Pomalidomide 1 Mg/2 Mg/3 Mg/4 Mg Capsules

POMALIDOMIDE FORRESTER in combination with dexamethasone is indicated for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least two prior treatment regimens, including both lenalidomide and a proteasome inhibitor (e.g. bortezomib), and have demonstrated disease progression on the last therapy.

Posology
Treatment must be initiated and monitored under the supervision of medical practitioner experienced in the management of multiple myeloma.
Dosage: The recommended starting dose of POMALIDOMIDE FORRESTER is 4 mg/day taken orally on Days 1-21 of repeated 28-day cycles (21/28 days) until disease progression. The recommended dose of dexamethasone is 40 mg/day on Days 1, 8, 15 and 22 of each 28-day treatment cycle. Dosing is continued or modified based upon clinical and laboratory findings.
POMALIDOMIDE FORRESTER dose modification or interruption: Instructions for dose interruptions and reductions for POMALIDOMIDE FORRESTER related to haematologic adverse reactions are outlined in the table below:
Dose modification instructions for POMALIDOMIDE FORRESTER for haematologic toxicities:
Toxicity
Dose modification
Neutropenia
u2022 ANC < 500/u03bcL or Febrile neutropenia (fever u2265 38,5. u00b0C and ANC <1 ,000/u03bcL)
u2022 ANC return to u2265 500/u03bcL
u2022 For each subsequent drop < 500/u03bcL
u2022 Return to u2265 500/u03bcL
Interrupt POMALIDOMIDE FORRESTER treatment, follow CBC weekly. Add G-CSF (at the discretion of the treating medical practitioner). Resume POMALIDOMIDE FORRESTER at 3 mg daily.
Interrupt POMALIDOMIDE FORRESTER treatment. Resume POMALIDOMIDE FORRESTER at 1 mg less than the previous dose.
Thrombocytopenia
u2022 Platelets < 25 000/u03bcL
u2022 Platelets return to > 50 000/u03bcL
u2022 For each subsequent drop < 25 000/u03bcL
Interrupt POMALIDOMIDE FORRESTER treatment, follow CBC weekly. Resume POMALIDOMIDE FORRESTER treatment at 3 mg daily.
Interrupt POMALIDOMIDE FORRESTER treatment. Resume POMALIDOMIDE FORRESTER at 1 mg less than the previous dose.
*ANC u2013 Absolute Neutrophil Count; ** CBC u2013 Complete Blood Count
To initiate a new cycle of POMALIDOMIDE FORRESTER the neutrophil count must be u2265 500/u03bcL, the platelet count must be u2265 50 000/u03bcL. For other Grade 3/4 toxicities judged to be related to POMALIDOMIDE FORRESTER, stop treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to u2264 Grade 2 at the medical practitioner's discretion. If toxicities occur after dose reductions to 1 mg, then the medicine should be discontinued.
Dexamethasone dose modification instructions:
Dexamethasone dose reduction levels:
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 u2265 Grade 3
Interrupt dose until symptoms are controlled. Add H2 blocker or equivalent and decrease one dose level when dose restarted.
Oedema u2265 Grade 3
Use diuretics as needed and decrease dose by one dose level.
Confusion or mood alteration u2265 Grade 2
Interrupt dose until symptoms resolve. When dose restarted decrease dose by one dose level.
Muscle weakness u2265 Grade 2
Interrupt dose until muscle weakness u2264 Grade 1. Restart with dose decreased by one level.
Hyperglycaemia u2265 Grade 3
Decrease dose by one dose level. Treat with insulin or oral hypoglycaemic agents as needed.
Acute pancreatitis
Discontinue patient from dexamethasone treatment regimen.
Other u2265 Grade 3 dexamethasone-related adverse events
Stop dexamethasone dosing until adverse event resolves to u2264 Grade 2. Resume with dose reduced by one level.
Dose reduction levels (u2264 75 years of age): Starting dose 40 mg; dose level -1 20 mg; dose level -2 10 mg on Days 1, 8, 15 and 22 of each 28-day treatment cycle.
Dose reduction levels (> 75 years of age): Starting dose 20 mg; dose level -1 12 mg; dose level -2 8 mg on Days 1, 8, 15 and 22 of each 28-day treatment cycle.
If recovery from toxicities is prolonged beyond 14 days, then the dose of dexamethasone will be decreased by one dose level.
Special populations
Elderly population
No dose adjustment is required for POMALIDOMIDE FORRESTER. 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 treatment cycle.
Renal impairment
A study in subjects with renal impairment has not been conducted with POMALIDOMIDE FORRESTER. Patients with moderate or severe renal impairment (creatinine clearance < 45 mL/min) were excluded from clinical studies. Patients with renal impairment should be carefully monitored for adverse reactions. POMALIDOMIDE FORRESTER should be avoided in patients with severe renal impairment (creatinine clearance < 30 mL/min/1,75 m2) and in patients with a serum creatinine concentration greater than 3,0 mg/dL.
Hepatic impairment
A study in subject with hepatic impairment has not been conducted with POMALIDOMIDE FORRESTER. Patients with serum total bilirubin > 2,0 mg/dL were excluded from clinical studies. POMALIDOMIDE FORRESTER should be avoided in patients with serum bilirubin greater than 2,0 mg/dL and AST or ALT greater than 3,0 mg/dL x ULN.
Paediatric population:
No data are available on administration of POMALIDOMIDE FORRESTER to paediatric or adolescent subjects (< 18 years of age).
Method of administration: Oral use. POMALIDOMIDE FORRESTER should be taken at the same time each day. The capsules should not be opened, broken or chewed. This medicine should be swallowed, preferably with water, with or without food.

• Hypersensitivity to POMALIDOMIDE FORRESTER (pomalidomide) or to any of the excipients listed in section 6.1.
• Pregnancy and lactation (see section 4.6)
• Females of childbearing potential, unless all the conditions of the pregnancy prevention programme are met (see section 4.4)
• Male patients unable to follow or comply with the required contraceptive measures (see section 4.4).

General: Pregnancy warning: Pomalidomide is a thalidomide analogue. 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. If POMALIDOMIDE FORRESTER is taken during pregnancy, a teratogenic effect of pomalidomide in humans is expected. The conditions of the Active Risk Management Program 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 female partner of a male patient is considered to have childbearing potential unless she meets at least one of the following criteria:
u2022 Age u2265 50 years and naturally amenorrhoeic for u2265 1 year*.
u2022 Premature ovarian failure confirmed by a specialist gynaecologist.
u2022 Previous bilateral salpingo-oophorectomy, or hysterectomy.
u2022 XY genotype, Turner syndrome, uterine agenesis.
* Amenorrhoea following cancer therapy or during breastfeeding does not rule out childbearing potential.
Counselling: For women of childbearing potential, POMALIDOMIDE FORRESTER is contraindicated unless all the following are met:
u2022 She understands the expected teratogenic risk to the unborn child.
u2022 She understands the need for effective contraception, without interruption, 4 weeks before starting treatment, throughout the entire duration of treatment including dose interruptions, and for 4 weeks after the end of treatment.
u2022 Even if a female of childbearing potential has amenorrhea she must follow all the advice on effective contraception.
u2022 She should be capable of complying with effective contraceptive measures.
u2022 She is informed and understands the potential consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy.
u2022 She understands the need to commence the treatment as soon as POMALIDOMIDE FORRESTER is dispensed following a negative pregnancy test.
u2022 She understands the need and accepts to undergo pregnancy testing every 4 weeks except in case of confirmed tubal sterilisation.
u2022 She acknowledges that she understands the hazards and necessary precautions associated with the use of POMALIDOMIDE FORRESTER.
The prescriber must ensure that for females of childbearing potential:
u2022 The patient complies with the conditions of the Active Risk Management Program, including confirmation that she has an adequate level of understanding.
u2022 The patients has acknowledged the aforementioned conditions.
For male patients taking POMALIDOMIDE FORRESTER, pharmacokinetic data has demonstrated that pomalidomide is present in human semen. As a precaution, all male patients taking POMALIDOMIDE FORRESTER must meet the following conditions:
u2022 He understands the expected teratogenic risk if engaged in sexual activity with a pregnant female or a female of childbearing potential.
u2022 He understands the need for the use of a condom if engaged in sexual activity with a pregnant female or a female of childbearing potential not using effective contraception, during treatment and for 4 weeks after dose interruptions and/or cessation of treatment. Vasectomised males should wear a condom if engaged in sexual activity with a pregnant female as seminal fluid may still contain pomalidomide in the absence of spermatozoa.
u2022 He understands that if his female partner becomes pregnant whilst he is taking POMALIDOMIDE FORRESTER or for 4 weeks after he has stopped taking POMALIDOMIDE FORRESTER, he should inform his treating medical practitioner immediately and that it is recommended to refer the female partner to a medical practitioner specialised or experienced in teratology for evaluation and advice.
Contraception: Females of childbearing potential must use two reliable methods of contraception for 4 weeks before therapy, during therapy including dose interruptions, and until 4 weeks after POMALIDOMIDE FORRESTER therapy unless the patient commits to absolute and continuous abstinence confirmed on a monthly basis. If not established on effective contraception, the patient must be referred to an appropriately trained health care professional for contraceptive advice in order that contraception can be initiated. The following can be considered to be examples of suitable methods of contraception:
Highly effective methods:
u2022 Intra-Uterine Device (IUD);
u2022 Hormonal (hormonal implants, levonorgestrel-releasing intrauterine system (IUS)), medroxyprogesterone acetate depot injections, ovulation inhibitory progesterone-only pills (e.g. desogestrel);
u2022 Tubal ligation;
u2022 Partneru2019s vasectomy.
Effective methods:
u2022 Male condom;
u2022 Diaphragm;
u2022 Cervical cap.
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 co-treatment 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 50 IU/mL must be performed for females of childbearing potential as outlined below. This requirement includes females 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 FORRESTER to females of childbearing potential should occur within 7 days of the last pregnancy test.
Prior to starting treatment: A medically supervised pregnancy test should be performed within 7 days prior to the patient starting POMALIDOMIDE FORRESTER 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 FORRESTER.
Follow-up and end of treatment: A medically supervised pregnancy test should be repeated every 4 weeks, including 4 weeks after the end of treatment, except in the case of confirmed tubal sterilisation. These pregnancy tests should be performed on the day of the prescribing visit or within the 7 days prior to the visit to the prescriber.
Men: Pomalidomide is present in human semen during treatment. As a precaution, and taking into account special populations with potentially prolonged elimination time such as renal impairment, all male patients taking POMALIDOMIDE FORRESTER, including those who have had a vasectomy, should use condoms throughout treatment duration, during dose interruption and for 4 weeks after cessation of treatment if their partner is pregnant or of childbearing potential and has no contraception. Male patients should not donate semen or sperm during treatment (including during dose interruptions) and for 4 weeks following discontinuation of POMALIDOMIDE FORRESTER.
Additional precautions: Patients should be instructed never to give POMALIDOMIDE FORRESTER to another person and to return any unused capsules to their pharmacist at the end of treatment. Patients should not donate blood during therapy including dose interruptions and for 4 weeks following discontinuation of POMALIDOMIDE FORRESTER. 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: In order to assist patients in avoiding fetal exposure to pomalidomide, educational material will be provided to healthcare providers to reinforce the warnings about the expected teratogenicity of POMALIDOMIDE FORRESTER, to provide advice on contraception before therapy is started, and to provide guidance on the need for pregnancy testing. Full patient information about the expected teratogenic risk and the strict pregnancy prevention measures as specified in the Active Risk Management Program should be given by the medical practitioner to females of childbearing potential and, as appropriate, to male patients. Ideally, pregnancy testing, issuing a prescription and dispensing should occur on the same day. Dispensing of 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.

Effect of POMALIDOMIDE FORRESTER on other medicines: POMALIDOMIDE FORRESTER does not cause clinically relevant enzyme 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 FORRESTER on exposure of oral contraceptives, has not been evaluated clinically.
Effect of other medicines on POMALIDOMIDE FORRESTER: Pomalidomide is partly metabolised by CYP1 A2 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 exposure to pomalidomide by 104 % with a 90 % confidence interval [88 % to 122 %] compared to pomalidomide plus ketoconazole. 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 FORRESTER, patients should be closely monitored for the occurrence of side effects.
Dexamethasone: Co-administration of multiple doses of 4 mg POMALIDOMIDE FORRESTER 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. Dexamethasone is a weak to moderate enzyme inducer and its effect on warfarin is unknown. Close monitoring of warfarin concentration is advised during treatment.

Women of childbearing potential/Contraception in males and females: Females of childbearing potential should use two effective methods of contraception. If pregnancy occurs in a female treated with POMALIDOMIDE FORRESTER, treatment must be stopped and the patient should be referred to a medical practitioner specialised or experienced in teratology for evaluation and advice. If pregnancy occurs in a partner of a male patient taking POMALIDOMIDE FORRESTER, it is recommended to refer the female partner to a medical practitioner specialised or experienced in teratology for evaluation and advice.
Pomalidomide is present in human semen. As a precaution, all male patients taking POMALIDOMIDE FORRESTER should use condoms throughout treatment duration, during dose interruption and for 4 weeks after cessation of treatment if their partner is pregnant or of childbearing potential and has no contraception (see sections 4.3 and 4.4).
Pregnancy: POMALIDOMIDE FORRESTER is contraindicated during pregnancy and in women of childbearing potential (see section 4.3). Pomalidomide was found to be teratogenic in embryo-foetal development toxicity studies in rats and rabbits. Pomalidomide crosses the placenta and was detected in foetal blood following administration to pregnant rabbits.
Breastfeeding: Breastfeeding of infants is contraindicated in mothers taking POMALIDOMIDE FORRESTER. Pomalidomide was detected in milk of lactating rats following administration to the mother.
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.

POMALIDOMIDE FORRESTER may cause confusion, fatigue, depressed level of consciousness and dizziness and affect mental and/or physical abilities to perform or execute tasks or activities requiring mental alertness, judgment and/or sound coordination and vision.

a. Summary of the safety profile
The frequently reported adverse reactions have been blood and lymphatic system disorders including anaemia, neutropenia and thrombocytopenia; in general disorders and administration site conditions including fatigue, pyrexia and peripheral oedema; and in infections and infestations including pneumonia. Peripheral neuropathy and venous embolic or thrombotic (VTE) adverse reactions were also reported. The frequently reported serious adverse reaction was pneumonia. Other serious adverse reactions reported included febrile neutropenia, neutropenia, thrombocytopenia and VTE adverse reactions.
System Organ Class: Frequency: Side effects
Infections and Infestations Frequent Frequency unknown Pneumonia (bacterial, viral and fungal infections, including opportunistic infections), neutropenic sepsis, septic shock, Clostridium difficile colitis, influenza, bronchiolitis, urinary tract infection, bronchopneumonia, bronchitis respiratory tract infection, upper respiratory tract infections, nasopharyngitis, herpes zoster Hepatitis B reactivation
Neoplasms benign, malignant and unspecified (including cysts and polyps) Less frequent Basal cell carcinoma of the skin, squamous cell carcinoma of the skin
Blood and lymphatic system disorders Frequent Neutropenia, thrombocytopenia, leucopenia, anaemia, febrile neutropenia, pancytopenia*
Immune system disorders Frequent Angioedema*, urticaria*
Metabolism and nutrition disorders Frequent Less frequent Decreased appetite, hyperkalaemia, hyponatraemia, hyperuricaemia*, hypokalaemia, hyperglycaemia, hypomagnaesaemia, hypocalcaemia, hypophosphataemia, hypercalcaemia Tumour lysis syndrome*
Psychiatric disorders Frequent Confusional state, insomnia, depression
Nervous system disorders Frequent Less frequent Depressed level of consciousness, peripheral sensory neuropathy, dizziness, tremor, intracranial haemorrhage*, paraesthesia, dysgeusia, syncope Cerebrovascular accident*
Ear and labyrinth disorders Frequent Vertigo
Eye disorders Frequent Cataract
Vascular disorders Frequent Deep vein thrombosis, hypotension, hypertension
Cardiac disorders Frequent Cardia failure*, atrial fibrillation*, myocardial infarction*
Respiratory, thoracic and mediastinal disorders Frequent Less frequent Dyspnoea, cough, pulmonary embolism, epistaxis*, interstitial lung disease* Pulmonary hypertension
Gastrointestinal disorders Frequent Diarrhoea, nausea, constipation, vomiting, gastrointestinal haemorrhage, abdominal pain, stomatitis, dry mouth, abdominal distension
Hepato-biliary disorders Less frequent Hyperbilirubinaemia, hepatitis*
Skin and subcutaneous tissue disorders Frequent Frequency unknown Rash, pruritus Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Toxic Epidermal Necrolysis, Stevens-Johnson Syndrome
Musculoskeletal, and connective tissue disorders Frequent Bone pain, muscle spasms, muscular weakness, back pain
Renal and urinary disorders Frequent Renal failure, urinary retention, acute kidney injury, chronic kidney injury
Reproductive system and breast disorders Frequent Pelvic pain
General disorders and administration site conditions Frequent Fatigue, pyrexia, peripheral oedema, non-cardiac chest pain
Investigations Frequent Decreased neutrophil count, decreased white blood cell count, decreased platelet count, increased alanine aminotransferase, increased blood uric acid*
Injury, poisoning and procedural complications Frequent Fall
* Identified from post marketing data.
Reporting of suspected adverse reactions: Reporting of suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

Adverse events will be an exaggeration of the side effects (see section 4.8). Treatment should be symptomatic and supportive. It is unknown whether pomalidomide or its metabolites are dialysable.