2.1 Recommended Evaluations Prior to Treatment Initiation

Before initiating TAVNEOS, consider performing the following evaluations:

• Liver Function Tests: Obtain liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], 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) [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].
• 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 [see Warnings and Precautions (5.3)].

2.2 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.

2.3 Dosage Modifications Due to CYP3A4 Inhibitors

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

5.1 Hepatotoxicity

Serious cases of hepatic injury have been observed in patients taking TAVNEOS. During controlled trials, the TAVNEOS treatment group had a higher incidence of transaminase elevations and hepatobiliary events, including serious and life-threatening events [see Adverse Reactions (6.1)].

Obtain liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating TAVNEOS, every 4 weeks after start of therapy for the first 6 months of treatment and as clinically indicated thereafter.

If a patient receiving treatment with TAVNEOS presents with an elevation in ALT or AST to >3 times the upper limit of normal, evaluate promptly and consider pausing treatment as clinically indicated.

If AST or ALT is >5 times the upper limit of normal, or if a patient develops transaminases >3 times the upper limit of normal with elevation of bilirubin to >2 times the upper limit of normal, discontinue TAVNEOS until TAVNEOS-induced liver injury is ruled out [see Adverse Reactions (6.1)].

TAVNEOS is not recommended for patients with active, untreated and/or uncontrolled chronic liver disease (e.g., chronic active hepatitis B, untreated hepatitis C, uncontrolled autoimmune hepatitis) and cirrhosis. Consider the risk and benefit before administering this drug to a patient with liver disease. Monitor patients closely for hepatic adverse reactions [see Use in Specific Populations (8.7)].

5.2 Hypersensitivity Reactions

TAVNEOS may cause angioedema [see Adverse Reactions (6.1)]. In clinical trials, two cases of angioedema occurred, including one serious event requiring hospitalization. If angioedema occurs, discontinue TAVNEOS immediately, provide appropriate therapy, and monitor for airway compromise. TAVNEOS must not be re-administered unless another cause has been established. Educate patients on recognizing the signs and symptoms of a hypersensitivity reaction and to seek immediate medical care should they develop.

5.3 Hepatitis B Virus (HBV) Reactivation

Hepatitis B virus (HBV) reactivation, including life threatening hepatitis B, was observed in the clinical program.

HBV reactivation is defined as an abrupt increase in HBV replication, manifesting as a rapid increase in serum HBV DNA levels or detection of HBsAg, in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels. 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 treatment with TAVNEOS. For patients who show evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during TAVNEOS treatment.

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis, or HBV reactivation during and for six months following TAVNEOS therapy.

In patients who develop reactivation of HBV while on TAVNEOS, immediately discontinue TAVNEOS and any concomitant therapy associated with HBV reactivation, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming TAVNEOS treatment in patients who develop HBV reactivation. Resumption of TAVNEOS treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HBV.

5.4 Serious Infections

Serious infections, including fatal infections, have been reported in patients receiving TAVNEOS. The most common serious infections reported in the TAVNEOS group were pneumonia and urinary tract infections.

Avoid use of TAVNEOS in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating TAVNEOS in patients:

• with chronic or recurrent infection
• who have been exposed to tuberculosis
• with a history of a serious or an opportunistic infection
• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
• with underlying conditions that may predispose them to infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with TAVNEOS. Interrupt TAVNEOS if a patient develops a serious or opportunistic infection. A patient who develops a new infection during treatment with TAVNEOS should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and TAVNEOS should be interrupted if the patient is not responding to antimicrobial therapy. TAVNEOS may be resumed once the infection is controlled.

6.1 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 TAVNEOS or prednisone [see Clinical Studies (14)]. 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.

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 reactieventsons 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.

7.1 CYP3A4 Inducers

Avacopan exposure is decreased when co-administered with strong CYP3A4 enzyme inducers such as rifampin [see Clinical Pharmacology (12.3)]. Avoid coadministration of strong and moderate CYP3A4 inducers with TAVNEOS.

7.2 CYP3A4 Inhibitors

Avacopan exposure is increased when co-administered with strong CYP3A4 enzyme inhibitors such as itraconazole [see Clinical Pharmacology (12.3)]. Administer TAVNEOS 30 mg once daily when coadministered with strong CYP3A4 inhibitors.

7.3 CYP3A4 Substrates

Avacopan is a CYP3A4 inhibitor. Closely monitor patients for adverse reactions and consider dose reduction of sensitive CYP3A4 substrates with a narrow therapeutic window when coadministered with TAVNEOS [see Clinical Pharmacology (12.3)].

8.1 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 [AUC] 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

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).

8.2 Lactation

Risk Summary

There are no available data on the effects of avacopan on the breastfed child or on milk production. It is unknown whether avacopan is secreted in human milk. Avacopan was detected in the plasma of undosed hamster pups nursing from drug-treated dams (see Animal Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TAVNEOS and any potential adverse effects on the breast-fed infant from TAVNEOS 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 pre- and post-natal development study with hamsters at a pup to maternal plasma ratio of 0.37. This finding suggests that avacopan is secreted into the milk of lactating hamsters. [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the 86 geriatric patients who received TAVNEOS in the phase 3 randomized clinical trial for ANCA-associated vasculitis [see Clinical Studies (14)], 62 patients were between 65-74 years and 24 were 75 years or older. No overall differences in safety or effectiveness were observed between geriatric patients and younger patients.

8.6 Patients with Renal Impairment

No dose adjustment is required for patients with mild, moderate, or severe renal impairment [see Clinical Pharmacology (12.3)]. TAVNEOS has not been studied in patients with ANCA-associated vasculitis who are on dialysis.

8.7 Patients with Hepatic Impairment

No dosage adjustment is recommended for patients with mild or moderate (as indicated by the Child-Pugh method) hepatic impairment [see Clinical Pharmacology (12.3)]. TAVNEOS has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).

12.1 Mechanism of Action

Avacopan is a complement 5a receptor (C5aR) antagonist that inhibits the interaction between C5aR and the anaphylatoxin C5a. Avacopan blocks C5a-mediated neutrophil activation and migration. The precise mechanism by which avacopan exerts a therapeutic effect in patients with ANCA-associated vasculitis has not been definitively established.

12.2 Pharmacodynamics

Avacopan blocks the C5a-induced upregulation of CD11b (integrin alpha M) on neutrophils taken from humans dosed with avacopan. The clinical significance of the pharmcodynamic effect is unclear.

Cardiac Electrophysiology

At the approved recommended dose, TAVNEOS does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

Based on population pharmacokinetic analysis, the mean steady state plasma exposure estimates of avacopan are 3466 ± 1921 ng•h/mL for the 12-hour area under the plasma drug concentration over time curve (AUC0-12hr) and 349 ± 169 ng/mL for the maximum plasma concentration (Cmax) in patients with ANCA-associated vasculitis receiving 30 mg avacopan twice daily. Steady state plasma levels of avacopan are reached by 13 weeks and the accumulation is approximately 4-fold.

Absorption

Co-administration of 30 mg in capsule formulation with a high-fat, high-calorie meal increases AUC and Cmax of avacopan by approximately 72% and 8%, respectively, and delays tmax by approximately 4 hours (from 2.0 hours to 6.0 hours).

Distribution

The plasma protein binding (e.g., to albumin and α1-acid glycoprotein) of avacopan and metabolite M1 is greater than 99.9%. The apparent volume of distribution of avacopan is estimated to be 345 L.

Elimination

Based on population pharmacokinetic analysis, the estimated total apparent body clearance (CL/F) of avacopan is 16.3 L/h. Following a single dose of 30 mg avacopan with food, the mean elimination half-lives of avacopan and M1 are 97.6 hours and 55.6 hours, respectively, in healthy subjects.

Metabolism

CYP3A4 is the major enzyme responsible for the clearance of avacopan and for the formation and clearance of the major circulating metabolite M1, a mono-hydroxylated product of avacopan. M1 was present at ~12% of the total drug-related materials in plasma and has approximately the same activity as avacopan on the C5aR.

Excretion

The main route of clearance of avacopan is metabolism followed by biliary excretion of the metabolites into feces. Following oral administration of radiolabelled avacopan, about 77% and 10% of the radioactivity was recovered in feces and urine, respectively, and 7% and <0.1% of the radioactive dose was recovered as unchanged avacopan in feces and urine, respectively.

Specific Populations

No clinically significant differences in plasma exposure of avacopan and metabolite M1 were observed based on race (White, Asian, Black), gender (female 31%), age (18 to 83 years), body weight (40.3-174 kg), and renal function (eGFR 14-170 mL/min/1.73m2 at baseline).

Patients with Hepatic Impairment

Mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment had no clinically relevant effect on avacopan and M1 plasma exposure. In subjects with mild or moderate hepatic impairment, avacopan AUC increased by 12% and 12%, respectively, Cmax decreased by 13% and 17%, respectively, compared to subjects with normal liver function. In subjects with mild or moderate hepatic impairment, M1 AUC increased by 11% and 18%, respectively, Cmax decreased by 5% and 16%, respectively, compared to subjects with normal liver function.

TAVNEOS has not been studied in subjects with severe hepatic impairment (Child-Pugh Class C).

Drug Interaction Studies

Effects of Other Drugs on TAVNEOS

Avacopan is primarily metabolized by CYP3A4. In vitro studies indicate that avacopan is not a substrate of BCRP and P-gp efflux, and OATP1B1 and OATP1B3 uptake transporters. M1 is a substrate of P-gp but is not a substrate of BCRP efflux, and OATP1B1 and OATP1B3 uptake transporters. Summary of results from a clinical study which evaluated the effect of co-administered drugs on avacopan and M1 plasma exposures is shown in Table 2.

Proton-pump inhibitors such as omeprazole are not expected to have a clinically relevant effect on avacopan plasma exposure.

Effect of TAVNEOS on Other Drug Substances

In vitro studies indicate that avacopan does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and does not induce CYP1A2 and CYP2B6, but shows induction and time-dependent inhibition of CYP3A4. In vitro studies indicate that M1 does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C19, and CYP2D6, and has a low potential to induce CYP3A4, CYP1A2 and CYP2B6, but may inhibit CYP2C9 and CYP3A4.

In vitro studies indicate that avacopan and M1 do not inhibit the transporters P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, and MATE2K at clinically relevant concentrations.

Summary of results from a clinical study which evaluated the effect of avacopan on other drugs is shown in Table 3.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year carcinogenicity studies in Sprague-Dawley rats and Syrian hamsters were conducted to assess the carcinogenic potential of avacopan. Avacopan demonstrated no tumorigenic potential in a study with rats that received oral doses up to 100 mg/kg/day (approximately 3 times the MRHD in adults on an AUC basis) and a study in hamsters that received oral doses up to 100 mg/kg/day (approximately 6 times the MRHD in adults on an AUC basis).

Mutagenesis

Avacopan was not mutagenic or clastogenic in the following assays: in vitro bacterial reverse mutation (Ames) test, in vitro mouse lymphoma assay, and in vivo rat micronucleus test.

Impairment of Fertility

Fertility and reproductive performance were unaffected in male and female hamsters that received avacopan by the oral route at dose levels up to 1000 mg/kg/day (approximately 7 times the MRHD on an AUC basis).