Axatilimab-csfr (Monograph)

Brand name: Niktimvo
Drug class: Other Miscellaneous Therapeutic Agents

Introduction

Humanized IgG₄ monoclonal antibody that binds to colony stimulating factor-1 receptor (CSF-1R).

Uses for Axatilimab-csfr

Chronic Graft-Versus-Host Disease

Treatment of chronic graft-versus-host disease (cGVHD) after failure of at least two prior lines of systemic therapy in adult and pediatric patients weighing ≥40 kg.

Designated an orphan drug by FDA for treatment of cGVHD.

Consensus recommendations from the European Society for Blood and Marrow Transplantation and other expert recommendations have been published for treatment of cGVHD. Corticosteroids are generally considered the standard of care for initial systemic treatment of cGVHD; however, many patients develop refractory disease and require additional systemic therapies. For patients with steroid-refractory disease, second and third line treatments include ibrutinib, ruxolitinib, and belumosudil. Axatilimab-csfr is not discussed since the drug was approved after these recommendations were published.

Axatilimab-csfr Dosage and Administration

General

Pretreatment Screening

Assess AST, ALT, alkaline phosphatase (ALP), creatine phosphokinase (CPK), amylase, and lipase prior to initiating axatilimab-csfr.
Verify pregnancy status in females of reproductive potential.

Patient Monitoring

Monitor AST, ALT, ALP, CPK, amylase, and lipase every 2 weeks for the first month, and every 1-2 months thereafter until any abnormalities are resolved.
Monitor patients for signs and symptoms of infusion-related reactions.
Monitor bone growth and development in pediatric patients.

Premedication and Prophylaxis

Premedicate with an antihistamine and antipyretic agent if patients have previously experienced an infusion-related reaction to axatilimab-csfr.

Administration

IV Administration

Administer as an IV infusion.

Supplied in single-dose vials as a 9 mg/0.18 mL, 22 mg/0.44 mL, or 50 mg/mL injection concentrate; must dilute prior to administration.

Do not shake vial.

Administer diluted infusion via infusion line that includes sterile, low-protein binding 0.2 micron in-line or add-on polyethersulfone filter.

Do not co-administer other medications through the same IV line.

Flush infusion line with 0.9% sodium chloride injection after infusion is completed.

Dilution

Withdraw required volume of axatilimab-csfr and add to a PVC, polyolefin, polyolefin with polyamide, or ethylene vinyl acetate (EVA) infusion bag containing 0.9% sodium chloride injection; final concentration should be 0.24-0.75 mg/mL.

Do not shake diluted solution; mix solution by gentle inversion.

Rate of Administration

Administer IV infusion over 30 minutes.

Dosage

Pediatric Patients

Chronic Graft-Versus-Host Disease

IV

Pediatric patients ≥40 kg: 0.3 mg/kg, up to maximum of 35 mg, every 2 weeks until progression or unacceptable toxicity.

Adults

Chronic Graft-Versus-Host Disease

IV

Adults ≥40 kg: 0.3 mg/kg, up to maximum of 35 mg, every 2 weeks until progression or unacceptable toxicity.

Dosage Modification for Adverse Reactions

Table 1: Recommended Dosage Modification for Axatilimab-csfr Adverse Reactions1
Adverse Reaction	Dosage Modification Based on Severity
Infusion-related reactions	Grade 1 or 2: Temporarily interrupt infusion until resolution or decrease infusion rate by 50%. Initiate symptomatic treatment (e.g., antihistamines or antipyretics). For subsequent infusions, premedicate and resume infusion at 50% of prior infusion rate. Grade 3 or 4: Permanently discontinue.
Elevation of AST or ALT (on day of dosing)	Grade 3 with total bilirubin ≤Grade 1: Withhold until recovery to Grade 2, then resume at 0.2 mg/kg (maximum 23 mg) every 2 weeks.
Elevation of AST or ALT (regardless of time of reaction)	ALT or AST ≥3 times ULN with total bilirubin ≥2 times ULN and ALP <2 times ULN: Withhold and investigate for drug-induced liver injury. If confirmed, permanently discontinue. Grade 4: Permanently discontinue.
Elevation of CPK, amylase, or lipase	Grade 3 or higher: If diagnostic evaluation results show no evidence of end-organ damage, continue without dose reduction. If diagnostic evaluation shows evidence of end-organ damage, permanently discontinue. Symptomatic Grade 3 or higher: Permanently discontinue.
Other nonhematologic adverse reactions	Grade 3: Withhold until recovery to Grade 2. If delayed by ≤4 weeks from planned infusion, resume at 0.2 mg/kg (maximum 23 mg) every 2 weeks. If delayed >4 weeks from planned infusion, permanently discontinue. Grade 4: Permanently discontinue.

Special Populations

Hepatic Impairment

No specific population dosage recommendations at this time.

Renal Impairment

No specific population dosage recommendations at this time.

Geriatric Patients

No specific population dosage recommendations at this time.

Cautions for Axatilimab-csfr

Contraindications

None.

Warnings/Precautions

Infusion-related Reactions

Infusion-related reactions including hypersensitivity may occur.

In patients with history of infusion-related reaction to axatilimab-csfr, premedicate with antihistamine and antipyretic. Monitor patients for signs and symptoms of infusion-related reactions, including fever, chills, rash, flushing, dyspnea, and hypertension. Interrupt or slow rate of infusion or permanently discontinue axatilimab-csfr depending on severity of reaction.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on its mechanism of action.

Advise pregnant females of potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment and for 30 days after last dose.

Immunogenicity

Treatment emergent anti-drug antibodies (ADA) and neutralizing antibodies (NAb) detected. Presence of ADAs and NAbs had no clinically meaningful effect on pharmacokinetics, pharmacodynamics, or effectiveness of axatilimab-csfr, although presence of NAb correlated with occurrence of hypersensitivity reactions.

Specific Populations

Pregnancy

No available human data. May cause fetal harm based on its mechanism of action.

Lactation

Unknown whether axatilimab-csfr is distributed into human milk, or if drug has any effects on breastfed infant or on milk production. Maternal IgG known to be distributed into human milk. Because of potential for serious adverse reactions in breastfed infants, advise women to not breastfeed during treatment and for 30 days after last dose.

Females and Males of Reproductive Potential

Advise females of reproductive potential to use effective contraception during treatment and for 30 days after last dose.

Pediatric Use

Safety and efficacy established in pediatric patients weighing ≥40 kg. Patients weighing <40 kg had lower maximum concentrations, trough concentration, and average concentration at same weight-based dosage compared to patients weighing ≥40 kg. Based on findings of thickness of growth plate and metaphysis and/or degeneration of growth plate in femur of animals, monitor bone growth and development in pediatric patients.

Geriatric Use

No differences in safety and efficacy observed between patients ≥65 years of age and younger patients.

Hepatic Impairment

No clinically significant differences in pharmacokinetics observed in patients with mild hepatic impairment. Safety and efficacy not studied in moderate to severe hepatic impairment.

Renal Impairment

No clinically significant differences in pharmacokinetics observed in patients with mild to moderate renal impairment. Safety and efficacy not studied in patients with severe renal impairment.

Common Adverse Effects

Most common adverse reactions (≥15%), including laboratory abnormalities: increased AST, infection (pathogen unspecified), increased ALT, decreased phosphate, decreased hemoglobin, viral infection, increased GGT, musculoskeletal pain, increased lipase, fatigue, increased amylase, increased calcium, increased CPK, increased ALP, nausea, headache, diarrhea, cough, bacterial infection, pyrexia, dyspnea.

Drug Interactions

No formal drug interaction studies to date. Due to its mechanism of action, low likelihood of drug interactions.

Axatilimab-csfr Pharmacokinetics

Elimination

Metabolism

Metabolized into small peptides by catabolic pathways.

Half-life

Dose dependent.

Stability

Storage

Parenteral

Injection Concentrate

Store unopened vials at 2–8ºC in the original carton to protect from light; do not freeze.

Diluted solution: Prior to use, store at room temperature (up to 25ºC) for up to 4 hours from time of preparation to end of infusion or refrigerated (2–8ºC) for up to 24 hours. If refrigerated, allow solution to come to room temperature prior to administration; administer within 4 hours, including infusion time, once it is removed from refrigerator.

Do not freeze diluted solution.

Actions

Humanized IgG₄ monoclonal antibody produced in Chinese hamster ovary cells.
Inhibits CSF-1R signaling, reducing levels of proinflammatory and profibrotic monocytes and monocyte-derived macrophages (essential mediators of end organ damage in chronic graft-versus-host disease (cGVHD).
Inhibits activity of pathogenic macrophages in tissues.
Causes a dose-dependent increase in CSF-1 and interleukin (IL)-34 concentrations and a dose-dependent reduction in levels of nonclassical monocytes in peripheral blood.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (Patient Information).
Advise patients and caregivers that reactions related to the infusion may occur during axatilimab treatment. Inform patients and caregivers of the signs and symptoms of infusion-related reactions and to seek medical care should signs and symptoms occur.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with axatilimab-csfr and for 30 days after the last dose.
Advise patients not to breastfeed during treatment and for 30 days after the last dose of axatilimab-csfr.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Axatilimab-csfr
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection concentrate, for IV use	9 mg/0.18 mL	Niktimvo	Incyte Corporation
		22 mg/0.44 mL	Niktimvo	Incyte Corporation
		50 mg/mL	Niktimvo	Incyte Corporation