Eurolen 5 mg. 10 mg. 15 mg & 25 mg Hard capsules

Myelodysplastic Syndromes (MDS): EUROLEN 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: EUROLEN in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy.

Myelodysplastic syndromes (MDS): Recommended dosage: The recommended starting dose of EUROLEN 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
• Return to u2265 50 x 10 9 /l
• Interrupt EUROLEN treatment
• Resume EUROLEN at 5 mg once a day continuously in repeating 28 day cycles

If baseline < 100 x 10 9 /l

• When platelets Recommend course
• Fall to 50 % of the baseline value
• If baseline u2265 60 x 10 9 /l and returns to u2265 50 x 10 9 /l
• If baseline < 60 x 10 9 /l and returns to u2265 30 x 10 9 /l
• Interrupt EUROLEN treatment
• Resume EUROLEN at 5 mg once a day continuously in repeating 28 day cycles
• Resume EUROLEN 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
• Return to u2265 30 x 10 9 /l (without signs of bleeding)
• Interrupt EUROLEN treatment
• Resume EUROLEN 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
• Return to u2265 30 x 10 9 /l (without signs of bleeding)
• Interrupt EUROLEN treatment
• Resume EUROLEN at 5 mg every other day

Neutrophils 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
• Return to u2265 1 x 10 9 /l
• Interrupt EUROLEN treatment
• Resume EUROLEN at 5 mg once a day continuously in repeating 28 day cycles

If baseline ANC < 1 x 10 9 /l

• When Neutrophils Recommend Course
• Fall to < 0,5 x 10 9 /l
• Return to u2265 0,5 x 10 9 /l
• Interrupt EUROLEN treatment
• Resume EUROLEN 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 EUROLEN treatment
• Return to u2265 0,5 x 10 9 /l
• + Absolute neutrophil count
• Resume EUROLEN at 5 mg once a day continuously in repeating 28 day cycles

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
• < 0,5x 10 9 /l for u2265 7 days or < 0,5 x 10 9 /l associated with fever (u2265 38,5 u00b0C)
• Return to u2265 0,5 x 10 9 /l
• + Absolute neutrophil count
• Interrupt EUROLEN treatment
• Resume EUROLEN at 5 mg every other day

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

Discontinuation of EUROLEN EUROLEN interruption or discontinuation should be considered for Grade 2-3 skin rash. EUROLEN 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 EUROLEN 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 EUROLEN .

Platelet counts Thrombocytopenia See table below entitled, u2018Dose Reduction Steps for EUROLEN in Previously Treated Multiple Myelomau2019.

Neutrophil counts (ANC) Neutropenia See table below entitled, u2018Dose Reduction Steps for EUROLEN in Previously Treated Multiple Myelomau2019.

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

Discontinuation of EUROLEN EUROLEN interruption or discontinuation should be considered for Grade 2-3 skin rash. EUROLEN 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.

...

• Hypersensitivity to lenalidomide or any of the excipients of EUROLEN .
• 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 EUROLEN is contraindicated during pregnancy.

EUROLEN is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects (see section 4.6). If EUROLEN is taken during pregnancy, a teratogenic effect of lenalidomide is expected. The conditions of the Eurolab Pregnancy Protection Programme must be fulfilled for all patients unless there is reliable evidence that the patient does not have childbearing potential.

Criteria for women of non-childbearing potential A female patient or a female partner of a male patient is considered to have childbearing potential unless she meets at least one of the following criteria:

• Age u2265 50 years and naturally amenorrhoeic for u2265 1 year (Amenorrhoea following cancer therapy or during breast-feeding does not rule out childbearing potential).
• Premature ovarian failure confirmed by a specialist gynaecologist.
• Previous bilateral salpingo-oophorectomy, or hysterectomy.
• XY genotype, Turner syndrome, uterine agenesis.

Counselling For women of childbearing potential, EUROLEN 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 EUROLEN 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 EUROLEN .

For male patients taking EUROLEN , 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 healthy individuals (see section 5.2). As a precaution, all male patients taking EUROLEN 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 pregnant woman or a woman of childbearing potential not using effective contraception (even if the man has had a vasectomy), during treatment and for at least 4 weeks after dose interruptions and/or cessation of treatment.
• Understand that if his female partner becomes pregnant whilst he is taking EUROLEN or shortly after he has stopped taking EUROLEN , he should inform his treating doctor immediately and that it is recommended to refer the female partner to a doctor specialised or experienced in teratology for evaluation and advice.

The prescriber must ensure that for women of childbearing potential:

• The patient complies with the conditions of the Eurolab Pregnancy Protection Programme, including confirmation that she has an adequate level of understanding.
• The patient has acknowledged the aforementioned conditions.

Contraception Women of childbearing potential must use two reliable methods of contraception for 4 weeks before therapy, during therapy including dose interruptions, and until 4 weeks after EUROLEN 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 (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 EUROLEN and dexamethasone, and in patients with myelodysplastic syndromes, 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.

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.

Effective methods

• Male condom;
• Diaphragm;
• Cervical cap

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 EUROLEN 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 EUROLEN 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 EUROLEN .

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 EUROLEN is present in human semen at extremely low levels during treatment and is undetectable in human semen 3 days after discontinuation of EUROLEN. 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 EUROLEN 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 EUROLEN .

Additional precautions Patients should be instructed never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of treatment for safe disposal.

Educational materials, prescribing and dispensing restrictions In order to assist patients in avoiding foetal exposure to EUROLEN , educational material will be provided to health care professionals to reinforce the warnings about the expected teratogenicity of EUROLEN , 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 Eurolab Pregnancy Protection Programme should be given by the medical practitioner to women of childbearing potential and, as appropriate, to male patients.

Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same day. Dispensing of lenalidomide to women of childbearing potential should occur within 7 days of the prescription and following a medically supervised negative pregnancy test result. Prescriptions for women of childbearing potential can be for a maximum duration of treatment of 4 weeks, and prescriptions for all other patients can be for a maximum duration of treatment of 12 weeks.

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 minimize all modifiable risk factors (eg. smoking, hypertension, and hyperlipidaemia).

Venous and arterial thromboembolic events (ATE) Predominantly deep venous thrombosis and pulmonary embolism occurs in multiple myeloma patients treated with EUROLEN combination therapy and in MDS patients treated with EUROLEN monotherapy.

In vitro studies demonstrate that EUROLEN 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 EUROLEN with dexamethasone (see sections 4.4 and 4.8).

Patients with multiple myeloma taking EUROLEN and dexamethasone, patients with MDS taking EUROLEN 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 Induction leading to reduced efficacy of medicines, including hormonal contraceptives, is not expected if EUROLEN 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 10 mg doses of EUROLEN has 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 EUROLEN . However, it is not known whether there is an interaction during clinical use (concomitant treatment with dexamethasone). Dexamethasone is a weak to moderate enzyme inducer and its effect on warfarin is unknown. Close monitoring of warfarin concentration is advised during the treatment.

Digoxin Concomitant administration with EUROLEN 10 mg once daily increases 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 clinical use (higher lenalidomide doses and concomitant treatment with dexamethasone). Therefore, monitoring of the digoxin concentration is advised during EUROLEN treatment.

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.

Dexamethasone In patients with multiple myeloma, co-administration of single or multiple doses of dexamethasone (40 mg once daily) has no clinically relevant effect on the multiple dose pharmacokinetics of EUROLEN (25 mg once daily).

Interactions with P-glycoprotein (P-gp) inhibitors In vitro , EUROLEN is a weak substrate of P-gp, but is not a P-gp inhibitor. Co-administration of multiple doses of the strong P-gp inhibitor quinidine (600 mg, twice daily) or the moderate P-gp inhibitor/substrate temsirolimus (25 mg) has no clinically relevant effect on the pharmacokinetics of EUROLEN (25 mg). Co-administration of EUROLEN does not alter the pharmacokinetics of temsirolimus.

EUROLEN is contraindicated in females who are pregnant or who could become pregnant. Women of childbearing potential/ Contraception in males and females Males: EUROLEN is present in human semen at extremely low levels during treatment and is undetectable in human semen 3 days after stopping lenalidomide. As a precaution, and taking into account special populations with prolonged elimination time such as renal impairment, all male patients taking EUROLEN should use condoms throughout treatment duration, during dose interruption and for 4 weeks after cessation of treatment if their partner is pregnant or of childbearing potential and has no contraception. EUROLEN 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 Women of childbearing potential should use effective method of contraception. If pregnancy occurs in a woman treated with EUROLEN , treatment must be stopped and the patient should be referred to a doctor specialised or experienced in teratology for evaluation and advice. If pregnancy occurs in a partner of a male patient taking EUROLEN , it is recommended to refer the female partner to a medical practitioner specialised or experienced in teratology for evaluation and advice. 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 EUROLEN is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. Therefore:

• Females of childbearing potential must use effective means of contraception for 28 days before therapy, during EUROLEN therapy including dose interruptions, and for 28 days following discontinuation of EUROLEN therapy, or continually abstain from sexual intercourse. There is an increased risk of VTE in patients with multiple myeloma taking EUROLEN and dexamethasone, and in patients with MDS taking EUROLEN 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 EUROLEN .
• If pregnancy does occur during treatment, EUROLEN should be immediately discontinued. Teratogenic effects of lenalidomide is expected, therefore EUROLEN is contraindicated during pregnancy (see section 4.3).

Breast-feeding It is not known whether lenalidomide is excreted in breast milk. Therefore, breastfeeding is contraindicated during therapy with EUROLEN .

Fertility EUROLEN has no adverse effects on fertility and no parental toxicity.

EUROLEN can influence the ability to drive and use machines. Fatigue, dizziness, somnolence, vertigo and blurred vision have been reported with the use of EUROLEN . Therefore, caution is recommended when driving or operating machines.

a. Summary of the safety profile Multiple myeloma: patients with at least one prior therapy The most serious adverse reactions observed more frequently with lenalidomide and dexamethasone combination therapy:

• Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see section 4.4)
• Grade 4 neutropenia (see section 4.4).

Myelodysplastic syndromes Serious adverse reactions include:

• Venous thromboembolism (deep vein thrombosis, pulmonary embolism) (see section 4.4)
• Grade 3 or 4 neutropenia, febrile neutropenia and grade 3 or 4 thrombocytopenia (see section 4.4).

Teratogenicity Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. If EUROLEN is taken during pregnancy, a teratogenic effect of lenalidomide in humans is expected.

Venous thromboembolism An increased risk of DVT and PE (deep vein thrombosis, pulmonary embolism) is associated with the use of the combination of lenalidomide with dexamethasone in patients with multiple myeloma. Concomitant administration of erythropoietic medicines or previous history of DVT may also increase thrombotic risk in these patients.

Myocardial infarction Myocardial infarction has been reported in patients receiving lenalidomide, particularly in those with known risk factors.

Allergic reactions Cases of allergic reaction/hypersensitivity reactions have been reported. A possible cross- reaction between lenalidomide and thalidomide has been reported.

Severe skin reactions Severe cutaneous reactions including SJS and TEN have been reported with the use of lenalidomide. Patients with a history of severe rash associated with thalidomide treatment should not receive lenalidomide (see section 4.4).

Hepatic disorders The following adverse reactions have been reported (frequency unknown): acute hepatic failure and cholestasis (both potentially fatal), toxic hepatitis, cytolytic hepatitis, mixed cytolytic/cholestatic hepatitis.

Rhabdomyolysis Rare cases of rhabdomyolysis have been observed, some of them when lenalidomide is administered with a statin.

Gastrointestinal disorders Gastrointestinal perforations have been reported during treatment with lenalidomide. Gastrointestinal perforations may lead to septic complications and may be associated with fatal outcome.

b. Tabulated summary of adverse reactions The following side effects to be considered in patients with Relapsed and Refractory Multiple Myeloma and Myelodysplastic Syndromes, treated with EUROLEN :

Infections and Infestations

• Frequent: Pneumonia, bronchitis, bacterial, viral and fungal infections (including opportunistic infections), upper respiratory tract infection, sinusitis
• Frequency unknown: Viral infections, including herpes zoster and hepatitis B virus reactivation

Neoplasms benign and malignant (including cysts and polyps)

• Frequent: B-cell lymphomas
• Less frequent: Tumour lysis syndrome
• Frequency unknown: Tumour flare reaction (TFR)

Blood and lymphatic system disorders

• Frequent: Neutropenia, thrombocytopenia, anaemia, leukopenia, febrile neutropenia
• Frequency unknown: Acquired haemophilia

Immune system disorders

• Less frequent: Hypersensitivity (also a possibility of cross-reaction with thalidomide)
• Frequency unknown: Solid organ transplant rejection, anaphylactic reaction

Endocrine disorders

• Frequent: Hypothyroidism, hyperthyroidism

Metabolism and nutrition disorders

• Frequent: Decreased appetite, hypokalaemia, hypocalcaemia, dehydration, dypomagnesaemia, iron overload, hypophosphataemia, hyperglycaemia, weight decreased
• Frequency unknown: Tumour Lysis syndrome (TLS)

Psychiatric disorders

• Frequent: Depression, altered mood

Nervous system disorders

• Frequent: Peripheral neuropathies (excluding motor neuropathy), dizziness, tremor, dysguesia, headache, lethargy, paraesthesia, syncope, cerebrovascular accident

Eye disorders

• Frequent: Blurred vision, cataracts

Cardiac disorders

• Frequent: Acute myocardial infarction, atrial fibrillation, tachycardia, cardiac failure congestive, cardiac failure

Vascular disorders

• Frequent: Venous thromboembolic events, predominantly deep vein thrombosis and pulmonary embolism (especially in combination therapy with dexamethasone and other erythropoietic medicines), hypertension, hypotension, haematoma

Respiratory, thoracic and mediastinal disorders

• Frequent: Dyspnoea, epistaxis, respiratory distress, bronchitis
• Frequency unknown: Interstitial pneumonitis, pulmonary hypertension

Gastrointestinal disorders

• Frequent: Diarrhoea, vomiting, nausea, constipation, abdominal Pain (including upper), dry mouth, dyspepsia, toothache
• Frequency unknown: Pancreatitis, gastrointestinal perforation (including diverticular, intestinal and large intestine perforations)

Hepato-biliary disorders

• Frequent: Abnormal liver function tests
• Frequency unknown: Acute hepatic failure, hepatitis toxic, cytolytic hepatitis, cholestatic hepatitis, mixed cytolytic/cholestatic hepatitis

Skin and subcutaneous tissue disorders

• Frequent: Rash, pruritus, dry skin, hyperhidrosis
• Less frequent: Angioedema , Stevens-Johnson Syndrome (SJS), Toxic epidermal necrolysis (TEN)
• Frequency unknown: Leukocytoclastic vasculitis, medicine reaction with eosinophilia and systemic symptoms, Second primary malignancies (mainly basal cell or squamous cell skin cancers)

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, back pain

Less frequent: Rhabdomyolysis, sometimes in combination with a statin

Renal and urinary disorders

• Frequent: Renal failure

Pregnancy, puerperium and perinatal conditions

• Frequency unknown: Teratogenic (causes severe life-threatening birth defects)

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, fall

Investigations

• Frequent: Decreased weight

Injury, poisoning and procedural complications

• Frequent: Fall

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u201c 6.04 Adverse Drug Reactions Reporting Form u201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

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