Avacopan is a complement 5a receptor (C5aR) antagonist indicated as 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. In the ADVOCATE study, adult patients with ANCA-associated vasculitis were randomized to either avacopan 30 mg PO twice daily or oral prednisone on a tapering schedule (60 mg/day PO tapered to discontinuation by week 21); patients also received either cyclophosphamide followed by azathioprine or rituximab. The first primary end point of remission at week 26 occurred in 72.3% (120 of 166 patients) of patients in the avacopan group and 70.1% (115 of 164 patients) of patients in the prednisone group; estimated common difference of 3.4% (95% CI: -6, 12.8; p less than 0.001 for noninferiority, p = 0.24 for superiority). The second primary end point of sustained remission at week 52 occurred in 65.7% (109 of 166 patients) of patients in the avacopan group and 54.9% (90 of 164 patients) of patients in the prednisone group; estimated common difference of 12.5% (95% CI: 2.6, 22.3; p less than 0.001 for noninferiority, p = 0.007 for superiority). Patients in both treatment groups were allowed to receive under pre-specified conditions; the mean glucocorticoid dose was higher in the prednisone group. Serious adverse events (excluding vasculitis events) occurred in 37.3% of patients in the avacopan group compared to 39% of patients in the prednisone group; serious adverse events included serious infections, serious opportunistic infections, hepatotoxicity, hepatitis B reactivation, and angioedema. Patients should be screened for hepatitis B virus (HBV) infection prior to starting avacopan treatment and monitored for HBV infection or reactivation during and for 6 months after avacopan therapy. Liver function tests (LFTs) should be obtained at baseline, every 4 weeks for first 6 months of therapy, and as clinically indicated thereafter.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer with food.
-Capsules should be swallowed whole. Do not crush, chew, or open capsules.
-Missed dose: Instruct the patient to skip the missed dose and take the next regular dose at the usual time.
The most commonly reported adverse reactions reported with avacopan treatment in the phase 3 trial vs. prednisone alone were nausea (23.5% of the avacopan group vs. 20.7% of the prednisone group), headache (20.5% vs. 14%), hypertension (18.1% vs. 17.7%), diarrhea (15.1% vs. 14%), vomiting (15.1% vs. 12.8%), rash (11.4% vs. 7.9%), fatigue (10.2% vs. 9.1%), upper abdominal pain (6.6% vs. 6.1%), dizziness (6.6% vs. 6.1%), and paresthesias (5.4% vs. 4.3%).
Hepatotoxicity, including serious hepatic injury, serious and life-threatening hepatobiliary events, and elevated hepatic enzymes, has been reported with avacopan therapy. In the phase 3 clinical trial, 13.3% of avacopan patients compared to 11.6% of prednisone patients experienced hepatobiliary adverse reactions and hepatic enzyme abnormalities and/or hyperbilirubinemia. Serious hepatic-related adverse events occurred in 9 patients (5.4%) in the avacopan group and 6 patients (3.7%) in the prednisone group. Study medication was paused or permanently discontinued secondary to hepatic-related adverse reactions in 9 patients (5.4%) in the avacopan group and 5 patients (3%) in the prednisone group. In addition, 4.2% of avacopan patients (vs. 1.2% of prednisone patients) withdrew from treatment due to hepatic-related adverse reactions, including hepatobiliary events, abnormalities in liver enzymes, and abnormal hepatic function (1.8%). A serious hepatic-related adverse reaction was also reported in one patient enrolled in the phase 2 study. Liver function tests (LFTs) should be obtained prior to the start of avacopan therapy, every 4 weeks for the first 6 months of treatment, and as clinically indicated thereafter. Advise patients to contact their health care provider immediately for signs or symptoms of liver problems such as jaundice, dark urine, pain on the upper right side of the stomach/abdomen, or unusual bleeding or bruising. Hepatitis B virus (HBV) reactivation resulting in hepatitis B exacerbation, including life-threatening hepatitis B, has been observed with avacopan therapy. 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. HBV reactivation is often followed by hepatitis (i.e., increase in transaminase level) and, in severe cases, increase in bilirubin levels, hepatic failure, and death. Evaluate patients at risk for hepatitis B reactivation by measuring HBsAg and anti-HBc prior to initiating treatment with avacopan. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for 6 months after avacopan therapy. In patients who develop HBV reactivation, immediately stop therapy and any concomitant therapy associated with HBV reactivation, and initiate appropriate treatment. There is insufficient data on whether avacopan therapy may be safely resumed following HBV reactivation. Consult with physicians with expertise in HBV management to discuss whether to resume avacopan therapy following resolution of HBV reactivation.
Angioedema was reported in 2 avacopan patients (1.2%) during clinical trials, including one serious event requiring hospitalization. If angioedema occurs, immediately discontinue avacopan, provide appropriate treatment, and monitor for airway compromise. Do not resume avacopan therapy unless another cause for the angioedema has been established. Patients should be educated on the signs and symptoms of a hypersensitivity reaction and to seek immediate medical care if these symptoms develop.
Serious infections, including fatal and life-threatening infections, have been reported in patients receiving avacopan. Serious infections and serious opportunistic infections occurred in 13.3% and 3.6% of avacopan patients, respectively, compared to 15.2% and 6.7% of prednisone patients, respectively during a phase 3 clinical trial. The most common serious infections reported were pneumonia (4.8% in the avacopan group vs. 3.7% in the prednisone group) and urinary tract infection (1.8% vs. 1.2%). There were 2 deaths (1.2%) in the avacopan group due worsening vasculitis and pneumonia and 4 deaths (2.4%) in the prednisone group. Closely monitor for signs and symptoms of infection during and after avacopan treatment. Interrupt avacopan therapy if a patient develops a serious or opportunistic infection. If a patient develops a new infection, promptly complete diagnostic testing appropriate for an immunocompromised patient; initiate appropriate antimicrobial therapy and closely monitor. Interrupt avacopan treatment if the patient does not respond to antimicrobial therapy. Avacopan may be resumed once the infection is controlled.
Renal failure (acute kidney injury) occurred in 1.8% of avacopan patients and 0.6% of prednisone patients. Elevated blood creatinine and elevated creatine phosphokinase were reported in 6% and 3.6% of avacopan patients, respectively, compared to 4.9% and 0.6% of prednisone patients, respectively. One avacopan patient discontinued treatment due to increased creatine phosphokinase.
Avacopan use is contraindicated in patients with a serious hypersensitivity to avacopan or the product excipients, including a history of angioedema to avacopan. Angioedema was reported in 2 patients, including a serious event that required hospitalization, during clinical trials. If angioedema occurs, immediately discontinue avacopan, provide appropriate treatment, and monitor for airway compromise. Do not resume avacopan unless another cause for the angioedema has been established. Patients should be educated on the signs and symptoms of a hypersensitivity reaction and to seek immediate medical care should they develop.
Avacopan is not recommended for patients with active, untreated or uncontrolled chronic hepatic disease, such as chronic active hepatitis B, untreated hepatitis C infection, uncontrolled autoimmune hepatitis, or cirrhosis. Serious cases of hepatotoxicity and hepatic injury have occurred in patients taking avacopan therapy. During clinical trials, patients taking avacopan had a higher incidence of elevated transaminase levels and hepatobiliary events, including serious and life-threatening events. Liver function tests (LFTs) should be evaluated at baseline, every 4 weeks for the first 6 months of therapy, and then as clinical indicated after that. If ALT or AST increase to greater than 3 times the upper limit of normal (ULN), promptly evaluate the patient and consider pausing treatment if clinically indicated. If ALT or AST increase to greater than 5 times ULN or if transaminases increase to more than 3 times ULN with elevation in bilirubin to more than 2 times ULN, discontinue avacopan treatment until the diagnosis of drug-induced liver injury is excluded. Hepatitis B virus (HBV) reactivation resulting in hepatitis B exacerbation, including life-threatening hepatitis B, has been observed with avacopan therapy. 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. HBV reactivation is often followed by hepatitis (i.e., increase in transaminase level) and, in severe cases, increase in bilirubin levels, liver failure, and death. Evaluate patients at risk for hepatitis B reactivation by measuring HBsAg and anti-HBc prior to initiating treatment with avacopan. In patients who demonstrate evidence of prior hepatitis B infection, consult with a physician with expertise in managing hepatitis B regarding monitoring recommendations and whether HBV antiviral therapy is needed before and/or during avacopan treatment. If avacopan is used in a patient with evidence of current or prior HBV infection, monitor for clinical and laboratory signs of hepatitis or HBV reactivation during and for 6 months after avacopan therapy. In patients who develop reactivation of HBV, immediately discontinue avacopan therapy and any concomitant therapy associated with HBC reactivation, and institute appropriate treatment. There is insufficient data on whether avacopan therapy may be safely resumed following HBV reactivation. Consult with physicians with expertise in HBV management to discuss whether to resume avacopan therapy following resolution of HBV reactivation.
Serious infections, including fatal and life-threatening infections, have been reported with avacopan therapy. Avoid use of avacopan in patients with an active, serious infection, including localized infections. The most common serious infections reported with avacopan in clinical trials were pneumonia and urinary tract infection. Consider the risks and benefits of avacopan receipt before drug initiation in patients with chronic or recurrent infection; who have been exposed to tuberculosis; with a history of 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 avacopan treatment. Interrupt avacopan therapy if a patient develops a serious or opportunistic infection. If a patient develops a new infection, promptly complete diagnostic testing appropriate for an immunocompromised patient and initiate appropriate antimicrobial therapy; closely monitor the patient. Interrupt avacopan treatment if the patient lacks a response to antimicrobial therapy. Avacopan may be resumed once the infection is controlled.
There are no adequate and well-controlled studies with avacopan during human pregnancy 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. An exposure of 5 times the MRHD in pregnant hamsters resulted in an increase in the incidence of a skeletal variation, described as supernumerary ribs.
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. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for avacopan and any potential adverse effects on the breastfed child from avacopan or from the underlying condition.
For the adjunctive treatment of severe, active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis) in combination with standard therapy including glucocorticoids:
Oral dosage:
Adults: 30 mg PO twice daily with food. Avacopan is taken along with standard therapy including glucocorticosteroids. Avacopan does not eliminate glucocorticoid use. Reduce dose to 30 mg PO once daily in patients concomitantly receiving a strong CYP3A4 inhibitor. Max: 60 mg/day.
Maximum Dosage Limits:
-Adults
60 mg/day PO.
-Geriatric
60 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Mild or moderate hepatic impairment (Child-Pugh A or B): No dosage adjustments are needed.
Severe hepatic impairment (Child-Pugh C), including cirrhosis: Avacopan has not been studied and is not recommended for use in these patients.
Hepatic dosage adjustments due to LFT elevations during therapy:
-Elevation in ALT or AST to greater than 3 times the upper limit of normal (ULN): Promptly evaluate and pause avacopan therapy as clinically indicated.
-Elevation in ALT or AST to greater than 5 times ULN, or if transaminases are more than 3 times ULN with bilirubin elevation more than 2 times the ULN: Discontinue therapy until avacopan-induced liver injury is ruled out.
Patients with Renal Impairment Dosing
No dosage adjustments are needed in patients with mild, moderate, or severe renal impairment. Avacopan has not been studied in patients receiving dialysis.
*non-FDA-approved indication
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. If avacopan is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with avacopan may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If avacopan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Avacopan is a weak inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with avacopan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of avacopan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If avacopan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Avacopan is a weak inhibitor of CYP3A.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like avacopan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If avacopan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. If avacopan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like avacopan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If avacopan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of adagrasib is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. If avacopan is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A substrate, and coadministration with CYP3A inhibitors like avacopan can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If avacopan is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alprazolam: (Major) Avoid coadministration of alprazolam and avacopan due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with avacopan, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A substrate and avacopan is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
Amobarbital: (Major) Avoid concomitant use of avacopan and barbiturates due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of clarithromycin is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Apalutamide: (Major) Avoid concomitant use of avacopan and apalutamide due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of avacopan. Patients receiving both a CYP2D6 inhibitor plus avacopan may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate; avacopan is a weak CYP3A inhibitor.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concomitant use of avacopan and barbiturates due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with avacopan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of avacopan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If avacopan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Avacopan is a weak inhibitor of CYP3A.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. If avacopan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like avacopan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If avacopan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of atazanavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Atazanavir; Cobicistat: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of atazanavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold. (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of cobicistat is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Barbiturates: (Major) Avoid concomitant use of avacopan and barbiturates due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Benzhydrocodone; Acetaminophen: (Moderate) Consider a reduced dose of benzhydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like avacopan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of benzhydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If avacopan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to benzhydrocodone.
Bexarotene: (Major) Avoid concomitant use of avacopan and bexarotene due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and bexarotene is a moderate CYP3A inducer.
Bosentan: (Major) Avoid concomitant use of avacopan and bosentan due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and bosentan is a moderate CYP3A inducer.
Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with avacopan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and avacopan is a weak CYP3A inhibitor.
Buprenorphine: (Major) Concomitant use of buprenorphine and avacopan can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when avacopan is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping avacopan, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If avacopan is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and avacopan is a CYP3A inhibitor.
Buprenorphine; Naloxone: (Major) Concomitant use of buprenorphine and avacopan can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when avacopan is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping avacopan, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If avacopan is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and avacopan is a CYP3A inhibitor.
Butalbital; Acetaminophen: (Major) Avoid concomitant use of avacopan and barbiturates due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid concomitant use of avacopan and barbiturates due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concomitant use of avacopan and barbiturates due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%. (Moderate) Concomitant use of codeine with avacopan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of avacopan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If avacopan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Avacopan is a weak inhibitor of CYP3A.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concomitant use of avacopan and barbiturates due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%. (Moderate) Concomitant use of codeine with avacopan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of avacopan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If avacopan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Avacopan is a weak inhibitor of CYP3A.
Carbamazepine: (Major) Avoid concomitant use of avacopan and carbamazepine due to the risk of decreased avacopan exposure which may reduce its efficacy. Carbamazepine exposure and the risk for carbamazepine-related adverse effects may also increase. Avacopan is a CYP3A substrate and weak CYP3A inhibitor; carbamazepine is a CYP3A substrate and strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with avacopan is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of avacopan, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Cenobamate: (Major) Avoid concomitant use of avacopan and cenobamate due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and cenobamate is a moderate CYP3A inducer.
Ceritinib: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of ceritinib is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and ceritinib is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Chloramphenicol: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of chloramphenicol is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and chloramphenicol is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with avacopan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of avacopan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If avacopan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Avacopan is a weak inhibitor of CYP3A.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like avacopan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If avacopan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Clarithromycin: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of clarithromycin is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with avacopan and monitor for adverse reactions. If avacopan is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A; avacopan is a weak CYP3A inhibitor.
Cobicistat: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of cobicistat is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Codeine: (Moderate) Concomitant use of codeine with avacopan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of avacopan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If avacopan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Avacopan is a weak inhibitor of CYP3A.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with avacopan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of avacopan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If avacopan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Avacopan is a weak inhibitor of CYP3A.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with avacopan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of avacopan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If avacopan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Avacopan is a weak inhibitor of CYP3A.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with avacopan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of avacopan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If avacopan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Avacopan is a weak inhibitor of CYP3A.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with avacopan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of avacopan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If avacopan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Avacopan is a weak inhibitor of CYP3A.
Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with avacopan is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A substrate and avacopan is a weak CYP3A inhibitor. For patients receiving both cyclosporine and letermovir, reduce the dose of avacopan to 30 mg once daily. Combination cyclosporine/letermovir acts as a strong CYP3A inhibitor; another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Dabrafenib: (Major) Avoid concomitant use of avacopan and dabrafenib due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and dabrafenib is a moderate CYP3A inducer.
Darunavir: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of darunavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Darunavir; Cobicistat: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of cobicistat is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold. (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of darunavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of cobicistat is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold. (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of darunavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Delavirdine: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of delavirdine is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and delavirdine is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with avacopan is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and avacopan is a CYP3A inhibitor.
Disopyramide: (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with avacopan is necessary as concurrent use may increase disopyramide exposure. Disopyramide is a CYP3A substrate and avacopan is a weak CYP3A inhibitor. Although specific drug interaction studies have not been done for disopyramide, cases of life-threatening interactions have been reported when disopyramide was coadministered with moderate and strong CYP3A inhibitors.
Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with avacopan is necessary as concurrent use may increase dofetilide exposure. Avacopan is a weak CYP3A inhibitor. Dofetilide is a minor CYP3A substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A inhibitors may increase the risk of arrhythmia (torsade de pointes).
Efavirenz: (Major) Avoid concomitant use of avacopan and efavirenz due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of avacopan and efavirenz due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of avacopan and efavirenz due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer.
Elagolix: (Major) Avoid concomitant use of avacopan and elagolix due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and elagolix is a moderate CYP3A inducer.
Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of avacopan and elagolix due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and elagolix is a moderate CYP3A inducer.
Eliglustat: (Major) Coadministration of eliglustat and avacopan is not recommended in poor CYP2D6 metabolizers (PMs). In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Avacopan is a weak CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of cobicistat is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of cobicistat is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Encorafenib: (Major) Avoid concomitant use of avacopan and encorafenib due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Enzalutamide: (Major) Avoid concomitant use of avacopan and enzalutamide due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and enzalutamide is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Eslicarbazepine: (Major) Avoid concomitant use of avacopan and eslicarbazepine due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and eslicarbazepine is a moderate CYP3A inducer.
Etravirine: (Major) Avoid concomitant use of avacopan and etravirine due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and etravirine is a moderate CYP3A inducer.
Felodipine: (Moderate) Concurrent use of felodipine and avacopan should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A substrate and avacopan is a weak CYP3A inhibitor. Concurrent use of another weak CYP3A inhibitor increased felodipine AUC and Cmax by approximately 50%.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. If avacopan is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like avacopan can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If avacopan is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or avacopan; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and avacopan is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A inhibitors, including avacopan, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the potential outcomes of combination therapy with multiple weak CYP3A inhibitors and flibanserin should be discussed with the patient.
Fosphenytoin: (Major) Avoid concomitant use of avacopan and phenytoin/fosphenytoin due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and phenytoin and fosphenytoin are strong CYP3A inducers. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Grapefruit juice: (Major) Advise patients to avoid grapefruit and grapefruit juice during avacopan treatment due to the risk of increased avacopan exposure and adverse reactions. Avacopan is a CYP3A substrate and grapefruit juice is a strong CYP3A inhibitor.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like avacopan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If avacopan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like avacopan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If avacopan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like avacopan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If avacopan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. If avacopan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like avacopan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If avacopan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Idelalisib: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of idelalisib is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Indinavir: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of indinavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and indinavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of avacopan and rifampin due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use decreased avacopan overall exposure by 93%.
Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of avacopan and rifampin due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use decreased avacopan overall exposure by 93%.
Isradipine: (Minor) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with avacopan is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and avacopan is a weak CYP3A inhibitor.
Itraconazole: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of itraconazole is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and itraconazole is a strong CYP3A inhibitor. Concomitant use increased avacopan overall exposure 2.19-fold.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of avacopan is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and avacopan is a weak CYP3A inhibitor.
Ketoconazole: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of ketoconazole is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of clarithromycin is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Lemborexant: (Major) Limit the dose of lemborexant to 5 mg PO once daily if coadministered with avacopan as concomitant use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A substrate; avacopan is a weak CYP3A inhibitor. Coadministration with a weak CYP3A inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
Levoketoconazole: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of ketoconazole is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with avacopan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and avacopan is a weak CYP3A inhibitor.
Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine toxicity if coadministration with avacopan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and avacopan is a weak CYP3A inhibitor.
Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with avacopan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and avacopan is a weak CYP3A inhibitor.
Lomitapide: (Major) Decrease the dose of lomitapide by one-half not to exceed 30 mg/day PO if coadministration with avacopan is necessary. Concomitant use may significantly increase the serum concentration of lomitapide. Avacopan is a weak CYP3A inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A inhibitors.
Lonafarnib: (Major) Avoid coadministration of lonafarnib and avacopan; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and reduce the dose of avacopan to 30 mg once daily. Closely monitor patients for adverse reactions. Lonafarnib is a sensitive CYP3A substrate and strong CYP3A inhibitor; avacopan is a CYP3A substrate and weak CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increase avacopan overall exposure 2.19-fold.
Lopinavir; Ritonavir: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of ritonavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Lorlatinib: (Major) Avoid concomitant use of avacopan and lorlatinib due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and lorlatinib is a moderate CYP3A inducer.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of avacopan and combination lumacaftor; ivacaftor due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and combination lumacaftor; ivacaftor is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of avacopan and combination lumacaftor; ivacaftor due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and combination lumacaftor; ivacaftor is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Mavacamten: (Major) Avoid concomitant use of avacopan and mavacamten due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and mavacamten is a moderate CYP3A inducer.
Mefloquine: (Moderate) Use mefloquine with caution if coadministration with avacopan is necessary as concurrent use may increase mefloquine exposure and mefloquine-related adverse events. Mefloquine is a substrate of CYP3A and avacopan is a weak CYP3A inhibitor.
Meperidine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. If avacopan is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A and avacopan is a weak CYP3A inhibitor. Concomitant use with avacopan can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine.
Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. If avacopan is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; avacopan is a weak CYP3A inhibitor. Concomitant use with avacopan can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone.
Methohexital: (Major) Avoid concomitant use of avacopan and barbiturates due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Midazolam: (Moderate) Use caution when midazolam is coadministered with avacopan. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and avacopan is a weak CYP3A inhibitor.
Mifepristone: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of chronic mifepristone therapy is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and mifepristone is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
Mitotane: (Major) Avoid concomitant use of avacopan and mitotane due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and mitotane is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Nafcillin: (Major) Avoid concomitant use of avacopan and nafcillin due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and nafcillin is a moderate CYP3A inducer.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of avacopan. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and avacopan is a weak CYP3A inhibitor.
Nefazodone: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of nefazodone is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Nelfinavir: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of nelfinavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and nelfinavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with avacopan is necessary. Concurrent use may increase nimodipine exposure. Nimodipine is a CYP3A substrate and avacopan is a weak CYP3A inhibitor.
Nirmatrelvir; Ritonavir: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of ritonavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with avacopan due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A substrate and avacopan is a CYP3A inhibitor. Coadministration with another CYP3A inhibitor increased the AUC of nisoldipine by 30% to 45%.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concomitant use of avacopan and rifabutin due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. If avacopan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like avacopan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If avacopan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Pentobarbital: (Major) Avoid concomitant use of avacopan and barbiturates due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Pexidartinib: (Major) Avoid concomitant use of avacopan and pexidartinib due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and pexidartinib is a moderate CYP3A inducer.
Phenobarbital: (Major) Avoid concomitant use of avacopan and barbiturates due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concomitant use of avacopan and barbiturates due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Phenytoin: (Major) Avoid concomitant use of avacopan and phenytoin/fosphenytoin due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and phenytoin is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Pimozide: (Major) Avoid concomitant use of pimozide and avacopan. Concomitant use may result in elevated pimozide concentrations resulting in QT prolongation, ventricular arrhythmias, and sudden death. Pimozide is CYP3A substrate, and avacopan is a weak CYP3A inhibitor.
Posaconazole: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of posaconazole is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and posaconazole is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Primidone: (Major) Avoid concomitant use of avacopan and barbiturates due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Propafenone: (Moderate) Monitor for increased propafenone toxicity if coadministered with avacopan; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and avacopan with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate; avacopan is a weak CYP3A inhibitor.
Repotrectinib: (Major) Avoid concomitant use of avacopan and repotrectinib due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and repotrectinib is a moderate CYP3A inducer.
Ribociclib: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of ribociclib is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Ribociclib; Letrozole: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of ribociclib is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and ribociclib is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Rifabutin: (Major) Avoid concomitant use of avacopan and rifabutin due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and rifabutin is a moderate CYP3A inducer.
Rifampin: (Major) Avoid concomitant use of avacopan and rifampin due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and rifampin is a strong CYP3A inducer. Concomitant use decreased avacopan overall exposure by 93%.
Rifapentine: (Major) Avoid concomitant use of avacopan and rifapentine due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and rifapentine is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Ritonavir: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of ritonavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Saquinavir: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of saquinavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and saquinavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Secobarbital: (Major) Avoid concomitant use of avacopan and barbiturates due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of avacopan. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and avacopan is a weak CYP3A inhibitor.
Sotorasib: (Major) Avoid concomitant use of avacopan and sotorasib due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and sotorasib is a moderate CYP3A inducer.
St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of avacopan and St. John's Wort due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if avacopan must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of avacopan is necessary. If avacopan is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A substrate, and coadministration with a weak CYP3A inhibitor like avacopan can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If avacopan is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with avacopan is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; avacopan is a weak CYP3A inhibitor.
Tipranavir: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of tipranavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and tipranavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with avacopan is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of avacopan, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with avacopan is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of avacopan, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with avacopan and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and avacopan is a weak CYP3A inhibitor.
Tucatinib: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of tucatinib is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and tucatinib is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with avacopan. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A substrate; avacopan is a weak CYP3A inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with avacopan is necessary. Vinorelbine is a CYP3A substrate and avacopan is a weak CYP3A inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of clarithromycin is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and clarithromycin is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Voriconazole: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of voriconazole is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and voriconazole is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with avacopan is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and avacopan is a weak CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Avacopan is a complement 5a receptor (C5aR) antagonist that inhibits the interaction between C5aR and the anaphylatoxin C5a. Activation of the alternative complement pathway is believed to play an important role in the pathogenesis of ANCA-associated vasculitis through terminal C5a production. Inflammatory cytokines, such as tumor necrosis factor (TNF) alpha, stimulate neutrophils to release C5a. C5a primes and activates neutrophils. C5a also activates endothelial cells leading to cell retraction and increasing vascular permeability. When C5a acts on the C5a receptor (C5aR), it becomes a potent neutrophil chemoattractant and agonist, increasing neutrophil adhesion, inducing neutrophil degranulation, and producing reactive oxygen intermediates. In addition, activation of C5aR slows neutrophils' ability to transverse small blood vessels, particularly in the presence of ANCA, by decreasing neutrophil deformability. Though avacopan is known to inhibit 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.
Avacopan is administered orally. Avacopan and its active metabolite, M1, are 99.9% bound to plasma proteins, such as albumin and alpha1-acid glycoprotein. The estimated volume of distribution (Vd) of avacopan is 345 L. The cytochrome P450 (CYP) 3A4 enzyme is the major enzyme responsible for the metabolism of avacopan, as well as, the formation and clearance of M1, a mono-hydroxylated product of avacopan and primary circulating metabolite. M1 has approximately the same inhibitory action as avacopan on the complement 5a receptor (C5aR) and accounts for about 12% of the total drug-related materials in the plasma. Following oral administration of radiolabeled avacopan, approximately 77% of the dose was recovered in the feces and 10% in the urine. In addition, 7% and less than 0.1% of the radiolabeled dose was excreted as unchanged avacopan in the feces and urine, respectively. Following administration of a single 30 mg avacopan dose with food to healthy subjects, the mean elimination half-lives of avacopan and M1 are 97.6 hours and 55.6 hours, respectively. The estimated rate of total body clearance (CL/F) of avacopan is 16.3 L/hour.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-glycoprotein (P-gp)
The major enzyme responsible for the metabolism of avacopan, as well as the formation and metabolism of the active metabolite, M1, is CYP3A4. M1 is also a substrate of P-gp. Adjust avacopan dosage when avacopan is coadministered with a strong CYP3A4 inhibitor. Coadministration with itraconazole, a strong CYP3A4 inhibitor, resulted in a 2.19-fold and 1.19-fold increase in the AUC of avacopan and M1, respectively. Avoid coadministration of strong and moderate CYP3A4 inducers with avacopan. Coadminstration of avacopan and rifampin, a strong CYP3A4 inducer, resulted in a 93% reduction in the AUC and a significant reduction in Cmax for both avacopan and M1. Avacopan is a CYP3A4 inhibitor; closely monitor patients for adverse reactions and consider dose reduction of sensitive CYP3A4 substrates with a narrow therapeutic index (NTI) when coadministered with avacopan. In vitro studies demonstrated avacopan induction and time-dependent inhibition of CYP3A4; M1 appears to have a low potential to induce CYP3A4, CYP1A2, and CYP2B6, but may inhibit CYP2C9 and CYP3A4. When coadministered with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam increased 1.81-fold and the Cmax by 1.55. The AUC and Cmax of celecoxib, a sensitive CYP2C9 substrate, increased by 1.15- and 1.64-fold, respectively, when coadministered with avacopan.
-Route-Specific Pharmacokinetics
Oral Route
Following administration avacopan 30 mg PO twice daily to ANCA-associated vasculitis patients, the mean steady-state 12 hour AUC was 3,466+/- 1,921 x ng/mL and the Cmax was 349 +/- 169 ng/mL. Steady-state plasma levels are reached by 13 weeks and the accumulation is approximately 4-fold. Oral administration of avacopan 30 mg capsule with a high-fat, high-calorie meal increases the AUC and Cmax by approximately 72% and 8%, respectively, and delays Tmax by approximately 4 hours (from 2 hours to 6 hours). The manufacturer states to administer the medication with food.
-Special Populations
Hepatic Impairment
In patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, the mean avacopan AUC increased by 12% and 12%, respectively and the Cmax decreased by 13% and 17%, respectively, compared to patients with normal hepatic function. In patients with mild and moderate hepatic impairment, the mean M1 AUC increased by 11% and 18%, respectively, and Cmax decreased by 5% and 16%, respectively, compared to patients with normal hepatic function. The changes in avacopan and M1 plasma exposures seen with mild and moderate hepatic impairment are not considered to be clinical relevant. Avacopan has not been studied in patients with severe hepatic impairment (Child-Pugh C).
Renal Impairment
Renal function (eGFR 14 to 170 mL/minute/1.73 m2 at baseline) was not shown to have a clinically significant effect on avacopan or the M1 metabolite plasma exposure.
Geriatric
Age (18 to 83 years) was not shown to have a clinically significant effect on avacopan or the M1 metabolite plasma exposure.
Gender Differences
Gender (31% female in clinical trials) was not shown to have a clinically significant effect on avacopan or the M1 metabolite plasma exposure.
Ethnic Differences
Race/ethnicity (White, Asian, Black) was not shown to have a clinically significant effect on avacopan or the M1 metabolite plasma exposure.
Obesity
Body weight (40.3 to 174 kg) was not shown to have a clinically significant effect on avacopan or the M1 metabolite plasma exposure.