Tavneos Drug Information

is indicated as an adjunctive treatment of adult patients with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis ) in combination with standard therapy including glucocorticoids. TAVNEOS does not eliminate glucocorticoid use. TAVNEOS is a complement 5a receptor (C5aR) antagonist indicated as an adjunctive treatment of adult patients with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis ) in combination with standard therapy including glucocorticoids.

TAVNEOS does not eliminate glucocorticoid use.

Recommended Evaluations

Prior to Treatment Initiation Before initiating TAVNEOS, perform the following evaluations: Liver Function Tests: Obtain liver test panel (serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin) before initiating TAVNEOS. TAVNEOS is not recommended for use in patients with cirrhosis, especially those with severe hepatic impairment (Child-Pugh C). Hepatitis B (HBV) Serology: Screen patients for HBV infection by measuring HBsAg and anti-HBc. For patients with evidence of prior or current HBV infection, consult with a physician with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before or during treatment with TAVNEOS.

Recommended Dosage and

Administration The recommended dose of TAVNEOS is 30 mg (three 10 mg capsules) twice daily, with food. Advise patients that TAVNEOS capsules should not be crushed, chewed or opened. If a dose is missed, instruct the patient to wait until the usual scheduled time to take the next regular dose.

Instruct the patient not to double the next dose.

Dosage Modifications Due to

CYP3A4 Inhibitors Reduce the dosage of TAVNEOS to 30 mg once daily when used concomitantly with strong CYP3A4 inhibitors.

Clinical Trials Experience

Because the clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The identification of potential adverse drug reactions was based on safety data from the phase 3 clinical trial in which 330 patients with ANCA-associated vasculitis were randomized 1:1 to either TAVNEOS or prednisone . The mean age of patients was 60.9 years (range of 13 to 88 years), with a predominance of men (56.4%) and Caucasians (84.2%). The cumulative exposure to TAVNEOS was 138.7 patient-years. Additionally, two phase 2 trials were conducted in ANCA-associated vasculitis.

The cumulative clinical trial exposure from the phase 2 and 3 trials equals 212.3 patient-years. The most frequent serious adverse reactions reported more frequently in patients treated with TAVNEOS than with prednisone were pneumonia (4.8% TAVNEOS vs. 3.7% prednisone), GPA (3.0% TAVNEOS vs. 0.6% prednisone), acute kidney injury (1.8% TAVNEOS vs. 0.6% prednisone), and urinary tract infection (1.8% TAVNEOS vs. 1.2% prednisone). Within 52 weeks, 4 patients in the prednisone treatment group (2.4%) and 2 patients in the TAVNEOS group (1.2%) died. There were no deaths in the phase 2 trials.

In the phase 3 trial, seven patients (4.2%) in the TAVNEOS treatment group and 2 patients (1.2%) in the prednisone treatment group discontinued treatment due to hepatic-related adverse reactions, including hepatobiliary adverse reactions and liver enzymes abnormalities. The most frequent adverse reaction that led to drug discontinuation reported by > 1 patient and more frequently reported in patients treated with TAVNEOS was hepatic function abnormal (1.8%). The most common adverse reactions that occurred in ≥5% of patients and higher in the TAVNEOS group as compared with the prednisone group are listed in Table 1. Table 1. Adverse Reactions Reported in ≥5% of Patients and Higher in TAVNEOS Group vs. Prednisone Group in Phase 3 Trial Adverse Reaction Prednisone (N = 164) n (%) TAVNEOS (N = 166) n (%) N = number of patients randomized to treatment group in the Safety Population; n = number of patients in specified category.

Nausea 34 39 Headache 23 34 Hypertension 29 30 Diarrhea 24 25 Vomiting 21 25 Rash 13 19 Fatigue 15 17 Upper abdominal pain 10 11 Dizziness 10 11 Blood creatinine increased 8 10 Paresthesia 7 9 Hepatotoxicity and Elevated Liver Function Tests In the phase 3 trial, a total of 19 patients (11.6%) in the prednisone group and 22 patients (13.3%) in the TAVNEOS group had hepatic-related adverse reactions, including hepatobiliary adverse reactions and liver enzyme abnormalities. Study medication was paused or discontinued permanently due to hepatic-related adverse reactions in 5 patients (3.0%) in the prednisone group and 9 patients (5.4%) in the TAVNEOS group. Serious hepatic-related adverse reactions were reported in 6 patients (3.7%) in the prednisone group and 9 patients (5.4%) in the TAVNEOS group.

A serious hepatic-related adverse reaction was reported in 1 patient in the TAVNEOS group in the phase 2 studies. Angioedema In the phase 3 trial, 2 patients (1.2%) in the TAVNEOS group had angioedema; one event was a serious adverse reaction requiring hospitalization. Elevated Creatine Phosphokinase In the phase 3 trial, 1 patient (0.6%) in the prednisone group and 6 patients (3.6%) in the TAVNEOS group had increased creatine phosphokinase.

One TAVNEOS-treated patient discontinued treatment due to increased creatine phosphokinase.

CYP3A4 Inducers Avacopan exposure is decreased when co-administered with strong

CYP3A4 enzyme inducers such as rifampin . Avoid coadministration of strong and moderate CYP3A4 inducers with TAVNEOS.

CYP3A4 Inhibitors Avacopan exposure is increased when co-administered with strong

CYP3A4 enzyme inhibitors such as itraconazole . Administer TAVNEOS 30 mg once daily when coadministered with strong CYP3A4 inhibitors.

CYP3A4 Substrates Avacopan is a moderate

CYP3A4 inhibitor. Co-administration of avacopan and 40 mg simvastatin increases the systemic exposure of simvastatin. While taking TAVNEOS, limit simvastatin dosage to 10 mg daily (or 20 mg daily for patients who have previously tolerated simvastatin 80 mg daily for at least one year without evidence of muscle toxicity). Consider dose reduction of CYP3A4 substrates when co-administering TAVNEOS with CYP3A4 substrates.

Consult the concomitant CYP3A4 substrate product information when considering administration of such products together with TAVNEOS .

Pregnancy Risk Summary There are no adequate and well-controlled studies with TAVNEOS in pregnant women to inform a drug-associated risk. In animal reproduction studies, oral administration of avacopan to pregnant hamsters and rabbits during the period of organogenesis produced no evidence of fetal harm with exposures up to approximately 5 and 0.6 times, respectively, the exposure at the maximum recommended human dose (MRHD) of 30 mg twice daily (on an area under the curve basis). Avacopan caused an increase in the number of abortions in rabbits at an exposure 0.6 times the MRHD (see Animal Data ). The background risk of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data Animal Data In an embryo-fetal development study with pregnant hamsters dosed by the oral route during the period of organogenesis from gestation days 6 to 12, avacopan produced an increase in the incidence of a skeletal variation, described as supernumerary ribs, at an exposure that was 5 times the MRHD (on an AUC basis with a maternal oral dose of 1000 mg/kg/day). No structural abnormalities were noted with exposures up to 5 times the MRHD (on an AUC basis with maternal oral doses up to 1000 mg/kg/day). In an embryo-fetal development study with pregnant rabbits dosed by the oral route during the period of organogenesis from gestation days 6 to 18, avacopan caused an increase in the number of abortions at an exposure 0.6 times the MRHD (on an AUC basis with a maternal oral dose of 200 mg/kg/day), however, no evidence of fetal harm was observed with such exposures. Maternal toxicity, as evidenced by decreased body weight gains, was observed at exposures 0.6 times and higher than the MRHD (on an AUC basis with maternal oral doses of 30 mg/kg/day and higher). In a prenatal and postnatal development study with pregnant hamsters dosed by the oral route during the periods of gestation and lactation from gestation day 6 to lactation day 20, avacopan had no effects on the growth and development of offspring with exposures up to approximately 5 times the MRHD (on an AUC basis with maternal oral doses up to 1000 mg/kg/day).

Pediatric Use The safety and effectiveness of TAVNEOS in pediatric patients have not been established.

is contraindicated in patients with serious hypersensitivity reaction to avacopan or to any of the excipients. Serious hypersensitivity to avacopan or to any of the excipients.