avacopan (Rx)

>10%

Nausea (23.5%)

Headache (20.5%)

Hypertension (18.1%)

Diarrhea (15.1%)

Vomiting (15.1%)

Hepatic-related adverse reactions (13.3%)

Rash (11.4%)

Fatigue (10.2%)

1-10%

Upper abdominal pain (6.6%)

Dizziness (6.6%)

Blood creatinine increased (6%)

Paresthesia (5.4%)

Elevated creatine phosphokinase (3.6%)

Angioedema (1.2%)

Contraindications

Hypersensitivity to avacopan or excipients

Cautions

May cause angioedema; if angioedema occurs, discontinue avacopan immediately, provide appropriate therapy, and monitor for airway compromise; do not readminister unless another cause has been established

Serious infection

• Serious infections, including fatal infections, reported; common infections reported included pneumonia and urinary tract infections
• Avoid use with active, serious infection, including localized infections
• Closely monitor for signs and symptoms of infection during and after treatment; interrupt treatment if a serious or opportunistic infection develops
• If a new infection develops during treatment, promptly complete diagnostic testing appropriate for an immunocompromised patient; initiate appropriate antimicrobial therapy and closely monitor
• Interrupt treatment if unresponsive to antimicrobial therapy; may resume once infection controlled

• Consider risks and benefits before initiating in patients

  • With chronic or recurrent infection
  • Who have been exposed to tuberculosis
  • With history of serious or opportunistic infection
  • Who have resided or traveled in areas of endemic tuberculosis or endemic mycoses
  • With underlying conditions that may predispose them to infection

HBV reactivation

• Hepatitis B virus (HBV) reactivation, including life-threatening hepatitis B, observed during clinical trials
• Reactivation of HBV replication is often followed by hepatitis; in severe cases, increase in bilirubin levels, liver failure, and death can occur
• Screen patients for HBV infection by measuring HBsAg and anti-HBc before initiating
• Refer to specialist if patient shows evidence of prior HBV infection to consider HBV antiviral therapy before and/or during avacopan treatment
• Insufficient data exist regarding safety of resuming avacopan in patients who develop HBV reactivation; consult specialist regarding resumption in patients whose HBV reactivation resolves

Hepatotoxicity

• Serious cases of hepatic injury observed; monitor closely for hepatic adverse reactions
• During controlled trials, a higher incidence of transaminase elevations and hepatobiliary events, including serious and life-threatening events, were reported
• Monitor liver enzymes before and during treatment
• ALT or AST >3x ULN: Evaluate promptly and consider pausing treatment as clinically indicated
• AST or ALT >5x ULN or AST or ALT >3x ULN with bilirubin >2x ULN: Discontinue until avacopan-induced liver injury is ruled out
• Not recommended with active, untreated, and/or uncontrolled chronic liver disease (eg, chronic active hepatitis B, untreated hepatitis C, uncontrolled autoimmune hepatitis) and cirrhosis

Drug interaction overview

• CYP3A4 substrate (major); shows induction and time-dependent inhibition of CYP3A4

• Strong CYP3A4 inhibitors

  • Decrease avacopan dose
  • Coadministration with strong CYP3A4 inhibitor increases avacopan systemic exposure

• Moderate and strong CYP3A4 inducers

  • Avoid coadministration
  • Coadministration with moderate or strong CYP3A4 inducers decreases avacopan systemic exposure

• CYP3A4 substrates

  • Closely monitor CYP3A4 substrates with a narrow therapeutic window; consider dose reduction
  • Avacopan inhibits CYP3A4 substrates

Pregnancy

There are no adequate and well-controlled studies in pregnant females to inform a drug-associated risk

Increased number of spontaneous abortions in rabbits observed

Animal data

• Oral administration to pregnant hamsters and rabbits during organogenesis produced no evidence of fetal harm with exposures up to ~5 and 0.6 times, respectively, the exposure at the maximum recommended human dose (MRHD)
• Avacopan caused increased abortions in rabbits at an exposure 0.6 times the MRHD

Lactation

Data are not available on secretion in human milk, effects on breastfed children, or on milk production

Consider developmental and health benefits of breastfeeding along with the mother’s clinical need for avacopan and any potential adverse effects on the breastfed infant from avacopan or from the underlying maternal condition

Animal data

• Avacopan has not been measured in the milk of lactating animals; however, it was detected in the plasma of nursing offspring in a prenatal and postnatal development study with hamsters at a pup-to-maternal plasma ratio of 0.37

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Complement 5a receptor (C5aR) antagonist that inhibits the interaction between C5aR and the anaphylatoxin C5a

Avacopan blocks C5a-mediated neutrophil activation and migration

Precise mechanism by which avacopan exerts its therapeutic effect in ANCA-associated vasculitis has not been definitively established

Absorption

Steady-state plasma levels

• Reached by 13 weeks; accumulation ~4-fold
• Peak plasma concentration: 349 ng/mL
• AUC_0-12hr: 3466 ng⋅h/mL

Food

• Coadministration with high-fat, high-calorie meal increases AUC and peak plasma concentration by ~72% and 8%, respectively, and delays peak plasma time by ~4 hr (from 2 hr to 6 hr)

Distribution

Protein bound: >99.9% (parent and metabolite)

Vd: 345 L

Metabolism

Major enzyme for avacopan and metabolite clearance: CYP3A4

Major circulating metabolite: M1, a mono-hydroxylated, present at ~12% of total drug-related materials in plasma; has approximately same activity as avacopan on C5a receptor

Elimination

Half-life: 97.6 hr (avacopan); 55.6 hr (M1)

Clearance: 16.3 L/hr

Excretion: Feces 77% (7% unchanged); urine 10% (<0.1% unchanged)

Oral Administration

Take with food

Swallow capsules whole; do not crush, chew, or open

Missed dose

• If dose missed, wait until usual scheduled time to take the next dose
• Instruct patient not to double the next dose

Storage

Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)