Xolremdi
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kosar Doraghi, M.D. [2]
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Black Box Warning
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Warnings: Embryo-fetal toxicity, QTc interval Prolongation
See full prescribing information for complete Boxed Warning.
Embryo-fetal toxicity: Expected to cause fetal harm. Advise women of reproductive potential to use effective contraception.
QTc Interval Prolongation
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Overview
Xolremdi is a CXC chemokine receptor 4 (CXCR4) antagonist that is FDA approved for the treatment of patients 12 years of age and older with WHIM syndrome (warts, hypogammaglobulinemia, infections and myelokathexis) to increase the number of circulating mature neutrophils and lymphocytes.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include thrombocytopenia, pityriasis, rash, rhinitis, epistaxis, vomiting, and dizziness.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
- For individuals weighing more than 50 kg: 400 mg orally once daily on an empty stomach, after an overnight fast, and at least 30 minutes before food.
- For individuals weighing 50 kg or less: 300 mg orally once daily on an empty stomach, after an overnight fast, and at least 30 minutes before food.
- Swallow the capsules whole; do not open, break, or chew them. If a dose is missed, take the next dose as scheduled. Do not take more than one dose per day.
- Capsules: 100 mg, opaque hard gelatin capsules with white body and light blue cap. The white capsule body is imprinted with "100 mg" in black ink, and the light blue capsule cap is imprinted
Off-Label Use and Dosage (Adult)
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Xolremdi FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Contraindications
Use with drugs highly dependent on CYP2D6 for clearance.
Warnings
|
Warnings: Embryo-fetal toxicity, QTc interval Prolongation
See full prescribing information for complete Boxed Warning.
Embryo-fetal toxicity: Expected to cause fetal harm. Advise women of reproductive potential to use effective contraception.
QTc Interval Prolongation
|
- Embryo-Fetal Toxicity
Based on its mechanism of action, XOLREMDI is expected to cause fetal harm when administered to a pregnant woman. Animal models link reductions in CXCR4/SDF-1 signaling to adverse outcomes in mammalian embryo-fetal development and abnormal placental development. Verify the pregnancy status of female patients of reproductive potential before starting XOLREMDI. Advise these patients to use effective contraception during treatment and for three weeks after the final dose.
- QTc Interval Prolongation
XOLREMDI causes concentration-dependent QTc interval prolongation, which may be exacerbated by concomitant medications that increase XOLREMDI exposure or have a known potential to prolong QT. Correct any modifiable risk factors for QTc prolongation, such as hypokalemia, assess QTc at baseline, and monitor QTc during treatment in patients at risk. A dose reduction or discontinuation of XOLREMDI may be necessary.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under varying conditions, adverse reaction rates observed in these trials cannot be directly compared to those in other trials and may not reflect real-world rates.
- The safety of XOLREMDI was evaluated in Study 1, a randomized placebo-controlled trial with 31 patients (adults and pediatric patients 12 years and older) with WHIM syndrome. Patients received either XOLREMDI (400 mg or 200 mg based on age and weight, N=14) or placebo (N=17). Thirteen patients received the 400 mg dose, and one patient received the 200 mg dose, which is recommended only for patients on strong CYP3A4 inhibitors. The standard dosage for other patients is 400 mg daily for those weighing more than 50 kg, or 300 mg daily for those weighing up to 50 kg, with adjustments needed for moderate CYP3A4 inhibitors or P-gp inhibitors.
- The following data are from the 52-week, placebo-controlled portion of the study. Twelve patients received XOLREMDI for at least six months, and ten patients for at least one year.
Postmarketing Experience
There is limited information regarding Xolremdi Postmarketing Experience in the drug label.
Drug Interactions
- Strong or Moderate CYP3A4 Inhibitors
Reduce the daily dosage of XOLREMDI when used with a strong CYP3A4 inhibitor.
- Monitor for adverse reactions when used with a moderate CYP3A4 inhibitor and reduce the daily dosage by steps of 100 mg if necessary, but not below 200 mg.
- Mavorixafor, the active ingredient in XOLREMDI, is a CYP3A4 substrate, and strong CYP3A4 inhibitors can increase its concentration, heightening the risk of adverse reactions.
- Strong CYP3A4 Inducers
Avoid using strong CYP3A4 inducers with XOLREMDI. As a CYP3A4 substrate, mavorixafor’s concentration and effectiveness can be reduced by strong CYP3A4 inducers.
- P-gp Inhibitors
Monitor for adverse reactions and reduce the dosage by steps of 100 mg if necessary, but not below 200 mg when used with P-gp inhibitors. Mavorixafor is a P-gp substrate, and P-gp inhibitors can increase its concentration, raising the risk of adverse reactions.
- Effect of XOLREMDI on Other Drugs
- CYP2D6 Substrates
XOLREMDI is contraindicated with drugs highly dependent on CYP2D6 for clearance. inhibits CYP2D6, increasing the risk of adverse reactions from CYP2D6 substrates.
- CYP3A4 Substrates
Monitor for adverse reactions when XOLREMDI is used with CYP3A4 substrates. Mavorixafor inhibits CYP3A4, potentially increasing the concentration and risk of adverse reactions from CYP3A4 substrates.
- P-gp Substrates
Monitor for adverse reactions when XOLREMDI is used with P-gp substrates. For digoxin, measure serum concentrations before and during concomitant use Mavorixafor inhibits P-gp, which can increase the concentration and risk of adverse reactions from P-gp substrates.
- Metformin
Monitor glycemic control and adjust metformin dosage as necessary. Mavorixafor may decrease metformin’s effectiveness by reducing its concentration, though the interaction mechanism is unknown.
- Drugs that Prolong the QTc Interval
Obtain an electrocardiogram when starting, during concomitant use, and as clinically indicated when using drugs that prolong the QTc interval. XOLREMDI causes QTc interval prolongation, and using it with other QTc-prolonging drugs can further increase the QTc interval, risking serious arrhythmias and sudden death.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Xolremdi in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Xolremdi in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Xolremdi during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Xolremdi in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Xolremdi in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Xolremdi in geriatric settings.
Gender
There is no FDA guidance on the use of Xolremdi with respect to specific gender populations.
Race
There is no FDA guidance on the use of Xolremdi with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Xolremdi in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Xolremdi in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Xolremdi in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Xolremdi in patients who are immunocompromised.
Administration and Monitoring
Administration
The recommended dosage of XOLREMDI is: Weight more than 50 kg: 400 mg orally once daily on an empty stomach after an overnight fast, and at least 30 minutes before food. Weight less than or equal to 50 kg: 300 mg orally once daily on an empty stomach after an overnight fast, and at least 30 minutes before food.
Monitoring
There is limited information regarding Xolremdi Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Xolremdi and IV administrations.
Overdosage
There is limited information regarding Xolremdi overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Xolremdi Pharmacology in the drug label.
Mechanism of Action
Mavorixafor is an orally bioavailable CXC Chemokine Receptor 4 (CXCR4) antagonist that blocks the binding of the CXCR4 ligand, stromal-derived factor-1α (SDF-1α)/CXC Chemokine Ligand 12 (CXCL12). SDF-1/CXCR4 plays a role in trafficking and homing of leukocytes to and from the bone marrow compartment. Gain of function mutations in the CXCR4 receptor gene that occur in patients with WHIM syndrome lead to increased responsiveness to CXCL12 and retention of leukocytes in the bone marrow. Mavorixafor inhibits the response to CXCL12 in both wild‑type and for mutated CXCR4 variants associated with WHIM syndrome. Treatment with mavorixafor results in increased mobilization of leukocytes and lymphocytes from the bone marrow into peripheral circulation.
Structure
Mavorixafor is an orally bioavailable CXC Chemokine Receptor 4 (CXCR4) antagonist
The chemical name of the active ingredient, mavorixafor, is N1-(1 H-benzimidazol-2-ylmethyl)- N1-(8 S)-5,6,7,8-tetrahydroquinolin-8-yl]butane-1,4-diamine. It has a molecular formula of C 21H 27N 5and a molecular weight of 349.48 g/mol. Mavorixafor is of the Sconfiguration and its structural formula is provided:
- Chemical Structure
Mavorixafor is optically active and is a white to pale yellow to light brown solid. Mavorixafor is hygroscopic above relative humidities of 70%.
- Mavorixafor is freely soluble in methanol, 95% ethanol and n-octanol, soluble in toluene, sparingly soluble in DMSO and acetonitrile, and very slightly soluble in HPLC grade water according to the USP solubility criteria.
Mavorixafor is soluble in pH 1.2 to 5.5 aqueous buffers and in pH 6.0 aqueous buffer, sparingly soluble in pH 6.8 aqueous buffer and slightly soluble in pH 7.5 aqueous buffer, according to the USP solubility criteria.
- XOLREMDI is a hard gelatin capsule for oral administration. Each capsule contains 100 mg of mavorixafor with the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate dihydrate, microcrystalline cellulose, sodium lauryl sulfate, and sodium stearyl fumarate. The hard gelatin capsule contains FD&C Blue #2, gelatin, and titanium dioxide. The Black Ink contains ammonium hydroxide 28%, ferrosoferric oxide/black iron oxide (E172), isopropyl alcohol, n-butyl alcohol, propylene glycol, and shellac glaze in ethanol.
Pharmacodynamics
ANC and ALC peaked at 4 hours after XOLREMDI dosing and returned towards baseline within 24 h after dosing. Over mavorixafor doses of 50 mg (0.125 times the maximum recommended dosage) to 400 mg once daily, higher mavorixafor exposure at steady state was associated with longer mean time (hours) above ANC threshold (TAT ANC) of 500 cells/µL and longer mean time (hours) above ALC threshold (TAT ALC) of 1,000 cells/µL over a 24-hour period.
- Cardiac Electrophysiology
In a thorough QT (TQT) study, the maximum mean increase in the QTc interval was 15.6 ms (upper bound of the 90% confidence interval = 19.8 ms) after administration of XOLREMDI 800 mg (2 times the maximum recommended dose) in healthy volunteers. In concentration-QT analysis the increase in the QTc interval was concentration-dependent.
Pharmacokinetics
Mavorixafor pharmacokinetic parameters are presented as geometric mean (CV%) in adults with WHIM syndrome unless otherwise specified. Mavorixafor steady state C maxis 3304 (58.6%) ng/mL and the AUC from 0 to 24 hours (AUC 0-24h) is 13970 (58.4%) ng*h/mL following 400 mg once daily. Mavorixafor demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in C maxand AUC 0-24over a dose range of 50 mg (0.125 times the recommended dosage) to 400 mg. Mavorixafor steady state is reached after approximately 9 to 12 days at the highest approved recommended dosage in healthy subjects.
- Absorption
Mavorixafor median (range) time to C max(T max) is 2.8 hours (1.9 to 4 hours) at the highest approved recommended dosage.
- Effect of Food
High Fat Meal:Mavorixafor C maxdecreased by 66% and AUC decreased by 55% following single-dose administration of XOLREMDI 400 mg with a high‑fat meal (1000 calories, 50% fat) to healthy subjects. Low Fat Meal:Mavorixafor C maxdecreased by 55% and AUC decreased by 51% following single-dose administration of XOLREMDI 400 mg with a low-fat meal (500 calories, 25% fat) to healthy subjects. In addition, a 14% higher mavorixafor C maxand 18% lower AUC was observed following single-dose administration of XOLREMDI 400 mg with a low-fat meal to healthy subjects after an overnight fast compared to fasting for an additional 4 hours after the XOLREMDI dose.
- Distribution
Mavorixafor volume of distribution is 768 L. Mavorixafor is >93% bound to human plasma proteins in vitro.
- Elimination
Mavorixafor's terminal half-life is 82 h (34%) with an apparent clearance of 62 L/h (40%) following single-dose administration of XOLREMDI 400 mg in health subjects. Mavorixafor exhibits at least partial nonlinear apparent clearance; however, this is not clinically significant at the approved recommended dosage.
- Metabolism
CYP3A4 and, to a lesser extent, CYP2D6 are primarily responsible for mavorixafor metabolism.
- Excretion
After a single oral dose of radiolabeled mavorixafor, 74.2% of the administered dose was recovered out of which 61.0% of administered radioactivity was recovered in feces and 13.2% (3% unchanged) was recovered in the urine over the 240-hour collection period in healthy subjects.
- Specific Populations
No clinically significant differences in the pharmacokinetics of mavorixafor were observed based on age (12 to 58 years), sex, or mild to moderate renal impairment (CLcr 30 to <90 mL/min as estimated by the Cockcroft-Gault formula). The effects of severe renal impairment (CLcr 15 to <30 mL/min), end-stage renal disease (CLcr <15 mL/min), and moderate to severe hepatic impairment on the pharmacokinetics of mavorixafor are unknown. Lower body weight was associated with lower mavorixafor clearance. Mavorixafor exposures in patients with WHIM syndrome are comparable between those weighing 50 kg or less who receive 300 mg once daily and those weighing greater than 50 kg who receive 400 mg once daily. Following 400 mg once daily, median C maxand AUC is 22% and 30% lower, respectively, in patients with higher body weight (85 kg and above) compared to patients with average body weight (50 to less than 85 kg). The difference in exposure between patients with average body weight and patients with higher body weight is not expected to have a clinically significant impact on patient outcomes.
Nonclinical Toxicology
There is limited information regarding Xolremdi Nonclinical Toxicology in the drug label.
Clinical Studies
The efficacy of XOLREMDI in patients aged 12 and older with WHIM syndrome was demonstrated in the 52-week, randomized, double-blind, placebo-controlled portion of Study1. Enrolled patients had a genotype-confirmed variant of CXCR4 consistent with WHIM syndrome, and a confirmed absolute neutrophil count (ANC) ≤400 cells/µL. Patients were permitted to continue (but not initiate) immunoglobulin therapy at the same dose. Use of other CXCR4 antagonists was not permitted.
Thirty-one patients were randomized 1:1 to receive either placebo (N=17) or XOLREMDI (N=14) once daily for 52 weeks. The efficacy of XOLREMDI in the treatment of patients with WHIM syndrome was based on improvement in absolute neutrophil counts (ANC), improvement in absolute lymphocyte counts (ALC), and a reduction in infections.
For ANC, the mean time (hours) above ANC threshold (TAT ANC) of 500 cells/µL over a 24-hour period was assessed 4 times throughout the study (every 3 months for 12 months). The results over the 52-week period showed that TAT ANCwas statistically significantly greater in patients treated with XOLREMDI (LS mean [SE] 15.0 [1.89] hours) compared with placebo (2.8 [1.52] hours) (p value <0.0001) For ALC, the mean time (hours) above ALC threshold (TAT ALC) of 1,000 cells/µL over a 24-hour period was assessed 4 times throughout the study (every 3 months for 12 months). The results over the 52-week period showed that TAT ALCwas statistically significantly greater in patients treated with XOLREMDI (LS mean [SE] 15.8 [1.39] hours) compared with placebo (4.6 [1.15] hours) (p value <0.0001). Analyses of the individual components of this composite endpoint showed an approximately 40% reduction of total infection score, weighted by infection severity, in XOLREMDI-treated patients compared with placebo-treated patients. The annualized infection rate was reduced approximately 60% in XOLREMDI-treated patients [LS mean (SE) 1.7(0.5)] compared with placebo-treated patients [LS mean (SE) 4.2(0.7)]. There was no difference in total wart change scores between the XOLREMDI and placebo treatment arms over the 52-week period.
How Supplied
XOLREMDI is supplied as an opaque white, hard gelatin capsule with a light blue cap, containing 100 mg of the active ingredient mavorixafor. The white capsule body is axially imprinted with "100 mg" in black ink, and the light blue capsule cap is axially imprinted with "MX4" in black ink. XOLREMDI is supplied in child-resistant bottles as follows:
- 60 count– NDC 83296-100-60
- 120 count– NDC 83296-100-12
Storage
Store XOLREMDI refrigerated at 2°C to 8°C (36°F to 46°F). Keep bottle tightly closed. Store in and dispense from original container to protect from moisture.
Images
Drug Images
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Package and Label Display Panel
NDC 83296-100-60
XOLREMDI™ (mavorixafor) capsules
100 mg
Swallow the capsules whole. Do not open, break, or chew capsules.
Rx only
60 capsules
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Patient Counseling Information
There is limited information regarding Xolremdi Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Xolremdi interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Xolremdi Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Xolremdi Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.