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Xpovio

Xpovio

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Xpovio is indicated in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody.

This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Xpovio Dosage and Administration Recommended Dosage

The recommended starting dosage of Xpovio is 80 mg (four 20 mg tablets) taken orally on Days 1 and 3 of each week until disease progression or unacceptable toxicity [see Clinical Studies (14.1)].

The recommended starting dosage of dexamethasone is 20 mg taken orally with each dose of Xpovio on Days 1 and 3 of each week. For additional information regarding the administration of dexamethasone, refer to its prescribing information.

Each Xpovio dose should be taken at approximately the same time of day, and each tablet should be swallowed whole with water. Do not break, chew, crush, or divide the tablets.

If a dose of Xpovio is missed or delayed, instruct patients to take their next dose at the next regularly scheduled time. If a patient vomits a dose of Xpovio, the patient should not repeat the dose and the patient should take the next dose on the next regularly scheduled day.

Recommended Monitoring for Safety

Monitor complete blood count (CBC), standard blood chemistry, and body weight at baseline and during treatment as clinically indicated. Monitor more frequently during the first two months of treatment [see Warning and Precautions (5.1, 5.2, 5.3, and 5.4)].

Recommended Concomitant Treatments

Advise patients to maintain adequate fluid and caloric intake throughout treatment.

Consider intravenous hydration for patients at risk of dehydration.

Provide prophylactic concomitant treatment with a 5-HT3 antagonist and/or other anti-nausea agents prior to and during treatment with Xpovio [see Warnings and Precautions (5.3)].

Dosage Modification for Adverse Reactions

Recommended Xpovio dosage reductions and dosage modifications for adverse reactions are presented in Table 1 and Table 2, respectively.

Refer to the dexamethasone prescribing information for dexamethasone dosage modifications due to adverse reactions.

Table 1: Xpovio Dosage Reduction Steps for Adverse Reactions
Recommended Starting Dosage First Reduction Second Reduction Third Reduction Discontinue
80 mg
Days 1 and 3 of each week
(160 mg total per week)
100 mg
once weekly
80 mg
once weekly
60 mg
once weekly
Table 2: Xpovio Dosage Modification Guidelines for Adverse Reactions

a. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.

Adverse Reactiona Occurrence Action
Hematologic Adverse Reactions
Thrombocytopenia
Platelet count 25,000 to less than 75,000/mcL Any
  • Reduce Xpovio by 1 dose level (see Table 1).
Platelet count 25,000 to less than 75,000/mcL with concurrent bleeding Any
  • Interrupt Xpovio.
  • Restart Xpovio at 1 dose level lower (see Table 1), after bleeding has resolved.
Platelet count less than 25,000/mcL Any
  • Interrupt Xpovio.
  • Monitor until platelet count returns to at least 50,000/mcL.
  • Restart Xpovio at 1 dose level lower (see Table 1).
Neutropenia
Absolute neutrophil count of 0.5 to 1.0 x 109/L without fever Any
  • Reduce Xpovio by 1 dose level (see Table 1).
Absolute neutrophil count less than 0.5 x 109/L
OR febrile neutropenia
Any
  • Interrupt Xpovio.
  • Monitor until neutrophil counts return to 1.0 x 109/L or higher.
  • Restart Xpovio at 1 dose level lower (see Table 1).
Anemia
Hemoglobin less than 8.0 g/dL Any
  • Reduce Xpovio by 1 dose level (see Table 1).
  • Administer blood transfusions and/or other treatments per clinical guidelines.
Life-threatening consequences
(urgent intervention indicated)
Any
  • Interrupt Xpovio.
  • Monitor hemoglobin until levels return to 8 g/dL or higher.
  • Restart Xpovio at 1 dose level lower (see Table 1).
  • Administer blood transfusions and/or other treatments per clinical guidelines.
Non-Hematologic Adverse Reactions
Hyponatremia
Sodium level 130 mmol/L or less Any
  • Interrupt Xpovio and provide appropriate supportive care.
  • Monitor until sodium levels return to 130 mmol/L or higher.
  • Restart Xpovio at 1 dose level lower (see Table 1).
Fatigue
Grade 2 lasting greater than 7 days
OR Grade 3
Any
  • Interrupt Xpovio.
  • Monitor until fatigue resolves to Grade 1 or baseline.
  • Restart Xpovio at 1 dose level lower (see Table 1).
Nausea and Vomiting
Grade 1 or 2 nausea (oral intake decreased without significant weight loss, dehydration or malnutrition)
OR Grade 1 or 2 vomiting (5 or fewer episodes per day)
Any
  • Maintain Xpovio and initiate additional anti-nausea medications.
Grade 3 nausea (inadequate oral caloric or fluid intake)
OR Grade 3 or higher vomiting (6 or more episodes per day)
Any
  • Interrupt Xpovio.
  • Monitor until nausea or vomiting has resolved to Grade 2 or lower or baseline.
  • Initiate additional anti-nausea medications.
  • Restart Xpovio at 1 dose level lower (see Table 1).
Diarrhea
Grade 2 (increase of 4 to 6 stools per day over baseline) 1st
  • Maintain Xpovio and institute supportive care.
2nd and subsequent
  • Reduce Xpovio by 1 dose level (see Table 1).
  • Institute supportive care.
Grade 3 or higher (increase of 7 stools or more per day over baseline; hospitalization indicated) Any
  • Interrupt Xpovio and institute supportive care.
  • Monitor until diarrhea resolves to Grade 2 or lower.
  • Restart Xpovio at 1 dose level lower (see Table 1).
Weight Loss and Anorexia
Weight loss of 10% to less than 20% OR anorexia associated with significant weight loss or malnutrition Any
  • Interrupt Xpovio and institute supportive care.
  • Monitor until weight returns to more than 90% of baseline weight.
  • Restart Xpovio at 1 dose level lower (see Table 1).
Other Non-Hematologic Adverse Reactions
Grade 3 or 4 (life threatening) Any
  • Interrupt Xpovio.
  • Monitor until resolved to Grade 2 or lower, restart Xpovio at 1 dose level lower (see Table 1).
Dosage Forms and Strengths

Tablets: 20 mg, blue, round, bi-convex, film-coated tablets with “K20” debossed on one side and nothing on the other side.

Contraindications

None.

Warnings and Precautions Thrombocytopenia

Xpovio can cause thrombocytopenia, leading to potentially fatal hemorrhage. Thrombocytopenia was reported as an adverse reaction in 74% of patients, and severe (Grade 3-4) thrombocytopenia occurred in 61% of patients treated with Xpovio. The median time to onset of the first event was 22 days. Bleeding occurred in 23% of patients with thrombocytopenia, clinically significant bleeding occurred in 5% of patients with thrombocytopenia and fatal hemorrhage occurred in 150 mg/dL) and high serum paraprotein levels. Treat hyponatremia per clinical guidelines (intravenous saline and/or salt tablets), including dietary review. Interrupt and/or reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.4) and Adverse Reactions (6.1)].

Infections

In patients receiving Xpovio, 52% of patients experienced any grade of infection. Upper respiratory tract infection of any grade occurred in 21%, pneumonia in 13%, and sepsis in 6% of patients. Grade ≥3 infections were reported in 25% of patients, and deaths resulting from an infection occurred in 4% of patients. The most commonly reported Grade ≥3 infections were pneumonia in 9% of patients, followed by sepsis in 6%. The median time to onset was 54 days for pneumonia and 42 days for sepsis. Most infections were not associated with neutropenia and were caused by non-opportunistic organisms [see Adverse Reactions (6.1)].

Neurological Toxicity

Neurological toxicities occurred in patients treated with Xpovio [see Adverse Reactions (6.1)].

Neurological adverse reactions including dizziness, syncope, depressed level of consciousness, and mental status changes (including delirium and confusional state) occurred in 30% of patients, and severe events (Grade 3-4) occurred in 9% of patients treated with Xpovio. Median time to the first event was 15 days.

Optimize hydration status, hemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes.

Embryo-Fetal Toxicity

Based on data from animal studies and its mechanism of action, Xpovio can cause fetal harm when administered to a pregnant woman. Selinexor administration to pregnant animals during organogenesis resulted in structural abnormalities and alterations to growth at exposures below those occurring clinically at the recommended dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with Xpovio and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3)].

Adverse Reactions

The following clinically significant adverse reactions are described in detail in other labeling sections:

  • Thrombocytopenia [see Warnings and Precautions (5.1)].
  • Neutropenia [see Warnings and Precautions (5.2)].
  • Gastrointestinal Toxicity [see Warnings and Precautions (5.3)].
  • Hyponatremia [see Warnings and Precautions (5.4)].
  • Infections [see Warnings and Precautions (5.5)].
  • Neurological Toxicity [see Warnings and Precautions (5.6)].
Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Xpovio plus dexamethasone in 202 patients with RRMM who received Xpovio 80 mg in combination with dexamethasone 20 mg on Days 1 and 3 of every week.

The median duration of Xpovio treatment was 8 weeks (range: 1 to 60 weeks). The median dose was 115.4 mg (range: 36 to 200 mg) per week.

The treatment discontinuation rate due to adverse reactions was 27%; 53% of patients had a reduction in the Xpovio dose, and 65.3% had the dose of Xpovio interrupted. The most frequent adverse reactions requiring permanent discontinuation in 4% or greater of patients who received Xpovio included fatigue, nausea, and thrombocytopenia. The rate of fatal adverse reactions was 8.9%.

The population had a median age of 64 years (range: 35 to 86 years), 54% were male, and the majority (73%) were White (17% were Black or African American).

Table 3 summarizes the most common (≥10% of patients) adverse reactions reported in patients with RRMM who received Xpovio and dexamethasone.

Table 3: Adverse Reactions with Xpovio 80 mg and Dexamethasone 20 mg Administered Twice Weekly

a. Thrombocytopenia includes thrombocytopenia and platelet count decreased.

b. Fatigue includes fatigue and asthenia.

c. Anemia includes anemia and hematocrit decreased.

d. Neutropenia includes neutropenia and neutrophil count decreased.

e. Dyspnea includes dyspnea, dyspnea exertional, and dyspnea at rest.

f. Upper respiratory tract infection includes upper respiratory tract infection, respiratory tract infection, pharyngitis, nasopharyngitis, bronchitis, bronchiolitis, respiratory syncytial virus infection, parainfluenza virus infection, rhinitis, rhinovirus infection, and adenovirus infection.

g. Cough includes cough, productive cough, and upper-airway cough syndrome.

h. Mental status changes includes mental status changes, confusional state, and delirium.

i. Hypercreatininemia includes hypercreatininemia and hypercreatinemia.

j. Pneumonia includes pneumonia, atypical pneumonia, lung infection, lower respiratory tract infection, pneumocystis jirovecii pneumonia, pneumonia aspiration, pneumonia influenzal, and pneumonia viral.

k. Includes fatal event.

Adverse Reaction Any Grade
(N = 202)
n (%)
Grade ≥3
(N = 202)
n (%)
Thrombocytopeniaa 149 (74) 124 (61)
Fatigueb 147 (73) 44 (22)
Nausea 146 (72) 18 (9)
Anemiac 119 (59) 81 (40)
Decreased appetite 108 (53) 9 (4.5)
Weight decreased 95 (47) 1 (0.5)
Diarrhea 89 (44) 13 (6)
Vomiting 82 (41) 7 (3.5)
Hyponatremia 78 (39) 44 (22)
Neutropeniad 68 (34) 43 (21)
Leukopenia 57 (28) 23 (11)
Constipation 50 (25) 3 (1.5)
Dyspneae 48 (24) 7 (3.5)k
Upper respiratory tract infectionf 42 (21) 6 (3)
Coughg 33 (16) 0
Mental status changesh 33 (16) 14 (7)
Pyrexia 32 (16) 1 (0.5)
Hyperglycemia 31 (15) 15 (7)
Dizziness 30 (15) 0
Insomnia 30 (15) 4 (2)
Lymphopenia 30 (15) 20 (10)
Dehydration 28 (14) 7 (3.5)
Hypercreatininemiai 28 (14) 4 (2)
Pneumoniaj 26 (13) 18 (9)k
Epistaxis 25 (12) 1 (0.5)
Hypokalemia 25 (12) 7 (3.5)
Dysgeusia 22 (11) 0
Vision blurred 21 (10) 1 (0.5)
Headache 20 (10) 0
USE IN SPECIFIC POPULATIONS Pregnancy

Risk Summary

Based on findings in animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], Xpovio can cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of selinexor to pregnant rats during organogenesis resulted in structural abnormalities and alterations to growth at exposures that were below those occurring clinically at the recommended dose (see Data). Advise pregnant women of the risks to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal data

In an embryo-fetal development study in pregnant rats, daily oral administration of selinexor at 0, 0.25, 0.75, or 2 mg/kg throughout organogenesis caused incomplete or delayed ossification, skeletal variations, and reduced fetal weight compared with controls at a dose of 0.75 mg/kg (approximately 0.08-fold of human area under the curve [AUC] at the recommended dose). Malformations were observed at 2 mg/kg, including microphthalmia, fetal edema, malpositioned kidney, and persistent truncus arteriosus.

Lactation

Risk Summary

There is no information regarding the presence of selinexor or its metabolites in human milk, or their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with Xpovio and for 1 week after the last dose.

Females and Males of Reproductive Potential

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating Xpovio [see Use in Specific Populations (8.1)].

Contraception

Xpovio can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise females of reproductive potential to use effective contraception during treatment with Xpovio and for 1 week after the last dose.

Males

Advise males with a female partner of reproductive potential to use effective contraception during treatment with Xpovio and for 1 week after the last dose.

Infertility

Females and Males

Based on findings in animals, Xpovio may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].

Pediatric Use

The safety and effectiveness of Xpovio have not been established in pediatric patients.

Geriatric Use

Of the 202 patients with RRMM who received Xpovio, 49% were 65 years of age and over, while 11% were 75 years of age and over. No overall difference in effectiveness was observed in patients over 65 years of age, including patients over 75 years of age, when compared with younger patients. When comparing patients 75 years of age and older to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (44% vs 27%), higher incidence of serious adverse reactions (70% vs 58%), and higher incidence of fatal adverse reactions (17% vs 9%).

Xpovio Description

Xpovio (selinexor) is an orally available nuclear export inhibitor.

Selinexor is (2Z)-3-{3-[3,5-bis(trifluoromethyl)phenyl]-1H-1,2,4-triazol-1-yl}-N'-(pyrazin-2-yl)prop-2-enehydrazide. It is a white to off-white powder and has the molecular formula C17H11F6N7O and a molecular mass of 443.31 g/mol.

The molecular structure is shown below:

Each Xpovio (selinexor) tablet contains 20 mg of selinexor as the active ingredient.

Xpovio tablets are blue, round, bi-convex, film-coated tablets with “K20” debossed on one side and nothing on the other side. The inactive ingredients are colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, Opadry 200 clear, Opadry II blue, povidone K30, and sodium lauryl sulfate.

Xpovio - Clinical Pharmacology Mechanism of Action

In nonclinical studies, selinexor reversibly inhibits nuclear export of tumor suppressor proteins (TSPs), growth regulators, and mRNAs of oncogenic proteins by blocking exportin 1 (XPO1). XPO1 inhibition by selinexor leads to accumulation of TSPs in the nucleus, reductions in several oncoproteins, such as c-myc and cyclin D1, cell cycle arrest, and apoptosis of cancer cells. Selinexor demonstrated pro-apoptotic activity in vitro in multiple myeloma cell lines and patient tumor samples, and in murine xenograft models.

Pharmacodynamics

Xpovio exposure-response relationships and the time course of pharmacodynamic responses are unknown.

Cardiac Electrophysiology

The effect of multiple doses of Xpovio, up to 175 mg (2.2 times the approved recommended dose) twice weekly, on the QTc interval was evaluated in patients with heavily pretreated hematologic malignancies. Xpovio had no large effect (i.e. no greater than 20 ms) on QTc interval at the therapeutic dose level.

Pharmacokinetics

Following a single-dose administration of Xpovio 80 mg, the mean (standard deviation) peak plasma concentration (Cmax) was 680 (124) ng/mL and the mean AUC was 5386 (1116) ng•h/mL. Selinexor Cmax and AUC increased proportionally over doses from 3 mg/m2 to 85 mg/m2 (0.06 to 1.8 times the approved recommended dose based on 1.7 m2 body surface area). No clinically relevant accumulation at steady state was observed.

Absorption

The Cmax is reached within 4 hours following oral administration of Xpovio.

Effect of Food

Concomitant administration of a high-fat meal (800 to 1,000 calories with approximately 50% of total caloric content of the meal from fat) did not affect the pharmacokinetics of selinexor to a clinically significant extent.

Distribution

The apparent volume of distribution of selinexor is 125 L in patients with cancer. The protein binding of selinexor is 95%.

Elimination

Following a single dose of Xpovio, the mean half-life is 6 to 8 hours. The apparent total clearance of selinexor is 17.9 L/h in patients with cancer.

Metabolism

Selinexor is metabolized by CYP3A4, multiple UDP-glucuronosyltransferases (UGTs) and glutathione S-transferases (GSTs).

Specific Populations

No clinically significant differences in the pharmacokinetics of selinexor were observed based on age (18 to 94 years old), sex, ethnicity, mild to severe renal impairment (CLCR: 15 to 89 mL/min, estimated by the Cockcroft-Gault equation). The effect of end-stage renal disease (CLCR

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