DRUG INTERACTIONS-(in brief)

• Strong and moderate CYP3A4 enzyme inducers: Avoid use.

 • Strong CYP3A4 enzyme inhibitors: Reduce avacopan dose to 30 mg once daily.

 • Sensitive CYP3A4 substrates: Monitor for adverse reactions and consider dose reduction of sensitive CYP3A4 substrates with narrow therapeutic window.

DRUG INTERACTIONS (details)

1. 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.

2 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.

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 

BRIEF SUMMARY

AVACOPAN- (Oct 2021)

Indn-     To treat severe active Anti-neutrophil cytoplastic   Auto antibody associated Vasculitis 

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

ADR-  he most common adverse reactions are: nausea, headache, hypertension, diarrhea, vomiting, rash, fatigue, upper abdominal pain, dizziness, blood creatinine increased, and paresthesia.

CI-  Serious hypersensitivity to avacopan or to any of the excipients.

 WARNINGS -

 • Hepatotoxicity: Increase in liver function tests occurred in clinical trials. Obtain liver function tests before use

Serious Hypersensitivity Reactions:                                                                           Cases of angioedema occurred in a clinical trial. Observe for signs and symptoms of angioedema and manage accordingly.

Pat Inform-

Dosage and Administration: Instruct the patient that it should be swallowed whole.  should not be chewed or crushed. If a dose is missed, instruct the patient to take the next scheduled dose

 • Hypersensitivity Reactions: Advise patients to seek immediate medical attention when experiencing any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, and difficulty in swallowing or breathing) and to discontinue the drug until they have consulted with the prescribing physician

===============================================================

U.S. FDA APPROVED DRUGS SURING 2021                                        

Serial No 42

Name of the Drug-    TAUNEOS

Active Ingredient -   Avacopan

Pharmacological Classification- To treat severe active Anti-neutrophil cytoplastic                                                                Auto antibody associated Vasculitis                                                                                                                                                                                                                                                                                                                 Date of Approval-          10/7/21    

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                                 TAVNEOS safely and effectively.

See full prescribing information for TAVNEOS. TAVNEOS (avacopan) capsules, for oral use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE-

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.

 ADVERSE REACTIONS-

The most common adverse reactions (=5%) are: nausea, headache, hypertension, diarrhea, vomiting, rash, fatigue, upper abdominal pain, dizziness, blood creatinine increased, and paresthesia.

 CONTRAINDICATIONS-

Serious hypersensitivity to avacopan or to any of the excipients.

 WARNINGS AND PRECAUTIONS-

 • Hepatotoxicity: Increase in liver function tests occurred in clinical trials. Obtain liver function tests before use

Serious Hypersensitivity Reactions:                                                                           Cases of angioedema occurred in a clinical trial. Observe for signs and symptoms of angioedema and manage accordingly.

 • Hepatitis B Virus (HBV) Reactivation:                                                                               Cases of HBV reactivation occurred in a clinical trial. Withhold TAVNEOS and institute appropriate anti-infective therapy.

• Serious Infections:                                                                                                    Avoid use of TAVNEOS in patients with active, serious infection, including localized infections.

(5.4) ADVERSE REACTIONS 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 ChemoCentryx, Inc. at 1-833-828-6367 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

___________________ DRUG 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) • Sensitive CYP3A4 substrates: Monitor for adverse reactions and consider dose reduction of sensitive CYP3A4 substrates with narrow therapeutic window. (7.3) See 17 for PATI

DOSAGE AND ADMINISTRATION-

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

DOSAGE FORMS AND STRENGTHS-                                                                          Capsules: 10 mg

PATIENT COUNSELING INFORMATION-

 Advise the patient to read the FDA-approved patient labeling (Medication Guide)

• Dosage and Administration: Instruct the patient that TAVNEOS should be swallowed whole. TAVNEOS should not be chewed or crushed. If a dose is missed, instruct the patient to take the next scheduled dose

 • Hypersensitivity Reactions: Advise patients to seek immediate medical attention when experiencing any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, and difficulty in swallowing or breathing) and to discontinue the drug until they have consulted with the prescribing physician

 • Hepatotoxicity: Inform patients of the signs and symptoms of hepatic adverse reactions. Advise patients to contact their healthcare provider immediately for signs or symptoms of liver problems; yellowing of the skin or the white part of the eyes (jaundice), dark or brown (tea colored) urine, pain on the upper right side of the stomach area (abdomen), bleeding or bruising

 • Infections: Inform patients that serious infections have been reported in patients receiving TAVNEOS, including reactivation of hepatitis B infection. Instruct patients to contact their healthcare provider immediately if they develop any signs or symptoms of an infection

 • Lactation: Consider benefits/risk during lactation

TAVNEOS is a trademark of ChemoCentryx, Inc. Copyright ©2021 ChemoCentryx, Inc. All rights reserved. Version 1.0 Manufactured for ChemoCentryx, Inc. by: Thermo Fisher Scientific 2110 East Galbraith Road Cincinnati, OH 45237 USA

CLINICAL PHARMACOLOGY

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.

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.

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 a1-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.

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 coadministered drugs on avacopan and M1 plasma exposures is shown in

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.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary -                                                                                   There are no adequate and well-controlled studies with TAVNEOS in pregnant women to inform a drug-associated risk

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.

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

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

4.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

 TAVNEOS has not been studied in patients with ANCAassociated vasculitis who are on dialysis

6.Patients with Hepatic Impairment-                                                                             No dosage adjustment is recommended for patients with mild or moderate (as indicated by the Child-Pugh method) hepatic impairment

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