Tavneos - Drug Monograph

Introduction

Tavneos (avacopan) is an orally administered, first-in-class selective complement 5a receptor (C5aR) inhibitor approved by the FDA in October 2021. It represents a novel therapeutic approach for the treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, offering a targeted mechanism that differs significantly from traditional glucocorticoid-based regimens.

Mechanism of Action

Tavneos exerts its therapeutic effect through highly selective inhibition of the complement C5a receptor (C5aR). The drug binds competitively to C5aR, blocking the interaction between C5a and its receptor. This inhibition prevents C5a-mediated neutrophil activation and migration, which are key drivers of the inflammatory process in ANCA-associated vasculitis. Unlike broad immunosuppressants, Tavneos specifically targets the alternative complement pathway while preserving the protective functions of the classical complement pathway.

Indications

Tavneos is indicated in combination with standard therapy (including glucocorticoids) for the treatment of severe active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis) in adult patients.

Dosage and Administration

• Standard dosing: 30 mg orally twice daily with food
• Treatment duration: Recommended for 52 weeks in combination with standard therapy
• Renal impairment: No dosage adjustment required for mild to moderate impairment. Use with caution in severe renal impairment (CrCl <30 mL/min)
• Hepatic impairment: Not recommended in patients with severe hepatic impairment (Child-Pugh Class C)
• Geriatric patients: No dosage adjustment required
• Administration: Should be taken with food to improve bioavailability

Pharmacokinetics

• Absorption: Median Tmax approximately 2 hours; food increases exposure by approximately 40%
• Distribution: Volume of distribution ~54 L; plasma protein binding >99.9%
• Metabolism: Primarily metabolized by CYP3A4; minor contributions from CYP2C9 and CYP2D6
• Elimination: Half-life approximately 4-5 hours; primarily excreted in feces (77%) with minor renal excretion (13%)
• Special populations: No clinically significant differences based on age, sex, race, or body weight

Contraindications

• Hypersensitivity to avacopan or any component of the formulation
• Concomitant use with strong CYP3A4 inducers (rifampin, carbamazepine, St. John's wort)
• Severe hepatic impairment (Child-Pugh Class C)

Warnings and Precautions

• Hepatotoxicity: Monitor liver enzymes at baseline and during treatment; discontinue if significant elevation occurs
• Serious infections: Increased risk of infections; monitor for signs and symptoms of infection
• Hypersensitivity reactions: Angioedema and rash have been reported
• CYP3A4 interactions: Avoid concomitant use with strong CYP3A4 inducers; dose reduction recommended with strong CYP3A4 inhibitors
• Pregnancy: Based on animal data, may cause fetal harm; advise women of reproductive potential of potential risk
• Vaccinations: Live vaccines should not be given concurrently

Drug Interactions

• Strong CYP3A4 inducers: Contraindicated (significantly decrease avacopan exposure)
• Strong CYP3A4 inhibitors: Reduce Tavneos dose to 30 mg once daily (increase avacopan exposure)
• Moderate CYP3A4 inhibitors: Monitor for adverse reactions
• CYP3A4 substrates: May increase concentrations of sensitive CYP3A4 substrates
• P-gp substrates: May increase concentrations of P-gp substrates

Adverse Effects

• Nausea (18%)
• Headache (17%)
• Fatigue (15%)
• Diarrhea (14%)
• Vomiting (12%)
• Abdominal pain (11%)
• Rash (10%)

• Hepatotoxicity
• Serious infections
• Hypersensitivity reactions
• Angioedema

Monitoring Parameters

• Liver function tests: ALT, AST, bilirubin at baseline and periodically during treatment
• Infection monitoring: Signs and symptoms of infection throughout treatment
• Renal function: Serum creatinine and urinalysis regularly
• Vasculitis activity: Birmingham Vasculitis Activity Score (BVAS) and other disease activity markers
• Complete blood count: Monitor for cytopenias
• Therapeutic response: Clinical symptoms and inflammatory markers

Patient Education

• Take Tavneos exactly as prescribed, twice daily with food
• Do not stop taking glucocorticoids unless instructed by your healthcare provider
• Report any signs of infection (fever, chills, cough), liver problems (yellowing skin, dark urine), or allergic reactions
• Inform all healthcare providers about all medications you are taking, including over-the-counter drugs and supplements
• Avoid grapefruit and grapefruit juice during treatment
• Use effective contraception during treatment and for 1 week after final dose
• Regular follow-up appointments are essential for monitoring safety and effectiveness

References

1. FDA prescribing information for Tavneos (avacopan). October 2021. 2. Jayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med. 2021;384(7):599-609. 3. Bekker P, Dairaghi D, Seitz L, et al. Characterization of pharmacologic and pharmacokinetic properties of CCX168, a potent and selective orally administered complement 5a receptor inhibitor, based on preclinical evaluation and randomized phase 1 clinical studies. PLoS One. 2016;11(10):e0164646. 4. Merkel PA, Jayne DR, Wang C, et al. Evaluation of the safety and efficacy of avacopan in patients with ANCA-associated vasculitis: rationale and protocol of a randomized, double-blind, active-controlled trial. Adv Ther. 2020;37(7):3230-3241. 5. ClinicalTrials.gov. Efficacy and Safety Study of Avacopan in Patients With ANCA-Associated Vasculitis (ADVOCATE). NCT02994927.