7.2 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 [see Contraindications (4)] .
Mavorixafor is a CYP2D6 inhibitor. Mavorixafor increases exposure of CYP2D6 substrates [see Clinical Pharmacology (12.3)] , 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 [see Clinical Pharmacology (12.3)] , which may increase the risk of adverse reactions from the CYP3A4 substrate.
P-gp Substrates
Monitor for P-gp substrate related adverse reactions more frequently, unless otherwise recommended in the substrate Prescribing Information, when XOLREMDI is used concomitantly with P-gp substrates where minimal substrate concentration changes may lead to serious adverse reactions.
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 [see Clinical Pharmacology (12.3)] .
Mavorixafor is an inhibitor of P-gp. Mavorixafor may increase the C max and AUC of P-gp substrates [see Clinical Pharmacology (12.3)] , which may increase the risk of adverse reactions from the P-gp substrate.
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.
7.3 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 [see Warnings and Precautions (5.2)] .
XOLREMDI causes QTc interval prolongation [see Clinical Pharmacology (12.2)] . Concomitant use of XOLREMDI with other products that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTc interval prolongation, including torsade de pointes, other serious arrythmias, and sudden death [see Warnings and Precautions (5.2)] .
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Based on its mechanism of action, XOLREMDI is expected to cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)] . 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 [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3)] .
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 2% to 4% and 15% to 20%, 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 [see Warnings and Precautions (5.1)].
8.2 Lactation
Risk Summary
There are no data on the presence of mavorixafor in human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise females that breastfeeding is not recommended during treatment with XOLREMDI and for three weeks after the final dose.
8.3 Females and Males of Reproductive Potential
XOLREMDI is expected to cause fetal harm when administered to pregnant women [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)] .
Pregnancy Testing
Verify the pregnancy status in females of reproductive potential prior to initiating XOLREMDI [see Use in Specific Populations (8.1)] .
Contraception
Advise females of reproductive potential to use an effective form of contraception during treatment with XOLREMDI and for three weeks after the final dose [see Use in Specific Populations (8.1)].
8.4 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 [see Clinical Pharmacology (12.3) and Clinical Studies (14)] .
The safety and effectiveness of XOLREMDI have not been established in pediatric patients younger than 12 years of age.
8.5 Geriatric Use
In clinical studies of XOLREMDI in patients with WHIM syndrome, 2 (5%) patients were aged 65 years and older, and no patients were aged 75 years and older. Clinical studies did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.
8.6 Renal Impairment
XOLREMDI is not recommended in patients with severe renal impairment (creatinine clearance [CLcr] 15 to less than 30 mL/min) or end-stage renal disease (CLcr less than 15 mL/min). No dosage adjustment is recommended in patients with mild to moderate renal impairment (CLcr 30 to less than 90 mL/min).
No clinically significant differences in the pharmaco*kinetics of mavorixafor were observed in mild to moderate renal impairment (CLcr 30 to less than 90 mL/min). The pharmaco*kinetics of mavorixafor have not been studied in subjects with severe renal impairment or end-stage renal disease [see Clinical Pharmacology (12.3)] .
8.7 Hepatic Impairment
XOLREMDI is not recommended for use in patients with moderate to severe hepatic impairment. No dosage adjustment is recommended in patients with mild hepatic impairment.
The pharmaco*kinetics of mavorixafor have not been studied in subjects with moderate to severe hepatic impairment [ see Clinical Pharmacology (12.3) ].
11 DESCRIPTION
Mavorixafor is an orally bioavailable CXC Chemokine Receptor 4 (CXCR4) antagonist [see Clinical Pharmacology (12.1)] .
The chemical name of the active ingredient, mavorixafor, is N 1 -(1 H -benzimidazol-2-ylmethyl)- N 1 -[(8 S)-5,6,7,8-tetrahydroquinolin-8-yl]butane-1,4-diamine. It has a molecular formula of C 21 H 27 N 5 and a molecular weight of 349.48 g/mol. Mavorixafor is of the S configuration and its structural formula is provided in Figure 1.
Figure 1: Structural Formula
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.
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