2.1 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.

2.2 Dosage Modifications for Strong CYP3A4 inhibitors

Reduce daily dosage of XOLREMDI to 200 mg when used concomitantly with strong CYP3A4 inhibitors [see Drug Interactions (7.1)] .

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 with "MX4" in black ink.

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/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 [see Use in Specific Populations (8.1,  8.3)] .

5.2 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 [see Drug Interactions (7.1,  7.3) and Clinical Pharmacology (12.2)].

6.1 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 [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 only recommended for use in patients receiving strong CYP3A4 inhibitors [see Dosage and Administration (2.1,  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 1 year.

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

Serious adverse reactions of thrombocytopenia occurred in 3 of the 14 patients who received XOLREMDI, 2 of which occurred in the setting of infection or febrile neutropenia.

7.1 Effect of Other Drugs on XOLREMDI

7.2 Effect of XOLREMDI on Other Drugs

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 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 [see Warnings and Precautions (5.2)] .

8.1 Pregnancy

8.2 Lactation

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)] .

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 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)] .

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

12.1 Mechanism of Action

Mavorixafor is an orally bioavailable 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.

12.2 Pharmacodynamics

12.3 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with mavorixafor have not been conducted.

Mavorixafor was not genotoxic in an in vitrobacterial reverse mutation assay (Ames test), in an in vitrohuman lymphocyte culture chromosome aberration assay, or an in vivorat bone marrow micronucleus assay.

Fertility studies have not been conducted with mavorixafor. Significant tubular degeneration/atrophy was observed in the testes of dogs at clinical exposure.

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.

Administration

Advise patients to take XOLREMDI on an empty stomach after an overnight fast, 30 minutes before food. Advise patients to swallow the capsules whole and not to open, break, or chew capsules [see Dosage and Administration (2.1)and Clinical Pharmacology (12.3)] .

Embryo-Fetal Toxicity

XOLREMDI is expected to cause fetal harm. Advise females of reproductive potential to use an effective form of contraception during treatment with XOLREMDI and for 3 weeks after the final dose. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.1)and Use In Specific Populations (8.1)] .

Lactation

Advise females that breastfeeding is not recommended during treatment with XOLREMDI and for 3 weeks after the final dose [see Use in Specific Populations (8.2)] .

Drug Interactions

Advise patients to avoid taking dietary supplements that include goldenseal, as it is a strong CYP3A4 inhibitor and may increase risk of adverse reactions to XOLREMDI.

Advise patients to avoid taking dietary supplements that include St. John's Wort, as it is an inducer of CYP3A4 and may reduce the efficacy of XOLREMDI [see Drug Interactions (7.2)] .

Food Interactions

Advise patients to avoid eating or drinking products with grapefruit, as grapefruit is a strong CYP3A4 inhibitor and may increase the risk of adverse reactions to XOLREMDI [see Drug Interactions (7.1)] .