AVACOPAN: 4,464 Adverse Event Reports & Safety Profile

TAVNEOS (avacopan) capsules contain avacopan, a C5aR antagonist. Avacopan is a chiral molecule containing two stereocenters and has a chemical name of (2 R ,3 S )-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methylbenzoyl)- N -[4-methyl-3-(trifluoromethyl)phenyl]piperidine-3-carboxamide. It has a molecular formula of C 33 H 35 F 4 N 3 O 2 and a molecular weight of 582 g/mol. Avacopan has the following structural formula: 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.

Chemical

Structure

AND USAGE 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. 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 [GPA] and microscopic polyangiitis [MPA]) in combination with standard therapy including glucocorticoids. TAVNEOS does not eliminate glucocorticoid use. ( 1 )

AND ADMINISTRATION The recommended dosage is 30 mg (three 10 mg capsules) twice daily, with food. ( 2 )

2.1 Recommended Evaluations Prior to Treatment Initiation Before initiating TAVNEOS, perform 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) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) and Use in Specific Populations (8.7) ]</span>. 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3) ]</span>.

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.

TAVNEOS is contraindicated in patients with serious hypersensitivity reaction to avacopan or to any of the excipients [see Warnings and Precautions (5.2) ]. Serious hypersensitivity to avacopan or to any of the excipients. ( 4 )

REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Hepatotoxicity [see Warnings and Precautions (5.1) ]

Hypersensitivity

Reactions [see Warnings and Precautions (5.2) ] Hepatitis B Virus (HBV) Reactivation [see Warnings and Precautions (5.3) ]

Serious

Infections [see Warnings and Precautions (5.4) ] The most common adverse reactions (≥5%) are: nausea, headache, hypertension, diarrhea, vomiting, rash, fatigue, upper abdominal pain, dizziness, blood creatinine increased, and paresthesia. To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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 <span class="opacity-50 text-xs">[see Clinical Studies (14) ]</span> . 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 (20.7) 39 (23.5)

Headache

23 (14.0) 34 (20.5)

Hypertension

29 (17.7) 30 (18.1)

Diarrhea

24 (14.6) 25 (15.1)

Vomiting

21 (12.8) 25 (15.1)

Rash

13 (7.9) 19 (11.4)

Fatigue

15 (9.1) 17 (10.2) Upper abdominal pain 10 (6.1) 11 (6.6)

Dizziness

10 (6.1) 11 (6.6) Blood creatinine increased 8 (4.9) 10 (6.0)

Paresthesia

7 (4.3) 9 (5.4) 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.

AND PRECAUTIONS 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 )

Serious Hypersensitivity

Reactions: Cases of angioedema occurred in a clinical trial. Observe for signs and symptoms of angioedema and manage accordingly. ( 5.2 ) Hepatitis B Virus (HBV) Reactivation: Cases of HBV reactivation occurred in a clinical trial. Withhold TAVNEOS and institute appropriate anti-infective therapy. ( 5.3 )

Serious

Infections: Avoid use of TAVNEOS in patients with active, serious infection, including localized infections. ( 5.4 )

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 <span class="opacity-50 text-xs">[see Adverse Reactions 6.1 ]</span> . 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 &gt;3 times the upper limit of normal, evaluate promptly and consider pausing treatment as clinically indicated. If AST or ALT is &gt;5 times the upper limit of normal, or if a patient develops transaminases &gt;3 times the upper limit of normal with elevation of bilirubin to &gt;2 times the upper limit of normal, discontinue TAVNEOS until TAVNEOS-induced liver injury is ruled out <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span>. 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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) ]</span> . 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: 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.

INTERACTIONS Strong and moderate CYP3A4 enzyme inducers: Avoid use. ( 7.1 ) Strong CYP3A4 enzyme inhibitors: Reduce avacopan dose to 30 mg once daily. ( 7.2 ) CYP3A4 substrates: Consider dose reduction of CYP3A4 substrates when co-administering TAVNEOS with CYP3A4 substrates. ( 7.3 )

7.1 CYP3A4 Inducers Avacopan exposure is decreased when co-administered with strong CYP3A4 enzyme inducers such as rifampin <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Administer TAVNEOS 30 mg once daily when coadministered 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .