Lenalidomide Drl 5 mg/10 mg/15 mg/25 mg Capsules

Myelodysplastic Syndromes (MDS)

LENALIDOMIDE DRL is indicated for the treatment of patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without other cytogenetic abnormalities.

Multiple Myeloma

LENALIDOMIDE DRL in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy.

Posology

Myelodysplastic syndromes (MDS)

Recommended dosage

The recommended starting dose of LENALIDOMIDE DRL is 10 mg given orally once a day on days 1-21 of repeating 28-day treatment cycles.

Recommended dose adjustments during treatment and restart of treatment

• Platelet counts

Patients who are dosed initially at 10 mg and who experience thrombocytopenia should have their dosage adjusted as follows:

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

• If baseline u2265 100 x 109/L

When platelets

• Fall to < 50 x 109/L

Interrupt LENALIDOMIDE DRL treatment

Return to u2265 50 x 109/L

Resume LENALIDOMIDE DRL at 5 mg once a day continuously in repeating 28 day cycles

If baseline < 100 x 109/L

When platelets

• Fall to 50 % of the baseline value

Interrupt LENALIDOMIDE DRL treatment

If baseline u2265 60 x 109/L and returns to u2265 50 x 109/L

Resume LENALIDOMIDE DRL at 5 mg once a day continuously in repeating 28 day cycles

If baseline < 60 x 109/L and returns to u2265 30 x 109/L

Resume LENALIDOMIDE DRL at 5 mg once a day continuously in repeating 28 day cycles

If thrombocytopenia develops AFTER 4 weeks of starting treatment at 10 mg:

• When platelets

Recommended course

• < 30 x 109/L or < 50 x 109/L with platelet transfusions

Interrupt LENALIDOMIDE DRL treatment

Return to u2265 30 x 109/L (without signs of bleeding)

Resume LENALIDOMIDE DRL at 5 mg once a day continuously in repeating 28 day cycles

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

If thrombocytopenia develops during treatment at 5 mg daily:

• When platelets

Recommended course

• < 30 x 109/L or < 50 x 109/L with platelet transfusions

Interrupt LENALIDOMIDE DRL treatment

Return to u2265 30 x 109/L (without signs of bleeding)

Resume LENALIDOMIDE DRL at 5 mg every other day

Neutrophil counts (ANC)

Patients who are dosed initially at 10 mg and experience neutropenia should have their dosage adjusted as follows:

If neutropenia develops WITHIN 4 weeks of starting treatment at 10 mg:

• If baseline ANC u2265 1 x 109/L

When Neutrophils

• Fall to < 0,75 x 109/L

Interrupt LENALIDOMIDE DRL treatment

Return to u2265 1 x 109/L

Resume LENALIDOMIDE DRL at 5 mg once a day continuously in repeating 28 day cycles

If baseline ANC < 1 x 109/L

When Neutrophils

• Fall to < 0,5 x 109/L

Interrupt LENALIDOMIDE DRL treatment

Return to u2265 0,5 x 109/L

Resume LENALIDOMIDE DRL at 5 mg once a day continuously in repeating 28 day cycles

If neutropenia develops AFTER 4 weeks of starting treatment at 10 mg:

• When Neutrophils

Recommended course

• < 0,5 x 109/L for u2265 7 days or < 0,5 x 109/L associated with fever (u2265 38,5 u00baC)

Interrupt LENALIDOMIDE DRL treatment

Return to u2265 0,5 x 109/L

Resume LENALIDOMIDE DRL at 5 mg once a day continuously in repeating 28 day cycles

Other Grade 3/4 Toxicities

For other Grade 3/4 toxicities judged to be related to LENALIDOMIDE DRL, stop treatment and restart at next lower dose level when toxicity has resolved to u2264 Grade 2 at the medical practitioneru2019s discretion.

Discontinuation of LENALIDOMIDE DRL

LENALIDOMIDE DRL interruption or discontinuation should be considered for Grade 2-3 skin rash. LENALIDOMIDE DRL must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected, and should not be resumed following discontinuation from these reactions.

Multiple Myeloma

Previously Treated Multiple Myeloma

Recommended dosage

The recommended starting dose of LENALIDOMIDE DRL is 25 mg/day orally on Days 1-21 of repeated 28-day cycles for multiple myeloma. The recommended dose of dexamethasone is 40 mg/day 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/day orally on Days 1-4 every 28 days. Treatment should be continued until disease progression or unacceptable toxicity.

Recommended dose adjustments during treatment and restart of treatment

Dose modification guidelines, 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 DRL.

Platelet counts

Thrombocytopenia

See table below entitled, u2018Dose Reduction Steps for LENALIDOMIDE DRL in Previously Treated Multiple Myelomau2019

Neutrophil counts (ANC)

Neutropenia

See table below entitled, u2018Dose Reduction Steps for LENALIDOMIDE DRL in Previously Treated Multiple Myelomau2019

Other Grade 3/4 Toxicities

For other Grade 3/4 toxicities judged to be related to LENALIDOMIDE DRL, stop treatment and restart at next lower dose level when toxicity has resolved to u2264 Grade 2 at the medical practitioneru2019s discretion.

• Hypersensitivity to lenalidomide or to any of the excipients listed in section 6.1.
• Pregnancy and lactation.
• Women of childbearing potential, except when all of the conditions for pregnancy prevention have been met (see sections 4.4 and 4.6).

General

When LENALIDOMIDE DRL is given in combination with other medicines, the corresponding professional information must be consulted prior to initiation of treatment.

A 3-month prescription (12 weeks supply) is allowed for males and females with a permanent non-childbearing potential.

Pregnancy warning

LENALIDOMIDE DRL is contra-indicated during pregnancy. 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 4.6). If LENALIDOMIDE DRL is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected.

The conditions of LEN PERM (PROGRAM FOR THE EVALUATION OF RISK AND MANAGEMENT) must be fulfilled for all patients unless there is reliable evidence that the patient does not have childbearing potential.

Counselling

For women of childbearing potential, LENALIDOMIDE DRL is contraindicated unless all of the following are met:

• She understands the expected teratogenic risk to the unborn child
• She understands the need for effective contraception, without interruption, 4 weeks before starting treatment, throughout the entire duration of treatment including dose interruptions, and for 4 weeks after the end of treatment
• Even if a woman of childbearing potential has amenorrhoea 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 DRL 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 DRL.

For male patients taking LENALIDOMIDE DRL, 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 discontinuation of lenalidomide in the healthy subject (see section 5.2). As a precaution all male patients taking LENALIDOMIDE DRL must meet the following conditions:

• Understand the expected teratogenic risk if engaged in sexual activity with a woman of childbearing potential.
• Understand 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 LEN PERM (PROGRAM FOR THE EVALUATION OF RISK AND MANAGEMENT), including confirmation that she has an adequate level of understanding
• The patient has acknowledged the aforementioned conditions.

Contraception

Women of childbearing potential must use two reliable methods of contraception for 4 weeks before therapy, during therapy including dose interruptions, and until 4 weeks after LENALIDOMIDE DRL therapy 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:

Highly effective methods

• Intra Uterine Device (IUD);
• Hormonal (hormonal implants, levonorgestrel-releasing intrauterine system (IUS)), medroxyprogesterone acetate depot injections, ovulation inhibitory progesterone-only pills (e.g. desogestrel);
• Tubal ligation;
• Partneru2019s vasectomy.

Effective methods

• Male condom;
• Diaphragm;
• Cervical cap.

Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking LENALIDOMIDE DRL and dexamethasone, and in patients with myelodysplastic syndromes taking LENALIDOMIDE DRL monotherapy, 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 two of the effective methods listed above.

The risk of venous thromboembolism continues for 4u22126 weeks after discontinuing combined oral contraception.

Pregnancy testing

Pregnancy must be excluded by testing blood and/or urine. According to local practice, medically supervised pregnancy tests with a minimum sensitivity of 50 IU/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 DRL 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 7 days prior to the patient starting LENALIDOMIDE DRL 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 DRL.

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 7 days prior to the visit to the prescriber.

Male fertility

LENALIDOMIDE DRL is present in human semen at extremely low levels during treatment and is undetectable in human semen 3 days after discontinuation of LENALIDOMIDE DRL 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 should use condoms throughout treatment duration, during dose interruption and for 4 weeks after cessation of treatment if their partner is of childbearing potential and is not established on suitable contraception (even if the male patient has undergone a vasectomy). Male patients taking LENALIDOMIDE DRL should not donate sperm or semen during treatment including dose interruptions and for 4 weeks following the discontinuation of treatment.

Additional precautions

Patients should not donate blood during therapy including dose interruptions and for 4 weeks following discontinuation of LENALIDOMIDE DRL.

Educational materials

In order to assist patients in avoiding foetal exposure to LENALIDOMIDE DRL, educational material will be provided to health care professionals to reinforce the warnings about the expected teratogenicity of LENALIDOMIDE DRL, 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 Len Perm Programme for the evaluation of risk management should be given by the medical practitioner to women of childbearing potential and, as appropriate, to male patients.

Other special warnings and precautions for use

Myocardial infarction

Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with known risk factors and within the first 12 months when used in combination with dexamethasone. Patients with known risk factors u2013 including prior thrombosis u2013 should be closely monitored, and action should be taken to try to minimise all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia).

Venous and arterial thromboembolic events

Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism), in multiple myeloma patients treated with LENALIDOMIDE DRL combination therapy and in MDS patients treated with LENALIDOMIDE monotherapy. In patients with multiple myeloma, the combination of lenalidomide with dexamethasone is associated with an increased risk of arterial thromboembolism (predominantly myocardial infarction and cerebrovascular event).

Pulmonary hypertension

Cases of pulmonary hypertension, some fatal, have been reported in patients treated with lenalidomide. Patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during LENALIDOMIDE DRL therapy.

Neutropenia and thrombocytopenia

The major dose limiting toxicities of lenalidomide include neutropenia and thrombocytopenia. A dose reduction may be required (see section 4.2). In case of neutropenia, the medical practitioner should monitor for signs of infection. Patients should be advised to promptly report febrile episodes. Patients and medical practitioners are advised to be observant for signs and symptoms of bleeding, including petechiae and epistaxes, especially in patients receiving concomitant medicines susceptible to induce bleeding. Co-administration of LENALIDOMIDE DRL with other myelosuppressive agents should be undertaken with caution.

Multiple myeloma: patients with at least one prior therapy

Haematologic toxicity (neutropenia and thrombocytopenia) in previously treated multiple myeloma patients treated with LENALIDOMIDE DRL combination therapy u2013 Complete blood cell counts should be monitored every 2 weeks for the first 12 weeks and then monthly thereafter. A dose interruption and/or dose reductions may be required (see section 4.2).

MDS

Haematologic toxicity (neutropenia and thrombocytopenia) in deletion 5q MDS u2013 A complete blood cell count, including white blood cell count with differential, platelet count, haemoglobin, and haematocrit should be performed weekly for first 8 weeks of LENALIDOMIDE DRL treatment and monthly thereafter to monitor for cytopenias. A dose reduction may be required (see section 4.2).

Second primary malignancies

Previously treated MM A numerical imbalance was observed in clinical trials in previously treated multiple myeloma patients with Lenalidomide/dexamethasone compared with controls comprising invasive primary malignancies and of basal cell and squamous cell skin cancers. Carefully evaluate patients before and during treatment using standard cancer screening for occurrence of second primary malignancies and institute treatment as appropriate.

Thyroid disorders

Cases of hypothyroidism and cases of hyperthyroidism have been reported. Before start of treatment, optimal control of co-morbid conditions influencing thyroid function is recommended. Baseline and ongoing monitoring of thyroid function is recommended.

Peripheral neuropathy

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

Tumour flare reaction and tumour lysis syndrome

Because lenalidomide has anti-neoplastic activity the complications of tumour lysis syndrome (TLS) may occur. TLS and tumour flare reaction (TFR) have commonly been observed in patients with chronic lymphocytic leukemia (CLL), and in patients with lymphomas, who were treated with lenalidomide. Fatal instances of TLS have been reported during treatment with lenalidomide. The patients at risk of TLS and TFR are those with high tumour burden prior to treatment. Caution should be practiced when introducing these patients to LENALIDOMIDE DRL. 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.

Allergic conditions / Severe skin reactions

Angioedema and severe cutaneous reactions including SJS, and TEN and DRESS have been reported. These events can be fatal. Patients should be advised of the signs and symptoms of these reactions by their medical practitioners and should be told to seek medical attention immediately if they develop these symptoms. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive LENALIDOMIDE DRL. LENALIDOMIDE DRL interruption or discontinuation should be considered for Grade 2-3 skin rash. LENALIDOMIDE DRL must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS, TEN or DRESS is suspected, and should not be resumed following discontinuation for these reactions.

Hepatic disorders

Hepatic failure, including fatal cases, has been reported in patients treated with lenalidomide in combination therapy: acute hepatic failure, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis have been reported. The mechanisms of severe drug-induced hepatotoxicity remain unknown. Lenalidomide is excreted by the kidneys. It is important to dose adjust patients with renal impairment in order to avoid plasma levels which may increase the risk for higher haematological adverse reactions or hepatotoxicity.

Infection with or without neutropenia

Patients with multiple myeloma are prone to develop infections including pneumonia. Patients with known risk factors for infections should be closely monitored. All patients should be advised to seek medical attention promptly at the first sign of infection (eg, cough, fever, etc) thereby allowing for early management to reduce severity.

Viral reactivation

Cases of viral reactivation have been reported in patients receiving lenalidomide, including serious cases of herpes zoster or hepatitis B virus (HBV) reactivation. Some of the cases of viral reactivation had a fatal outcome. Some of the cases of herpes zoster reactivation resulted in disseminated herpes zoster, meningitis herpes zoster or ophthalmic herpes zoster requiring a temporary hold or permanent discontinuation of the treatment with lenalidomide and adequate antiviral treatment. Reactivation of hepatitis B has been reported rarely in patients receiving lenalidomide who have previously been infected with the hepatitis B virus (HBV). Some of these cases have progressed to acute hepatic failure resulting in discontinuation of lenalidomide and adequate antiviral treatment. Hepatitis B virus status should be established before initiating treatment with lenalidomide. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Caution should be exercised when LENALIDOMIDE DRL is used in patients previously infected with HBV, including patients who are anti-HBc positive but HBsAg negative. These patients should be closely monitored for signs and symptoms of active HBV infection throughout therapy.

Progressive multifocal leukoencephalopathy

Cases of progressive multifocal leukoencephalopathy (PML), including fatal cases, have been reported with lenalidomide. PML was reported several months to several years after starting the treatment with lenalidomide. Cases have generally been reported in patients taking concomitant dexamethasone or prior treatment with other immunosuppressive chemotherapy. Medical practitioners should monitor patients at regular intervals and should consider PML in the differential diagnosis in patients with new or worsening neurological symptoms, cognitive or behavioural signs or symptoms. Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of. The evaluation for PML should be based on neurological examination, magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JC virus (JCV) DNA by polymerase chain reaction (PCR) or a brain biopsy with testing for JCV.

Cataract

Cataract has been reported with a higher frequency in patients receiving lenalidomide in combination with dexamethasone. Regular monitoring of visual ability is recommended.

Lenalidomide is not a substrate, inhibitor or inducer of cytochrome P450 enzymes in vitro. Hence, co-administration of cytochrome P450 substrates or inhibitors with LENALIDOMIDE DRL is not likely to result in clinically relevant medicine interactions.

In vitro studies demonstrate that lenalidomide is not a substrate of human multidrug resistance protein MRP1, MRP2 or MRP3 efflux transporters as well as human organic anion and cation uptake transporters OAT1, OAT3, OATP1B1 (OATP2) or OCT1.

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 DRL with dexamethasone (see sections 4.4 and 4.8).

Patients with multiple myeloma taking LENALIDOMIDE DRL and dexamethasone, patients with MDS taking LENALIDOMIDE DRL monotherapy, as well as patients taking combined oral contraceptive pills or hormone replacement therapy, have an increased risk of venous thromboembolic events (VTE).

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 medicines, including hormonal contraceptives, is not expected if LENALIDOMIDE DRL 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).

Warfarin

Co-administration of multiple doses of 10 mg of lenalidomide had no effect on the single dose pharmacokinetics and pharmacodynamics of R- and S-warfarin. Coadministration of a single 25 mg dose of warfarin had no effect on the pharmacokinetics of lenalidomide. 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

When digoxin was co-administered with lenalidomide (10 mg/day) the digoxin Cmax and AUC0-u221e were 14 % higher than when digoxin was administered concomitantly with placebo. Periodic, monitoring of the digoxin concentration is advised during LENALIDOMIDE DRL treatment.

Statins

There is an increased risk of rhabdomyolysis when statins are administered with LENALIDOMIDE DRL, which may be simply additive. Enhanced laboratory and clinical monitoring is warranted notably during the first weeks of treatment.

Dexamethasone

In patients with multiple myeloma, co-administration of single or multiple doses of dexamethasone (40 mg once daily) had no significant effect on the multiple dose pharmacokinetics of lenalidomide (25 mg once daily).

Interactions with P-glycoprotein (P-gp) inhibitors

In vitro, lenalidomide is a weak substrate, but is not an inhibitor of P-glycoprotein (P-gp).

LENALIDOMIDE DRL is contraindicated in females who are pregnant or who could become pregnant.

Pregnancy

LENALIDOMIDE DRL is teratogenic to animals. The teratogenic effect of lenalidomide in humans cannot be ruled out. Therefore:

• Females of childbearing potential must use effective means of contraception for 28 days before therapy, during LENALIDOMIDE DRL therapy including dose interruptions, and for 28 days following discontinuation of LENALIDOMIDE DRL therapy, or continually abstain from sexual intercourse. There is an increased risk of VTE in patients with multiple myeloma taking LENALIDOMIDE DRL and dexamethasone, and in patients with MDS taking LENALIDOMIDE DRL monotherapy, and an increased risk of VTE in patients taking combined oral contraceptive pills.
• Females of childbearing potential should undergo regular pregnancy testing during treatment with LENALIDOMIDE DRL.
• If pregnancy does occur during treatment, LENALIDOMIDE DRL should be immediately discontinued.

Males:

Clinical data has demonstrated the presence of lenalidomide in human semen. Therefore, male patients taking LENALIDOMIDE DRL should use a condom during LENALIDOMIDE DRL therapy including dose interruptions and for 4 weeks after cessation of treatment. Male patients taking LENALIDOMIDE DRL should not donate sperm or semen during treatment including dose interruptions and for 4 weeks following the discontinuation of treatment.

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 u2265 50 years and naturally amenorrhoeic for u2265 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.

Lactation

Breastfeeding is contra-indicated during therapy with LENALIDOMIDE DRL.

LENALIDOMIDE DRL may affect the ability to drive and use machines. Fatigue, dizziness, somnolence, vertigo and blurred vision have been reported with the use of LENALIDOMIDE DRL. Therefore, caution is recommended when driving or using machines.

Overall reported Adverse Drug Reactions (ADRu2019s) in Relapsed and Refractory Multiple Myeloma and Myelodysplastic Syndromes: Adverse reactions observed in patients are listed below by system organ class/preferred term and frequency. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

System Organ Class/Preferred Term Frequency of ADRs

All ADRs Grade 3/4 ADRs SADRs

General Disorders and Administration Site Conditions Frequent Pyrexia, oedema (including peripheral), influenza like illness syndrome (including pyrexia, cough, rhinitis, myalgia, musculoskeletal pain, pharyngitis, headache and rigors), fatigue, asthenia, chest pain Fatigue, pyrexia, asthenia, fall

Gastrointestinal Disorders Frequent Diarrhoea @, vomiting @, nausea @, constipation, abdominal pain (including upper) @, dry mouth, dyspepsia Diarrhoea @, nausea @, constipation, toothache Diarrhoea @

Musculoskeletal and Connective Tissue Disorders Frequent Musculoskeletal and connective tissue pain and discomfort (including back pain and pain in extremity), bone pain, muscle spasms, arthralgia, myalgia Muscular weakness, musculoskeletal and connective tissue pain and discomfort, back pain Back pain

Nervous System Disorders Frequent Peripheral neuropathies (excluding motor neuropathy), dizziness, tremor, dysguesia, headache, lethargy, paraesthesia Syncope, dizziness Cerebrovascular accident @

Respiratory, Thoracic and Mediastinal Disorders Frequent Dyspnoea, epistaxis Respiratory distress @, bronchitis Less frequent Pulmonary hypertension Pulmonary hypertension

Infections and Infestations# Frequent Pneumonia @, bronchitis, bacterial, viral and fungal infections (including opportunistic infections), upper respiratory tract infection, sinusitis Pneumonia @, bacterial, viral and fungal infections (including opportunistic infections) Pneumonia @, bacterial, viral and fungal infections (including opportunistic infections)

Skin and Subcutaneous Tissue Disorders Frequent Rash +, pruritus, dry skin, hyperhidrosis Rash, pruritus

Blood and Lymphatic System Disorders Frequent Neutropenia %, thrombocytopenia @, anaemia @, leukopenia Neutropenia %, thrombocytopenia @ anaemia @, leukopenia, febrile neutropenia % Anaemia @, febrile neutropenia %, neutropenia %, thrombocytopenia @

Metabolism and Nutrition Disorders Frequent Decreased appetite, hypokalaemia, hypocalcaemia, dehydration, hypomagnesaemia, iron overload Hypokalaemia, hypocalcaemia, hypophosphataemia, hyperglycaemia %, decreased appetite Hyperglycaemia %

Eye Disorders Frequent Blurred vision Cataracts

Renal and Urinary Disorders Frequent Renal failure @ Renal failure @

Vascular Disorders Frequent Venous thromboembolic events, predominantly deep vein thrombosis and pulmonary embolism @, hypertension, hypotension, haematoma Venous thromboembolic events, predominantly deep vein thrombosis and pulmonary embolism @ Venous thromboembolic events, predominantly deep vein thrombosis and pulmonary embolism @

Psychiatric Disorders Frequent Depression Altered mood

Cardiac Disorders Frequent Acute myocardial infarction @, atrial fibrillation @, tachycardia, cardiac failure congestive @, cardiac failure @ Acute myocardial infarction @, atrial fibrillation @, cardiac failure congestive @, cardiac failure @

Neoplasms Benign, Malignant and Unspecified (including cysts and polyps Frequent B-cell lymphomas

Immune System Disorders Less frequent Hypersensitivity

Hepatobiliary Frequent Abnormal liver function tests Abnormal liver function tests

Investigations Frequent Decreased weight @ - ADRs with Death as an outcome % - ADRs which were considered to be Life Threatening (if the outcome of the event was death, it is included with death cases) # - All PTs under SOC of Infections except for rare infections of Public Health interest will be considered listed +-All PTs under HLT of Rash will be considered listed

The following adverse drug reactions have been identified from the worldwide postmarketing experience with lenalidomide. Allergic conditions (angioedema, SJS, TEN), tumour lysis syndrome (TLS) and tumour flare reaction (TFR), pneumonitis, and transient abnormal liver laboratory tests have been reported, but the frequency is unknown.

Hepatic Disorders

Transient liver laboratory abnormalities (predominantly transaminases) were reported in patients treated with lenalidomide. Treatment with LENALIDOMIDE DRL should be interrupted and restarted once the levels return to baseline. Successful re-challenge without recurrence of liver laboratory elevation was reported in some patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

There is no specific experience in the management of LENALIDOMIDE DRL overdose in patients. The dose limiting toxicity in these studies was essentially haematological. In the event of overdose, supportive care is advised.