Imnovid 1mg, 2 mg, 3mg, 4mg Hard capsules

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

IMNOVID in combination with dexamethasone (Pd) 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 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.

In combination with Bortezomib and Dexamethasone (PBd) - patients with relapsed or refractory multiple myeloma after at least one prior therapy including lenalidomide:

Recommended dosage: The recommended starting dose of IMNOVID is: 4 mg orally once daily on days 1-14 for each 21-day cycle.

The recommended dose of bortezomib is: For cycles 1-8: 1.3mg/m2 on Days 1, 4, 8 and 11 of a 21-day cycle. From cycle 9 onwards: 1.3mg/m2 on Days 1 and 8 of a 21-day cycle.

The recommended dose of dexamethasone is: For cycles 1-8: 20 mg orally once daily on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle. From cycle 9 onwards: 20 mg orally once daily on days 1, 2, 8, and 9 of a 21-day cycle.

For patients greater than 75 years of age, see section below. Dosing is continued or modified based upon clinical and laboratory findings. Treatment should be discontinued upon progression of disease.

In combination with Dexamethasone (Pd) u2013 patients with relapsed and refractory multiple myeloma after at least two prior therapies including lenalidomide and a proteasome inhibitor:

Recommended dosage: The recommended starting dose of 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.

• Hypersensitivity to IMNOVID (pomalidomide) or to any of the excipients.
• Pregnancy and lactation (see section 4.6 Fertility, pregnancy and lactation)
• Females of childbearing potential, unless all the conditions of the pregnancy prevention programme are met (see section 4.4 Special warnings and precautions for use)
• Male patients unable to follow or comply with the required contraceptive measures (see section 4.4 Special warnings and precautions for use)

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 IMNOVID is taken during pregnancy, a teratogenic effect of pomalidomide in humans is expected.

The conditions of the Key Assist Risk Management Programme must be fulfilled for all patients unless there is reliable evidence that the patient does not have childbearing potential.

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

• Age u2265 50 years and naturally amenorrhoeic for u2265 2 years.
• Premature ovarian failure confirmed by a specialist gynaecologist.
• Previous bilateral salpingo-oophorectomy, or hysterectomy.
• XY genotype, Turner syndrome, uterine agenesis.

*Amenorrhoea following cancer therapy or during breast-feeding does not rule out childbearing potential.

Counselling For females of childbearing potential, IMNOVID is contraindicated unless all of the following are met:

• She understands the expected teratogenic risk to the unborn child.
• She understands the need for effective contraception, without interruption, 4 weeks before starting treatment, throughout the entire duration of treatment including dose interruptions, and for 4 weeks after the end of treatment.
• Even if a female 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 IMNOVID is dispensed following a negative pregnancy test.
• She understands the need and accepts to undergo pregnancy testing every 4 weeks except in case of confirmed tubal sterilization.
• She acknowledges that she understands the hazards and necessary precautions associated with the use of IMNOVID.

The prescriber must ensure that for females of childbearing potential:

• The patient complies with the conditions of the Key Assist Risk Management Programme, including confirmation that she has an adequate level of understanding.
• The patient has acknowledged the aforementioned conditions.

For male patients taking IMNOVID, pharmacokinetic data has demonstrated that pomalidomide is present in human semen. As a precaution, all male patients taking IMNOVID must meet the following conditions:

• He understands the expected teratogenic risk if engaged in sexual activity with a pregnant female or a female of childbearing potential.
• 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.
• He understands that if his female partner becomes pregnant whilst he is taking IMNOVID or for 4 weeks after he has stopped taking IMNOVID, 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 IMNOVID therapy unless the patient commits to absolute and continuous abstinence confirmed on a monthly basis. If not established on effective contraception, the patient must be referred to an appropriately trained health care professional for contraceptive advice in order that contraception can be initiated.

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

Highly effective methods

• Intra Uterine Device (IUD).
• Hormonal (hormonal implants, levonorgestrel-releasing intrauterine system (IUS)), medroxyprogesterone acetate depot injections, ovulation inhibitory progesterone-only pills (e.g. desogestrel).
• Tubal ligation.
• Partneru2019s vasectomy.

Effective methods

• Male condom.
• Diaphragm.
• Cervical cap.

Because there is an increased risk of venous thromboembolism (VTE) in patients taking combined oral contraceptive pills, medical practitioners should discuss the risk/benefit of contraceptive methods with their patients.

Pregnancy testing According to local practice, medically supervised pregnancy tests with a minimum sensitivity of 50 mIU/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 IMNOVID 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 IMNOVID 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 IMNOVID.

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 IMNOVID, 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 IMNOVID.

Additional precautions Patients should be instructed never to give IMNOVID 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 IMNOVID.

Educational materials In order to assist patients in avoiding foetal exposure to pomalidomide, Key Oncologics will provide educational material to healthcare professionals to reinforce the warnings about the expected teratogenicity of IMNOVID, to provide advice on contraception before therapy is started, and to provide guidance on the need for pregnancy testing. Full patient information about the expected teratogenic risk and the strict pregnancy prevention measures as specified in the Key Assist Risk Management Programme should be given by the medical practitioner to females of childbearing potential and, as appropriate, to male patients.

Effect of IMNOVID on other medicines IMNOVID 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 IMNOVID on exposure of oral contraceptives, has not been evaluated clinically.

Effect of other medicines on IMNOVID 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 exposure to pomalidomide by 104 % with a 90 % confidence interval [88 % to 122 %] 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 156 %] compared to pomalidomide alone.

If strong inhibitors of CYP1A2 are co-administered with pomalidomide, reduce the pomalidomide dose either by 50 % for patients with multiple myeloma (based on the recommended starting doses) (see Section 4.2).

Dexamethasone Co-administration of multiple doses of 4 mg IMNOVID 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 IMNOVID, 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 IMNOVID, 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 IMNOVID 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 section 4.4 Special warnings and precautions for use)

Pregnancy IMNOVID is contraindicated during pregnancy and in women of childbearing potential (see section 4.3 Contraindications) 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 IMNOVID. Pomalidomide was detected in milk of lactating rats following administration to the mother.

IMNOVID 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 PBd Treatment Regimen - Pomalidomide Adverse Drug Reactions (ADRs) in Relapsed and Refractory Multiple Myeloma Clinical Trial (MM-007) u2013 After at least one prior therapy including lenalidomide: The adverse drug reactions (ADRs) observed in patients treated with pomalidomide/bortezomib dexamethasone (PBd) are listed below by system organ class and frequency for all ADRs, grade 3/4 ADRs and serious ADRs. The ADRs in this section have been assessed as being at least possibly related to pomalidomide when used in combination with low-dose dexamethasone and bortezomib and are presented in accordance with the CIOMS Working Groups III and V guidance document, with frequency categories defined as: very common (u2265 1/10), common (u2265 1/100 to < 1/10); and uncommon (u2265 1/1 000 to < 1/100).

Considerations for determining an ADR included: biological/pharmacological plausibility for a drug-event relationship, known morbidities of target population and disease being treated, adverse reactions suspected with drugs of this class, and weight of evidence (e.g., positive rechallenge, positive dechallenge, time to onset, lack of confounding factors). Additionally, medical judgment was applied to determine exceptions for inclusion and exclusion, as necessary.

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