Get your patient on Tavneos (Avacopan)

TAVNEOS is indicated as an adjunctive treatment of adult patients with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]) in combination with standard therapy including glucocorticoids. TAVNEOS does not eliminate glucocorticoid use.

The recommended dosage is 30 mg (three 10 mg capsules) twice daily, with food. (

Capsules: 10 mg, opaque, yellow and light orange with CCX168 printed in black.

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

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.

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

• Hepatotoxicity: Increase in liver function tests occurred in clinical trials. Obtain liver function tests before initiation of therapy and monitor as clinically indicated. (
  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

  [seeAdverse 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

  [seeAdverse 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 TAVNEOS to a patient with liver disease. Monitor patients closely for hepatic adverse reactions [

  seeUse in Specific Populations (8.7)].
  )
• Serious Hypersensitivity Reactions: Cases of angioedema occurred in a clinical trial. Observe for signs and symptoms of angioedema and manage accordingly. (
  5.2 Hypersensitivity Reactions

  TAVNEOS may cause angioedema

  [seeAdverse 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.
  )
• Hepatitis B Virus (HBV) Reactivation: Cases of HBV reactivation occurred in a clinical trial. Withhold TAVNEOS and institute appropriate anti-infective therapy. (
  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.
  )
• Serious Infections: Avoid use of TAVNEOS in patients with active, serious infection, including localized infections. (
  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.
  )

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Hepatotoxicity
  [see

  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

  [seeAdverse 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

  [seeAdverse 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 TAVNEOS to a patient with liver disease. Monitor patients closely for hepatic adverse reactions [

  seeUse in Specific Populations (8.7)].

  ]
• Hypersensitivity Reactions
  [see

  5.2 Hypersensitivity Reactions

  TAVNEOS may cause angioedema

  [seeAdverse 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.

  ]
• Hepatitis B Virus (HBV) Reactivation
  [see

  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.

  ]
• Serious Infections
  [see

  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.

  ]

• Strong and moderate CYP3A4 enzyme inducers: Avoid use. (
  7.1 CYP3A4 Inducers

  Avacopan exposure is decreased when co-administered with strong CYP3A4 enzyme inducers such as rifampin

  [seeClinical Pharmacology (12.3)]

  . Avoid coadministration of strong and moderate CYP3A4 inducers with TAVNEOS.
  )
• Strong CYP3A4 enzyme inhibitors: Reduce avacopan dose to 30 mg once daily. (
  7.2 CYP3A4 Inhibitors

  Avacopan exposure is increased when co-administered with strong CYP3A4 enzyme inhibitors such as itraconazole

  [seeClinical Pharmacology (12.3)]

  . Administer TAVNEOS 30 mg once daily when coadministered with strong CYP3A4 inhibitors.
  )
• CYP3A4 substrates: Consider dose reduction of CYP3A4 substrates when co-administering TAVNEOS with CYP3A4 substrates. (
  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

  [seeClinical Pharmacology (12.3)]

  .
  )

TAVNEOS (avacopan) capsules contain avacopan, a C5aR antagonist. Avacopan is a chiral molecule containing two stereocenters and has a chemical name of (2

Avacopan is a white to pale yellow crystalline solid that is soluble in organic solvents and practically insoluble in water.

TAVNEOS is available as a 10 mg capsule for oral administration. The capsules include the following inactive ingredients: Polyethylene glycol 4000 (PEG-4000), Polyoxyl-40 hydrogenated castor oil. The capsules are a light orange and yellow opaque bicolor gelatin capsule with a clear gelatin sealing band. The top half of the capsule is printed with "CCX168" in black ink. The capsule shell contains gelatin, red iron oxide, yellow iron oxide, and titanium dioxide, and the capsule sealing band contains gelatin and polysorbate 80.

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.

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).

The efficacy and safety of TAVNEOS was evaluated in a double-blind, active-controlled, phase 3 clinical trial (NCT02994927) in 330 patients with newly diagnosed or relapsed ANCA-associated vasculitis who were randomized 1:1 to one of the following treatment groups:

• TAVNEOS group (N = 166): Patients received 30 mg avacopan twice daily for 52 weeks plus prednisone-matching placebo for 20 weeks
• Prednisone group (N = 164): Patients received avacopan-matched placebo twice daily for 52 weeks plus prednisone (tapered from 60 mg/day to 0 over 20 weeks)

All patients in both groups received one of the following standard immunosuppressive regimens:

• IV cyclophosphamide 15 mg/kg IV up to 1.2 g maximum every 2 to 3 weeks for 13 weeks followed by oral azathioprine 1 mg/kg/day with titration up to 2 mg/kg/day (or mycophenolate mofetil at a target dose of 2 g/day if azathioprine was contraindicated) from Week 15 onwards
• Oral cyclophosphamide 2 mg/kg/day (maximum 200 mg/day) for 14 weeks followed by azathioprine 1 mg/kg/day with titration up to 2 mg/kg/day (or mycophenolate mofetil at a target dose of 2 g/day if azathioprine was contraindicated) from Week 15 onwards
• IV rituximab 375 mg/m² once weekly for 4 weeks without azathioprine or mycophenolate mofetil

Glucocorticoids were allowed as pre-medication for rituximab to reduce hypersensitivity reactions, taper after glucocorticoids given during the Screening period, treatment of persistent vasculitis, worsening of vasculitis, or relapses, as well as for non-vasculitis reasons such as adrenal insufficiency.

Randomization was stratified based on 3 factors: newly-diagnosed or relapsing ANCA-associated vasculitis, proteinase 3 positive or myeloperoxidase positive ANCA-associated vasculitis, and standard immunosuppressive regimen. The primary endpoints of the study were disease remission at Week 26 and sustained disease remission at Week 52. Disease remission was defined as achieving a Birmingham Vasculitis Activity Score (BVAS) of 0 and no use of glucocorticoids for treatment of ANCA-associated vasculitis from Week 22 to Week 26. Sustained remission was defined as remission at Week 26 and remission at Week 52, without relapse between Week 26 and Week 52. Remission at Week 52 was defined as BVAS of 0 and no use of glucocorticoids for treatment of ANCA-associated vasculitis from Week 48 to Week 52. Relapse was defined as occurrence of one major item, at least 3 non-major items, or 1 or 2 non-major items for at least 2 consecutive visits on the BVAS after remission (BVAS of 0) had been achieved.

The two treatment groups were well balanced regarding baseline demographics and disease characteristics of patients in this trial. The mean patient age was 60.9 years. Most patients were male (56.4%), Caucasian (84.2%), and had newly diagnosed disease (69.4%). Patients had either GPA (54.8%) or MPA (45.2%) and had presence of anti-PR3 (43.0%) or anti-MPO (57.0%) antibodies. Mean baseline BVAS was 16.2; patients most commonly had manifestations within the renal component (81.2%), general component (68.2%), ear/nose/throat component (43.6%), and chest component (43.0%). Approximately 65% of patients received rituximab, 31% received IV cyclophosphamide, and 4% received oral cyclophosphamide.

TAVNEOS (avacopan) capsule is supplied as a 10 mg, hard, opaque yellow and light orange capsule with "CCX168" printed in black.

• Bottle containing 180 capsules with child resistant induction seal closure (NDC 73556-168-01)
• Bottle containing 30 capsules with child resistant induction seal closure (NDC 73556-168-02)

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.