Avacopan 10 Mg Oral Capsule

2.1 Recommended Evaluations Prior to Treatment Initiation

Before initiating TAVNEOS, perform the following evaluations:

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)].

In the postmarketing setting, vanishing bile duct syndrome (VBDS) as a consequence of liver injury, including cases with a fatal outcome, has been reported. These events occurred predominantly in Japan in patients aged 65 years and older, but VBDS may affect patients of any age or ethnicity who are receiving TAVNEOS [see Adverse Reactions (6.2)].

Obtain liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], 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.

For patients of Japanese descent, consider more frequent laboratory testing: every 2 weeks after the start of therapy for the first 3 months, followed by laboratory testing every 4 weeks for the next 3 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 (ULN), or ALT or AST > 3 times the ULN with total bilirubin > 2 times the ULN, or ALP ≥ 2 times the ULN, or if the patient has clinical symptoms such as jaundice or pruritus, discontinue TAVNEOS until TAVNEOS-induced liver injury is ruled out [see Adverse Reactions (6.1)].

Immediately and permanently discontinue TAVNEOS if VBDS is suspected.

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 TAVNEOS 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 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:

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 either 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of TAVNEOS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or definitively establish a causal relationship to drug exposure.

Hepatobiliary disorders: vanishing bile duct syndrome [see Warnings and Precautions (5.1) ]

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 co-administration 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 co-administered with strong CYP3A4 inhibitors.

7.3 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 [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

8.2 Lactation

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) [see Warnings and Precautions (5.1)].

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 pharmacodynamic effect is unclear.

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 (AUC_0-12hr) and 349 ± 169 ng/mL for the maximum plasma concentration (C_max) 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Remission at Week 26 and Sustained Remission at Week 52

Remission was achieved by 72.3% of patients in the TAVNEOS group and 70.1% of patients in the prednisone group at Week 26 (treatment difference: 3.4%, 95% CI [-6.0%, 12.8%]). At Week 52, a significantly higher percentage of patients had sustained remission in TAVNEOS group (65.7%) compared to the prednisone group (54.9%), as presented in Table 4.

In pre-specified subgroup efficacy analyses, sustained remission at 52 weeks in patients was examined based on stratification factors and GPA/MPA disease. The results are displayed in Figure 1 below.

Figure 1. Forest Plot of Sustained Remission at Week 52 Based on Disease Related Variables

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Do not use if seal is broken or missing.