Lenalidomide 5 MG, 10mg, 15mg Hard Capsules SMPC - Taj Pharmaceuticals

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RX Lenalidomide 25 mg hard capsules

White capsules, size 0, 21.7 mm.
LENALIDOMIDE HARD
4. CLINICAL PARTICULARS
CAPSULES
4.1 Therapeutic indications
5 MG, 10 MG, 25 MG Multiple myeloma
1.NAME OF THE MEDICINAL Lenalidomide as monotherapy is indicated for

PRODUCT the maintenance treatment of adult patients with
newly diagnosed multiple myeloma who have
Lenalidomide 5 mg hard capsules undergone autologous stem cell transplantation.
Lenalidomide 10 mg hard capsules Lenalidomide as combination therapy (see
Lenalidomide 25 mg hard capsules section 4.2) is indicated for the treatment of
adult patients with previously untreated multiple
2. QUALITATIVE AND myeloma who are not eligible for transplant.
QUANTITATIVE COMPOSITION Lenalidomide in combination with
Lenalidomide 5 mg hard capsules dexamethasone is indicated for the treatment of
multiple myeloma in adult patients who have
Each capsule contains 5 mg of lenalidomide. received at least one prior therapy.
Excipient(s) with known effect Myelodysplastic syndromes
Each capsule contains 147 mg of lactose (as Lenalidomide as monotherapy is indicated for
anhydrous lactose). the treatment of adult patients with transfusion-
Lenalidomide 10 mg hard capsules dependent anemia due to low- or intermediate-1-
risk myelodysplastic syndromes associated with
Each capsule contains 10 mg of lenalidomide. an isolated deletion 5q cytogenetic abnormality
Excipient(s) with known effect when other therapeutic options are insufficient
or inadequate.
Each capsule contains 294 mg of lactose (as
anhydrous lactose). Mantle cell lymphoma
Lenalidomide as monotherapy is indicated for
Lenalidomide 25 mg hard capsules
the treatment of adult patients with relapsed or
Each capsule contains 25 mg of lenalidomide. refractory mantle cell lymphoma (see sections
4.4 and 5.1).
Excipient(s) with known effect
4.2 Posology and method of
Each capsule contains 200 mg of lactose (as
anhydrous lactose). administration
For the full list of excipients, see section 6.1. Lenalidomide treatment should be supervised
by a physician experienced in the use of anti-
3. PHARMACEUTICAL FORM cancer therapies.
Hard capsule. For all indications described below:
Lenalidomide 5 mg hard capsules • Dose is modified based upon clinical and
laboratory findings (see section 4.4).
White capsules, size 2, 18.0 mm.
• Dose adjustments, during treatment and restart
Lenalidomide 10 mg hard capsules of treatment, are recommended to manage grade
Blue-green/pale yellow capsules, size 0, 21.7 3 or 4 thrombocytopenia, neutropenia, or other
mm grade 3 or 4 toxicity judged to be related to .
• In case of neutropenia, the use of growth

factors in patient management should be When platelets Recommended course
9
considered. Fall to < 30 x 10 /L Interrupt treatment
• If less than 12 hours has elapsed since missing Return to ≥ 30 x 109/L Resume at dose level -1 once
a dose, the patient can take the dose. If more daily
than 12 hours has elapsed since missing a dose For each subsequent drop below Interrupt treatment
at the normal time, the patient should not take 30 x 109/L
the dose, but take the next dose at the normal Return to ≥ 30 x 109/L Resume at next lower dose
time on the following day. level once daily
• Neutropenia
Posology
Newly diagnosed multiple myeloma (NDMM) When neutrophils Recommended coursea
• maintenance in patients who have undergone

Fall to < 0.5 x 109/L Interrupt treatment
autologous stem cell transplantation (ASCT)
maintenance should be initiated after adequate Return to ≥ 0.5 x 109/L Resume at dose level -1 once
haematologic recovery following ASCT in daily
patients without evidence of progression. must For each subsequent drop below < Interrupt treatment
not be started if the Absolute Neutrophil Count 0.5 x 109/L
(ANC) is < 1.0 x 109/L, and/or platelet counts Return to ≥ 0.5 x 109/L Resume at next lower dose
are < 75 x 109/L. level once daily
a
Recommended dose At the physician's discretion, if neutropenia is
the only toxicity at any dose level, add
The recommended starting dose is 10 mg orally
granulocyte colony stimulating factor (G-CSF)
once daily continuously (on days 1 to 28 of
and maintain the dose level of .
repeated 28-day cycles) given until disease
progression or intolerance. After 3 cycles of • in combination with dexamethasone until
maintenance, the dose can be increased to 15 mg disease progression in patients who are not
orally once daily if tolerated. eligible for transplant
• Dose reduction steps
treatment must not be started if the ANC is <
Starting dose (10 mg) If dose increased (15 1.0 x 109/L, and/or platelet counts are < 50 x
mg) a 109/L.
Dose 5 mg 10 mg
level -1 Recommended dose
Dose 5 mg (days 1-21 every 5 mg The recommended starting dose of is 25 mg
level -2 28 days)
orally once daily on days 1 to 21 of repeated 28-
Dose Not applicable 5 mg (days 1-21 every day cycles.
level -3 28 days)
Do not dose below 5 mg (days 1-21 every 28 The recommended dose of dexamethasone is 40
days) mg orally once daily on days 1, 8, 15 and 22 of
repeated 28-day cycles. Patients may continue
a and dexamethasone therapy until disease
After 3 cycles of maintenance, the dose can be progression or intolerance.
increased to 15 mg orally once daily if tolerated.
• Thrombocytopenia
• Dose reduction steps with a platelet count ≥ 100 x 109/L at the

beginning of a new cycle).
a
Dexamethasonea
• in combination with melphalan and
Starting dose 25 mg 40 mg prednisone followed by maintenance in patients
who are not eligible for transplant
Dose level -1 20 mg 20 mg
treatment must not be started if the ANC is <
Dose level -2 15 mg 12 mg 1.5 x 109/L, and/or platelet counts are < 75 x
Dose level -3 10 mg 8 mg 109/L.
Recommended dose
Dose level- 4 5 mg 4 mg
The recommended starting dose is 10 mg orally
Dose level -5 2.5 mg Not applicable
once daily on days 1 to 21 of repeated 28-day
ª Dose reduction for both products can be cycles for up to 9 cycles, melphalan 0.18 mg/kg
managed independently orally on days 1 to 4 of repeated 28-day cycles,
prednisone 2 mg/kg orally on days 1 to 4 of
• Thrombocytopenia repeated 28-day cycles. Patients who complete 9
cycles or who are unable to complete the
When platelets Recommended course combination therapy due to intolerance are
treated with monotherapy as follows: 10 mg
Fall to < 25 x 109/L Stop dosing for remainder of orally once daily on days 1 to 21 of repeated 28-
cycleª
day cycles given until disease progression.
Return to ≥ 50 x 109/L Decrease by one dose level
when dosing resumed at next • Dose reduction steps
cycle
Melphalan Prednisone
ª If Dose limiting toxicity (DLT) occurs on >
day15 of a cycle, dosing will be interrupted for Starting dose 10 mgª 0.18 mg/kg 2 mg/kg
at least the remainder of the current 28-day
Dose level -1 7.5 mg 0.14 mg/kg 1 mg/kg
cycle.
Dose level -2 5 mg 0.10 mg/kg 0.5 mg/kg
• Neutropenia
Dose level -3 2.5 mg Not applicable 0.25 mg/kg
When neutrophils Recommended course
ª If neutropenia is the only toxicity at any dose
First fall to < 0.5 x 10 /L 9
Interrupt treatment level, add granulocyte colony stimulating factor
(G-CSF) and maintain the dose level of
Return to ≥ 1 x 109/L when Resume at starting dose once
neutropenia is the only observed daily • Thrombocytopenia
toxicity
Return to ≥ 0.5 x 109/L when dose- Resume at dose level -1 once When platelets Recommended course
dependent haematological daily 9
toxicities other than neutropenia First fall to < 25 x 10 /L Interrupt treatment
are observed
For each subsequent drop below < Interrupt treatment Return to ≥ 25 x 109/L Resume and melphalan at dose
0.5 x 109/L level -1
Return to ≥ 0.5 x 109/L Resume at next lower dose For each subsequent drop below 30 x Interrupt treatment
level once daily. 109/L
For hematologic toxicity the dose of may be re- Return to ≥ 30 x 109/L Resume at next lower dose level
introduced to the next higher dose level (up to (dose level -2 or -3) once daily.
the starting dose) upon improvement in bone
marrow function (no hematologic toxicity for at
least 2 consecutive cycles: ANC ≥1,5 x 109/L
• Neutropenia
When neutrophils Recommended course Starting dose 25 mg
9
First fall to < 0.5 x 10 /Lª Interrupt treatment Dose level -1 15 mg
Dose level -2 10 mg
Return to ≥ 0.5 x 109/L when Resume at starting dose once Dose level -3 5 mg
neutropenia is the only observed daily
toxicity • Thrombocytopenia
Return to ≥ 0.5 x 109/L when Resume at dose level -1 once
When platelets Recommended course
dose-dependent haematological daily
toxicities other than neutropenia First fall to < 30 x 109/L Interrupt treatment
are observed 9
Return to ≥ 30 x 10 /L Resume at dose level -1
For each subsequent drop below < Interrupt treatment For each subsequent drop below 30 Interrupt treatment
0.5 x 109/L x 109/L
Return to ≥ 0.5 x 109/L Resume at next lower dose Return to ≥ 30 x 109/L Resume at next lower dose
level once daily. level (dose level -2 or -3)
once daily. Do not dose
ªIf the subject has not been receiving G-CSF below 5 mg once daily.
therapy, initiate G-CSF therapy. On day 1 of • Neutropenia
next cycle, continue G-CSF as needed and
When neutrophils Recommended course
maintain dose of if neutropenia was the only
DLT. Otherwise, decrease by one dose level at First fall to < 0.5 x 109/L Interrupt treatment
9
start of next cycle. Return to ≥ 0.5 x 10 /L when Resume at starting dose once
neutropenia is the only observed daily
Multiple myeloma with at least one prior toxicity
therapy Return to ≥ 0.5 x 109/L when Resume at dose level -1 once
dose-dependent haematological daily
treatment must not be started if the ANC < 1.0 x toxicities other than neutropenia
109/L, and/or platelet counts < 75 x 109/L or, are observed
dependent on bone marrow infiltration by For each subsequent drop below < Interrupt treatment
plasma cells, platelet counts < 30 x 109/L. 0.5 x 109/L
Return to ≥ 0.5 x 109/L Resume at next lower dose
Recommended dose level (dose level -1, -2 or -3)
once daily. Do not dose below
The recommended starting dose of is 25 mg 5 mg once daily.
orally once daily on days 1 to 21 of repeated 28- Myelodysplastic syndromes (MDS)
day cycles. The recommended dose of
dexamethasone is 40 mg orally once daily on treatment must not be started if the ANC < 0.5 x
days 1 to 4, 9 to 12, and 17 to 20 of each 28-day 109/L and/or platelet counts < 25 x 109/L.
cycle for the first 4 cycles of therapy and then 40
mg once daily on days 1 to 4 every 28 days.
Recommended dose
Prescribing physicians should carefully evaluate
which dose of dexamethasone to use, taking into The recommended starting dose of is 10 mg
account the condition and disease status of the orally once daily on days 1 to 21 of repeated 28-
patient. day cycles.
• Dose reduction steps 1

- In countries where the 2.5 mg capsule is available.
Starting dose 25 mg once daily on days 1 to 21, every 28 days Starting dose 25 mg once daily on days 1 to 21, every 28 days
Dose Level -1 20 mg once daily on days 1 to 21, every 28 days

Dose Level -2 15 mg once daily on days 1 to 21, every 28 days Dose Level -3 10 mg once daily on days 1 to 21, every 28 days
Dose Level -3 10 mg once daily on days 1 to 21, every 28 days Dose Level -4 5 mg once daily on days 1 to 21, every 28 days
1
Dose Level -5 2.5 mg once daily on days 1 to 21, every 28 days
Dose Level -4 5 mg once daily on days 1 to 21, every 28 days 5 mg every other day on days 1 to 21, every 28 days
Dose Level -5 2.5 mg once daily on days 1 to 21, every 28 days1 • Thrombocytopenia
5 mg every other day on days 1 to 21, every 28
days
When platelets Recommended Course
• Thrombocytopenia Fall to < 50 x 109/L Interrupt treatment and

conduct Complete Blood
When platelets Recommended course Count (CBC) at least every 7
days
Fall to < 25 x 109/L Interrupt treatment Return to ≥ 60 x 109/L Resume at next lower level
(dose level -1)
Return to ≥ 25 x 109/L - < 50 x 109/L Resume at next lower dose For each subsequent drop below Interrupt treatment and
on at least 2 occasions for ≥ 7 days or level (dose level -1, -2 or -3)
50 x 109/L conduct the CBC at least
when the platelet count recovers to ≥
50 x 109/L at any time Return to ≥60 x 109/L every 7 days
Resume at next lower level
(dose level -2, -3, -4 or -5).
Do not dose below dose level
• Neutropenia -5
• Neutropenia
When neutrophils Recommended course When neutrophils Recommended Course

Fall to < 1 x 109/L for at least 7 Interrupt treatment and
Fall to < 0.5 x 109/L Interrupt treatment
days or conduct the CBC at least
Return to ≥ 0.5 x 109/L Resume at next lower dose Falls to < 1 x 109/L with every 7 days
level (dose level -1, -2 or -3) associated fever (body
temperature ≥ 38.5°C) or
Falls to < 0.5 x 109/L
Discontinuation of Return to ≥ 1 x 109/L Resume at next lower dose
level (dose level -1)
Patients without at least a minor erythroid For each subsequent drop below 1 Interrupt treatment
response within 4 months of therapy initiation, x 109/L for at least 7 days or drop
demonstrated by at least a 50% reduction in to < 1 x 109/L with associated
transfusion requirements or, if not transfused, a fever (body temperature ≥ 38.5°C)
or drop to < 0.5 x 109/L
1g/dl rise in haemoglobin, should discontinue
treatment. Returns to ≥1 x 109/L Resume at next lower dose
level (dose level -2, -3, -4, -5).
Mantle cell lymphoma (MCL) Do not dose below dose level
-5
Recommended dose
The recommended starting dose of is 25 mg
orally once daily on days 1 to 21 of repeated 28-
day cycles. Tumour flare reaction

may be continued in patients with Grade 1 or 2 carefully assessed before treatment is considered
tumour flare reaction (TFR) without interruption (see section 4.4).
or modification, at the physician's discretion. In
patients with Grade 3 or 4 TFR, withhold For patients older than 75 years of age treated
treatment with until TFR resolves to ≤ Grade 1 with in combination with dexamethasone, the
and patients may be treated for management of starting dose of dexamethasone is 20 mg once
symptoms per the guidance for treatment of daily on days 1, 8, 15 and 22 of each 28-day
Grade 1 and 2 TFR (see section 4.4). treatment cycle.
All indications No dose adjustment is proposed for patients

older than 75 years who are treated with in
For other grade 3 or 4 toxicities judged to be combination with melphalan and prednisone.
related to , treatment should be stopped and only
restarted at next lower dose level when toxicity In patients with newly diagnosed multiple
has resolved to ≤ grade 2 depending on the myeloma aged 75 years and older who received ,
physician's discretion. there was a higher incidence of serious adverse
reactions and adverse reactions that led to
interruption or discontinuation should be treatment discontinuation.
considered for grade 2 or 3 skin rash. must be
discontinued for angioedema, grade 4 rash, combined therapy was less tolerated in newly
exfoliative or bullous rash, or if Stevens-Johnson diagnosed multiple myeloma patients older than
syndrome (SJS), toxic epidermal necrolysis 75 years of age compared to the younger
(TEN) or Drug Reaction with Eosinophilia and population. These patients discontinued at a
Systemic Symptoms (DRESS) is suspected, and higher rate due to intolerance (Grade 3 or 4
should not be resumed following discontinuation adverse events and serious adverse events),
from these reactions. when compared to patients < 75 years.
Special populations Multiple myeloma: patients with at least one

prior therapy
• Paediatric population
The percentage of multiple myeloma patients
Lenalidomide should not be used in children aged 65 or over was not significantly different
and adolescents from birth to less than 18 years between the /dexamethasone and
because of safety concerns (see section 5.1). placebo/dexamethasone groups. No overall
difference in safety or efficacy was observed
• Elderly
between these patients and younger patients, but
Currently available pharmacokinetic data are greater pre-disposition of older individuals
described in section 5.2. has been used in cannot be ruled out.
clinical trials in multiple myeloma patients up to Myelodysplastic syndromes
91 years of age, in myelodysplastic syndromes
patients up to 95 years of age and in mantle cell For myelodysplastic syndromes patients treated
lymphoma patients up to 88 years of age (see with , no overall difference in safety and
section 5.1). efficacy was observed between patients aged
over 65 and younger patients.
Because elderly patients are more likely to have
decreased renal function, care should be taken in Mantle cell lymphoma
dose selection and it would be prudent to
monitor renal function. For mantle cell lymphoma patients treated with ,
no overall difference in safety and efficacy was
Newly diagnosed multiple myeloma: patients observed between patients aged 65 years or over
who are not eligible for transplant compared with patients aged under 65 years of
age.
Patients with newly diagnosed multiple
myeloma aged 75 years and older should be • Patients with renal impairment
is primarily excreted by the kidney; patients cycles)

with greater degrees of renal impairment can
have impaired treatment tolerance (see section Dose level - 2.5 mg once daily
1* (days 1 to 28 of repeated 28-day
4.4). Care should be taken in dose selection and cycles)
monitoring of renal function is advised. Dose level - 2.5 mg once every other day
No dose adjustments are required for patients cycles)
with mild renal impairment and multiple Severe renal impairment Starting dose 2.5 mg once daily
myeloma, myelodysplastic syndromes or mantle (CLcr < 30 mL/min, not (days 1 to 21 of repeated 28-day
requiring dialysis) cycles)
cell lymphoma.
Dose level - 2.5 mg every other day
The following dose adjustments are 1* (days 1 to 28 of repeated 28-day
cycles)
recommended at the start of therapy and
Dose level - 2.5 mg twice a week
throughout treatment for patients with moderate 2* (days 1 to 28 of repeated 28-day
or severe impaired renal function or end stage cycles)
renal disease. End Stage Renal Disease Starting dose 2.5 mg once daily
(ESRD) (days 1 to 21 of repeated 28-day
There are no phase III trial experiences with End (CLcr < 30 mL/min, requiring cycles)
dialysis)
Stage Renal Disease (ESRD) (CLcr < 30 On dialysis days, the dose
Dose level - 2.5 mg every other day
mL/min, requiring dialysis). should be administered cycles)
following dialysis.
* Recommended dose reduction steps during
treatment and restart of treatment to manage
grade 3 or 4 neutropenia or thrombocytopenia,
Multiple myeloma or other grade 3 or 4 toxicity judged to be
Renal function (CLcr) Dose adjustment
related to , as described above.
(days 1 to 21 of repeated 28-day Mantle cell lymphoma
cycles)
Moderate renal 10 mg once daily1 Renal function (CLcr) Dose adjustment
impairment (days 1 to 21 of repeated 28-
(30 ≤ CLcr < 50 mL/min) day cycles)
Severe renal impairment 7.5 mg once daily2 Moderate renal impairment 10 mg once daily1
(CLcr < 30 mL/min, not 15 mg every other day (30 ≤ CLcr < 50 mL/min)
requiring dialysis)
Severe renal impairment 7.5 mg once daily2
End Stage Renal Disease 5 mg once daily. On dialysis (CLcr < 30 mL/min, not 15 mg every other day
(ESRD) days, the dose should be requiring dialysis)
(CLcr < 30 mL/min, administered following dialysis.
requiring dialysis) End Stage Renal Disease 5 mg once daily. On dialysis
1 (ESRD) days, the dose should be
The dose may be escalated to 15 mg once daily (CLcr < 30 mL/min, requiring administered following
after 2 cycles if patient is not responding to dialysis) dialysis.
1
treatment and is tolerating the treatment. The dose may be escalated to 15 mg once daily
2 after 2 cycles if patient is not responding to
In countries where the 7.5 mg capsule is
treatment and is tolerating the treatment.
available.
2
In countries where the 7.5 mg capsule is
available.
After initiation of therapy, subsequent dose
Myelodysplastic syndromes modification in renally impaired patients should
be based on individual patient treatment
tolerance, as described above.
Renal function (CLcr) Dose adjustment
• Patients with hepatic impairment
Moderate renal impairment Starting dose 5 mg once daily
(30 ≤ CLcr < 50 mL/min) (days 1 to 21 of repeated 28-day
has not formally been studied in patients with potential unless she meets at least one of the
impaired hepatic function and there are no following criteria:
specific dose recommendations.
• Age ≥ 50 years and naturally amenorrhoeic for
Method of administration ≥ 1 year (Amenorrhoea following cancer therapy
or during breast-feeding does not rule out
Oral use. childbearing potential).
Lenalidomide capsules should be taken orally at • Premature ovarian failure confirmed by a
about the same time on the scheduled days. The specialist gynaecologist
capsules should not be opened, broken or
chewed. The capsules should be swallowed • Previous bilateral salpingo-oophorectomy, or
whole, preferably with water, either with or hysterectomy
without food.
• XY genotype, Turner syndrome, uterine
It is recommended to press only on one end of agenesis.
the capsule to remove it from the blister thereby
Counselling
reducing the risk of capsule deformation or
breakage. For women of childbearing potential, is
contraindicated unless all of the following are
met:
4.3 Contraindications
• Hypersensitivity to the active substance or to • She understands the expected teratogenic risk
to the unborn child
any of the excipients listed in section 6.1.
• She understands the need for effective
• Women who are pregnant.
contraception, without interruption, 4 weeks
• Women of childbearing potential unless all of before starting treatment, throughout the entire
the conditions of the Pregnancy Prevention duration of treatment, and 4 weeks after the end
Programme are met (see sections 4.4 and 4.6). of treatment
• Even if a woman of childbearing potential has
4.4 Special Warnings and precautions for amenorrhea she must follow all the advice on
use effective contraception
Pregnancy warning • She should be capable of complying with

effective contraceptive measures
is structurally related to thalidomide.
Thalidomide is a known human teratogenic • She is informed and understands the potential
active substance that causes severe life- consequences of pregnancy and the need to
threatening birth defects. induced in monkeys rapidly consult if there is a risk of pregnancy
malformations similar to those described with • She understands the need to commence the
thalidomide (see sections 4.6 and 5.3). If is treatment as soon as is dispensed following a
taken during pregnancy, a teratogenic effect of negative pregnancy test
in humans is expected.
• She understands the need and accepts to
The conditions of the Pregnancy Prevention undergo pregnancy testing every 4 weeks except
Programme must be fulfilled for all patients in case of confirmed tubal sterilisation
unless there is reliable evidence that the patient
does not have childbearing potential. • She acknowledges that she understands the
hazards and necessary precautions associated
Criteria for women of non-childbearing potential with the use of .
A female patient or a female partner of a male For male patients taking , pharmacokinetic data
patient is considered to have childbearing has demonstrated that is present in human
semen at extremely low levels during treatment The following can be considered to be examples
and is undetectable in human semen 3 days after of suitable methods of contraception:
stopping the substance in the healthy subject
• Implant
(see section 5.2). As a precaution and taking into
account special populations with prolonged • Levonorgestrel-releasing intrauterine system
elimination time such as renal impairment, all (IUS)
male patients taking must meet the following
conditions: • Medroxyprogesterone acetate depot
• Understand the expected teratogenic risk if • Tubal sterilisation

engaged in sexual activity with a pregnant • Sexual intercourse with a vasectomised male
woman or a woman of childbearing potential partner only; vasectomy must be confirmed by
• Understand the need for the use of a condom if two negative semen analyses
engaged in sexual activity with a pregnant • Ovulation inhibitory progesterone-only pills
woman or a woman of childbearing potential not (i.e. desogestrel)
using effective contraception (even if the man
has had a vasectomy), during treatment and for 1 Because of the increased risk of venous
week after dose interruptions and/or cessation of thromboembolism in patients with multiple
treatment. myeloma taking in combination therapy, and to
a lesser extent in patients with multiple
• Understand that if his female partner becomes myeloma, myelodysplastic syndromes and
pregnant whilst he is taking Lenalidomide or mantle cell lymphoma taking monotherapy,
shortly after he has stopped taking Lenalidomide combined oral contraceptive pills are not
, he should inform his treating physician recommended (see also section 4.5). If a patient
immediately and that it is recommended to refer is currently using combined oral contraception
the female partner to a physician specialised or the patient should switch to one of the effective
experienced in teratology for evaluation and methods listed above. The risk of venous
advice. thromboembolism continues for 4−6 weeks after
The prescriber must ensure that for women of discontinuing combined oral contraception. The
childbearing potential: efficacy of contraceptive steroids may be
reduced during co-treatment with
• The patient complies with the conditions of the dexamethasone (see section 4.5).
Pregnancy Prevention Programme, including
confirmation that she has an adequate level of Implants and levonorgestrel-releasing
understanding intrauterine systems are associated with an
increased risk of infection at the time of
• The patient has acknowledged the insertion and irregular vaginal bleeding.
aforementioned conditions. Prophylactic antibiotics should be considered
Contraception particularly in patients with neutropenia.
Women of childbearing potential must use one Copper-releasing intrauterine devices are
effective method of contraception for 4 weeks generally not recommended due to the potential
before therapy, during therapy, and until 4 risks of infection at the time of insertion and
weeks after therapy and even in case of dose menstrual blood loss which may compromise
patients with neutropenia or thrombocytopenia.
interruption unless the patient commits to
absolute and continuous abstinence confirmed Pregnancy testing
on a monthly basis. If not established on
effective contraception, the patient must be According to local practice, medically
referred to an appropriately trained health care supervised pregnancy tests with a minimum
professional for contraceptive advice in order sensitivity of 25 mIU/mL must be performed for
that contraception can be initiated. women of childbearing potential as outlined
below. This requirement includes women of
childbearing potential who practice absolute and national controlled distribution system has been
continuous abstinence. Ideally, pregnancy implemented in collaboration with each National
testing, issuing a prescription and dispensing Competent Authority. The controlled
should occur on the same day. Dispensing of to distribution system includes the use of a patient
women of childbearing potential should occur card and/or equivalent tool for prescribing
within 7 days of the prescription. and/or dispensing controls, and the collecting of
detailed data relating to the indication in order to
Prior to starting treatment
monitor closely the off-label use within the
A medically supervised pregnancy test should be national territory. Ideally, pregnancy testing,
performed during the consultation, when is issuing a prescription and dispensing should
prescribed, or in the 3 days prior to the visit to occur on the same day. Dispensing of to women
the prescriber once the patient had been using of childbearing potential should occur within 7
effective contraception for at least 4 weeks. The days of the prescription and following a
test should ensure the patient is not pregnant medically supervised negative pregnancy test
when she starts treatment with . result. Prescriptions for women of childbearing
potential can be for a maximum duration of 4
Follow-up and end of treatment weeks, and prescriptions for all other patients
A medically supervised pregnancy test should be can be for a maximum duration of 12 weeks.
repeated every 4 weeks, including 4 weeks after Other special warnings and precautions for use
the end of treatment, except in the case of
confirmed tubal sterilisation. These pregnancy Myocardial infarction
tests should be performed on the day of the Myocardial infarction has been reported in
prescribing visit or in the 3 days prior to the visit patients receiving , particularly in those with
to the prescriber.
known risk factors and within the first 12
Additional precautions months when used in combination with
dexamethasone. Patients with known risk factors
Patients should be instructed never to give this – including prior thrombosis – should be closely
medicinal product to another person and to monitored, and action should be taken to try to
return any unused capsules to their pharmacist at minimize all modifiable risk factors (eg.
the end of treatment for safe disposal. smoking, hypertension, and hyperlipidaemia).
Patients should not donate blood during therapy Venous and arterial thromboembolic events
or for 1 week following discontinuation of .
In patients with multiple myeloma, the
Educational materials, prescribing and combination of with dexamethasone is
dispensing restrictions associated with an increased risk of venous
In order to assist patients in avoiding foetal thromboembolism (predominantly deep vein
exposure to , the marketing authorisation holder thrombosis and pulmonary embolism) and was
will provide educational material to health care seen to a lesser extent with in combination with
professionals to reinforce the warnings about the melphalan and prednisone.
expected teratogenicity of , to provide advice on In patients with multiple myeloma,
contraception before therapy is started, and to myelodysplastic syndromes and mantle cell
provide guidance on the need for pregnancy lymphoma, treatment with monotherapy was
testing. The prescriber must inform male and associated with a lower risk of venous
female patients about the expected teratogenic thromboembolism (predominantly deep vein
risk and the strict pregnancy prevention thrombosis and pulmonary embolism) than in
measures as specified in the Pregnancy patients with multiple myeloma treated with in
Prevention Programme and provide patients with combination therapy (see sections 4.5 and 4.8).
appropriate patient educational brochure, patient
card and/or equivalent tool in accordance to the In patients with multiple myeloma, the
national implemented patient card system. A combination of with dexamethasone is
associated with an increased risk of arterial Neutropenia and thrombocytopenia

thromboembolism (predominantly myocardial
infarction and cerebrovascular event) and was The major dose limiting toxicities of include
seen to a lesser extent with in combination with neutropenia and thrombocytopenia. A complete
melphalan and prednisone. The risk of ATE is blood cell count, including white blood cell
lower in patients with multiple myeloma treated count with differential count, platelet count,
with monotherapy than in patients with multiple haemoglobin, and haematocrit should be
myeloma treated with in combination therapy. performed at baseline, every week for the first 8
weeks of treatment and monthly thereafter to
Consequently, patients with known risk factors monitor for cytopenias. In mantle cell lymphoma
for thromboembolism – including prior patients, the monitoring scheme should be every
thrombosis – should be closely monitored. 2 weeks in Cycles 3 and 4, and then at the start
Action should be taken to try to minimize all of each cycle. A dose reduction may be required
modifiable risk factors (e.g. smoking, (see section 4.2).
hypertension, and hyperlipidaemia).
Concomitant administration of erythropoietic In case of neutropenia, the physician should
agents or previous history of thromboembolic consider the use of growth factors in patient
events may also increase thrombotic risk in these management. Patients should be advised to
promptly report febrile episodes.
patients. Therefore, erythropoietic agents, or
other agents that may increase the risk of Patients and physicians are advised to be
thrombosis, such as hormone replacement observant for signs and symptoms of bleeding,
therapy, should be used with caution in multiple including petechiae and epistaxes, especially in
myeloma patients receiving with patients receiving concomitant medicinal
dexamethasone. A haemoglobin concentration products susceptible to induce bleeding (see
above 12 g/dl should lead to discontinuation of section 4.8, Haemorrhagic disorders).
erythropoietic agents.
Co-administration of with other
Patients and physicians are advised to be myelosuppressive agents should be undertaken
observant for the signs and symptoms of with caution.
thromboembolism. Patients should be instructed
to seek medical care if they develop symptoms • Newly diagnosed multiple myeloma: patients
such as shortness of breath, chest pain, arm or who have undergone ASCT treated with
leg swelling. Prophylactic antithrombotic maintenance
medicines should be recommended, especially in The adverse reactions from CALGB 100104
patients with additional thrombotic risk factors. included events reported post-high dose
The decision to take antithrombotic prophylactic melphalan and ASCT (HDM/ASCT) as well as
measures should be made after careful events from the maintenance treatment period. A
assessment of an individual patient's underlying second analysis identified events that occurred
risk factors. after the start of maintenance treatment. In IFM
If the patient experiences any thromboembolic 2005-02, the adverse reactions were from the
events, treatment must be discontinued and maintenance treatment period only.
standard anticoagulation therapy started. Once Overall, grade 4 neutropenia was observed at a
the patient has been stabilised on the higher frequency in the maintenance arms
anticoagulation treatment and any complications compared to the placebo maintenance arms in
of the thromboembolic event have been the 2 studies evaluating maintenance in NDMM
managed, the treatment may be restarted at the patients who have undergone ASCT (32.1% vs
original dose dependent upon a benefit risk 26.7% [16.1% vs 1.8% after the start of
assessment. The patient should continue maintenance treatment] in CALGB 100104 and
anticoagulation therapy during the course of 16.4% vs 0.7% in IFM 2005-02, respectively).
treatment. Treatment-emergent AEs of neutropenia leading
to discontinuation were reported in 2.2% of
patients in CALGB 100104 and 2.4% of patients The combination of with melphalan and
in IFM 2005-02, respectively. Grade 4 febrile prednisone in clinical trials of newly diagnosed
neutropenia was reported at similar frequencies multiple myeloma patients is associated with a
in the maintenance arms compared to placebo higher incidence of grade 4 neutropenia (34.1%
maintenance arms in both studies (0.4% vs 0.5% in melphalan, prednisone and arm followed by
[0.4% vs 0.5% after the start of maintenance [MPR+R] and melphalan, prednisone and
treatment] in CALGB 100104 and 0.3% vs 0% followed by placebo [MPR+p] treated patients
in IFM 2005-02, respectively). Patients should compared with 7.8% in MPp+p-treated patients;
be advised to promptly report febrile episodes, a see section 4.8). Grade 4 febrile neutropenia
treatment interruption and/or dose reductions episodes were observed infrequently (1.7% in
may be required (see section 4.2). MPR+R/MPR+p treated patients compared to
0.0 % in MPp+p treated patients; see section
Grade 3 or 4 thrombocytopenia was observed at 4.8).
a higher frequency in the maintenance arms
compared to the placebo maintenance arms in The combination of with melphalan and
studies evaluating maintenance in NDMM prednisone in multiple myeloma patients is
patients who have undergone ASCT (37.5% vs associated with a higher incidence of grade 3
30.3% [17.9% vs 4.1% after the start of and grade 4 thrombocytopenia (40.4% in
maintenance treatment] in CALGB 100104 and MPR+R/MPR+p treated patients, compared with
13.0% vs 2.9% in IFM 2005-02, respectively). 13.7% in MPp+p-treated patients; see section
Patients and physicians are advised to be 4.8).
observant for signs and symptoms of bleeding,
• Multiple myeloma: patients with at least one
including petechiae and epistaxes, especially in
prior therapy
patients receiving concomitant medicinal
products susceptible to induce bleeding (see The combination of with dexamethasone in
section 4.8, Haemorrhagic disorders). multiple myeloma patients with at least one prior
• Newly diagnosed multiple myeloma: patients therapy is associated with a higher incidence of
grade 4 neutropenia (5.1% in /dexamethasone-
who are not eligible for transplant treated with
in combination with low dose dexamethasone treated patients compared with 0.6% in
placebo/dexamethasone-treated patients; see
Grade 4 neutropenia was observed in the arms section 4.8). Grade 4 febrile neutropenia
in combination with low dose dexamethasone to episodes were observed infrequently (0.6% in
a lesser extent than in the comparator arm (8.5% /dexamethasone-treated patients compared to
in the Rd [continuous treatment] and Rd18 0.0% in placebo/dexamethasone treated patients;
[treatment for 18 four-week cycles] compared see section 4.8).
with 15% in the
melphalan/prednisone/thalidomide arm, see The combination of with dexamethasone in
multiple myeloma patients is associated with a
section 4.8). Grade 4 febrile neutropenia
episodes were consistent with the comparator higher incidence of grade 3 and grade 4
arm (0.6 % in the Rd and Rd18 /dexamethasone- thrombocytopenia (9.9% and 1.4%, respectively,
treated patients compared with 0.7% in the in /dexamethasone-treated patients compared to
melphalan/prednisone/thalidomide arm, see 2.3% and 0.0% in placebo/dexamethasone-
treated patients; see section 4.8).
section 4.8).
• Myelodysplastic syndromes
Grade 3 or 4 thrombocytopenia was observed to
a lesser extent in the Rd and Rd18 arms than in treatment in myelodysplastic syndromes
the comparator arm (8.1% vs 11.1%, patients is associated with a higher incidence of
respectively). grade 3 and 4 neutropenia and thrombocytopenia
• Newly diagnosed multiple myeloma: patients compared to patients on placebo (see section
4.8).
in combination with melphalan and prednisone • Mantle cell lymphoma
treatment in mantle cell lymphoma patients is at increased risk of early death, there were 16/81
associated with a higher incidence of grade 3 (20%) early deaths in the arm and 2/28 (7%)
and 4 neutropenia compared with patients on the early deaths in the control arm. Within 52 weeks
control arm (see section 4.8). corresponding figures were 32/81 (40%) and
6/28 (21%) (See section 5.1).
Thyroid disorders
Adverse events
Cases of hypothyroidism and cases of
hyperthyroidism have been reported. Optimal In study MCL-002, during treatment cycle 1,
control of co-morbid conditions influencing 11/81 (14%) patients with high tumour burden
thyroid function is recommended before start of were withdrawn from therapy in the arm vs.
treatment. Baseline and ongoing monitoring of 1/28 (4%) in the control group. The main reason
thyroid function is recommended. for treatment withdrawal for patients with high
tumour burden during treatment cycle 1 in the
Peripheral neuropathy
arm was adverse events, 7/11 (64%).
is structurally related to thalidomide, which is Patients with high tumour burden should
known to induce severe peripheral neuropathy. therefore be closely monitored for adverse
There was no increase in peripheral neuropathy
reactions (see Section 4.8) including signs of
observed with long term use of for the treatment tumour flare reaction (TFR). Please refer to
of newly diagnosed multiple myeloma.
section 4.2 for dose adjustments for TFR.
Tumour flare reaction and tumour lysis High tumour burden was defined as at least one
syndrome lesion ≥5 cm in diameter or 3 lesions ≥3 cm.
Because has anti-neoplastic activity the Tumour flare reaction
complications of tumour lysis syndrome (TLS)
may occur. TLS and tumour flare reaction (TFR) • Mantle cell lymphoma
have commonly been observed in patients with
chronic lymphocytic leukemia (CLL), and Careful monitoring and evaluation for TFR is
recommended. Patients with high mantle cell
uncommonly in patients with lymphomas, who
were treated with . Fatal instances of TLS have lymphoma International Prognostic Index
been reported during treatment with . The (MIPI) at diagnosis or bulky disease (at least one
lesion that is ≥ 7 cm in the longest diameter) at
patients at risk of TLS and TFR are those with
high tumour burden prior to treatment. Caution baseline may be at risk of TFR. Tumour flare
reaction may mimic progression of disease (PD).
should be practiced when introducing these
patients to . These patients should be monitored Patients in studies MCL-002 and MCL-001 that
closely, especially during the first cycle or dose- experienced Grade 1 and 2 TFR were treated
escalation, and appropriate precautions taken. with corticosteroids, non-steroidal anti-
There have been rare reports of TLS in patients inflammatory drugs (NSAIDs) and/or narcotic
with MM treated with , and no reports in analgesics for management of TFR symptoms.
patients with MDS treated with . The decision to take therapeutic measures for
TFR should be made after careful clinical
Tumour burden assessment of the individual patient (see section
4.2).
• Mantle cell lymphoma
Allergic reactions
is not recommended for the treatment of
patients with high tumour burden if alternative Cases of allergic reaction/hypersensitivity
treatment options are available. reactions have been reported in patients treated
with (see section 4.8). Patients who had
Early death previous allergic reactions while treated with
In study MCL-002 there was overall an apparent thalidomide should be monitored closely, as a
increase in early (within 20 weeks) deaths. possible cross-reaction between and
Patients with high tumour burden at baseline are thalidomide has been reported in the literature.
Severe skin reactions In patients receiving in combination with

dexamethasone until progression or for 18
Severe cutaneous reactions including SJS, and months, the hematologic SPM incidence rate
TEN and DRESS have been reported with the (0.16 per 100 person-years) was not increased as
use of . Patients should be advised of the signs compared to thalidomide in combination with
and symptoms of these reactions by their melphalan and prednisone (0.79 per 100 person-
prescribers and should be told to seek medical years).
attention immediately if they develop these
symptoms. must be discontinued for exfoliative A 1.3-fold increase in incidence rate of solid
or bullous rash, or if SJS, TEN or DRESS is tumour SPM has been observed in patients
suspected, and should not be resumed following receiving in combination with dexamethasone
discontinuation for these reactions. Interruption until progression or for 18 months (1.58 per 100
or discontinuation of should be considered for person-years) compared to thalidomide in
other forms of skin reaction depending on combination with melphalan and prednisone
severity. Patients with a history of severe rash (1.19 per 100 person-years).
associated with thalidomide treatment should not
receive . The increased risk of secondary primary
malignancies associated with is relevant also in
Lactose intolerance the context of NDMM after stem cell
transplantation. Though this risk is not yet fully
Lenalidomide capsules contain lactose. Patients characterized, it should be kept in mind when
with rare hereditary problems of galactose considering and using Lenalidomide in this
intolerance, the Lapp lactase deficiency or setting.
glucose-galactose malabsorption should not take
this medicinal product. The incidence rate of hematologic malignancies,
most notably AML, MDS and B-cell
Second primary malignancies
malignancies (including Hodgkin's lymphoma),
An increase of second primary malignancies was 1.31 per 100 person-years for the arms and
(SPM) has been observed in clinical trials in 0.58 per 100 person-years for the placebo arms
previously treated myeloma patients receiving (1.02 per 100 person-years for patients exposed
/dexamethasone (3.98 per 100 person-years) to after ASCT and 0.60 per 100 person-years
compared to controls (1.38 per 100 person- for patients not-exposed to after ASCT). The
years). Non-invasive SPM comprise basal cell or incidence rate of solid tumour SPMs was 1.36
squamous cell skin cancers. Most of the invasive per 100 person-years for the arms and 1.05 per
SPMs were solid tumour malignancies. 100 person-years for the placebo arms (1.26 per
100 person-years for patients exposed to after
In clinical trials of newly diagnosed multiple ASCT and 0.60 per 100 person-years for
myeloma patients not eligible for transplant, a patients not-exposed to after ASCT).
4.9-fold increase in incidence rate of
hematologic SPM (cases of AML, MDS) has The risk of occurrence of hematologic SPM
been observed in patients receiving in must be taken into account before initiating
combination with melphalan and prednisone treatment with either in combination with
until progression (1.75 per 100 person-years) melphalan or immediately following high-dose
compared with melphalan in combination with melphalan and ASCT. Physicians should
prednisone (0.36 per 100 person-years). carefully evaluate patients before and during
treatment using standard cancer screening for
A 2.12-fold increase in incidence rate of solid occurrence of SPM and institute treatment as
tumour SPM has been observed in patients indicated.
receiving (9 cycles) in combination with
melphalan and prednisone (1.57 per 100 person- Progression to acute myeloid leukaemia in low-
years) compared with melphalan in combination and intermediate-1-risk MDS
with prednisone (0.74 per 100 person-years). • Karyotype
Baseline variables including complex Abnormal liver function tests were commonly
cytogenetics are associated with progression to reported and were generally asymptomatic and
AML in subjects who are transfusion dependent reversible upon dosing interruption. Once
and have a Del (5q) abnormality. In a combined parameters have returned to baseline, treatment
analysis of two clinical trials of in low- or at a lower dose may be considered.
intermediate-1-risk myelodysplastic syndromes,
subjects who had a complex cytogenetics had is excreted by the kidneys. It is important to
dose adjust patients with renal impairment in
the highest estimated 2-year cumulative risk of
order to avoid plasma levels which may increase
progression to AML (38.6%). The estimated 2-
year rate of progression to AML in patients with the risk for higher haematological adverse
an isolated Del (5q) abnormality was 13.8%, reactions or hepatotoxicity. Monitoring of liver
compared to 17.3% for patients with Del (5q) function is recommended, particularly when
and one additional cytogenetic abnormality. there is a history of or concurrent viral liver
infection or when is combined with medicinal
As a consequence, the benefit/risk ratio of when products known to be associated with liver
MDS is associated with Del (5q) and complex dysfunction.
cytogenetics is unknown.
Infection with or without neutropenia
• TP53 status
Patients with multiple myeloma are prone to
A TP53 mutation is present in 20 to 25% of develop infections including pneumonia. A
lower-risk MDS Del 5q patients and is higher rate of infections was observed with in
associated with a higher risk of progression to combination with dexamethasone than with
acute myeloid leukaemia (AML). In a post-hoc MPT in patients with NDMM who are not
analysis of a clinical trial of in low- or eligible for transplant, and with maintenance
intermediate-1-risk myelodysplastic syndromes compared to placebo in patients with NDMM
(MDS-004), the estimated 2-year rate of who had undergone ASCT. Grade ≥ 3 infections
progression to AML was 27.5 % in patients with occurred within the context of neutropenia in
IHC-p53 positivity (1% cut-off level of strong less than one-third of the patients. Patients with
nuclear staining, using immunohistochemical known risk factors for infections should be
assessment of p53 protein as a surrogate for closely monitored. All patients should be
TP53 mutation status) and 3.6% in patients with advised to seek medical attention promptly at the
IHC-p53 negativity (p=0.0038) (see section 4.8) first sign of infection (eg, cough, fever, etc)
thereby allowing for early management to
Progression to other malignancies in mantle cell reduce severity.
lymphoma
Cases of viral reactivation have been reported in
In mantle cell lymphoma, AML, B-cell
patients receiving , including serious cases of
malignancies and non-melanoma skin cancer herpes zoster or hepatitis B virus (HBV)
(NMSC) are potential risks. reactivation.
Hepatic disorders
Some of the cases of viral reactivation had a
Hepatic failure, including fatal cases, has been fatal outcome.
reported in patients treated with in combination Some of the cases of herpes zoster reactivation
therapy: acute hepatic failure, toxic hepatitis, resulted in disseminated herpes zoster,
cytolytic hepatitis, cholestatic hepatitis, and
meningitis herpes zoster or ophthalmic herpes
mixed cytolytic/cholestatic hepatitis have been zoster requiring a temporary hold or permanent
reported. The mechanisms of severe drug- discontinuation of the treatment with and
induced hepatotoxicity remain unknown adequate antiviral treatment.
although, in some cases, pre-existing viral liver
disease, elevated baseline liver enzymes, and Reactivation of hepatitis B has been reported
possibly treatment with antibiotics might be risk rarely in patients receiving who have previously
factors. been infected with the hepatitis B virus (HBV).
Some of these cases have progressed to acute reduced efficacy of medicinal products,
hepatic failure resulting in discontinuation of including hormonal contraceptives, is not
and adequate antiviral treatment. Hepatitis B expected if is administered alone. However,
virus status should be established before dexamethasone is known to be a weak to
initiating treatment with . For patients who test moderate inducer of CYP3A4 and is likely to
positive for HBV infection, consultation with a also affect other enzymes as well as transporters.
physician with expertise in the treatment of It may not be excluded that the efficacy of oral
hepatitis B is recommended. Caution should be contraceptives may be reduced during treatment.
exercised when is used in patients previously Effective measures to avoid pregnancy must be
infected with HBV, including patients who are taken (see sections 4.4 and 4.6).
anti-HBc positive but HBsAg negative. These
patients should be closely monitored for signs Warfarin
and symptoms of active HBV infection Co-administration of multiple 10 mg doses of
throughout therapy. had no effect on the single dose
• Newly diagnosed multiple myeloma patients pharmacokinetics of R- and S- warfarin. Co-
administration of a single 25 mg dose of
There was a higher rate of intolerance (grade 3 warfarin had no effect on the pharmacokinetics
or 4 adverse events, serious adverse events, of . However, it is not known whether there is an
discontinuation) in patients with age > 75 years, interaction during clinical use (concomitant
ISS stage III, ECOG PS≤2 or CLcr<60 mL/min treatment with dexamethasone). Dexamethasone
when is given in combination. Patients should is a weak to moderate enzyme inducer and its
be carefully assessed for their ability to tolerate effect on warfarin is unknown. Close monitoring
in combination, with consideration to age, ISS of warfarin concentration is advised during the
stage III, ECOG PS≤2 or CLcr<60 mL/min (see treatment.
sections 4.2 and 4.8).
Digoxin
Cataract
Concomitant administration with 10 mg once
Cataract has been reported with a higher daily increased the plasma exposure of digoxin
frequency in patients receiving in combination (0.5 mg, single dose) by 14% with a 90% CI
with dexamethasone particularly when used for (confidence interval) [0.52%-28.2%]. It is not
a prolonged time. Regular monitoring of visual known whether the effect will be different in the
ability is recommended. clinical use (higher doses and concomitant
treatment with dexamethasone). Therefore,
monitoring of the digoxin concentration is
4.5 Interaction with other medicinal advised during treatment.
products and other forms of interaction Statins
Erythropoietic agents, or other agents that may There is an increased risk of rhabdomyolysis
increase the risk of thrombosis, such as hormone when statins are administered with , which may
replacement therapy, should be used with be simply additive. Enhanced clinical and
caution in multiple myeloma patients receiving laboratory monitoring is warranted notably
with dexamethasone (see sections 4.4 and 4.8). during the first weeks of treatment.
Oral contraceptives Dexamethasone
No interaction study has been performed with Co-administration of single or multiple doses of
oral contraceptives. is not an enzyme inducer. dexamethasone (40 mg once daily) has no
In an in vitro study with human hepatocytes, , at clinically relevant effect on the multiple dose
various concentrations tested did not induce pharmacokinetics of (25 mg once daily).
CYP1A2, CYP2B6, CYP2C9, CYP2C19 and
CYP3A4/5. Therefore, induction leading to Interactions with P-glycoprotein (P-gp)
inhibitors
In vitro, is a substrate of P-gp, but is not a P-gp 5.3). Therefore, a teratogenic effect of is
inhibitor. Co-administration of multiple doses of expected and is contraindicated during
the strong P-gp inhibitor quinidine (600 mg, pregnancy (see section 4.3).
twice daily) or the moderate P-gp
Breast-feeding
inhibitor/substrate temsirolimus (25 mg) has no
clinically relevant effect on the It is not known whether is excreted in human
pharmacokinetics of (25 mg). Co-administration milk. Therefore breast-feeding should be
of does not alter the pharmacokinetics of discontinued during therapy with .
temsirolimus.
Fertility
4.6 Fertility, pregnancy and lactation
A fertility study in rats with doses up to 500
Due to the teratogenic potential, must be mg/kg (approximately 200 to 500 times the
prescribed under a Pregnancy Prevention human doses of 25 mg and 10 mg, respectively,
Programme (see section 4.4) unless there is based on body surface area) produced no
reliable evidence that the patient does not have adverse effects on fertility and no parental
childbearing potential. toxicity.
Women of childbearing potential / 4.7 Effects on ability to drive and use
Contraception in males and females machines
Women of childbearing potential should use
effective method of contraception. If pregnancy has minor or moderate influence on the ability
occurs in a woman treated with , treatment must to drive and use machines. Fatigue, dizziness,
be stopped and the patient should be referred to somnolence, vertigo and blurred vision have
a physician specialised or experienced in been reported with the use of . Therefore,
teratology for evaluation and advice. If caution is recommended when driving or
pregnancy occurs in a partner of a male patient operating machines.
taking , it is recommended to refer the female 4.8 Undesirable Effects
partner to a physician specialised or experienced
in teratology for evaluation and advice.
Summary of the safety profile
is present in human semen at extremely low
Newly diagnosed multiple myeloma: patients
levels during treatment and is undetectable in
who have undergone ASCT treated with
human semen 3 days after stopping the
maintenance
substance in the healthy subject (see section
5.2). As a precaution, and taking into account A conservative approach was applied to
special populations with prolonged elimination determine the adverse reactions from CALGB
time such as renal impairment, all male patients 100104. The adverse reactions described in
taking should use condoms throughout Table 1 included events reported post-
treatment duration, during dose interruption and HDM/ASCT as well as events from the
for 1 week after cessation of treatment if their maintenance treatment period. A second analysis
partner is pregnant or of childbearing potential that identified events that occurred after the start
and has no contraception. of maintenance treatment suggests that the
frequencies described in Table 1 may be higher
Pregnancy
than actually observed during the maintenance
is structurally related to thalidomide. treatment period. In IFM 2005-02, the adverse
Thalidomide is a known human teratogenic reactions were from the maintenance treatment
active substance that causes severe life- period only.
threatening birth defects.
The serious adverse reactions observed more
induced in monkeys malformations similar to frequently (≥5%) with maintenance than
those described with thalidomide (see section placebo were:
• Pneumonias (10.6%; combined term) from melphalan, prednisone and followed by placebo
IFM 2005-02 (MPR+p) than melphalan, prednisone and
placebo followed by placebo (MPp+p) were:
• Lung infection (9.4% [9.4% after the start of
maintenance treatment]) from CALGB 100104 • Febrile neutropenia (6.0%)
In the IFM 2005-02 study, the adverse reactions • Anemia (5.3%)
observed more frequently with maintenance
than placebo were neutropenia (60.8%), The adverse reactions observed more frequently
bronchitis (47.4%), diarrhoea (38.9%), with MPR+R or MPR+p than MPp+p were:
nasopharyngitis (34.8%), muscle spasms neutropenia (83.3%), anemia (70.7%),
thrombocytopenia (70.0%), leukopenia (38.8%),
(33.4%), leucopenia (31.7%), asthenia (29.7%),
constipation (34.0%), diarrhoea (33.3%), rash
cough (27.3%), thrombocytopenia (23.5%),
gastroenteritis (22.5%) and pyrexia (20.5%). (28.9%), pyrexia (27.0%), peripheral oedema
(25.0%), cough (24.0%), decreased appetite
In the CALGB 100104 study, the adverse (23.7%), and asthenia (22.0%).
reactions observed more frequently with
maintenance than placebo were neutropenia Multiple myeloma: patients with at least one
prior therapy
(79.0% [71.9% after the start of maintenance
treatment]), thrombocytopenia (72.3% [61.6%]), In two phase III placebo-controlled studies, 353
diarrhoea (54.5% [46.4%]), rash (31.7% patients with multiple myeloma were exposed to
[25.0%]), upper respiratory tract infection the /dexamethasone combination and 351 to the
(26.8% [26.8%]), fatigue (22.8% [17.9%]), placebo/dexamethasone combination.
leucopenia (22.8% [18.8%]) and anemia (21.0%
[13.8%]). The most serious adverse reactions observed
more frequently in /dexamethasone than
Newly diagnosed multiple myeloma: patients placebo/dexamethasone combination were:
in combination with low dose dexamethasone • Venous thromboembolism (deep vein
thrombosis, pulmonary embolism) (see section
The serious adverse reactions observed more 4.4)
frequently (≥5%) with in combination with low
dose dexamethasone (Rd and Rd18) than with • Grade 4 neutropenia (see section 4.4).
melphalan, prednisone and thalidomide (MPT) The observed adverse reactions which occurred
were: more frequently with and dexamethasone than
• Pneumonia (9.8%) placebo and dexamethasone in pooled multiple
myeloma clinical trials (MM-009 and MM-010)
• Renal failure (including acute) (6.3%) were fatigue (43.9%), neutropenia (42.2%),
The adverse reactions observed more frequently constipation (40.5%), diarrhoea (38.5%), muscle
with Rd or Rd18 than MPT were: diarrhoea cramp (33.4%), anemia (31.4%),
thrombocytopenia (21.5%), and rash (21.2%).
(45.5%), fatigue (32.8%), back pain (32.0%),
asthenia (28.2%), insomnia (27.6%), rash Myelodysplastic syndromes
(24.3%), decreased appetite (23.1%), cough
(22.7%), pyrexia (21.4%), and muscle spasms The overall safety profile of in patients with
(20.5%). myelodysplastic syndromes is based on data
from a total of 286 patients from one phase II
Newly diagnosed multiple myeloma: patients study and one phase III study (see section 5.1).
who are not eligible for transplant treated with In the phase II, all 148 patients were on
in combination withmelphalan and prednisone treatment. In the phase III study, 69 patients
were on 5 mg, 69 patients on 10 mg and 67
The serious adverse reactions observed more
frequently (≥5%) with melphalan, prednisone patients were on placebo during the double-blind
phase of the study.
and followed by maintenance (MPR+R) or
Most adverse reactions tended to occur during early deaths in the arm and 2/28 (7%) early
the first 16 weeks of therapy with . deaths in the control arm. Within 52 weeks
corresponding figures were 32/81 (39.5%) and
Serious adverse reactions include: 6/28 (21%) (see section 5.1).
• Venous thromboembolism (deep vein During treatment cycle 1, 11/81 (14%) patients
thrombosis, pulmonary embolism) (see section with high tumour burden were withdrawn from
4.4)
therapy in the arm vs. 1/28 (4%) in the control
• Grade 3 or 4 neutropenia, febrile neutropenia group. The main reason for treatment
and grade 3 or 4 thrombocytopenia (see section
4.4). System Organ All Grade 3-4 ADRs/Frequency
Class/Preferred Term ADRs/Frequency
The most commonly observed adverse reactions Very Common Very Common
◊,a ◊,a
Pneumonias , Pneumonias , Neutropenic
which occurred more frequently in the groups Upper respiratory infection
tract infection, Common
compared to the control arm in the phase III Neutropenic
◊,b
Sepsis , Bacteraemia, Lung
study were neutropenia (76.8%), infection, Bronchitis◊, infection◊, Lower respiratory
Influenza◊, tract infection bacterial,
thrombocytopenia (46.4%), diarrhoea (34.8%), Gastroenteritis◊, Bronchitis◊, Influenza◊,
Infections and
constipation (19.6%), nausea (19.6%), pruritus Sinusitis, Gastroenteritis◊, Herpes
Infestations
Nasopharyngitis, zoster◊, Infection◊
(25.4%), rash (18.1%), fatigue (18.1%) and Rhinitis
muscle spasms (16.7%). Common
Infection◊, Urinary
tract infection◊,*,
Mantle cell lymphoma Lower respiratory
tract infection, Lung
The overall safety profile of in patients with infection◊
mantle cell lymphoma is based on data from 254 Neoplasms Benign, Common
Malignant and Myelodysplastic
patients from a phase II randomised, controlled Unspecified (incl syndrome◊,*
cysts and polyps)
study MCL-002 (see section 5.1).
Very Common Very Common
Neutropenia^,◊, Neutropenia^,◊, Febrile
Additionally, adverse drug reactions from Febrile neutropenia^,◊,
,◊ ,◊
supportive study MCL-001 have been included Blood and Lymphatic neutropenia^ , Thrombocytopenia^ ,
System Disorders Thrombocytopenia^,◊, Anemia, Leucopenia◊,
in table 3. Anemia, Lymphopenia
Leucopenia◊, Common
The serious adverse reactions observed more Lymphopenia Pancytopenia◊
frequently in study MCL-002 (with a difference Metabolism and Very Common Common
Nutrition Disorders Hypokalaemia Hypokalaemia, Dehydration
of at least 2 percentage points) in the arm
Very Common Common
compared with the control arm were: Paraesthesia Headache
Nervous System
Common
• Neutropenia (3.6%) Disorders
Peripheral
neuropathyc
• Pulmonary embolism (3.6%) Common Common
Vascular Disorders Pulmonary Deep vein thrombosis^,◊,d
embolism◊,*
• Diarrhoea (3.6%)
Very Common Common
Respiratory, Thoracic Cough Dyspnoea◊
The most frequently observed adverse reactions and Mediastinal Common
which occurred more frequently in the arm Disorders Dyspnoea◊,
Rhinorrhoea
compared with the control arm in study MCL-
Very Common Common
002 were neutropenia (50.9%), anemia (28.7%), Diarrhoea, Diarrhoea, Vomiting, Nausea
diarrhoea (22.8%), fatigue (21.0%), constipation Constipation,
Gastrointestinal Abdominal pain,
(17.4%), pyrexia (16.8%), and rash (including Disorders Nausea
Common
dermatitis allergic) (16.2%). Vomiting, Abdominal
pain upper
In study MCL-002 there was overall an apparent Very Common Common
Hepatobiliary
increase in early (within 20 weeks) deaths. Disorders
Abnormal liver Abnormal liver function tests
function tests
Patients with high tumour burden at baseline are
Skin and Very Common Common
at increased risk of early death, 16/81 (20%) Subcutaneous Tissue Rash, Dry skin Rash, Pruritus
Disorders
Very Common
Musculoskeletal and Muscle spasms
Connective Tissue Common
Disorders Myalgia,
Musculoskeletal pain
General Disorders and Very Common Common
Administration Site Fatigue, Asthenia, Fatigue, Asthenia
Conditions Pyrexia
withdrawal for patients with high tumour burden legionella, Pneumonia mycoplasmal, Pneumonia
during treatment cycle 1 in the arm was adverse pneumococcal, Pneumonia streptococcal,
events, 7/11 (64%). Pneumonia viral, Lung disorder, Pneumonitis
High tumour burden was defined as at least one b
“Sepsis” combined AE term includes the
lesion ≥5 cm in diameter or 3 lesions ≥3 cm. following PTs: Bacterial sepsis, Pneumococcal
sepsis, Septic shock, Staphylococcal sepsis
Tabulated list of adverse reactions
c
“Peripheral neuropathy” combined AE term
The adverse reactions observed in patients includes the following preferred terms (PTs):
treated with are listed below by system organ Neuropathy peripheral, Peripheral sensory
class and frequency. Within each frequency neuropathy, Polyneuropathy
grouping, adverse reactions are presented in
order of decreasing seriousness. Frequencies are d
“Deep vein thrombosis” combined AE term
defined as: very common (≥ 1/10); common (≥ includes the following PTs: Deep vein
1/100 to < 1/10); uncommon (≥ 1/1,000 to < thrombosis, Thrombosis, Venous thrombosis
1/100); rare (≥ 1/10,000 to < 1/1,000); very rare
(< 1/10,000), not known (cannot be estimated Tabulated summary for combination therapy in
from the available data). MM
The following table is derived from data
Adverse reactions have been included under the
appropriate category in the table below gathered during the multiple myeloma studies
according to the highest frequency observed in with combination therapy. The data were not
any of the main clinical trials. adjusted according to the longer duration of
treatment in the -containing arms continued until
Tabulated summary for monotherapy in MM disease progression versus the comparator arms
in the pivotal multiple myeloma studies (see
The following table is derived from data section 5.1).
gathered during NDMM studies in patients who
have undergone ASCT treated with Table 2. ADRs reported in clinical studies in
maintenance. The data were not adjusted patients with multiple myeloma treated with
according to the longer duration of treatment in in combination with dexamethasone, or with
the -containing arms continued until disease melphalan and prednisone
progression versus the placebo arms in the
pivotal multiple myeloma studies (see section
5.1).
Table 1. ADRs reported in clinical trials in
System Organ All ADRs/Frequency Grade 3−4
patients with multiple myeloma treated with Class / ADRs/Frequency
maintenance therapy Preferred Term
Infections and Very Common Common
Infestations Pneumonia◊, Upper Pneumonia◊, Bacterial,
respiratory tract infection◊, viral and fungal
◊ Bacterial, viral and fungal infections (including
Adverse reactions reported as serious in clinical infections (including opportunistic
trials in patients with NDMM who had opportunistic infections)◊, infections)◊, Cellulitis◊,
Nasopharyngitis, Pharyngitis, Sepsis◊, Bronchitis◊
undergone ASCT Bronchitis◊
Common
* Applies to serious adverse drug reactions only Sepsis◊, Sinusitis◊
Neoplasms Uncommon Common
^ See section 4.8 description of selected adverse Benign, Basal cell carcinoma^,◊, Acute myeloid
Malignant and Squamous skin cancer^,◊,* leukaemia◊,
reactions Unspecified Myelodysplastic
(incl cysts and syndrome◊, Squamous
a
“Pneumonias” combined AE term includes the polyps) cell carcinoma of
skin^,◊,**
following PTs: Bronchopneumonia, Lobar Uncommon
pneumonia, Pneumocystis jiroveci pneumonia, T-cell type acute
leukaemia◊, Basal cell
Pneumonia, Pneumonia klebsiella, Pneumonia carcinoma^,◊, Tumour
◊ ◊ ◊
lysis syndrome Disorders Diarrhoea , Constipation , Diarrhoea ,
Abdominal pain◊, Nausea, Constipation◊,
Blood and Very Common Very Common ◊
,◊ ,◊ Vomiting, Dyspepsia Abdominal pain ,
Lymphatic Neutropenia^ , Neutropenia^ ,
Common Nausea, Vomiting
System Thrombocytopenia^,◊, Thrombocytopenia^,◊,
◊ ◊ Gastrointestinal haemorrhage
Disorders Anemia , Haemorrhagic Anemia , Leucopenias
(including rectal
disorder^, Leucopenias Common
,◊ haemorrhage, haemorrhoidal
Common Febrile neutropenia^ ,
,◊ ◊ haemorrhage, peptic ulcer
Febrile neutropenia^ , Pancytopenia ,
◊ haemorrhage and gingival
Pancytopenia Haemolytic anemia
bleeding)^, Dry mouth,
Uncommon Uncommon
Stomatitis, Dysphagia
Haemolysis, Autoimmune Hypercoagulation,
Uncommon
haemolytic anemia, Coagulopathy
Colitis, Caecitis
Haemolytic anemia
Hepatobiliary Common Common
Immune System Uncommon ◊ ◊
Disorders Abnormal liver function tests Cholestasis , Abnormal
Disorders Hypersensitivity^
Uncommon liver function tests◊
Endocrine Common Hepatic failure^ Uncommon
Disorders Hypothyroidism Hepatic failure^
Metabolism and Very Common Common Skin and Very Common Common
Nutrition Hypokalaemia◊, Hypokalaemia◊, Subcutaneous Rashes, Pruritus Rashes
Disorders Hyperglycaemia, Hyperglycaemia, Tissue Common
Hypocalcaemia◊, Decreased Hypocalcaemia◊, Disorders Urticaria, Hyperhidrosis, Dry
appetite, Weight decreased Diabetes mellitus◊, skin, Skin hyperpigmentation,
Common Hypophosphataemia, Eczema, Erythema
Hypomagnesaemia, Hyponatraemia◊, Uncommon
Hyperuricaemia, Hyperuricaemia, Gout, Skin discolouration,
Dehydration◊, Decreased appetite, Photosensitivity reaction
Hypercalcaemia+ Weight decreased
Musculoskeletal Very Common Common
Psychiatric Very Common Common and Connective Muscle spasms, Bone pain◊, Muscular weakness,
Disorders Depression, Insomnia Depression, Insomnia Tissue Musculoskeletal and Bone pain◊,
Uncommon Disorders connective tissue pain and Musculoskeletal and
Loss of libido discomfort (including back connective tissue pain
Nervous Very Common Common pain◊), Arthralgia◊ and discomfort
System Peripheral neuropathies Cerebrovascular Common (including back pain◊)
Disorders (excluding motor neuropathy), accident◊, Dizziness, Muscular weakness, Joint Uncommon
Dizziness, Tremor, Syncope swelling, Myalgia Joint swelling
Dysgeusia, Headache Uncommon Renal and Very Common Uncommon
Common Intracranial Urinary Renal failure (including Renal tubular necrosis
Ataxia, Balance impaired haemorrhage^, Disorders acute)◊
Transient ischaemic Common
attack, Cerebral Haematuria^, Urinary
ischemia retention, Urinary
Eye Disorders Very Common Common incontinence
Cataracts, Blurred vision Cataract Uncommon
Common Uncommon Acquired Fanconi syndrome
Reduced visual acuity Blindness Reproductive Common
Ear and Common System and Erectile dysfunction
Labyrinth Deafness (Including Breast
Disorders Hypoacusis), Tinnitus Disorders
Cardiac Common Common General Very Common Common

Disorders Atrial fibrillation◊, Bradycardia Myocardial infarction Disorders and Fatigue◊, Oedema (including Fatigue◊, Pyrexia◊,
◊
Uncommon (including acute)^,◊, Administration peripheral oedema), Pyrexia , Asthenia
Arrhythmia, QT prolongation, Atrial fibrillation◊, Site Conditions Asthenia, Influenza like illness
Atrial flutter, Ventricular Congestive cardiac syndrome (including pyrexia,
extrasystoles failure◊, Tachycardia, cough, myalgia,
Cardiac failure◊, musculoskeletal pain,
Myocardial ischemia◊ headache and rigors)
Common
Vascular Very Common Very Common Chest pain, Lethargy
Disorders Venous thromboembolic Venous thromboembolic
events, predominantly deep events, predominantly Investigations Common
vein thrombosis and deep vein thrombosis C-reactive protein increased
pulmonary embolism^,◊ and pulmonary Injury, Common
Common embolism^,◊ Poisoning and Fall, Contusion^
Hypotension◊, Hypertension, Common Procedural
Ecchymosis^ Vasculitis Complications
Uncommon
Ischemia, Peripheral ^See section 4.8 description of selected adverse
ischemia, Intracranial reactions
venous sinus
thrombosis ◊
Respiratory, Very Common Common
Adverse reactions reported as serious in clinical
Thoracic and Dyspnoea◊, Epistaxis^ Respiratory distress◊, trials in patients with multiple myeloma treated
Mediastinal Dyspnoea◊
Disorders
with in combination with dexamethasone, or
Gastrointestinal Very Common Common with melphalan and prednisone
+ Applies to serious adverse drug reactions only Gastrointestinal Very Common Common
Disorders Diarrhoea◊, Abdominal Diarrhoea◊, Nausea,
pain (including upper), Toothache
* Squamous skin cancer was reported in clinical Nausea, Vomiting,
trials in previously treated myeloma patients Constipation
Common
with /dexamethasone compared to controls Dry mouth, Dyspepsia
Hepatobiliary Common Common
** Squamous cell carcinoma of skin was Disorders Abnormal liver function Abnormal liver function
reported in a clinical trial in newly diagnosed tests tests
myeloma patients with /dexamethasone Subcutaneous Rashes, Dry Skin, Rashes, Pruritus
compared to controls Tissue Disorders Pruritus
Tabulated summary from monotherapy and Connective Muscle spasms, Back pain
◊
Tissue Disorders Musculoskeletal pain

(including back pain◊ and
The following tables are derived from data pain in extremity),
gathered during the main studies in monotherapy Arthralgia, Myalgia
for myelodysplastic syndromes and mantle cell Renal and Urinary Common
Disorders Renal failure◊
lymphoma.
General Disorders Very Common Common
and Fatigue, Peripheral Pyrexia
Table 3. ADRs reported in clinical trials in Administration oedema, Influenza like
patients with myelodysplastic syndromes Site Conditions illness syndrome
(including pyrexia, cough,
treated with # pharyngitis, myalgia,
musculoskeletal pain,
System Organ All ADRs/Frequency Grade 3−4 headache)
Class / Preferred ADRs/Frequency Injury, Poisoning Common
Term
and Procedural Fall
Infections and Very Common Very Common Complications
Infestations Bacterial, viral and fungal Pneumonia◊
infections (including Common ^see section 4.8 description of selected adverse
opportunistic infections)◊ Bacterial, viral and reactions
fungal infections
(including opportunistic ◊
infections)◊, Bronchitis Adverse events reported as serious in
Blood and Very Common Very Common myelodysplastic syndromes clinical trials
Lymphatic System Thrombocytopenia^,◊, Thrombocytopenia^ ,
,◊
Disorders Neutropenia^,◊, Neutropenia^,◊, ~Altered mood was reported as a common

Leucopenias Leucopenias
Common serious adverse event in the myelodysplastic
Febrile neutropenia^,◊ syndromes phase III study; it was not reported as
Endocrine Very Common
Disorders Hypothyroidism
a grade 3 or 4 adverse event
Metabolism and Very Common Common Algorithm applied for inclusion in the SmPC:
Nutrition Decreased appetite Hyperglycaemia◊,
Disorders Common Decreased appetite All ADRs captured by the phase III study
Iron overload, Weight
decreased
algorithm are included in the EU SmPC. For
Psychiatric Common these ADRs, an additional check of the
Disorders Altered mood◊,~ frequency of the ADRs captured by the phase II
Nervous System Very Common study algorithm was undertaken and, if the
Disorders Dizziness, Headache
Common frequency of the ADRs in the phase II study was
Paraesthesia higher than in the phase III study, the event was
Cardiac Disorders Common included in the EU SmPC at the frequency it
Acute myocardial
infarction^,◊, Atrial occurred in the phase II study.
fibrillation◊, Cardiac
failure◊ # Algorithm applied for myelodysplastic
Vascular Common Common syndromes:
Disorders Hypertension, Venous thromboembolic
Haematoma events, predominantly
deep vein thrombosis • Myelodysplastic syndromes phase III study
and pulmonary (double-blind safety population, difference
embolism^,◊
Respiratory, Very Common
between 5/10mg and placebo by initial dosing
Thoracic and Epistaxis^ regimen occurring in at least 2 subjects)
Mediastinal
Disorders
o All treatment-emergent adverse events with ≥ Disorders
5% of subjects in and at least 2% difference in

proportion between and placebo Cardiac Common
Disorders Myocardial infarction
,◊
(including acute)^ ,
o All treatment-emergent grade 3 or 4 adverse Cardiac failure
events in 1% of subjects in and at least 1% Vascular Common Common
Disorders Hypotension◊ Deep vein thrombosis◊,
difference in proportion between and placebo ,◊
pulmonary embolism^ ,
◊
Hypotension
o All treatment-emergent serious adverse events Respiratory, Very Common Common
in 1% of subjects in and at least 1% difference Thoracic and Dyspnoea◊ Dyspnoea◊
Mediastinal
in proportion between and placebo Disorders
Gastrointestinal Very Common Common
• Myelodysplastic syndromes phase II study Disorders ◊ ◊
Diarrhoea , Nausea ,
◊
Diarrhoea , Abdominal
◊ ◊
Vomiting , Constipation pain , Constipation
o All treatment-emergent adverse events with ≥ Common
◊
Abdominal pain
5% of treated subjects
Subcutaneous Rashes (including Rashes
o All treatment-emergent grade 3 or 4 Tissue dermatitis allergic),
adverse\events in 1% of treated subjects Disorders Pruritus
Common
Night sweats, Dry skin
o All treatment-emergent serious adverse events
in 1% of treated subjects and Connective Muscle spasms, Back Back pain, Muscular
Tissue pain weakness◊, Arthralgia,
Disorders Common Pain in extremity
Arthralgia, Pain in
extremity, Muscular
Table 4. ADRs reported in clinical trials in weakness◊
patients with mantle cell lymphoma treated Renal and Common
with Urinary Renal failure◊
Disorders
System Organ All ADRs/Frequency Grade 3−4 General Very Common Common
Class / ADRs/Frequency Disorders and Fatigue, Asthenia◊, Pyrexia◊, Asthenia◊,
Preferred Term Administration Peripheral oedema, Fatigue
Site Conditions Influenza like illness
Infections and Very Common Common syndrome (including
Infestations Bacterial, viral and fungal Bacterial, viral and fungal pyrexia◊, cough)
infections (including infections (including Common
opportunistic infections)◊, opportunistic infections)◊, Chills
Nasopharyngitis, Pneumonia◊
Pneumonia◊ ^see section 4.8 description of selected adverse
Common
Sinusitis reactions
Neoplasms Common Common ◊
Benign, Tumour flare reaction Tumour flare reaction, Adverse events reported as serious in mantle
Malignant and Squamous skin cell lymphoma clinical trialsAlgorithm applied
Unspecified cancer^,◊,Basal cell
(incl cysts and carcinoma^,◊ for mantle cell lymphoma:
polyps)
Blood and Very Common Very Common • Mantle cell lymphoma controlled phase II
Lymphatic Thrombocytopenia^, Thrombocytopenia^, study
System Neutropenia^,◊, Neutropenia^,◊, Anemia◊
Disorders Leucopenias◊, Anemia◊ Common
Common Febrile neutropenia^,◊, o All treatment-emergent adverse events with ≥
Febrile neutropenia^,◊ Leucopenias◊ 5% of subjects in arm and at least 2% difference
Metabolism and Very Common Common
Nutrition Decreased appetite, Dehydration◊,
in proportion between and control arm
Disorders Weight decreased, Hyponatraemia,
Hypokalaemia Hypocalcaemia o All treatment-emergent grade 3 or 4 adverse
Common
Dehydration◊,,
events in ≥1% of subjects in arm and at least
Psychiatric Common 1.0% difference in proportion between and
Disorders Insomnia control arm
Nervous Common Common
System Dysgeuesia, Headache, Peripheral sensory o All Serious treatment-emergent adverse events
Disorders neuropathy peripheral neuropathy, Lethargy in ≥1% of subjects in arm and at least 1.0%
Ear and Common difference in proportion between and control
Labyrinth Vertigo
arm
• Mantle cell lymphoma single arm phase II Hepatobiliary Not Known Not Known
Disorders Acute hepatic failure^, Acute hepatic
study Hepatitis toxic^, Cytolytic failure^, Hepatitis
hepatitis^, Cholestatic toxic^
o All treatment-emergent adverse events with ≥ hepatitis^, Mixed
cytolytic/cholestatic hepatitis^
5% of subjects
Skin and Uncommon
Subcutaneous Angioedema
o All grade 3 or 4 treatment-emergent adverse Tissue Disorders Rare
events reported in 2 or more subjects Stevens-Johnson
Syndrome^, Toxic
epidermal
o All Serious treatment-emergent adverse events necrolysis^
reported in 2 or more subjects Not Known
Leukocytoclastic
vasculitis, Drug
Tabulated summary of post-marketing adverse Reaction with
reactions Eosinophilia and
Systemic
Symptoms^
In addition to the above adverse reactions
identified from the pivotal clinical trials, the ^see section 4.8 description of selected adverse
following table is derived from data gathered reactions
from post-marketing data.
Description of selected adverse reactions
Teratogenicity
is structurally related to thalidomide.
Table 5. ADRs reported in post-marketing Thalidomide is a known human teratogenic
use in patients treated with active substance that causes severe life-
System Organ All ADRs/Frequency Grade 3−4
threatening birth defects. induced in monkeys
Class / Preferred ADRs/Frequency malformations similar to those described with
Term
thalidomide (see sections 4.6 and 5.3). If is
Infections and Not Known Not Known taken during pregnancy, a teratogenic effect of
Infestations Viral infections, including Viral infections,
herpes zoster and hepatitis B including herpes
in humans is expected.
virus reactivation zoster and hepatitis
B virus reactivation Neutropenia and thrombocytopenia
Neoplasms
Benign, Malignant
Rare
Tumour lysis
• Newly diagnosed multiple myeloma: patients
and Unspecified syndrome who have undergone ASCT treated with
(incl cysts and
polyps) maintenance
Blood and Not Known maintenance after ASCT is associated with a
Lymphatic Acquired haemophilia
System Disorders higher frequency of grade 4 neutropenia
compared to placebo maintenance (32.1% vs
Immune System Not Known
Disorders Solid organ transplant rejection 26.7% [16.1% vs 1.8% after the start of
maintenance treatment] in CALGB 100104 and
Endocrine Common
16.4% vs 0.7% in IFM 2005-02, respectively).
Disorders Hyperthyroidism Treatment-emergent AEs of neutropenia leading
to discontinuation were reported in 2.2% of
Respiratory, Not Known patients in CALGB 100104 and 2.4% of patients
Thoracic and Interstitial
Mediastinal pneumonitis in IFM 2005-02, respectively. Grade 4 febrile
Disorders neutropenia was reported at similar frequencies
Gastrointestinal Not Known in the maintenance arms compared to placebo
Disorders Pancreatitis,
Gastrointestinal maintenance arms in both studies (0.4% vs 0.5%
perforation (including
diverticular, intestinal
[0.4% vs 0.5% after the start of maintenance
and large intestine treatment] in CALGB 100104 and 0.3% vs 0%
perforations)^
in IFM 2005-02, respectively).
maintenance after ASCT is associated with a /dexamethasone-treated patients compared with

higher frequency of grade 3 or 4 0.6% in placebo/dexamethasone-treated
thrombocytopenia compared to placebo patients). Grade 4 febrile neutropenia episodes
maintenance (37.5% vs 30.3% [17.9% vs 4.1% were observed infrequently (0.6% in
after the start of maintenance treatment] in /dexamethasone-treated patients compared to
CALGB 100104 and 13.0% vs 2.9% in IFM 0.0% in placebo/dexamethasone treated
2005-02, respectively). patients).
• Newly diagnosed multiple myeloma: patients The combination of with dexamethasone in
who are not eligible for transplant treated with multiple myeloma patients is associated with a
in combination with low dose dexamethasone higher incidence of grade 3 and grade 4
thrombocytopenia (9.9% and 1.4%, respectively,
The combination of with low dose in /dexamethasone-treated patients compared to
dexamethasone in newly diagnosed multiple 2.3% and 0.0% in placebo/dexamethasone-
myeloma patients is associated with a lower treated patients).
frequency of grade 4 neutropenia (8.5% in Rd
and Rd18, compared with MPT (15%). Grade 4 • Myelodysplastic syndromes patients
febrile neutropenia was observed infrequently
(0.6% in Rd and Rd18 compared with 0.7% in In myelodysplastic syndromes patients, is
MPT). associated with a higher incidence of grade 3 or
4 neutropenia (74.6% in -treated patients
The combination of with low dose compared with 14.9% in patients on placebo in
dexamethasone in newly diagnosed multiple the phase III study). Grade 3 or 4 febrile
myeloma patients is associated with a lower neutropenia episodes were observed in 2.2% of -
frequency of grade 3 and 4 thrombocytopenia treated patients compared with 0.0% in patients
(8.1% in Rd and Rd18) compared with MPT on placebo). is associated with a higher
(11%). incidence of grade 3 or 4 thrombocytopenia
(37% in -treated patients compared with 1.5% in
• Newly diagnosed multiple myeloma: patients patients on placebo in the phase III study).
in combination with melphalan and prednisone • Mantle cell lymphoma patients
The combination of with melphalan and In mantle cell lymphoma patients, is associated
prednisone in newly diagnosed multiple with a higher incidence of grade 3 or 4
myeloma patients is associated with a higher neutropenia (43.7% in -treated patients
frequency of grade 4 neutropenia (34.1% in compared with 33.7% in patients in the control
MPR+R/MPR+p) compared with MPp+p arm in the phase II study). Grade 3 or 4 febrile
(7.8%). There was a higher frequency of grade 4 neutropenia episodes were observed in 6.0% of -
febrile neutropenia observed (1.7% in treated patients compared with 2.4% in patients
MPR+R/MPR+p compared to 0.0% in MPp+p). on control arm.
The combination of with melphalan and Venous thromboembolism
prednisone in newly diagnosed multiple
An increased risk of DVT and PE is associated
myeloma patients is associated with a higher
frequency of grade 3 and grade 4 with the use of the combination of with
thrombocytopenia (40.4% in MPR+R/MPR+p) dexamethasone in patients with multiple
compared with MPp+p (13.7%). myeloma, and to a lesser extent in patients
treated with in combination with melphalan and
• Multiple myeloma: patients with at least one prednisone or in patients with multiple
prior therapy myeloma, myelodysplastic syndromes and
mantle cell lymphoma treated with
The combination of with dexamethasone in monotherapy (see section 4.5).
multiple myeloma patients is associated with a
higher incidence of grade 4 neutropenia (5.1% in
Concomitant administration of erythropoietic diagnosed multiple myeloma in patients taking

agents or previous history of DVT may also in combination with low dose dexamethasone
increase thrombotic risk in these patients. compared to thalidomide in combination with
melphalan and prednisone.
Myocardial infarction
• Myelodysplastic syndromes
Myocardial infarction has been reported in
patients receiving , particularly in those with Baseline variables including complex
known risk factors. cytogenetics and TP53 mutation are associated
with progression to AML in subjects who are
Haemorrhagic disorders transfusion dependent and have a Del (5q)
Haemorrhagic disorders are listed under several abnormality (see section 4.4). The estimated 2-
system organ classes: Blood and lymphatic year cumulative risk of progression to AML
system disorders; nervous system disorders were 13.8% in patients with an isolated Del (5q)
(intracranial haemorrhage); respiratory, thoracic abnormality compared to 17.3% for patients
and mediastinal disorders (epistaxis); with Del (5q) and one additional cytogenetic
gastrointestinal disorders (gingival bleeding, abnormality and 38.6% in patients with a
haemorrhoidal haemorrhage, rectal complex karyotype.
haemorrhage); renal and urinary disorders In a post-hoc analysis of a clinical trial of in
(haematuria); injury, poisoning and procedural myelodysplastic syndromes, the estimated 2-
complications (contusion) and vascular disorders year rate of progression to AML was 27.5 % in
(ecchymosis). patients with IHC-p53 positivity and 3.6% in
Allergic reactions patients with IHC-p53 negativity (p=0.0038). In
the patients with IHC-p53 positivity, a lower
Cases of allergic reaction/hypersensitivity rate of progression to AML was observed
reactions have been reported. A possible cross- amongst patients who achieved a transfusion
reaction between and thalidomide has been independence (TI) response (11.1%) compared
reported in the literature. to a non-responder (34.8%).
Severe skin reactions Hepatic disorders
Severe cutaneous reactions including SJS, TEN The following post-marketing adverse reactions
and DRESS have been reported with the use of . have been reported (frequency unknown): acute
Patients with a history of severe rash associated hepatic failure and cholestasis (both potentially
with thalidomide treatment should not receive fatal), toxic hepatitis, cytolytic hepatitis, mixed
(see section 4.4). cytolytic/cholestatic hepatitis.
Second primary malignancies Rhabdomyolysis
In clinical trials in previously treated myeloma Rare cases of rhabdomyolysis have been
patients with /dexamethasone compared to observed, some of them when is administered
controls, mainly comprising of basal cell or with a statin.
squamous cell skin cancers.
Thyroid disorders
Acute myeloid leukaemia
Cases of hypothyroidism and cases of
• Multiple myeloma hyperthyroidism have been reported (see section
Cases of AML have been observed in clinical 4.4 Thyroid disorders).
trials of newly diagnosed multiple myeloma in Tumour flare reaction and tumour lysis
patients taking treatment in combination with syndrome
melphalan or immediately following
HDM/ASCT (see section 4.4). This increase was In study MCL-002, approximately 10% of -
not observed in clinical trials of newly treated patients experienced TFR compared to
0% in the control arm. The majority of the
events occurred in cycle 1, all were assessed as cells and those with deletions of chromosome 5),
treatment-related, and the majority of the reports enhances T cell- and Natural Killer (NK) cell-
were Grade 1 or 2. Patients with high MIPI at mediated immunity and increases the number of
diagnosis or bulky disease (at least one lesion NK T cells, inhibits angiogenesis by blocking
that is ≥ 7 cm in the longest diameter) at the migration and adhesion of endothelial cells
baseline may be at risk of TFR. In study MCL- and the formation of microvessels, augments
002, TLS was reported for one patient in each of foetal haemoglobin production by CD34+
the two treatment arms. In the supportive study haematopoietic stem cells, and inhibits
MCL-001, approximately 10% of subjects production of pro-inflammatory cytokines (e.g.,
experienced TFR; all report were Grade 1 or 2 in TNF-α and IL-6) by monocytes.
severity and all were assessed as treatment-
related. The majority of the events occurred in In MDS Del (5q), was shown to selectively
cycle 1. There were no reports of TLS in study inhibit the abnormal clone by increasing the
MCL-001 (see section 4.4). apoptosis of Del (5q) cells.
Gastrointestinal disorders binds directly to cereblon, a component of a

cullin ring E3 ubiquitin ligase enzyme complex
Gastrointestinal perforations have been reported that includes deoxyribonucleic acid (DNA)
during treatment with . Gastrointestinal damage-binding protein 1(DDB1), cullin 4
perforations may lead to septic complications (CUL4), and regulator of cullins 1 (Roc1). In the
and may be associated with fatal outcome. presence of , cereblon binds substrate proteins
Aiolos and Ikaros which are lymphoid
Reporting of suspected adverse reactions
transcriptional factors, leading to their
Reporting suspected adverse reactions after ubiquitination and subsequent degradation
authorisation of the medicinal product is resulting in cytotoxic and immunomodulatory
important. It allows continued monitoring of the effects.
benefit/risk balance of the medicinal product.
Clinical efficacy and safety
4.9 Overdose efficacy and safety have been evaluated in five
There is no specific experience in the phase III studies in newly diagnosed multiple
management of overdose in patients, although myeloma, two phase III studies in relapsed
in dose-ranging studies some patients were refractory multiple myeloma, one phase III study
exposed to up to 150 mg, and in single-dose and one phase II study in myelodysplastic
studies, some patients were exposed to up to 400 syndromes and one phase II study in mantle cell
mg. The dose limiting toxicity in these studies lymphoma as described below.
was essentially haematological. In the event of
overdose, supportive care is advised. Newly diagnosed multiple myeloma
5. PHARMACOLOGICAL • maintenance in patients who have undergone

PROPERTIES ASCT
5.1 Pharmacodynamic properties The efficacy and safety of maintenance was

assessed in two phase 3 multicenter,
randomised, double-blind 2-arm, parallel group,
Pharmacotherapeutic group: Other
placebo-controlled studies: CALGB 100104 and
immunosuppressants.
IFM 2005-02
Mechanism of action
CALGB 100104
The mechanism of action includes anti-
Patients between 18 and 70 years of age with
neoplastic, anti-angiogenic, pro-erythropoietic,
active MM requiring treatment and without prior
and immunomodulatory properties. Specifically,
progression after initial therapy were eligible.
inhibits proliferation of certain haematopoietic
tumour cells (including MM plasma tumour
Patients were randomised 1:1 within 90-100 HR [95% CI]c; p-valued 0.61 (0.48, 0.76); <0.001
days after ASCT to receive either or placebo PFS2 e
maintenance. The maintenance dose was 10 mg Mediana PFS2 time, months 80.2 (63.3, 52.8 (41.3,
once daily on days 1-28 of repeated 28-day (95% CI) b 101.8) 64.0)
cycles (increased up to 15 mg once daily after 3 HR [95% CI]c ; p-valued 0.61 (0.48, 0.78); <0.001
months in the absence of dose-limiting toxicity), Overall survival
and treatment was continued until disease
Mediana OS time, months 111.0 (101.8, 84.2 (71.0,
progression. (95% CI)b NE) 102.7)
The primary efficacy endpoint in the study was 8-year survival rate, % (SE) 60.9 (3.78) 44.6 (3.98)
c d
progression free survival (PFS) from HR [95% CI] ; p-value 0.61 (0.46, 0.81); <0.001
randomisation to the date of progression or Follow-up
death, whichever occurred first; the study was Medianf (min, max), 81.9 (0.0, 81.0 (4.1,
not powered for the overall survival endpoint. In months: all surviving 119.8) 119.5
total 460 patients were randomised: 231 patients patients
to and 229 patients to placebo. The CI = confidence interval; HR = hazard ratio;
demographic and disease-related characteristics max = maximum; min = minimum; NE = not
were balanced across both arms. estimable; OS = overall survival; PFS =
progression-free survival;
The study was unblinded upon the
a
recommendations of the data monitoring The median is based on the Kaplan-Meier
committee after surpassing the threshold for a estimate.
preplanned interim analysis of PFS. After b
The 95% CI about the median.
unblinding, patients in the placebo arm were
c
allowed to cross over to receive before disease Based on Cox proportional hazards model
progression. comparing the hazard functions associated with
the indicated treatment arms.
The results of PFS at unblinding, following a
d
preplanned interim analysis, using a cut-off of The p-value is based on the unstratified log-
17 December 2009 (15.5 months follow up) rank test of Kaplan-Meier curve differences
showed a 62% reduction in risk of disease between the indicated treatment arms.
progression or death favoring (HR = 0.38; 95% e
CI 0.27, 0.54; p <0.001). The median overall Exploratory endpoint (PFS2). received by
PFS was 33.9 months (95% CI NE, NE) in the subjects in the placebo arm who crossed over
arm versus 19.0 months (95% CI 16.2, 25.6) in prior to PD upon study unblinding was not
the placebo arm. considered as a second-line therapy.
f
The PFS benefit was observed both in the Median follow-up post-ASCT for all surviving
subgroup of patients with CR and in the subjects.
subgroup of patients who had not achieved a Data cuts: 17 Dec 2009 and 01 Feb 2016
CR.
IFM 2005-02
The results for the study, using a cut-off of 1
February 2016, are presented in Table 6 Patients aged < 65 years at diagnosis who had
undergone ASCT and had achieved at least a
Table 6: Summary of overall efficacy data stable disease response at the time of
Placebo hematologic recovery were eligible. Patients
(N = 231) (N = 229) were randomised 1:1 to receive either or
placebo maintenance (10 mg once daily on days
Investigator-assessed
1-28 of repeated 28-day cycles increased up to
PFS 15 mg once daily after 3 months in the absence
Mediana PFS time, months 56.9 (41.9, 29,4 (20.7, of dose-limiting toxicity) following 2 courses of
(95% CI)b 71.7) 35.5) consolidation (25 mg/day, days 1-21 of a 28-day
cycle). Treatment was to be continued until • in combination with dexamethasone in

disease progression. patients who are not eligible for stem cell
transplantation
The primary endpoint was PFS defined from
randomisation to the date of progression or The safety and efficacy of was assessed in a
death, whichever occurred first; the study was phase III, multicenter, randomised, open-label,
not powered for the overall survival endpoint. In 3-arm study (MM-020) of patients who were at
total 614 patients were randomised: 307 patients least 65 years of age or older or, if younger than
to and 307 patients to placebo. 65 years of age, were not candidates for stem
cell transplantation because they declined to
The study was unblinded upon the
undergo stem cell transplantation or stem cell
recommendations of the data monitoring transplantation is not available to the patient due
committee after surpassing the threshold for a to cost or other reason.The study (MM-020)
preplanned interim analysis of PFS. After compared and dexamethasone (Rd) given for 2
unblinding, patients receiving placebo were not
different durations of time (i.e., until progressive
crossed over to therapy prior to progressive disease [Arm Rd] or for up to eighteen 28-day
disease. The arm was discontinued, as a cycles [72 weeks, Arm Rd18]) to melphalan,
proactive safety measure, after observing an prednisone and thalidomide (MPT) for a
imbalance of SPMs (see Section 4.4).
maximum of twelve 42-day cycles (72 weeks).
The results of PFS at unblinding, following a Patients were randomised (1:1:1) to 1 of 3
preplanned interim analysis, using a cut-off of 7 treatment arms. Patients were stratified at
July 2010 (31.4 months follow up) showed a randomisation by age (≤75 versus >75 years),
48% reduction in risk of disease progression or stage (ISS Stages I and II versus Stage III), and
death favoring (HR = 0.52; 95% CI 0.41, 0.66; country.
p <0.001). The median overall PFS was 40.1 Patients in the Rd and Rd18 arms took 25 mg
months (95% CI 35.7, 42.4) in the arm versus once daily on days 1 to 21 of 28-day cycles
22.8 months (95% CI 20.7, 27.4) in the placebo according to protocol arm. Dexamethasone 40
arm.
mg was dosed once daily on days 1, 8, 15, and
The PFS benefit was less in the subgroup of 22 of each 28-day cycle. Initial dose and
patients with CR than in the subgroup of patients regimen for Rd and Rd18 were adjusted
who had not achieved a CR. according to age and renal function (see section
4.2). Patients >75 years received a
The updated PFS, using a cut-off of 1 February dexamethasone dose of 20 mg once daily on
2016 (96.7 months follow up) continues to show days 1, 8, 15, and 22 of each 28-day cycle. All
a PFS advantage: HR = 0.57 (95% CI 0.47, 0.68; patients received prophylactic anticoagulation
p < 0.001). The median overall PFS was 44.4 (low molecular weight heparin, warfarin,
months (39.6, 52.0) in the arm versus 23.8 heparin, low-dose aspirin) during the study.
months (95% CI 21.2, 27.3) in the placebo arm.
For PFS2, the observed HR was 0.80 (95% CI The primary efficacy endpoint in the study was
0.66, 0.98; p = 0.026) for versus placebo. The progression free survival (PFS). In total 1623
median overall PFS2 was 69.9 months (95% CI patients were enrolled into the study, with 535
58.1, 80.0) in the arm versus 58.4 months (95% patients randomised to Rd, 541 patients
CI 51.1, 65.0) in the placebo arm. For OS, the randomised to Rd18 and 547 patients
observed HR was 0.90: (95% CI 0.72, 1.13; p = randomised to MPT. The demographics and
0.355) for versus placebo. The median overall disease-related baseline characteristics of the
survival time was 105.9 months (95% CI 88.8, patients were well balanced in all 3 arms. In
NE) in the arm versus 88.1 months (95% CI general, study subjects had advanced-stage
80.7, 108.4) in the placebo arm. 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 and OS International Myeloma Working Group; IRAC =
using a cut off of 3 March 2014 where the Independent Response Adjudication Committee;
median follow-up time for all surviving subjects M = melphalan; max = maximum; min =
was 45.5 months, the results of the study are minimum; NE = not estimable; OS = overall
presented in Table 7: survival; P = prednisone; PFS = progression-free
survival; PR = partial response; R = ; Rd = Rd
Table 7. Summary of overall efficacy data given until documentation of progressive
disease; Rd18 = Rd given for ☐ 18 cycles; SE =
MPT standard error; T = thalidomide; VGPR = very
Rd Rd18
(N = 547)
(N = 535) (N = 541) good partial response; vs = versus.
Investigator-assessed
a
PFS - (months) The median is based on the Kaplan-Meier
a
Median PFS time, months 26.0 (20.7, 21.0 (19.7, 21.9 (19.8, estimate.
(95% CI)b 29.7) 22.4) 23.9)
b
HR [95% CI]c; p-valued The 95% CI about the median.
Rd vs MPT 0.69 (0.59, 0.80); <0.001 c
Based on Cox proportional hazards model
Rd vs Rd18 0.71 (0.61, 0.83); <0.001 comparing the hazard functions associated with
Rd18 vs MPT 0.99 (0.86, 1.14); 0.866 the indicated treatment arms.
e
PFS2 - (months) d
The p-value is based on the unstratified log-
Mediana PFS2 time, 42.9 (38.1, 40.0 (36.2, 35.0 (30.4, rank test of Kaplan-Meier curve differences
months (95% CI)b 47.4) 44.2) 37.8)
between the indicated treatment arms.
HR [95% CI]c; p-valued
e
Rd vs MPT 0.74 (0.63, 0.86); <0.001 Exploratory endpoint (PFS2)
Rd vs Rd18 0.92 (0.78, 1.08); 0.316 f
The median is the univariate statistic without
Rd18 vs MPT 0.80 (0.69, 0.93); 0.004 adjusting for censoring.
Overall survival (months)
g
Mediana OS time, months 58.9 (56.0, 56.7 (50.1, 48.5 (44.2,
Best assessment of adjudicated response during
(95% CI)b NE) NE) 52.0) the treatment phase of the study (for definitions
HR [95% CI]c; p-valued of each response category, Data cut-off date =
Rd vs MPT 0.75 (0.62, 0.90); 0.002 24 May 2013).
Rd vs Rd18 0.91 (0.75, 1.09); 0.305 h
data cut 24 May 2013
Rd18 vs MPT 0.83 (0.69, 0.99); 0.034
• in combination with melphalan and
Follow-up (months)
prednisone followed by maintenance therapy in
Medianf (min, max): all 40.8 (0.0, 40.1 (0.4, 38.7 (0.0, patients who are not eligible for transplant
patients 65.9) 65.7) 64.2)
Myeloma responseg n (%) The safety and efficacy of was assessed in a
CR 81 (15.1) 77 (14.2) 51 (9.3) phase III multicenter, randomised double blind 3
VGPR 152 (28.4) 154 (28.5) 103 (18.8) arm study (MM-015) of patients who were 65
PR 169 (31.6) 166 (30.7) 187 (34.2)
years or older and had a serum creatinine < 2.5
mg/dL. The study compared in combination
Overall response: CR,
402 (75.1) 397 (73.4) 341 (62.3) with melphalan and prednisone (MPR) with or
VGPR, or PR
Duration of response - without maintenance therapy until disease
(months)h progression, to that of melphalan and prednisone
Mediana (95% CI)b 35.0 (27.9, 22.1 (20.3, 22.3 (20.2, for a maximum of 9 cycles. Patients were
43.4) 24.0) 24.9) 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;
AMT = antimyeloma therapy; CI = confidence
Stages I and II vs. stage III).
interval; CR = complete response; d = low-dose
dexamethasone; HR = hazard ratio; IMWG =
This study investigated the use of combination HR [95% CI]; p-value

therapy of MPR (melphalan 0.18 mg/kg orally MPR+R vs MPp+p 0.70 (0.54, 0.92); 0.009
on days 1 to 4 of repeated 28-day cycles;
prednisone 2 mg/kg orally on days 1 to 4 of MPR+R vs MPR+p 0.77 (0.59, 1.02); 0.065
repeated 28-day cycles; and 10 mg/day orally MPR+p vs MPp +p 0.92 (0.71, 1.19); 0.051
on days 1 to 21 of repeated 28-day cycles) for
Overall survival (months)
induction therapy, up to 9 cycles. Patients who
completed 9 cycles or who were unable to Mediana OS time, months 55.9 (49.1, 51.9 (43.1, 53.9 (47.3,
complete 9 cycles due to intolerance proceeded (95% CI) 67.5) 60.6) 64.2)
to maintenance therapy starting with 10 mg HR [95% CI]; p-value
orally on days 1 to 21 of repeated 28-day cycles MPR+R vs MPp+p 0.95 (0.70, 1.29); 0.736
until disease progression.
MPR+R vs MPR+p 0.88 (0.65, 1.20); 0.43
The primary efficacy endpoint in the study was
MPR+p vs MPp +p 1.07 (0.79, 1.45); 0.67
progression free survival (PFS). In total 459
patients were enrolled into the study, with 152 Follow-up (months)
patients randomised to MPR+R, 153 patients
Median (min, max): all 48.4 (0.8, 46.3 (0.5, 50.4 (0.5,
randomised to MPR+p and 154 patients patients 73.8) 71.9) 73.3)
randomised to MPp+p. The demographics and Investigator-assessed
disease-related baseline characteristics of the Myeloma response n (%)
patients were well balanced in all 3 arms; CR 30 (19.7) 17 (11.1) 9 (5.8)
notably, approximately 50% of the patients
PR 90 (59.2) 99 ( 64.7) 75 (48.7)
enrolled in each arm had the following
characteristics; ISS Stage III, and creatinine Stable Disease (SD) 24 (15.8) 31 (20.3) 63 (40.9)
clearance < 60 mL/min. The median age was 71 Response Not Evaluable
in the MPR+R and MPR+p arms and 72 in the 8 (5.3) 4 (2.6) 7 (4.5)
(NE)
MPp+p arm. Investigator-assessed
Duration of response
In an analysis of PFS, PFS2, OS using a cut-off (CR+PR) - (months)
of April 2013 where the median follow up time Mediana (95% CI) 26.5 (19.4, 12.4 (11.2, 12.0 (9.4,
for all surviving subjects was 62.4 months, the 35.8) 13.9) 14.5)
results of the study are presented in Table 8: CI = confidence interval; CR = complete
response; HR = Hazard Rate; M = melphalan;
Table 8. Summary of overall efficacy data NE = not estimable; OS = overall survival; p =
placebo; P = prednisone;
PD = progressive disease; PR = partial response;
MPR+p R = ; SD = stable disease; VGPR = very good
MPR+R (N = 153) MPp +p
(N = 152) (N = 154)
partial response.
Investigator-assessed ª The median is based on the Kaplan-Meier
PFS - (months)
estimate
Mediana PFS time, months 27.4 (21.3, 14.3 (13.2, 13.1 (12.0,
(95% CI) 35.0) 15.7) 14.8) ¤
PFS2 (an exploratory endpoint) was defined for
HR [95% CI]; p-value all patients (ITT) as time from randomisation to
MPR+R vs MPp+p 0.37 (0.27, 0.50); <0.001 start of 3rd line antimyeloma therapy (AMT) or
death for all randomised patients
MPR+R vs MPR+p 0.47 (0.35, 0.65); <0.001
Supportive newly diagnosed multiple myeloma
MPR+p vs MPp +p 0.78 (0.60, 1.01); 0.059
studies
PFS2 - (months) ¤
An open-label, randomised, multicenter, phase
Mediana PFS2 time, months 39.7 (29.2, 27.8 (23.1, 28.8 (24.3, III study (ECOG E4A03) was conducted in 445
(95% CI) 48.4) 33.1) 33.8)
patients with newly diagnosed multiple
myeloma; 222 patients were randomised to the dexamethasone orally once daily on days 1 to 4,
/low dose dexamethasone arm, and 223 were 9 to 12, and 17 to 20 of each 28-day cycle for
randomised to the /standard dose dexamethasone the first 4 cycles of therapy. The dose of
arm. Patients randomised to the /standard dose dexamethasone was reduced to 40 mg orally
dexamethasone arm received 25 mg/day, days 1 once daily on days 1 to 4 of each 28-day cycle
to 21 every 28 days plus dexamethasone 40 after the first 4 cycles of therapy. In both studies,
mg/day on days 1 to 4, 9 to 12, and 17 to 20 treatment was to continue until disease
every 28 days for the first four cycles. Patients progression. In both studies, dose adjustments
randomised to the /low dose dexamethasone arm were allowed based on clinical and laboratory
received 25 mg/day, days 1 to 21 every 28 days finding.
plus low dose dexamethasone – 40 mg/day on
days 1, 8, 15, and 22 every 28 days. In the /low The primary efficacy endpoint in both studies
dose dexamethasone group, 20 patients (9.1%) was time to progression (TTP). In total, 353
underwent at least one dose interruption patients were evaluated in the MM-009 study;
compared to 65 patients (29.3%) in the /standard 177 in the len/dex group and 176 in the
dose dexamethasone arm. placebo/dex group and, in total, 351 patients
were evaluated in the MM-010 study; 176 in the
In a post-hoc analysis, lower mortality was len/dex group and 175 in the placebo/dex group.
observed in the /low dose dexamethasone arm
6.8% (15/220) compared to the /standard dose In both studies, the baseline demographic and
dexamethasone arm 19.3% (43/223), in the disease-related characteristics were comparable
between the len/dex and placebo/dex groups.
newly diagnosed multiple myeloma patient
Both patient populations presented a median age
population, with a median follow up of 72.3
weeks. of 63 years, with a comparable male to female
ratio. The ECOG performance status was
However with a longer follow-up, the difference comparable between both groups, as was the
in overall survival in favour of / low dose number and type of prior therapies.
dexamethasone tends to decrease.
Pre-planned interim analyses of both studies
Multiple myeloma with at least one prior showed that len/dex was statistically
therapy significantly superior (p < 0.00001) to
dexamethasone alone for the primary efficacy
The efficacy and safety of were evaluated in endpoint, TTP (median follow-up duration of
two phase III multi-centre, randomised, double- 98.0 weeks). Complete response and overall
blind, placebo-controlled, parallel-group response rates in the len/dex arm were also
controlled studies (MM-009 and MM-010) of
significantly higher than the placebo/dex arm in
plus dexamethasone therapy versus
both studies. Results of these analyses
dexamethasone alone in previously treated subsequently led to an unblinding in both
patients with multiple myeloma. Out of 353
studies, in order to allow patients in the
patients in the MM-009 and MM-010 studies placebo/dex group to receive treatment with the
who received /dexamethasone, 45.6% were aged len/dex combination.
65 or over. Of the 704 patients evaluated in the
MM-009 and MM-010 studies, 44.6% were aged An extended follow-up efficacy analysis was
65 or over. conducted with a median follow-up of 130.7
weeks. Table 9 summarises the results of the
In both studies, patients in the /dexamethasone follow-up efficacy analyses – pooled studies
(len/dex) group took 25 mg of orally once daily MM-009 and MM-010.
on days 1 to 21 and a matching placebo capsule
once daily on days 22 to 28 of each 28-day In this pooled extended follow-up analysis, the
cycle. Patients in the placebo/dexamethasone median TTP was 60.1 weeks (95% CI: 44.3,
(placebo/dex) group took 1 placebo capsule on 73.1) in patients treated with len/dex (N = 353)
days 1 to 28 of each 28-day cycle. Patients in versus 20.1 weeks (95% CI: 17.7, 20.3) in
both treatment groups took 40 mg of patients treated with placebo/dex (N = 351). The
median progression free survival was 48.1 Overall 212 75 (21.4) 5.53 [3.97,
weeks (95% CI: 36.4, 62.1) in patients treated response [n, %] (60.1) 11 (3.1) 7.71], p < 0.001
Complete 58 6.08 [3.13,
with len/dex versus 20.0 weeks (95% CI: 16.1, response [n, %] (16.4) 11.80], p <
20.1) in patients treated with placebo/dex. The 0.001
median duration of treatment was 44.0 weeks a: Two-tailed log rank test comparing survival
(min: 0.1, max: 254.9) for len/dex and 23.1 curves between treatment groups.
weeks (min: 0.3, max: 238.1) for placebo/dex.
b: Two-tailed continuity-corrected chi-square
Complete response (CR), partial response (PR)
test.
and overall response (CR+PR) rates in the
len/dex arm remain significantly higher than in Myelodysplastic syndromes
the placebo/dex arm in both studies. The median
overall survival in the extended follow-up The efficacy and safety of were evaluated in
analysis of the pooled studies is 164.3 weeks patients with transfusion-dependent anemia due
(95% CI: 145.1, 192.6) in patients treated with to low- or intermediate-1-risk myelodysplastic
len/dex versus 136.4 weeks (95% CI: 113.1, syndromes associated with a deletion 5q
161.7) in patients treated with placebo/dex. cytogenetic abnormality, with or without
Despite the fact that 170 out of the 351 patients additional cytogenetic abnormalities, in two
randomised to placebo/dex received after main studies: a phase III, multicentre,
disease progression or after the studies were randomised, double-blind, placebo-controlled, 3-
unblinded, the pooled analysis of overall arm study of two doses of oral (10 mg and 5
survival demonstrated a statistically significant mg) versus placebo (MDS-004); and a phase II,
survival advantage for len/dex relative to a multicentre, single-arm, open-label study of
placebo/dex (HR = 0.833, 95% CI = [0.687, (10 mg) (MDS-003).
1.009], p=0.045). The results presented below represent the intent-
Table 9. Summary of results of efficacy to-treat population studied in MDS-003 and
analyses as of cut-off date for extended MDS-004; with the results in the isolated Del
follow-up — pooled studies MM-009 and (5q) sub-population also shown separately.
MM-010 (cut-offs 23 July 2008 and 2 March In study MDS-004, in which 205 patients were
2008, respectively) equally randomised to receive 10 mg, 5 mg or
Endpoint len/dex placebo/dex(N=351) placebo, the primary efficacy analysis consisted
(N=353) of a comparison of the transfusion-independence
response rates of the 10 mg and 5 mg arms
versus the placebo arm (double-blind phase 16
Time to event HR [95% CI], to 52 weeks and open-label up to a total of 156
p-value a
weeks). Patients who did not have evidence of at
Time to 60.1 20.1 [17.7, 20.3] 0.350 [0.287, least a minor erythroid response after 16 weeks
progression [44.3, 0.426], p <
Median [95% 73.1] 0.001 were to be discontinued from treatment. Patients
CI], weeks who had evidence of at least a minor erythroid
Progression free 48.1 20.0 [16.1, 20.1] 0.393 [0.326,
response could continue therapy until erythroid
survival [36.4, 0.473], p < relapse, disease progression or unacceptable
Median [95% 62.1] 0.001 toxicity. Patients, who initially received placebo
CI], weeks
or 5 mg and did not achieve at least a minor
Overall survival 164.3 136.4 [113.1, 161.7] 0.833 [0.687, erythroid response after 16 weeks of treatment
Median [95% [145.1, 75% 1.009], p = were permitted to switch from placebo to 5 mg
CI], weeks 192.6] 0.045
1-year Overall 82% or continue treatment at higher dose (5 mg to 10
survival rate mg).
Response rate Odds ratio In, study MDS-003, in which 148 patients
[95% CI], p-
value b received at a dose of 10 mg, the primary
efficacy analysis consisted of an evaluation of
the efficacy of treatments to achieve (57.4%) achieved red blood cell transfusion
haematopoietic improvement in subjects with independence.
low- or intermediate-1 risk myelodysplastic
syndromes. The median time to transfusion independence in
the 10 mg arm was 4.6 weeks. The median
Table 10. Summary of efficacy results – duration of transfusion independence was not
studies MDS-004 (double-blind phase) and reached in any of the treatment arms, but should
MDS-003, intent-to-treat populationEndpoint exceed 2 years for the -treated subjects. The
median increase in haemoglobin (Hgb) from
MDS-004 MDS-003
N = 205 N = 148 baseline in the 10 mg arm was 6.4 g/dL.
Additional endpoints of the study included
cytogenetic response (in the 10 mg arm major
and minor cytogenetic responses were observed
10 mg† 5 mg†† Placebo* 10 mg
in 30.0% and 24.0% of subjects, respectively),
N = 69 N = 69 N = 67 N = 148 assessment of Health Related Quality of Life
(HRQoL) and progression to acute myeloid
Transfusion 38 24 4 (6.0%) 86 (58.1%) leukaemia. Results of the cytogenetic response
Independence (55.1%) (34.8%) and HRQoL were consistent with the findings of
(≥ 182 days) # the primary endpoint and in favour of treatment
Transfusion 42 33 5 (7.5%) 97 (65.5%) compared to placebo.
Independence (60.9%) (47.8%)
(≥ 56 days) # In MDS-003, a large proportion of patients with
Median Time to 4.6 4.1 0.3 4.1
myelodysplastic syndromes achieved transfusion
Transfusion independence (>182 days) on 10 mg (58.1%).
Independence The median time to transfusion independence
(weeks)
was 4.1 weeks. The median duration of
Median Duration of NR∞ NR NR 114.4
Transfusion transfusion independence was 114.4 weeks. The
Independence median increase in haemoglobin (Hgb) was 5.6
(weeks) g/dL. Major and minor cytogenetic responses
Median Increase in 6.4 5.3 2.6 5.6 were observed in 40.9% and 30.7% of subjects,
Hgb, g/dL
respectively.
† Subjects treated with 10 mg on 21 days of 28-
day cycles A large proportion of subjects enrolled in MDS-
003 (72.9%) and MDS-004 (52.7%) had
†† Subjects treated with 5 mg on 28 days of 28- received prior erythropoiesis-stimulating agents.
day cycles
Mantle cell lymphoma
* The majority of patients on placebo
discontinued the double-blind treatment for lack The efficacy and safety of were evaluated in
of efficacy after 16 weeks of treatment before patients with mantle cell lymphoma in a phase
entering the open-label phase II, multicenter, randomised open-label study
versus single agent of investigator's choice in
#
Associated with an increase in Hgb of ≥ 1g/dL patients who were refractory to their last
∞ Not reached (i.e. the median was not reached) regimen or had relapsed one to three times
(study MCL-002).
In MDS-004, a significant larger proportion of
patients with myelodysplastic syndromes Patients who were at least 18 years of age with
achieved the primary endpoint of transfusion histologically-proven MCL and CT-measurable
independence (>182 days) on 10 mg compared disease were enrolled. Patients were required to
with placebo (55.1% vs. 6.0%). Amongst the 47 have received adequate previous treatment with
patients with an isolated Del (5q) cytogenetic at least one prior combination chemotherapy
abnormality and treated with 10 mg, 27 patients regimen. Also, patients had to be ineligible for
intensive chemotherapy and/or transplant at time
of inclusion in the study. Patients were Duration of 69.6 [41.1, 45.1 [36.3,
randomised 2:1 to the or the control arm. The Response, mediana [95% 86.7] 80.9]
CI] (weeks)
investigator's choice treatment was selected Overall Survival
before randomisation and consisted of
HR [95% CI]c 0.89 [0.62, 1.28]
monotherapy with either chlorambucil,
Log-rank test, p-value 0.520
cytarabine, rituximab, fludarabine, or
gemcitabine. CI = confidence interval; CRR = complete
response rate; CR = complete response; CRu =
was administered orally 25 mg once daily for complete response unconfirmed; DMC = Data
the first 21 days (D1 to D21) of repeating 28-day Monitoring Committee; ITT = intent-to-treat;
cycles until progression or unacceptable toxicity. HR = hazard ratio; KM = Kaplan-Meier; MIPI =
Patients with moderate renal insufficiency were Mantle Cell Lymphoma International Prognostic
to receive a lower starting dose of 10 mg daily Index; NA = not applicable; ORR = overall
on the same schedule. response rate; PD = progressive disease; PFS =
progression-free survival; PR= partial response;
The baseline demographic were comparable
SCT = stem cell transplantation; SD = stable
between the arm and control arm. Both patient
disease; SE = standard error.
populations presented a median age of 68.5
a
years with comparable male to female ratio. The The median was based on the KM estimate.
ECOG performance status was comparable b
between both groups, as was the number of prior Range was calculated as 95% CIs about the
therapies. median survival time.
c
The primary efficacy endpoint in study MCL- The mean and median are the univariate
002 was progression-free survival (PFS). statistics without adjusting for censoring.
d
The efficacy results for the Intent-to-Treat (ITT) The stratification variables included time from
population were assessed by the Independent diagnosis to first dose (< 3 years and ≥ 3 years),
Review Committee (IRC), and are presented in time from last prior systemic anti-lymphoma
the table below. therapy to first dose (< 6 months and ≥ 6
months), prior SCT (yes or no), and MIPI at
Table 11. Summary of efficacy results – study baseline (low, intermediate, and high risk).
MCL-002, intent-to-treat population e
Sequential test was based on a weighted mean
Arm Control Arm of a log-rank test statistic using the unstratified
log-rank test for sample size increase and the
N = 170 N = 84
unstratified log-rank test of the primary analysis.
PFS The weights are based on observed events at the
PFS, mediana [95% 37.6 [24.0, 22.7 [15.9,
CI]b (weeks) 52.6] 30.1] time the third DMC meeting was held and based
Sequential HR [95% CI]e 0.61 [0.44, 0.84] on the difference between observed and
Sequential log-rank test, p- 0.004 expected events at the time of the primary
valuee analysis. The associated sequential HR and the
Responsea, n (%) corresponding 95% CI are presented.
Complete response (CR) 8 (4.7) 0 (0.0)
Partial response (PR) 60 (35.3) 9 (10.7)
In study MCL-002 in the ITT population, there
b was an overall apparent increase in deaths within
Stable disease (SD) 50 (29.4) 44 (52.4)
20 weeks in the arm 22/170 (13%) versus 6/84
Progressive disease (PD) 34 (20.0) 26 (31.0)
(7%) in the control arm. In patients with high
Not done/Missing 18 (10.6) 5 (6.0)
tumour burden, corresponding figures were
ORR (CR, CRu, PR), n (%) 68 (40.0) 9 (10.7)d [5.02,
[95% CI]c [32.58, 47.78] 19.37] 16/81 (20%) and 2/28 (7%) (see section 4.4).
p-valuee < 0.001 Paediatric population
CRR (CR, CRu), n (%) [95% 8 (4.7) [2.05, 0 (0.0) [95.70,
CI]c 9.06] 100.00] The European Medicines Agency has waived the
p-valuee 0.043 obligation to submit the results of studies with
in all subsets of the paediatric population in and 29% in multiple myeloma patients and
multiple myeloma, myelodysplastic syndromes healthy volunteers, respectively.
and mantle cell lymphoma (see section 4.2 for
information on paediatric use). is present in human semen (< 0.01% of the
dose) after administration of 25 mg/day and the
medicinal product is undetectable in semen of a
5.2 Pharmacokinetic properties healthy subject 3 days after stopping the
substance (see section 4.4).
has an asymmetric carbon atom and can Biotransformation and elimination

therefore exist as the optically active forms S(-) Results from human in vitro metabolism studies
and R(+). is produced as a racemic mixture. is indicate that is not metabolised by cytochrome
generally more soluble in organic solvents but P450 enzymes suggesting that administration of
exhibits the greatest solubility in 0.1N HCl with medicinal products that inhibit cytochrome
buffer. P450 enzymes is not likely to result in metabolic
Absorption medicinal product interactions in humans. In
vitro studies indicate that has no inhibitory
is rapidly absorbed following oral effect on CYP1A2, CYP2C9, CYP2C19,
administration in healthy volunteers, under CYP2D6, CYP2E1, CYP3A, or UGT1A1.
fasting conditions, with maximum plasma Therefore, is unlikely to cause any clinically
concentrations occurring between 0.5 and 2 relevant medicinal product interactions when co-
hours post-dose. In patients, as well as in healthy administered with substrates of these enzymes.
volunteers, the maximum concentration (Cmax)
and area-under-the-concentration time curve In vitro studies indicate that is not a substrate of
(AUC) increase proportionally with increases in human breast cancer resistance protein (BCRP),
dose. Multiple dosing does not cause marked multidrug resistance protein (MRP) transporters
medicinal product accumulation. In plasma, the MRP1, MRP2, or MRP3, organic anion
relative exposures of the S- and R- enantiomers transporters (OAT) OAT1 and OAT3, organic
of are approximately 56% and 44%, anion transporting polypeptide 1B1
respectively. (OATP1B1), organic cation transporters (OCT)
OCT1 and OCT2, multidrug and toxin extrusion
Co-administration with a high-fat and high- protein (MATE) MATE1, and organic cation
calorie meal in healthy volunteers reduces the transporters novel (OCTN) OCTN1 and
extent of absorption, resulting in an OCTN2.
approximately 20% decrease in area under the
concentration versus time curve (AUC) and 50% In vitro studies indicate that has no inhibitory
decrease in Cmax in plasma. However, in the effect on human bile salt export pump (BSEP),
main multiple myeloma and myelodysplastic BCRP, MRP2, OAT1, OAT3, OATP1B1,
syndromes registration trials where the efficacy OATP1B3, and OCT2.
and safety were established for , the medicinal A majority of is eliminated through urinary
product was administered without regard to food excretion. The contribution of renal excretion to
intake. Thus, can be administered with or total clearance in subjects with normal renal
without food. function was 90%, with 4% of eliminated in
Population pharmacokinetic analyses indicate faeces.
that the oral absorption rate of is similar among is poorly metabolized as 82% of the dose is
MM, MDS and MCL patients. excreted unchanged in urine. Hydroxy- and N-
Distribution acetyl- represent 4.59% and 1.83% of the
excreted dose, respectively. The renal clearance
In vitro (14C)- binding to plasma proteins was of exceeds the glomerular filtration rate and
low with mean plasma protein binding at 23% therefore is at least actively secreted to some
extent.
At doses of 5 to 25 mg/day, half-life in plasma is Population pharmacokinetic analyses included

approximately 3 hours in healthy volunteers and patients with mild hepatic impairment (N=16,
ranges from 3 to 5 hours in patients with total bilirubin >1 to ≤1.5 x ULN or AST > ULN)
multiple myeloma, myelodysplastic syndromes and indicate that mild hepatic impairment does
or mantle cell lymphoma. not influence clearance (exposure in plasma).
There are no data available for patients with
Older people moderate to severe hepatic impairment.
No dedicated clinical studies have been Other intrinsic factors
conducted to evaluate pharmacokinetics of in
the elderly. Population pharmacokinetic analyses Population pharmacokinetic analyses indicate
included patients with ages ranging from 39 to that body weight (33- 135 kg), gender, race and
85 years old and indicate that age does not type of haematological malignancy (MM, MDS
influence clearance (exposure in plasma). or MCL) do not have a clinically relevant effect
Because elderly patients are more likely to have on clearance in adult patients.
decreased renal function, care should be taken in
dose selection and it would be prudent to 5.3 Preclinical safety data
monitor renal function. An embryofoetal development study has been
Renal impairment conducted in monkeys administered at doses
from 0.5 and up to 4 mg/kg/day. Findings from
The pharmacokinetics of was studied in subjects this study indicate that produced external
with renal impairment due to nonmalignant malformations including non-patent anus and
conditions. In this study, two methods were used malformations of upper and lower extremities
to classify renal function: the urinary creatinine (bent, shortened, malformed, malrotated and/or
clearance measured over 24 hours and the absent part of the extremities, oligo and/or
creatinine clearance estimated by Cockcroft- polydactyly) in the offspring of female monkeys
Gault formula. The results indicate that as renal who received the active substance during
function decreases (< 50 mL/min), the total pregnancy.
clearance decreases proportionally resulting in
an increase in AUC. The AUC was increased by Various visceral effects (discoloration, red foci
approximately 2.5, 4 and 5-fold in subjects with at different organs, small colourless mass above
moderate renal impairment, severe renal atrio-ventricular valve, small gall bladder,
impairment, and end-stage renal disease, malformed diaphragm) were also observed in
respectively, compared to the group combining single foetuses.
subjects with normal renal function and subjects has a potential for acute toxicity; minimum
with mild renal impairment. The half-life of lethal doses after oral administration were >
increased from approximately 3.5 hours in 2000 mg/kg/day in rodents. Repeated oral
subjects with creatinine clearance > 50 mL/min administration of 75, 150 and 300 mg/kg/day to
to more than 9 hours in subjects with reduced rats for up to 26 weeks produced a reversible
renal function < 50 mL/min. However, renal treatment-related increase in kidney pelvis
impairment did not alter the oral absorption of . mineralisation in all 3 doses, most notably in
The Cmax was similar between healthy subjects females. The no observed adverse effect level
and patients with renal impairment. (NOAEL) was considered to be less than 75
Approximately 30% of the medicinal product in mg/kg/day, and is approximately 25-fold greater
the body was removed during a single 4-hour than the human daily exposure based on AUC
dialysis session. Recommended dose exposure. Repeated oral administration of 4 and
adjustments in patients with impaired renal 6 mg/kg/day to monkeys for up to 20 weeks
function are described in section 4.2. produced mortality and significant toxicity
Hepatic impairment (marked weight loss, reduced red and white
blood cell and platelet counts, multiple organ
haemorrhage, gastrointestinal tract
inflammation, lymphoid, and bone marrow Titanium dioxide (E171)

atrophy). Repeated oral administration of 1 and Printing ink
2 mg/kg/day to monkeys for up to 1 year Shellac
produced reversible changes in bone marrow Propylene glycol
cellularity, a slight decrease in Black iron oxide (E172)
myeloid/erythroid cell ratio and thymic atrophy. Potassium hydroxide
Mild suppression of white blood cell count was
observed at 1 mg/kg/day corresponding to
approximately the same human dose based on 6.2 Incompatibilities
AUC comparisons.
Not applicable.
In vitro (bacterial mutation, human lymphocytes,
mouse lymphoma, Syrian Hamster Embryo cell 6.3 Shelf life
transformation) and in vivo (rat micronucleus)
mutagenicity studies revealed no drug related 3 years.
effects at either the gene or chromosomal level.
Carcinogenicity studies with have not been
conducted. 6.4 Special precautions for storage
Developmental toxicity studies were previously
This medicinal product does not require any
conducted in rabbits. In these studies, rabbits
special storage conditions.
were administered 3, 10 and 20 mg/kg/day
orally. An absence of the intermediate lobe of 6.5 Nature and contents of container
the lung was observed at 10 and 20 mg/kg/day
with dose dependence and displaced kidneys Polyvinylchloride (PVC) /
were observed at 20 mg/kg/day. Although it was Polychlorotrifluoroethylene (PCTFE) /
observed at maternotoxic levels they may be Aluminium foil blisters containing 7 hard
attributable to a direct effect. Soft tissue and capsules.
skeletal variations in the foetuses were also
observed at 10 and 20 mg/kg/day. Lenalidomide 2.5 mg/5 mg/ 10 mg/ 15 mg hard
capsules
6. PHARMACEUTICAL
PARTICULARS Pack size of 7 or 21 capsules. Not all pack sizes
may be available.
6.1 List of excipients Lenalidomide 7.5 mg/ 20 mg/ 25 mg hard
capsules
Capsule contents
Pack size of 21 capsules.
Anhydrous lactose
Microcrystalline cellulose
Croscarmellose sodium
Magnesium stearate 6.6 Special precautions for disposal and
Capsule shell other handling
Lenalidomide 2.5 mg/ 10 mg/ 20 mg hard Capsules should not be opened or crushed. If
capsules powder from makes contact with the skin, the
Gelatin skin should be washed immediately and
Titanium dioxide (E171) thoroughly with soap and water. If makes
Indigo carmine (E132) contact with the mucous membranes, they
Yellow iron oxide (E172) should be thoroughly flushed with water.
Lenalidomide 5 mg/ 25 mg hard capsules
Gelatin
Any unused product or waste material should be

returned to the pharmacist for safe disposal in
accordance with local requirements.
7. MANUFACTURER:
Manufactured in India by:

TAJ PHARMACEUTICALS LTD.
Mumbai, India
Survey No.188/1 to 189/1,190/1 to 4,
Athiyawad, Dabhel,
Daman- 396210 (INDIA)

Lenalidomide 5 MG, 10mg, 15mg Hard Capsules SMPC - Taj Pharmaceuticals

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1.NAME OF THE MEDICINAL Lenalidomide as monotherapy is indicated for

• In case of neutropenia, the use of growth

• maintenance in patients who have undergone

• Dose reduction steps with a platelet count ≥ 100 x 109/L at the

• Dose reduction steps 1

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

• Thrombocytopenia Fall to < 50 x 109/L Interrupt treatment and

When neutrophils Recommended course When neutrophils Recommended Course

• Dose reduction steps

All indications No dose adjustment is proposed for patients

Special populations Multiple myeloma: patients with at least one

is primarily excreted by the kidney; patients cycles)

Pregnancy warning • She should be capable of complying with

• Understand the expected teratogenic risk if • Tubal sterilisation

associated with an increased risk of arterial Neutropenia and thrombocytopenia

Severe skin reactions In patients receiving in combination with

Cardiac Common Common General Very Common Common

Tissue Disorders Musculoskeletal pain

Disorders Neutropenia^,◊, Neutropenia^,◊, ~Altered mood was reported as a common

o All treatment-emergent adverse events with ≥ Disorders

5% of subjects in and at least 2% difference in

maintenance after ASCT is associated with a /dexamethasone-treated patients compared with

Concomitant administration of erythropoietic diagnosed multiple myeloma in patients taking

Gastrointestinal disorders binds directly to cereblon, a component of a

5. PHARMACOLOGICAL • maintenance in patients who have undergone

5.1 Pharmacodynamic properties The efficacy and safety of maintenance was

cycle). Treatment was to be continued until • in combination with dexamethasone in

This study investigated the use of combination HR [95% CI]; p-value

has an asymmetric carbon atom and can Biotransformation and elimination

At doses of 5 to 25 mg/day, half-life in plasma is Population pharmacokinetic analyses included

inflammation, lymphoid, and bone marrow Titanium dioxide (E171)

Any unused product or waste material should be

Manufactured in India by:

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