Selinexor

Selinexor is a reversible covalent selective inhibitor of nuclear export (SINE) that specifically blocks exportin 1 (XPO1). XPO1 is the main carrier that moves many cargo proteins out of the cell nucleus, among them tumour suppressor proteins, growth regulators and the messenger RNAs of growth-promoting (oncogenic) proteins. Keeping these cargoes in the nucleus works against the tumour cell.

Mechanism of Action

• XPO1 blockade: selinexor binds exportin 1 and stops it carrying its cargo out of the nucleus.
• Tumour suppressor build-up: tumour suppressor proteins accumulate in the nucleus, which arrests the cell cycle, lowers oncoproteins such as c-Myc and cyclin D1, and leads to apoptosis of cancer cells. Nuclear retention of the inhibitor of NF-κB, with lower NF-κB activity, is also described.
• Combination effect: with dexamethasone and/or bortezomib, selinexor had synergistic cytotoxic effects in multiple myeloma in vitro and greater anti-tumour activity in mouse xenograft models, including models resistant to proteasome inhibitors.
• Cardiac electrophysiology: the QTc interval was studied with multiple doses up to 175 mg twice weekly in patients with heavily pre-treated haematological malignancies. Selinexor had no large effect (no more than 20 ms) at the therapeutic dose level.

Pharmacokinetics

• Absorption: peak plasma concentration is reached within 4 hours of an oral dose. A high-fat meal (800–1,000 calories, about half from fat) had no clinically significant effect on exposure.
• Distribution: 95.0% bound to human plasma proteins; apparent volume of distribution about 133 L in cancer patients (population analysis).
• Metabolism: by CYP3A4, several UDP-glucuronosyltransferases (UGTs) and glutathione S-transferases (GSTs).
• Elimination: mean half-life 6–8 hours after a single 80 mg dose; apparent total clearance about 18.6 L/h in cancer patients.
• Special populations: age (18–94 years), sex and race had no clinically significant effect. Renal function, including severe impairment (creatinine clearance 15–29 mL/min), did not alter exposure. Mild and moderate hepatic impairment had no clinically relevant effect; in severe impairment (total bilirubin above 3 times the upper limit of normal) dose-normalised exposure was up to 32% higher.

Nexpovio is indicated in adults with multiple myeloma:

• In combination with bortezomib and dexamethasone: treatment of adult patients with multiple myeloma who have received at least one prior therapy.
• In combination with dexamethasone: treatment of multiple myeloma in adult patients who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, two immunomodulatory agents and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on the last therapy.

• Hypersensitivity to selinexor or to any of the excipients.

With bortezomib and dexamethasone (SVd, 195 patients) the most frequent reactions (≥30%) were thrombocytopenia (62%), nausea (50%), fatigue (42%), anaemia (37%), decreased appetite (35%), diarrhoea (33%) and peripheral neuropathy (33%). With dexamethasone (Sd, 214 patients, 83 of them with penta-refractory disease) they were nausea (75%), thrombocytopenia (75%), fatigue (66%), anaemia (60%), decreased appetite (56%), decreased weight (49%), diarrhoea (47%), vomiting (43%), hyponatraemia (40%), neutropenia (36%) and leukopenia (30%). The most commonly reported serious reactions (≥3%) were pneumonia, cataract, sepsis, diarrhoea, vomiting and anaemia with SVd, and pneumonia, sepsis, thrombocytopenia, acute kidney injury and anaemia with Sd.

With bortezomib and dexamethasone (SVd)

Very common (≥1/10): pneumonia, upper respiratory tract infection, bronchitis, nasopharyngitis, thrombocytopenia, anaemia, neutropenia (including febrile neutropenia), decreased appetite, insomnia, peripheral neuropathy, dizziness, headache, cataract, blurred vision, cough, nausea, diarrhoea, vomiting, constipation, fatigue, pyrexia, asthenia, decreased weight.

Common (≥1/100 to <1/10): sepsis, lower respiratory tract infection, leukopenia, lymphopenia, hyponatraemia, dehydration, hypokalaemia, hypocalcaemia, hypophosphataemia, hyperkalaemia, hypomagnesaemia, confusional state, syncope, amnesia (including memory impairment), balance disorder, dysgeusia, ageusia, vertigo, tachycardia, hypotension, dyspnoea, epistaxis, abdominal pain, dyspepsia, dry mouth, flatulence, alopecia, night sweats, pruritus, raised blood creatinine, acute kidney injury, general physical health deterioration, malaise, raised aspartate and alanine aminotransferases, fall, contusion.

With dexamethasone (Sd)

Very common (≥1/10): pneumonia, upper respiratory tract infection, thrombocytopenia, anaemia, neutropenia, leukopenia, lymphopenia, hyponatraemia, dehydration, decreased appetite, hyperglycaemia, hypokalaemia, confusional state, insomnia, dizziness, dysgeusia, headache, blurred vision, dyspnoea, epistaxis, cough, nausea, diarrhoea, vomiting, abdominal pain, constipation, fatigue, pyrexia, asthenia, decreased weight.

Common (≥1/100 to <1/10): sepsis, bacteraemia, febrile neutropenia, hypocalcaemia, hypophosphataemia, hyperkalaemia, hypomagnesaemia, hyperamylasaemia, hyperuricaemia, hyperlipasaemia, delirium, hallucination, peripheral neuropathy, syncope, ageusia, taste disorder, balance disorder, cognitive disorder, disturbance in attention, memory impairment, cataract, visual impairment, tachycardia, hypotension, dyspepsia, dry mouth, abdominal discomfort, flatulence, alopecia, night sweats, pruritus, muscle spasms, raised blood creatinine, acute kidney injury, general physical health deterioration, malaise, gait disturbance, chills, raised aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase, fall.

Uncommon (≥1/1,000 to <1/100): tumour lysis syndrome, encephalopathy.

Thrombocytopenia (occasionally with serious bleeding), neutropenia with infection, severe nausea, vomiting and diarrhoea, hyponatraemia, new or worsening cataract and tumour lysis syndrome are the reactions to watch most closely; see Special Instructions.

Few interaction data are available, and none showed a clinically significant effect on selinexor.

• Strong CYP3A4 and UGT inducer: carbamazepine (up to 300 mg twice daily) caused no clinically significant difference in selinexor exposure.
• Strong CYP3A4 inhibitor: clarithromycin (500 mg twice daily for 7 days) caused no clinically significant difference.
• Paracetamol: up to 1,000 mg daily caused no clinically significant difference.
• Medicines that cause dizziness or confusion: patients should not take them without medical advice, because selinexor can cause these effects itself.
• Combination partners: interactions of bortezomib and dexamethasone are described in their own SmPCs.
• Food: tablets can be taken with or without food.

Treatment must be initiated and monitored under the supervision of physicians experienced in the management of multiple myeloma. Nexpovio is for oral use. The tablet is swallowed whole with water, at about the same time on each dosing day. It must not be crushed, chewed, broken or divided, to avoid the risk of skin irritation from the active substance. It can be taken with or without food. Prophylactic concomitant treatment with a 5-HT3 antagonist and/or other anti-nausea agents should be provided prior to and during treatment.

Recommended Doses

• With bortezomib and dexamethasone (SVd), 35-day cycle: selinexor 100 mg orally once weekly on day 1 of each week (the dose should not exceed 70 mg/m² per dose); bortezomib 1.3 mg/m² subcutaneously once weekly on day 1 of each week for 4 weeks, followed by 1 week off; dexamethasone 20 mg orally twice weekly on days 1 and 2 of each week. Treatment continues until disease progression or unacceptable toxicity.
• With dexamethasone (Sd): selinexor 80 mg orally on days 1 and 3 of each week, with dexamethasone 20 mg orally on days 1 and 3 of each week. Treatment continues until disease progression or unacceptable toxicity.
• For the doses and dose changes of bortezomib and dexamethasone, see their own SmPCs.

Dose Adjustments for Side Effects

• SVd dose levels: starting dose 100 mg once weekly; first reduction 80 mg once weekly; second reduction 60 mg once weekly; third reduction 40 mg once weekly.
• Sd dose levels: starting dose 80 mg on days 1 and 3 of each week (160 mg per week); first reduction 100 mg once weekly; second reduction 80 mg once weekly; third reduction 60 mg once weekly.
• If symptoms do not resolve, treatment should be discontinued.
• Table 2 of the SmPC gives the action for each adverse reaction by grade (for example, a platelet count of 25,000 to below 75,000/µL calls for a reduction of one dose level). Blood counts, sodium, body weight and nutritional status are checked more often in the first two months.

Special Populations

• Elderly: no dose adjustment for patients over 65 years.
• Renal impairment: no adjustment in mild, moderate or severe impairment; no data in end-stage renal disease or haemodialysis, so no dose recommendation can be made.
• Hepatic impairment: no adjustment in mild impairment (total bilirubin ≤1 times the upper limit of normal with AST above 1 times, or bilirubin above 1 to 1.5 times with any AST) or moderate impairment (bilirubin above 1.5 to 3 times with any AST). In severe impairment (bilirubin above 3 times with any AST) the starting dose is reduced to 80 mg once weekly with SVd or 100 mg once weekly with Sd; later doses can be raised or lowered according to safety and tolerability.
• Children and adolescents: safety and efficacy below 18 years have not been established; no data.

Missed, Delayed or Vomited Dose

If a dose is missed or delayed, or the patient vomits after a dose, the dose is not repeated. The next dose is taken on the next regularly scheduled day.

Combination Partners

Before starting, read the SmPC of each medicine given with selinexor, including its warnings, precautions and recommended concomitant treatments.

Supportive Care

Patients should keep up adequate fluid and calorie intake throughout treatment; intravenous hydration should be considered for those at risk of dehydration. Prophylaxis with a 5-HT3 antagonist and/or other anti-nausea agents is provided before and during treatment.

Thrombocytopenia and Neutropenia

Complete blood counts are checked at baseline, during treatment and as clinically indicated, more often in the first two months. Grade 3/4 thrombocytopenia can lead to clinically significant bleeding and, in rare cases, potentially fatal haemorrhage; patients are watched for signs of bleeding. It can be managed with dose interruptions or modifications and platelet transfusions. Severe neutropenia has been reported, in a few cases with concurrent infection; patients are watched for signs of infection, and colony-stimulating factors can be used.

Gastrointestinal Toxicity, Weight Loss and Anorexia

Nausea, vomiting and diarrhoea can be severe and may need anti-emetic and anti-diarrhoeal medicines; fluids with electrolytes prevent dehydration in patients at risk. Selinexor can also cause weight loss and anorexia: body weight, nutritional status and volume are checked at baseline, during treatment and as indicated. Dose modification, appetite stimulants and nutritional consultation may be needed.

Confusional State and Dizziness

Patients should avoid situations where dizziness or confusion could be a problem and should not take other medicines that may cause them without medical advice. They should not drive or operate heavy machinery until symptoms resolve.

Hyponatraemia

Sodium levels are checked at baseline, during treatment and as indicated, more often in the first two months. Sodium is corrected for concurrent hyperglycaemia (serum glucose above 150 mg/dL) and high serum paraprotein. Hyponatraemia is treated per medical guidelines (intravenous sodium chloride and/or salt tablets, with dietary review) and may need a dose interruption or modification.

Cataract

New onset or worsening of cataract can occur. An eye examination may be done as clinically indicated, and cataract is treated per medical guidelines, including surgery if warranted.

Tumour Lysis Syndrome

Tumour lysis syndrome has been reported. Patients at high risk are monitored closely and it is treated promptly per institutional guidelines.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should avoid becoming pregnant or abstain from sexual intercourse during treatment and for at least 1 week after the last dose; a pregnancy test is recommended before starting. Women of childbearing potential and male patients of reproductive potential should use effective contraception, or abstain from sexual activity, during treatment and for at least 1 week after the last dose.
• Pregnancy: no data in pregnant women; animal studies showed foetal harm. Selinexor is not recommended during pregnancy or in women of childbearing potential not using contraception. If pregnancy occurs, selinexor is stopped at once and the patient is told of the potential hazard to the foetus.
• Breastfeeding: it is unknown whether selinexor or its metabolites pass into human milk and a risk to the breast-fed child cannot be excluded. Breastfeeding should be stopped during treatment and for 1 week after the last dose.
• Fertility: based on animal findings, selinexor may impair fertility in females and males.

Sodium

Each 20 mg tablet contains less than 1 mmol sodium (23 mg), that is, it is essentially sodium-free.

Effect on Driving

Selinexor may have a major influence on the ability to drive and use machines. It can cause fatigue, confusional state and dizziness, and patients with these symptoms should not drive or operate machines.

Nexpovio does not require any special storage conditions. The tablets are supplied in PVC/PCTFE/PVC–aluminium blisters, packed in child-resistant inner cartons (four per outer carton). Not all pack sizes may be marketed.

5 years.

Prescription only (Rx). Treatment is started and monitored by a physician experienced in the management of multiple myeloma. Nexpovio is a tablet taken by mouth on the dosing days, so it is supplied to the patient or to the treating clinic on prescription.