Mavorixafor

When used concomitantly with a strong CYP3A4 inhibitor, daily dose should be reduced to 200 mg. When used concomitantly with a moderate CYP3A4 inhibitor, mavorixafor adverse reactions that may be associated with an increase in mavorixafor exposure should be monitored more frequently, and the mavorixafor daily dose should be reduced by steps of 100 mg, as clinically necessary, but not to a dose less than 200 mg.

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.

Mavorixafor is a CYP3A4 inhibitor. When used concomitantly with CYP3A4 substrates, where minimal substrate concentration changes may lead to serious adverse reactions, CYP3A4 substrate related adverse reactions should be monitored more frequently.

When used concomitantly with a P-gp inhibitor, mavorixafor adverse reactions that may be associated with an increase in mavorixafor exposure should be monitored more frequently, and the mavorixafor daily dose should be reduced by steps of 100 mg, as clinically necessary, but not to a dose less than 200 mg.

Digoxin:

When mavorixafor is used concomitantly with digoxin, the serum concentrations of digoxin should be measured before initiating concomitant use of mavorixafor, and monitoring of serum digoxin concentrations should be continued as recommended in the digoxin SmPC.

Other P-gp substrates:

When mavorixafor is used concomitantly with other P-gp substrates where minimal substrate concentration changes may lead to serious adverse reactions, P-gp substrate related adverse reactions should be monitored more frequently.

When used concomitantly with a strong CYP3A4 inhibitor, daily dose should be reduced to 200 mg.

Food

Patients should be advised to avoid eating or drinking products with grapefruit, as grapefruit is a strong CYP3A4 inhibitor and may increase the risk of adverse reactions from mavorixafor.

When used concomitantly with a moderate CYP3A4 inhibitor, mavorixafor adverse reactions that may be associated with an increase in mavorixafor exposure should be monitored more frequently, and the mavorixafor daily dose should be reduced by steps of 100 mg, as clinically necessary, but not to a dose less than 200 mg.

Mavorixafor is a CYP3A4 substrate. Concomitant use with a strong CYP3A4 inducer is expected to decrease the concentration of mavorixafor, which may reduce the therapeutic effect of mavorixafor. Concomitant use is not recommended.

The effect of mavorixafor on human fertility is unknown. The effect of mavorixafor on male or female fertility was not studied in designated reproductive toxicology studies. In chronic duration repeat-dose toxicity studies, testicular changes were observed in one study in which treatment was initiated in young prepubertal dogs. The relevance of these findings for male patients is not known.

There are no or a limited amount of data from the use of mavorixafor in pregnant women.

Based on its mechanism of action, mavorixafor may cause foetal harm when administered to a pregnant woman.

Mavorixafor is contraindicated during pregnancy.

If exposure to mavorixafor during pregnancy has occurred, the female patient should contact their doctor promptly and treatment with mavorixafor discontinued.

Mavorixafor has not been studied in breast-feeding women. It is unknown whether mavorixafor/metabolites are excreted in human and animal milk.

A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue breast-feeding during treatment and for three weeks after the final dose or to discontinue mavorixafor therapy, considering the benefit of breast-feeding for the child and the benefit of mavorixafor therapy for the woman.

Women of childbearing potential/Contraception in males and females

The pregnancy status of female patients of childbearing potential who are engaging in activities of reproductive potential should be verified prior to starting mavorixafor. Female patients of childbearing potential must avoid becoming pregnant by using an effective method of contraception (e.g., double-barrier contraception) during treatment with mavorixafor and for three weeks after the final dose.

Male patients with female partners of childbearing potential should use condoms during sexual intercourse while taking mavorixafor and for at least three weeks after stopping treatment.

Fertility

The effect of mavorixafor on human fertility is unknown. The effect of mavorixafor on male or female fertility was not studied in designated reproductive toxicology studies. In chronic duration repeat-dose toxicity studies, testicular changes were observed in one study in which treatment was initiated in young prepubertal dogs. The relevance of these findings for male patients is not known.

Mavorixafor may have influence on the ability to drive and use machines. Patients should be advised not to drive or use machines if they are experiencing nervous system adverse reactions.

Summary of the safety profile

The safety data described below reflect exposure in 38 patients with WHIM syndrome treated with mavorixafor, with a treatment duration range from less than 6 months (7 patients) to 4 years (7 patients), with median duration of exposure of 2 years. The most common adverse reactions observed, of any grade reported, were gastrointestinal effects [nausea (21.1%), diarrhoea (18.4%), vomiting (13.2%), dyspepsia (10.5%), abdominal pain (10.5%)], rash (13.2%), and headache (10.5%).

Gastrointestinal effects may occur after starting mavorixafor; these reactions usually resolve within the first 3 months even if mavorixafor is continued.

Tabulated list of adverse reactions

Adverse reactions reported in clinical trials with mavorixafor are listed below in the table below. These included two clinical trials in which 38 patients with WHIM syndrome were treated with mavorixafor. The adverse reactions are listed in the table according to MedDRA system organ class and frequency.

The frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000), and not known (cannot be estimated from the available data).

Adverse reactions:

^* the following grouping contain the following MedDRA preferred terms:
Rash: rash macular, rash pruritic, rash papular

Paediatric population

In the pivotal Phase 3 study X4P-001-103, 7 of 14 patients treated with mavorixafor were aged between 12 to <18 years. No patients in the Phase 2 study X4P-001-MKKA were younger than 18 years.

The safety profile in patients 12 to <18 years of age was similar to that observed in the overall population, including adults and adolescent patients.