Datrenal 25 Mg/2,5 mg/5 mg/7,5 mg/10 mg/15 mg/20 mg Capsules

DATRENAL is indicated for:

1. Myelodysplastic Syndromes (MDS): DATRENAL 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.
2. Multiple Myeloma: DATRENAL 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 DATRENAL 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 10 9 /L When platelets

Recommended course

• Fall to < 50 x 10 9 /L Interrupt DATRENAL treatment
• Return to u2265 50 x 10 9 /L Resume DATRENAL at 5 mg once a day continuously in repeating 28 day cycles

If baseline < 100 x 10 9 /L When platelets

• Recommended course

Fall to 50 % of the baseline value Interrupt DATRENAL treatment

If baseline u2265 60 x 10 9 /Land returns to u2265 50 x 10 9 /L Resume DATRENAL at 5 mg once a day continuously in repeating 28 day cycles

If baseline < 60 x 10 9 /L and returns to u2265 30 x 10 9 / Resume DATRENAL 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 10 9 /L or < 50 x 10 9 /L with platelet transfusions Interrupt DATRENAL treatment

Return to u2265 30 x 10 9 /L (without signs of bleeding) Resume DATRENAL 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 10 9 /L or < 50 x 10 9 /L with platelet transfusions Interrupt DATRENAL treatment

Return to u2265 30 x 10 9 /L (without signs of bleeding) Resume DATRENAL 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 10 9 /L

When neutrophils

• Recommended course

Fall to < 0,75 x 10 9 /L Interrupt DATRENAL treatment

Return to u2265 1 x 10 9 /L Resume DATRENAL at 5 mg once a day continuously in repeating 28 day cycles

If baseline ANC < 1 x 10 9 /L

When neutrophils

• Recommended course

Fall to < 0,5 x 10 9 /L Interrupt DATRENAL treatment

Return to u2265 0,5 x 10 9 /L Resume DATRENAL 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 10 9 /L for u2265 7 days or < 0,5 x 10 9 /L associated with fever (u2265 38,5 u00b0C) Interrupt DATRENAL treatment

Return to u2265 0,5 x 10 9 /L Resume DATRENAL at 5 mg once a day continuously in repeating 28 day cycles

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

If neutropenia develops during treatment at 5 mg daily

When neutrophils

• Recommended course

< 0,5 x 10 9 /L for u2265 7 days or < 0,5 x 10 9 /L associated with fever (u2265 38,5 u00b0C) Interrupt DATRENAL treatment

Return to u2265 0,5 x 10 9 /L Resume DATRENAL at 5 mg once every other day

Other Grade u00be Toxicities For other Grade u00be toxicities judged to be related to DATRENAL, stop treatment and restart at next lower dose level when toxicity has resolved to u2264 Grade 2 . Discontinuation of DATRENAL DATRENAL interruption or discontinuation should be considered for Grade 2-3 skin rash. DATRENAL 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 DATRENAL 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 DATRENAL.

Platelet counts Thrombocytopenia See table below entitled, u2018Dose Reduction Steps for DATRENAL in Previously Treated Multiple Myelomau2019 Neutrophil counts (ANC) Neutropenia See table below entitled, u2018Dose Reduction Steps for DATRENAL in Previously Treated Multiple Myelomau2019 Other Grade u00be Toxicities For other Grade u00be toxicities judged to be related to DATRENAL, stop treatment and restart at next lower dose level when toxicity has resolved to u2264 Grade 2 . Discontinuation of DATRENAL DATRENAL interruption or discontinuation should be considered for Grade 2-3 skin rash. DATRENAL 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.

Recommended dose adjustment for previously treated multiple myeloma: Dosing is continued or modified based upon clinical and laboratory findings.

Dose Reduction Steps for DATRENAL in Previously Treated Multiple Myeloma: Platelet counts Thrombocytopenia When platelets Recommended course Dose levels Previously treated Multiple Myeloma (combination with dexamethasone) Days 1-21/28 day cycle Fall to < 30 x 10 9 /L Interrupt DATRENAL treatment and follow CBC weekly Starting dose 25 mg Return to u2265 30 x 10 9 /L Resume DATRENAL at dose level u2013 1 Dose level u2013 1 15 mg For each subsequent drop below < 30 x 10 9 /L Interrupt DATRENAL treatment Dose level u2013 2 10 mg Dose level u2013 3 5 mg

DATRENAL is contraindicated:

• Hypersensitivity to lenalidomide or any of the excipients (see section 6.1)
• In 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: Pregnancy warning DATRENAL is contra - indicated during pregnancy. DATRENAL 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 DATRENAL is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected. The conditions of the Key Assist Risk Management Program 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, DATRENAL 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 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 DATRENAL 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 DATRENAL.

For male patients taking DATRENAL, 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 DATRENAL 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 the Key Assist Risk Management Program, 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 DATRENAL 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 DATRENAL and dexamethasone, and in patients with myelodysplastic syndromes taking DATRENAL monotherapy, combined oral contraceptive pills are not recommended (see 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 4-6 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 DATRENAL 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 DATRENAL, 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 DATRENAL.

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 DATRENAL is present in human semen at extremely low levels during treatment and is undetectable in human semen 3 days after discontinuation of DATRENAL 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 DATRENAL should not donate sperm or semen during treatment including dose interruptions and for 4 weeks following the end of treatment.

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

Educational materials In order to assist patients in avoiding foetal exposure to DATRENAL, educational material will be provided to health care professionals to reinforce the warnings about the expected teratogenicity of DATRENAL, 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 Key Assist Risk Management Program 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:

• Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism), in multiple myeloma patients treated with DATRENAL combination therapy and in MDS patients treated with DATRENAL monotherapy.
• Allergic Conditions : Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive DATRENAL. DATRENAL interruption or discontinuation should be considered for Grade 2-3 skin rash. DATRENAL 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 for these reactions.
• Tumour Lysis Syndrome and Tumour Flare Reaction Tumour lysis syndrome (TLS) and tumour flare reaction (TFR) have been observed in patients with Chronic Lymphocytic Leukemia (CLL), and in patients with other lymphomas, who were treated with lenalidomide. Fatal instances of TLS have been reported during treatment with lenalidomide. Patients at risk for TLS and TFR are those with high tumour burden prior to treatment. Caution should be practiced when introducing these patients to DATRENAL. These patients should be monitored closely, especially during the first cycle or dose-escalation, and appropriate precautions taken. There have been reports of TLS in patients with MM treated with lenalidomide.
• 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 minimize all modifiable risk factors (eg. smoking, hypertension, and hyperlipidaemia).
• Neutropenia and thrombocytopenia: The major dose limiting toxicities of DATRENAL include neutropenia and thrombocytopenia. 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 DATRENAL treatment and monthly thereafter to monitor for cytopenias. A dose reduction may be required (see section 4.2). In case of neutropenia, the medical practitioner should consider the use of growth factors in patient management. Patients should be advised to promptly report febrile episodes.
• Patients and physicians are advised to be observant for signs and symptoms of bleeding, including petechiae and epistaxis, especially in patients receiving concomitant medicines susceptible to induce bleeding. Co-administration of DATRENAL with other myelosuppressive agents should be undertaken with caution.
• Myelodysplastic syndromes (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 DATRENAL treatment and monthly thereafter to monitor for cytopenias. A dose reduction may be required (see section 4.2).
• Multiple myeloma: Haematological toxicities : u2022 Previously treated MM: Haematologic toxicity (neutropenia and thrombocytopenia) in previously treated multiple myeloma patients treated with DATRENAL 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).
• Second Primary Malignancies u2022 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.

Lenalidomide is not a substrate, inhibitor or inducer of cytochrome P450 enzymes in vitro. Hence, co-administration of cytochrome P450 substrates or inhibitors with DATRENAL is not likely to result in clinically relevant medicine interactions. Co-administration of multiple doses of 10 mg of DATRENAL had no effect on the single dose pharmacokinetics and pharmacodynamic of R- and S-warfarin. Coadministration of a single 25 mg dose of warfarin had no effect on the pharmacokinetics of DATRENAL. It is not known whether there is an interaction during 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 treatment. When digoxin was co-administered with lenalidomide (10 mg/day) the digoxin C max and AUC 0- u221e were 14 % higher than when digoxin was administered concomitantly with placebo. Periodic monitoring of digoxin plasma levels is recommended during administration of DATRENAL. In patients with multiple myeloma, co-administration of single or multiple doses of dexamethasone (40 mg/day) had no significant effect on the multiple dose pharmacokinetics of DATRENAL (25 mg/day). In vitro , DATRENAL is a weak substrate, but is not an inhibitor of P-glycoprotein (P-gp). 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 medicines, or other medicines that may increase the risk of thrombosis, such as hormone replacement therapy, should be used with caution in multiple myeloma patients receiving DATRENAL with dexamethasone (see section 4.4 and 4.8). Patients with multiple myeloma taking DATRENAL and dexamethasone, patients with MDS taking DATRENAL monotherapy, as well as patients taking combined oral contraceptive pills or hormone replacement therapy, have an increased risk of venous thromboembolic events (VTE).

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

Women of childbearing potential/Contraception in males and female DATRENAL 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 DATRENAL therapy including dose interruptions, and for 28 days following discontinuation of DATRENAL therapy, or continually abstain from sexual intercourse. There is an increased risk of VTE in patients with multiple myeloma taking DATRENAL and dexamethasone, and in patients with MDS taking DATRENAL 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 DATRENAL.

Males Clinical data has demonstrated the presence of lenalidomide in human semen. Therefore, male patients taking DATRENAL should use a condom during DATRENAL therapy including dose interruptions and for 4 weeks after cessation of treatment. Male patients taking DATRENAL 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.

Pregnancy DATRENAL is contraindicated in pregnancy. If pregnancy occurs, DATRENAL should be immediately discontinued.

Breastfeeding Breastfeeding is contraindicated during therapy with DATRENAL.

Fertility No clinical data available.

No studies on the effects on the ability to drive or use machines have been performed. DATRENAL may affect the ability to drive and use machines. Fatigue, dizziness, somnolence and blurred vision have been reported with the use of DATRENAL. Therefore, caution is recommended when driving or operating machines.

Frequency categories are expressed as: Frequent = very common and common; Less frequent = uncommon, rare and very rare; Frequency unknown = cannot be estimated and post-marketing.

a. Tabulated list of adverse reactions

System Organ Class/ Preferred Term Frequency All ADRs Grade 3/4 ADRs SADRs General disorders and administration site conditions Frequent Pyrexia, oedema (including peripheral), influenza like illness syndrome (including pyrexia, Fatigue, pyrexia, asthenia, fall cough, rhinitis, myalgia, musculoskeletal pain, pharyngitis, headache and rigors), fatigue, asthenia, chest pain 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 Infections and infestations # Frequent Pneumonia@, bronchitis, bacterial, viral and fungal infections (including opportunistic infections), upper respiratory tract infection, sinusitis Pneumonia @, , bacterial,vi ral 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, dypomagnesaemia, iron overload Hypokalaemia, hypocalcaemia, hypophosphataemi a, hyperglycaemia % , decreased appetite Hyperglycaemia % Eye disorders Frequent Blurred vision Cataracts Renal 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 disorders Frequent Abnormal liver function tests 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

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