XOLREMDI Capsule Ref.[109813] Active ingredients: Mavorixafor

5.1 Embryo-Fetal Toxicity

Based on its mechanism of action, XOLREMDI is expected to cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.2)]. Animal models link reductions in CXCR4/SDF1 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 three weeks after the final dose [see Use in Specific Populations (8.1 and 8.3)].

5.2 QTc Interval Prolongation

XOLREMDI causes concentration-dependent QTc interval prolongation. QT 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 QT. 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 the QTc interval. A dose reduction in XOLREMDI or discontinuation of XOLREMDI may be required [see Drug Interactions (7.1, 7.3) and Clinical Pharmacology (12.2)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• QTc Interval Prolongation [see Warnings and Precautions (5.2)]

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 [see Clinical Studies (14)]. 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 recommended for use in patients receiving strong CYP3A4 inhibitors [see Dosage and Administration (2.1 and 2.2)]. 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 [see Drug Interactions (7.1)].

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 one year.

Table 1 summarizes the most common adverse reactions (>10%) in Study 1, which were thrombocytopenia, pityriasis, rash, rhinitis, epistaxis, vomiting, and dizziness.

Table 1. Adverse Reactions in >10% Patients with WHIM Syndrome Receiving XOLREMDI and More Frequently Reported than Placebo During Study 1:

Serious adverse reactions of thrombocytopenia occurred in 3 of the 14 patients who received XOLREMDI, two of which occurred in the setting of infection or febrile neutropenia.

7.1 Effect of Other Drugs on XOLREMDI

Strong or Moderate CYP3A4 Inhibitors

Reduce XOLREMDI daily dosage when used concomitantly with a strong CYP3A4 inhibitor [see Dosage and Administration (2.2)].

Monitor more frequently for XOLREMDI adverse reactions that may be associated with an increase in mavorixafor exposure when used concomitantly with a 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) [see Clinical Pharmacology (12.3)], which may increase the risk of XOLREMDI adverse reactions.

Strong CYP3A4 Inducers

Avoid concomitant use with a strong CYP3A4 inducer.

Mavorixafor is a CYP3A4 substrate. Concomitant use with a strong CYP3A4 inducer is predicted to decrease mavorixafor C_max and AUC based upon a mechanistic understanding of its elimination [see Clinical Pharmacology (12.3)], which may reduce XOLREMDI’s effectiveness.

P-gp Inhibitors

Monitor more frequently for XOLREMDI adverse reactions that may be associated with an increase in mavorixafor exposure when used concomitantly with P-gp inhibitors 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 P-gp substrate. Concomitant use with a P-gp inhibitor increases mavorixafor C_max and AUC [see Clinical Pharmacology (12.3)], which may increase the risk of XOLREMDI adverse reactions.

7.2 Effect of XOLREMDI on Other Drugs

CYP2D6 Substrates

The use of XOLREMDI with drugs that are 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)].

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 also 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)].

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.

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)].

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.

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.

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 pharmacokinetics of mavorixafor were observed in mild to moderate renal impairment (CLcr 30 to less than 90 mL/min). The pharmacokinetics of mavorixafor have not been studied in subjects with severe renal impairment or end-stage renal disease [see Clinical Pharmacology (12.3)].

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 pharmacokinetics of mavorixafor have not been studied in subjects with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)].