 mg/day, days 1 to 21 every 28 days plus

dexamethasone 40 mg/day on days 1 to 4, 9 to 12, and 17 to 20 every 28 days for the first four

cycles.

Patients

randomised

lenalidomide/low

dose

dexamethasone

received

lenalidomide 25 mg/day, days 1 to 21 every 28 days plus low dose dexamethasone – 40 mg/day

on days 1, 8, 15, and 22 every 28 days. In the lenalidomide/low dose dexamethasone group, 20

patients (9.1%) underwent at least one dose interruption compared to 65 patients (29.3%) in the

lenalidomide/standard dose dexamethasone arm.

In a post-hoc analysis, lower mortality was observed in the lenalidomide/low dose dexamethasone

arm 6.8% (15/220) compared to the lenalidomide/standard dose dexamethasone arm 19.3%

(43/223), in the newly diagnosed multiple myeloma patient population, with a median follow up

of 72.3 weeks.

However, with a longer follow-up, the difference in overall survival in favour of lenalidomide/

low dose dexamethasone tends to decrease.

13.2 Multiple myeloma with at least one prior therapy

Two randomised studies (Studies 1 and 2) were conducted to evaluate the efficacy and safety of

REVLIMID. These multicenter, multinational, double-blind, placebo-controlled studies

compared REVLIMID plus oral pulse high-dose dexamethasone therapy to dexamethasone

therapy alone in patients with multiple myeloma who had received at least one prior treatment.

These studies enrolled patients with absolute neutrophil counts (ANC) ≥ 1000/mm

, platelet

counts ≥ 75,000/mm

, 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 REVLIMID

orally once daily on days 1 to 21 and a matching placebo hard capsule once daily on days 22 to

28 of each 28-day cycle. Patients in the placebo/dexamethasone group took 1 placebo hard

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 (2.2)

.

Table 10 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.

Table 10: Baseline Demographic and Disease-Related Characteristics – Studies 1 and 2

Study 1

Study 2

REVLIMID/De

x

N=177

Placebo/De

x

N=176

REVLIMID/De

x

N=176

Placebo/De

x

N=175

Patient Characteristics

Age (years)

Median

Min, Max

36, 86

37, 85

33, 84

40, 82

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)

microglobuli

n (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

≥ 2

Types of Prior

Therapies

Stem Cell

Transplantation

Thalidomide

Dexamethasone

Bortezomib

Melphalan

Doxorubicin

The primary efficacy endpoint in both studies was time to progression (TTP). TTP was defined

as the time from randomisation 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).

Table 11: TTP Results in Study 1 and Study 2

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]

[3.7, 4.9]

12.1

[9.5, NE]

[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

<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]

Figure 1: Kaplan-Meier Estimate of Time to Progression — Study 1

Revlimid/Dex

Placebo/Dex

Log Rank p < 0.001

HR (95% CI) = 0.285 (0.210-0.386)

Time to Progression (months)

Proportion of Subjects

Figure 2: Kaplan-Meier Estimate of Time to Progression — Study 2

13.3 Myelodysplastic Syndromes (MDS) with a Deletion 5q Cytogenetic

Abnormality

The efficacy and safety of REVLIMID 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 (2.3)

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/mm

, platelet counts ≥ 50,000/mm

, 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 12.

Table 12: Baseline Demographic and Disease-Related Characteristics in the MDS

Study

Overall

(N=148)

Age (years)

Median

71.0

Min, Max

37.0, 95.0

Gender

n

(%)

Male

(34.5)

Female

(65.5)

Race

n

(%)

White

(96.6)

Other

(3.4)

Duration of MDS (years)

Median

Min, Max

0.1, 20.7

Del 5 (q31-33) Cytogenetic Abnormality

n

(%)

(100.0)

Other cytogenetic abnormalities

(25.2)

IPSS Score

[a]

n

(%)

Low (0)

(37.2)

Intermediate-1 (0.5-1.0)

(43.9)

Intermediate-2 (1.5-2.0)

(4.1)

High (≥2.5)

(1.4)

Missing

(13.5)

FAB Classification

[b]

from central review

n

(%)

(52.0)

RARS

(10.8)

RAEB

(20.3)

CMML

(2.0)

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)

French-American-British (FAB) classification of MDS.

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 REVLIMID 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).

13.4 Mantle Cell Lymphoma

The efficacy and safety of lenalidomide were evaluated in patients with mantle cell lymphoma in

a phase II, multicenter, randomised open-label study versus single agent of investigator’s choice

in patients who were refractory to their last regimen or had relapsed one to three times (Study

MCL-002).

Patients who were at least 18 years of age with histologically-proven MCL and CT-measurable

disease were enrolled. Patients were required to have received adequate previous treatment with

at least one prior combination chemotherapy regimen. Also, patients had to be ineligible for

intensive chemotherapy and/or transplant at time of inclusion in the study. Patients were

randomised 2:1 to the lenalidomide or the control arm. The investigator’s choice treatment was

selected before randomisation and consisted of monotherapy with either chlorambucil, cytarabine,

rituximab, fludarabine, or gemcitabine.

Lenalidomide was administered orally 25 mg once daily for the first 21 days (D1 to D21) of

repeating 28-day cycles until progression or unacceptable toxicity. Patients with moderate renal

insufficiency were to receive a lower starting dose of lenalidomide 10 mg daily on the same

schedule.

The baseline demographics were comparable between the lenalidomide arm and control arm.

Both patient populations presented a median age of 68.5 years with comparable male to female

ratio. The ECOG performance status was comparable between both groups, as was the number of

prior therapies.

The primary efficacy endpoint in Study MCL-002 was progression-free survival (PFS).

The efficacy results for the Intent-to-Treat (ITT) population were assessed by the Independent

Review Committee (IRC), and are presented in the table 13 below.

Table 13: Summary of efficacy results – study MCL-002, intent-to-treat population

Lenalidomide Arm

Control Arm

N = 170

N = 84

PFS

PFS,

median

[95% CI]

(weeks)

37.6 [24.0, 52.6]

22.7 [15.9, 30.1]

Sequential HR

[95% CI]

0.61 [0.44, 0.84]

Sequential log-rank test, p-value

0.004

Response

, n (%)

Complete response (CR)

8 (4.7)

0 (0.0)

Partial response (PR)

60 (35.3)

9 (10.7)

Stable disease (SD)

50 (29.4)

44 (52.4)

Progressive disease (PD)

34 (20.0)

26 (31.0)

Not done/Missing

18 (10.6)

5 (6.0)

ORR (CR, CRu, PR)

, n (%) [95% CI]

68 (40.0) [32.58, 47.78]

9 (10.7)

[5.02, 19.37]

p-value

< 0.001

CRR (CR, CRu)

, n (%) [95% CI]

8 (4.7) [2.05, 9.06]

0 (0.0) [95.70, 100.00]

p-value

0.043

Duration of Response,

median

[95% CI]

(weeks)

69.6 [41.1, 86.7]

45.1 [36.3, 80.9]

Overall Survival

HR

[95% CI]

0.89 [0.62, 1.28]

Log-rank test, p-value

0.520

CI = confidence interval; CRR = complete response rate; CR = complete response; CRu = complete response unconfirmed; DMC = Data

Monitoring Committee; ITT = intent-to-treat; HR = hazard ratio; KM = Kaplan-Meier; MIPI = Mantle Cell Lymphoma International

Prognostic Index; NA = not applicable; ORR = overall response rate; PD = progressive disease; PFS = progression-free survival; PR= partial

response; SCT = stem cell transplantation; SD = stable disease; SE = standard error.

The median was based on the KM estimate.

Range was calculated as 95% CIs about the median survival time.

The mean and median are the univariate statistics without adjusting for censoring.

The stratification variables included time from diagnosis to first dose (< 3 years and ≥ 3 years), time from last prior systemic anti-lymphoma

therapy to first dose (< 6 months and ≥ 6 months), prior SCT (yes or no), and MIPI at baseline (low, intermediate, and high risk).

Sequential test was based on a weighted mean of a log-rank test statistic using the unstratified log-rank test for sample size increase and the

unstratified log-rank test of the primary analysis. The weights are based on observed events at the time the third DMC meeting was held and

based on the difference between observed and expected events at the time of the primary analysis. The associated sequential HR and the

corresponding 95% CI are presented.

In study MCL-002 in the ITT population, there was an overall apparent increase in deaths within

20 weeks in the lenalidomide arm 22/170 (13%) versus 6/84 (7%) in the control arm. In patients

with high tumour burden, corresponding figures were 16/81 (20%) and 2/28 (7%).

14.

REFERENCES

OSHA Hazardous Drugs.

OSHA

[Accessed on 29 January 2013, from

http://www.osha.gov/SLTC/hazardousdrugs/index.html]

15.

HOW SUPPLIED/STORAGE AND HANDLING

15.1

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 blisters of 21

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

ink:

5 mg blisters of 21

Pale yellow/white hard capsules marked “REV 7.5 mg”

7.5 mg blisters of 21.

Blue/green and pale yellow opaque hard capsules imprinted “REV” on one half and “10 mg” on

the other half in black ink:

10 mg blisters of 21

Powder blue and white opaque hard capsules imprinted “REV” on one half and “15 mg” on the

other half in black ink:

15 mg blisters of 21

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 blisters of 21

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

ink:

25 mg blisters of 21

15.2 Storage

DO NOT STORE ABOVE 25°C.

15.2

Handling and Disposal

Care should be exercised in the handling of REVLIMID. REVLIMID hard capsules should not

be opened or crushed. If powder from REVLIMID contacts the skin, wash the skin immediately

and thoroughly with soap and water. If REVLIMID contacts the mucous membranes, they

should be thoroughly flushed with water. Procedures for the proper handling and disposal of

anticancer drugs should be considered. Several guidelines on the subject have been published.

Dispense no more than a 28-day supply.

Registration No.

Revlimid 2.5mg: 33894

Revlimid 5mg: 31660

Revlimid 7.5mg: 33896

Revlimid 10mg: 31661

Revlimid 15mg: 31662

Revlimid 20mg: 33965

Revlimid 25mg: 31663

Manufacturers

Celgene International Sarl, Boudry, Switzerland

Registration Holder

Neopharm Scientific Ltd. P.O.B 7063, Petach Tiqva 49170

The format of this leaflet has defined by the Ministry of Health; its content has been checked and

approved in 08/2019

.