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Xpovio

Generic Name: Selinexor
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. Last updated on Jun 15, 2020.

Introduction

Antineoplastic agent; a nuclear export inhibitor.1 2 4 6 8

Uses for Xpovio

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 antibody1 2 12 (designated an orphan drug by FDA for treatment of this cancer).10

Accelerated FDA approval based on response rate; continued approval may be contingent on verification and description of clinical benefit in a confirmatory study.1

Xpovio Dosage and Administration

General

  • Monitor CBC, standard blood chemistry tests, and body weight at baseline, during treatment, and as clinically indicated; monitor more frequently during the first 2 months of treatment.1 (See Warnings/Precautions under Cautions.)

  • Advise patients to maintain adequate fluid and caloric intake throughout treatment.1 Consider IV hydration for patients at risk of dehydration.1

  • Administer prophylaxis with a 5-HT3 receptor antagonist and/or other antiemetics prior to and during treatment.1

Restricted Distribution

  • Obtain selinexor through a limited network of specialty pharmacies and specialty distributors.9 Consult Xpovio website ([Web]) for specific availability information.9

Administration

Oral Administration

Administer orally.1 Take each selinexor dose with a dose of oral dexamethasone at approximately the same time of day.1

Available as 20-mg tablets provided in different therapy packs designed to provide a 4-week supply of specific indicated dosage regimens (i.e., 80 mg twice weekly or 60, 80, or 100 mg once weekly).1

Swallow selinexor tablets whole with water; do not break, chew, crush, or divide.1

Consult dexamethasone prescribing information for additional information regarding administration of dexamethasone.1

Dosage

Adults

Relapsed or Refractory Multiple Myeloma
Oral

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.1 Continue combination therapy until disease progression or unacceptable toxicity occurs.1

If a dose is missed or delayed, instruct patients to take the next dose at the next regularly scheduled time.1 If a dose is vomited, instruct patients not to repeat the dose and to take the next dose on the next regularly scheduled day.1

Dosage Modification for Toxicity
Oral

If dosage reduction from 80 mg on days 1 and 3 of each week (i.e., total of 160 mg each week) is necessary, initially reduce dosage to 100 mg once weekly.1 If further dosage reduction from 100 mg once weekly is necessary, reduce dosage to 80 mg once weekly.1 If further dosage reduction from 80 mg once weekly is necessary, reduce dosage to 60 mg once weekly.1

If a dosage of 60 mg once weekly is not tolerated, discontinue the drug.1

Consult dexamethasone prescribing information for dosage modifications for adverse reactions associated with dexamethasone.1

Thrombocytopenia
Oral

Platelet count <75,000 but ≥25,000/mm3 without bleeding: Continue selinexor at a reduced dosage.1

Platelet count <75,000 but ≥25,000/mm3 with bleeding: Interrupt selinexor.1 Once bleeding is resolved, may resume selinexor at a reduced dosage.1 Administer platelet transfusions and/or other supportive care (e.g., thrombopoietin-receptor agonists such as romiplostim and eltrombopag) as clinically indicated.1 2 3 11

Platelet count <25,000/mm3: Interrupt selinexor and monitor.1 Once platelet count ≥50,000/mm3, may resume selinexor at a reduced dosage.1 Administer platelet transfusions and/or other supportive care (e.g., thrombopoietin-receptor agonists such as romiplostim and eltrombopag) as clinically indicated.1 2 3 11 (See Thrombocytopenia under Cautions.)

Neutropenia
Oral

ANC 500–1000/mm3 without fever: Continue selinexor at a reduced dosage.1

ANC <500/mm3 or febrile neutropenia: Interrupt selinexor and monitor ANC.1 Once ANC ≥1000/mm3, may resume selinexor at a reduced dosage.1 Consider supportive care (e.g., anti-infectives, granulocyte colony-stimulating factors [G-CSFs]) as clinically indicated.1

Anemia
Oral

Hemoglobin <8 g/dL: Continue selinexor at a reduced dosage.1 Administer blood transfusions and/or other supportive care as clinically indicated.1

Life-threatening anemia requiring urgent intervention: Interrupt selinexor and monitor hemoglobin.1 Once hemoglobin ≥8 g/dL, may resume selinexor at a reduced dosage.1 Administer blood transfusions and/or other supportive care as clinically indicated.1

Hyponatremia
Oral

Serum sodium concentrations ≤130 mmol/L: Interrupt selinexor and provide appropriate supportive care.1 Monitor patient.1 Upon recovery of serum sodium concentrations to ≥130 mmol/L, may resume selinexor at a reduced dosage.1 (See Hyponatremia under Cautions.)

Fatigue
Oral

Grade 2 fatigue lasting >7 days or grade 3 fatigue: Interrupt selinexor until recovery to grade 1 or baseline; may then resume selinexor at a reduced dosage.1

Nausea/Vomiting
Oral

Grade 1 or 2 nausea (decreased oral intake without clinically important weight loss, dehydration, or malnutrition) or grade 1 or 2 vomiting (≤5 episodes per day): Initiate additional antiemetic therapy; may continue selinexor without dosage reduction.1

Grade 3 nausea (inadequate oral caloric or fluid intake) or grade 3 or higher vomiting (≥6 episodes per day): Interrupt selinexor and initiate additional antiemetic therapy.1 Monitor patient until nausea or vomiting resolves to grade 2 or less or baseline; may then resume selinexor at a reduced dosage.1 (See GI Toxicity under Cautions.)

Diarrhea
Oral

Grade 2 diarrhea (increase of 4–6 stools per day over baseline): Initiate supportive care with first occurrence.1 If grade 2 diarrhea recurs, reduce selinexor dosage and administer supportive care.1

Grade 3 or 4 diarrhea (increase of ≥7 stools per day over baseline or hospitalization indicated): Interrupt selinexor and initiate supportive care.1 Once diarrhea resolves to grade 2 or less, may resume selinexor at a reduced dosage.1 (See GI Toxicity under Cautions.)

Weight Loss/Anorexia
Oral

Weight loss of 10 to <20% of body weight or anorexia associated with clinically important weight loss or malnutrition: Interrupt selinexor and initiate supportive care.1 Monitor patient until body weight returns to >90% of baseline; may then resume selinexor at a reduced dosage.1 (See GI Toxicity under Cautions.)

Other Nonhematologic Toxicities
Oral

Other grade 3 or 4 (i.e., life-threatening) nonhematologic toxicity: Interrupt selinexor and monitor patient until toxicity improves to grade 2 or less; may then resume selinexor at a reduced dosage.1

Special Populations

Hepatic Impairment

No specific dosage recommendations.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations.1 (See Geriatric Use under Cautions.)

Cautions for Xpovio

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Thrombocytopenia

Thrombocytopenia commonly develops during selinexor therapy and appears to be a dose-related adverse effect.1 11 Median time to onset of 22 days.1 Bleeding reported, including rarely fatal hemorrhage.1

Monitor platelet count at baseline, during therapy, and as clinically indicated.1 Monitor more frequently during first 2 months of therapy.1 Promptly evaluate any signs or symptoms of bleeding.1 Administer platelet transfusions and/or other supportive care (e.g., thrombopoietin-receptor agonists such as romiplostim and eltrombopag) as clinically indicated.1 2 3 11 Treatment interruption or dosage reduction may be necessary.1 11 (See Thrombocytopenia under Dosage and Administration.)

Neutropenia

Neutropenia, including febrile neutropenia, may occur, potentially increasing the risk of infection.1 Median time to first onset of 25 days.1

Monitor ANC at baseline, during selinexor therapy, and as clinically indicated.1 Monitor more frequently during first 2 months of therapy.1 Monitor patients for signs or symptoms of infection and evaluate promptly.1 Administer supportive care, including anti-infectives and growth factors such granulocyte colony-stimulating factors (G-CSFs), as clinically indicated.1 Treatment interruption or dosage reduction may be necessary.1 (See Neutropenia under Dosage and Administration.)

GI Toxicity

GI toxicity is common.1 Nausea, vomiting, diarrhea, or anorexia reported in 72, 41, 44, or 53% of patients treated with selinexor, respectively.1 Median time to onset of first nausea or vomiting event was 3 or 5 days, respectively.1 Median time to onset of anorexia was 8 days and median time to onset of diarrhea or weight loss was 15 days.1

Administer prophylactic antiemetic therapy with a 5-HT3 receptor antagonist and/or other antiemetics prior to and during selinexor treatment.1

Monitor body weight at baseline, during therapy, and as clinically indicated.1 Monitor weight more frequently during first 2 months of therapy.1

Manage GI toxicities as clinically indicated (e.g., antiemetics, antidiarrhea agents, appetite stimulants, nutritional support).1 Treatment interruption or dosage reduction may be necessary.1 (See Dosage Modification for Toxicity under Dosage and Administration.) Patients should maintain adequate fluid and caloric intake throughout treatment.1 Administer IV fluids and electrolyte replacements in patients at risk of dehydration.1

Hyponatremia

Hyponatremia often develops during selinexor therapy.1 2 3 Median time to onset of the first event was 8 days.1

Monitor serum sodium concentrations (correcting for concurrent hyperglycemia and high serum paraprotein concentrations) at baseline, during selinexor therapy, and as clinically indicated.1 Monitor more frequently during first 2 months of therapy.1 Correct sodium concentrations for concurrent hyperglycemia (serum glucose concentrations >150 mg/dL) and high serum paraprotein concentrations.1 Treat hyponatremia as clinically appropriate (e.g., IV saline and/or oral sodium supplementation), including dietary review.1 Treatment interruption or dosage reduction may be necessary.1 (See Hyponatremia under Dosage and Administration.)

Infectious Complications

Infections, sometimes fatal, reported.1 Most commonly reported infections include upper respiratory tract infection, pneumonia, and sepsis.1 Most infections were not associated with neutropenia and were caused by non-opportunistic organisms.1 Median time to onset of pneumonia or sepsis was 54 or 42 days, respectively.1

Monitor for signs and symptoms of infection and treat any infection promptly.1

Neurologic Toxicity

Adverse neurologic effects, including dizziness, syncope, decreased level of consciousness, and mental status changes (including delirium and confusional state), can occur.1 Median time to first neurologic adverse reaction in clinical trials was 15 days.1

Optimize hydration status, hemoglobin concentrations, and concomitant drug therapy to avoid potential exacerbation of dizziness or mental status changes.1 Avoid situations where dizziness or confusional state may be a problem.1 (See Advice to Patients.)

Embryofetal Toxicity

May cause fetal harm based on its mechanism of action and animal findings; teratogenicity and growth alterations demonstrated in animals.1

Assess pregnancy status prior to initiation of selinexor therapy.1 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.1 Apprise patients of potential fetal risk.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Embryofetal Toxicity under Cautions.)

Lactation

Not known whether selinexor or its metabolites are distributed into milk.1 Effects on nursing infants or on milk production also not known.1

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

Pediatric Use

Safety and efficacy not established.1

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 (70 versus 58%) and fatal adverse reactions (17 versus 9%) and were more likely to discontinue treatment because of adverse reactions (44 versus 27%) compared with younger adults.1 (See Special Populations under Pharmacokinetics.)

Hepatic Impairment

Pharmacokinetics not substantially affected by mild hepatic impairment; effects of moderate or severe hepatic impairment on pharmacokinetics not known.1

Renal Impairment

Pharmacokinetics not affected by mild to severe renal impairment (Clcr15–89 mL/minute).1 Effects of end-stage renal disease (Clcr <15 mL/minute) or hemodialysis on pharmacokinetics not known.1

Common Adverse Effects

Adverse effects reported in ≥20% of patients receiving selinexor in combination with dexamethasone for relapsed or refractory multiple myeloma: Thrombocytopenia,1 fatigue,1 nausea,1 anemia,1 decreased appetite,1 weight loss,1 diarrhea,1 vomiting,1 hyponatremia,1 neutropenia,1 leukopenia,1 constipation,1 dyspnea,1 upper respiratory tract infection.1

Interactions for Xpovio

No formal drug interaction studies conducted to date.1

Principally metabolized by CYP3A4 and multiple UGTs, and glutathione S-transferases (GSTs).1

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

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

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.1

Xpovio Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations achieved within 4 hours following oral administration.1

Peak plasma concentrations and AUC are dose proportional over a dose range of 3–85 mg/m2 (0.06–1.8 times the recommended dose based on 1.7 m2 body surface area).1

Clinically relevant accumulation at steady state not observed.1

Food

Administration with a high-fat meal does not have clinically important effects on pharmacokinetics.1

Special Populations

No clinically important effect on pharmacokinetics by mild hepatic impairment or mild to severe renal impairment (Clcr 15–89 mL/minute).1

Effects of moderate or severe hepatic impairment, end-stage renal disease (Clcr <15 mL/minute), or hemodialysis on pharmacokinetics not known.1

Age (18–94 years), sex, and race/ethnicity do not substantially affect pharmacokinetics.1

Distribution

Extent

Not known whether selinexor or its metabolites are distributed into milk.1

Plasma Protein Binding

95%.1

Elimination

Metabolism

Selinexor is metabolized by CYP3A4 and multiple UGTs and GSTs.1

Half-life

6–8 hours.1

Stability

Storage

Oral

Tablets

≤30°C.1

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]).1

  • XPO1 overexpression is observed in a variety of malignancies, including multiple myeloma, and is associated with poor prognosis in multiple myeloma.2 4 5 6 7

  • 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.1 2 4 5

  • In preclinical studies, demonstrated proapoptotic activity in vitro in multiple myeloma cell lines and patient tumor samples and antitumor activity in murine xenograft models.1 2 8

Advice to Patients

  • Importance of advising patients to read the manufacturer's medication guide.1

  • Importance of instructing patients to take selinexor exactly as prescribed.1 Tablets should be swallowed whole with water and should not be broken, chewed, crushed, or divided.1

  • 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.1 An extra dose should not be taken to replace a missed or vomited dose.1

  • Importance of patients taking concomitant dexamethasone and prophylactic antiemetics exactly as prescribed.1

  • 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 2 months of treatment.1

  • Risk of hematologic adverse effects, including thrombocytopenia, anemia, and neutropenia.1 Importance of contacting 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.1

  • Risk of adverse GI effects such as nausea, vomiting, and diarrhea.1 Importance of contacting clinician if any of these adverse reactions occurs or persists.1

  • Importance of advising patients that fatigue commonly occurs during selinexor therapy.1

  • Risk of weight loss and decreased appetite.1 Advise patients to report decreased appetite and weight loss to their clinician.1

  • Importance of patients maintaining appropriate fluid and caloric intake during selinexor therapy.1

  • Risk of confusion and dizziness.1 Importance of advising patients to immediately notify their clinician if symptoms of neurological toxicity occur.1 Importance of advising patients to avoid driving or operating machinery until effects of the drug are known.1

  • Risk of hyponatremia.1 Importance of informing patients that hyponatremia may not be associated with specific symptoms.1

  • Risk of serious infections.1 Importance of instructing patients to notify their clinician if infection-related signs or symptoms (e.g., chills, fever) occur.1

  • Risk of fetal harm.1 Necessity of advising 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.1 Importance of advising patients to inform their clinicians if they are pregnant or think they may be pregnant.1

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

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

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.

Distribution of selinexor is restricted.9 (See Restricted Distribution under Dosage and Administration.)

Selinexor

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

20 mg

Xpovio 60 mg Once Weekly Therapy Pack (contains 4 blister packs [3 tablets per blister pack; 12 tablets total] for 4 weeks of therapy)

Karyopharm

Xpovio 80 mg Once Weekly Therapy Pack (contains 4 blister packs [4 tablets per blister pack; 16 tablets total] for 4 weeks of therapy)

Karyopharm

Xpovio 100 mg Once Weekly Therapy Pack (contains 4 blister packs [5 tablets per blister pack; 20 tablets total] for 4 weeks of therapy)

Karyopharm

Xpovio 80 mg Twice Weekly Therapy Pack (contains 4 blister packs [8 tablets per blister pack; 32 tablets total] for 4 weeks of therapy)

Karyopharm

AHFS DI Essentials™. © Copyright 2020, Selected Revisions June 15, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Karyopharm Therapeutics Inc. Xpovio (selinexor) tablets prescribing information. Newton, MA; 2019 Jul.

2. Chari A, Vogl DT, Gavriatopoulou M et al. Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. N Engl J Med. 2019; 381:727-738. http://www.ncbi.nlm.nih.gov/pubmed/31433920?dopt=AbstractPlus

3. Vogl DT, Dingli D, Cornell RF et al. Selective Inhibition of Nuclear Export With Oral Selinexor for Treatment of Relapsed or Refractory Multiple Myeloma. J Clin Oncol. 2018; 36:859-866. http://www.ncbi.nlm.nih.gov/pubmed/29381435?dopt=AbstractPlus

4. Gandhi UH, Senapedis W, Baloglu E et al. Clinical Implications of Targeting XPO1-mediated Nuclear Export in Multiple Myeloma. Clin Lymphoma Myeloma Leuk. 2018; 18:335-345. http://www.ncbi.nlm.nih.gov/pubmed/29610030?dopt=AbstractPlus

5. Sun Q, Chen X, Zhou Q et al. Inhibiting cancer cell hallmark features through nuclear export inhibition. Signal Transduct Target Ther. 2016; 1:16010. http://www.ncbi.nlm.nih.gov/pubmed/29263896?dopt=AbstractPlus

6. Gravina GL, Senapedis W, McCauley D et al. Nucleo-cytoplasmic transport as a therapeutic target of cancer. J Hematol Oncol. 2014; 7:85. http://www.ncbi.nlm.nih.gov/pubmed/25476752?dopt=AbstractPlus

7. Das A, Wei G, Parikh K et al. Selective inhibitors of nuclear export (SINE) in hematological malignancies. Exp Hematol Oncol. 2015; 4:7. http://www.ncbi.nlm.nih.gov/pubmed/25745591?dopt=AbstractPlus

8. Parikh K, Cang S, Sekhri A et al. Selective inhibitors of nuclear export (SINE)--a novel class of anti-cancer agents. J Hematol Oncol. 2014; 7:78. http://www.ncbi.nlm.nih.gov/pubmed/25316614?dopt=AbstractPlus

9. Karyopharm Therapeutics, Inc. Xpovio (selinexor) product information. From Xpovio website. Accessed 2020 Feb 27. https://xpoviopro.com/

10. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2019 Nov 4. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm

11. Machlus KR, Wu SK, Vijey P et al. Selinexor-induced thrombocytopenia results from inhibition of thrombopoietin signaling in early megakaryopoiesis. Blood. 2017; 130:1132-1143. http://www.ncbi.nlm.nih.gov/pubmed/28630120?dopt=AbstractPlus

12. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 212306Orig1s000: Multi-discipline Review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/212306Orig1s000MultidisciplineR.pdf