Ixazomib

Registered South African indications:

• Recurrent or relapsed multiple myeloma

Contraindications 

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

• Pregnancy
• Breastfeeding
• Severe renal impairment (CrCl <30ml/min) or ESRD (including haemodialysis)
• Moderate to severe hepatic impairment
  - Hepatoxicity
• Elderly
• Pre-existing gastrointestinal toxicities
• Pre-existing peripheral neuropathy
• Pre-existing peripheral oedema
• Cutaneous reactions
• Coadministration with strong CYP3A inducers
• Coadministration with oral contraceptives (See additional prescribing points)
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: cap

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Used for the treatment of

• Multiple myeloma (Additional agents required) 
  - In combination with lenalidomide and dexamethasone for the treatment of patients who have received at least one prior therapy

Consult specialist for dosages and regimens

South African manufacturer recommendations

Used for the treatment of

• Recurrent or relapsed multiple myeloma (Additional agents required) 
  - In combination with lenalidomide and dexamethasone for the treatment of patients who have received at least one prior therapy

Consult specialist for dosages and regimens

Not established for use in children below 18 years

Pregnancy

• Caution; not recommended
• Ixazomib is not recommended during pregnancy as it can cause foetal harm when administered to a pregnant woman. Therefore, women should avoid becoming pregnant while being treated with ixazomib
• There are no data for the use of ixazomib in pregnant women. Studies in animals have shown reproductive toxicity
• Ixazomib is given in combination with lenalidomide. Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. If lenalidomide is taken during pregnancy, a teratogenic effect in humans is expected. The conditions of the Pregnancy Prevention Programme for lenalidomide must be fulfilled for all patients unless there is reliable evidence that the patient does not have childbearing potential
• Male and female patients who are able to have children must use effective contraceptive measures during and for 90 days following treatment. Ixazomib is not recommended in women of childbearing potential not using contraception
• When ixazomib is administered together with dexamethasone, which is known to be a weak to moderate inducer of CYP3A4 as well as other enzymes and transporters, the risk for reduced efficacy of oral contraceptives needs to be considered. Therefore, women using oral hormonal contraceptives should additionally use a barrier method of contraception

Breastfeeding

• Caution; not recommended
• It is unknown whether ixazomib or its metabolites are excreted in human milk. No animal data are available. A risk to newborns/ infants cannot be excluded and therefore breastfeeding should be discontinued
• Ixazomib will be given in combination with lenalidomide and breastfeeding should be stopped because of the use of lenalidomide

Fertility

• Fertility studies have not been conducted with ixazomib

Renal Impairment

• Mild to moderate (CrCl ≥30ml/min): No dose adjustment recommended
• Severe (CrCl <30 ml/min) or ESRD (including haemodialysis): Caution; dose adjustment required
  The reduced dose of 3mg is recommended
  Ixazomib is not dialysable and, therefore, can be administered without regard to the timing of dialysis 

Hepatic Impairment

• Mild: No dose adjustment recommended 
• Moderate to severe: Caution; dose adjustment recommended
  The reduced dose of 3mg is recommended in patients with moderate (total bilirubin >1.5-3 x ULN) or severe (total bilirubin >3 x ULN) hepatic impairment  

Elderly

• Caution; no dose adjustment recommended
  Discontinuations in patients >75 years of age were reported in 13 patients (28%) in the ixazomib regimen and 10 patients (16%) in the placebo regimen. Cardiac arrhythmias in patients >75 years of age were observed in 10 patients (21%) in the ixazomib regimen and 9 patients (15%) in the placebo regimen

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Peripheral neuropathies
• Posterior reversible encephalopathy disorders
• Transverse myelitis
• Fatigue

Cardiovascular Disorders

• Hypotension
• Heart failure
• Arrhythmia

Respiratory Disorders

• Upper respiratory tract infection
• Fungal and viral pneumonia 

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Constipation

Hepatobiliary Disorders

• Hepatic impairment, including enzyme changes

Endocrine and Metabolic Disorders

• Tumour lysis syndrome
• Hypokalaemia
• Decreased appetite 

Musculoskeletal Disorders

• Back pain

Skin and Subcutaneous Tissue Disorders

• Rash
  - Macular rash
  - Maculopapular rash
• Stevens-Johnson syndrome
• Acute febrile neutrophilic dermatosis

Immune, Blood and Lymphatic System Disorders

• Herpes zoster
• Thrombocytopenia
• Neutropenia
• Thrombotic microangiopathy
• Thrombotic thrombocytopenic purpura
• Peripheral oedema

Sensory Disorders

• Eye disorders
• Blurred vision 
• Dry eye
• Conjunctivitis
• Cataract 

• CYP3A inducers
• Carbamazepine
• Phenytoin
• Rifampicin
• Oral hormonal contraceptives

Other interactions

• St. John's Wort (Hypericum perforatum)

• Full blood count (with differential)
• Platelet count
• Renal function
• Hepatic function

Some cases may require

• Pregnancy test
• Hepatitis B screening
  - Hepatitis B surface antigen
  - Hepatitis B core antibody
  - Total Ig or IgG and antibody to hepatitis B surface antigen

Additional observations

• Signs and symptoms of:
  - Gastrointestinal toxicity
  - Dermatologic toxicity
  - Peripheral neuropathy
  - Peripheral oedema
  - Thrombotic microangiopathy

Method of administration

• Ixazomib should be taken at approximately the same time on days 1, 8, and 15 of each treatment cycle at least 1 hour before or at least 2 hours after food
• The capsule should be swallowed whole with water. It should not be crushed, chewed, or opened

Treatment duration

• Treatment should be continued until disease progression or unacceptable toxicity. Treatment with ixazomib in combination with lenalidomide and dexamethasone for longer than 24 cycles should be based on an individual benefit risk assessment, as the data on the tolerability and toxicity beyond 24 cycles are limited

Dose modifications

• The ixazomib dose reduction steps are presented below:

• An alternating dose modification approach is recommended for ixazomib and lenalidomide for overlapping toxicities of thrombocytopenia, neutropenia and rash. For these toxicities, the first dose modification step is to withhold/ reduce lenalidomide

Delayed or missed doses

• In the event that an ixazomib dose is delayed or missed, the dose should be taken only if the next scheduled dose is ≥72 hours away. A missed dose should not be taken within 72 hours of the next scheduled dose. A double dose should not be taken to make up for a missed dose
• If a patient vomits after taking a dose, the patient should not repeat the dose but should resume dosing at the time of the next scheduled dose

Coadministration with other medicinal products

• Antiviral prophylaxis should be considered in patients being treated with ixazomib to decrease the risk of herpes zoster reactivation. Patients included in studies with ixazomib who received antiviral prophylaxis had a lower incidence of herpes zoster infection compared to patients who did not receive prophylaxis
• Thromboprophylaxis is recommended in patients being treated with ixazomib in combination with lenalidomide and dexamethasone and should be based on an assessment of the patient's underlying risks and clinical status
• For other concomitant medicinal products that may be required, refer to the current medicine information for lenalidomide and dexamethasone

Oral contraceptives

• When ixazomib is administered together with dexamethasone, which is known to be a weak to moderate inducer of CYP3A4 as well as other enzymes and transporters, the risk for reduced efficacy of oral contraceptives needs to be considered
• Women using hormonal contraceptives should additionally use a barrier method of contraception

Ixazomib citrate, a prodrug, is a substance that rapidly hydrolyses under physiological conditions to its biologically active form, ixazomib. Ixazomib is an oral, highly selective and reversible proteasome inhibitor. Ixazomib preferentially binds and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome. Ixazomib induced apoptosis of several tumour cell types in vitro. Ixazomib demonstrated in vitro cytotoxicity against myeloma cells from patients who had relapsed after multiple prior therapies, including bortezomib, lenalidomide, and dexamethasone. The combination of ixazomib and lenalidomide demonstrated synergistic cytotoxic effects in multiple myeloma cell lines. In vivo, ixazomib demonstrated antitumour activity in various tumour xenograft models, including models of multiple myeloma. In vitro, ixazomib affected cell types found in the bone marrow microenvironment including vascular endothelial cells, osteoclasts and osteoblasts.

Capsule 2.3mg

• Ninlaro (Takeda) originator

Capsule 3mg

• Ninlaro (Takeda) originator

Capsule 4mg

• Ninlaro (Takeda) originator