Revlimid(r) (lenalidomide) capsules Product Information

Teratogenic effects:

Revlimid (lenalidomide) is structurally related to thalidomide. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is taken during pregnancy, it may cause birth defects or death to an unborn baby. Women should be advised to avoid pregnancy whilst taking Revlimid (lenalidomide) and for 4 weeks after stopping the drug.

Name of the medicine

Revlimid (lenalidomide), 3-(4'-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione, is an immunomodulatory agent with anti-angiogenic and anti-neoplastic properties. The Chemical Abstract Service (CAS) registry number for lenalidomide is 191732-72-6 and the ATC code is L04 AX04. The trade name for lenalidomide is Revlimid(r) (lenalidomide) capsules. The chemical structure of lenalidomide is as follows:

Description

Lenalidomide has an empirical formula of C13H13N3O3 and a molecular weight of 259.25. It is an off- white to pale-yellow solid, with a melting point of approximately 265oC to 270oC. Lenalidomide is generally more soluble in organic solvents but exhibits the greatest solubility in 0.1N HCl buffer. The solubility of lenalidomide in water and at pH 1.21 is < 1.5 mg/mL and 18 mg/mL, respectively.

List of Excipients

Revlimid capsules contain the following excipients: lactose, anhydrous; cellulose, microcrystalline; croscarmellose sodium; magnesium stearate. The capsule shell is composed of gelatin and titanium dioxide, and may also contain indigo carmine CI73015 and iron oxide yellow CI77492 (10 mg capsules), or indigo carmine CI73015 (15 mg capsules). The printing ink is composed of shellac; iron oxide black CI77499; ethanol; isopropyl alcohol; butan-1-ol; propylene glycol; water-purified; ammonium hydroxide; potassium hydroxide.

Pharmacology

Pharmacodynamic properties

Pharmacotherapeutic group: Immunomodulating agent. Lenalidomide has immunomodulatory, anti-angiogenic, and anti-neoplastic properties. The mechanism of action of lenalidomide includes immunomodulatory, anti-neoplastic, anti-angiogenic and pro-erythropoietic 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 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-a and IL-6) by monocytes.

Pharmacokinetic properties

Lenalidomide is an off-white to pale-yellow solid powder. 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 with a net optical rotation of zero.

Absorption

Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration with maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose. 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 the maximum concentration (Cmax) in plasma. The Cmax and AUC increase proportionately 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. The absolute bioavailability of lenalidomide has not been determined.

Distribution

In vitro (14C)-lenalidomide binding to plasma proteins was low with mean plasma protein binding at 22.7% and 29.2% in multiple myeloma patients and healthy volunteers, respectively.

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 unchanged through urinary excretion. The contribution of renal excretion to total clearance in subjects with normal renal function was 65 - 85%. The half-life (t1/2) of elimination has been observed to increase with dose, from approximately 3 hours at 5 mg up to approximately 9 hours at doses of 400 mg (the higher dose is believed to provide a better estimate of t1/2). Steady-state levels are achieved by Day 4. Pharmacokinetic 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 Cmax was similar between healthy subjects and patients with renal impairment. Recommended dose adjustments in patients with impaired renal function are described in section x. [Dosage and administration]. Pharmacokinetic analyses based on multiple myeloma studies indicate that lenalidomide is rapidly absorbed at all dose levels, with maximum plasma concentrations occurring between 0.5 and 4.0 hours post-dose both on Days 1 and 28. The Cmax and AUC values increase proportionally with dose following single and multiple doses in multiple myeloma patients. Exposure in multiple myeloma patients is slightly higher based on Cmax and AUC values as compared to healthy male volunteers since the clearance/bioavailable fraction of a drug (CL/F) in multiple myeloma patients is lower (approximately 200 mL/min compared to 300 mL/min) than it is in healthy volunteers. This is consistent with the compromised renal function in the multiple myeloma patients, possibly as a consequence of their age (average patient age of 58 vs. 29 for healthy volunteers) and their disease. The pharmacokinetics of lenalidomide were very similar in subjects with myelodysplastic syndromes (MDS). In patients with low- or intermediate-1-risk MDS, a single 10 mg oral dose of lenalidomide was rapidly absorbed with a median tmax of around 1 hour post-dose. The mean terminal half-life was approximately 4 hours. Following multiple dosing of 10 mg per day for 14 days there was no accumulation of lenalidomide in plasma, with the mean plasma exposure (Cmax and AUC) and renal clearance at the steady-state comparable to those observed with a single dose. The plasma concentrations 1 hour after dosing were relatively stable for 280 days.

Clinical trials

Multiple Myeloma (MM)

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 high dose dexamethasone therapy versus high dose 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.

Table 1 summarises TTP and response rates based on the best response assessments for studies MM-009 and MM-010.

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. Complete response (CR) and overall response (OR) rates in the lenalidomide/dexamethasone arm were also significantly higher than the dexamethasone/placebo arm in both studies.

Table 1: Summary of Efficacy Analysis - Studies MM-009 and MM-010

1. Len = Revlimid and Dex = dexamethasone.

2. Time-to-progression was calculated as the time from randomisation to the first occurrence of any of the following events: 1) disease progression based on the myeloma response criteria developed by Blade et al, 2) discontinuation from the treatment phase due to disease progression according to the investigator whether or not confirmed by the Blade et al criteria (TTP was measured to the last date of visit), or death due to disease progression during the treatment period (TTP was measured to the date of death if death occurred on or before treatment discontinuation). The TTP was censored at the date of the last response assessment for subjects who 1) had not progressed at the time of the analysis, 2) withdrew from the treatment phase before documented progression, including those who died of causes not related to multiple myeloma, or 3) were given another antimyeloma therapy without documented progression or experienced intolerable adverse events (for these subjects, the date of their last response assessment prior to taking other antimyeloma therapy was used as the censor date).

3. The p-value is based on a one-tailed unstratified log rank test of survival curve differences between the treatment groups. For MM-009, the z-score from the log-rank test was 6.522 (one-tailed p < 0.00000000004). For MM-010, the z-score was 6.618 (one-tailed p < 0.00000000002).

Myelodysplastic Syndromes (MDS)

The efficacy and safety of Revlimid were evaluated in low- or intermediate-1-risk MDS patients with a deletion-5q (q31-33) cytogenetic abnormality, with or without additional cytogenetic abnormalities. MDS-004 was a Phase III, multi-centre, randomised, double-blind, placebo-controlled study in red blood cell (RBC) transfusion-dependent subjects. The 52-week double-blind treatment phase included 205 subjects who were randomised to receive 10 mg lenalidomide for 21 days of a 28-day cycle, 5 mg lenalidomide continuously, or placebo. The primary efficacy endpoint was transfusion independence at 182 days. The median age of patients was 68.0 years (range 36 to 86), the median duration of MDS was 2.6 years (range 0.2 to 29.2) and 76.1% of patients were females. The study enrolled patients with absolute neutrophil counts (ANC) >= 0.5 x 109/L, platelet counts >= 25 x 109/L, serum creatinine <= 2.0 mg/dL, serum SGOT/AST or SGPT/ALT <= 3.0 x upper limit of normal (ULN), and serum total bilirubin <= 1.5 mg/dL. An overview of the efficacy results for the Intent-to-Treat (ITT) populations from MDS-004 receiving either cyclic lenalidomide dosing at 10 mg, or placebo, is presented in Table 2. Study MDS-003 was a Phase II open-label, single-arm, multi-centre study of 148 patients who were RBC transfusion-dependent. Dosing was primarily at a continuous dose of 10 mg once daily for 28 days, with some experience at a dose of 10 mg daily for 21 of 28 days. The primary efficacy endpoint was RBC transfusion independence of at least 2 months duration, as defined by the MDS International Working Group (IWG) criteria. The median age of patients was 71.0 years (range 37 to 95), the median duration of MDS was 2.5 years (range 0.1 to 20.7) and 65.5% of patients were females. The study enrolled patients with absolute neutrophil counts (ANC) >= 0.5 x 109/L, platelet counts >= 50 x 109/L, serum creatinine <= 2.5 mg/dL, serum SGOT/AST or SGPT/ALT <= 3.0 x upper limit of normal (ULN), and serum direct bilirubin <= 2.0 mg/dL. Table 2 summarises the efficacy results for the ITT population from MDS-003. In both MDS-003 and MDS-004, granulocyte colony-stimulating factor was permitted for patients who developed neutropenia or fever in association with neutropenia.

Table 2: Summary of Results of Efficacy Analyses for Studies MDS-003 and MDS-004

N = number of patients; nr = not reported; Cont = continuous (28 days of a 28-day cycle); Cyclic = (21 days of a 28-day cycle); CI = Confidence Interval; NE = Not estimable.

*: Based on RBC-transfusion independence response for subjects who became RBC-transfusion independent for at least 56 days.

A: transfusion independence was defined as the absence of any RBC transfusion during any consecutive 56 days during the treatment period accompanied by at least a 1 g/dL increase in Hb from screening/baseline.

B: RBC-transfusion independence response for subjects who became RBC-transfusion independent for at least 182 days. C: Measured from the day of the first dose of study drug to the first day of the first 56-day RBC transfusion-free period.

D: Measured from the first of the consecutive 56 days during which the subject was free of RBC transfusions to the date of the first RBC transfusion after this period.

Contraindications

• Women who are pregnant.

• Women of childbearing potential unless all of the conditions of the i-access(r) Program are met (see section vii. [Precautions]).

• Hypersensitivity to the active substance or to any of the excipients.

Precautions

Effects on fertility

A fertility and early embryonic development study in male and female rats, with administration of lenalidomide up to 500 mg/kg/day, produced no parental toxicity and no adverse effects on fertility or early embryonic development. The systemic exposure in rats at 500 mg/kg was > 70-fold higher than the human exposure at 25 mg/day, based on AUC.

Use in Pregnancy (Pregnancy Category X)

For lenalidomide, no clinical data on exposed pregnancies are available. Because lenalidomide is a structural analogue of thalidomide, a known human teratogen, and has shown teratogenic effects in animal studies, lenalidomide must not be used in pregnant women. Women of childbearing potential must use effective means of contraception. Embryofoetal development studies were conducted in monkeys and rabbits. In monkeys, lenalidomide was teratogenic at systemic exposures (based on plasma AUC) well below that anticipated clinically, and a NOEL for the teratogenic effects could not be established in the study. In rabbits treated with 3, 10 and 20 mg/kg/day orally, developmental toxicity was noted at 10 and 20 mg/kg/day. The toxicity was characterised by slightly reduced foetal body weights, increased incidences of post-implantation loss, and gross external findings in the foetuses associated with maternal toxicity of lenalidomide. Increased incidences of soft tissue and skeletal variations in the foetuses were also observed at 10 and 20 mg/kg/day. The NOEL for developmental toxicity of lenalidomide in rabbits was identified as 3 mg/kg/day, which is associated with a plasma AUC value equivalent to that anticipated clinically at the 25 mg/day dose in humans.

Special Prescribing Requirements for Revlimid (lenalidomide)

Revlimid (lenalidomide) is available under a restricted distribution program (i-access(r)). Only physicians and pharmacists registered with this program can prescribe and dispense the product. In addition, Revlimid (lenalidomide) must only be dispensed to patients who are registered and meet all the conditions of the program. The conditions of the i-access(r) Program must be fulfilled for all patients. 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 potential teratogenic risk to the unborn child. She understands and agrees to comply with 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 medically supervised pregnancy testing every 4 weeks. She acknowledges that she understands the hazards and necessary precautions associated with the use of lenalidomide. For male patients taking lenalidomide, clinical data has demonstrated the presence of lenalidomide in human semen. Male patients taking lenalidomide must meet the following conditions: Understand the potential teratogenic risk if engaged in sexual activity with a woman of childbearing potential. Understand and comply with the need for the use of a condom if engaged in sexual activity with a woman of childbearing potential. The prescriber must ensure that for women of childbearing potential: The patient complies with the conditions of the i-access(r) Program, including confirmation that she has an adequate level of understanding. The patient has acknowledged and agreed to comply with 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, 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: Contraceptive 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. If a patient is currently using combined oral contraception the patient should switch to one of the effective methods 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. 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. 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. 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. Similarly, if pregnancy occurs in a partner of a male patient taking lenalidomide, the female partner should be referred to a physician specialised or experienced in teratology for evaluation and advice.

Pregnancy testing

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. For women of childbearing potential, dispensing of lenalidomide should occur within a maximum of 7 days of the prescription.

Prior to starting treatment

A medically supervised pregnancy test should be performed when lenalidomide is prescribed. The test should occur either at the time of consultation, or in the 3 days prior to the visit to the prescriber and at a point where the patient has been using effective contraception for at least 4 weeks. The test should ensure the patient is not pregnant when she starts treatment with lenalidomide. This requirement includes women of childbearing potential who practice absolute and continuous abstinence.

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. 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. This requirement includes women of childbearing potential who practice absolute and continuous abstinence.

Men

Clinical data has demonstrated the presence of lenalidomide in human semen. Therefore all male patients should use condoms throughout treatment duration, during dose interruption and for 1 week after cessation of treatment if their partner is of childbearing potential and has no contraception. Male patients taking lenalidomide must not donate sperm during therapy or for 1 week following discontinuation of lenalidomide.

Additional Precautions for Pregnancy

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, Celgene Pty Ltd will provide educational material to healthcare professionals to reinforce the warnings about the potential 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 potential teratogenic risk and the strict pregnancy prevention measures as specified in the i-access(r) Program should be given by a healthcare professional to women of childbearing potential and, as appropriate, to male patients.

Use during lactation

It is not known whether lenalidomide is excreted in human milk. Therefore breast-feeding should be discontinued during therapy with lenalidomide.

Paediatric use

There is no experience in treating children and adolescents with Revlimid. Therefore, lenalidomide should not be used in the paediatric age group (0-18 years).

Use in the elderly

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 iii. [Pharmacology]). The percentage of patients aged 65 or over was not significantly different between the lenalidomide/dexamethasone and placebo/dexamethasone groups. No overall difference in effectiveness was observed between these patients and younger patients. However, overall serious adverse events, in particular the serious vascular events (including DVT and pulmonary embolism) and serious cardiovascular events (including atrial fibrillation), were all more frequent in lenalidomide-treated patients 65 years and over. Lenalidomide has also been used in MDS clinical trials in patients up to 95 years of age. Of the 395 patients in the MDS clinical trials who received 10 mg lenalidomide, 72.2% were aged 65 and over. No overall difference in safety was observed between these patients and younger patients, but greater pre-disposition of older individuals to drug-related toxicities cannot be ruled out. Lenalidomide is known to be substantially excreted by the kidney. The risk of adverse reactions to this drug may be greater in patients with impaired renal function. Elderly patients are more likely to have decreased renal function, so care should be taken in dose selection for such patients. Renal function should therefore be monitored (see section x. [Dosage and administration]).

Genotoxicity/Carcinogenicity

In vitro (mutation in bacteria, chromosomal aberration in human lymphocytes, mutation in mouse lymphoma cells, Syrian Hamster Embryo cell transformation) and in vivo (rat micronucleus) genotoxicity studies revealed no drug related-effects at either the gene or chromosomal level. Carcinogenicity studies with lenalidomide have not been conducted.

Second Primary Malignancies

Based on a low number of cases, a numerical imbalance in second primary malignancies (comprising mainly of basal cell and squamous cell skin cancers) has been observed in clinical trials in previously treated multiple myeloma patients with lenalidomide/dexamethasone compared with placebo/dexamethasone. Both the benefit achieved with Revlimid and the risk of second primary malignancies should be considered before initiating treatment with the product. Physicians should also carefully evaluate patients before and during treatment using standard cancer screening for occurrence of second primary malignancies and institute treatment as appropriate.

Venous thromboembolism

The combination of lenalidomide with dexamethasone is associated with an increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma. In clinical studies of patients with del 5q MDS, lenalidomide as monotherapy was also associated with an increased risk of DVT. Concomitant administration of erythropoietic agents or previous history of DVT 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 120 g/L 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, such as low molecular weight heparins or warfarin, 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.

Neutropenia and thrombocytopenia

In clinical studies of patients with del 5q MDS, lenalidomide as monotherapy was associated with significant neutropenia and thrombocytopenia. Grade 3 or 4 haematologic toxicity was seen in 80% of patients. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2- 170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days). Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require the use of blood product support and/or growth factors (see section x. [Dosage and administration]). The combination of lenalidomide with dexamethasone in multiple myeloma patients is associated with a higher incidence of Grade 4 neutropenia (4.8% in lenalidomide/dexamethasone-treated patients compared with 0.6% in placebo/dexamethasone-treated patients; see section ix. [Adverse Effects]). 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 ix. [Adverse Effects]). Patients should be advised to promptly report febrile episodes. A dose reduction may be required (see section x. [Dosage and administration]). 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 (10.8% and 1.4%, respectively, in lenalidomide/dexamethasone-treated patients compared to 5.4% and 0.9% in placebo/dexamethasone- treated patients; see section iv. [Clinical trials]). Patients and physicians are advised to be observant for signs and symptoms of bleeding, including petechiae and epistaxes. A dose reduction may be required (see section x. [Dosage and administration]). 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.

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 and Tumour Flare Reaction

Tumour lysis syndrome (TLS) and tumour flare reaction (TFR) have commonly been observed in patients with CLL, and uncommonly in patients with other lymphomas, who were treated with lenalidomide. Fatal instances of TLS have been reported during treatment with lenalidomide. Patients at risk of TLS and TFR are those with high tumour burden prior to treatment. Caution should be practiced when introducing these patients to lenalidomide. These patients should be monitored closely, especially during the first cycle or dose-escalation, and appropriate precautions taken. There have been rare reports of TLS in patients with MM treated with lenalidomide, and no reports in patients with MDS treated with lenalidomide.

Angioedema, dermatological reactions

Rare cases of angioedema and serious dermatological reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported from post-marketing experience. These events have the potential to be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive lenalidomide. Revlimid interruption or discontinuation should be considered for Grade 2-3 skin rash. Revlimid must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected. Revlimid should not be resumed following the discontinuation for these reactions.

Atrial fibrillation

In the two pivotal randomised controlled trials in MM patients, atrial fibrillation occurred in 14 (4.0%) subjects treated with lenalidomide/dexamethasone compared to 4 (1.1%) subjects treated with placebo/dexamethasone (unadjusted for the longer on-study observation time for patients receiving lenalidomide). Careful review of these cases revealed the presence of multiple risk factors for atrial fibrillation (e.g. infections, hypertension, congestive heart failure, electrolyte imbalance), and a causal relationship to lenalidomide treatment has not yet been determined.

Use in patients with impaired thyroid function

Cases of hypothyroidism have been reported and monitoring of thyroid function should be considered.

Use in patients with 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.

Effects on ability to drive and use machines

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.

Interaction with other medicines

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 section vii. [Precautions], and section ix. [Adverse Effects]). 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.

Oral contraceptives

No interaction study has been performed with oral contraceptives. Lenalidomide is not an enzyme inducer (see below). 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. 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. 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 in combination with agents metabolised by these enzymes.

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

Lenalidomide is a weak substrate but not an inhibitor of P-glycoprotein. 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. In the same study, the co-administration of digoxin (a P-glycoprotein substrate) did not significantly affect the pharmacokinetics of lenalidomide.

Renal Drug Interactions

Renal drug-drug interaction studies have not been performed. The renal clearance of lenalidomide is slightly greater than the glomerular filtration rate, suggesting that active secretion contributes to a minor extent (<= 25%) of renal clearance. Hence, the inhibition of the active secretion of lenalidomide will most likely not result in a clinically relevant drug-drug interaction.

Dosage and administration

Treatment must be initiated and monitored under the supervision of a registered Specialist Physician experienced in the management of haematological and oncological malignancies.

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 and either one hour before or two hours after 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.

Haematological testing

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.

Multiple Myeloma

Recommended dosage

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. Treatment should be continued until disease progression or unacceptable toxicity. Dosing is continued or modified based upon clinical and laboratory findings (see section vii. [Precautions]). Lenalidomide treatment must not be started if the Absolute Neutrophil Counts (ANC) < 1.0 x 109/L, and/or platelet counts < 75 x 109/L or, dependent on bone marrow infiltration by plasma cells, platelet counts < 30 x 109/L.

Recommended dosage adjustments during treatment and re-initiation of treatment

Dose adjustments, as summarised below, are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia, or other Grade 3 or 4 toxicities judged to be related to lenalidomide.

Dose reduction steps

Platelet counts

Absolute Neutrophil counts (ANC)

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

Myelodysplastic Syndromes (MDS)

Recommended dosage

The recommended starting dose of lenalidomide is 10 mg given orally once a day on days 1 to 21 of repeating 28-day treatment cycles. Dosing is continued or modified based upon clinical and laboratory findings. Lenalidomide treatment must not be started if the ANC < 0.5 x 109/L, and/or platelet counts < 50 x 109/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 toxicities judged to be related to lenalidomide. For patients who experience thrombocytopenia or neutropenia within the first 4 weeks of treatment:

Platelet counts

Absolute Neutrophil counts (ANC)

For patients who experience thrombocytopenia after the first 4 weeks of treatment:

Platelet counts

If thrombocytopenia develops during treatment at 10 mg/day,

If thrombocytopenia develops during treatment at 5 mg/day,

Absolute Neutrophil counts (ANC)

If neutropenia develops during treatment at 10 mg/day,

If neutropenia develops during treatment at 5 mg/day,

Other dose adjustments for MM and MDS

Grade 3/4 Toxicities

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

Discontinuation of Revlimid

Revlimid interruption or discontinuation should be considered for Grade 2-3 skin rash. Revlimid must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected. Revlimid should not be resumed following the discontinuation for these reactions.

Use in patients with impaired renal function

Lenalidomide is substantially excreted by the kidney. With patients with impaired renal function, care should be taken in dose selection. Monitoring of renal function is advised in patients with renal impairment. 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.

* In MM, 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. CLcr = creatinine clearance.

Monitoring of patients with impaired renal function for signs and symptoms of neutropenia or thrombocytopenia should be done on a weekly basis for the first 8 weeks after the initiation of lenalidomide therapy.

Use in patients with impaired hepatic function:

Revlimid has not formally been studied in patients with impaired hepatic function and there are no specific dose recommendations. For further information regarding Revlimid's compatibility with other drugs and monitoring advice, please refer to the 'Precautions' section.

Overdosage

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 50 mg. The dose limiting toxicity in these studies was essentially haematological. In the event of overdose, supportive care is advised. In Australia, contact the Poisons Advisory Centre on 13 11 26 for advice on management. In New Zealand, contact the National Poison Centre on 0800 POISON or 0800 764 766 for advice on management.

Presentation and storage conditions

Presentation

Revlimid 5 mg capsules, hard: White size 2 capsules marked "5 mg REV". Each 5 mg capsule contains 5 mg lenalidomide. Blister packs containing 21 capsules. Revlimid 10 mg capsules, hard: Yellow/blue-green size 0 capsules marked "10 mg REV". Each 10 mg capsule contains 10 mg lenalidomide. Blister packs containing 21 capsules. Revlimid 15 mg capsules, hard: White/blue size 0 capsules marked "15 mg REV". Each 15 mg capsule contains 15 mg lenalidomide. Blister packs containing 21 capsules. Revlimid 25 mg capsules, hard: White size 0 capsules marked "25 mg REV". Each 25 mg capsule contains 25 mg lenalidomide. Blister packs containing 21 capsules.

Composition Active

Lenalidomide

Storage conditions

Store below 25C. Store in the original package.

Container type

Polychlorotrifluoroethylene (PCTFE) / polyvinylchloride (PVC) / Aluminium foil blisters.

Name and address of the sponsor

Celgene Pty Limited Level 7, 607 St Kilda Road, Melbourne, VIC 3004, Australia.

Poison Schedule of the medicine

Schedule 4 (Prescription Only Medicine)

Date of first inclusion in the Australian Register of Therapeutic Goods (the ARTG)

20 December 2007

Date of most recent amendment

22 October 2013