Brand name: Xolremdi
Drug class: Hematopoietic Agents

Medically reviewed by Drugs.com on Dec 10, 2024. Written by ASHP.

[Web]

Introduction

CXC chemokine receptor 4 (CXCR4) antagonist; hematopoietic agent.

Uses for Mavorixafor

WHIM Syndrome

Treatment of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome in adults and pediatric patients ≥12 years of age (designated an orphan drug by FDA for this use).

A practice parameter by the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) recommends IgG replacement, granulocyte colony-stimulating factor therapy, or both for the treatment of WHIM syndrome. Human papillomavirus vaccination and hematopoietic stem cell transplantation may also be considered. Mavorixafor was not approved at the time of guideline publication and its place in therapy relative to other agents remains unclear. Some experts suggest that inhibitors of CXCR4 (e.g., plerixafor, mavorixafor) may provide an opportunity for more targeted therapy in WHIM syndrome.

Mavorixafor Dosage and Administration

General

Pretreatment Screening

• Verify pregnancy status in females of reproductive potential.

• Assess QT interval corrected for rate (QT_c interval) at baseline in patients with risk factors for QT_c prolongation.

Patient Monitoring

• Assess QT_c interval during mavorixafor therapy as clinically indicated in patients with risk factors for QT_c prolongation.

Administration

Oral Administration

Available as capsules containing 100 mg of the drug.

Administer capsules on empty stomach after an overnight fast, ≥30 minutes before food.

Swallow capsules whole; do not open, break, or chew capsules.

If a dose of mavorixafor is missed, take next dose as scheduled. Do not take more than 1 dose each day.

Dosage

Pediatric Patients

WHIM Syndrome

Oral

≥12 years of age and weight ≤50 kg: 300 mg once daily.

≥12 years of age and weight >50 kg: 400 mg once daily.

Adults

WHIM Syndrome

Oral

Weight ≤50 kg: 300 mg once daily.

Weight >50 kg: 400 mg once daily.

Special Populations

Hepatic Impairment

No dosage adjustment recommended in patients with mild hepatic impairment.

Not recommended for use in patients with moderate to severe hepatic impairment.

Renal Impairment

No dosage adjustment recommended in patients with mild to moderate renal impairment (Cl_cr 30 to <90 mL/minute).

Not recommended for use in patients with severe renal impairment (Cl_cr 15 to <30 mL/minute) or end-stage renal disease (Cl_cr <15 mL/minute).

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Mavorixafor

Contraindications

• Use with drugs that are highly dependent on CYP2D6 for clearance.

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

Expected to cause fetal harm based on mechanism of action.

Animal models link reductions in CXC chemokine receptor 4 (CXCR4)/stromal-derived factor (SDF-1) signaling to adverse outcomes in mammalian embryo-fetal development and to abnormal placental development.

Verify pregnancy status in females of reproductive potential prior to initiating mavorixafor. Apprise pregnant women of potential fetal hazard.

Advise females of reproductive potential to use effective method of contraception during treatment with mavorixafor and for 3 weeks after the last dose.

QTCInterval Prolongation

Causes concentration-dependent prolongation of QT interval corrected for rate (QT_c interval). QT_c interval prolongation may occur with concomitant use of drugs that increase mavorixafor exposure and/or drugs with known potential to prolong QT_c interval.

Correct any modifiable risk factors for QT_c interval prolongation (e.g., hypokalemia).

Assess QT_c interval at baseline. Monitor QT_c interval during treatment as clinically indicated in patients with risk factors for QT_c interval prolongation, such as those receiving concomitant medications that increase mavorixafor exposure and/or drugs known to prolong QT_c interval. Reduction in mavorixafor dosage or discontinuation of mavorixafor may be necessary.

Specific Populations

Pregnancy

Expected to cause fetal harm based on mechanism of action.

No data available on use in pregnant women to inform risk of embryo-fetal developmental toxicities. Animal models link reductions in CXCR4/SDF-1 signaling to adverse outcomes in mammalian embryo-fetal development and to abnormal placental development. No definitive animal studies performed to study effects of mavorixafor on reproduction and fetal development.

Verify pregnancy status in females of reproductive potential prior to initiating mavorixafor. Apprise pregnant women of potential fetal hazard. Advise females of reproductive potential to use effective method of contraception during treatment and for 3 weeks after the last dose.

Lactation

No data on presence in human or animal milk, effects on breast-fed child, or effects on milk production.

Advise patients not to breast-feed during treatment and for 3 weeks after the last dose.

Females and Males of Reproductive Potential

Perform pregnancy testing in females of reproductive potential prior to initiating mavorixafor.

Advise females of reproductive potential to use effective method of contraception during treatment and for 3 weeks after the last dose.

Pediatric Use

Safety and effectiveness established in pediatric patients ≥12 years of age. No clinically important differences in mavorixafor pharmacokinetics identified in pediatric patients 12 to <17 years of age with WHIM syndrome compared to adults after accounting for differences in body weight.

Safety and effectiveness not established in pediatric patients <12 years of age.

Geriatric Use

Clinical studies did not include sufficient numbers of patients ≥65years of age to determine whether they respond differently from younger patients.

Hepatic Impairment

Pharmacokinetics not studied in individuals with moderate to severe hepatic impairment; use not recommended in this population.

Renal Impairment

No clinically important differences in pharmacokinetics observed in patients with mild to moderate renal impairment (Cl_cr30 to <90 mL/minute).

Pharmacokinetics not studied in individuals with severe renal impairment (Cl_cr 15 to <30 mL/minute) or end-stage renal disease (Cl_cr <15 mL/minute); use not recommended in these populations.

Common Adverse Effects

Most common adverse effects (incidence >10% and at a frequency higher than placebo): thrombocytopenia, pityriasis, rash, rhinitis, epistaxis, vomiting, dizziness.

Drug Interactions

Substrate of CYP3A4, CYP2D6, CYP3A5, and CYP2C19; not a substrate of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, or CYP4A11. Inhibitor of CYP3A4 (time dependent), CYP3A5, CYP2D6, CYP2B6, CYP1A2, CYP2C8, CYP2C9, and CYP2C19. Inducer of CYP1A2; not an inducer of CYP2B6, CYP2C8, CYP2C9, or CYP3A4.

Substrate of P-glycoprotein (P-gp); not a substrate of organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, multidrug and toxin extrusion (MATE) 1, or MATE2-K. Inhibitor of P-gp, OCT2, and MATE1; not an inhibitor of breast cancer resistance protein (BCRP), OATP1B1, OATP1B3, OAT1, OAT3, and MATE2-K.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Strong CYP3A4 Inhibitors

Concomitant use increases mavorixafor peak plasma concentration and AUC, which may increase risk of adverse reactions associated with mavorixafor.

Reduce daily dosage of mavorixafor to 200 mg when used concomitantly with a strong CYP3A4 inhibitor.

Moderate CYP3A4 Inhibitors

Concomitant use may increase mavorixafor exposure, which may increase risk of adverse reactions associated with mavorixafor.

If used concomitantly, reduce daily dosage of mavorixafor by decrements of 100 mg, if necessary, but not to less than 200 mg. Monitor more frequently for adverse reactions associated with increase in mavorixafor exposure.

Strong CYP3A4 Inducers

Concomitant use predicted to decrease mavorixafor peak plasma concentration and AUC, which may reduce effectiveness of mavorixafor.

Avoid concomitant use.

CYP3A4 Substrates

Concomitant use may increase peak plasma concentration and AUC of CYP3A4 substrates, which may increase risk of adverse reactions associated with the substrates.

When mavorixafor is used concomitantly with CYP3A4 substrates where minimal substrate concentration changes may lead to serious adverse reactions, monitor more frequently for adverse reactions related to the CYP3A4 substrate, unless otherwise recommended in the prescribing information for the substrate.

CYP2D6 Substrates

Concomitant use increases exposure of CYP2D6 substrates, which may increase risk of adverse reactions related to these substrates.

Use of mavorixafor with drugs highly dependent on CYP2D6 for clearance is contraindicated.

Drugs Affecting or Affected by Transport Systems

P-gp Inhibitors

Concomitant use increases mavorixafor peak plasma concentration and AUC, which may increase risk of adverse reactions associated with mavorixafor.

If used concomitantly, reduce daily dosage of mavorixafor by decrements of 100 mg, if necessary, but not to less than 200 mg. Monitor more frequently for adverse reactions associated with increase in mavorixafor exposure.

P-gp Substrates

Concomitant use may increase peak plasma concentration and AUC of P-gp substrates, which may increase risk of adverse reactions associated with the substrates.

When mavorixafor is used concomitantly with P-gp substrates where minimal substrate concentration changes may lead to serious adverse reactions, monitor more frequently for adverse reactions related to the P-gp substrate, unless otherwise recommended in the prescribing information for the substrate.

Drugs that Prolong the QTc Interval

Mavorixafor prolongs QT interval corrected for rate (QT_cinterval). Concomitant use with other drugs that prolong QT_c interval may result in greater increase in QT_c interval and adverse reactions associated with QT_c interval prolongation (e.g., torsade de pointes, other serious arrythmias, sudden death).

Obtain an electrocardiogram when initiating, during concomitant use, and as clinically indicated in patients receiving concomitant drugs with known potential to prolong QT_c interval.

Specific Drugs

Mavorixafor Pharmacokinetics

Absorption

Bioavailability

Demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in peak plasma concentration and AUC over dosage range of 50–400 mg.

Steady state reached after approximately 9–12 days at highest approved recommended dosage.

Median time to peak plasma concentration is 2.8 hours (range 1.9–4 hours) at highest approved recommended dosage.

Onset

ANC and absolute lymphocyte count (ALC) peaked at 4 hours after dosing.

Duration

ANC and ALC returned towards baseline within 24 hours after dosing.

Food

Peak plasma concentration and AUC decreased by 66 and 55%, respectively, following single-dose administration of 400 mg with high‑fat meal (1000 calories, 50% fat) in healthy subjects.

Peak plasma concentration and AUC decreased by 55 and 51%, respectively, following single-dose administration of 400 mg with low-fat meal (500 calories, 25% fat) in healthy subjects.

14% higher peak plasma concentration and 18% lower AUC observed following single-dose administration of 400 mg with low-fat meal to healthy subjects after an overnight fast compared to fasting for an additional 4 hours after dose.

Distribution

Extent

Unknown if distributed into human or animal milk.

Plasma Protein Binding

>93%.

Elimination

Metabolism

Primarily metabolized by CYP3A4 and, to a lesser extent, by CYP2D6.

Elimination Route

Fecal excretion: 61%.

Renal excretion: 13.2% (3% unchanged).

Half-life

82 hours.

Special Populations

No clinically important differences in pharmacokinetics observed based on age (12–58 years), sex, or mild to moderate renal impairment.

Lower body weight associated with lower clearance.

Exposures comparable between patients weighing ≤50 kg who receive 300 mg once daily and those weighing >50 kg who receive 400 mg once daily.

Following administration of 400 mg once daily, median peak plasma concentration and AUC is 22 and 30% lower, respectively, in patients with higher body weight (≥85 kg) compared to those with average body weight (50 kg to <85 kg); not expected to have clinically important impact on patient outcomes.

Stability

Storage

Oral

Capsules

Refrigerated at 2–8°C. Keep bottle tightly closed. Store and dispense in original container to protect from moisture.

Actions

• Orally bioavailable CXC chemokine receptor 4 (CXCR4) antagonist.

• Prevents binding of CXCR4 ligand, stromal-derived factor-1α (SDF-1α)/CXC chemokine ligand 12 (CXCL12), which plays a role in trafficking and homing of leukocytes to and from the bone marrow compartment.

• Inhibits response to CXCL12 in both wild‑type and mutated CXCR4 variants associated with WHIM syndrome, resulting in increased mobilization of neutrophils and lymphocytes into peripheral circulation.

Advice to Patients

• Advise patients to take mavorixafor on an empty stomach after an overnight fast, at least 30 minutes before food. Advise patients to swallow the capsules whole and not to open, break, or chew the capsules.

• Advise patients that mavorixafor may cause fetal harm. Advise females to inform their clinician of a known or suspected pregnancy. Advise females of reproductive potential to use an effective form of contraception during treatment with mavorixafor and for 3 weeks after the last dose.

• Advise females that breast-feeding is not recommended during treatment with mavorixafor and for 3 weeks after the last dose.

• 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 to avoid taking dietary supplements that include goldenseal or St. John’s wort, since goldenseal may increase the risk of adverse reactions from mavorixafor and St. John’s wort may reduce the efficacy of mavorixafor.

• Advise patients to avoid eating or drinking products with grapefruit, since grapefruit may increase the risk of adverse reactions from mavorixafor.

• Inform patients of other important precautionary information.

Additional Information

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.

Mavorixafor is obtained through designated specialty pharmacies. Contact the manufacturer or consult the Xolremdi website ([Web]) for specific availability information.

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