Ixazomib

Ixazomib citrate is a prodrug that hydrolyses rapidly under physiological conditions to ixazomib, its biologically active form. Ixazomib is an oral, highly selective and reversible inhibitor of the proteasome, the protein complex through which cells break down regulatory and damaged proteins. Blocking this pathway favours the death of tumour cells.

Mechanism of Action

• Target: ixazomib preferentially binds to and inhibits the chymotrypsin-like activity of the beta 5 subunit of the 20S proteasome (half-maximal inhibitory concentration about 3.4 nmol/L). At higher concentrations it may also inhibit the caspase-like (beta 1) and trypsin-like (beta 2) sites. The inhibition is reversible and time-dependent.
• Pathway effects: the ubiquitin–proteasome pathway controls protein degradation and the activation of the transcription factor NF-κB, which raises the expression of growth and angiogenic factors and blocks apoptosis. Inhibiting the proteasome induced apoptosis in several tumour cell types in vitro.
• Activity in relapsed disease: ixazomib was cytotoxic in vitro to myeloma cells from patients who had relapsed after multiple prior therapies, including bortezomib, lenalidomide and dexamethasone. Together with lenalidomide it showed synergistic cytotoxicity in myeloma cell lines, and it had antitumour activity in xenograft models, including multiple myeloma.
• Bone marrow microenvironment: in vitro it affected vascular endothelial cells, osteoclasts and osteoblasts; DrugBank also describes antiangiogenic activity and reduced osteoclast formation and bone resorption.
• Cardiac electrophysiology: no QTc prolongation at clinically relevant exposures (analysis of data from 245 patients; estimated mean change 0.07 msec at the 4 mg dose).

Pharmacokinetics

• Absorption: rapid, with peak plasma concentrations about 1 hour after the dose; mean absolute oral bioavailability 58%. Exposure rises in proportion to dose over 0.2–10.6 mg. A high-fat meal lowered the AUC by 28% (and, in a single-dose study at 4 mg, the peak concentration by 69%), which is why the capsule is taken away from food.
• Distribution: 99% bound to plasma proteins; distributes into red blood cells (blood-to-plasma AUC ratio 10); steady-state volume of distribution 543 L.
• Metabolism: ixazomib accounted for 70% of drug-related material in plasma. Clearance is mainly by metabolism through several CYP enzymes and non-CYP proteins, and at clinical concentrations no single CYP enzyme predominates. At concentrations above those seen clinically, CYP3A4 (about 42%), 1A2 (26%), 2B6 (16%), 2C8 (6%), 2D6 (5%), 2C19 (5%) and 2C9 (below 1%) contributed. The main pathways are hydrolysis, deboronation and N-dealkylation, and the metabolites are not expected to be pharmacologically active.
• Elimination: multi-exponential disposition; systemic clearance about 1.86 L/h (inter-individual variability 44%); terminal half-life 9.5 days; the AUC about doubles by Day 15 of weekly dosing. After a radiolabelled dose, 62% of the radioactivity was in urine and 22% in faeces; unchanged ixazomib made up below 3.5% of the dose recovered in urine.
• Special populations: exposure is similar with normal liver function and mild hepatic impairment. Ixazomib is not dialysable. The reduced dose for moderate or severe hepatic impairment and for severe renal impairment is described under Administration and Dosage.

• Multiple myeloma: in combination with lenalidomide and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.

• Hypersensitivity to ixazomib or to any of the excipients.
• Ixazomib is always given with lenalidomide and dexamethasone, so the contraindications in the SmPCs of those medicines also apply.

Ixazomib is given with lenalidomide and dexamethasone, so the side effects of the whole regimen apply; the SmPCs of the partner medicines list the others. In 418 patients on the ixazomib regimen and 417 on the placebo regimen, the most frequent reactions (20% or more) were diarrhoea (47% vs 38%), thrombocytopenia (41% vs 24%), neutropenia (37% vs 36%), constipation (31% vs 24%), upper respiratory tract infection (28% vs 24%), peripheral neuropathy (28% vs 22%), nausea (28% vs 20%), back pain (25% vs 21%), rash (25% vs 15%), peripheral oedema (24% vs 19%), vomiting (23% vs 12%) and bronchitis (20% vs 15%). Serious reactions in at least 2% of patients were diarrhoea (3%), thrombocytopenia (2%) and bronchitis (2%).

Very common (≥1/10): upper respiratory tract infection, bronchitis, thrombocytopenia, neutropenia, peripheral neuropathies, diarrhoea, constipation, nausea, vomiting, rash, back pain, arthralgia, peripheral oedema, pyrexia.

Common (≥1/100 to <1/10): herpes zoster.

Uncommon (≥1/1,000 to <1/100): drug-induced liver injury, hepatocellular injury, hepatic steatosis, cholestatic hepatitis, hepatotoxicity (the frequency given in the warnings section of the SmPC).

Rare (≥1/10,000 to <1/1,000): thrombotic microangiopathy, thrombotic thrombocytopenic purpura, anaphylactic reaction, angioedema, tumour lysis syndrome, posterior reversible encephalopathy syndrome, transverse myelitis, Stevens-Johnson syndrome, acute febrile neutrophilic dermatosis, toxic epidermal necrolysis.

Several of the rare reactions were reported outside the phase 3 studies. Grade 3 thrombocytopenia and neutropenia were each very common. Other points from the SmPC:

• Thrombocytopenia: a platelet count of 10,000/mm³ or less was reached by 2% of patients in both regimens, and thrombocytopenia did not increase haemorrhagic events or platelet transfusions.
• Rash: mostly maculo-papular or macular; grade 3 in 3% of patients (2% with placebo).
• Peripheral neuropathy: mostly sensory (21% vs 15%); motor neuropathy was reported in fewer than 1%; grade 3 in 2% (1% with placebo).
• Eye disorders: many different terms, 34% overall (28% with placebo), including blurred vision, dry eye, conjunctivitis (8% vs 2%) and cataract.
• Electrolytes and other findings: severe (grade 3–4) hypokalaemia was more frequent with the ixazomib regimen (7% vs 2%). Fatigue, decreased appetite, hypotension, heart failure, arrhythmia and liver impairment including enzyme changes (11% vs 9%) occurred at similar rates in both regimens.
• Infections: fungal and viral pneumonia with fatal outcome were rarely reported with the combination.
• Stopping treatment: for each reaction, one or more of the three medicines was stopped in 3% or fewer of patients on the ixazomib regimen.

Ixazomib is cleared by several CYP enzymes and non-CYP pathways, so no single enzyme is critical, and it is not expected to alter the metabolism of other medicines.

• Strong CYP3A inhibitors: with clarithromycin, ixazomib Cmax fell by 4% and AUC rose by 11%, which is not clinically meaningful. No dose change is needed.
• Strong CYP1A2 inhibitors: no clinically meaningful change in exposure (population pharmacokinetic analysis). No dose change is needed.
• Strong CYP3A inducers: rifampicin lowered ixazomib Cmax by 54% and AUC by 74%. Co-administration of strong CYP3A inducers is not recommended. St John’s wort, which induces CYP3A4, should also be avoided.
• Effect of ixazomib on other medicines: it is not a reversible or time-dependent inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5, did not induce CYP1A2, 2B6 or 3A4/5, and does not inhibit P-gp, BCRP, MRP2, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1 or MATE2-K. Interactions through these routes are not expected. Ixazomib itself is a low-affinity P-gp substrate and not a substrate of BCRP, MRP2 or hepatic OATPs.
• Oral hormonal contraceptives: dexamethasone is a weak to moderate inducer of CYP3A4 and other enzymes and transporters, so contraceptive efficacy may fall. Women using hormonal contraception should also use a barrier method.
• Food: take the capsule at least 1 hour before or 2 hours after food; a high-fat meal reduces absorption.
• Partner medicines: the interactions of lenalidomide and dexamethasone are described in their own SmPCs.

Treatment must be started and monitored by a physician experienced in managing multiple myeloma. Ixazomib is taken by mouth with lenalidomide and dexamethasone, which are dosed according to their own SmPCs. The capsule is swallowed whole with water at about the same time on Days 1, 8 and 15 of each cycle, at least 1 hour before or at least 2 hours after food. It must not be crushed, chewed or opened.

Recommended Dose

• Ixazomib: 4 mg once a week on Days 1, 8 and 15 of a 28-day cycle.
• Lenalidomide (starting dose): 25 mg daily on Days 1 to 21 of the 28-day cycle.
• Dexamethasone (starting dose): 40 mg on Days 1, 8, 15 and 22 of the 28-day cycle.
• Before each new cycle: absolute neutrophil count at least 1,000/mm³, platelet count at least 75,000/mm³, and non-haematological toxicities generally recovered to baseline or grade 1 or below, at the physician’s discretion.
• Duration: until disease progression or unacceptable toxicity. Beyond 24 cycles, treatment should rest on an individual benefit–risk assessment because data on tolerability and toxicity are limited.

Dose Adjustments for Side Effects

• Reduction steps: 4 mg, then 3 mg, then 2.3 mg, then discontinue.
• Alternating approach: for the overlapping toxicities thrombocytopenia, neutropenia and rash, the first step is to withhold or reduce lenalidomide (see its SmPC). For further occurrences the changes alternate between lenalidomide and ixazomib.
• Thrombocytopenia (platelets below 30,000/mm³): withhold ixazomib and lenalidomide until the count is at least 30,000/mm³; resume lenalidomide at the next lower dose and ixazomib at its most recent dose. If it recurs, resume ixazomib at the next lower dose and lenalidomide at its most recent dose.
• Neutropenia (neutrophils below 500/mm³): the same pattern, withholding both until the count is at least 500/mm³; consider G-CSF.
• Rash: grade 2 or 3, withhold lenalidomide until grade 1 or below and resume at the next lower dose; if it recurs, withhold both and resume ixazomib at the next lower dose. Grade 4: discontinue the regimen.
• Peripheral neuropathy: grade 1 with pain, or grade 2: withhold ixazomib until grade 1 or below without pain (or baseline), then resume at the most recent dose. Grade 2 with pain, or grade 3: withhold until recovery, then resume at the next lower dose. Grade 4: discontinue the regimen.
• Other grade 3 or 4 non-haematological toxicities: withhold ixazomib until recovery to baseline or grade 1 at most; if attributable to ixazomib, resume at the next lower dose.
• Reduced starting dose: 3 mg is recommended in moderate or severe hepatic impairment, severe renal impairment and end-stage renal disease needing dialysis.

Supportive Medicines

• Antiviral prophylaxis: should be considered to lower the risk of herpes zoster reactivation; patients who received it in studies had fewer cases.
• Thromboprophylaxis: recommended with ixazomib, lenalidomide and dexamethasone, based on the patient’s underlying risks and clinical status.

Special Populations

• Elderly: no dose adjustment over 65 years. In patients over 75, treatment was discontinued in 28% on the ixazomib regimen and 16% on placebo, and cardiac arrhythmias occurred in 21% and 15%.
• Hepatic impairment: no adjustment in mild impairment (total bilirubin at or below the upper limit of normal with AST above it, or total bilirubin up to 1.5 times the limit with any AST). 3 mg in moderate (total bilirubin above 1.5 to 3 times the limit) or severe (above 3 times) impairment.
• Renal impairment: no adjustment in mild or moderate impairment (creatinine clearance 30 mL/min or more). 3 mg in severe impairment (below 30 mL/min) or end-stage renal disease needing dialysis. Ixazomib is not dialysable and can be given regardless of dialysis timing. The lenalidomide SmPC gives its own renal dosing.
• Children and adolescents: safety and efficacy below 18 years have not been established.

Missed or Vomited Dose

• A delayed or missed dose is taken only if the next scheduled dose is at least 72 hours away. It is not taken within 72 hours of the next dose, and a double dose is never taken.
• If vomiting follows a dose, do not repeat it; resume at the next scheduled dose.

Combination Treatment

Ixazomib is always given with lenalidomide and dexamethasone. Their SmPCs contain further contraindications, warnings, side effects and pregnancy information that apply to the whole regimen.

Thrombocytopenia

Platelet nadirs typically occur between Days 14 and 21 of each 28-day cycle, with recovery to baseline by the start of the next cycle. Platelet counts should be checked at least monthly, and more often during the first three cycles as set out in the lenalidomide SmPC. It is managed with dose changes and platelet transfusion according to standard guidelines.

Gastrointestinal Toxicity

Diarrhoea, constipation, nausea and vomiting can occur and sometimes need antiemetic or antidiarrhoeal medicines and supportive care. The dose is adjusted for severe (grade 3–4) symptoms, and serum potassium should be monitored after severe gastrointestinal events.

Peripheral Neuropathy and Peripheral Oedema

Patients should be monitored for symptoms of peripheral neuropathy; new or worsening neuropathy may need a dose change. For peripheral oedema, underlying causes should be looked for and supportive care given; the dexamethasone or ixazomib dose is adjusted for grade 3 or 4 symptoms.

Skin Reactions

Rash is managed with supportive care, or with a dose change if grade 2 or higher. Severe cutaneous adverse reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome, can be life-threatening or fatal and have rarely been reported. Patients should be told the signs and symptoms at the time of prescription and be monitored closely. If such a reaction is suspected, ixazomib is withdrawn immediately and an alternative treatment considered. After a serious reaction such as Stevens-Johnson syndrome or toxic epidermal necrolysis, ixazomib must never be restarted.

Thrombotic Microangiopathy

Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome, some of them fatal, have been reported. Signs and symptoms should be watched for; if the diagnosis is suspected, ixazomib is stopped and the patient evaluated. If it is excluded, ixazomib can be restarted. The safety of restarting after confirmed thrombotic microangiopathy is not known.

Hepatotoxicity

Drug-induced liver injury, hepatocellular injury, hepatic steatosis, cholestatic hepatitis and hepatotoxicity have been reported uncommonly. Liver enzymes should be checked regularly and the dose adjusted for grade 3 or 4 events.

Pregnancy, Breastfeeding and Fertility

• Contraception: male and female patients who can have children must use effective contraception during treatment and for 90 days afterwards. Ixazomib is not recommended in women of childbearing potential who are not using contraception.
• Pregnancy: not recommended, because it can cause foetal harm. There are no human data, and animal studies showed reproductive toxicity. Women should avoid becoming pregnant during treatment.
• Lenalidomide: it is structurally related to thalidomide, a known human teratogen that causes severe, life-threatening birth defects. The conditions of the lenalidomide Pregnancy Prevention Programme must be met unless there is reliable evidence that the patient cannot have children.
• Hormonal contraceptives: because of the effect of dexamethasone, women using oral hormonal contraceptives should also use a barrier method.
• Breastfeeding and fertility: the SmPC refers to the SmPCs of lenalidomide and dexamethasone for information on fertility and lactation.

Effect on Driving

Ixazomib has a minor influence on the ability to drive or use machines. Fatigue and dizziness have been seen in clinical trials; patients who have them should not drive or operate machines.

Do not store above 30 °C. Do not freeze. Keep the capsules in the original package to protect them from moisture. They are supplied in PVC–aluminium/aluminium blister strips of three capsules sealed in a wallet pack, one wallet pack per carton. No cold chain is needed. Keep out of the sight and reach of children.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), on restricted medical prescription (Annex II B). Treatment is started and monitored by a physician experienced in managing multiple myeloma. Ixazomib capsules are taken at home once a week, so they are supplied to the patient or to the treating clinic on prescription, for use together with lenalidomide and dexamethasone, whose own supply conditions (including the lenalidomide Pregnancy Prevention Programme) also apply.