POMALIDOMIDE ACCORD 1mg capsules medication leaflet

Pomalidomide Accord 1 mg hard capsules

Pomalidomide Accord 2 mg hard capsules

Pomalidomide Accord 3 mg hard capsules

Pomalidomide Accord 4 mg hard capsules

Pomalidomide Accord 1 mg hard capsules

Each hard capsule contains 1 mg of pomalidomide.

Pomalidomide Accord 2 mg hard capsules

Each hard capsule contains 2 mg of pomalidomide.

Pomalidomide Accord 3 mg hard capsules

Each hard capsule contains 3 mg of pomalidomide.

Pomalidomide Accord 4 mg hard capsules

Each hard capsule contains 4 mg of pomalidomide.

For the full list of excipients, see section 6.1.

Hard capsule

Pomalidomide Accord 1 mg hard capsules

Hard gelatin capsule, with a yellow body and red cap, with “PLM 1” printed in white ink on thecapsule body. Capsule size 4 (approximately 14 mm in length).

Pomalidomide Accord 2 mg hard capsules

Hard gelatin capsule, with an orange body and red cap, with “PLM 2” printed in white ink on thecapsule body. Capsule size 2 (approximately 18 mm in length).

Pomalidomide Accord 3 mg hard capsules

Hard gelatin capsule, with a turquoise body and red cap, with “PLM 3” printed in white ink on thecapsule body. Capsule size 2 (approximately 18 mm in length).

Pomalidomide Accord 4 mg hard capsules

Hard gelatin capsule, with a dark blue body and red cap, with “PLM 4” printed in white ink on thecapsule body. Capsule size 2 (approximately 18 mm in length).

Pomalidomide Accord in combination with bortezomib and dexamethasone is indicated in thetreatment of adult patients with multiple myeloma who have received at least one prior treatmentregimen including lenalidomide.

Pomalidomide Accord in combination with dexamethasone is indicated in the treatment of adultpatients with relapsed and refractory multiple myeloma who have received at least two prior treatmentregimens, including both lenalidomide and bortezomib, and have demonstrated disease progression onthe last therapy.

Treatment must be initiated and monitored under the supervision of physicians experienced in themanagement of multiple myeloma.

Dosing is continued or modified based upon clinical and laboratory findings (see section 4.4).

Pomalidomide in combination with bortezomib and dexamethasone

The recommended starting dose of pomalidomide is 4 mg taken orally once daily on Days 1 to 14 ofrepeated 21- day cycles.

Pomalidomide is administered in combination with bortezomib and dexamethasone, as shown in Table1.

The recommended starting dose of bortezomib is 1.3 mg/m2 intravenous or subcutaneous once daily,on the days shown in Table 1. The recommended dose of dexamethasone is 20 mg taken orally oncedaily, on the days shown in Table 1.

Treatment with pomalidomide combined with bortezomib and dexamethasone should be given untildisease progression or until unacceptable toxicity occurs.

Table 1. Recommended dosing scheme for pomalidomide in combination with bortezomib anddexamethasone

Cycle 1-8 Day (of 21-day cycle)1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Pomalidomide (4 mg) * * * * * * * * * * * * * *

Bortezomib (1.3 mg/m2) * * * *

Dexamethasone (20 mg) * * * * * * * * *

Cycle 9 onwards Day (of 21-day cycle)1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Pomalidomide (4 mg) * * * * * * * * * * * * * *

Bortezomib (1.3 mg/m2) * *

Dexamethasone (20 mg) * * * * *

* For patients > 75 years of age, see Special populations.

Pomalidomide dose modification or interruption

To initiate a new cycle of pomalidomide, the neutrophil count must be ≥ 1 x 109/l and the plateletcount must be ≥ 50 x 109/l.

Instructions on dose interruptions or reductions for pomalidomide related adverse reactions areoutlined in the Table 2 and dose levels are defined in Table 3 below:

Table 2. Pomalidomide dose modification instructions∞

Toxicity Dose modification

Neutropenia* Interrupt pomalidomide treatment for remainder

ANC** < 0.5 x 109/l or febrile neutropenia of cycle. Follow CBC*** weekly.(fever ≥38.5°C and ANC <1 x 109/l)

ANC return to ≥ 1 x 109/l Resume pomalidomide treatment at one doselevel lower than previous dose.

For each subsequent drop < 0.5 x 109/l Interrupt pomalidomide treatment.

ANC return to ≥ 1 x 109/l Resume pomalidomide treatment at one doselevel lower than the previous dose.

Thrombocytopenia Interrupt pomalidomide treatment for remainder

Platelet count < 25 x 109/l of cycle. Follow CBC*** weekly.

Platelet count return to ≥ 50 x 109/l Resume pomalidomide treatment at one doselevel lower than previous dose.

For each subsequent drop < 25 x 109/l Interrupt pomalidomide treatment.

Platelet count return to ≥ 50 x 109/l Resume pomalidomide treatment at one doselevel lower than the previous dose.

Rash Consider dose interruption or discontinuation of

Rash = Grade 2-3 pomalidomide treatment.

Rash = Grade 4 or blistering (including Permanently discontinue treatment (see sectionangioedema, anaphylactic reaction, exfoliative 4.4).or bullous rash or if Stevens-Johnson syndrome(SJS), Toxic Epidermal Necrolysis (TEN) or

Drug Reaction with Eosinophilia and Systemic

Symptoms (DRESS) is suspected)

Other Interrupt pomalidomide treatment for remainder

Other ≥ Grade 3 pomalidomide-related adverse of cycle. Resume at one dose level lower thanevents previous dose at next cycle (adverse event mustbe resolved or improved to ≤ Grade 2 beforerestarting dosing).

∞Dose modification instructions in this table are applicable to pomalidomide in combination with bortezomib anddexamethasone and to pomalidomide in combination with dexamethasone.

*In case of neutropenia, the physician should consider the use of growth factors. **ANC - Absolute Neutrophil Count;

***CBC - Complete Blood Count.

Table 3. Pomalidomide dose reduction∞

Dose level Oral pomalidomide dose

Starting dose 4 mg

Dose level -1 3 mg

Dose level -2 2 mg

Dose level -3 1 mg∞Dose reduction in this table is applicable to pomalidomide in combination with bortezomib and dexamethasone and topomalidomide in combination with dexamethasone.

If adverse reactions occur after dose reductions to 1 mg, then the treatment should be discontinued.

Strong CYP1A2 inhibitors

If strong inhibitors of CYP1A2 (e.g. ciprofloxacin, enoxacin and fluvoxamine) are co-administeredwith pomalidomide, the dose of pomalidomide should be reduced by 50% (see sections 4.5 and 5.2).

Bortezomib dose modification or interruption

For instructions on dose interruptions or reductions for bortezomib related adverse reactions,physicians should refer to bortezomib Summary of Product Characteristics (SmPC).

Dexamethasone dose modification or interruption

Instructions on dose interruptions or reductions for low-dose dexamethasone related adverse reactionsare outlined in Tables 4 and 5 below. However, dose interruption or resumption decisions are at thephysician’s discretion per Summary of Product Characteristics (SmPC).

Table 4. Dexamethasone dose modification instructions

Toxicity Dose Modification

Dyspepsia = Grade 1-2 Maintain dose and treat with histamine (H2)blockers or equivalent. Decrease by one doselevel if symptoms persist.

Dyspepsia ≥ Grade 3 Interrupt dose until symptoms are controlled. Add

H2 blocker or equivalent and resume at one doselevel lower than previous dose.

Oedema ≥ Grade 3 Use diuretics as needed and decrease dose by onedose level.

Confusion or mood alteration ≥ Grade 2 Interrupt dose until symptoms resolve. Resume atone dose level lower than previous dose.

Muscle weakness ≥ Grade 2 Interrupt dose until muscle weakness ≤ Grade 1.

Resume at one dose level lower than previousdose.

Hyperglycaemia ≥ Grade 3 Decrease dose by one dose level. Treat withinsulin or oral hypoglycaemic agents as needed.

Acute pancreatitis Discontinue dexamethasone from treatmentregimen.

Other ≥ Grade 3 dexamethasone-related adverse Stop dexamethasone dosing until the adverseevents event resolves to ≤ Grade 2. Resume at one doselevel lower than previous dose.

If recovery from toxicities is prolonged beyond 14 days, then the dose of dexamethasone will beresumed at one dose level lower than the previous dose.

Table 5. Dexamethasone dose reduction

Dose Level ≤ 75 years old > 75 years old

Dose (Cycle 1-8: Days 1, 2, 4, 5, 8, Dose (Cycle 1-8: Days 1, 2, 4, 5, 8,9, 11, 9,12 of a 21-day cycle 11, 12 of a 21-day cycle

Cycle ≥ 9: Days 1, 2, 8, 9 of a 21- Cycle ≥ 9: Days 1, 2, 8, 9 of a 21-day daycycle) cycle)

Starting Dose 20 mg 10 mg

Dose Level -1 12 mg 6 mg

Dose Level -2 8 mg 4 mg

Dexamethasone should be discontinued if the patient is unable to tolerate 8 mg if ≤ 75 years old or 4mg if > 75 years old.

In case of permanent discontinuation of any component of the treatment regimen, continuation of theremaining medicinal products is at the physician’s discretion.

Pomalidomide in combination with dexamethasone

The recommended starting dose of pomalidomide is 4 mg taken orally once daily on Days 1 to 21 ofeach 28-day cycle.

The recommended dose of dexamethasone is 40 mg taken orally once daily on Days 1, 8, 15 and 22 ofeach 28-day cycle.

Treatment with pomalidomide combined with dexamethasone should be given until diseaseprogression or until unacceptable toxicity occurs.

Pomalidomide dose modification or interruption

Instructions for dose interruptions or reductions for pomalidomide related adverse reactions areoutlined in Table 2 and 3.

Dexamethasone dose modification or interruption

Instructions for dose modification for dexamethasone related adverse reactions are outlined in Table 4.

Instructions for dose reduction for dexamethasone related adverse reactions are outlined in Table 6below. However, dose interruption/resumption decisions are at physician’s discretion per the current

Summary of Product Characteristics (SmPC).

Table 6. Dexamethasone dose reduction≤ 75 years old > 75 years old

Dose Level Days 1, 8, 15 and 22 of each 28- Days 1, 8, 15 and 22 of each 28-day cycle day cycle

Starting Dose 40 mg 20 mg

Dose Level -1 20 mg 12 mg

Dose Level -2 10 mg 8 mg

Dexamethasone should be discontinued if the patient is unable to tolerate 10 mg if ≤ 75 years old or 8mg if > 75 years old.

No dose adjustment is required for pomalidomide.

Pomalidomide in combination with bortezomib and dexamethasone

For patients >75 years of age, the starting dose of dexamethasone is:

- For Cycles 1 to 8: 10 mg once daily on Days 1, 2, 4, 5, 8, 9, 11 and 12 of each 21-day cycle

- For Cycles 9 and onwards: 10 mg once daily on Days 1, 2, 8 and 9 of each 21-day cycle.

Pomalidomide in combination with dexamethasone

For patients > 75 years of age, the starting dose of dexamethasone is:

- 20 mg once daily on days 1, 8, 15 and 22 of each 28-day cycle.

Patients with serum total bilirubin > 1.5 x ULN (upper limit of normal range) were excluded fromclinical studies. Hepatic impairment has a modest effect on the pharmacokinetics of pomalidomide(see section 5.2). No adjustment of the starting dose of pomalidomide is required for patients withhepatic impairment as defined by the Child-Pugh criteria. However, patients with hepatic impairmentshould be carefully monitored for adverse reactions and dose reduction or interruption ofpomalidomide should be used as needed.

No dose adjustment of pomalidomide is required for patients with renal impairment. On haemodialysisdays, patients should take their pomalidomide dose following haemodialysis.

There is no relevant use of pomalidomide in children aged 0-17 years for the indication of multiplemyeloma.

Outside its authorised indications, pomalidomide has been studied in children aged 4 to 18 years withrecurrent or progressive brain tumours, however the results of studies did not allow to conclude thatthe benefits of such use outweigh the risks. Currently available data are described in sections 4.8, 5.1and 5.2.

Oral use.

Pomalidomide Accord hard capsules should be taken orally at the same time each day. The capsulesshould not be opened, broken or chewed (see section 6.6). The capsules should be swallowed whole,preferably with water, with or without food. If the patient forgets to take a dose of pomalidomide onone day, then the patient should take the normal prescribed dose as scheduled on the next day. Patientsshould not adjust the dose to make up for a missing dose on previous days.

It is recommended to press only on one end of the capsule to remove it from the blister therebyreducing the risk of capsule deformation or breakage.

- Pregnancy.

- Women of childbearing potential, unless all the conditions of the pregnancy preventionprogramme are met (see sections 4.4 and 4.6).

- Male patients unable to follow or comply with the required contraceptive measures (see section4.4).

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Pomalidomide must not be taken during pregnancy, since a teratogenic effect is expected.

Pomalidomide is structurally related to thalidomide. Thalidomide is a known human teratogen thatcauses severe life-threatening birth defects. Pomalidomide was found to be teratogenic in both rats andrabbits when administered during the period of major organogenesis (see section 5.3).

The conditions of the Pregnancy Prevention Programme must be fulfilled for all patients unless there isreliable 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 of non-childbearing potential if shemeets at least one of the following criteria:

- Age ≥ 50 years and naturally amenorrhoeic for ≥ 1 year (amenorrhoea following cancer therapy orduring 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.

For women of childbearing potential, pomalidomide is contraindicated unless all of the following aremet:

- She understands the expected teratogenic risk to the unborn child

- She understands the need for effective contraception, without interruption, at least 4 weeks beforestarting treatment, throughout the entire duration of treatment, and at least 4 weeks after the end oftreatment

- Even if a woman of childbearing potential has amenorrhoea she must follow all the advice oneffective 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 rapidlyconsult if there is a risk of pregnancy

- She understands the need to commence the treatment as soon as pomalidomide is dispensedfollowing a negative pregnancy test

- She understands the need and accepts to undergo pregnancy testing at least every 4 weeks except incase of confirmed tubal sterilisation

- She acknowledges that she understands the hazards and necessary precautions associated with theuse of pomalidomide.

The prescriber must ensure that for women of childbearing potential:

- The patient complies with the conditions of the Pregnancy Prevention Programme, includingconfirmation that she has an adequate level of understanding

- The patient has acknowledged the aforementioned conditions.

For male patients taking pomalidomide, pharmacokinetic data has demonstrated that pomalidomide ispresent in human semen during treatment. As a precaution, and taking into account special populationswith potentially prolonged elimination time such as hepatic impairment, all male patients takingpomalidomide must meet the following conditions:

- He understands the expected teratogenic risk if engaged in sexual activity with a pregnant womanor a woman of childbearing potential

- He understands the need for the use of a condom if engaged in sexual activity with a pregnantwoman or a woman of childbearing potential not using effective contraception, throughouttreatment duration, during dose interruption and for 7 days after dose interruptions and/or cessationof treatment. This includes vasectomised males who should wear a condom if engaged in sexualactivity with a pregnant woman or a woman of childbearing potential as seminal fluid may stillcontain pomalidomide in the absence of spermatozoa.

- He understands that if his female partner becomes pregnant whilst he is taking pomalidomide or7 days after he has stopped taking pomalidomide, he should inform his treating physicianimmediately and that it is recommended to refer the female partner to a physician specialised orexperienced in teratology for evaluation and advice.

Women of childbearing potential must use at least one effective method of contraception for at least4 weeks before therapy, during therapy, and until at least 4 weeks after pomalidomide therapy and evenin case of dose interruption unless the patient commits to absolute and continuous abstinence confirmedon a monthly basis. If not established on effective contraception, the patient must be referred to anappropriately trained health care professional for contraceptive advice in order that contraception can beinitiated.

The following can be considered to be examples of suitable methods of contraception:

- Implant

- Levonorgestrel-releasing intrauterine system

- Medroxyprogesterone acetate depot

- Tubal sterilisation

- Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by twonegative semen analyses

- Ovulation inhibitory progesterone-only pills (i.e. desogestrel)

Because of the increased risk of venous thromboembolism in patients with multiple myeloma takingpomalidomide and dexamethasone, combined oral contraceptive pills are not recommended (see alsosection 4.5). If a patient is currently using combined oral contraception the patient should switch to oneof the effective methods listed above. The risk of venous thromboembolism continues for4-6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive steroids maybe reduced during cotreatment with dexamethasone (see section 4.5).

Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk ofinfection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should beconsidered particularly in patients with neutropenia.

Insertion of copper-releasing intrauterine devices is not recommended due to the potential risks ofinfection at the time of insertion and menstrual blood loss which may compromise patients with severeneutropenia or severe thrombocytopenia.

According to local practice, medically supervised pregnancy tests with a minimum sensitivity of 25mIU/mL must be performed for women of childbearing potential as outlined below. This requirementincludes women of childbearing potential who practice absolute and continuousabstinence. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the sameday. Dispensing of pomalidomide to women of childbearing potential should occur within 7 days of theprescription.

Prior to starting treatment

A medically supervised pregnancy test should be performed during the consultation, whenpomalidomide is prescribed, or in the 3 days prior to the visit to the prescriber once the patient had beenusing effective contraception for at least 4 weeks. The test should ensure the patient is not pregnantwhen she starts treatment with pomalidomide.

Follow-up and end of treatment

A medically supervised pregnancy test should be repeated at least every 4 weeks, including at least4 weeks after the end of treatment, except in the case of confirmed tubal sterilisation. These pregnancytests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to theprescriber.

Additional precautions

Patients should be instructed never to give this medicinal product to another person and to return anyunused capsules to their pharmacist at the end of treatment.

Patients should not donate blood, semen or sperm during treatment (including during dose interruptions)and for at least 7 days following discontinuation of pomalidomide.

Healthcare professionals and caregivers should wear disposable gloves when handling the blister orcapsule. Women who are pregnant or suspect they may be pregnant should not handle the blister orcapsule (see section 6.6)

Educational materials, prescribing and dispensing restrictions

In order to assist patients in avoiding foetal exposure to pomalidomide, the Marketing Authorisation

Holder will provide educational material to healthcare professionals to reinforce the warnings about theexpected teratogenicity of pomalidomide, to provide advice on contraception before treatment is started,and to provide guidance on the need for pregnancy testing. The prescriber must inform the patient aboutthe expected teratogenic risk and the strict pregnancy prevention measures as specified in the Pregnancy

Prevention Programme and provide patients with appropriate patient educational brochure, patient cardand/or equivalent tool as agreed with each National Competent Authority. In collaboration with each

National Competent Authority, a controlled access programme has been implemented which includesthe use of a patient card and/or equivalent tool for prescribing and /or dispensing controls, and thecollection of information relating to the indication in order to monitor the off-label use within thenational territory. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on thesame day. Dispensing of pomalidomide to women of childbearing potential should occur within 7 daysof the prescription and following a medically supervised negative pregnancy test result. Prescriptionsfor women of childbearing potential can be for a maximum duration of treatment of 4 weeks accordingto the approved indications dosing regimens (see section 4.2), and prescriptions for all other patients canbe for a maximum duration of 12 weeks.

Haematological events

Neutropenia was the most frequently reported Grade 3 or 4 haematological adverse reaction in patientswith relapsed/refractory multiple myeloma, followed by anaemia and thrombocytopenia. Patientsshould be monitored for haematological adverse reactions, especially neutropenia. Patients should beadvised to report febrile episodes promptly. Physicians should observe patients for signs of bleedingincluding epistaxes, especially with use of concomitant medicinal products known to increase the riskof bleeding (see section 4.8). Complete blood counts should be monitored at baseline, weekly for thefirst 8 weeks and monthly thereafter. A dose modification may be required (see section 4.2). Patientsmay require use of blood product support and /or growth factors.

Patients receiving pomalidomide either in combination with bortezomib and dexamethasone or incombination with dexamethasone have developed venous thromboembolic events (predominantly deepvein thrombosis and pulmonary embolism) and arterial thrombotic events (myocardial infarction andcerebrovascular accident) (see section 4.8). Patients with known risk factors for thromboembolism -including prior thrombosis - should be closely monitored. Action should be taken to try to minimise allmodifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia). Patients and physicians areadvised to be observant for the signs and symptoms of thromboembolism. Patients should be instructedto seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or legswelling. Anti-coagulation therapy (unless contraindicated) is recommended, (such as acetylsalicylicacid, warfarin, heparin or clopidogrel), especially in patients with additional thrombotic risk factors. Adecision to take prophylactic measures should be made after a careful assessment of the individualpatient’s underlying risk factors. In clinical studies, patients received prophylactic acetylsalicylic acid oralternative anti-thrombotic therapy. The use of erythropoietic agents carries a risk of thrombotic eventsincluding thromboembolism. Therefore, erythropoietic agents, as well as other agents that may increasethe risk of thromboembolic events, should be used with caution.

Thyroid disorders

Cases of hypothyroidism have been reported. Optimal control of co-morbid conditions influencingthyroid function is recommended before start of treatment. Baseline and ongoing monitoring of thyroidfunction is recommended.

Patients with ongoing ≥ Grade 2 peripheral neuropathy were excluded from clinical studies withpomalidomide. Appropriate caution should be exercised when considering the treatment of suchpatients with pomalidomide.

Significant cardiac dysfunction

Patients with significant cardiac dysfunction (congestive heart failure [NY Heart Association Class IIIor IV]; myocardial infarction within 12 months of starting study; unstable or poorly controlled anginapectoris) were excluded from clinical studies with pomalidomide. Cardiac events, including congestivecardiac failure, pulmonary oedema and atrial fibrillation (see section 4.8), have been reported, mainly inpatients with pre-existing cardiac disease or cardiac risk factors. Appropriate caution should beexercised when considering the treatment of such patients with pomalidomide, including periodicmonitoring for signs or symptoms of cardiac events.

Patients at greatest risk of tumour lysis syndrome are those with high tumour burden prior to treatment.

These patients should be monitored closely and appropriate precautions taken.

Second primary malignancies

Second primary malignancies, such as non-melanoma skin cancer, have been reported in patientsreceiving pomalidomide (see section 4.8). Physicians should carefully evaluate patients before andduring treatment using standard cancer screening for occurrence of second primary malignancies andinstitute treatment as indicated.

Allergic reactions and severe skin reactions

Angioedema, anaphylactic reaction and severe dermatologic reactions including SJS, TEN and DRESShave been reported with the use of pomalidomide (see section 4.8). Patients should be advised of thesigns and symptoms of these reactions by their prescribers and should be told to seek medical attentionimmediately if they develop these symptoms. Pomalidomide must be discontinued for exfoliative orbullous rash, or if SJS, TEN or DRESS is suspected, and should not be resumed followingdiscontinuation for these reactions. Patients with a prior history of serious allergic reactions associatedwith thalidomide or lenalidomide were excluded from clinical studies. Such patients may be at higherrisk of hypersensitivity reactions and should not receive pomalidomide. Pomalidomide interruption ordiscontinuation should be considered for Grade 2-3 skin rash. Pomalidomide must be discontinuedpermanently for angioedema and anaphylactic reaction.

Dizziness and confusion

Dizziness and confusional state have been reported with pomalidomide. Patients must avoid situationswhere dizziness or confusion may be a problem and not to take other medicinal products that maycause dizziness or confusion without first seeking medical advice.

Interstitial lung disease (ILD)

ILD and related events, including cases of pneumonitis, have been observed with pomalidomide.

Careful assessment of patients with an acute onset or unexplained worsening of pulmonary symptomsshould be performed to exclude ILD. Pomalidomide should be interrupted pending investigation ofthese symptoms and if ILD is confirmed, appropriate treatment should be initiated. Pomalidomideshould only be resumed after a thorough evaluation of the benefits and the risks.

Hepatic disorders

Markedly elevated levels of alanine aminotransferase and bilirubin have been observed in patientstreated with pomalidomide (see section 4.8). There have also been cases of hepatitis that resulted indiscontinuation of pomalidomide. Regular monitoring of liver function is recommended for the first 6months of treatment with pomalidomide and as clinically indicated thereafter.

Reactivation of hepatitis B has been reported rarely in patients receiving pomalidomide in combinationwith dexamethasone who have previously been infected with the hepatitis B virus (HBV). Some ofthese cases have progressed to acute hepatic failure, resulting in discontinuation of pomalidomide.

Hepatitis B virus status should be established before initiating treatment with pomalidomide. Forpatients who test positive for HBV infection, consultation with a physician with expertise in thetreatment of hepatitis B is recommended. Caution should be exercised when pomalidomide incombination with dexamethasone is used in patients previously infected with HBV, including patientswho are anti-HBc positive but HBsAg negative. These patients should be closely monitored for signsand symptoms of active HBV infection throughout therapy.

Cases of progressive multifocal leukoencephalopathy, including fatal cases, have been reported withpomalidomide. PML was reported several months to several years after starting the treatment withpomalidomide. Cases have generally been reported in patients taking concomitant dexamethasone orprior treatment with other immunosuppressive chemotherapy. Physicians should monitor patients atregular intervals and should consider PML in the differential diagnosis in patients with new orworsening neurological symptoms, cognitive or behavioural signs or symptoms. Patients should alsobe advised to inform their partner or caregivers about their treatment, since they may notice symptomsthat the patient is not aware of.

The evaluation for PML should be based on neurological examination, magnetic resonance imaging ofthe brain, and cerebrospinal fluid analysis for JC virus (JCV) DNA by polymerase chain reaction(PCR) or a brain biopsy with testing for JCV. A negative JCV PCR does not exclude PML. Additionalfollow-up and evaluation may be warranted if no alternative diagnosis can be established.

If PML is suspected, further dosing must be suspended until PML has been excluded. If PML isconfirmed, pomalidomide must be permanently discontinued.

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to sayessentially ‘sodium-free’.

Effect of pomalidomide on other medicinal products

Pomalidomide is not anticipated to cause clinically relevant pharmacokinetic interactions due to P450isoenzyme inhibition or induction or transporter inhibition when co-administered with substrates ofthese enzymes or transporters. The potential for such interactions, including the potential impact ofpomalidomide on the pharmacokinetics of combined oral contraceptives, has not been evaluatedclinically (see section 4.4 Teratogenicity).

Effect of other medicinal products on pomalidomide

Pomalidomide is partly metabolised by CYP1A2 and CYP3A4/5. It is also a substrate for P-glycoprotein. Co-administration of pomalidomide with the strong CYP3A4/5 and P-gp inhibitorketoconazole, or the strong CYP3A4/5 inducer carbamazepine, had no clinically relevant effect onexposure to pomalidomide. Co-administration of the strong CYP1A2 inhibitor fluvoxamine withpomalidomide in the presence of ketoconazole, increased mean exposure to pomalidomide by 107%with a 90% confidence interval [91% to 124%] compared to pomalidomide plus ketoconazole. In asecond study to evaluate the contribution of a CYP1A2 inhibitor alone to metabolism changes, co-administration of fluvoxamine alone with pomalidomide increased mean exposure to pomalidomide by125% with a 90% confidence interval [98% to 157%] compared to pomalidomide alone. If stronginhibitors of CYP1A2 (e.g. ciprofloxacin, enoxacin and fluvoxamine) are co-administered withpomalidomide, reduce the dose of pomalidomide by 50%.

Dexamethasone

Co-administration of multiple doses of up to 4 mg pomalidomide with 20 mg to 40 mg dexamethasone(a weak to moderate inducer of several CYP enzymes including CYP3A) to patients with multiplemyeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomideadministered alone.

The effect of dexamethasone on warfarin is unknown. Close monitoring of warfarin concentration isadvised during treatment.

Women of childbearing potential should use effective method of contraception. If pregnancy occurs ina woman treated with pomalidomide, treatment must be stopped and the patient should be referred to aphysician specialised or experienced in teratology for evaluation and advice. If pregnancy occurs in apartner of a male patient taking pomalidomide, it is recommended to refer the female partner to aphysician specialised or experienced in teratology for evaluation and advice. Pomalidomide is presentin human semen. As a precaution, all male patients taking pomalidomide should use condomsthroughout treatment duration, during dose interruption and for 7 days after cessation of treatment iftheir partner is pregnant or of childbearing potential and has no contraception (see sections 4.3 and4.4).

A teratogenic effect of pomalidomide in humans is expected. Pomalidomide is contraindicated duringpregnancy and in women of childbearing potential, except when all the conditions for pregnancyprevention have been met (see sections 4.3 and 4.4).

It is unknown whether pomalidomide is excreted in human milk. Pomalidomide was detected in milkof lactating rats following administration to the mother. Because of the potential for adverse reactionsin breastfed infants from pomalidomide, a decision must be made whether to discontinue breast-feeding or to discontinue the medicinal product, taking into account the benefit of breast-feeding forthe child and the benefit of the therapy for the woman.

Pomalidomide was found to impact negatively on fertility and be teratogenic in animals.

Pomalidomide crossed the placenta and was detected in foetal blood following administration topregnant rabbits, see section 5.3.

Pomalidomide has minor or moderate influence on the ability to drive and use machines. Fatigue,depressed level of consciousness, confusion, and dizziness have been reported with the use ofpomalidomide. If affected, patients should be instructed not to drive cars, use machines or performhazardous tasks while being treated with pomalidomide.

Pomalidomide in combination with bortezomib and dexamethasone

The most commonly reported blood and lymphatic system disorders were neutropenia (54.0%),thrombocytopenia (39.9%) and anaemia (32.0%). Other most frequently reported adverse reactionsincluded peripheral sensory neuropathy (48.2%), fatigue (38.8%), diarrhoea (38.1%), constipation(38.1%), and oedema peripheral (36.3%). The most commonly reported Grade 3 or 4 adverse reactionswere blood and lymphatic system disorders including neutropenia (47.1%), thrombocytopenia (28.1%)and anaemia (15.1%). The most commonly reported serious adverse reaction was pneumonia (12.2%).

Other serious adverse reactions reported included pyrexia (4.3%), lower respiratory tract infection(3.6%), influenza (3.6%), pulmonary embolism (3.2%), atrial fibrillation (3.2%), and acute kidneyinjury (2.9%).

Pomalidomide in combination with dexamethasone

The most commonly reported adverse reactions in clinical studies have been blood and lymphaticsystem disorders including anaemia (45.7%), neutropenia (45.3%) and thrombocytopenia (27%); ingeneral disorders and administration site conditions including fatigue (28.3%), pyrexia (21%) andoedema peripheral (13%); and in infections and infestations including pneumonia (10.7%). Peripheralneuropathy adverse reactions were reported in 12.3% of patients and venous embolic or thrombotic(VTE) adverse reactions were reported in 3.3% of patients. The most commonly reported Grade 3 or 4adverse reactions were in the blood and lymphatic system disorders including neutropenia (41.7%),anaemia (27%) and thrombocytopenia (20.7%); in infections and infestations including pneumonia(9%); and in general disorders and administration site conditions including fatigue (4.7%), pyrexia(3%) and oedema peripheral (1.3%). The most commonly reported serious adverse reaction waspneumonia (9.3%). Other serious adverse reactions reported included febrile neutropenia (4.0%),neutropenia (2.0%), thrombocytopenia (1.7%) and VTE adverse reactions (1.7 %).

Adverse reactions tended to occur more frequently within the first 2 cycles of treatment withpomalidomide.

The adverse reactions observed in patients treated with pomalidomide in combination with bortezomiband dexamethasone, pomalidomide in combination with dexamethasone and from post-marketingsurveillance are listed in Table 7 by system organ class (SOC) and frequency for all adverse reactionsand for Grade 3 or 4 adverse reactions.

Frequencies are defined in accordance with current guidance, as: very common (≥1/10), common(≥1/100 to <1/10) and uncommon (≥1/1,000 to <1/100) and not known (frequency cannot bedetermined).

Table 7. Adverse reactions(ADRs) reported in clinical trials and post-market settings

Combination of treatment Pomalidomide/ Pomalidomide/bortezomib/dexamethasone dexamethasone

System Organ Class All Grade All Grade/Preferred term ADRs 3−4 ADRs 3−4

ADRs ADRs

Pneumonia Very common Very common - -

Pneumonia (bacterial, viral - - Very common Commonand fungal infections,including opportunisticinfections)

Bronchitis Very common Common Common Uncommon

Upper respiratory tract Very common Common Common Commoninfection

Viral upper respiratory tract Very common - - -infection

Sepsis Common Common - -

Septic shock Common Common - -

Neutropenic sepsis - - Common Common

Clostridium difficile colitis Common Common - -

Bronchopneumonia - - Common Common

Respiratory tract infection Common Common Common Common

Lower respiratory tract Common Common - -infection

Lung infection Common Uncommon - -

Influenza Very common Common - -

Bronchiolitis Common Common - -

Combination of treatment Pomalidomide/ Pomalidomide/bortezomib/dexamethasone dexamethasone

System Organ Class All Grade All Grade/Preferred term ADRs 3−4 ADRs 3−4

ADRs ADRs

Urinary tract infection Very common Common - -

Nasopharyngitis - - Common -

Herpes zoster - - Common Uncommon

Hepatitis B reactivation - - Not known* Not known*

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Basal cell carcinoma Common Uncommon - -

Basal cell carcinoma of the - - Uncommon Uncommonskin

Squamous cell carcinoma of - - Uncommon Uncommonthe skin

Neutropenia Very common Very common Very common Very common

Thrombocytopenia Very common Very common Very common Very common

Leucopenia Very common Common Very common Common

Anaemia Very common Very common Very common Very common

Febrile neutropenia Common Common Common Common

Lymphopenia Common Common - -

Pancytopenia - - Common* Common*

Angioedema - - Common* Uncommon*

Urticaria - - Common* Uncommon*

Anaphylactic reaction Not known* Not known* - -

Solid organ transplant Not known* - - -rejection

Hypothyroidism Uncommon* - - --

Hypokalaemia Very common Common - -

Hyperglycaemia Very common Common - -

Hypomagnesaemia Common Common - -

Hypocalcaemia Common Common - -

Hypophosphataemia Common Common - -

Hyperkalaemia Common Common Common Common

Hypercalcaemia Common Common - -

Hyponatraemia - - Common Common

Decreased appetite - - Very common Uncommon

Hyperuricaemia - - Common* Common*

Tumour lysis syndrome - - Uncommon* Uncommon*

Insomnia Very common Common - -

Combination of treatment Pomalidomide/ Pomalidomide/bortezomib/dexamethasone dexamethasone

System Organ Class All Grade All Grade/Preferred term ADRs 3−4 ADRs 3−4

ADRs ADRs

Depression Common Common - -

Confusional state - - Common Common

Peripheral sensory Very common Common Common Uncommonneuropathy

Dizziness Very common Uncommon Common Uncommon

Tremor Very common Uncommon Common Uncommon

Syncope Common Common - -

Peripheral sensorimotor Common Common - -neuropathy

Paraesthesia Common - - -

Dysgeusia Common - - -

Depressed level of - - Common Commonconsciousness

Intracranial haemorrhage - - Common* Uncommon*

Cerebrovascular accident - - Uncommon* Uncommon*

Cataract Common Common - -

Ear and labyrinth disorders

Vertigo - - Common Common

Atrial fibrillation Very common Common Common* Common*

Cardiac failure - - Common* Common*

Myocardial infarction - - Common* Uncommon*

Deep vein thrombosis Common Uncommon Common Uncommon

Hypotension Common Common - -

Hypertension Common Common - -

Dyspnoea Very common Common Very common Common

Cough Very common - Very common Uncommon

Pulmonary embolism Common Common Common Uncommon

Epistaxis - - Common* Uncommon*

Interstitial lung disease - - Common* Uncommon*

Diarrhoea Very common Common Very common Common

Vomiting Very common Common Common Common

Nausea Very common Uncommon Very common Uncommon

Constipation Very common Common Very common Common

Abdominal pain Very common Common - -

Combination of treatment Pomalidomide/ Pomalidomide/bortezomib/dexamethasone dexamethasone

System Organ Class All Grade All Grade/Preferred term ADRs 3−4 ADRs 3−4

ADRs ADRs

Abdominal pain upper Common Uncommon - -

Stomatitis Common Uncommon - -

Dry mouth Common - - -

Abdominal distension Common Uncommon - -

Gastrointestinal - - Common Uncommonhaemorrhage

Hyperbilirubinaemia - - Uncommon Uncommon

Hepatitis - - Uncommon* -

Rash Very common Common Common Common

Pruritus - - Common -

Drug Reaction with - - Not known* Not known*

Eosinophilia and Systemic

Toxic Epidermal Necrolysis - - Not known* Not known*

Stevens-Johnson Syndrome - - Not known* Not known*

Muscular weakness Very common Common - -

Back pain Very common Common - -

Bone pain Common Uncommon Very common Common

Muscle spasms Very common - Very common Uncommon

Acute kidney injury Common Common - -

Chronic kidney injury Common Common - -

Urinary retention Common Common Common Uncommon

Renal failure - - Common Common

Pelvic pain Common Common

Fatigue Very common Common Very common Common

Pyrexia Very common Common Very common Common

Oedema peripheral Very common Common Very common Common

Non-cardiac chest pain Common Common - -

Oedema Common Common - -

Alanine aminotransferase Common Common Common Commonincreased

Weight decreased Common Common - -

Neutrophil count decreased - - Common Common

Combination of treatment Pomalidomide/ Pomalidomide/bortezomib/dexamethasone dexamethasone

System Organ Class All Grade All Grade/Preferred term ADRs 3−4 ADRs 3−4

ADRs ADRs

White blood cell count - - Common Commondecreased

Platelet count decreased - - Common Common

Blood uric acid increased - - Common* Uncommon*

Fall Common Common - -

* Reported during post-marketing use.

The frequencies in this section are from clinical studies in patients receiving pomalidomide treatmentin combination either with bortezomib and dexamethasone (Pom+Btz+Dex) or with dexamethasone(Pom+Dex).

Pomalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic activesubstance that causes severe life-threatening birth defects. Pomalidomide was found to be teratogenicin both rats and rabbits when administered during the period of major organogenesis (see sections 4.6and 5.3). If pomalidomide is taken during pregnancy, a teratogenic effect of pomalidomide in humansis expected (see section 4.4).

Neutropenia and thrombocytopenia

Neutropenia occurred in up to 54.0% (Pom+Btz+Dex) patients (47.1% (Pom+Btz+Dex) Grade 3 or 4).

Neutropenia led to pomalidomide discontinuation in 0.7% of any patients and was infrequentlyserious.

Febrile neutropenia (FN) was reported in 3.2% (Pom+Btz+Dex) patients and 6.7% (Pom+Dex)patients and was serious in 1.8% (Pom+Btz+Dex) patients and 4.0% (Pom+Dex) patients (see sections4.2 and 4.4).

Thrombocytopenia occurred in 39.9% (Pom+Btz+Dex) patients and 27.0% (Pom+Dex) patients.

Thrombocytopenia was Grade 3 or 4 in 28.1% (Pom+Btz+Dex) patients and 20.7% (Pom+Dex)patients, led to pomalidomide discontinuation in 0.7% (Pom+Btz+Dex) patients and 0.7% (Pom+Dex)patients, and was serious in 0.7% (Pom+Btz+Dex) and 1.7% (Pom+Dex) patients (see sections 4.2 and4.4).

Neutropenia and thrombocytopenia tended to occur more frequently within the first 2 cycles oftreatment with pomalidomide in combination either with bortezomib and dexamethasone or withdexamethasone

Infection

Infection was the most common non haematological toxicity.

Infection occurred in 83.1% (Pom+Btz+Dex) patients and 55.0% (Pom+Dex) patients (34.9%(Pom+Btz+Dex) and 24.0% (Pom+Dex) Grade 3 or 4). Upper respiratory tract infection andpneumonia were the most frequently occurring infections. Fatal infections (Grade 5) occurred in 4.0%(Pom+Btz+Dex) patients and 2.7% (Pom+Dex) patients. Infections led to pomalidomidediscontinuation in 3.6% (Pom+Btz+Dex) patients and 2.0% (Pom+Dex) patients.

Prophylaxis with acetylsalicylic acid (and other anticoagulants in high-risk patients) was mandatoryfor all patients in clinical studies. Anticoagulation therapy (unless contraindicated) is recommended(see section 4.4).

Venous thromboembolic events (VTE) occurred in 12.2% (Pom+Btz+Dex) and 3.3% (Pom+Dex)patients (5.8 % (Pom+Btz+Dex) and 1.3% (Pom+Dex) Grade 3 or 4). VTE was reported as serious in4.7% (Pom+Btz+Dex) and 1.7% (Pom+Dex) patients, no fatal reactions were reported, and VTE wasassociated with pomalidomide discontinuation in up to 2.2% (Pom+Btz+Dex) of patients.

Peripheral neuropathy - Pomalidomide in combination with bortezomib and dexamethasone

Patients with ongoing peripheral neuropathy ≥ Grade 2 with pain within 14 days prior torandomisation were excluded from clinical trials. Peripheral neuropathy occurred in 55.4 % of patients(10.8% Grade 3; 0.7% Grade 4). Exposure-adjusted rates were comparable across treatment arms.

Approximately 30% of the patients experiencing peripheral neuropathy had a history of neuropathy atbaseline. Peripheral neuropathy led to discontinuation of bortezomib in approximately 14.4% ofpatients, pomalidomide in 1.8% and dexamethasone in 1.8% of patients in the Pom+Btz+Dex arm and8.9% of patients in the Btz+Dex arm.

Peripheral neuropathy - Pomalidomide in combination with dexamethasone

Patients with ongoing peripheral neuropathy ≥ Grade 2 were excluded from clinical studies. Peripheralneuropathy occurred in 12.3% of patients (1.0% Grade 3 or 4). No peripheral neuropathy reactionswere reported as serious, and peripheral neuropathy led to dose discontinuation in 0.3% of patients(see section 4.4).

Haemorrhagic disorders have been reported with pomalidomide, especially in patients with risk factorssuch as concomitant medicinal products that increase susceptibility to bleeding. Haemorrhagic eventshave included epistaxis, intracranial haemorrhage and gastrointestinal haemorrhage.

Allergic reactions and severe skin reactions

Angioedema, anaphylactic reaction and severe cutaneous reactions including SJS, TEN and DRESShave been reported with the use of pomalidomide. Patients with a history of severe rash associatedwith lenalidomide or thalidomide should not receive pomalidomide (see section 4.4).

Adverse reactions reported in paediatric patients (aged 4 to 18 years) with recurrent or progressivebrain tumours were consistent with the known pomalidomide safety profile in adult patients (seesection 5.1).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Pomalidomide doses as high as 50 mg as a single dose in healthy volunteers have been studied withoutreporting serious adverse reactions related to overdose. Doses as high as 10 mg once-daily multipledoses in multiple myeloma patients have been studied without reported serious adverse reactionsrelated to overdose. The dose-limiting toxicity was myelosuppression. In studies, pomalidomide wasfound to be removed by haemodialysis.

In the event of overdose, supportive care is advised.

Pharmacotherapeutic group: Immunosuppressants, Other immunosuppressants, ATC code: L04AX06

Pomalidomide has direct anti-myeloma tumoricidal activity, immunomodulatory activities and inhibitsstromal cell support for multiple myeloma tumour cell growth. Specifically, pomalidomide inhibitsproliferation and induces apoptosis of haematopoietic tumour cells. Additionally, pomalidomideinhibits the proliferation of lenalidomide-resistant multiple myeloma cell lines and synergises withdexamethasone in both lenalidomide-sensitive and lenalidomide-resistant cell lines to induce tumourcell apoptosis. Pomalidomide enhances T cell- and natural killer (NK) cell-mediated immunity andinhibits production of pro-inflammatory cytokines (e.g., TNF-α and IL-6) by monocytes.

Pomalidomide also inhibits angiogenesis by blocking the migration and adhesion of endothelial cells.

Pomalidomide binds directly to the protein cereblon (CRBN), which is part of an E3 ligase complexthat includes deoxyribonucleic acid (DNA) damage-binding protein 1(DDB1), cullin 4 (CUL4), andregulator of cullins-1 (Roc1), and can inhibit the auto-ubiquitination of CRBN within the complex. E3ubiquitin ligases are responsible for the poly-ubiquitination of a variety of substrate proteins, and maypartially explain the pleiotropic cellular effects observed with pomalidomide treatment.

In the presence of pomalidomide in vitro, substrate proteins Aiolos and Ikaros are targeted forubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects.

In vivo, pomalidomide therapy led to reduction in the levels of Ikaros in patients with relapsedlenalidomide-refractory multiple myeloma.

Pomalidomide in combination with bortezomib and dexamethasone

The efficacy and safety of pomalidomide in combination with bortezomib and low-dosedexamethasone (Pom+Btz+LD-Dex) was compared with bortezomib and low-dose dexamethasone(Btz+LD-Dex) in a Phase III multi-centre, randomised, open-label study (CC-4047-MM-007), inpreviously treated adult patients with multiple myeloma, who had received at least one prior regimen,including lenalidomide and have demonstrated disease progression on or after the last therapy. A totalof 559 patients were enrolled and randomised in the study: 281 in the Pom+Btz+LD-Dex arm and 278in the Btz+LD-Dex arm. 54% of patients were male with median age for the overall population of 68years (min, max: 27, 89 years). Approximately 70% of patients were refractory to lenalidomide(71.2% in Pom+Btz+LD-Dex, 68.7 % in Btz+LD-Dex). Approximately 40% of patients were in 1strelapse and approximately 73% of patients received bortezomib as prior treatment.

Patients in the Pom+Btz+LD-Dex arm were administered 4 mg pomalidomide orally on Days 1 to 14of each 21-day cycle. Bortezomib (1.3 mg/m2/dose) was administered to patients in both study arms on

Days 1, 4, 8 and 11 of a 21-day cycle for Cycles 1 to 8; and on Days 1 and 8 of a 21-day cycle for

Cycles 9 and onwards. Low-dose dexamethasone (20 mg/day [≤ 75 years old] or 10 mg/day [> 75years old]) was administered to patients in both study arms on Days 1, 2, 4, 5, 8, 9, 11 and 12 of a 21-day cycle for Cycles 1 to 8; and on Days 1, 2, 8 and 9 of each subsequent 21-day cycle from Cycles 9onwards. Doses were reduced and treatment was temporarily interrupted or stopped as needed tomanage toxicity (see section 4.2).

The primary efficacy endpoint was Progression Free Survival (PFS) assessed by an Independent

Response Adjudication Committee (IRAC) according to the IMWG criteria using the intent to treatpopulation (ITT). After a median follow-up of 15.9 months, median PFS time was 11.20 months (95%

CI: 9.66, 13.73) in the Pom+Btz+LD-Dex arm. In the Btz+LD-Dex arm, median PFS time was 7.1months (95% CI: 5.88, 8.48).

Summary of overall efficacy data are presented in Table 8 using a cut-off date of 26 Oct 2017. Kaplan-

Meier curve for PFS for the ITT population is provided in Figure 1.

Table 8. Summary of overall efficacy data

Pom+Btz+LD-Dex Btz+LD-Dex(N = 281) (N = 278)

PFS (months)

Median a time (95% CI) b 11.20 (9.66, 13.73) 7.10 (5.88, 8.48)

HR c (95% CI), p-value d 0.61 (0.49, 0.77), <0.0001

ORR, n (%) 82.2% 50.0%sCR 9 (3.2) 2 (0.7)

CR 35 (12.5) 9 (3.2)

VGPR 104 (37.0) 40 (14.4)

PR 83 (29.5) 88 (31.7)

OR (95% CI) e, p-valuef 5.02 (3.35, 7.52), <0.001

DoR (months)

Mediana time (95% CI) b 13.7 (10.94, 18.10) 10.94 (8.11, 14.78)

HRc (95% CI) 0.76 (0.56, 1.02)

Btz = bortezomib; CI = Confidence interval; CR = Complete response; DoR = Duration of response; HR = Hazard Ratio;

LD-Dex = low-dose dexamethasone; OR = Odds ratio; ORR = Overall response rate; PFS = Progression free survival; POM =pomalidomide; PR = Partial Response; sCR = Stringent complete response VGPR = Very good partial response.a

The median is based on the Kaplan-Meier estimate.

b95% CI about the median.

c

Based on Cox proportional hazards model.

d

The p-value is based on a stratified log-rank test.

e

Odds ratio is for Pom+Btz+LD-Dex:Btz+LD-Dex.

f

The p-value is based on a CMH test, stratified by age (<=75 vs >75), Prior number of antimyeloma regimens (1 vs >1), and Beta-2microglobulin at screening (< 3.5 mg/L versus ≥ 3.5 mg/L — ≤ 5.5 mg/L versus > 5.5 mg/L).

The median duration of treatment was 8.8 months (12 treatment cycles) in the Pom+Btz+LD-Dex armand 4.9 months (7 treatment cycles) in the Btz+LD-Dex arm.

The PFS advantage was more pronounced in patients who received only one prior line of therapy. Inpatients who received 1 prior antimyeloma line, median PFS time was 20.73 months (95% CI: 15.11,27.99) in the Pom + Btz + LD-Dex arm and 11.63 months (95% CI: 7.52, 15.74) in the Btz + LD-Dexarm. A 46% risk reduction was observed with Pom + Btz + LD-Dex treatment (HR = 0.54, 95% CI:0.36, 0.82).

Figure 1. Progression Free Survival Based on IRAC Review of Response by IMWG Criteria(Stratified Log Rank Test) (ITT Population).

Data cutoff: 26 Oct 2017

Final analysis for Overall Survival (OS), using a cut-off of 13 May 2022 (median follow-up period of64.5 months), median OS time from Kaplan-Meier estimates was 35.6 months for the Pom + Btz +

LD-Dex arm and 31.6 months for the Btz + LD-Dex arm; HR =0.94, 95% CI: -0.77, 1.15, with anoverall event rate of 70.0%. The OS analysis was not adjusted to account for subsequent therapiesreceived.

Pomalidomide in combination with dexamethasone

The efficacy and safety of pomalidomide in combination with dexamethasone were evaluated in a

Phase III multi-centre, randomised, open-label study (CC-4047-MM-003), where pomalidomide pluslow-dose dexamethasone therapy (Pom+LD-Dex) was compared to high-dose dexamethasone alone(HD-Dex) in previously treated adult patients with relapsed and refractory multiple myeloma, whohave received at least two prior treatment regimens, including both lenalidomide and bortezomib, andhave demonstrated disease progression on the last therapy. A total of 455 patients were enrolled in thestudy: 302 in the Pom+LD-Dex arm and 153 in the HD-Dex arm. The majority of patients were male(59%) and white (79%); the median age for the overall population was 64 years (min, max: 35, 87years).

Patients in the Pom+LD-Dex arm were administered 4 mg pomalidomide orally on days 1 to 21 ofeach 28-day cycle. LD-Dex (40 mg) was administered once per day on days 1, 8, 15 and 22 of a 28-day cycle. For the HD-Dex arm, dexamethasone (40 mg) was administered once per day on days 1through 4, 9 through 12, and 17 through 20 of a 28-day cycle. Patients > 75 years of age startedtreatment with 20 mg dexamethasone. Treatment continued until patients had disease progression.

The primary efficacy endpoint was progression free survival by International Myeloma Working

Group (IMWG criteria). For the intention to treat (ITT) population, median PFS time by Independent

Review Adjudication Committee (IRAC) review based on IMWG criteria was 15.7 weeks (95% CI:13.0, 20.1) in the Pom + LD-Dex arm; the estimated 26-week event-free survival rate was 35.99%(±3.46%). In the HD-Dex arm, median PFS time was 8.0 weeks (95% CI: 7.0, 9.0); the estimated 26-week event-free survival rate was 12.15% (±3.63%).

PFS was evaluated in several relevant subgroups: gender, race, ECOG performance status,stratification factors (age, disease population, prior anti-myeloma therapies [2, > 2]), selectedparameters of prognostic significance (baseline beta-2 microglobulin level, baseline albumin levels,baseline renal impairment, and cytogenetic risk), and exposure and refractoriness to prior anti-myeloma therapies. Regardless of the subgroup evaluated, PFS was generally consistent with thatobserved in the ITT population for both treatment groups.

PFS is summarised in Table 9 for the ITT population. Kaplan-Meier curve for PFS for the ITTpopulation is provided in Figure 2.

Table 9. Progression Free Survival Time by IRAC Review Based on IMWG Criteria (Stratified

Log Rank Test) (ITT Population)

Pom+LD-Dex HD-Dex(N=302) (N=153)

Progression free survival (PFS), N 302 (100.0) 153 (100.0)

Censored, n (%) 138 (45.7) 50 (32.7)

Progressed/Died, n (%) 164 (54.3) 103 (67.3)

Progression Free Survival Time (weeks)

Mediana 15.7 8.0

Two sided 95% CIb [13.0,20.1] [7.0,9.0]

Hazard Ratio (Pom+LD-Dex:HD-Dex) 2-Sided 0.45 [0.35,0.59]95% CI c

Log-Rank Test Two sided P-Value d <0.001

Note: CI=Confidence interval; IRAC=Independent Review Adjudication Committee; NE = Not Estimable.a

The median is based on Kaplan-Meier estimate.

b95% confidence interval about the median progression free survival time.

c

Based on Cox proportional hazards model comparing the hazard functions associated with treatment groups, stratified by age(≤75 vs >75),diseases population (refractory to both lenalidomide and bortezomib vs not refractory to both active substances), and priornumber of anti myeloma therapy (=2 vs >2).d The p-value is based on a stratified log-rank test with the same stratification factors as the above Cox model.

Data cutoff: 07 Sep 2012

Figure 2. Progression Free Survival Based on IRAC Review of Response by IMWG Criteria(Stratified Log Rank Test) (ITT Population)

Data cutoff: 07 Sep 2012

Overall Survival was the key secondary study endpoint. A total of 226 (74.8%) of the Pom + LD-Dexpatients and 95 (62.1%) of the HD-Dex patients were alive as of the cutoff date (07 Sep 2012). Median

OS time from Kaplan-Meier estimates has not been reached for the Pom + LD-Dex, but would beexpected to be at least 48 weeks, which is the lower boundary of the 95% CI. Median OS time for the

HD-Dex arm was 34 weeks (95% CI: 23.4, 39.9). The 1-year event free rate was 52.6% (± 5.72%) forthe Pom + LD-Dex arm and 28.4% (± 7.51%) for the HD-Dex arm. The difference in OS between thetwo treatment arms was statistically significant (p < 0.001).

Overall survival is summarised in Table 10 for the ITT population. Kaplan-Meier curve for OS for the

ITT population is provided in Figure 3.

Based on the results of both PFS and OS endpoints, the Data Monitoring Committee established forthis study recommended that the study be completed and patients in the HD-Dex arm be crossed overto the Pom + LD-Dex arm.

Table 10. Overall Survival: ITT Population

Statistics Pom+LD-Dex HD-Dex(N=302) (N=153)

N 302 (100.0) 153 (100.0)

Censored n (%) 226 (74.8) 95 (62.1)

Died n (%) 76 (25.2) 58 (37.9)

Survival Time (weeks) Mediana NE 34.0

Two sided 95% CIb [48.1, NE] [23.4, 39.9]

Hazard Ratio (Pom+LD-Dex:HD-Dex) [Two sided 95% CIc] 0.53[0.37, 0.74]

Log-Rank Test Two sided P-Valued <0.001

Note: CI=Confidence interval. NE = Not Estimable.a

The median is based on Kaplan-Meier estimate.

b95% confidence interval about the median overall survival time.

c

Based on Cox proportional hazards model comparing the hazard functions associated with treatment groups.

d

The p-value is based on an unstratified log-rank test.

Data cutoff: 07 Sep 2012

Figure 3. Kaplan-Meier Curve of Overall Survival (ITT Population)cutoff: 07 Sep 2012

In a Phase 1 single-arm, open-label, dose escalation study, the maximum tolerated dose (MTD) and/orrecommended Phase2 dose (RP2D) of pomalidomide in paediatric patients was determined to be 2.6mg/m2/day administered orally on Day 1 to Day 21 of a repeated 28-day cycle.

Efficacy was not demonstrated in a Phase 2 multi-centre, open-label, parallel-group study conducted in52 pomalidomide-treated paediatric patients, aged 4 to 18 years with recurrent or progressive high-grade glioma, medulloblastoma, ependymoma or diffuse intrinsic pontine glioma (DIPG) with primarylocation in the central nervous system (CNS).

In the Phase 2 study, two patients in the high-grade glioma group (N=19) achieved a response asdefined by protocol; one of these patients achieved a partial response (PR) and the other patientachieved a long term stable disease (SD), which resulted in an objective response (OR) and long-term

SD rate of 10.5% (95% CI: 1.3, 33.1). One patient in the ependymoma group (N=9) achieved a long-term SD which resulted in an OR and long-term SD rate of 11.1% (95% CI: 0.3, 48.2). No confirmed

OR or long-term SD was observed in any of the evaluable patients in either the diffuse intrinsicpontine glioma (DIPG) group (N=9) or medulloblastoma group (N=9). None of the 4 parallel groupsassessed in this Phase 2 study met the primary endpoint of objective response or long-term stabledisease rate.

The overall safety profile of pomalidomide in paediatric patients was consistent with the known safetyprofile in adults. Pharmacokinetic (PK) parameters were evaluated in an Integrated PK Analysis of the

Phase 1 and Phase 2 studies and were found to have no significant difference to those observed inadult patients (see section 5.2).

Pomalidomide is absorbed with a maximum plasma concentration (Cmax) occurring between 2 and 3hours and is at least 73% absorbed following administration of single oral dose. The systemicexposure (AUC) of pomalidomide increases in an approximately linear and dose proportional manner.

Following multiple doses, pomalidomide has an accumulation ratio of 27 to 31% on AUC.

Coadministration with a high-fat and high-calorie meal slows the rate of absorption, decreasing meanplasma Cmax by approximately 27%, but has minimal effect on the overall extent of absorption withan 8% decrease in mean AUC. Therefore, pomalidomide can be administered without regard to foodintake.

Pomalidomide has a mean apparent volume of distribution (Vd/F) between 62 and 138 L at steadystate. Pomalidomide is distributed in semen of healthy subjects at a concentration of approximately67% of plasma level at 4 hours post-dose (approximately Tmax) after 4 days of once daily dosing at2 mg. In vitro binding of pomalidomide enantiomers to proteins in human plasma ranges from 12% to44% and is not concentration dependent.

Pomalidomide is the major circulating component (approximately 70% of plasma radioactivity) invivo in healthy subjects who received a single oral dose of [14C]-pomalidomide (2 mg). Nometabolites were present at >10% relative to parent or total radioactivity in plasma.

The predominant metabolic pathways of excreted radioactivity are hydroxylation with subsequentglucuronidation, or hydrolysis. In vitro, CYP1A2 and CYP3A4 were identified as the primaryenzymes involved in the CYP-mediated hydroxylation of pomalidomide, with additional minorcontributions from CYP2C19 and CYP2D6. Pomalidomide is also a substrate of P-glycoprotein invitro. Co-administration of pomalidomide with the strong CYP3A4/5 and P-gp inhibitor ketoconazole,or the strong CYP3A4/5 inducer carbamazepine, had no clinically relevant effect on exposure topomalidomide. Co-administration of the strong CYP1A2 inhibitor fluvoxamine with pomalidomide inthe presence of ketoconazole, increased mean exposure to pomalidomide by 107% with a 90%confidence interval [91% to 124%] compared to pomalidomide plus ketoconazole. In a second study toevaluate the contribution of a CYP1A2 inhibitor alone to metabolism changes, co-administration offluvoxamine alone with pomalidomide increased mean exposure to pomalidomide by 125% with a90% confidence interval [98% to 157%] compared to pomalidomide alone. If strong inhibitors of

CYP1A2 (e.g. ciprofloxacin, enoxacin and fluvoxamine) are co-administered with pomalidomide,reduce the dose of pomalidomide to 50%. Administration of pomalidomide in smokers, with smokingtobacco known to induce the CYP1A2 isoform, had no clinically relevant effect on exposure topomalidomide compared to that exposure to pomalidomide observed in non-smokers.

Based on in vitro data, pomalidomide is not an inhibitor or inducer of cytochrome P-450 isoenzymes,and does not inhibit any drug transporters that were studied. Clinically relevant interactions are notanticipated when pomalidomide is coadministered with substrates of these pathways.

Pomalidomide is eliminated with a median plasma half-life of approximately 9.5 hours in healthysubjects and approximately 7.5 hours in patients with multiple myeloma. Pomalidomide has a meantotal body clearance (CL/F) of approximately 7-10 L/hr.

Following a single oral administration of [14C] -pomalidomide (2 mg) to healthy subjects,approximately 73% and 15% of the radioactive dose was eliminated in urine and faeces, respectively,with approximately 2% and 8% of the dosed radiocarbon eliminated as pomalidomide in urine andfaeces.

Pomalidomide is extensively metabolised prior to excretion, with the resulting metabolites eliminatedprimarily in the urine. The 3 predominant metabolites in urine (formed via hydrolysis or hydroxylationwith subsequent glucuronidation) account for approximately 23%, 17%, and 12%, respectively, of thedose in the urine.

CYP dependent metabolites account for approximately 43% of the total excreted radioactivity, whilenon-CYP dependent hydrolytic metabolites account for 25%, and excretion of unchangedpomalidomide accounted for 10% (2% in urine and 8% in faeces).

Population Pharmacokinetics (PK)

Based on population PK analysis using a two-compartment model, healthy subjects and MM patientshad comparable apparent clearance (CL/F) and apparent central volume of distribution (V2/F). Inperipheral tissues, pomalidomide was preferentially taken up by tumours with apparent peripheraldistribution clearance (Q/F) and apparent peripheral volume of distribution (V3/F) 3.7-fold and 8-foldhigher, respectively, than that of healthy subjects.

Following a single oral dose of pomalidomide in children and young adults with recurrent orprogressive primary brain tumour, the median Tmax was 2 to 4 hours post-dose and corresponded togeometric mean Cmax (CV%) values of 74.8 (59.4%), 79.2 (51.7%), and 104 (18.3%) ng/mL at the1.9, 2.6, and 3.4 mg/m2 dose levels, respectively. AUC0-24 and AUC0-inf followed similar trends,with total exposure in the range of approximately 700 to 800 h·ng/mL at the lower 2 doses, andapproximately 1200 h·ng/mL at the high dose. Estimates of half-life were in the range ofapproximately 5 to 7 hours. There were no clear trends attributable to stratification by age and steroiduse at the MTD.

Overall, data suggest that AUC increased nearly proportional to the increase in pomalidomide dose,while the increase in Cmax was generally less than proportional.

The pharmacokinetics of pomalidomide following oral administration dose levels of 1.9 mg/m2/day to3.4 mg/m2/day were determined in 70 patients with ages from 4 to 20 years in an integrated analysis ofa Phase 1 and Phase 2 study in recurrent or progressive paediatric brain tumours. Pomalidomideconcentration-time profiles were adequately described with a one compartment PK model with first-order absorption and elimination. Pomalidomide exhibited linear and time-invariant PK with moderatevariability. The typical values of CL/F, Vc/F, Ka, lag time of pomalidomide were 3.94 L/h, 43.0 L,1.45 h-1 and 0.454 h respectively. The terminal elimination half-life of pomalidomide was 7.33 hours.

Except for body surface area (BSA), none of the tested covariates including age and sex had effect onpomalidomide PK. Although BSA was identified as a statistically significant covariate ofpomalidomide CL/F and Vc/F, the impact of BSA on exposure parameters was not deemed clinicallyrelevant.

In general, there is no significant difference of pomalidomide PK between children and adult patients.

Based on population pharmacokinetic analyses in healthy subjects and multiple myeloma patients, nosignificant influence of age (19-83 years) on oral clearance of pomalidomide was observed. In clinicalstudies, no dose adjustment was required in elderly (> 65 years) patients exposed to pomalidomide(see section 4.2).

Population pharmacokinetic analyses showed that the pomalidomide pharmacokinetic parameters werenot remarkably affected in renally impaired patients (defined by creatinine clearance or estimatedglomerular filtration rate [eGFR]) compared to patients with normal renal function(CrCl ≥60 mL/minute). Mean normalised AUC exposure to pomalidomide was 98.2% with a 90%confidence interval [77.4% to 120.6%] in moderate renal impairment patients (eGFR ≥30 to≤45 mL/minute/1.73 m2) compared to patients with normal renal function. Mean normalised AUCexposure to pomalidomide was 100.2% with a 90% confidence interval [79.7% to 127.0%] in severerenal impairment patients not requiring dialysis (CrCl <30 or eGFR <30 mL/minute/1.73 m2)compared to patients with normal renal function. Mean normalised AUC exposure to pomalidomideincreased by 35.8% with a 90% CI [7.5% to 70.0%] in severe renal impairment patients requiringdialysis (CrCl <30mL/minute requiring dialysis) compared to patients with normal renal function. Themean changes in exposure to pomalidomide in each of these renal impairment groups are not of amagnitude that requires dose adjustments.

The pharmacokinetic parameters were modestly changed in hepatically impaired patients (defined by

Child-Pugh criteria) compared to healthy subjects. Mean exposure to pomalidomide increased by 51%with a 90% confidence interval [9% to 110%] in mildly hepatically impaired patients compared tohealthy subjects. Mean exposure to pomalidomide increased by 58% with a 90% confidence interval[13% to 119%] in moderately hepatically impaired patients compared to healthy subjects. Meanexposure to pomalidomide increased by 72% with a 90% confidence interval [24% to 138%] inseverely hepatically impaired patients compared to healthy subjects. The mean increases in exposureto pomalidomide in each of these impairment groups are not of a magnitude for which adjustments inschedule or dose are required (see section 4.2).

Repeat-dose toxicology studies

In rats, chronic administration of pomalidomide at doses of 50, 250, and 1000 mg/kg/day for 6 monthswas well tolerated. No adverse findings were noted up to 1000 mg/kg/day (175-fold exposure ratiorelative to a 4 mg clinical dose).

In monkeys, pomalidomide was evaluated in repeat-dose studies of up to 9 months in duration. Inthese studies, monkeys exhibited greater sensitivity to pomalidomide effects than rats. The primarytoxicities observed in monkeys were associated with the haematopoietic/lymphoreticular systems. Inthe 9-month study in monkeys with doses of 0.05, 0.1, and 1 mg/kg/day, morbidity and earlyeuthanasia of 6 animals were observed at the dose of 1 mg/kg/day and were attributed toimmunosuppressive effects (staphylococcal infection, decreased peripheral blood lymphocytes,chronic inflammation of the large intestine, histologic lymphoid depletion, and hypocellularity of bonemarrow) at high exposures of pomalidomide (15-fold exposure ratio relative to a 4 mg clinical dose).

These immunosuppressive effects resulted in early euthanasia of 4 monkeys due to poor healthcondition (watery stool, inappetence, reduced food intake, and weight loss); histopathologic evaluationof these animals showed chronic inflammation of the large intestine and villous atrophy of the smallintestine. Staphylococcal infection was observed in 4 monkeys; 3 of these animals responded toantibiotic treatment and 1 died without treatment. In addition, findings consistent with acutemyelogenous leukemia led to euthanasia of 1 monkey; clinical observations and clinical pathologyand/or bone marrow alterations observed in this animal were consistent with immunosuppression.

Minimal or mild bile duct proliferation with associated increases in ALP and GGT were also observedat 1 mg/kg/day. Evaluation of recovery animals indicated that all treatment-related findings werereversible after 8 weeks of dosing cessation, except for proliferation of intrahepatic bile ducts observedin 1 animal in the 1 mg/kg/day group. The No Observed Adverse Effect Level (NOAEL) was 0.1mg/kg/day (0.5-fold exposure ratio relative to a 4 mg clinical dose).

Pomalidomide was not mutagenic in bacterial and mammalian mutation assays, and did not inducechromosomal aberrations in human peripheral blood lymphocytes or micronuclei formation inpolychromatic erythrocytes in bone marrow of rats administered doses up to 2000 mg/kg/day.

Carcinogenicity studies have not been conducted.

Fertility and early embryonic development

In a fertility and early embryonic development study in rats, pomalidomide was administered to malesand females at doses of 25, 250, and 1000 mg/kg/day. Uterine examination on Gestation Day 13showed a decrease in mean number of viable embryos and an increase in postimplantation loss at alldose levels. Therefore, the NOAEL for these observed effects was < 25 mg/kg/day (AUC 24h was39960 ng*h/mL (nanogram*hour/millilitres) at this lowest dose tested, and the exposure ratio was 99-fold relative to a 4 mg clinical dose). When treated males on this study were mated with untreatedfemales, all uterine parameters were comparable to the controls. Based on these results, the observedeffects were attributed to the treatment of females.

Embryo-foetal development

Pomalidomide was found to be teratogenic in both rats and rabbits when administered during theperiod of major organogenesis. In the rat embryofoetal developmental toxicity study, malformations ofabsence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar andthoracic vertebral elements (central and/or neural arches) were observed at all dose levels (25, 250, and1000 mg/kg/day).

There was no maternal toxicity observed in this study. Therefore, the maternal NOAEL was 1000mg/kg/day, and the NOAEL for developmental toxicity was < 25 mg/kg/day (AUC24h was34340 ng*h/mL on Gestation Day 17 at this lowest dose tested, and the exposure ratio was 85-foldrelative to a 4 mg clinical dose). In rabbits, pomalidomide at doses ranging from 10 to 250 mg/kgproduced embryo-foetal developmental malformations. Increased cardiac anomalies were seen at alldoses with significant increases at 250 mg/kg/day. At 100 and 250 mg/kg/day, there were slightincreases in post-implantation loss and slight decreases in fetal body weights. At 250 mg/kg/day, fetalmalformations included limb anomalies (flexed and/or rotated fore- and/or hindlimbs, unattached orabsent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx andmetacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia); moderate dilation ofthe lateral ventricle in the brain; abnormal placement of the right subclavian artery; absentintermediate lobe in the lungs; low-set kidney; altered liver morphology; incompletely or not ossifiedpelvis; an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals.

Slight reduction in maternal body weight gain, significant reduction in triglycerides, and significantdecrease in absolute and relative spleen weights were observed at 100 and 250 mg/kg/day. Thematernal NOAEL was 10 mg/kg/day, and the developmental NOAEL was <10 mg/kg/day (AUC24hwas 418 ng*h/mL on Gestation Day 19 at this lowest dose tested, which was similar to that obtainedfrom a 4 mg clinical dose).

Cellulose, microcrystalline

Maltodextrin

Sodium stearyl fumarate

Pomalidomide Accord 1 mg hard capsules

Gelatin

Titanium dioxide (E171)

Iron Oxide Yellow (E172)

Iron Oxide Red (E172)

Pomalidomide Accord 2 mg hard capsules

Gelatin

Titanium dioxide (E171)

Iron Oxide Yellow (E172)

Iron Oxide Red (E172)

Pomalidomide Accord 3 mg hard capsules

Gelatin

Titanium dioxide (E171)

Indigo carmine aluminium lake (E132)

Iron Oxide Yellow (E172)

Iron Oxide Red (E172)

Pomalidomide Accord 4 mg hard capsules

Gelatin

Titanium dioxide (E171)

Iron Oxide Yellow (E172)

Iron Oxide Red (E172)

Indigo carmine aluminium lake (E132)

Erythrosine (E127)

Printing ink (white ink)

Shellac

Titanium dioxide (E171)

Propylene glycol (E1520)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

7, 14 or 21 capsules in oPA/Al/PVC/Al blister packs or perforated unit dose blisters of 7 x 1,14 x 1 or 21 x 1 capsules.

Not all pack sizes may be marketed.

Capsules should not be opened or crushed. If powder from pomalidomide makes contact with the skin,the skin should be washed immediately and thoroughly with soap and water. If pomalidomide makescontact with the mucous membranes, they should be thoroughly flushed with water.

Healthcare professionals and caregivers should wear disposable gloves when handling the blister orcapsule. Gloves should then be removed carefully to prevent skin exposure, placed in a sealable plasticpolyethylene bag and disposed of in accordance with local requirements. Hands should then be washedthoroughly with soap and water. Women who are pregnant or suspect they may be pregnant should nothandle the blister or capsule (see section 4.4).

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements. Unused medicinal product should be returned to the pharmacist at the end of treatment.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona, s/n,

Edifici Est, 6a Planta,08039 Barcelona,

Spain

1 mg Capsule, hard

EU/1/24/1831/001 7 capsules

EU/1/24/1831/002 14 capsules

EU/1/24/1831/003 21 capsules

EU/1/24/1831/004 7 x 1 capsules (unit dose)

EU/1/24/1831/005 14 x 1 capsules (unit dose)

EU/1/24/1831/006 21 x 1 capsules (unit dose)2 mg Capsule, hard

EU/1/24/1831/007 7 capsules

EU/1/24/1831/008 14 capsules

EU/1/24/1831/009 21 capsules

EU/1/24/1831/010 7 x 1 capsules (unit dose)

EU/1/24/1831/011 14 x 1 capsules (unit dose)

EU/1/24/1831/012 21 x 1 capsules (unit dose)3 mg Capsule, hard

EU/1/24/1831/013 7 capsules

EU/1/24/1831/014 14 capsules

EU/1/24/1831/015 21 capsules

EU/1/24/1831/016 7 x 1 capsules (unit dose)

EU/1/24/1831/017 14 x 1 capsules (unit dose)

EU/1/24/1831/018 21 x 1 capsules (unit dose)4 mg Capsule, hard

EU/1/24/1831/019 7 capsules

EU/1/24/1831/020 14 capsules

EU/1/24/1831/021 21 capsules

EU/1/24/1831/022 7 x 1 capsules (unit dose)

EU/1/24/1831/023 14 x 1 capsules (unit dose)

EU/1/24/1831/024 21 x 1 capsules (unit dose)

Date of first authorisation:

Detailed information on this medicinal product is available on the European Medicines Agencywebsite: http://www.ema.europa.eu.