Avacopan (Monograph)

Brand name: Tavneos
Drug class: Complement Inhibitors
Chemical name: (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)-N-[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide
Molecular formula: C₃₃H₃₅F₄N₃O₂
CAS number: 1346623-17-3

Medically reviewed by Drugs.com on Dec 27, 2022. Written by ASHP.

Introduction

Complement 5a receptor (C5aR) antagonist.

Uses for Avacopan

Anti-neutrophil Cytoplasmic Autoantibody (ANCA)-Associated Vasculitis

Use for severe active ANCA-associated vasculitis, including granulomatosis with polyangiitis and microscopic polyangiitis. Designated an orphan drug by the Food and Drug Administration for this use.

Use as adjunct with standard therapy; not intended to eliminate need for glucocorticoids.

Kidney Disease: Improving Global Outcomes (KDIGO) treatment guidelines include avacopan as alternative to glucocorticoids for ANCA-associated vasculitis.

Avacopan Dosage and Administration

General

Pretreatment Screening

• The manufacturer recommends liver function test assessment (including ALT, AST, alkaline phosphatase, and total bilirubin) prior to starting avacopan.

• Hepatitis B virus screening (hepatitis B surface antigen [HBsAg] and anti-hepatitis B core antibody [anti-HBc] assays) is also recommended prior to therapy. If patients have evidence of hepatitis B virus, a physician experienced in managing hepatitis B should be consulted regarding monitoring and potential treatment prior to starting or during avacopan therapy.

Patient Monitoring

• Monitor for drug-drug interactions. Patients may require an avacopan dosage reduction for concomitant use of strong cytochrome P-450 (CYP) 3A4 inhibitors; patients may require a dosage reduction of concomitant sensitive CYP3A4 substrates with a narrow therapeutic index.

• Monitor liver test panel every 4 weeks for the first 6 months of therapy, and then as often as clinically indicated. Promptly evaluate any patients with elevations in ALT or AST >3 times the upper limit of normal (ULN) and consider holding avacopan therapy. Discontinue avacopan in patients with AST or ALT elevations >5 times the ULN, or transaminases >3 times the ULN with bilirubin elevation >2 times the ULN.

• Monitor patients for angioedema during therapy; do not rechallenge patients on avacopan unless an alternative cause is identified.

• In patients with evidence of hepatitis B virus who receive avacopan, monitor for signs of hepatitis and viral reactivation during and for 6 months following avacopan therapy. Discontinue avacopan in patients with hepatitis B viral reactivation.

• Monitor for signs and symptoms of infection during and after avacopan therapy; withhold therapy if a serious or opportunistic infection develops. Once the infection is controlled with appropriate therapy, avacopan may be resumed.

Oral

Administer capsules whole; do not crush, chew, or open.

Administer doses with food.

Dosage

Adults

Anti-neutrophil Cytoplasmic Autoantibody (ANCA)-Associated Vasculitis

Oral

30 mg twice daily.

Dosage Modifications for Drug Interactions

Oral

Adjustments necessary when used in conjunction with strong CYP3A4 inhibitors. Decrease dosage to 30 mg once daily.

Special Populations

Hepatic Impairment

Mild or moderate (Child-Pugh class A or B): Manufacturer makes no specific dosage recommendations.

Severe (Child-Pugh class C): No data.

Renal Impairment

Mild, moderate, or severe: Manufacturer makes no specific dosage recommendations.

Dialysis: No data.

Geriatric Use

Manufacturer makes no specific dosage recommendations.

Pediatric Use

Not studied.

Cautions for Avacopan

Contraindications

• Hypersensitivity to avacopan or its excipients.

Warnings/Precautions

Hepatotoxicity

Potential for serious hepatic injury, including life-threatening events. Reactions include transaminase elevations and hepatobiliary events. Abnormal hepatic function most common adverse reaction leading to discontinuation in clinical trial.

Avoid avacopan in patients with active, untreated, or uncontrolled chronic liver disease. Consider risks and benefits of avacopan in patients with liver disease.

Monitor patients on avacopan for signs and symptoms of hepatotoxicity. Obtain a liver test panel prior to starting avacopan, every 4 weeks for the first 6 months, and then as clinically indicated. Discontinue avacopan for elevations in ALT or AST >5 times the ULN or transaminase elevations >3 times the ULN with an elevated bilirubin >2 times the ULN; do not restart avacopan unless avacopan is ruled out as the cause of the hepatotoxicity.

Hypersensitivity Reactions

Potential for hypersensitivity, including angioedema.

Discontinue avacopan for angioedema; do not restart avacopan unless alternative cause established.

Hepatitis B Virus Reactivation

Potential for hepatitis B virus reactivation. Screen patients for hepatitis B virus using hepatitis B surface antigen (HBsAg) and anti-hepatitis B core antibody (anti-HBc) assays prior to starting avacopan. Consult clinicians experienced in managing hepatitis B prior to starting or during avacopan therapy for patients either HBsAg positive or HBsAg negative plus anti-HBc positive.

Monitor patients with current or prior hepatitis B virus infection for signs of hepatitis or viral reactivation during and for 6 months after avacopan therapy. Discontinue avacopan and initiate appropriate therapy for patients who develop hepatitis B virus reactivation. Consult an expert clinician in managing hepatitis B if considering restarting avacopan in patients who develop hepatitis B virus reactivation.

Serious Infections

Potential for serious, including fatal, infections. Pneumonia and urinary tract infections most commonly reported. Avoid avacopan in patients with active, serious infection. Consider the risks and benefits of avacopan in patients with chronic or recurrent infection, exposure to tuberculosis, prior serious or opportunistic infection, history of living or travel to areas with endemic tuberculosis or mycoses, or underlying conditions that predispose to infection.

Monitor patients for infection during and after avacopan therapy. Manage patients who develop a new infection during avacopan therapy similar to an immunocompromised patient. Hold avacopan for patients receiving treatment for infection who do not respond to antimicrobial therapy; avacopan may be restarted once infection is controlled.

Specific Populations

Pregnancy

Insufficient data in humans; animal studies suggest no fetal harm, but increased number of abortions in pregnant rabbits.

Lactation

No data in humans; animal data suggest potential to distribute into milk. Consider risk-benefit assessment prior to using avacopan during breastfeeding.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

Differences in safety or efficacy not observed.

Hepatic Impairment

Mild or moderate (Child-Pugh class A or B): No clinically important effect.

Severe (Child-Pugh class C): Not studied.

Renal Impairment

eGFR between 14–170 mL/minute per 1.73 m²: No clinically important effect.

Common Adverse Effects

Adverse effects reported in ≥5% include nausea, headache, hypertension, diarrhea, vomiting, rash, fatigue, upper abdominal pain, dizziness, increased blood creatinine, and paresthesia.

Drug Interactions

Metabolized principally by CYP3A4.

Avacopan inhibits CYP3A4. It does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. The M1 metabolite may inhibit CYP2C9 and CYP3A4. It does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C19, or CYP2D6. The M1 metabolite may induce CYP3A4, CYP1A2, and CYP2B6.

Avacopan is not a substrate of breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), organic anion transporting polypeptide 1B1 (OATP1B1), or OATP1B3. It does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, organic cation transporter 2 (OCT2), organic anion transporter 1 (OAT1), OAT3, multidrug and toxin extrusion transporter 1 (MATE1), or MATE2K. The M1 metabolite is a substrate of P-gp. M1 is not a substrate of BCRP, OATP1B1, or OATP1B3. M1 does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, or MATE2K.

Drugs Affecting Hepatic Microsomal Enzymes

Moderate and strong CYP3A4 inducers: Decreased avacopan exposure and peak plasma concentrations. Avoid concomitant use.

Strong CYP3A4 inhibitors: Increased avacopan exposure and peak plasma concentrations. Reduce avacopan dosage to 30 mg once daily.

Drugs Metabolized by Hepatic Microsomal Enzymes

Sensitive CYP3A4 substrates: Potential pharmacokinetic interaction (increased plasma concentrations and AUC of substrate). Monitor for need to adjust dosage of substrate.

Drugs Affecting Gastric Acidity

Proton pump inhibitors: No evidence of pharmacokinetic interaction.

Specific Drugs and Foods

Avacopan Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained approximately 2 hours after oral administration without food.

Steady-state concentrations are achieved in approximately 13 weeks.

Accumulation is approximately fourfold.

Food

Administration with a high-fat, high-calorie meal increases peak plasma concentrations and AUC by 8 and 72%, respectively; time to maximum plasma concentrations delayed by about 4 hours. Administer avacopan doses with food.

Special Populations

Mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment: Avacopan AUC increased by 12% (both classes) and peak plasma concentrations decreased by 13 and 17%, respectively. M1 AUC increased by 11 and 18%, respectively, and peak plasma concentrations decreased by 5 and 16%, respectively. Not expected to be clinically important.

Severe (Child-Pugh class C) hepatic impairment: Not studied.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

>99.9%.

Elimination

Metabolism

Principally metabolized by CYP3A4.

Metabolized to active metabolite, M1, that has approximately same activity as parent drug on C5aR.

Elimination Route

Eliminated in feces (77%) and urine (10%); 7 and <0.1% eliminated as unchanged drug, respectively.

Half-life

Avacopan: 97.6 hours.

M1: 55.6 hours.

Special Populations

Age, weight, sex, race, body weight, and renal function do not substantially affect pharmacokinetics of avacopan.

Stability

Storage

Oral

Capsules

20–25°C (excursions permitted to 15–30°C).

Actions

• Blocks binding of C5a with C5aR by selectively antagonizing C5aR.

• Inhibits neutrophil recruitment and activation.

• Exact mechanism in ANCA-associated vasculitis not well understood.

Advice to Patients

• Importance of instructing the patient that avacopan should be swallowed whole. Avacopan should not be chewed or crushed. If a dose is missed, instruct the patient to take the next scheduled dose; do not double dose.

• Importance of the risk of hypersensitivity reactions. Advise patients to seek immediate medical attention when experiencing any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, and difficulty in swallowing or breathing) and to discontinue the drug until they have consulted with the prescribing physician.

• Importance of the risk of hepatotoxicity. Inform patients of the signs and symptoms of hepatic adverse reactions. Advise patients to contact their healthcare provider immediately for signs or symptoms of liver problems; yellowing of the skin or the white part of the eyes (jaundice), dark or brown (tea colored) urine, pain on the upper right side of the stomach area (abdomen), bleeding or bruising.

• Importance of the risk of infectious complications. Inform patients that serious infections have been reported in patients receiving avacopan, including reactivation of hepatitis B infection. Instruct patients to contact their healthcare provider immediately if they develop any signs or symptoms of an infection.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing 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.

Avacopan can only be obtained through designated specialty pharmacies. Contact manufacturer or consult the Tavneos website ([Web]) for specific availability information.

Reload page with references included

Medical Disclaimer