Mavorixafor

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 mavorixafor exposure and drug products with a known potential to prolong the QTc interval. A dose reduction in mavorixafor or discontinuation of mavorixafor may be required.

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.

Concomitant use of mavorixafor 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.

Monitor for CYP3A4 substrate related adverse reactions more frequently, unless otherwise recommended in the substrate’s Prescribing Information, when mavorixafor 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.

Monitor more frequently for mavorixafor adverse reactions that may be associated with an increase in mavorixafor exposure when used concomitantly with P-gp inhibitors and reduce the mavorixafor 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, which may increase the risk of mavorixafor adverse reactions.

Monitor for P-gp substrate related adverse reactions more frequently, unless otherwise recommended in the substrate Prescribing Information, when mavorixafor 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 mavorixafor, and continue monitoring serum digoxin concentrations as recommended in the Prescribing Information for digoxin.

Mavorixafor is an inhibitor of P-gp. Mavorixafor may increase the C_max and AUC of P-gp substrates, 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.

Reduce daily dosage of mavorixafor to 200 mg when used concomitantly with strong CYP3A4 inhibitors.

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 mavorixafor adverse reactions.

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

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 mavorixafor.

Monitor more frequently for mavorixafor adverse reactions that may be associated with an increase in mavorixafor exposure when used concomitantly with a moderate CYP3A4 inhibitor and reduce the mavorixafor daily dosage by steps of 100 mg, if necessary, but not to a dose less than 200 mg.

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, which may reduce mavorixafor’s effectiveness.

Risk Summary

Based on its mechanism of action, mavorixafor is expected to cause fetal harm when administered to a pregnant woman. There are no available data on mavorixafor 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 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.

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 mavorixafor and for three weeks after the final dose.

Carcinogenicity studies with mavorixafor have not been conducted.

Mavorixafor was not genotoxic in an in vitro bacterial reverse mutation assay (Ames test), in an in vitro human lymphocyte culture chromosome aberration assay, or in an in vivo rat 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.

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 mavorixafor 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 mavorixafor 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 mavorixafor daily dose is 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 mavorixafor for at least 6 months, and 10 patients received mavorixafor 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 Mavorixafor and More Frequently Reported than Placebo During Study 1:

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