Selinexor (Monograph)

Brand name: Xpovio
Drug class: Antineoplastic Agents
- Nuclear Export Inhibitors
- Selective Inhibitors of Nuclear Export
- SINEs
Chemical name: (2Z)-3-{3-[3,5-Bis(trifluoromethyl)phenyl]-1H-1,2,4-triazol-1-yl}-N'-(pyrazin-2-yl)prop-2-enehydrazide
Molecular formula: C₁₇H₁₁F₆N₇O
CAS number: 1393477-72-9

Medically reviewed by Drugs.com on Feb 25, 2023. Written by ASHP.

Introduction

Antineoplastic agent; a nuclear export inhibitor.

Uses for Selinexor

Relapsed or Refractory Multiple Myeloma

In combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma in patients who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 immunomodulatory agents, and an anti-CD38 monoclonal antibody (designated an orphan drug by FDA for treatment of this cancer).

In combination with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.

Guidelines recommend triplet therapy with 2 novel agents (immunomodulatory drug, proteasome inhibitor, or monoclonal antibody) plus a steroid for treatment of relapsed or refractory disease. No preference of one regimen over another is given due to lack of comparative trials.

Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. The accelerated approval of selinexor for this indication is based on response rate; continued FDA approval for this indication may be contingent on verification and description of clinical benefit of selinexor in a confirmatory study. Designated an orphan drug by FDA for the treatment of DLBCL.

Selinexor Dosage and Administration

General

Pretreatment Screening

• Obtain platelet count prior to initiating therapy.

• Obtain white blood cell count with differential prior to initiating therapy.

• Check patient’s weight and nutritional and volume status prior to initiating therapy.

• Obtain sodium level prior to initiation of therapy.

• Perform a pregnancy test prior to initiating therapy in females of reproductive potential; if positive, advise patient of the potential risk to the fetus

Patient Monitoring

• Monitor platelet counts throughout treatment and more frequently in the first 3 months of treatment. Monitor patients for signs and symptoms of bleeding and evaluate promptly.

• Monitor white blood cell counts with differential throughout treatment and more frequently in the first 3 months of treatment. Monitor patients for signs and symptoms of concomitant infection and evaluate promptly.

• Monitor weight and nutritional and volume status throughout treatment and more frequently in the first 3 months of treatment.

• Monitor for diarrhea.

• Monitor sodium level throughout treatment and more frequently in the first 2 months of treatment.

• Monitor for signs and symptoms of infection; evaluate and treat promptly.

• Monitor for dizziness and mental status changes. Institute fall precautions as appropriate.

• Monitor for signs and symptoms of cataract.

Premedication Prophylaxis

• Administer prophylaxis with a type 3 serotonin (5-HT₃) receptor antagonist and/or other antiemetics prior to and during treatment with selinexor.

Other General Considerations

• Advise patients to maintain adequate fluid and caloric intake throughout selinexor treatment. Consider IV hydration for patients at risk of dehydration.

Administration

Oral Administration

Administer orally. Take each selinexor dose with a dose of oral dexamethasone at approximately the same time of day.

Available as 20-, 40-, 50-, and 60-mg tablets provided in different therapy packs designed to provide a 4-week supply of specific indicated dosage regimens (i.e., 40, 60, or 80 mg twice weekly, or 40, 60, 80, or 100 mg once weekly).

If a dose of selinexor is missed or delayed, take the next dose at the next regularly scheduled time. If a dose is vomited, do not repeat the dose and take the next dose on the next regularly scheduled day.

Swallow selinexor tablets whole with water; do not break, chew, crush, or divide.

Consult dexamethasone prescribing information for additional information regarding administration of dexamethasone.

Dosage

Adults

Relapsed or Refractory Multiple Myeloma

Oral

In combination with dexamethasone: Initially, 80 mg on days 1 and 3 of each week (i.e., 80 mg twice weekly; total of 160 mg each week), in combination with dexamethasone (initial dosage of 20 mg) orally on days 1 and 3 of each week. Continue combination therapy until disease progression or unacceptable toxicity occurs.

In combination with bortezomib and dexamethasone: 100 mg once weekly on day 1 of each week plus bortezomib 1.3 mg/m² administered subcutaneously once weekly on day 1 of each week for 4 weeks followed by 1 week off plus dexamethasone 20 mg orally twice weekly on days 1 and 2 of each week.

Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Oral

60 mg on days 1 and 3 of each week until disease progression or unacceptable toxicity.

Dosage Modification for Toxicity

Modify dose based on indication for use and type of toxicity as indicated in Tables 1 to 4.

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Selinexor

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Thrombocytopenia

Thrombocytopenia commonly develops during selinexor therapy and appears to be a dose-related adverse effect. Median time to onset varies by dose and indication; range 22–28 days. Bleeding reported, including rarely fatal hemorrhage.

Monitor platelet count at baseline, during therapy, and as clinically indicated. Monitor more frequently during first 3 months of therapy. Promptly evaluate any signs or symptoms of bleeding. Administer platelet transfusions and/or other supportive care (e.g., thrombopoietin-receptor agonists such as romiplostim and eltrombopag) as clinically indicated. Treatment interruption, dosage reduction, or treatment discontinuation may be necessary.

Neutropenia

Neutropenia, including febrile neutropenia, may occur, potentially increasing the risk of infection. Median time to onset varies by dose and indication; range 23–32 days.

Monitor ANC at baseline, during selinexor therapy, and as clinically indicated. Monitor more frequently during first 3 months of therapy. Monitor patients for signs or symptoms of infection and evaluate promptly. Administer supportive care, including anti-infectives and growth factors such granulocyte colony-stimulating factors (G-CSFs), as clinically indicated. Treatment interruption, dosage reduction, or permanent discontinuation may be necessary. (See Neutropenia under Dosage and Administration.)

GI Toxicity

GI toxicity is common and includes nausea, vomiting, diarrhea, or anorexia. Median time to onset of first nausea or vomiting varies by dose and indication; range was 3–6 days and 5–8 days, respectively. Median time to onset of anorexia 8 days with the 80 mg twice weekly dose and 35 days with the 100 mg once weekly dose. Median time to onset of diarrhea ranged from 12–50 days and for weight loss median time to onset was 15 days with the 80 mg twice weekly and 58 days with the 100 mg once weekly dose.

Administer prophylactic antiemetic therapy with a 5-HT₃ receptor antagonist and/or other antiemetics prior to and during selinexor treatment.

Monitor body weight and nutritional and volume status at baseline, during therapy, and as clinically indicated. Monitor weight more frequently during first 3 months of therapy.

Manage GI toxicities as clinically indicated (e.g., antiemetics, antidiarrhea agents, appetite stimulants, nutritional support). Treatment interruption, dosage reduction, or permanent discontinuation may be necessary. Patients should maintain adequate fluid and caloric intake throughout treatment. Provide nutritional support, fluids, and electrolyte repletion as clinically indicated.

Hyponatremia

Hyponatremia often develops during selinexor therapy. Median time to onset of the first event was 8 days with 80 mg twice weekly and 21 days with 100 mg once weekly.

Monitor serum sodium concentrations (correcting for concurrent hyperglycemia and high serum paraprotein concentrations) at baseline, during selinexor therapy, and as clinically indicated. Monitor more frequently during first 2 months of therapy. Correct sodium concentrations for concurrent hyperglycemia (serum glucose concentrations >150 mg/dL) and high serum paraprotein concentrations. Treat hyponatremia as clinically appropriate (e.g., IV saline and/or oral sodium supplementation), including dietary review. Treatment interruption, dosage reduction, or permanent discontinuation may be necessary.

Serious Infection

Infections, sometimes fatal, reported. Most commonly reported infections include upper respiratory tract infection, pneumonia, and sepsis. Most infections were not associated with neutropenia and were caused by non-opportunistic organisms. Median time to onset of grade 3 or higher infections, pneumonia, or sepsis was 42, 54, or 42 days, respectively.

Monitor for signs and symptoms of infection and treat any infection promptly.

Neurological Toxicity

Adverse neurologic effects, including dizziness, syncope, depressed level of consciousness, vertigo, amnesia, somnolence, hallucinations, and mental status changes (including delirium and confusional state), can occur. Median time to first neurologic adverse reaction in clinical trials ranged from 15 to 29 days.

Optimize hydration status, hemoglobin concentrations, and concomitant drug therapy to avoid potential exacerbation of dizziness or mental status changes. Avoid situations where dizziness or confusional state may be a problem. Implement fall precautions when indicated.

Embryofetal Toxicity

May cause fetal harm based on its mechanism of action and animal findings; teratogenicity and growth alterations demonstrated in animals.

Assess pregnancy status prior to initiation of selinexor therapy. Advise women of reproductive potential and men who are partners of such women to use effective contraception during treatment and for 1 week after the last dose. Apprise patients of potential fetal risk.

Cataract

New onset or exacerbation of cataract can occur. Median time to new onset of cataract was 228 days and 237 days for worsening cataract in patients presenting with cataract at the start of selinexor treatment.

May cause new or worsening cataract. Monitor for changes in vision.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

Not known whether selinexor or its metabolites are distributed into milk. Effects on nursing infants or on milk production also not known.

Discontinue nursing during selinexor treatment and for 1 week after the last dose.

Females and Males of Reproductive Potential

Verify pregnancy status before starting treatment. Inform patients of use of effective contraception during treatment and for 1 week after last dose. May impair male and female fertility.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in efficacy relative to younger adults with relapsed or refractory multiple myeloma, but patients ≥75 years of age had a higher frequency of serious adverse reactions and fatal adverse reactions and were more likely to discontinue treatment because of adverse reactions compared with younger adults. Insufficient experience when used for diffuse large B-cell lymphoma in patients ≥65 years of age to determine whether efficacy or safety are similar to younger adults.

Hepatic Impairment

Pharmacokinetics not substantially affected by mild hepatic impairment; effects of moderate or severe hepatic impairment on pharmacokinetics not known.

Renal Impairment

Pharmacokinetics not affected by mild to severe renal impairment (Cl_cr15–89 mL/minute). Effects of end-stage renal disease (Cl_cr <15 mL/minute) or hemodialysis on pharmacokinetics not known.

Common Adverse Effects

Adverse effects reported in at least 20% of patients receiving selinexor in combination with dexamethasone for relapsed or refractory multiple myeloma include thrombocytopenia, fatigue, nausea, anemia, decreased appetite, weight loss, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection.

Adverse effects reported in at least 20% of patients receiving selinexor in combination with bortezomib and dexamethasone for multiple myeloma include fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, weight loss, cataract, and vomiting. Grade 3 or 4 laboratory abnormalities reported in at least 10% of patients include thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia, and neutropenia.

Adverse effects reported in at least 20% of patients receiving selinexor for treatment of DLBCL, include fatigue, nausea, diarrhea, decreased appetite, weight loss, constipation, vomiting, and pyrexia. Grade 3 or 4 laboratory abnormalities reported in at least 15% of patients include thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia.

Drug Interactions

Principally metabolized by CYP3A4 and multiple UGTs, and glutathione S-transferases (GSTs).

In vitro, does not inhibit CYP 1A2, 2B6, 2C8, 2C9, 2C19, or 3A4/5 and does not induce CYP 3A4, 1A2, or 2B6.

Inhibits organic anion transporting polypeptide (OATP) 1B3; does not inhibit other solute carrier (SLC) transporters.

Not a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), OATP1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 1, or MATE2-K.

Specific Drugs

Selinexor Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations achieved within 4 hours following oral administration.

Peak plasma concentrations and AUC are dose proportional over a dose range of 3–85 mg/m² (0.05–1.44 times the recommended dose based on 1.7 m² body surface area).

Clinically relevant accumulation at steady state not observed.

Food

Administration with a high-fat meal does not have clinically important effects on pharmacokinetics.

Special Populations

No clinically important effect on pharmacokinetics by mild hepatic impairment or mild to severe renal impairment (Cl_cr 15–89 mL/minute).

Effects of moderate or severe hepatic impairment, end-stage renal disease (Cl_cr <15 mL/minute), or hemodialysis on pharmacokinetics not known.

Age (18–94 years), sex, body weight (36–168 kg), disease type (hematological non-diffuse large B-cell lymphoma (DLBCL), solid tumor, DLBCL), and race/ethnicity do not substantially affect pharmacokinetics.

Distribution

Extent

Not known whether selinexor or its metabolites are distributed into milk.

Plasma Protein Binding

95%.

Elimination

Metabolism

Selinexor is metabolized by CYP3A4 and multiple UGTs and GSTs.

Half-life

6–8 hours.

Stability

Storage

Oral

Tablets

≤30°C.

Actions

• Inhibits nuclear export of macromolecules, including tumor suppressor proteins (e.g., p53), cell cycle regulators, and messenger RNAs (mRNAs) encoding for oncogenic proteins (e.g., c-myc, cyclin D1) by blocking exportin 1 (XPO1; also known as chromosomal region maintenance 1 [CRM1]).

• XPO1 overexpression is observed in a variety of malignancies, including multiple myeloma, and is associated with poor prognosis in multiple myeloma.

• XPO1 inhibition results in retention and activation of tumor suppressor proteins in the nucleus, inhibition of oncogenic mRNA translation and oncogenic protein synthesis, cell cycle arrest, and apoptosis of cancer cells.

• In preclinical studies, demonstrated proapoptotic activity in vitro in multiple myeloma cell lines and patient tumor samples and antitumor activity in murine xenograft models.

Advice to Patients

• Advise patients to read the manufacturer's medication guide.

• Instruct patients to take selinexor exactly as prescribed. Tablets should be swallowed whole with water and should not be broken, chewed, crushed, or divided.

• If a dose is missed or delayed or if vomiting occurs after a dose is taken, the next dose should be taken at the next regularly scheduled time and day. An extra dose should not be taken to replace a missed or vomited dose.

• Advise patients of the importance of patients taking concomitant dexamethasone and prophylactic antiemetics exactly as prescribed.

• Advise patients that blood tests and body weight will be monitored at baseline and during treatment as clinically indicated, and monitoring will be more frequent during the first 3 months of treatment.

• Risk of hematologic adverse effects, including thrombocytopenia, anemia, and neutropenia. Inform patients to contact their clinician if signs or symptoms of thrombocytopenia (e.g., bleeding, easy bruising), anemia (e.g., fatigue, shortness of breath), or neutropenia (e.g., infection) occur.

• Risk of adverse GI effects such as nausea, vomiting, and diarrhea. Inform patients to contact their clinician if any of these adverse reactions occur or persist.

• Inform patients that fatigue commonly occurs during selinexor therapy.

• Risk of weight loss and decreased appetite. Advise patients to report decreased appetite and weight loss to their clinician.

• Inform patients to maintain appropriate fluid and caloric intake during selinexor therapy.

• Risk of confusion and dizziness. Advise patients to immediately notify their clinician if symptoms of neurological toxicity occur. Inform patients to avoid driving or operating machinery until effects of the drug are known.

• Risk of hyponatremia. Inform patients that hyponatremia may not be associated with specific symptoms.

• Risk of serious infections. Instruct patients to notify their clinician if infection-related signs or symptoms (e.g., chills, fever) occur.

• Risk of fetal harm. Advise women of reproductive potential and men with female partners of reproductive potential to use effective contraception during selinexor therapy and for 1 week after the last dose of the drug. Advise patients to inform their clinicians if they are pregnant or think they may be pregnant.

• Risk of new or worsening cataracts. Advise patients to inform their clinician of any changes in their vision.

• Advise women to avoid breast-feeding during selinexor therapy and for 1 week after the last dose of the drug.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Advise patients of other important precautionary information. (See Cautions.)

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web]. The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Selinexor is obtained through specialty pharmacy distributors. Contact the manufacturer or consult the Xpovio website ([Web]) for specific information and updates regarding availability.

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