Xolremdi Drug Information
Generic name: MAVORIXAFOR
CXC Chemokine Receptor 4 Antagonist [EPC]
Uses of Xolremdi
XOLREMDI is indicated in patients 12 years of age and older with WHIM syndrome (warts, hypogammaglobulinemia, infections and myelokathexis) to increase the number of circulating mature neutrophils and lympocytes.
Dosage & Administration of Xolremdi
Recommended Dosage
- 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. Swallow the capsules whole. Do not open, break, or chew capsules. If a dose of XOLREMDI is missed, the next dose should be taken as scheduled. Do not take more than 1 XOLREMDI dose each day.
Dosage Modifications for Strong
CYP3A4 inhibitors Reduce daily dosage of XOLREMDI to 200 mg when used concomitantly with strong CYP3A4 inhibitors.
Side Effects of Xolremdi
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 safety of XOLREMDI was evaluated in Study 1, a randomized placebo-controlled trial of 31 adult and pediatric patients 12 years and older with WHIM syndrome. Patients received XOLREMDI 400 mg or 200 mg, based on age and body weight (N=14) or placebo (N=17).
One patient received the 200 mg dose, and 13 patients received the 400 mg dose. Note that the 200 mg XOLREMDI daily dose is only recommended for use in patients receiving strong CYP3A4 inhibitors. For all other patients, the recommended dosage is either 400 mg daily (if weighing more than 50 kg) or 300 mg daily (if weighing up to 50 kg), unless dose reductions are needed due to concomitant use with moderate CYP3A4 inhibitors or P-gp inhibitors.
The data below are based on the 52-week, placebo-controlled portion of the study. Twelve patients received XOLREMDI for at least 6 months, and 10 patients received XOLREMDI for at least 1 year. Table 1 summarizes the most common adverse reactions (>10%) in Study 1, which were thrombocytopenia, pityriasis, rash, rhinitis, epistaxis, vomiting, and dizziness.
| Number (N) and Percent (%) of Patients | ||
|---|---|---|
| Adverse Reaction | XOLREMDI (N=14) | Placebo (N=17) |
| Thrombocytopenia | 3 (21%) | 0 |
| Pityriasis | 2 (14%) | 0 |
| Rash | 2 (14%) | 0 |
| Rhinitis | 2 (14%) | 0 |
| Epistaxis | 2 (14%) | 1 (6%) |
| Vomiting | 2 (14%) | 1 (6%) |
| Dizziness | 2 (14%) | 1 (6%) |
Warnings & Cautions for Xolremdi
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 to abnormal placental development. Verify the pregnancy status of female patients of reproductive potential prior to starting XOLREMDI.
Advise females of reproductive potential to use an effective method of contraception during treatment with XOLREMDI and for 3 weeks after the final dose.
QTc Interval Prolongation
XOLREMDI causes concentration-dependent QTc interval prolongation. QTc interval prolongation may occur when XOLREMDI is taken with concomitant medications that increase XOLREMDI exposure and/or drug products with a known potential to prolong QTc. Correct any modifiable risk factors for QTc prolongation (e.g., hypokalemia), assess QTc at baseline and monitor QTc during treatment as clinically indicated in patients with risk factors for QTc prolongation such as those receiving concomitant medications that increase XOLREMDI exposure and drug products with a known potential to prolong QTc.
A dose reduction in XOLREMDI or discontinuation of XOLREMDI may be required.
Drug Interactions with Xolremdi
Effect of Other Drugs on XOLREMDI Strong or Moderate CYP3A4 Inhibitors Reduce XOLREMDI daily dosage to 200 mg when used concomitantly with a strong CYP3A4 inhibitor. Monitor more frequently for XOLREMDI adverse reactions that may be associated with an increase in mavorixafor exposure when used concomitantly with moderate CYP3A4 inhibitor and reduce the XOLREMDI daily dosage by steps of 100 mg, if necessary, but not to a dose less than 200 mg. Mavorixafor is a CYP3A4 substrate.
Concomitant use with a strong CYP3A4 inhibitor increases mavorixafor maximal concentrations (C max ) and area under the concentration-time curve (AUC), which may increase the risk of XOLREMDI adverse reactions. Strong CYP3A4 Inducers Avoid concomitant use with a strong CYP3A4 inducer. Concomitant use with a strong CYP3A4 inducer is predicted to decrease mavorixafor C max and AUC based upon a mechanistic understanding of its elimination, which may reduce XOLREMDI's effectiveness.
Mavorixafor is a P-gp substrate. Concomitant use with a P-gp inhibitors increases mavorixafor C max and AUC, which may increase the risk of XOLREMDI adverse reactions.
Effect of XOLREMDI on Other Drugs CYP2D6 Substrates
The use of XOLREMDI with drugs that are another drug highly dependent on CYP2D6 for clearance is contraindicated. Mavorixafor is a CYP2D6 inhibitor. Mavorixafor increases exposure of CYP2D6 substrates, which may increase the risk of adverse reactions related to these substrates.
CYP3A4 Substrates Monitor for CYP3A4 substrate related adverse reactions more frequently, unless otherwise recommended in the substrate's Prescribing Information, when XOLREMDI is used concomitantly with CYP3A4 substrates where minimal substrate concentration changes may lead to serious adverse reactions. Mavorixafor is an inhibitor of CYP3A4. Mavorixafor may increase the C max and AUC of CYP3A4 substrates, which may increase the risk of adverse reactions from the CYP3A4 substrate.
Digoxin: Measure serum digoxin concentrations before initiating concomitant use with XOLREMDI, and continue monitoring serum digoxin concentrations as recommended in the Prescribing Information for digoxin. Mavorixafor is an inhibitor of P-gp. Metformin: Monitor for glycemic control and adjust the dose of metformin as necessary.
Mavorixafor may decrease the mean C max and AUC of metformin, which may reduce metformin's effectiveness. The mechanism of this interaction is unknown.
Drugs that Prolong the QTc Interval Obtain an electrocardiogram when initiating, during concomitant use, and as clinically indicated in patients receiving concomitant medications with a known potential to prolong the QTc interval. XOLREMDI causes QTc interval prolongation. Concomitant use of XOLREMDI with other products that prolong QTc interval may result in a greater increase in QTc interval and adverse reactions associated with QTc interval prolongation, including torsade de pointes, other serious arrythmias, and sudden death.
Pregnancy Safety for Xolremdi
Pregnancy Risk Summary Based on its mechanism of action, XOLREMDI is expected to cause fetal harm when administered to a pregnant woman. There are no available data on XOLREMDI use in pregnant women informing the risk of embryo-fetal developmental toxicities. Animal models link reductions in CXCR4/SDF-1 signaling to adverse outcomes in mammalian embryo-fetal development (see Data ).
No definitive animal studies have been conducted to evaluate the effect of mavorixafor on reproduction and fetal development. Advise pregnant women of the potential risk to the fetus and to use effective contraception. The estimated background risk of major birth defects and miscarriages 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 respectively. Data Animal Data Animal reproduction studies have not been conducted with mavorixafor to evaluate effects on reproduction and embryo-fetal development.
CXCR4/SDF-1 signaling plays an important role in mammalian embryo-fetal and placental development. In mice, CXCR4-/- knockout is embryo lethal and causes multiple developmental toxicities, most notably in the hematopoietic, cardiovascular and nervous systems. CXCR4/SDF-1 levels have a key role in stimulating trophoblast proliferation and differentiation necessary for appropriate placental growth and function in humans.
Pediatric Use of Xolremdi
Pediatric Use The safety and effectiveness of XOLREMDI in WHIM syndrome for increasing the number of circulating mature neutrophils and lymphocytes have been established in pediatric patients aged 12 years and older. Use of XOLREMDI for this indication is supported by evidence from an adequate and well-controlled study in adults and pediatric patients aged 12 years and older. The safety and effectiveness of XOLREMDI have not been established in pediatric patients younger than 12 years of age.
Contraindications for Xolremdi
Use of XOLREMDI is contraindicated with drugs that are highly dependent on CYP2D6 for clearance.
Clinical Studies of Xolremdi
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 Study 1. 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. Baseline patient demographics are shown in Table 2. 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.
Table 3 Mean Time (hours) Above ANC Threshold (TAT ANC ) in Study 1 - 1 - The results are based on an MMRM analysis with time above threshold as a dependent variable; treatment, visit Weeks treatment*visit, Ig use (randomization strata), and baseline time above threshold as covariates; and patient as the repeated random effect. The results over the 52-week period showed that TAT ALC was statistically significantly greater in patients treated with XOLREMDI (LS mean 15.8 hours) compared with placebo (4.6 hours) (p value <0.0001). The efficacy of XOLREMDI was further assessed in a composite endpoint consisting of total infection score and total wart change score using a Win-Ratio method (Table 4).
The Win-Ratio of 2.76 is the number of pairs of XOLREMDI-treated patient "wins" divided by the number of pairs of placebo patient "wins." Table 4: Win-Ratio Analysis The method compared each XOLREMDI-treated patient to each placebo-treated patient in a pair-wise manner that proceeded in a hierarchical fashion using total infection score, followed by total wart change score if patients could not be differentiated based on total infection score. The total infection score was calculated by summing up the number of infection events weighted by severity and divided by the total exposure time (in years). Total wart change score was calculated by summing up the regional wart change scores from all 3 target regions (lesions). for the Composite Clinical Efficacy Endpoint Based on Total Infection Score and Total Wart Change Score 1 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 compared with placebo-treated patients. There was no difference in total wart change scores between the XOLREMDI and placebo treatment arms over the 52-week period. Figure 2
| Demographics and Disease Characteristics | XOLREMDI (N = 14) | Placebo (N = 17) |
|---|---|---|
| Abbreviations: SD = standard deviation; Ig = immunoglobulin. | ||
| Note: Percentages are calculated based on the number of patients within each characteristic as denominator. | ||
| Demographics | ||
| Age (years) Mean (SD) | 22.1 (12.20) | 30.9 (21.25) |
| Age group, n (%) | ||
| 12 to <18 years | 7 (50) | 8 (47.1) |
| ≥18 years | 7 (50) | 9 (52.9) |
| Sex, n (%) | ||
| Male | 5 (35.7) | 8 (47.1) |
| Female | 9 (64.3) | 9 (52.9) |
| Race, n (%) | ||
| White | 13 (93) | 16 (94) |
| Asian | 0 | 1 (6) |
| Other | 1 (7) | 0 |
| Ethnicity, n (%) | ||
| Not Hispanic or Latino | 13 (93) | 17 (100) |
| Hispanic or Latino | 1 (7) | 0 |
| Disease Characteristics | ||
| Baseline Ig use, n (%) | ||
| Yes | 6 (42.9) | 8 (47.1) |
| Baseline mean absolute neutrophil count (ANC) (cells/µL) Mean (SD) | 155 (93.8) | 281 (232.7) |
| Baseline mean absolute lymphocyte count (ALC) (cells/µL) Mean (SD) | 501 (204.8) | 563 (199.1) |
| XOLREMDI (N = 14) | Placebo (N = 17) | ||
|---|---|---|---|
| Abbreviations: ANC = absolute neutrophil count; CI = confidence interval; LS = least squares; MMRM = mixed-model repeated measures; SD = standard deviation; SE = standard error; TAT = time above threshold of 500 cells/µL. | |||
| TAT ANC (hours) | |||
| Baseline | Mean (SD) | 0.0 (0.0) | 3.6 (5.7) |
| Overall MMRM results | LS mean (SE) | 15.0 (1.89) | 2.8 (1.52) |
| LS mean 95% CI | (11.2, 18.9) | (0.0, 5.9) | |
| Difference from placebo: | |||
| LS mean difference (SE) | 12.3 (2.49) | - | |
| LS mean difference 95% CI | (7.2, 17.4) | - | |
| P-value | <0.0001 | - | |
| Category | n n is number of wins. | Win-Ratio (95%CI) |
|---|---|---|
| XOLREMDI wins on total infection score | 174 | 2.76 (1.60, 4.76) |
| Placebo wins on total infection score | 63 | |
| XOLREMDI wins on total wart change score | 0 | |
| Placebo wins on total wart change score | 0 | |
| None of the above (tie) | 1 |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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