ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Revlimid 5 mg hard capsules
2.
Each capsule contains 5 mg of lenalidomide.
Excipient:
Each capsule contains 147 mg of anhydrous lactose.
For a full list of excipients, see section 6.1.
3.
Hard capsule.
White capsules marked “REV 5 mg”.
4.
Revlimid in combination with dexamethasone is indicated for the treatment of multiple myeloma
patients who have received at least one prior therapy.
Treatment must be initiated and monitored under the supervision of physicians experienced in the
management of multiple myeloma (MM).
Administration
Revlimid capsules should be taken at about the same time each day. The capsules should not be
opened, broken or chewed. The capsules should be swallowed whole, preferably with water, either
with or without food. If less than 12 hours has elapsed since missing a dose, the patient can take the
dose. If more than 12 hours has elapsed since missing a dose at the normal time, the patient should not
take the dose, but take the next dose at the normal time on the following day.
Recommended dose
The recommended starting dose of lenalidomide is 25 mg orally once daily on days 1-21 of repeated
28-day cycles. The recommended dose of dexamethasone is 40 mg orally once daily on days 1-4,
9-12, and 17-20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg once daily on
days 1-4 every 28 days. Dosing is continued or modified based upon clinical and laboratory findings
(see section 4.4). Prescribing physicians should carefully evaluate which dose of dexamethasone to
use, taking into account the condition and disease status of the patient.
Lenalidomide treatment must not be started if the Absolute Neutrophil Counts (ANC) < 1.0 x 10
9
/l,
and/or platelet counts < 75 x 10
9
/l or, dependent on bone marrow infiltration by plasma cells, platelet
counts < 30 x 10
9
/l.
Recommended dose adjustments during treatment and restart of treatment
Dose adjustments, as summarised below, are recommended to manage grade 3 or 4 neutropenia or
thrombocytopenia, or other grade 3 or 4 toxicity judged to be related to lenalidomide.
2
•
Dose reduction steps
Starting dose
25 mg
Dose level 1
15 mg
Dose level 2
10 mg
Dose level 3
5 mg
•
Platelet counts
Thrombocytopenia
When platelets
Recommended Course
First fall to < 30 x 10
9
/l
Interrupt lenalidomide treatment
Return to ≥ 30 x 10
9
/l
Resume lenalidomide at Dose Level 1
For each subsequent drop below 30 x 10
9
/l
Interrupt lenalidomide treatment
Return to ≥ 30 x 10
9
/l
Resume lenalidomide at next lower dose
level (Dose Level 2 or 3) once daily. Do
not dose below 5 mg once daily.
•
Absolute Neutrophil counts (ANC)
Neutropenia
When neutrophils
Recommended Course
First fall to < 0.5 x 10
9
/l
Interrupt lenalidomide treatment
Return to ≥ 0.5 x 10
9
/l when neutropenia is
the only observed toxicity
Resume lenalidomide at Starting Dose
once daily
Return to ≥ 0.5 x 10
9
/l when dose-dependent
haematological toxicities other than
neutropenia are observed
Resume lenalidomide at Dose Level 1
once daily
For each subsequent drop below < 0.5 x 10
9
/l Interrupt lenalidomide treatment
Return to ≥ 0.5 x 10
9
/l
Resume lenalidomide at next lower dose
level (Dose Level 1, 2 or 3) once daily.
Do not dose below 5 mg once daily.
In case of neutropenia, the physician should consider the use of growth factors in patient management.
Paediatric patients
There is no experience in children and adolescents. Therefore, lenalidomide should not be used in the
paediatric age group (0-17 years).
Elderly patients
The effects of age on the pharmacokinetics of lenalidomide have not been studied. Lenalidomide has
been used in clinical trials in multiple myeloma patients up to 86 years of age (see section 5.1). The
percentage of patients aged 65 or over was not significantly different between the
lenalidomide/dexamethasone and placebo/dexamethasone groups. No overall difference in safety or
efficacy was observed between these patients and younger patients, but greater pre-disposition of older
individuals cannot be ruled out. Because elderly patients are more likely to have decreased renal
function, care should be taken in dose selection and it would be prudent to monitor renal function.
Use in patients with impaired renal function
Lenalidomide is substantially excreted by the kidney, therefore care should be taken in dose selection
and monitoring of renal function is advised.
3
No dose adjustments are required for patients with mild renal impairment. The following dose
adjustments are recommended at the start of therapy for patients with moderate or severe impaired
renal function or end stage renal disease.
Renal Function (CLcr)
Dose Adjustment
Moderate renal impairment
(30 ≤ CLcr < 50 ml/min)
10 mg once daily*
Severe renal impairment
(CLcr < 30 ml/min, not requiring dialysis)
15 mg every other day**
5 mg once daily. On dialysis
days, the dose should be
administered following dialysis.
* The dose may be escalated to 15 mg once daily after 2 cycles if patient is not responding to treatment
and is tolerating the treatment.
** The dose may be escalated to 10 mg once daily if the patient is tolerating the treatment
End Stage Renal Disease (ESRD)
(CLcr < 30 ml/min, requiring dialysis)
After initiation of lenalidomide therapy, subsequent lenalidomide dose modification in renally
impaired patients should be based on individual patient treatment tolerance, as described above.
Use in patients with impaired hepatic function
Lenalidomide has not formally been studied in patients with impaired hepatic function and there are
no specific dose recommendations.
•
Women who are pregnant.
•
Women of childbearing potential unless all of the conditions of the Pregnancy Prevention
Programme are met (see sections 4.4 and 4.6).
•
Hypersensitivity to the active substance or to any of the excipients.
Pregnancy warning
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active
substance that causes severe life-threatening birth defects. Lenalidomide induced in monkeys
malformations similar to those described with thalidomide (see sections 4.6 and 5.3). If lenalidomide
is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected.
The conditions of the Pregnancy Prevention Programme must be fulfilled for all patients unless there
is reliable evidence that the patient does not have childbearing potential.
Criteria for women of non-childbearing potential
A female patient or a female partner of a male patient is considered to have childbearing potential
unless she meets at least one of the following criteria:
•
Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year*
•
Premature ovarian failure confirmed by a specialist gynaecologist
•
Previous bilateral salpingo-oophorectomy, or hysterectomy
•
XY genotype, Turner syndrome, uterine agenesis.
*Amenorrhoea following cancer therapy does not rule out childbearing potential
.
Counselling
For women of childbearing potential, lenalidomide is contraindicated unless all of the following are
met:
•
She understands the expected teratogenic risk to the unborn child
4
•
She understands the need for effective contraception, without interruption, 4 weeks before
starting treatment, throughout the entire duration of treatment, and 4 weeks after the end of
treatment
•
Even if a woman of childbearing potential has amenorrhea she must follow all the advice on
effective contraception
•
She should be capable of complying with effective contraceptive measures
•
She is informed and understands the potential consequences of pregnancy and the need to
rapidly consult if there is a risk of pregnancy
•
She understands the need to commence the treatment as soon as lenalidomide is dispensed
following a negative pregnancy test
•
She understands the need and accepts to undergo pregnancy testing every 4 weeks except in case
of confirmed tubal sterilisation
•
She acknowledges that she understands the hazards and necessary precautions associated with
the use of lenalidomide.
For male patients taking lenalidomide, pharmacokinetic data has demonstrated that lenalidomide is
present in human semen at extremely low levels during treatment and is undetectable in human semen
3 days after stopping the drug in the healthy subject (see section 5.2). As a precaution, all male
patients taking lenalidomide must meet the following conditions:
•
Understand the expected teratogenic risk if engaged in sexual activity with a pregnant woman or
a woman of childbearing potential
•
Understand the need for the use of a condom if engaged in sexual activity with a pregnant
woman or a woman of childbearing potential.
The prescriber must ensure that for women of childbearing potential:
•
The patient complies with the conditions of the Pregnancy Prevention Programme, including
confirmation that she has an adequate level of understanding
•
The patient has acknowledged the aforementioned conditions.
Contraception
Women of childbearing potential must use one effective method of contraception for 4 weeks before
therapy, during therapy, and until 4 weeks after lenalidomide therapy and even in case of dose
interruption unless the patient commits to absolute and continuous abstinence confirmed on a monthly
basis. If not established on effective contraception, the patient must be referred to an appropriately
trained health care professional for contraceptive advice in order that contraception can be initiated.
The following can be considered to be examples of suitable methods of contraception:
•
Implant
•
Levonorgestrel-releasing intrauterine system (IUS)
•
Medroxyprogesterone acetate depot
•
Tubal sterilisation
•
Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two
negative semen analyses
•
Ovulation inhibitory progesterone-only pills (i.e., desogestrel)
Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking
lenalidomide and dexamethasone, combined oral contraceptive pills are not recommended (see also
section 4.5). If a patient is currently using combined oral contraception the patient should switch to
one of the effective method listed above. The risk of venous thromboembolism continues for
4−6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive steroids
may be reduced during co-treatment with dexamethasone (see section 4.5).
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of
infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be
considered particularly in patients with neutropenia.
5
Copper-releasing intrauterine devices are generally not recommended due to the potential risks of
infection at the time of insertion and menstrual blood loss which may compromise patients with
neutropenia or thrombocytopenia.
Pregnancy testing
According to local practice, medically supervised pregnancy tests with a minimum sensitivity of
25 mIU/ml must be performed for women of childbearing potential as outlined below. This
requirement includes women of childbearing potential who practice absolute and continuous
abstinence. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same
day. Dispensing of lenalidomide to women of childbearing potential should occur within 7 days of the
prescription.
Prior to starting treatment
A medically supervised pregnancy test should be performed during the consultation, when
lenalidomide is prescribed, or in the 3 days prior to the visit to the prescriber once the patient had been
using effective contraception for at least 4 weeks. The test should ensure the patient is not pregnant
when she starts treatment with lenalidomide.
Follow-up and end of treatment
A medically supervised pregnancy test should be repeated every 4 weeks, including 4 weeks after the
end of treatment, except in the case of confirmed tubal sterilisation. These pregnancy tests should be
performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber.
Men
Lenalidomide is present in human semen at extremely low levels during treatment and is undetectable
in human semen 3 days after stopping the drug in the healthy subject (see section 5.2). As a
precaution, and taking into account special populations with prolonged elimination time such as renal
impairment, all male patients taking lenalidomide should use condoms throughout treatment duration,
during dose interruption and for 1 week after cessation of treatment if their partner is pregnant or of
childbearing potential and has no contraception.
Additional precautions
Patients should be instructed never to give this medicinal product to another person and to return any
unused capsules to their pharmacist at the end of treatment.
Patients should not donate blood during therapy or for 1 week following discontinuation of
lenalidomide.
Educational materials
In order to assist patients in avoiding foetal exposure to lenalidomide, the Marketing Authorisation
Holder will provide educational material to health care professionals to reinforce the warnings about
the expected teratogenicity of lenalidomide, to provide advice on contraception before therapy is
started, and to provide guidance on the need for pregnancy testing. Full patient information about the
expected teratogenic risk and the strict pregnancy prevention measures as specified in the Pregnancy
Prevention Programme should be given by the physician to women of childbearing potential and, as
appropriate, to male patients.
Other special warnings and precautions for use
Cardiovascular disorders
Myocardial Infarction
Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with
known risk factors. Patients with known risk factors – including prior thrombosis – should be closely
monitored, and action should be taken to try to minimize all modifiable risk factors (eg. smoking,
hypertension, and hyperlipidaemia).
6
Venous and arterial thromboembolic events
In patients with multiple myeloma, the combination of lenalidomide with dexamethasone is associated
with an increased risk of venous thromboembolism (predominantly deep vein thrombosis and
pulmonary embolism) and arterial thromboembolism (predominantly myocardial infarction and
cerebrovascular event) – see sections 4.5 and 4.8.
Consequently, patients with known risk factors for thromboembolism – including prior thrombosis –
should be closely monitored. Action should be taken to try to minimize all modifiable risk factors (e.g.
smoking, hypertension, and hyperlipidaemia). Concomitant administration of erythropoietic agents or
previous history of thromboembolic events may also increase thrombotic risk in these patients.
Therefore, erythropoietic agents, or other agents that may increase the risk of thrombosis, such as
hormone replacement therapy, should be used with caution in multiple myeloma patients receiving
lenalidomide with dexamethasone. A haemoglobin concentration above 12 g/dl should lead to
discontinuation of erythropoietic agents.
Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism.
Patients should be instructed to seek medical care if they develop symptoms such as shortness of
breath, chest pain, arm or leg swelling. Prophylactic antithrombotic medicines should be
recommended, especially in patients with additional thrombotic risk factors. The decision to take
antithrombotic prophylactic measures should be made after careful assessment of an individual
patient’s underlying risk factors.
If the patient experiences any thromboembolic events, treatment must be discontinued and standard
anticoagulation therapy started. Once the patient has been stabilised on the anticoagulation treatment
and any complications of the thromboembolic event have been managed, the lenalidomide treatment
may be restarted at the original dose dependent upon a benefit risk assessment. The patient should
continue anticoagulation therapy during the course of lenalidomide treatment.
Neutropenia and thrombocytopenia
The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with
a higher incidence of grade 4 neutropenia (5.1% in lenalidomide/dexamethasone-treated patients
compared with 0.6% in placebo/dexamethasone-treated patients; see section 4.8). Grade 4 febrile
neutropenia episodes were observed infrequently (0.6% in lenalidomide/dexamethasone-treated
patients compared to 0.0% in placebo/dexamethasone treated patients; see section 4.8). Patients should
be advised to promptly report febrile episodes. A dose reduction may be required (see section 4.2). In
case of neutropenia, the physician should consider the use of growth factors in patient management.
The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with
a higher incidence of grade 3 and grade 4 thrombocytopenia (9.9% and 1.4%, respectively, in
lenalidomide/dexamethasone-treated patients compared to 2.3% and 0.0% in
placebo/dexamethasone-treated patients; see section 4.8). Patients and physicians are advised to be
observant for signs and symptoms of bleeding, including petechiae and epistaxes, especially in case of
concomitant medication susceptible to induce bleeding (see Section 4.8 Haemorrhagic disorders). A
dose reduction of lenalidomide may be required (see section 4.2).
A complete blood cell count, including white blood cell count with differential count, platelet count,
haemoglobin, and haematocrit should be performed at baseline, every week for the first 8 weeks of
lenalidomide treatment and monthly thereafter to monitor for cytopenias.
The major dose limiting toxicities of lenalidomide include neutropenia and thrombocytopenia.
Therefore, co-administration of lenalidomide with other myelosuppressive agents should be
undertaken with caution.
Renal impairment
Lenalidomide is substantially excreted by the kidney. Therefore care should be taken in dose selection
and monitoring of renal function is advised in patients with renal impairment (see section 4.2).
7
Thyroid function
Cases of hypothyroidism have been reported and monitoring of thyroid function should be considered.
Peripheral neuropathy
Lenalidomide is structurally related to thalidomide, which is known to induce severe peripheral
neuropathy. At this time, the neurotoxic potential of lenalidomide associated with long-term use
cannot be ruled out.
Tumour Lysis Syndrome
Because lenalidomide has anti-neoplastic activity the complications of tumour lysis syndrome may
occur. The patients at risk of tumour lysis syndrome are those with high tumour burden prior to
treatment. These patients should be monitored closely and appropriate precautions taken.
Allergic Reactions
Cases of allergic reaction/hypersensitivity reactions have been reported (see section 4.8). Patients who
had previous allergic reactions while treated with thalidomide should be monitored closely, as a
possible cross-reaction between lenalidomide and thalidomide has been reported in the literature.
Severe skin reactions
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported.
Lenalidomide must be discontinued for exfoliative or bullous rash, or if SJS or TEN is suspected, and
should not be resumed following discontinuation for these reactions. Interruption or discontinuation of
lenalidomide should be considered for other forms of skin reaction depending on severity. Patients
with a history of severe rash associated with thalidomide treatment should not receive lenalidomide.
Lactose intolerance
Revlimid capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Unused capsules
Patients should be advised never to give this medicinal product to another person and to return any
unused capsules to their pharmacist at the end of the treatment.
Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as hormone
replacement therapy, should be used with caution in multiple myeloma patients receiving lenalidomide
with dexamethasone (see sections 4.4 and 4.8).
Oral contraceptives
No interaction study has been performed with oral contraceptives. Lenalidomide is not an enzyme
inducer. In an
in vitro
study with human hepatocytes, lenalidomide, at various concentrations tested
did not induce CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4/5. Therefore, induction leading
to reduced efficacy of drugs, including hormonal contraceptives, is not expected if lenalidomide is
administered alone. However, dexamethasone is known to be a weak to moderate inducer of CYP3A4
and is likely to also affect other enzymes as well as transporters. It may not be excluded that the
efficacy of oral contraceptives may be reduced during treatment. Effective measures to avoid
pregnancy must be taken (see sections 4.4 and 4.6).
Results from human
in vitro
metabolism studies indicate that lenalidomide is not metabolised by
cytochrome P450 enzymes suggesting that administration of lenalidomide with drugs that inhibit
cytochrome P450 enzymes is not likely to result in metabolic drug interactions in man.
In vitro
studies
indicate that lenalidomide has no inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6,
CYP2E1 or CYP3A.
8
Warfarin
Co-administration of multiple doses of 10 mg of lenalidomide had no effect on the single dose
pharmacokinetics of R- and S- warfarin. Co-administration of a single 25 mg dose of warfarin had no
effect on the pharmacokinetics of lenalidomide. However, it is not known whether there is an
interaction during clinical use (concomitant treatment with dexamethasone). Dexamethasone is a weak
to moderate enzyme inducer and its effect on warfarin is unknown. Close monitoring of warfarin
concentration is advised during the treatment.
Digoxin
Concomitant administration with lenalidomide 10 mg/day increased the plasma exposure of digoxin
(0.5 mg, single dose) by 14% with a 90% CI (confidence interval) [0.52%-28.2%]. It is not known
whether the effect will be different in the therapeutic situation (higher lenalidomide doses and
concomitant treatment with dexamethasone). Therefore, monitoring of the digoxin concentration is
advised during lenalidomide treatment.
Pregnancy (see also sections 4.3 and 4.4)
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active
substance that causes severe life-threatening birth defects.
Lenalidomide induced in monkeys malformations similar to those described with thalidomide (see
section 5.3). Therefore, a teratogenic effect of lenalidomide is expected and lenalidomide is
contraindicated during pregnancy (see section 4.3).
Women of childbearing potential should use effective method of contraception. If pregnancy occurs in
a woman treated with lenalidomide, treatment must be stopped and the patient should be referred to a
physician specialised or experienced in teratology for evaluation and advice. If pregnancy occurs in a
partner of a male patient taking lenalidomide, it is recommended to refer the female partner to a
physician specialised or experienced in teratology for evaluation and advice.
Lenalidomide is present in human semen at extremely low levels during treatment and is undetectable
in human semen 3 days after stopping the drug in the healthy subject (see section 5.2). As a
precaution, and taking into account special populations with prolonged elimination time such as renal
impairment, all male patients taking lenalidomide should use condoms throughout treatment duration,
during dose interruption and for 1 week after cessation of treatment if their partner is pregnant or of
childbearing potential and has no contraception.
Lactation
It is not known whether lenalidomide is excreted in human milk. Therefore breast-feeding should be
discontinued during therapy with lenalidomide.
No studies on the effects on the ability to drive and use machines have been performed. Lenalidomide
may have minor or moderate influence on the ability to drive and use machines. Fatigue, dizziness,
somnolence and blurred vision have been reported with the use of lenalidomide. Therefore, caution is
recommended when driving or operating machines.
a.
Summary of the safety profile in patients with multiple myeloma
In two Phase III placebo-controlled studies, 353 patients with multiple myeloma were exposed to the
lenalidomide/dexamethasone combination and 351 to the placebo/dexamethasone combination. The
median duration of exposure to study treatment was significantly longer (44.0 weeks) in the
lenalidomide/dexamethasone group as compared to placebo/dexamethasone (23.1 weeks). The
9
difference was accounted for by a lower rate of discontinuation from study treatment due to lower
progression of disease in patients exposed to lenalidomide/dexamethasone (39.7%) than in
placebo/dexamethasone patients (70.4%).
325 (92%) of the patients in the lenalidomide/dexamethasone group experienced at least one adverse
reaction compared to 288 (82%) in the placebo/dexamethasone group.
The most serious adverse reactions were:
•
Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see section 4.4)
•
Grade 4 neutropenia (see section 4.4).
The most frequently observed adverse reactions which occurred significantly more frequently in the
lenalidomide/dexamethasone group compared to the placebo/dexamethasone group were neutropenia
(39.4%), fatigue (27.2%), asthenia (17.6%), constipation (23.5%), muscle cramp (20.1%),
thrombocytopenia (18.4%), anaemia (17.0%), diarrhoea (14.2%) and rash (10.2%).
The adverse reactions observed in patients treated with lenalidomide/dexamethasone are listed below
by system organ class and frequency. Within each frequency grouping, adverse reactions are presented
in order of decreasing seriousness. Frequencies are defined as: very common (≥ 1/10); common
(≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare
(< 1/10,000 including isolated reports), unknown (cannot be estimated from the available data).
b.
Tabulated summary of adverse reactions
The following table is derived from data gathered during the pivotal studies. The data were not
adjusted according to the greater duration of treatment in the lenalidomide/dexamethasone versus the
placebo/dexamethasone arms in the pivotal studies (See section 5.1).
Table 1: ADRs reported in clinical studies in patients with multiple myeloma treated with
lenalidomide
System Organ Class
/ Preferred Term
All ADRs/Frequency
Grade 3−4 ADRs/Frequency
Infections
and Infestations
Very Common
Pneumonia, Upper respiratory tract
infection
Common
Sepsis, Bacterial, viral and fungal
infections (including opportunistic
infections), Sinusitis
Common
Pneumonia, Bacterial, viral and
fungal infections (including
opportunistic infections)
Neoplasms benign,
malignant and
unspecified
Uncommon
Basal cell carcinoma
Blood and Lymphatic
System Disorders
Very Common
Thrombocytopenia^, Neutropenias^,
Anaemia,
Haemorrhagic disorder^,
Leucopenias
Common
Pancytopenia
Uncommon
Haemolysis, Autoimmune
haemolytic anaemia, Haemolytic
anaemia
Very Common
Thrombocytopenia^,
Neutropenias^, Leucopenias
Common
Febrile Neutropenia, Anaemia
Uncommon
Hypercoagulation, Coagulopathy
Immune System
Disorders
Uncommon
Hypersensitivity^
Endocrine Disorders
Common
Hypothyroidism
10
System Organ Class
/ Preferred Term
All ADRs/Frequency
Grade 3−4 ADRs/Frequency
Metabolism and
Nutrition Disorders
Very Common
Hypokalaemia, Decreased appetite
Common
Hypomagnesaemia, Hypocalcaemia,
Dehydration
Common
Hypokalaemia, Hypocalcaemia,
Hypophosphataemia
Psychiatric Disorder
Uncommon
Loss of libido
Common
Depression
Nervous System
disorders
Very Common
Peripheral neuropathies (excluding
motor neuropathy), Dizziness,
Tremor, Dysgeusia, Headache
Common
Ataxia, Balance impaired
Common
Cerebrovascular Accident,
Dizziness, Syncope
Uncommon
Intracranial haemorrhage^,
Transient ischaemic attack,
Cerebral ischaemia
Eye Disorders
Very Common
Blurred vision
Common
Reduced visual acuity, Cataract
Common
Cataract
Uncommon
Blindness
Ear and
Labyrinth Disorders
Common
Deafness (Including Hypoacusis),
Tinnitus
Cardiac Disorders
Common
Atrial Fibrillation, Bradycardia
Uncommon
Arrhythmia, QT prolongation, Atrial
flutter, Ventricular extrasystoles
Common
Myocardial infarction^, Atrial
Fibrillation, Congestive Cardiac,
Failure, Tachycardia
Vascular Disorders
Very Common
Venous Thromboembolic Events,
predominantly Deep Vein
Thrombosis and Pulmonary
Embolism^
Common
Hypotension, Hypertension,
Ecchymosis^
Very Common
Venous Thromboembolic Events,
predominantly Deep Vein
Thrombosis and Pulmonary
Embolism^
Uncommon
Ischemia, Peripheral ischemia,
Intracranial venous sinus
thrombosis
Respiratory,
Thoracic
and Mediastinal
Disorders
Very common
Dyspnoea, Nasopharyngitis,
Pharyngitis, Bronchitis, Epistaxis^
Common
Respiratory Distress
Gastrointestinal
Disorders
Very Common
Constipation, Diarrhoea, Nausea,
Vomiting
Common
Gastrointestinal Haemorrhage
(including rectal haemorrhage,
haemorrhoidal haemorrhage, peptic
ulcer haemorrhage and gingival
bleeding)^, Abdominal Pain, Dry
Mouth, Stomatitis, Dysphagia
Uncommon
Colitis, Caecitis
Common
Diarrhoea, Constipation, Nausea
Hepatobiliary
Disorders
Common
Abnormal Liver Function Tests
Common
Abnormal Liver Function Tests
11
System Organ Class
/ Preferred Term
All ADRs/Frequency
Grade 3−4 ADRs/Frequency
Skin and
Subcutaneous
tissue Disorders
Very Common
Rashes
Common
Urticaria, Hyperhidrosis, Dry Skin,
Pruritus, Skin Hyperpigmentation,
Eczema
Uncommon
Skin discolouration, Photosensitivity
reaction
Common
Rashes
Musculoskeletal
and connective
tissue disorders
Very Common
Muscle Spasms, Bone Pain,
Musculoskeletal and connective
tissue pain and discomfort
Common
Joint swelling
Common
Muscle Weakness, Bone Pain
Uncommon
Joint swelling
Renal and
Urinary
Disorders
Common
Haematuria^, Urinary retention ,
Urinary incontinence
Uncommon
Acquired Fanconi syndrome
Common
Renal failure
Uncommon
Renal tubular necrosis
Reproductive System
and Breast Disorders
Common
Erectile Dysfunction
General disorders
and administration
site conditions
Very Common
Fatigue, Oedema (including
peripheral oedema), Pyrexia,
Influenza like illness syndrome
(including pyrexia, myalgia,
musculoskeletal pain, headache and
rigors)
Common
Chest Pain, Lethargy
Common
Fatigue
Injury, poisoning and
procedural
complications
Common
Contusion^
^See section 4.8c.
In addition to the above adverse drug reactions identified from the pivotal trials, the following table is
derived from data gathered during post-marketing experience.
Table 2: Summary of adverse drug reactions identified from post-marketing data in patients
treated with lenalidomide
System organ class Reactions/frequency
Neoplasms benign, malignant and unspecified
Rare:
Tumour lysis syndrome
Respiratory, Thoracic and Mediastinal Disorders
Unknown:
Interstitial pneumonitis
Gastrointestinal disorders
Unknown:
Pancreatitis
Uncommon:
Angioedema
Rare:
Stevens-Johnson Syndrome^, toxic
epidermal necrolysis^
Skin and subcutaneous system disorders
^see section 4.8c
c.
Description of selected adverse reactions
Teratogenicity
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active
substance that causes severe life-threatening birth defects. Lenalidomide induced in monkeys
12
malformations similar to those described with thalidomide (see sections 4.6 and 5.3). If lenalidomide
is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected.
Neutropenia and thrombocytopenia
The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with
a higher incidence of grade 4 neutropenia (5.1% in lenalidomide/dexamethasone-treated patients
compared with 0.6% in placebo/dexamethasone-treated patients). Grade 4 febrile neutropenia episodes
were observed infrequently (0.6% in lenalidomide/dexamethasone-treated patients compared to 0.0%
in placebo/dexamethasone treated patients).
The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with
a higher incidence of grade 3 and grade 4 thrombocytopenia (9.9% and 1.4%, respectively, in
lenalidomide/dexamethasone-treated patients compared to 2.3% and 0.0% in
placebo/dexamethasone-treated patients).
Venous thromboembolism
The combination of lenalidomide with dexamethasone is associated with an increased risk of DVT and
PE in patients with multiple myeloma (see section 4.5). Concomitant administration of erythropoietic
agents or previous history of DVT may also increase thrombotic risk in these patients.
Myocardial Infarction
Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with
known risk factors.
Haemorrhagic disorders
Haemorrhagic disorders are listed under several system organ classes: Blood and lymphatic system
disorders; nervous system disorders (intracranial haemorrhage); respiratory, thoracic and mediastinal
disorders (epistaxis); gastrointestinal disorders (gingival bleeding, haemorrhoidal haemorrhage, rectal
haemorrhage); renal and urinary disorders (haematuria); Injury, poisoning and procedural
complications (contusion) and vascular disorders (ecchymosis).
Allergic Reactions
Cases of allergic reaction/hypersensitivity reactions have been reported. A possible cross-reaction
between lenalidomide and thalidomide has been reported in the literature.
Severe skin reactions
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. Patients
with a history of severe rash associated with thalidomide treatment should not receive lenalidomide.
There is no specific experience in the management of lenalidomide overdose in multiple myeloma
patients, although in dose-ranging studies some patients were exposed to up to 150 mg, and in single-
dose studies, some patients were exposed to up to 400 mg. The dose limiting toxicity in these studies
was essentially haematological. In the event of overdose, supportive care is advised.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunomodulating agent. ATC code: L04 AX04.
The lenalidomide mechanism of action includes anti-neoplastic, anti-angiogenic, pro-erythropoietic,
and immunomodulatory properties. Specifically, lenalidomide inhibits proliferation of certain
haematopoietic tumour cells (including MM plasma tumour cells and those with deletions of
chromosome 5), enhances T cell- and Natural Killer (NK) cell-mediated immunity and increases the
13
number of NK T cells, inhibits angiogenesis by blocking the migration and adhesion of endothelial
cells and the formation of microvessels, augments foetal haemoglobin production by CD34+
haematopoietic stem cells, and inhibits production of pro-inflammatory cytokines (e.g., TNF-α and
IL-6) by monocytes.
Clinical trials
The efficacy and safety of lenalidomide were evaluated in two Phase III multi-centre, randomised,
double-blind, placebo-controlled, parallel-group controlled studies (MM-009 and MM-010) of
lenalidomide plus dexamethasone therapy versus dexamethasone alone in previously treated patients
with multiple myeloma. Out of 353 patients in the MM-009 and MM-010 studies who received
lenalidomide/dexamethasone, 45.6% were aged 65 or over. Of the 704 patients evaluated in the
MM-009 and MM-010 studies, 44.6% were aged 65 or over.
In both studies, patients in the lenalidomide/dexamethasone (len/dex) group took 25 mg of
lenalidomide orally once daily on Days 1 to 21 and a matching placebo capsule once daily on Days 22
to 28 of each 28-day cycle. Patients in the placebo/dexamethasone (placebo/dex) group took 1 placebo
capsule on Days 1 to 28 of each 28-day cycle. Patients in both treatment groups took 40 mg of
dexamethasone orally once daily on Days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the
first 4 cycles of therapy. The dose of dexamethasone was reduced to 40 mg orally once daily on
Days 1 to 4 of each 28-day cycle after the first 4 cycles of therapy. In both studies, treatment was to
continue until disease progression. In both studies, dose adjustments were allowed based on clinical
and laboratory finding.
The primary efficacy endpoint in both studies was time to progression (TTP). In total, 353 patients
were evaluated in the MM-009 study; 177 in the lenalidomide/dexamethasone group and 176 in the
placebo/dexamethasone group and, in total, 351 patients were evaluated in the MM-010 study; 176 in
the lenalidomide/dexamethasone group and 175 in the placebo/dexamethasone group.
In both studies, the baseline demographic and disease-related characteristics were comparable between
the lenalidomide/dexamethasone and placebo/dexamethasone groups. Both patient populations
presented a median age of 63 years, with a comparable male to female ratio. The ECOG performance
status was comparable between both groups, as was the number and type of prior therapies.
Pre-planned interim analyses of both studies showed that lenalidomide/dexamethasone was
statistically significantly superior (p < 0.00001) to dexamethasone alone for the primary efficacy
endpoint, TTP (median follow-up duration of 98.0 weeks). Complete response and overall response
rates in the lenalidomide/dexamethasone arm were also significantly higher than the
dexamethasone/placebo arm in both studies. Results of these analyses subsequently led to an
unblinding in both studies, in order to allow patients in the placebo/dexamethasone group to receive
treatment with the lenalidomide/dexamethasone combination.
An extended follow-up efficacy analysis was conducted with a median follow-up of 130.7 weeks.
Table 1 summarises the results of the follow-up efficacy analyses – pooled studies MM-009 and
MM-010.
In this pooled extended follow-up analysis, the median TTP was 60.1 weeks (95% CI: 44.3, 73.1) in
patients treated with lenalidomide/dexamethasone (N = 353) versus 20.1 weeks (95% CI: 17.7, 20.3)
in patients treated with placebo/dexamethasone (N = 351). The median progression free survival was
48.1 weeks (95% CI: 36.4, 62.1) in patients treated with lenalidomide/dexamethasone versus 20.0
weeks (95% CI: 16.1, 20.1) in patients treated with placebo/dexamethasone. The median duration of
treatment was 44.0 weeks (min: 0.1, max: 254.9) for lenalidomide/dexamethasone and 23.1 weeks
(min: 0.3, max: 238.1) for placebo/dexamethasone. Complete response (CR), partial response (PR)
and overall response (CR+PR) rates in the lenalidomide/dexamethasone arm remain significantly
higher than in the dexamethasone/placebo arm in both studies. The median overall survival in the
extended follow-up analysis of the pooled studies is 164.3 weeks (95% CI: 145.1, 192.6) in patients
treated with lenalidomide/dexamethasone versus 136.4 weeks (95% CI: 113.1, 161.7) in patients
treated with placebo/dexamethasone. Despite the fact that 170 out of the 351 patients randomised to
14
placebo/dexamethasone received lenalidomide after disease progression or after the studies were
unblinded, the pooled analysis of overall survival demonstrated a statistically significant survival
advantage for lenalidomide/dexamethasone relative to placebo/dexamethasone (hazard ratio = 0.833,
95% CI = [0.687, 1.009], p=0.045).
Table 1:
Summary of Results of Efficacy Analyses as of cut-off date for extended follow-
up — Pooled Studies MM-009 and MM-010 (cut-offs 23 July 2008 and 2 March
2008, respectively)
Endpoint
len/dex
(N=353)
placebo/dex
(N=351)
Time to Event
Hazard ratio [95% CI],
p-value
a
Time To Progression
Median [95% CI], weeks
60.1 [44.3,
73.1]
20.1 [17.7,
20.3]
0.350 [0. 287, 0. 426]
,
p < 0.001
Progression Free Survival
Median [95% CI], weeks
48.1
[36. 4, 62.1]
20.0 [16.1,
20.1]
0.393 [0.326, 0.473]
p < 0.001
Overall Survival
Median [95% CI], weeks
1-year Overall Survival rate
164.3 [145.1,
192.6]
82%
136.4
[113.1,
161.7]
75%
0.833 [0.687, , 1.009]
p = 0.045
Response rate
Odds ratio [95% CI], p-value
b
Overall Response [n, %]
Complete Response [n, %]
212 (60.1)
58 (16.4)
75 (21.4)
11 (3.1)
5.53 [3.97, 7.71], p < 0.001
6.08 [3.13, 11.80], p < 0.001
a: Two-tailed log rank test comparing survival curves between treatment groups.
b: Two-tailed continuity-corrected chi-square test.
Exploratory study
An open-label, randomized, multicenter, Phase 3 study was conducted in 445 patients with newly
diagnosed multiple myeloma; 222 patients were randomized to the lenalidomide/low dose
dexamethasone arm, and 223 were randomized to the lenalidomide/standard dose dexamethasone arm.
Patients randomized to the lenalidomide/standard dose dexamethasone arm received lenalidomide 25
mg/day, Days 1 to 21 every 28 days plus dexamethasone 40 mg/day on Days 1 to 4, 9 to 12, and 17 to
20 every 28 days for the first four cycles. Patients randomized to the lenalidomide/low dose
dexamethasone arm received lenalidomide 25 mg/day, Days 1 to 21 every 28 days plus low dose
dexamethasone – 40 mg/day on Days 1, 8, 15, and 22 every 28 days. In the lenalidomide/low dose
dexamethasone group, 20 patients (9.1%) underwent at least one dose interruption compared to 65
patients (29.3%) in the lenalidomide/standard dose dexamethasone arm.
In a post-hoc analysis, lower mortality was observed in the lenalidomide/low dose dexamethasone arm
6.8% (15/220) compared to the lenalidomide/standard dose dexamethasone arm 19.3% (43/223), in the
newly diagnosed multiple myeloma patient population, with a median follow up of 72.3 weeks.
However with a longer follow-up, the difference in overall survival in favour of low dose
dexamethasone tends to decrease.
Considering that the patient population differs from the authorised indication, these results should be
interpreted with caution.
5.2 Pharmacokinetic properties
Lenalidomide has an asymmetric carbon atom and can therefore exist as the optically active forms S(-)
and R(+). Lenalidomide is produced as a racemic mixture. Lenalidomide is generally more soluble in
organic solvents but exhibits the greatest solubility in 0.1N HCl buffer.
15
Absorption
Lenalidomide is rapidly absorbed following oral administration in healthy volunteers, under fasting
conditions, with maximum plasma concentrations occurring between 0.5 and 2 hours post-dose. In
patients, as well as in healthy volunteers, the maximum concentration (C
max
) and area-under-the-
concentration time curve (AUC) increase proportionally with increases in dose. Multiple dosing does
not cause marked drug accumulation. In plasma, the relative exposures of the S- and R- enantiomers of
lenalidomide are approximately 56% and 44%, respectively.
Co-administration with a high-fat and high-calorie meal in healthy volunteers reduces the extent of
absorption, resulting in an approximately 20% decrease in area under the concentration versus time
curve (AUC) and 50% decrease in Cmax in plasma. However, in the pivotal multiple myeloma
registration trials where the efficacy and safety were established for lenalidomide, the drug was
administered without regard to food intake. Thus, lenalidomide can be administered with or without
food.
Distribution
In vitro
(
14
C)-lenalidomide binding to plasma proteins was low with mean plasma protein binding at
23% and 29% in multiple myeloma patients and healthy volunteers, respectively.
Lenalidomide is present in human semen (< 0.01% of the dose) after administration of 25 mg/day and
the drug is undetectable in semen of a healthy subject 3 days after stopping the drug (see section 4.4).
Metabolism and excretion
In vitro
studies indicate that lenalidomide has no inhibitory effect on CYP1A2, CYP2C9, CYP2C19,
CYP2D6, CYP2E1, and CYP3A.
A majority of lenalidomide is eliminated through urinary excretion. The contribution of renal
excretion to total clearance in subjects with normal renal function was 90%, with 4% of lenalidomide
eliminated in faeces.
Lenalidomide is poorly metabolized as 82% of the dose is excreted unchanged in urine. Hydroxy-
lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose,
respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate and therefore is
at least actively secreted to some extent.
At recommended doses (5 to 25 mg/day), half-life in plasma is approximately 3 hours in healthy
volunteers and patients with multiple myeloma.
Pharmacokinetics analyses in patients with impaired renal function indicate that as renal function
decreases (< 50 ml/min), the total drug clearance decreases proportionally resulting in an increase in
AUC. The half-life of lenalidomide increased from approximately 3.5 hours in subjects with creatinine
clearance > 50 ml/min to more than 9 hours in subjects with reduced renal function < 50 ml/min.
However, renal impairment did not alter the oral absorption of lenalidomide. The C
max
was similar
between healthy subjects and patients with renal impairment. Recommended dose adjustments in
patients with impaired renal function are described in section 4.2.
5.3 Preclinical safety data
An embryofoetal development study has been conducted in monkeys administered lenalidomide at
doses from 0.5 and up to 4 mg/kg/day. Findings from this study indicate that lenalidomide produced
external malformations including non-patent anus and malformations of upper and lower extremities
(bent, shortened, malformed, malrotated and/or absent part of the extremities, oligo and/or
polydactyly) in the offspring of female monkeys who received the drug during pregnancy.
Various visceral effects (discoloration, red foci at different organs, small colorless mass above atrio-
ventricular valve, small gall bladder, malformed diaphragm) were also observed in single fetuses.
16
Lenalidomide has a potential for acute toxicity; minimum lethal doses after oral administration were
> 2000 mg/kg/day in rodents. Repeated oral administration of 75, 150 and 300 mg/kg/day to rats for
up to 26 weeks produced a reversible treatment-related increase in kidney pelvis mineralisation in all
3 doses, most notably in females. The no observed adverse effect level (NOAEL) was considered to be
less than 75 mg/kg/day, and is approximately 25-fold greater than the human daily exposure based on
AUC exposure. Repeated oral administration of 4 and 6 mg/kg/day to monkeys for up to 20 weeks
produced mortality and significant toxicity (marked weight loss, reduced red and white blood cell and
platelet counts, multiple organ haemorrhage, gastrointestinal tract inflammation, lymphoid, and bone
marrow atrophy). Repeated oral administration of 1 and 2 mg/kg/day to monkeys for up to 1 year
produced reversible changes in bone marrow cellularity, a slight decrease in myeloid:erythroid cell
ratio and thymic atrophy. Mild suppression of white blood cell count was observed at 1 mg/kg/day
corresponding to approximately the same human dose based on AUC comparisons.
In vitro
(bacterial mutation, human lymphocytes, mouse lymphoma, Syrian Hamster Embryo cell
transformation) and
in vivo
(rat micronucleus) mutagenicity studies revealed no drug related effects at
either the gene or chromosomal level. Carcinogenicity studies with lenalidomide have not been
conducted.
Developmental toxicity studies were previously conducted in rabbits. In these studies, rabbits were
administered 3, 10 and 20 mg/kg/day orally. An absence of the intermediate lobe of the lung was
observed at 10 and 20 mg/kg/day with dose dependence and displaced kidneys were observed at
20 mg/kg/day. Although it was observed at maternotoxic levels they may be attributable to a direct
effect. Soft tissue and skeletal variations in the foetuses were also observed at 10 and 20 mg/kg/day.
6.
6.1 List of excipients
Capsule contents: Lactose, anhydrous
Cellulose, microcrystalline
Croscarmellose sodium
Magnesium stearate
Capsule shell:
Gelatin
Titanium dioxide (E171)
Printing ink:
Shellac
Propylene glycol
Black iron oxide (E172)
Potassium hydroxide
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
17
6.5 Nature and contents of container
The capsules are provided in carton packs. Each pack contains three Polyvinylchloride (PVC) /
Polychlorotrifluoroethylene (PCTFE) / Aluminium foil blisters, each with seven capsules. This gives a
total of 21 capsules per pack.
6.6 Special precautions for disposal
Unused medicinal product should be returned to the pharmacist.
7.
Celgene Europe Limited
Riverside House
Riverside Walk
Windsor
Berkshire
SL4 1NA
United Kingdom
8.
EU/1/07/391/001
9.
14/06/2007
Detailed information on this medicine is available on the website of the European Medicines Agency:
http://www.ema.europa.eu/.
18
1.
Revlimid 10 mg hard capsules
2.
Each capsule contains 10 mg of lenalidomide.
Excipient:
Each capsule contains 294 mg of anhydrous lactose.
For a full list of excipients, see section 6.1.
3.
Hard capsule.
Blue-green/pale yellow capsules marked “REV 10 mg”.
4.
Revlimid in combination with dexamethasone is indicated for the treatment of multiple myeloma
patients who have received at least one prior therapy.
Treatment must be initiated and monitored under the supervision of physicians experienced in the
management of multiple myeloma (MM).
Administration
Revlimid capsules should be taken at about the same time each day. The capsules should not be
opened, broken or chewed. The capsules should be swallowed whole, preferably with water, either
with or without food. If less than 12 hours has elapsed since missing a dose, the patient can take the
dose. If more than 12 hours has elapsed since missing a dose at the normal time, the patient should not
take the dose, but take the next dose at the normal time on the following day.
Recommended dose
The recommended starting dose of lenalidomide is 25 mg orally once daily on days 1-21 of repeated
28-day cycles. The recommended dose of dexamethasone is 40 mg orally once daily on days 1-4,
9-12, and 17-20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg once daily on
days 1-4 every 28 days. Dosing is continued or modified based upon clinical and laboratory findings
(see section 4.4). Prescribing physicians should carefully evaluate which dose of dexamethasone to
use, taking into account the condition and disease status of the patient.
Lenalidomide treatment must not be started if the Absolute Neutrophil Counts (ANC) < 1.0 x 10
9
/l,
and/or platelet counts < 75 x 10
9
/l or, dependent on bone marrow infiltration by plasma cells, platelet
counts < 30 x 10
9
/l.
Recommended dose adjustments during treatment and restart of treatment
Dose adjustments, as summarised below, are recommended to manage grade 3 or 4 neutropenia or
thrombocytopenia, or other grade 3 or 4 toxicity judged to be related to lenalidomide.
19
•
Dose reduction steps
Starting dose
25 mg
Dose level 1
15 mg
Dose level 2
10 mg
Dose level 3
5 mg
•
Platelet counts
Thrombocytopenia
When platelets
Recommended Course
First fall to < 30 x 10
9
/l
Interrupt lenalidomide treatment
Return to ≥ 30 x 10
9
/l
Resume lenalidomide at Dose Level 1
For each subsequent drop below 30 x 10
9
/l
Interrupt lenalidomide treatment
Return to ≥ 30 x 10
9
/l
Resume lenalidomide at next lower dose
level (Dose Level 2 or 3) once daily. Do
not dose below 5 mg once daily.
•
Absolute Neutrophil counts (ANC)
Neutropenia
When neutrophils
Recommended Course
First fall to < 0.5 x 10
9
/l
Interrupt lenalidomide treatment
Return to ≥ 0.5 x 10
9
/l when neutropenia is
the only observed toxicity
Resume lenalidomide at Starting Dose
once daily
Return to ≥ 0.5 x 10
9
/l when dose-dependent
haematological toxicities other than
neutropenia are observed
Resume lenalidomide at Dose Level 1
once daily
For each subsequent drop below < 0.5 x 10
9
/l Interrupt lenalidomide treatment
Return to ≥ 0.5 x 10
9
/l
Resume lenalidomide at next lower dose
level (Dose Level 1, 2 or 3) once daily.
Do not dose below 5 mg once daily.
In case of neutropenia, the physician should consider the use of growth factors in patient management.
Paediatric patients
There is no experience in children and adolescents. Therefore, lenalidomide should not be used in the
paediatric age group (0-17 years).
Elderly patients
The effects of age on the pharmacokinetics of lenalidomide have not been studied. Lenalidomide has
been used in clinical trials in multiple myeloma patients up to 86 years of age (see section 5.1). The
percentage of patients aged 65 or over was not significantly different between the
lenalidomide/dexamethasone and placebo/dexamethasone groups. No overall difference in safety or
efficacy was observed between these patients and younger patients, but greater pre-disposition of older
individuals cannot be ruled out. Because elderly patients are more likely to have decreased renal
function, care should be taken in dose selection and it would be prudent to monitor renal function.
Use in patients with impaired renal function
Lenalidomide is substantially excreted by the kidney, therefore care should be taken in dose selection
and monitoring of renal function is advised.
20
No dose adjustments are required for patients with mild renal impairment. The following dose
adjustments are recommended at the start of therapy for patients with moderate or severe impaired
renal function or end stage renal disease.
Renal Function (CLcr)
Dose Adjustment
Moderate renal impairment
(30 ≤ CLcr < 50 ml/min)
10 mg once daily*
Severe renal impairment
(CLcr < 30 ml/min, not requiring dialysis)
15 mg every other day**
5 mg once daily. On dialysis
days, the dose should be
administered following dialysis.
* The dose may be escalated to 15 mg once daily after 2 cycles if patient is not responding to treatment
and is tolerating the treatment.
** The dose may be escalated to 10 mg once daily if the patient is tolerating the treatment
End Stage Renal Disease (ESRD)
(CLcr < 30 ml/min, requiring dialysis)
After initiation of lenalidomide therapy, subsequent lenalidomide dose modification in renally
impaired patients should be based on individual patient treatment tolerance, as described above.
Use in patients with impaired hepatic function
Lenalidomide has not formally been studied in patients with impaired hepatic function and there are
no specific dose recommendations.
•
Women who are pregnant.
•
Women of childbearing potential unless all of the conditions of the Pregnancy Prevention
Programme are met (see sections 4.4 and 4.6).
•
Hypersensitivity to the active substance or to any of the excipients.
Pregnancy warning
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active
substance that causes severe life-threatening birth defects. Lenalidomide induced in monkeys
malformations similar to those described with thalidomide (see sections 4.6 and 5.3). If lenalidomide
is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected.
The conditions of the Pregnancy Prevention Programme must be fulfilled for all patients unless there
is reliable evidence that the patient does not have childbearing potential.
Criteria for women of non-childbearing potential
A female patient or a female partner of a male patient is considered to have childbearing potential
unless she meets at least one of the following criteria:
•
Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year*
•
Premature ovarian failure confirmed by a specialist gynaecologist
•
Previous bilateral salpingo-oophorectomy, or hysterectomy
•
XY genotype, Turner syndrome, uterine agenesis.
*Amenorrhoea following cancer therapy does not rule out childbearing potential
.
Counselling
For women of childbearing potential, lenalidomide is contraindicated unless all of the following are
met:
•
She understands the expected teratogenic risk to the unborn child
21
•
She understands the need for effective contraception, without interruption, 4 weeks before
starting treatment, throughout the entire duration of treatment, and 4 weeks after the end of
treatment
•
Even if a woman of childbearing potential has amenorrhea she must follow all the advice on
effective contraception
•
She should be capable of complying with effective contraceptive measures
•
She is informed and understands the potential consequences of pregnancy and the need to
rapidly consult if there is a risk of pregnancy
•
She understands the need to commence the treatment as soon as lenalidomide is dispensed
following a negative pregnancy test
•
She understands the need and accepts to undergo pregnancy testing every 4 weeks except in case
of confirmed tubal sterilisation
•
She acknowledges that she understands the hazards and necessary precautions associated with
the use of lenalidomide.
For male patients taking lenalidomide, pharmacokinetic data has demonstrated that lenalidomide is
present in human semen at extremely low levels during treatment and is undetectable in human semen
3 days after stopping the drug in the healthy subject (see section 5.2). As a precaution, all male
patients taking lenalidomide must meet the following conditions:
•
Understand the expected teratogenic risk if engaged in sexual activity with a pregnant woman or
a woman of childbearing potential
•
Understand the need for the use of a condom if engaged in sexual activity with a pregnant
woman or a woman of childbearing potential.
The prescriber must ensure that for women of childbearing potential:
•
The patient complies with the conditions of the Pregnancy Prevention Programme, including
confirmation that she has an adequate level of understanding
•
The patient has acknowledged the aforementioned conditions.
Contraception
Women of childbearing potential must use one effective method of contraception for 4 weeks before
therapy, during therapy, and until 4 weeks after lenalidomide therapy and even in case of dose
interruption unless the patient commits to absolute and continuous abstinence confirmed on a monthly
basis. If not established on effective contraception, the patient must be referred to an appropriately
trained health care professional for contraceptive advice in order that contraception can be initiated.
The following can be considered to be examples of suitable methods of contraception:
•
Implant
•
Levonorgestrel-releasing intrauterine system (IUS)
•
Medroxyprogesterone acetate depot
•
Tubal sterilisation
•
Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two
negative semen analyses
•
Ovulation inhibitory progesterone-only pills (i.e., desogestrel)
Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking
lenalidomide and dexamethasone, combined oral contraceptive pills are not recommended (see also
section 4.5). If a patient is currently using combined oral contraception the patient should switch to
one of the effective method listed above. The risk of venous thromboembolism continues for
4−6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive steroids
may be reduced during co-treatment with dexamethasone (see section 4.5).
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of
infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be
considered particularly in patients with neutropenia.
22
Copper-releasing intrauterine devices are generally not recommended due to the potential risks of
infection at the time of insertion and menstrual blood loss which may compromise patients with
neutropenia or thrombocytopenia.
Pregnancy testing
According to local practice, medically supervised pregnancy tests with a minimum sensitivity of
25 mIU/ml must be performed for women of childbearing potential as outlined below. This
requirement includes women of childbearing potential who practice absolute and continuous
abstinence. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same
day. Dispensing of lenalidomide to women of childbearing potential should occur within 7 days of the
prescription.
Prior to starting treatment
A medically supervised pregnancy test should be performed during the consultation, when
lenalidomide is prescribed, or in the 3 days prior to the visit to the prescriber once the patient had been
using effective contraception for at least 4 weeks. The test should ensure the patient is not pregnant
when she starts treatment with lenalidomide.
Follow-up and end of treatment
A medically supervised pregnancy test should be repeated every 4 weeks, including 4 weeks after the
end of treatment, except in the case of confirmed tubal sterilisation. These pregnancy tests should be
performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber.
Men
Lenalidomide is present in human semen at extremely low levels during treatment and is undetectable
in human semen 3 days after stopping the drug in the healthy subject (see section 5.2). As a
precaution, and taking into account special populations with prolonged elimination time such as renal
impairment, all male patients taking lenalidomide should use condoms throughout treatment duration,
during dose interruption and for 1 week after cessation of treatment if their partner is pregnant or of
childbearing potential and has no contraception.
Additional precautions
Patients should be instructed never to give this medicinal product to another person and to return any
unused capsules to their pharmacist at the end of treatment.
Patients should not donate blood during therapy or for 1 week following discontinuation of
lenalidomide.
Educational materials
In order to assist patients in avoiding foetal exposure to lenalidomide, the Marketing Authorisation
Holder will provide educational material to health care professionals to reinforce the warnings about
the expected teratogenicity of lenalidomide, to provide advice on contraception before therapy is
started, and to provide guidance on the need for pregnancy testing. Full patient information about the
expected teratogenic risk and the strict pregnancy prevention measures as specified in the Pregnancy
Prevention Programme should be given by the physician to women of childbearing potential and, as
appropriate, to male patients.
Other special warnings and precautions for use
Cardiovascular disorders
Myocardial Infarction
Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with
known risk factors. Patients with known risk factors – including prior thrombosis – should be closely
monitored, and action should be taken to try to minimize all modifiable risk factors (eg. smoking,
hypertension, and hyperlipidaemia).
23
Venous and arterial thromboembolic events
In patients with multiple myeloma, the combination of lenalidomide with dexamethasone is associated
with an increased risk of venous thromboembolism (predominantly deep vein thrombosis and
pulmonary embolism) and arterial thromboembolism (predominantly myocardial infarction and
cerebrovascular event) – see sections 4.5 and 4.8.
Consequently, patients with known risk factors for thromboembolism – including prior thrombosis –
should be closely monitored. Action should be taken to try to minimize all modifiable risk factors (e.g.
smoking, hypertension, and hyperlipidaemia). Concomitant administration of erythropoietic agents or
previous history of thromboembolic events may also increase thrombotic risk in these patients.
Therefore, erythropoietic agents, or other agents that may increase the risk of thrombosis, such as
hormone replacement therapy, should be used with caution in multiple myeloma patients receiving
lenalidomide with dexamethasone. A haemoglobin concentration above 12 g/dl should lead to
discontinuation of erythropoietic agents.
Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism.
Patients should be instructed to seek medical care if they develop symptoms such as shortness of
breath, chest pain, arm or leg swelling. Prophylactic antithrombotic medicines should be
recommended, especially in patients with additional thrombotic risk factors. The decision to take
antithrombotic prophylactic measures should be made after careful assessment of an individual
patient’s underlying risk factors.
If the patient experiences any thromboembolic events, treatment must be discontinued and standard
anticoagulation therapy started. Once the patient has been stabilised on the anticoagulation treatment
and any complications of the thromboembolic event have been managed, the lenalidomide treatment
may be restarted at the original dose dependent upon a benefit risk assessment. The patient should
continue anticoagulation therapy during the course of lenalidomide treatment.
Neutropenia and thrombocytopenia
The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with
a higher incidence of grade 4 neutropenia (5.1% in lenalidomide/dexamethasone-treated patients
compared with 0.6% in placebo/dexamethasone-treated patients; see section 4.8). Grade 4 febrile
neutropenia episodes were observed infrequently (0.6% in lenalidomide/dexamethasone-treated
patients compared to 0.0% in placebo/dexamethasone treated patients; see section 4.8). Patients should
be advised to promptly report febrile episodes. A dose reduction may be required (see section 4.2). In
case of neutropenia, the physician should consider the use of growth factors in patient management.
The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with
a higher incidence of grade 3 and grade 4 thrombocytopenia (9.9% and 1.4%, respectively, in
lenalidomide/dexamethasone-treated patients compared to 2.3% and 0.0% in
placebo/dexamethasone-treated patients; see section 4.8). Patients and physicians are advised to be
observant for signs and symptoms of bleeding, including petechiae and epistaxes, especially in case of
concomitant medication susceptible to induce bleeding (see Section 4.8 Haemorrhagic disorders). A
dose reduction of lenalidomide may be required (see section 4.2).
A complete blood cell count, including white blood cell count with differential count, platelet count,
haemoglobin, and haematocrit should be performed at baseline, every week for the first 8 weeks of
lenalidomide treatment and monthly thereafter to monitor for cytopenias.
The major dose limiting toxicities of lenalidomide include neutropenia and thrombocytopenia.
Therefore, co-administration of lenalidomide with other myelosuppressive agents should be
undertaken with caution.
Renal impairment
Lenalidomide is substantially excreted by the kidney. Therefore care should be taken in dose selection
and monitoring of renal function is advised in patients with renal impairment (see section 4.2).
24
Thyroid function
Cases of hypothyroidism have been reported and monitoring of thyroid function should be considered.
Peripheral neuropathy
Lenalidomide is structurally related to thalidomide, which is known to induce severe peripheral
neuropathy. At this time, the neurotoxic potential of lenalidomide associated with long-term use
cannot be ruled out.
Tumour Lysis Syndrome
Because lenalidomide has anti-neoplastic activity the complications of tumour lysis syndrome may
occur. The patients at risk of tumour lysis syndrome are those with high tumour burden prior to
treatment. These patients should be monitored closely and appropriate precautions taken.
Allergic Reactions
Cases of allergic reaction/hypersensitivity reactions have been reported (see section 4.8). Patients who
had previous allergic reactions while treated with thalidomide should be monitored closely, as a
possible cross-reaction between lenalidomide and thalidomide has been reported in the literature.
Severe skin reactions
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported.
Lenalidomide must be discontinued for exfoliative or bullous rash, or if SJS or TEN is suspected, and
should not be resumed following discontinuation for these reactions. Interruption or discontinuation of
lenalidomide should be considered for other forms of skin reaction depending on severity. Patients
with a history of severe rash associated with thalidomide treatment should not receive lenalidomide.
Lactose intolerance
Revlimid capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Unused capsules
Patients should be advised never to give this medicinal product to another person and to return any
unused capsules to their pharmacist at the end of the treatment.
Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as hormone
replacement therapy, should be used with caution in multiple myeloma patients receiving lenalidomide
with dexamethasone (see sections 4.4 and 4.8).
Oral contraceptives
No interaction study has been performed with oral contraceptives. Lenalidomide is not an enzyme
inducer. In an
in vitro
study with human hepatocytes, lenalidomide, at various concentrations tested
did not induce CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4/5. Therefore, induction leading
to reduced efficacy of drugs, including hormonal contraceptives, is not expected if lenalidomide is
administered alone. However, dexamethasone is known to be a weak to moderate inducer of CYP3A4
and is likely to also affect other enzymes as well as transporters. It may not be excluded that the
efficacy of oral contraceptives may be reduced during treatment. Effective measures to avoid
pregnancy must be taken (see sections 4.4 and 4.6).
Results from human
in vitro
metabolism studies indicate that lenalidomide is not metabolised by
cytochrome P450 enzymes suggesting that administration of lenalidomide with drugs that inhibit
cytochrome P450 enzymes is not likely to result in metabolic drug interactions in man.
In vitro
studies
indicate that lenalidomide has no inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6,
CYP2E1 or CYP3A.
25
Warfarin
Co-administration of multiple doses of 10 mg of lenalidomide had no effect on the single dose
pharmacokinetics of R- and S- warfarin. Co-administration of a single 25 mg dose of warfarin had no
effect on the pharmacokinetics of lenalidomide. However, it is not known whether there is an
interaction during clinical use (concomitant treatment with dexamethasone). Dexamethasone is a weak
to moderate enzyme inducer and its effect on warfarin is unknown. Close monitoring of warfarin
concentration is advised during the treatment.
Digoxin
Concomitant administration with lenalidomide 10 mg/day increased the plasma exposure of digoxin
(0.5 mg, single dose) by 14% with a 90% CI (confidence interval) [0.52%-28.2%]. It is not known
whether the effect will be different in the therapeutic situation (higher lenalidomide doses and
concomitant treatment with dexamethasone). Therefore, monitoring of the digoxin concentration is
advised during lenalidomide treatment.
Pregnancy (see also sections 4.3 and 4.4)
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active
substance that causes severe life-threatening birth defects.
Lenalidomide induced in monkeys malformations similar to those described with thalidomide (see
section 5.3). Therefore, a teratogenic effect of lenalidomide is expected and lenalidomide is
contraindicated during pregnancy (see section 4.3).
Women of childbearing potential should use effective method of contraception. If pregnancy occurs in
a woman treated with lenalidomide, treatment must be stopped and the patient should be referred to a
physician specialised or experienced in teratology for evaluation and advice. If pregnancy occurs in a
partner of a male patient taking lenalidomide, it is recommended to refer the female partner to a
physician specialised or experienced in teratology for evaluation and advice.
Lenalidomide is present in human semen at extremely low levels during treatment and is undetectable
in human semen 3 days after stopping the drug in the healthy subject (see section 5.2). As a
precaution, and taking into account special populations with prolonged elimination time such as renal
impairment, all
male patients taking lenalidomide should use condoms throughout treatment duration,
during dose interruption and for 1 week after cessation of treatment if their partner is pregnant or of
childbearing potential and has no contraception.
Lactation
It is not known whether lenalidomide is excreted in human milk. Therefore breast-feeding should be
discontinued during therapy with lenalidomide.
No studies on the effects on the ability to drive and use machines have been performed. Lenalidomide
may have minor or moderate influence on the ability to drive and use machines. Fatigue, dizziness,
somnolence and blurred vision have been reported with the use of lenalidomide. Therefore, caution is
recommended when driving or operating machines.
a.
Summary of the safety profile in patients with multiple myeloma
In two Phase III placebo-controlled studies, 353 patients with multiple myeloma were exposed to the
lenalidomide/dexamethasone combination and 351 to the placebo/dexamethasone combination. The
median duration of exposure to study treatment was significantly longer (44.0 weeks) in the
lenalidomide/dexamethasone group as compared to placebo/dexamethasone (23.1 weeks). The
26
difference was accounted for by a lower rate of discontinuation from study treatment due to lower
progression of disease in patients exposed to lenalidomide/dexamethasone (39.7%) than in
placebo/dexamethasone patients (70.4%).
325 (92%) of the patients in the lenalidomide/dexamethasone group experienced at least one adverse
reaction compared to 288 (82%) in the placebo/dexamethasone group.
The most serious adverse reactions were:
•
Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see section 4.4)
•
Grade 4 neutropenia (see section 4.4).
The most frequently observed adverse reactions which occurred significantly more frequently in the
lenalidomide/dexamethasone group compared to the placebo/dexamethasone group were neutropenia
(39.4%), fatigue (27.2%), asthenia (17.6%), constipation (23.5%), muscle cramp (20.1%),
thrombocytopenia (18.4%), anaemia (17.0%), diarrhoea (14.2%) and rash (10.2%).
The adverse reactions observed in patients treated with lenalidomide/dexamethasone are listed below
by system organ class and frequency. Within each frequency grouping, adverse reactions are presented
in order of decreasing seriousness. Frequencies are defined as: very common (≥ 1/10); common
(≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare
(< 1/10,000 including isolated reports), unknown (cannot be estimated from the available data).
The following table is derived from data gathered during the pivotal studies. The data were not
adjusted according to the greater duration of treatment in the lenalidomide/dexamethasone versus the
placebo/dexamethasone arms in the pivotal studies (See section 5.1).
b.
Tabulated summary of adverse reactions
Table 1: ADRs reported in clinical studies in patients with multiple myeloma treated with
lenalidomide
System Organ Class
/ Preferred Term
All ADRs/Frequency
Grade 3−4 ADRs/Frequency
Infections
and Infestations
Very Common
Pneumonia, Upper respiratory tract
infection
Common
Sepsis, Bacterial, viral and fungal
infections (including opportunistic
infections), Sinusitis
Common
Pneumonia, Bacterial, viral and
fungal infections (including
opportunistic infections)
Neoplasms benign,
malignant and
unspecified
Uncommon
Basal cell carcinoma
Blood and Lymphatic
System Disorders
Very Common
Thrombocytopenia^,
Neutropenias^, Anaemia,
Haemorrhagic disorder^,
Leucopenias
Common
Pancytopenia
Uncommon
Haemolysis, Autoimmune
haemolytic anaemia, Haemolytic
anaemia
Very Common
Thrombocytopenia^,
Neutropenias^, Leucopenias
Common
Febrile Neutropenia, Anaemia
Uncommon
Hypercoagulation, Coagulopathy
Immune System
Disorders
Uncommon
Hypersensitivity^
Endocrine Disorders
Common
Hypothyroidism
27
System Organ Class
/ Preferred Term
All ADRs/Frequency
Grade 3−4 ADRs/Frequency
Metabolism and
Nutrition Disorders
Very Common
Hypokalaemia, Decreased appetite
Common
Hypomagnesaemia,
Hypocalcaemia, Dehydration
Common
Hypokalaemia, Hypocalcaemia,
Hypophosphataemia
Psychiatric Disorder
Uncommon
Loss of libido
Common
Depression
Nervous System
disorders
Very Common
Peripheral neuropathies (excluding
motor neuropathy), Dizziness,
Tremor, Dysgeusia, Headache
Common
Ataxia, Balance impaired
Common
Cerebrovascular Accident,
Dizziness, Syncope
Uncommon
Intracranial haemorrhage^,
Transient ischaemic attack,
Cerebral ischaemia
Eye Disorders
Very Common
Blurred vision
Common
Reduced visual acuity, Cataract
Common
Cataract
Uncommon
Blindness
Ear and
Labyrinth Disorders
Common
Deafness (Including Hypoacusis),
Tinnitus
Cardiac Disorders
Common
Atrial Fibrillation, Bradycardia
Uncommon
Arrhythmia, QT prolongation,
Atrial flutter, Ventricular
extrasystoles
Common
Myocardial infarction^, Atrial
Fibrillation, Congestive Cardiac,
Failure, Tachycardia
Vascular Disorders
Very Common
Venous Thromboembolic Events,
predominantly Deep Vein
Thrombosis and Pulmonary
Embolism^
Common
Hypotension, Hypertension,
Ecchymosis^
Very Common
Venous Thromboembolic Events,
predominantly Deep Vein
Thrombosis and Pulmonary
Embolism^
Uncommon
Ischemia, Peripheral ischemia,
Intracranial venous sinus
thrombosis
Respiratory,
Thoracic
and Mediastinal
Disorders
Very common
Dyspnoea, Nasopharyngitis,
Pharyngitis, Bronchitis, Epistaxis^
Common
Respiratory Distress
Gastrointestinal
Disorders
Very Common
Constipation, Diarrhoea, Nausea,
Vomiting
Common
Gastrointestinal Haemorrhage
(including rectal haemorrhage,
haemorrhoidal haemorrhage, peptic
ulcer haemorrhage and gingival
bleeding)^, Abdominal Pain, Dry
Mouth, Stomatitis, Dysphagia
Uncommon
Colitis, Caecitis
Common
Diarrhoea, Constipation, Nausea
Hepatobiliary
Disorders
Common
Abnormal Liver Function Tests
Common
Abnormal Liver Function Tests
28
System Organ Class
/ Preferred Term
All ADRs/Frequency
Grade 3−4 ADRs/Frequency
Skin and
Subcutaneous
tissue Disorders
Very Common
Rashes
Common
Urticaria, Hyperhidrosis, Dry Skin,
Pruritus, Skin Hyperpigmentation,
Eczema
Uncommon
Skin discolouration,
Photosensitivity reaction
Common
Rashes
Musculoskeletal
and connective
tissue disorders
Very Common
Muscle Spasms, Bone Pain,
Musculoskeletal and connective
tissue pain and discomfort
Common
Joint swelling
Common
Muscle Weakness, Bone Pain
Uncommon
Joint swelling
Renal and
Urinary
Disorders
Common
Haematuria^, Urinary retention ,
Urinary incontinence
Uncommon
Acquired Fanconi syndrome
Common
Renal failure
Uncommon
Renal tubular necrosis
Reproductive System
and Breast Disorders
Common
Erectile Dysfunction
General disorders
and administration
site conditions
Very Common
Fatigue, Oedema (including
peripheral oedema), Pyrexia,
Influenza like illness syndrome
(including pyrexia, myalgia,
musculoskeletal pain, headache and
rigors)
Common
Chest Pain, Lethargy
Common
Fatigue
Injury, poisoning and
procedural
complications
Common
Contusion^
^See section 4.8c.
In addition to the above adverse drug reactions identified from the pivotal trials, the following table is
derived from data gathered during post-marketing experience.
Table 2: Summary of adverse drug reactions identified from post-marketing data in patients
treated with lenalidomide
System organ class Reactions/frequency
Neoplasms benign, malignant and unspecified
Rare:
Tumour lysis syndrome
Respiratory, Thoracic and Mediastinal Disorders
Unknown:
Interstitial pneumonitis
Gastrointestinal disorders
Unknown:
Pancreatitis
Uncommon:
Angioedema
Rare:
Stevens-Johnson Syndrome^, toxic
epidermal necrolysis^
Skin and subcutaneous system disorders
^see section 4.8c
c.
Description of selected adverse reactions
Teratogenicity
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active
substance that causes severe life-threatening birth defects. Lenalidomide induced in monkeys
29
malformations similar to those described with thalidomide (see sections 4.6 and 5.3). If lenalidomide
is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected.
Neutropenia and thrombocytopenia
The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with
a higher incidence of grade 4 neutropenia (5.1% in lenalidomide/dexamethasone-treated patients
compared with 0.6% in placebo/dexamethasone-treated patients). Grade 4 febrile neutropenia episodes
were observed infrequently (0.6% in lenalidomide/dexamethasone-treated patients compared to 0.0%
in placebo/dexamethasone treated patients).
The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with
a higher incidence of grade 3 and grade 4 thrombocytopenia (9.9% and 1.4%, respectively, in
lenalidomide/dexamethasone-treated patients compared to 2.3% and 0.0% in
placebo/dexamethasone-treated patients).
Venous thromboembolism
The combination of lenalidomide with dexamethasone is associated with an increased risk of DVT and
PE in patients with multiple myeloma (see section 4.5). Concomitant administration of erythropoietic
agents or previous history of DVT may also increase thrombotic risk in these patients.
Myocardial Infarction
Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with
known risk factors.
Haemorrhagic disorders
Haemorrhagic disorders are listed under several system organ classes: Blood and lymphatic system
disorders; nervous system disorders (intracranial haemorrhage); respiratory, thoracic and mediastinal
disorders (epistaxis); gastrointestinal disorders (gingival bleeding, haemorrhoidal haemorrhage, rectal
haemorrhage); renal and urinary disorders (haematuria); Injury, poisoning and procedural
complications (contusion) and vascular disorders (ecchymosis).
Allergic Reactions
Cases of allergic reaction/hypersensitivity reactions have been reported. A possible cross-reaction
between lenalidomide and thalidomide has been reported in the literature.
Severe skin reactions
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. Patients
with a history of severe rash associated with thalidomide treatment should not receive lenalidomide.
There is no specific experience in the management of lenalidomide overdose in multiple myeloma
patients, although in dose-ranging studies some patients were exposed to up to 150 mg, and in single-
dose studies, some patients were exposed to up to 400 mg. The dose limiting toxicity in these studies
was essentially haematological. In the event of overdose, supportive care is advised.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunomodulating agent. ATC code: L04 AX04.
The lenalidomide mechanism of action includes anti-neoplastic, anti-angiogenic, pro-erythropoietic,
and immunomodulatory properties. Specifically, lenalidomide inhibits proliferation of certain
haematopoietic tumour cells (including MM plasma tumour cells and those with deletions of
chromosome 5), enhances T cell- and Natural Killer (NK) cell-mediated immunity and increases the
30
number of NK T cells, inhibits angiogenesis by blocking the migration and adhesion of endothelial
cells and the formation of microvessels, augments foetal haemoglobin production by CD34+
haematopoietic stem cells, and inhibits production of pro-inflammatory cytokines (e.g., TNF-α and
IL-6) by monocytes.
Clinical trials
The efficacy and safety of lenalidomide were evaluated in two Phase III multi-centre, randomised,
double-blind, placebo-controlled, parallel-group controlled studies (MM-009 and MM-010) of
lenalidomide plus dexamethasone therapy versus dexamethasone alone in previously treated patients
with multiple myeloma. Out of 353 patients in the MM-009 and MM-010 studies who received
lenalidomide/dexamethasone, 45.6% were aged 65 or over. Of the 704 patients evaluated in the
MM-009 and MM-010 studies, 44.6% were aged 65 or over.
In both studies, patients in the lenalidomide/dexamethasone (len/dex) group took 25 mg of
lenalidomide orally once daily on Days 1 to 21 and a matching placebo capsule once daily on Days 22
to 28 of each 28-day cycle. Patients in the placebo/dexamethasone (placebo/dex) group took 1 placebo
capsule on Days 1 to 28 of each 28-day cycle. Patients in both treatment groups took 40 mg of
dexamethasone orally once daily on Days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the
first 4 cycles of therapy. The dose of dexamethasone was reduced to 40 mg orally once daily on
Days 1 to 4 of each 28-day cycle after the first 4 cycles of therapy. In both studies, treatment was to
continue until disease progression. In both studies, dose adjustments were allowed based on clinical
and laboratory finding.
The primary efficacy endpoint in both studies was time to progression (TTP). In total, 353 patients
were evaluated in the MM-009 study; 177 in the lenalidomide/dexamethasone group and 176 in the
placebo/dexamethasone group and, in total, 351 patients were evaluated in the MM-010 study; 176 in
the lenalidomide/dexamethasone group and 175 in the placebo/dexamethasone group.
In both studies, the baseline demographic and disease-related characteristics were comparable between
the lenalidomide/dexamethasone and placebo/dexamethasone groups. Both patient populations
presented a median age of 63 years, with a comparable male to female ratio. The ECOG performance
status was comparable between both groups, as was the number and type of prior therapies.
Pre-planned interim analyses of both studies showed that lenalidomide/dexamethasone was
statistically significantly superior (p < 0.00001) to dexamethasone alone for the primary efficacy
endpoint, TTP (median follow-up duration of 98.0 weeks). Complete response and overall response
rates in the lenalidomide/dexamethasone arm were also significantly higher than the
dexamethasone/placebo arm in both studies. Results of these analyses subsequently led to an
unblinding in both studies, in order to allow patients in the placebo/dexamethasone group to receive
treatment with the lenalidomide/dexamethasone combination.
An extended follow-up efficacy analysis was conducted with a median follow-up of 130.7 weeks.
Table 1 summarises the results of the follow-up efficacy analyses – pooled studies MM-009 and
MM-010.
In this pooled extended follow-up analysis, the median TTP was 60.1 weeks (95% CI: 44.3, 73.1) in
patients treated with lenalidomide/dexamethasone (N = 353) versus 20.1 weeks (95% CI: 17.7, 20.3)
in patients treated with placebo/dexamethasone (N = 351). The median progression free survival was
48.1 weeks (95% CI: 36.4, 62.1) in patients treated with lenalidomide/dexamethasone versus 20.0
weeks (95% CI: 16.1, 20.1) in patients treated with placebo/dexamethasone. The median duration of
treatment was 44.0 weeks (min: 0.1, max: 254.9) for lenalidomide/dexamethasone and 23.1 weeks
(min: 0.3, max: 238.1) for placebo/dexamethasone. Complete response (CR), partial response (PR)
and overall response (CR+PR) rates in the lenalidomide/dexamethasone arm remain significantly
higher than in the dexamethasone/placebo arm in both studies. The median overall survival in the
extended follow-up analysis of the pooled studies is 164.3 weeks (95% CI: 145.1, 192.6) in patients
treated with lenalidomide/dexamethasone versus 136.4 weeks (95% CI: 113.1, 161.7) in patients
treated with placebo/dexamethasone. Despite the fact that 170 out of the 351 patients randomised to
31
placebo/dexamethasone received lenalidomide after disease progression or after the studies were
unblinded, the pooled analysis of overall survival demonstrated a statistically significant survival
advantage for lenalidomide/dexamethasone relative to placebo/dexamethasone (hazard ratio = 0.833,
95% CI = [0.687, 1.009], p=0.045).
Table 1:
Summary of Results of Efficacy Analyses as of cut-off date for extended follow-
up — Pooled Studies MM-009 and MM-010 (cut-offs 23 July 2008 and 2 March
2008, respectively)
Endpoint
len/dex
(N=353)
placebo/dex(N
=351)
Time to Event
Hazard ratio [95% CI],
p-value
a
Time To Progression
Median [95% CI], weeks
60.1 [44.3,
73.1]
20.1 [17.7,
20.3]
0.350 [0.287, 0.426], p < 0.001
Progression Free Survival
Median [95% CI], weeks
48.1
[36.4, 62.1]
20.0
[16.1, 20.1]
0.393 [0.326, 0.473]
p < 0.001
b
Overall Survival
Median [95% CI], weeks
1-year Overall Survival rate
164.3 [145.1,
192.6]
82%
136.4 [113.1,
161.7]
75%
0.833 [0. 687, 1.009]
p = 0.045
Response rate
Odds ratio [95% CI], p-value
b
Overall Response [n, %]
Complete Response [n, %]
212 (60.1)
58 (16.4)
75 (21.4)
11 (3.1)
5.53 [3.97, 7.71], p < 0.001
6.08 [3.13, 11.80], p < 0.001
a: Two-tailed log rank test comparing survival curves between treatment groups.
b: Two-tailed continuity-corrected chi-square test.
Exploratory study
An open-label, randomized, multicenter, Phase 3 study was conducted in 445 patients with newly
diagnosed multiple myeloma; 222 patients were randomized to the lenalidomide/low dose
dexamethasone arm, and 223 were randomized to the lenalidomide/standard dose dexamethasone arm.
Patients randomized to the lenalidomide/standard dose dexamethasone arm received lenalidomide 25
mg/day, Days 1 to 21 every 28 days plus dexamethasone 40 mg/day on Days 1 to 4, 9 to 12, and 17 to
20 every 28 days for the first four cycles. Patients randomized to the lenalidomide/low dose
dexamethasone arm received lenalidomide 25 mg/day, Days 1 to 21 every 28 days plus low dose
dexamethasone – 40 mg/day on Days 1, 8, 15, and 22 every 28 days. In the lenalidomide/low dose
dexamethasone group, 20 patients (9.1%) underwent at least one dose interruption compared to 65
patients (29.3%) in the lenalidomide/standard dose dexamethasone arm.
In a post-hoc analysis, lower mortality was observed in the lenalidomide/low dose dexamethasone arm
6.8% (15/220) compared to the lenalidomide/standard dose dexamethasone arm 19.3% (43/223), in the
newly diagnosed multiple myeloma patient population, with a median follow up of 72.3 weeks.
However with a longer follow-up, the difference in overall survival in favour of low dose
dexamethasone tends to decrease.
Considering that the patient population differs from the authorised indication, these results should be
interpreted with caution.
5.2 Pharmacokinetic properties
Lenalidomide has an asymmetric carbon atom and can therefore exist as the optically active forms S(-)
and R(+). Lenalidomide is produced as a racemic mixture. Lenalidomide is generally more soluble in
organic solvents but exhibits the greatest solubility in 0.1N HCl buffer.
32
Absorption
Lenalidomide is rapidly absorbed following oral administration in healthy volunteers, under fasting
conditions, with maximum plasma concentrations occurring between 0.5 and 2 hours post-dose. In
patients, as well as in healthy volunteers, the maximum concentration (C
max
) and area-under-the-
concentration time curve (AUC) increase proportionally with increases in dose. Multiple dosing does
not cause marked drug accumulation. In plasma, the relative exposures of the S- and R- enantiomers of
lenalidomide are approximately 56% and 44%, respectively.
Co-administration with a high-fat and high-calorie meal in healthy volunteers reduces the extent of
absorption, resulting in an approximately 20% decrease in area under the concentration versus time
curve (AUC) and 50% decrease in Cmax in plasma. However, in the pivotal multiple myeloma
registration trials where the efficacy and safety were established for lenalidomide, the drug was
administered without regard to food intake. Thus, lenalidomide can be administered with or without
food.
Distribution
In vitro
(
14
C)-lenalidomide binding to plasma proteins was low with mean plasma protein binding at
23% and 29% in multiple myeloma patients and healthy volunteers, respectively.
Lenalidomide is present in human semen (< 0.01% of the dose) after administration of 25 mg/day and
the drug is undetectable in semen of a healthy subject 3 days after stopping the drug (see section 4.4).
Metabolism and excretion
In vitro
studies indicate that lenalidomide has no inhibitory effect on CYP1A2, CYP2C9, CYP2C19,
CYP2D6, CYP2E1, and CYP3A.
A majority of lenalidomide is eliminated through urinary excretion. The contribution of renal
excretion to total clearance in subjects with normal renal function was 90%, with 4% of lenalidomide
eliminated in faeces.
Lenalidomide is poorly metabolized as 82% of the dose is excreted unchanged in urine. Hydroxy-
lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose,
respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate and therefore is
at least actively secreted to some extent.
At recommended doses (5 to 25 mg/day), half-life in plasma is approximately 3 hours in healthy
volunteers and patients with multiple myeloma.
Pharmacokinetics analyses in patients with impaired renal function indicate that as renal function
decreases (< 50 ml/min), the total drug clearance decreases proportionally resulting in an increase in
AUC. The half-life of lenalidomide increased from approximately 3.5 hours in subjects with creatinine
clearance > 50 ml/min to more than 9 hours in subjects with reduced renal function < 50 ml/min.
However, renal impairment did not alter the oral absorption of lenalidomide. The C
max
was similar
between healthy subjects and patients with renal impairment. Recommended dose adjustments in
patients with impaired renal function are described in section 4.2.
5.3 Preclinical safety data
An embryofoetal development study has been conducted in monkeys administered lenalidomide at
doses from 0.5 and up to 4 mg/kg/day. Findings from this study indicate that lenalidomide produced
external malformations including non-patent anus and malformations of upper and lower extremities
(bent, shortened, malformed, malrotated and/or absent part of the extremities, oligo and/or
polydactyly) in the offspring of female monkeys who received the drug during pregnancy.
Various visceral effects (discoloration, red foci at different organs, small colorless mass above atrio-
ventricular valve, small gall bladder, malformed diaphragm) were also observed in single fetuses.
33
Lenalidomide has a potential for acute toxicity; minimum lethal doses after oral administration were
> 2000 mg/kg/day in rodents. Repeated oral administration of 75, 150 and 300 mg/kg/day to rats for
up to 26 weeks produced a reversible treatment-related increase in kidney pelvis mineralisation in all
3 doses, most notably in females. The no observed adverse effect level (NOAEL) was considered to be
less than 75 mg/kg/day, and is approximately 25-fold greater than the human daily exposure based on
AUC exposure. Repeated oral administration of 4 and 6 mg/kg/day to monkeys for up to 20 weeks
produced mortality and significant toxicity (marked weight loss, reduced red and white blood cell and
platelet counts, multiple organ haemorrhage, gastrointestinal tract inflammation, lymphoid, and bone
marrow atrophy). Repeated oral administration of 1 and 2 mg/kg/day to monkeys for up to 1 year
produced reversible changes in bone marrow cellularity, a slight decrease in myeloid:erythroid cell
ratio and thymic atrophy. Mild suppression of white blood cell count was observed at 1 mg/kg/day
corresponding to approximately the same human dose based on AUC comparisons.
In vitro
(bacterial mutation, human lymphocytes, mouse lymphoma, Syrian Hamster Embryo cell
transformation) and
in vivo
(rat micronucleus) mutagenicity studies revealed no drug related effects at
either the gene or chromosomal level. Carcinogenicity studies with lenalidomide have not been
conducted.
Developmental toxicity studies were previously conducted in rabbits. In these studies, rabbits were
administered 3, 10 and 20 mg/kg/day orally. An absence of the intermediate lobe of the lung was
observed at 10 and 20 mg/kg/day with dose dependence and displaced kidneys were observed at
20 mg/kg/day. Although it was observed at maternotoxic levels they may be attributable to a direct
effect. Soft tissue and skeletal variations in the foetuses were also observed at 10 and 20 mg/kg/day.
6.
6.1 List of excipients
Capsule contents: Lactose, anhydrous
Cellulose, microcrystalline
Croscarmellose sodium
Magnesium stearate
Capsule shell:
Gelatin
Titanium dioxide (E171)
Indigo carmine (E132)
Yellow iron oxide (E172)
Printing ink:
Shellac
Propylene glycol
Black iron oxide (E172)
Potassium hydroxide
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
34
6.5 Nature and contents of container
The capsules are provided in carton packs. Each pack contains three Polyvinylchloride (PVC) /
Polychlorotrifluoroethylene (PCTFE) / Aluminium foil blisters, each with seven capsules. This gives a
total of 21 capsules per pack.
6.6 Special precautions for disposal
Unused medicinal product should be returned to the pharmacist.
7.
Celgene Europe Limited
Riverside House
Riverside Walk
Windsor
Berkshire
SL4 1NA
United Kingdom
8.
EU/1/07/391/002
9.
14/06/2007
Detailed information on this medicine is available on the website of the European Medicines Agency:
http://www.ema.europa.eu/.
35
1.
Revlimid 15 mg hard capsules
2.
Each capsule contains 15 mg of lenalidomide.
Excipient:
Each capsule contains 289 mg of anhydrous lactose.
For a full list of excipients, see section 6.1.
3.
Hard capsule.
Pale blue/white capsules marked “REV 15 mg”.
4.
Revlimid in combination with dexamethasone is indicated for the treatment of multiple myeloma
patients who have received at least one prior therapy.
Treatment must be initiated and monitored under the supervision of physicians experienced in the
management of multiple myeloma (MM).
Administration
Revlimid capsules should be taken at about the same time each day. The capsules should not be
opened, broken or chewed. The capsules should be swallowed whole, preferably with water, either
with or without food. If less than 12 hours has elapsed since missing a dose, the patient can take the
dose. If more than 12 hours has elapsed since missing a dose at the normal time, the patient should not
take the dose, but take the next dose at the normal time on the following day.
Recommended dose
The recommended starting dose of lenalidomide is 25 mg orally once daily on days 1-21 of repeated
28-day cycles. The recommended dose of dexamethasone is 40 mg orally once daily on days 1-4,
9-12, and 17-20 of each 28-day cycle for the first 4 cycles of therapy and then 40 mg once daily on
days 1-4 every 28 days. Dosing is continued or modified based upon clinical and laboratory findings
(see section 4.4). Prescribing physicians should carefully evaluate which dose of dexamethasone to
use, taking into account the condition and disease status of the patient.
Lenalidomide treatment must not be started if the Absolute Neutrophil Counts (ANC) < 1.0 x 10
9
/l,
and/or platelet counts < 75 x 10
9
/l or, dependent on bone marrow infiltration by plasma cells, platelet
counts < 30 x 10
9
/l.
Recommended dose adjustments during treatment and restart of treatment
Dose adjustments, as summarised below, are recommended to manage grade 3 or 4 neutropenia or
thrombocytopenia, or other grade 3 or 4 toxicity judged to be related to lenalidomide.
36
•
Dose reduction steps
Starting dose
25 mg
Dose level 1
15 mg
Dose level 2
10 mg
Dose level 3
5 mg
•
Platelet counts
Thrombocytopenia
When platelets
Recommended Course
First fall to < 30 x 10
9
/l
Interrupt lenalidomide treatment
Return to ≥ 30 x 10
9
/l
Resume lenalidomide at Dose Level 1
For each subsequent drop below 30 x 10
9
/l
Interrupt lenalidomide treatment
Return to ≥ 30 x 10
9
/l
Resume lenalidomide at next lower dose
level (Dose Level 2 or 3) once daily. Do
not dose below 5 mg once daily.
•
Absolute Neutrophil counts (ANC)
Neutropenia
When neutrophils
Recommended Course
First fall to < 0.5 x 10
9
/l
Interrupt lenalidomide treatment
Return to ≥ 0.5 x 10
9
/l when neutropenia is
the only observed toxicity
Resume lenalidomide at Starting Dose
once daily
Return to ≥ 0.5 x 10
9
/l when dose-dependent
haematological toxicities other than
neutropenia are observed
Resume lenalidomide at Dose Level 1
once daily
For each subsequent drop below < 0.5 x 10
9
/l Interrupt lenalidomide treatment
Return to ≥ 0.5 x 10
9
/l
Resume lenalidomide at next lower dose
level (Dose Level 1, 2 or 3) once daily.
Do not dose below 5 mg once daily.
In case of neutropenia, the physician should consider the use of growth factors in patient management.
Paediatric patients
There is no experience in children and adolescents. Therefore, lenalidomide should not be used in the
paediatric age group (0-17 years).
Elderly patients
The effects of age on the pharmacokinetics of lenalidomide have not been studied. Lenalidomide has
been used in clinical trials in multiple myeloma patients up to 86 years of age (see section 5.1). The
percentage of patients aged 65 or over was not significantly different between the
lenalidomide/dexamethasone and placebo/dexamethasone groups. No overall difference in safety or
efficacy was observed between these patients and younger patients, but greater pre-disposition of older
individuals cannot be ruled out. Because elderly patients are more likely to have decreased renal
function, care should be taken in dose selection and it would be prudent to monitor renal function.
Use in patients with impaired renal function
Lenalidomide is substantially excreted by the kidney, therefore care should be taken in dose selection
and monitoring of renal function is advised.
37
No dose adjustments are required for patients with mild renal impairment. The following dose
adjustments are recommended at the start of therapy for patients with moderate or severe impaired
renal function or end stage renal disease.
Renal Function (CLcr)
Dose Adjustment
Moderate renal impairment
(30 ≤ CLcr < 50 ml/min)
10 mg once daily*
Severe renal impairment
(CLcr < 30 ml/min, not requiring dialysis)
15 mg every other day**
5 mg once daily. On dialysis
days, the dose should be
administered following dialysis.
* The dose may be escalated to 15 mg once daily after 2 cycles if patient is not responding to treatment
and is tolerating the treatment.
** The dose may be escalated to 10 mg once daily if the patient is tolerating the treatment
End Stage Renal Disease (ESRD)
(CLcr < 30 ml/min, requiring dialysis)
After initiation of lenalidomide therapy, subsequent lenalidomide dose modification in renally
impaired patients should be based on individual patient treatment tolerance, as described above.
Use in patients with impaired hepatic function
Lenalidomide has not formally been studied in patients with impaired hepatic function and there are
no specific dose recommendations.
•
Women who are pregnant.
•
Women of childbearing potential unless all of the conditions of the Pregnancy Prevention
Programme are met (see sections 4.4 and 4.6).
•
Hypersensitivity to the active substance or to any of the excipients.
Pregnancy warning
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active
substance that causes severe life-threatening birth defects. Lenalidomide induced in monkeys
malformations similar to those described with thalidomide (see sections 4.6 and 5.3). If lenalidomide
is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected.
The conditions of the Pregnancy Prevention Programme must be fulfilled for all patients unless there
is reliable evidence that the patient does not have childbearing potential.
Criteria for women of non-childbearing potential
A female patient or a female partner of a male patient is considered to have childbearing potential
unless she meets at least one of the following criteria:
•
Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year*
•
Premature ovarian failure confirmed by a specialist gynaecologist
•
Previous bilateral salpingo-oophorectomy, or hysterectomy
•
XY genotype, Turner syndrome, uterine agenesis.
*Amenorrhoea following cancer therapy does not rule out childbearing potential
.
Counselling
For women of childbearing potential, lenalidomide is contraindicated unless all of the following are
met:
•
She understands the expected teratogenic risk to the unborn child
38
•
She understands the need for effective contraception, without interruption, 4 weeks before
starting treatment, throughout the entire duration of treatment, and 4 weeks after the end of
treatment
•
Even if a woman of childbearing potential has amenorrhea she must follow all the advice on
effective contraception
•
She should be capable of complying with effective contraceptive measures
•
She is informed and understands the potential consequences of pregnancy and the need to
rapidly consult if there is a risk of pregnancy
•
She understands the need to commence the treatment as soon as lenalidomide is dispensed
following a negative pregnancy test
•
She understands the need and accepts to undergo pregnancy testing every 4 weeks except in case
of confirmed tubal sterilisation
•
She acknowledges that she understands the hazards and necessary precautions associated with
the use of lenalidomide.
For male patients taking lenalidomide, pharmacokinetic data has demonstrated that lenalidomide is
present in human semen at extremely low levels during treatment and is undetectable in human semen
3 days after stopping the drug in the healthy subject (see section 5.2). As a precaution, all male
patients taking lenalidomide must meet the following conditions:
•
Understand the expected teratogenic risk if engaged in sexual activity with a pregnant woman or
a woman of childbearing potential
•
Understand the need for the use of a condom if engaged in sexual activity with a pregnant
woman or a woman of childbearing potential.
The prescriber must ensure that for women of childbearing potential:
•
The patient complies with the conditions of the Pregnancy Prevention Programme, including
confirmation that she has an adequate level of understanding
•
The patient has acknowledged the aforementioned conditions.
Contraception
Women of childbearing potential must use one effective method of contraception for 4 weeks before
therapy, during therapy, and until 4 weeks after lenalidomide therapy and even in case of dose
interruption unless the patient commits to absolute and continuous abstinence confirmed on a monthly
basis. If not established on effective contraception, the patient must be referred to an appropriately
trained health care professional for contraceptive advice in order that contraception can be initiated.
The following can be considered to be examples of suitable methods of contraception:
•
Implant
•
Levonorgestrel-releasing intrauterine system (IUS)
•
Medroxyprogesterone acetate depot
•
Tubal sterilisation
•
Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two
negative semen analyses
•
Ovulation inhibitory progesterone-only pills (i.e., desogestrel)
Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking
lenalidomide and dexamethasone, combined oral contraceptive pills are not recommended (see also
section 4.5). If a patient is currently using combined oral contraception the patient should switch to
one of the effective method listed above. The risk of venous thromboembolism continues for
4−6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive steroids
may be reduced during co-treatment with dexamethasone (see section 4.5).
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of
infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be
considered particularly in patients with neutropenia.
39
Copper-releasing intrauterine devices are generally not recommended due to the potential risks of
infection at the time of insertion and menstrual blood loss which may compromise patients with
neutropenia or thrombocytopenia.
Pregnancy testing
According to local practice, medically supervised pregnancy tests with a minimum sensitivity of
25 mIU/ml must be performed for women of childbearing potential as outlined below. This
requirement includes women of childbearing potential who practice absolute and continuous
abstinence. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same
day. Dispensing of lenalidomide to women of childbearing potential should occur within 7 days of the
prescription.
Prior to starting treatment
A medically supervised pregnancy test should be performed during the consultation, when
lenalidomide is prescribed, or in the 3 days prior to the visit to the prescriber once the patient had been
using effective contraception for at least 4 weeks. The test should ensure the patient is not pregnant
when she starts treatment with lenalidomide.
Follow-up and end of treatment
A medically supervised pregnancy test should be repeated every 4 weeks, including 4 weeks after the
end of treatment, except in the case of confirmed tubal sterilisation. These pregnancy tests should be
performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber.
Men
Lenalidomide is present in human semen at extremely low levels during treatment and is undetectable
in human semen 3 days after stopping the drug in the healthy subject (see section 5.2). As a
precaution, and taking into account special populations with prolonged elimination time such as renal
impairment, all male patients taking lenalidomide should use condoms throughout treatment duration,
during dose interruption and for 1 week after cessation of treatment if their partner is pregnant or of
childbearing potential and has no contraception.
Additional precautions
Patients should be instructed never to give this medicinal product to another person and to return any
unused capsules to their pharmacist at the end of treatment.
Patients should not donate blood during therapy or for 1 week following discontinuation of
lenalidomide.
Educational materials
In order to assist patients in avoiding foetal exposure to lenalidomide, the Marketing Authorisation
Holder will provide educational material to health care professionals to reinforce the warnings about
the expected teratogenicity of lenalidomide, to provide advice on contraception before therapy is
started, and to provide guidance on the need for pregnancy testing. Full patient information about the
expected teratogenic risk and the strict pregnancy prevention measures as specified in the Pregnancy
Prevention Programme should be given by the physician to women of childbearing potential and, as
appropriate, to male patients.
Other special warnings and precautions for use
Cardiovascular disorders
Myocardial Infarction
Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with
known risk factors. Patients with known risk factors – including prior thrombosis – should be closely
monitored, and action should be taken to try to minimize all modifiable risk factors (eg. smoking,
hypertension, and hyperlipidaemia).
40
Venous and arterial thromboembolic events
In patients with multiple myeloma, the combination of lenalidomide with dexamethasone is associated
with an increased risk of venous thromboembolism (predominantly deep vein thrombosis and
pulmonary embolism) and arterial thromboembolism (predominantly myocardial infarction and
cerebrovascular event) – see sections 4.5 and 4.8.
Consequently, patients with known risk factors for thromboembolism – including prior thrombosis –
should be closely monitored. Action should be taken to try to minimize all modifiable risk factors (e.g.
smoking, hypertension, and hyperlipidaemia). Concomitant administration of erythropoietic agents or
previous history of thromboembolic events may also increase thrombotic risk in these patients.
Therefore, erythropoietic agents, or other agents that may increase the risk of thrombosis, such as
hormone replacement therapy, should be used with caution in multiple myeloma patients receiving
lenalidomide with dexamethasone. A haemoglobin concentration above 12 g/dl should lead to
discontinuation of erythropoietic agents.
Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism.
Patients should be instructed to seek medical care if they develop symptoms such as shortness of
breath, chest pain, arm or leg swelling. Prophylactic antithrombotic medicines should be
recommended, especially in patients with additional thrombotic risk factors. The decision to take
antithrombotic prophylactic measures should be made after careful assessment of an individual
patient’s underlying risk factors.
If the patient experiences any thromboembolic events, treatment must be discontinued and standard
anticoagulation therapy started. Once the patient has been stabilised on the anticoagulation treatment
and any complications of the thromboembolic event have been managed, the lenalidomide treatment
may be restarted at the original dose dependent upon a benefit risk assessment. The patient should
continue anticoagulation therapy during the course of lenalidomide treatment.
Neutropenia and thrombocytopenia
The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with
a higher incidence of grade 4 neutropenia (5.1% in lenalidomide/dexamethasone-treated patients
compared with 0.6% in placebo/dexamethasone-treated patients; see section 4.8). Grade 4 febrile
neutropenia episodes were observed infrequently (0.6% in lenalidomide/dexamethasone-treated
patients compared to 0.0% in placebo/dexamethasone treated patients; see section 4.8). Patients should
be advised to promptly report febrile episodes. A dose reduction may be required (see section 4.2). In
case of neutropenia, the physician should consider the use of growth factors in patient management.
The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with
a higher incidence of grade 3 and grade 4 thrombocytopenia (9.9% and 1.4%, respectively, in
lenalidomide/dexamethasone-treated patients compared to 2.3% and 0.0% in
placebo/dexamethasone-treated patients; see section 4.8). Patients and physicians are advised to be
observant for signs and symptoms of bleeding, including petechiae and epistaxes, especially in case of
concomitant medication susceptible to induce bleeding (see Section 4.8 Haemorrhagic disorders). A
dose reduction of lenalidomide may be required (see section 4.2).
A complete blood cell count, including white blood cell count with differential count, platelet count,
haemoglobin, and haematocrit should be performed at baseline, every week for the first 8 weeks of
lenalidomide treatment and monthly thereafter to monitor for cytopenias.
The major dose limiting toxicities of lenalidomide include neutropenia and thrombocytopenia.
Therefore, co-administration of lenalidomide with other myelosuppressive agents should be
undertaken with caution.
Renal impairment
Lenalidomide is substantially excreted by the kidney. Therefore care should be taken in dose selection
and monitoring of renal function is advised in patients with renal impairment (see section 4.2).
41
Thyroid function
Cases of hypothyroidism have been reported and monitoring of thyroid function should be considered.
Peripheral neuropathy
Lenalidomide is structurally related to thalidomide, which is known to induce severe peripheral
neuropathy. At this time, the neurotoxic potential of lenalidomide associated with long-term use
cannot be ruled out.
Tumour Lysis Syndrome
Because lenalidomide has anti-neoplastic activity the complications of tumour lysis syndrome may
occur. The patients at risk of tumour lysis syndrome are those with high tumour burden prior to
treatment. These patients should be monitored closely and appropriate precautions taken.
Allergic Reactions
Cases of allergic reaction/hypersensitivity reactions have been reported (see section 4.8). Patients who
had previous allergic reactions while treated with thalidomide should be monitored closely, as a
possible cross-reaction between lenalidomide and thalidomide has been reported in the literature.
Severe skin reactions
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported.
Lenalidomide must be discontinued for exfoliative or bullous rash, or if SJS or TEN is suspected, and
should not be resumed following discontinuation for these reactions. Interruption or discontinuation of
lenalidomide should be considered for other forms of skin reaction depending on severity. Patients
with a history of severe rash associated with thalidomide treatment should not receive lenalidomide.
Lactose intolerance
Revlimid capsules contain lactose. Patients with rare hereditary problems of galactose intolerance, the
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Unused capsules
Patients should be advised never to give this medicinal product to another person and to return any
unused capsules to their pharmacist at the end of the treatment.
Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as hormone
replacement therapy, should be used with caution in multiple myeloma patients receiving lenalidomide
with dexamethasone (see sections 4.4 and 4.8).
Oral contraceptives
No interaction study has been performed with oral contraceptives. Lenalidomide is not an enzyme
inducer. In an
in vitro
study with human hepatocytes, lenalidomide, at various concentrations tested
did not induce CYP1A2, CYP2B6, CYP2C9, CYP2C19 and CYP3A4/5. Therefore, induction leading
to reduced efficacy of drugs, including hormonal contraceptives, is not expected if lenalidomide is
administered alone. However, dexamethasone is known to be a weak to moderate inducer of CYP3A4
and is likely to also affect other enzymes as well as transporters. It may not be excluded that the
efficacy of oral contraceptives may be reduced during treatment. Effective measures to avoid
pregnancy must be taken (see sections 4.4 and 4.6).
Results from human
in vitro
metabolism studies indicate that lenalidomide is not metabolised by
cytochrome P450 enzymes suggesting that administration of lenalidomide with drugs that inhibit
cytochrome P450 enzymes is not likely to result in metabolic drug interactions in man.
In vitro
studies
indicate that lenalidomide has no inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6,
CYP2E1 or CYP3A.
42
Warfarin
Co-administration of multiple doses of 10 mg of lenalidomide had no effect on the single dose
pharmacokinetics of R- and S- warfarin. Co-administration of a single 25 mg dose of warfarin had no
effect on the pharmacokinetics of lenalidomide. However, it is not known whether there is an
interaction during clinical use (concomitant treatment with dexamethasone). Dexamethasone is a weak
to moderate enzyme inducer and its effect on warfarin is unknown. Close monitoring of warfarin
concentration is advised during the treatment.
Digoxin
Concomitant administration with lenalidomide 10 mg/day increased the plasma exposure of digoxin
(0.5 mg, single dose) by 14% with a 90% CI (confidence interval) [0.52%-28.2%]. It is not known
whether the effect will be different in the therapeutic situation (higher lenalidomide doses and
concomitant treatment with dexamethasone). Therefore, monitoring of the digoxin concentration is
advised during lenalidomide treatment.
Pregnancy (see also sections 4.3 and 4.4)
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active
substance that causes severe life-threatening birth defects.
Lenalidomide induced in monkeys malformations similar to those described with thalidomide (see
section 5.3). Therefore, a teratogenic effect of lenalidomide is expected and lenalidomide is
contraindicated during pregnancy (see section 4.3).
Women of childbearing potential should use effective method of contraception. If pregnancy occurs in
a woman treated with lenalidomide, treatment must be stopped and the patient should be referred to a
physician specialised or experienced in teratology for evaluation and advice. If pregnancy occurs in a
partner of a male patient taking lenalidomide, it is recommended to refer the female partner to a
physician specialised or experienced in teratology for evaluation and advice.
Lenalidomide is present in human semen at extremely low levels during treatment and is undetectable
in human semen 3 days after stopping the drug in the healthy subject (see section 5.2). As a
precaution, and taking into account special populations with prolonged elimination time such as renal
impairment, all
male patients taking lenalidomide should use condoms throughout treatment duration,
during dose interruption and for 1 week after cessation of treatment if their partner is pregnant or of
childbearing potential and has no contraception.
Lactation
It is not known whether lenalidomide is excreted in human milk. Therefore breast-feeding should be
discontinued during therapy with lenalidomide.
No studies on the effects on the ability to drive and use machines have been performed. Lenalidomide
may have minor or moderate influence on the ability to drive and use machines. Fatigue, dizziness,
somnolence and blurred vision have been reported with the use of lenalidomide. Therefore, caution is
recommended when driving or operating machines.
a.
Summary of the safety profile in patients with multiple myeloma
In two Phase III placebo-controlled studies, 353 patients with multiple myeloma were exposed to the
lenalidomide/dexamethasone combination and 351 to the placebo/dexamethasone combination. The
median duration of exposure to study treatment was significantly longer (44.0 weeks) in the
lenalidomide/dexamethasone group as compared to placebo/dexamethasone (23.1 weeks). The
43
difference was accounted for by a lower rate of discontinuation from study treatment due to lower
progression of disease in patients exposed to lenalidomide/dexamethasone (39.7%) than in
placebo/dexamethasone patients (70.4%).
325 (92%) of the patients in the lenalidomide/dexamethasone group experienced at least one adverse
reaction compared to 288 (82%) in the placebo/dexamethasone group.
The most serious adverse reactions were:
•
Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see section 4.4)
•
Grade 4 neutropenia (see section 4.4).
The most frequently observed adverse reactions which occurred significantly more frequently in the
lenalidomide/dexamethasone group compared to the placebo/dexamethasone group were neutropenia
(39.4%), fatigue (27.2%), asthenia (17.6%), constipation (23.5%), muscle cramp (20.1%),
thrombocytopenia (18.4%), anaemia (17.0%), diarrhoea (14.2%) and rash (10.2%).
The adverse reactions observed in patients treated with lenalidomide/dexamethasone are listed below
by system organ class and frequency. Within each frequency grouping, adverse reactions are presented
in order of decreasing seriousness. Frequencies are defined as: very common (≥ 1/10); common
(≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare
(< 1/10,000 including isolated reports), unknown (cannot be estimated from the available data).
The following table is derived from data gathered during the pivotal studies. The data were not
adjusted according to the greater duration of treatment in the lenalidomide/dexamethasone versus the
placebo/dexamethasone arms in the pivotal studies (See section 5.1).
b.
Tabulated summary of adverse reactions
Table 1: ADRs reported in clinical studies in patients with multiple myeloma treated with
lenalidomide
System Organ Class
/ Preferred Term
All ADRs/Frequency
Grade 3−4 ADRs/Frequency
Infections
and Infestations
Very Common
Pneumonia, Upper respiratory tract
infection
Common
Sepsis, Bacterial, viral and fungal
infections (including opportunistic
infections), Sinusitis
Common
Pneumonia, Bacterial, viral and
fungal infections (including
opportunistic infections)
Neoplasms benign,
malignant and
unspecified
Uncommon
Basal cell carcinoma
Blood and Lymphatic
System Disorders
Very Common
Thrombocytopenia^,
Neutropenias^, Anaemia,
Haemorrhagic disorder^,
Leucopenias
Common
Pancytopenia
Uncommon
Haemolysis, Autoimmune
haemolytic anaemia, Haemolytic
anaemia
Very Common
Thrombocytopenia^,
Neutropenias^, Leucopenias
Common
Febrile Neutropenia, Anaemia
Uncommon
Hypercoagulation, Coagulopathy
Immune System
Disorders
Uncommon
Hypersensitivity^
Endocrine Disorders
Common
Hypothyroidism
44
System Organ Class
/ Preferred Term
All ADRs/Frequency
Grade 3−4 ADRs/Frequency
Metabolism and
Nutrition Disorders
Very Common
Hypokalaemia, Decreased appetite
Common
Hypomagnesaemia,
Hypocalcaemia, Dehydration
Common
Hypokalaemia, Hypocalcaemia,
Hypophosphataemia
Psychiatric Disorder
Uncommon
Loss of libido
Common
Depression
Nervous System
disorders
Very Common
Peripheral neuropathies (excluding
motor neuropathy), Dizziness,
Tremor, Dysgeusia, Headache
Common
Ataxia, Balance impaired
Common
Cerebrovascular Accident,
Dizziness, Syncope
Uncommon
Intracranial haemorrhage^,
Transient ischaemic attack,
Cerebral ischaemia
Eye Disorders
Very Common
Blurred vision
Common
Reduced visual acuity, Cataract
Common
Cataract
Uncommon
Blindness
Ear and
Labyrinth Disorders
Common
Deafness (Including Hypoacusis),
Tinnitus
Cardiac Disorders
Common
Atrial Fibrillation, Bradycardia
Uncommon
Arrhythmia, QT prolongation,
Atrial flutter, Ventricular
extrasystoles
Common
Myocardial infarction^, Atrial
Fibrillation, Congestive Cardiac,
Failure, Tachycardia
Vascular Disorders
Very Common
Venous Thromboembolic Events,
predominantly Deep Vein
Thrombosis and Pulmonary
Embolism^
Common
Hypotension, Hypertension,
Ecchymosis^
Very Common
Venous Thromboembolic Events,
predominantly Deep Vein
Thrombosis and Pulmonary
Embolism^
Uncommon
Ischemia, Peripheral ischemia,
Intracranial venous sinus
thrombosis
Respiratory,
Thoracic
and Mediastinal
Disorders
Very common
Dyspnoea, Nasopharyngitis,
Pharyngitis, Bronchitis, Epistaxis^
Common
Respiratory Distress
Gastrointestinal
Disorders
Very Common
Constipation, Diarrhoea, Nausea,
Vomiting
Common
Gastrointestinal Haemorrhage
(including rectal haemorrhage,
haemorrhoidal haemorrhage, peptic
ulcer haemorrhage and gingival
bleeding)^, Abdominal Pain, Dry
Mouth, Stomatitis, Dysphagia
Uncommon
Colitis, Caecitis
Common
Diarrhoea, Constipation, Nausea
Hepatobiliary
Disorders
Common
Abnormal Liver Function Tests
Common
Abnormal Liver Function Tests
45
System Organ Class
/ Preferred Term
All ADRs/Frequency
Grade 3−4 ADRs/Frequency
Skin and
Subcutaneous
tissue Disorders
Very Common
Rashes
Common
Urticaria, Hyperhidrosis, Dry Skin,
Pruritus, Skin Hyperpigmentation,
Eczema
Uncommon
Skin discolouration,
Photosensitivity reaction
Common
Rashes
Musculoskeletal
and connective
tissue disorders
Very Common
Muscle Spasms, Bone Pain,
Musculoskeletal and connective
tissue pain and discomfort
Common
Joint swelling
Common
Muscle Weakness, Bone Pain
Uncommon
Joint swelling
Renal and
Urinary
Disorders
Common
Haematuria^, Urinary retention ,
Urinary incontinence
Uncommon
Acquired Fanconi syndrome
Common
Renal failure
Uncommon
Renal tubular necrosis
Reproductive System
and Breast Disorders
Common
Erectile Dysfunction
General disorders
and administration
site conditions
Very Common
Fatigue, Oedema (including
peripheral oedema), Pyrexia,
Influenza like illness syndrome
(including pyrexia, myalgia,
musculoskeletal pain, headache and
rigors)
Common
Chest Pain, Lethargy
Common
Fatigue
Injury, poisoning and
procedural
complications
Common
Contusion^
^See section 4.8c.
In addition to the above adverse drug reactions identified from the pivotal trials, the following table is
derived from data gathered during post-marketing experience.
Table 2: Summary of adverse drug reactions identified from post-marketing data in patients
treated with lenalidomide
System organ class Reactions/frequency
Neoplasms benign, malignant and unspecified
Rare:
Tumour lysis syndrome
Respiratory, Thoracic and Mediastinal Disorders
Unknown:
Interstitial pneumonitis
Gastrointestinal disorders
Unknown:
Pancreatitis
Uncommon:
Angioedema
Rare:
Stevens-Johnson Syndrome^, toxic
epidermal necrolysis^
Skin and subcutaneous system disorders
^see section 4.8c
c.
Description of selected adverse reactions
Teratogenicity
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active
substance that causes severe life-threatening birth defects. Lenalidomide induced in monkeys
46
malformations similar to those described with thalidomide (see sections 4.6 and 5.3). If lenalidomide
is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected.
Neutropenia and thrombocytopenia
The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with
a higher incidence of grade 4 neutropenia (5.1% in lenalidomide/dexamethasone-treated patients
compared with 0.6% in placebo/dexamethasone-treated patients). Grade 4 febrile neutropenia episodes
were observed infrequently (0.6% in lenalidomide/dexamethasone-treated patients compared to 0.0%
in placebo/dexamethasone treated patients).
The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with
a higher incidence of grade 3 and grade 4 thrombocytopenia (9.9% and 1.4%, respectively, in
lenalidomide/dexamethasone-treated patients compared to 2.3% and 0.0% in
placebo/dexamethasone-treated patients).
Venous thromboembolism
The combination of lenalidomide with dexamethasone is associated with an increased risk of DVT and
PE in patients with multiple myeloma (see section 4.5). Concomitant administration of erythropoietic
agents or previous history of DVT may also increase thrombotic risk in these patients.
Myocardial Infarction
Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with
known risk factors.
Haemorrhagic disorders
Haemorrhagic disorders are listed under several system organ classes: Blood and lymphatic system
disorders; nervous system disorders (intracranial haemorrhage); respiratory, thoracic and mediastinal
disorders (epistaxis); gastrointestinal disorders (gingival bleeding, haemorrhoidal haemorrhage, rectal
haemorrhage); renal and urinary disorders (haematuria); Injury, poisoning and procedural
complications (contusion) and vascular disorders (ecchymosis).
Allergic Reactions
Cases of allergic reaction/hypersensitivity reactions have been reported. A possible cross-reaction
between lenalidomide and thalidomide has been reported in the literature.
Severe skin reactions
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. Patients
with a history of severe rash associated with thalidomide treatment should not receive lenalidomide.
There is no specific experience in the management of lenalidomide overdose in multiple myeloma
patients, although in dose-ranging studies some patients were exposed to up to 150 mg, and in single-
dose studies, some patients were exposed to up to 400 mg. The dose limiting toxicity in these studies
was essentially haematological. In the event of overdose, supportive care is advised.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunomodulating agent. ATC code: L04 AX04.
The lenalidomide mechanism of action includes anti-neoplastic, anti-angiogenic, pro-erythropoietic,
and immunomodulatory properties. Specifically, lenalidomide inhibits proliferation of certain
haematopoietic tumour cells (including MM plasma tumour cells and those with deletions of
chromosome 5), enhances T cell- and Natural Killer (NK) cell-mediated immunity and increases the
47
number of NK T cells, inhibits angiogenesis by blocking the migration and adhesion of endothelial
cells and the formation of microvessels, augments foetal haemoglobin production by CD34+
haematopoietic stem cells, and inhibits production of pro-inflammatory cytokines (e.g., TNF-α and
IL-6) by monocytes.
Clinical trials
The efficacy and safety of lenalidomide were evaluated in two Phase III multi-centre, randomised,
double-blind, placebo-controlled, parallel-group controlled studies (MM-009 and MM-010) of
lenalidomide plus dexamethasone therapy versus dexamethasone alone in previously treated patients
with multiple myeloma. Out of 353 patients in the MM-009 and MM-010 studies who received
lenalidomide/dexamethasone, 45.6% were aged 65 or over. Of the 704 patients evaluated in the
MM-009 and MM-010 studies, 44.6% were aged 65 or over.
In both studies, patients in the lenalidomide/dexamethasone (len/dex) group took 25 mg of
lenalidomide orally once daily on Days 1 to 21 and a matching placebo capsule once daily on Days 22
to 28 of each 28-day cycle. Patients in the placebo/dexamethasone (placebo/dex) group took 1 placebo
capsule on Days 1 to 28 of each 28-day cycle. Patients in both treatment groups took 40 mg of
dexamethasone orally once daily on Days 1 to 4, 9 to 12, and 17 to 20 of each 28-day cycle for the
first 4 cycles of therapy. The dose of dexamethasone was reduced to 40 mg orally once daily on
Days 1 to 4 of each 28-day cycle after the first 4 cycles of therapy. In both studies, treatment was to
continue until disease progression. In both studies, dose adjustments were allowed based on clinical
and laboratory finding.
The primary efficacy endpoint in both studies was time to progression (TTP). In total, 353 patients
were evaluated in the MM-009 study; 177 in the lenalidomide/dexamethasone group and 176 in the
placebo/dexamethasone group and, in total, 351 patients were evaluated in the MM-010 study; 176 in
the lenalidomide/dexamethasone group and 175 in the placebo/dexamethasone group.
In both studies, the baseline demographic and disease-related characteristics were comparable between
the lenalidomide/dexamethasone and placebo/dexamethasone groups. Both patient populations
presented a median age of 63 years, with a comparable male to female ratio. The ECOG performance
status was comparable between both groups, as was the number and type of prior therapies.
Pre-planned interim analyses of both studies showed that lenalidomide/dexamethasone was
statistically significantly superior (p < 0.00001) to dexamethasone alone for the primary efficacy
endpoint, TTP (median follow-up duration of 98.0 weeks). Complete response and overall response
rates in the lenalidomide/dexamethasone arm were also significantly higher than the
dexamethasone/placebo arm in both studies. Results of these analyses subsequently led to an
unblinding in both studies, in order to allow patients in the placebo/dexamethasone group to receive
treatment with the lenalidomide/dexamethasone combination.
An extended follow-up efficacy analysis was conducted with a median follow-up of 130.7 weeks.
Table 1 summarises the results of the follow-up efficacy analyses – pooled studies MM-009 and
MM-010.
In this pooled extended follow-up analysis, the median TTP was 60.1 weeks (95% CI: 44.3, 73.1) in
patients treated with lenalidomide/dexamethasone (N = 353) versus 20.1 weeks (95% CI: 17.7, 20.3)
in patients treated with placebo/dexamethasone (N = 351). The median progression free survival was
48.1 weeks (95% CI: 36.4, 62.1) in patients treated with lenalidomide/dexamethasone versus 20.0
weeks (95% CI: 16.1, 20.1) in patients treated with placebo/dexamethasone. The median duration of
treatment was 44.0 weeks (min: 0.1, max: 254.9) for lenalidomide/dexamethasone and 23.1 weeks
(min: 0.3, max: 238.1) for placebo/dexamethasone ). Complete response (CR), partial response (PR)
and overall response (CR+PR) rates in the lenalidomide/dexamethasone arm remain significantly
higher than in the dexamethasone/placebo arm in both studies. The median overall survival in the
extended follow-up analysis of the pooled studies is 164.3 weeks (95% CI: 145.1, 192.6) in patients
treated with lenalidomide/dexamethasone versus 136.4 weeks (95% CI: 113.1, 161.7) in patients
treated with placebo/dexamethasone. Despite the fact that 170 out of the 351 patients randomised to
48
placebo/dexamethasone received lenalidomide after disease progression or after the studies were
unblinded, the pooled analysis of overall survival demonstrated a statistically significant survival
advantage for lenalidomide/dexamethasone relative to placebo/dexamethasone (hazard ratio = 0.833,
95% CI = [0.687, 1.009], p=0.045).
Table 1:
Summary of Results of Efficacy Analyses as of cut-off date for extended follow-
up — Pooled Studies MM-009 and MM-010 (cut-offs 23 July 2008 and 2 March
2008, respectively)
Endpoint
len/dex
(N=353)
placebo/dex
(N=351)
Time to Event
Hazard ratio [95% CI],
p-value
a
Time To Progression
Median [95% CI], weeks
60.1 [44.3,
73.1]
20.1 [17.7,
20.3]
0.350 [0.287, 0.426], p < 0.001
Progression Free Survival
Median [95% CI], weeks
48.1
[36. 4, 62.1]
20.0
[16.1, 20.1]
0.393 [0.326, 0.473]
p < 0.001
b
Overall Survival
Median [95% CI], weeks
1-year Overall Survival rate
164.3
[145.1,
192.6]
82%
136.4
[113.1,
161.7]
75%
0.833 [0. 687, 1.009]
p = 0.045
Response rate
Odds ratio [95% CI], p-value
b
Overall Response [n, %]
Complete Response [n, %]
212 (60.1)
58 (16.4)
75 (21.4)
11 (3.1)
5.53 [3.97, 7.71], p < 0.001
6.08 [3.13, 11.80], p < 0.001
a: Two-tailed log rank test comparing survival curves between treatment groups.
b: Two-tailed continuity-corrected chi-square test.
Exploratory study
An open-label, randomized, multicenter, Phase 3 study was conducted in 445 patients with newly
diagnosed multiple myeloma; 222 patients were randomized to the lenalidomide/low dose
dexamethasone arm, and 223 were randomized to the lenalidomide/standard dose dexamethasone arm.
Patients randomized to the lenalidomide/standard dose dexamethasone arm received lenalidomide 25
mg/day, Days 1 to 21 every 28 days plus dexamethasone 40 mg/day on Days 1 to 4, 9 to 12, and 17 to
20 every 28 days for the first four cycles. Patients randomized to the lenalidomide/low dose
dexamethasone arm received lenalidomide 25 mg/day, Days 1 to 21 every 28 days plus low dose
dexamethasone – 40 mg/day on Days 1, 8, 15, and 22 every 28 days. In the lenalidomide/low dose
dexamethasone group, 20 patients (9.1%) underwent at least one dose interruption compared to 65
patients (29.3%) in the lenalidomide/standard dose dexamethasone arm.
In a post-hoc analysis, lower mortality was observed in the lenalidomide/low dose dexamethasone arm
6.8% (15/220) compared to the lenalidomide/standard dose dexamethasone arm 19.3% (43/223), in the
newly diagnosed multiple myeloma patient population, with a median follow up of 72.3 weeks.
However with a longer follow-up, the difference in overall survival in favour of low dose
dexamethasone tends to decrease.
Considering that the patient population differs from the authorised indication, these results should be
interpreted with caution.
5.2 Pharmacokinetic properties
Lenalidomide has an asymmetric carbon atom and can therefore exist as the optically active forms S(-)
and R(+). Lenalidomide is produced as a racemic mixture. Lenalidomide is generally more soluble in
organic solvents but exhibits the greatest solubility in 0.1N HCl buffer.
49
Absorption
Lenalidomide is rapidly absorbed following oral administration in healthy volunteers, under fasting
conditions, with maximum plasma concentrations occurring between 0.5 and 2 hours post-dose. In
patients, as well as in healthy volunteers, the maximum concentration (C
max
) and area-under-the-
concentration time curve (AUC) increase proportionally with increases in dose. Multiple dosing does
not cause marked drug accumulation. In plasma, the relative exposures of the S- and R- enantiomers of
lenalidomide are approximately 56% and 44%, respectively.
Co-administration with a high-fat and high-calorie meal in healthy volunteers reduces the extent of
absorption, resulting in an approximately 20% decrease in area under the concentration versus time
curve (AUC) and 50% decrease in Cmax in plasma. However, in the pivotal multiple myeloma
registration trials where the efficacy and safety were established for lenalidomide, the drug was
administered without regard to food intake. Thus, lenalidomide can be administered with or without
food.
Distribution
In vitro
(
14
C)-lenalidomide binding to plasma proteins was low with mean plasma protein binding at
23% and 29% in multiple myeloma patients and healthy volunteers, respectively.
Lenalidomide is present in human semen (< 0.01% of the dose) after administration of 25 mg/day and
the drug is undetectable in semen of a healthy subject 3 days after stopping the drug (see section 4.4).
Metabolism and excretion
In vitro
studies indicate that lenalidomide has no inhibitory effect on CYP1A2, CYP2C9, CYP2C19,
CYP2D6, CYP2E1, and CYP3A.
A majority of lenalidomide is eliminated through urinary excretion. The contribution of renal
excretion to total clearance in subjects with normal renal function was 90%, with 4% of lenalidomide
eliminated in faeces.
Lenalidomide is poorly metabolized as 82% of the dose is excreted unchanged in urine. Hydroxy-
lenalidomide and N-acetyl-lenalidomide represent 4.59% and 1.83% of the excreted dose,
respectively. The renal clearance of lenalidomide exceeds the glomerular filtration rate and therefore is
at least actively secreted to some extent.
At recommended doses (5 to 25 mg/day), half-life in plasma is approximately 3 hours in healthy
volunteers and patients with multiple myeloma.
Pharmacokinetics analyses in patients with impaired renal function indicate that as renal function
decreases (< 50 ml/min), the total drug clearance decreases proportionally resulting in an increase in
AUC. The half-life of lenalidomide increased from approximately 3.5 hours in subjects with creatinine
clearance > 50 ml/min to more than 9 hours in subjects with reduced renal function < 50 ml/min.
However, renal impairment did not alter the oral absorption of lenalidomide. The C
max
was similar
between healthy subjects and patients with renal impairment. Recommended dose adjustments in
patients with impaired renal function are described in section 4.2.
5.3 Preclinical safety data
An embryofoetal development study has been conducted in monkeys administered lenalidomide at
doses from 0.5 and up to 4 mg/kg/day. Findings from this study indicate that lenalidomide produced
external malformations including non-patent anus and malformations of upper and lower extremities
(bent, shortened, malformed, malrotated and/or absent part of the extremities, oligo and/or
polydactyly) in the offspring of female monkeys who received the drug during pregnancy.
Various visceral effects (discoloration, red foci at different organs, small colorless mass above atrio-
ventricular valve, small gall bladder, malformed diaphragm) were also observed in single fetuses.
Lenalidomide has a potential for acute toxicity; minimum lethal doses after oral administration were
> 2000 mg/kg/day in rodents. Repeated oral administration of 75, 150 and 300 mg/kg/day to rats for
50
up to 26 weeks produced a reversible treatment-related increase in kidney pelvis mineralisation in all
3 doses, most notably in females. The no observed adverse effect level (NOAEL) was considered to be
less than 75 mg/kg/day, and is approximately 25-fold greater than the human daily exposure based on
AUC exposure. Repeated oral administration of 4 and 6 mg/kg/day to monkeys for up to 20 weeks
produced mortality and significant toxicity (marked weight loss, reduced red and white blood cell and
platelet counts, multiple organ haemorrhage, gastrointestinal tract inflammation, lymphoid, and bone
marrow atrophy). Repeated oral administration of 1 and 2 mg/kg/day to monkeys for up to 1 year
produced reversible changes in bone marrow cellularity, a slight decrease in myeloid:erythroid cell
ratio and thymic atrophy. Mild suppression of white blood cell count was observed at 1 mg/kg/day
corresponding to approximately the same human dose based on AUC comparisons.
In vitro
(bacterial mutation, human lymphocytes, mouse lymphoma, Syrian Hamster Embryo cell
transformation) and
in vivo
(rat micronucleus) mutagenicity studies revealed no drug related effects at
either the gene or chromosomal level. Carcinogenicity studies with lenalidomide have not been
conducted.
Developmental toxicity studies were previously conducted in rabbits. In these studies, rabbits were
administered 3, 10 and 20 mg/kg/day orally. An absence of the intermediate lobe of the lung was
observed at 10 and 20 mg/kg/day with dose dependence and displaced kidneys were observed at
20 mg/kg/day. Although it was observed at maternotoxic levels they may be attributable to a direct
effect. Soft tissue and skeletal variations in the foetuses were also observed at 10 and 20 mg/kg/day.
6.
6.1 List of excipients
Capsule contents: Lactose, anhydrous
Cellulose, microcrystalline
Croscarmellose sodium
Capsule shell:
Titanium dioxide (E171)
Indigo carmine (E132)
Printing ink:
Shellac
Propylene glycol
Black iron oxide (E172)
Potassium hydroxide
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
51
Magnesium stearate
Gelatin
6.5 Nature and contents of container
The capsules are provided in carton packs. Each pack contains three Polyvinylchloride (PVC) /
Polychlorotrifluoroethylene (PCTFE) / Aluminium foil blisters, each with seven capsules. This gives a
total of 21 capsules per pack.
6.6 Special precautions for disposal
Unused medicinal product should be returned to the pharmacist.
7.
Celgene Europe Limited
Riverside House
Riverside Walk
Windsor
Berkshire
SL4 1NA
United Kingdom
8.
EU/1/07/391/003
9.
14/06/2007
Detailed information on this medicine is available on the website of the European Medicines Agency:
http://www.ema.europa.eu/.
52
1.
FURTHER INFORMATION
What Revlimid contains
Revlimid 5 mg hard capsules:
•
The active substance is lenalidomide. Each capsule contains 5 mg of lenalidomide.
•
The other ingredients are:
-
capsule contents: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and
magnesium stearate
-
capsule shell: gelatine and titanium dioxide (E171)
-
printing ink: shellac, propylene glycol, potassium hydroxide and black iron oxide (E172).
Revlimid 10 mg hard capsules:
•
The active substance is lenalidomide. Each capsule contains 10 mg of lenalidomide.
•
The other ingredients are:
-
capsule contents: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and
magnesium stearate
-
capsule shell: gelatine, titanium dioxide (E171), indigo carmine (E132) and yellow iron
oxide (E172)
-
printing ink: shellac, propylene glycol, potassium hydroxide and black iron oxide (E172).
Revlimid 15 mg hard capsules:
•
The active substance is lenalidomide. Each capsule contains 15 mg of lenalidomide.
•
The other ingredients are:
-
capsule contents: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium and
magnesium stearate
-
capsule shell: gelatine, titanium dioxide (E171) and indigo carmine (E132)
-
printing ink: shellac, propylene glycol, potassium hydroxide and black iron oxide (E172).
95
