4.1. Therapeutic indications

Pomalidomide Zentiva in combination with bortezomib and dexamethasone is indicated in the treatment of adult patients with multiple myeloma who have received at least one prior treatment regimen including lenalidomide.

Pomalidomide Zentiva in combination with dexamethasone is indicated in the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy.

4.2. Posology and method of administration

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

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

Posology

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 of repeated 21- day cycles.

Pomalidomide is administered in combination with bortezomib and dexamethasone, as shown in table 1.

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 once daily, on the days shown in table 1.

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

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

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 platelet count must be ≥ 50 x 109/l.

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

Table 2. Pomalidomide dose modification instructions∞

Toxicity

Dose modification

Neutropenia *

ANC** < 0.5 x 109/l or febrile neutropenia (fever ≥ 38.5 °C and ANC < 1 x 109/l)

Interrupt pomalidomide treatment for remainder of cycle. Follow CBC*** weekly.

ANC return to ≥ 1 x 109/l

Resume pomalidomide treatment at one dose level 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 dose level lower than the previous dose.

Thrombocytopenia

Platelet count < 25 x 109/l

Interrupt pomalidomide treatment for remainder of cycle. Follow CBC*** weekly.

Platelet count return to ≥ 50 x 109/l

Resume pomalidomide treatment at one dose level 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 dose level lower than the previous dose.

Rash

Rash = Grade 2-3

Consider dose interruption or discontinuation of pomalidomide treatment.

Rash = Grade 4 or blistering (including angioedema, anaphylactic reaction, exfoliative or bullous rash or if Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) or Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is suspected)

Permanently discontinue treatment (see section 4.4).

Other

Other ≥ Grade 3 pomalidomide-related adverse events

Interrupt pomalidomide treatment for remainder of cycle. Resume at one dose level lower than previous dose at next cycle (adverse event must be resolved or improved to ≤ Grade 2 before restarting dosing).

∞Dose modification instructions in this table are applicable to pomalidomide in combination with bortezomib and dexamethasone 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 to pomalidomide 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-administered with 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 reactions are outlined in tables 4 and 5 below. However, dose interruption or resumption decisions are at the physician's discretion per 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 dose level if symptoms persist.

Dyspepsia ≥ Grade 3

Interrupt dose until symptoms are controlled. Add H2 blocker or equivalent and resume at one dose level lower than previous dose.

Oedema ≥ Grade 3

Use diuretics as needed and decrease dose by one dose level.

Confusion or mood alteration ≥ Grade 2

Interrupt dose until symptoms resolve. Resume at one dose level lower than previous dose.

Muscle weakness ≥ Grade 2

Interrupt dose until muscle weakness ≤ Grade 1. Resume at one dose level lower than previous dose.

Hyperglycaemia ≥ Grade 3

Decrease dose by one dose level. Treat with insulin or oral hypoglycaemic agents as needed.

Acute pancreatitis

Discontinue dexamethasone from treatment regimen.

Other ≥ Grade 3 dexamethasone-related adverse events

Stop dexamethasone dosing until the adverse event resolves to ≤ Grade 2. Resume at one dose level lower than previous dose.

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

Table 5. Dexamethasone dose reduction

Dose Level

≤ 75 years old

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

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

> 75 years old

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

Cycle ≥ 9: Days 1, 2, 8, 9 of a 21-day 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 4 mg if > 75 years old.

In case of permanent discontinuation of any component of the treatment regimen, continuation of the remaining 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 of each 28-day cycle.

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

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

Pomalidomide dose modification or interruption

Instructions for dose interruptions or reductions for pomalidomide related adverse reactions are outlined 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 6 below. However, dose interruption / resumption decisions are at physician's discretion per the current SmPC.

Table 6. Dexamethasone dose reduction

Dose level

≤ 75 years old

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

> 75 years old

Days 1, 8, 15 and 22 of each 28-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 8 mg if > 75 years old.

Special populations

Elderly

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.

Hepatic impairment

Patients with serum total bilirubin > 1.5 x ULN (upper limit of normal range) were excluded from clinical 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 with hepatic impairment as defined by the Child-Pugh criteria. However, patients with hepatic impairment should be carefully monitored for adverse reactions and dose reduction or interruption of pomalidomide should be used as needed.

Renal impairment

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

Paediatric population

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

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

Method of administration

Oral use.

Pomalidomide Zentiva hard capsules should be taken orally at the same time each day. The capsules should 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 on one day, then the patient should take the normal prescribed dose as scheduled on the next day. Patients should 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 thereby reducing the risk of capsule deformation or breakage.

4.3. Contraindications

• Pregnancy.

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

• Male patients unable to follow or comply with the required contraceptive measures (see section 4.4).

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

4.4. Special warnings and precautions for use

Teratogenicity

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 that causes severe life-threatening birth defects. Pomalidomide was found to be teratogenic in both rats and rabbits 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 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 of non-childbearing potential if she meets at least one of the following criteria:

• Age ≥ 50 years and naturally amenorrhoeic for ≥ 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, pomalidomide 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, at least 4 weeks before starting treatment, throughout the entire duration of treatment, and at least 4 weeks after the end of treatment

• Even if a woman of childbearing potential has amenorrhoea she must follow all the advice on effective contraception

• She should be capable of complying with effective contraceptive measures

• She is informed and understands the potential consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy

• She understands the need to commence the treatment as soon as pomalidomide is dispensed following a negative pregnancy test

• She understands the need and accepts to undergo pregnancy testing at least 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 pomalidomide.

The prescriber must ensure that for women of childbearing potential:

• The patient complies with the conditions of the Pregnancy Prevention Programme, including confirmation 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 is present in human semen during treatment. As a precaution, and taking into account special populations with potentially prolonged elimination time such as hepatic impairment, all male patients taking pomalidomide must meet the following conditions:

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

• He understands 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, throughout treatment duration, during dose interruption and for 7 days after dose interruptions and/or cessation of treatment. This includes vasectomised males who should wear a condom if engaged in sexual activity with a pregnant woman or a woman of childbearing potential as seminal fluid may still contain pomalidomide in the absence of spermatozoa.

• He understands that if his female partner becomes pregnant whilst he is taking pomalidomide or 7 days after he has stopped taking pomalidomide, he should inform his treating physician immediately and that it is recommended to refer the female partner to a physician specialised or experienced in teratology for evaluation and advice.

Contraception

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

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

• Implant

• Levonorgestrel-releasing intrauterine system

• Medroxyprogesterone acetate depot

• Tubal sterilisation

• Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two negative semen analyses

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

Because of the increased risk of venous thromboembolism in patients with multiple myeloma taking pomalidomide and dexamethasone, 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 one of the effective methods listed above. The risk of venous thromboembolism continues for 4-6 weeks after discontinuing combined oral contraception. The efficacy of contraceptive steroids may be reduced during cotreatment with dexamethasone (see section 4.5).

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.

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

Pregnancy testing

According to local practice, medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/ml must be performed for women of childbearing potential as outlined below. This requirement includes women of childbearing potential who practice absolute and continuous abstinence. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same day. Dispensing of pomalidomide 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 during the consultation, when pomalidomide is prescribed, or in the 3 days prior to the visit to the prescriber 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 pomalidomide.

Follow-up and end of treatment

A medically supervised pregnancy test should be repeated at least every 4 weeks, including at least 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 3 days prior to the visit to the prescriber.

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.

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

Healthcare professionals and caregivers should wear disposable gloves when handling the blister or capsule. Women who are pregnant or suspect they may be pregnant should not handle the blister or capsule (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 health care professionals to reinforce the warnings about the expected teratogenicity of pomalidomide, to provide advice on contraception before therapy is started, and to provide guidance on the need for pregnancy testing. The prescriber must inform the patient about the 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 card and/or equivalent tool in accordance with the national implemented patient card system. A national controlled distribution system has been implemented in collaboration with each National Competent Authority. The controlled distribution system includes the use of a patient card and/or equivalent tool for prescribing and /or dispensing controls, and the collection of detailed data relating to the indication in order to monitor the off-label use within the national territory. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same day. Dispensing of pomalidomide 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 according to the approved indications dosing regimens (see section 4.2), and prescriptions for all other patients can be for a maximum duration of 12 weeks.

Haematological events

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

Thromboembolic events

Patients receiving pomalidomide either in combination with bortezomib and dexamethasone or in combination with dexamethasone have developed venous thromboembolic events (predominantly deep vein thrombosis and pulmonary embolism) and arterial thrombotic events (myocardial infarction and cerebrovascular 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 all modifiable risk factors (e.g. smoking, hypertension, and hyperlipidaemia). Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or leg swelling. Anti-coagulation therapy (unless contraindicated) is recommended, (such as acetylsalicylic acid, warfarin, heparin or clopidogrel), especially in patients with additional thrombotic risk factors. A decision to take prophylactic measures should be made after a careful assessment of the individual patient's underlying risk factors. In clinical studies, patients received prophylactic acetylsalicylic acid or alternative anti-thrombotic therapy. The use of erythropoietic agents carries a risk of thrombotic events including thromboembolism. Therefore, erythropoietic agents, as well as other agents that may increase the risk of thromboembolic events, should be used with caution.

Thyroid disorders

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

Peripheral neuropathy

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

Significant cardiac dysfunction

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

Tumour lysis syndrome

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 patients receiving pomalidomide (see section 4.8). Physicians should carefully evaluate patients before and during treatment using standard cancer screening for occurrence of second primary malignancies and institute treatment as indicated.

Allergic reactions and severe skin reactions

Angioedema, anaphylactic reaction and severe dermatologic reactions including SJS, TEN and DRESS have been reported with the use of pomalidomide (see section 4.8). Patients should be advised of the signs and symptoms of these reactions by their prescribers and should be told to seek medical attention immediately if they develop these symptoms. Pomalidomide must be discontinued for exfoliative or bullous rash, or if SJS, TEN or DRESS is suspected, and should not be resumed following discontinuation for these reactions. Patients with a prior history of serious allergic reactions associated with thalidomide or lenalidomide were excluded from clinical studies. Such patients may be at higher risk of hypersensitivity reactions and should not receive pomalidomide. Pomalidomide interruption or discontinuation should be considered for Grade 2-3 skin rash. Pomalidomide must be discontinued permanently for angioedema and anaphylactic reaction.

Dizziness and confusion

Dizziness and confusional state have been reported with pomalidomide. Patients must avoid situations where dizziness or confusion may be a problem and not to take other medicinal products that may cause 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 symptoms should be performed to exclude ILD. Pomalidomide should be interrupted pending investigation of these symptoms and if ILD is confirmed, appropriate treatment should be initiated. Pomalidomide should 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 patients treated with pomalidomide (see section 4.8). There have also been cases of hepatitis that resulted in discontinuation of pomalidomide. Regular monitoring of liver function is recommended for the first 6 months of treatment with pomalidomide and as clinically indicated thereafter.

Infections

Reactivation of hepatitis B has been reported rarely in patients receiving pomalidomide in combination with dexamethasone who have previously been infected with the hepatitis B virus (HBV). Some of these cases have progressed to acute hepatic failure, resulting in discontinuation of pomalidomide. Hepatitis B virus status should be established before initiating treatment with pomalidomide. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Caution should be exercised when pomalidomide in combination with dexamethasone is used in patients previously infected with HBV, including patients who are anti-HBc positive but HBsAg negative. These patients should be closely monitored for signs and symptoms of active HBV infection throughout therapy.

Progressive multifocal leukoencephalopathy (PML)

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

The evaluation for PML should be based on neurological examination, magnetic resonance imaging of the brain, and cerebrospinal fluid analysis for JC virus (JCV) DNA by polymerase chain reaction (PCR) or a brain biopsy with testing for JCV. A negative JCV PCR does not exclude PML. Additional follow-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 is confirmed, pomalidomide must be permanently discontinued.

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Effect of pomalidomide on other medicinal products

Pomalidomide is not anticipated to cause clinically relevant pharmacokinetic interactions due to P450 isoenzyme inhibition or induction or transporter inhibition when co-administered with substrates of these enzymes or transporters. The potential for such interactions, including the potential impact of pomalidomide on the pharmacokinetics of combined oral contraceptives, has not been evaluated clinically (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 inhibitor ketoconazole, or the strong CYP3A4/5 inducer carbamazepine, had no clinically relevant effect on exposure to pomalidomide. Co-administration of the strong CYP1A2 inhibitor fluvoxamine with pomalidomide 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 a second 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 by 125% with a 90% 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 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 multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone.

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

4.6. Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in males and females

Women of childbearing potential should use effective method of contraception. If pregnancy occurs in a woman treated with pomalidomide, treatment must be stopped and the patient should be referred to a physician specialised or experienced in teratology for evaluation and advice. If pregnancy occurs in a partner of a male patient taking pomalidomide, it is recommended to refer the female partner to a physician specialised or experienced in teratology for evaluation and advice. Pomalidomide is present in human semen. As a precaution, all male patients taking pomalidomide should use condoms throughout treatment duration, during dose interruption and for 7 days after cessation of treatment if their partner is pregnant or of childbearing potential and has no contraception (see sections 4.3 and 4.4).

Pregnancy

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

Breast-feeding

It is unknown whether pomalidomide is excreted in human milk. Pomalidomide was detected in milk of lactating rats following administration to the mother. Because of the potential for adverse reactions in 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 for the child and the benefit of the therapy for the woman.

Fertility

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 to pregnant rabbits (see section 5.3).

4.7. Effects on ability to drive and use machines

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 of pomalidomide. If affected, patients should be instructed not to drive cars, use machines or perform hazardous tasks while being treated with pomalidomide.

4.8. Undesirable effects

Summary of the safety profile

Pomalidomide in combination with bortezomib and dexamethasone

The most commonly reported blood and lymphatic system disorders were neutropenia (46.8%), thrombocytopenia (36.7%) and anaemia (28.4%). The most frequently reported adverse reaction was peripheral sensory neuropathy (47.8%). The most commonly reported Grade 3 or 4 adverse reactions were blood and lymphatic system disorders including neutropenia (41.7%), thrombocytopenia (27.3%) and anaemia (14.0%). The most commonly reported serious adverse reaction was pneumonia (11.5%). Other serious adverse reactions reported included pyrexia (4.0%), lower respiratory tract infection (2.9%), pulmonary embolism (2.9%), influenza (2.9%), and acute kidney injury (2.9%).

Pomalidomide in combination with dexamethasone

The most commonly reported adverse reactions in clinical studies have been blood and lymphatic system disorders including anaemia (45.7%), neutropenia (45.3%) and thrombocytopenia (27%); in general disorders and administration site conditions including fatigue (28.3%), pyrexia (21%) and oedema peripheral (13%); and in infections and infestations including pneumonia (10.7%). Peripheral neuropathy 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 4 adverse 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 was pneumonia (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 with pomalidomide.

Tabulated list of adverse reactions

The adverse reactions observed in patients treated with pomalidomide in combination with bortezomib and dexamethasone, pomalidomide in combination with dexamethasone and from post-marketing surveillance are listed in table 7 by system organ class (SOC) and frequency for all adverse reactions and 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 be determined).

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

Combination of treatment

Pomalidomide/ bortezomib/dexamethasone

Pomalidomide/ dexamethasone

System Organ Class /Preferred term

All ADRs

Grade 3−4

ADRs

All ADRs

Grade 3−4

ADRs

Infections and infestations

Pneumonia

Very common

Very common

-

-

Pneumonia (bacterial, viral and fungal infections, including opportunistic infections)

-

-

Very common

Common

Bronchitis

Very common

Common

Common

Uncommon

Upper respiratory tract infection

Very common

Common

Common

Common

Viral upper respiratory tract infection

Very common

-

-

-

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 infection

Common

Common

-

-

Lung infection

Very Common

Common

-

-

Influenza

Common

Common

-

-

Bronchiolitis

Common

Common

-

-

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 skin

-

-

Uncommon

Uncommon

Squamous cell carcinoma of the skin

-

-

Uncommon

Uncommon

Blood and lymphatic system disorders

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*

Immune system disorders

Angioedema

-

-

Common*

Uncommon*

Urticaria

-

-

Common*

Uncommon*

Anaphylactic reaction

Not known*

Not known*

-

-

Solid organ transplant rejection

Not known*

-

-

-

Endocrine disorders

Hypothyroidism

Uncommon*

-

-

-

Metabolism and nutrition disorders

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*

Psychiatric disorders

Insomnia

Very common

Common

-

-

Depression

Common

Common

-

-

Confusional state

-

-

Common

Common

Nervous system disorders

Peripheral sensory neuropathy

Very common

Common

Common

Uncommon

Dizziness

Very common

Uncommon

Common

Uncommon

Tremor

Very common

Uncommon

Common

Uncommon

Syncope

Common

Common

-

-

Peripheral sensorimotor neuropathy

Common

Common

-

-

Paraesthesia

Common

-

-

-

Dysgeusia

Common

-

-

-

Depressed level of consciousness

-

-

Common

Common

Intracranial haemorrhage

-

-

Common*

Uncommon*

Cerebrovascular accident

-

-

Uncommon*

Uncommon*

Eye disorders

Cataract

Common

Common

-

-

Ear and labyrinth disorders

Vertigo

-

-

Common

Common

Cardiac disorders

Atrial fibrillation

Common

Common

Common*

Common*

Cardiac failure

-

-

Common*

Common*

Myocardial infarction

-

-

Common*

Uncommon*

Vascular disorders

Deep vein thrombosis

Common

Uncommon

Common

Uncommon

Hypotension

Common

Common

-

-

Hypertension

Common

Common

-

-

Respiratory, thoracic and mediastinal disorders

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*

Gastrointestinal disorders

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

-

-

Abdominal pain upper

Common

Uncommon

-

-

Stomatitis

Common

Uncommon

-

-

Dry mouth

Common

-

-

-

Abdominal distension

Common

Uncommon

-

-

Gastrointestinal haemorrhage

-

-

Common

Uncommon

Hepatobiliary disorders

Hyperbilirubinaemia

-

-

Uncommon

Uncommon

Hepatitis

-

-

Uncommon*

-

Skin and subcutaneous tissue disorders

Rash

Common

Common

Common

Common

Pruritus

-

-

Common

-

Drug Reaction with Eosinophilia and Systemic Symptoms

-

-

Not known*

Not known*

Toxic Epidermal Necrolysis

-

-

Not known*

Not known*

Stevens-Johnson Syndrome

-

-

Not known*

Not known*

Musculoskeletal and connective tissue disorders

Muscular weakness

Very common

Common

-

-

Back pain

Very common

Common

-

-

Bone pain

Common

Uncommon

Very common

Common

Muscle spasms

Very Common

-

Very common

Uncommon

Renal and urinary disorders

Acute kidney injury

Common

Common

-

-

Chronic kidney injury

Common

Common

-

-

Urinary retention

Common

Common

Common

Uncommon

Renal failure

-

-

Common

Common

Reproductive system and breast disorders

Pelvic pain

-

-

Common

Common

General disorders and administration site conditions

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

-

-

Investigations

Alanine aminotransferase increased

Common

Common

Common

Common

Weight decreased

Common

Common

Neutrophil count decreased

-

-

Common

Common

White blood cell count decreased

-

-

Common

Common

Platelet count decreased

-

-

Common

Common

Blood uric acid increased

-

-

Common*

Uncommon*

Injury, poisoning and procedural complications

Fall

Common

Common

-

-

* Reported during post-marketing use.

Description of selected adverse reactions

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

Teratogenicity

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

Neutropenia and thrombocytopenia

Neutropenia occurred in up to 54% (Pom+Btz+Dex) of patients [47.1% (Pom+Btz+Dex) Grade 3 or 4]. Neutropenia did not lead to pomalidomide discontinuation in 0.7% of any patient and was infrequently serious.

Febrile neutropenia (FN) was reported in 3.2% (Pom+Btz+Dex) and 6.7% (Pom+Dex) of patients and was serious in 1.8% (Pom+Btz+Dex) and 4.0% (Pom+Dex) of patients (see sections 4.2 and 4.4).

Thrombocytopenia occurred in 39.0% (Pom+Btz+Dex) and 27.7% (Pom +Dex) of patients. Thrombocytopenia was Grade 3 or 4 in 28.1% (Pom+Btz+Dex) 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) of patients (see sections 4.2 and 4.4).

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

Infection

Infection was the most common non haematological toxicity.

Infection occurred in 83.1% (Pom+Btz+Dex) and 55.0% (Pom +Dex) of patients [34.9% (Pom+Btz+Dex) and 24.0% (Pom +Dex) Grade 3 or 4]. Upper respiratory tract infection and pneumonia were the most frequently occurring infections. Fatal infections (Grade 5) occurred in 4% (Pom+Btz+Dex) patients and 2.0% (Pom +Dex) of patients. Infections led to pomalidomide discontinuation in 3.6% (Pom+Btz+Dex) and 2.0% (Pom +Dex) of patients.

Thromboembolic events

Prophylaxis with acetylsalicylic acid (and other anticoagulants in high risk patients) was mandatory for 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) of patients (5.8 % (Pom+Btz+Dex) and (1.3% (Pom +Dex) Grade 3 or 4). VTE was reported as serious in 4.7% (Pom+Btz+Dex) and 1.7% (Pom +Dex) of patients, no fatal reactions were reported, and VTE was associated 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 to randomisation 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 at baseline. Peripheral neuropathy led to discontinuation of bortezomib in approximately 14.4% of patients, pomalidomide in 1.8% and dexamethasone in 1.8% of patients in the Pom+Btz+Dex arm and 8.9% 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. Peripheral neuropathy occurred in 12.3% of patients (1.0% Grade 3 or 4). No peripheral neuropathy reactions were reported as serious, and peripheral neuropathy led to dose discontinuation in 0.3% of patients (see section 4.4).

Haemorrhage

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

Allergic reactions and severe skin reactions

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

Paediatric population

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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

In the event of overdose, supportive care is advised.