14/19. Selinexor- (XPOVIO) @ ( June 2019)- Multiple Myeloma
Drug Name:14/19. Selinexor- (XPOVIO) @ ( June 2019)- Multiple Myeloma
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
Drug Interaction Studies
Clinical Studies- No dedicated drug interaction studies have been performed with XPOVIO.
Indication:
Instruct patients to take exactly as prescribed. Advise patients to swallow the tablet whole with water. The tablet should not be broken, chewed, crushed, or divided.
If a patient misses a dose, advise them to take their next dose at its regularly scheduled time. If a patient vomits or misses a dose , advise them to take the next dose on the next regularly scheduled day.
Adverse Reaction:
ADVERSE REACTIONS
The most common adverse reactions (incidence =20%) are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection
Contra-Indications:
Neutropenia: Monitor neutrophil counts at baseline, during treatment, and as clinically indicated. Manage with dose interruption and/or reduction and granulocyte colony-stimulating factors (G-CSFs)
• Gastrointestinal Toxicity: Nausea, vomiting, diarrhea, anorexia, and weight loss may occur. Provide antiemetic prophylaxis. Manage with dose interruption and/or reduction, antiemetics, and supportive care
• Hyponatremia: Monitor serum sodium levels at baseline, during treatment, and as clinically indicated. Correct for concurrent hyperglycemia and high serum paraprotein levels
• Infections: Monitor for signs/symptoms of infection and treat promptly
• Neurological Toxicity: Avoid taking XPOVIO with other medications that may cause dizziness or confusion. Avoid situations where dizziness or confusional state may be a problem. Optimize hydration status, blood counts and concomitant medications to avoid dizziness or confusion
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential, and males with a female partner of reproductive potential, of the potential risk to a fetus and use of effective contraception
Dosages/ Overdosage Etc:
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Dosing Instructions:
Instruct patients to take XPOVIO exactly as prescribed. ? Advise patients to swallow the tablet whole with water. The tablet should not be broken, chewed, crushed, or divided.
If a patient misses a dose, advise them to take their next dose at its regularly scheduled time. If a patient vomits or misses a dose of XPOVIO, advise them to take the next dose on the next regularly scheduled day.
Advise patients that XPOVIO comes in a child-resistant blister pack.
Advise patients to take their prescribed dexamethasone and prophylactic anti-nausea medications exactly as prescribed
Advise patients that blood tests and body weight will be monitored at baseline and during treatment as clinically indicated, with more frequent monitoring during the first two months of treatment
Advise patients to maintain appropriate fluid and caloric intake throughout their treatment
Hematologic Adverse Reactions
Thrombocytopenia Advise patients that they may develop low platelet counts (thrombocytopenia). Symptoms of thrombocytopenia may include bleeding and easy bruising.
Advise patients that platelet counts will be monitored at baseline, during treatment, and as clinically indicated, with more frequent monitoring during the first 2 months of treatment.
Advise patients to report signs of bleeding right away
Anemia
Advise patients that they may develop anemia. Symptoms of anemia may includefatigue and shortness of breath. Advise patients to report signs or symptoms of anemia
Neutropenia
Advise patients that they may develop low neutrophil counts which may increase their susceptibility to infection
Advise patients that neutrophil counts will be monitored at baseline, during treatment, and as clinically indicated, with more frequent monitoring during the first 2 months of treatment.
Gastrointestinal Adverse Reactions
Advise patients they may experience nausea/vomiting or diarrhea and to contact their physician if these adverse reactions occur or persist
Fatigue Advise patients that they may experience fatigue Anorexia/Weight Loss
Advise patients that they may experience weight loss or decreased appetite. Advise patients to report decreased appetite and weight loss
Confusional State and Dizziness
Advise patients that they may experience confusion and dizziness. Advise patients not to operate motorized vehicles until they know how XPOVIO affects their abilities.
Advise patients to report symptoms of neurological toxicity right away.
Advise patients to avoid driving or operating machinery until they know how XPOVIO affects their abilities
Hyponatremia
Advise patients that they may develop low sodium levels (hyponatremia). Most cases of hyponatremia were not associated with specific symptoms.
Advise patients that levels of sodium will be monitored at baseline and during treatment as clinically indicated, with more frequent monitoring during the first two months of treatment
Infections
Advise patients of the possibility of serious infections. Instruct patients to report infection-related signs or symptoms (e.g., chills, fever)
Embryo-Fetal Toxicity
Advise females of reproductive potential of the potential risk to a fetus.
Prengancy
Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with XPOVIO
Females and Males of Reproductive Potential
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 final dose of XPOVIO
Lactation
Advise women not to breastfeed during treatment with XPOVIO and for 1 week after the final dose of XPOVIO
Concomitant Medications
Advise patients to take 5-HT3 antagonist prophylactic treatment and/or other anti-nausea agents prior to and during treatment with XPOVIO
Advise patients to speak with their physician about other medications they are currently taking and before starting any new medication.
Manufactured for and marketed by:
Karyopharm Therapeutics Inc., 85 Wells Avenue, Newton, MA, 02459. XPOVIO is a trademark of Karyopharm Therapeutics Inc. ©2019 Karyopharm Therapeutics Inc.
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. 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. 2.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.
3. 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 <15 mL/min) or hemodialysis on selinexor pharmacokinetics is unknown.
Mild hepatic impairment had no clinically significant effect on the pharmacokinetics of selinexor. The effect of moderate and severe hepatic impairment on selinexor pharmacokinetics is unknown.
Drug Interaction Studies
Clinical Studies- No dedicated drug interaction studies have been performed with XPOVIO.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy Risk Summary
Based on findings in animal studies and its mechanism of action , 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.
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.
2 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.
3. Females and Males of Reproductive Potential -Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating XPOVIO
Contraception XPOVIO can cause fetal harm when administered to a pregnant woman
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
4. Pediatric Use
The safety and effectiveness of XPOVIO have not been established in pediatric patients.
5. 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%).
