Danicopan is an oral complement factor D inhibitor indicated for the treatment of extravascular hemolysis in adults with paroxysmal nocturnal hemoglobinuria (PNH) as add-on therapy to eculizumab or ravulizumab. Danicopan increases the risk of serious, life-threatening, or fatal infections caused by encapsulated bacteria; vaccination against encapsulated bacteria is recommended to be completed at least 2 weeks prior to starting danicopan. Danicopan increases total cholesterol and low-density lipoprotein cholesterol (LDL-C), and hepatic enzyme elevations have also been reported with danicopan; serum lipid concentration and liver function test monitoring is recommended during treatment.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer with or without food.
-Missed dose: If a dose is missed, administer the missed dose as soon as possible. If it is within 3 hours prior to the next dose, skip the missed dose and administer the next dose at the regularly scheduled time. Do not take 2 or more doses at the same time.
Extremity pain (5%), fever (7%), and headache (11%) were reported with danicopan during clinical trials.
Hypertension was reported with danicopan in 5% of subjects during clinical trials.
Danicopan increases total cholesterol and low-density lipoprotein cholesterol (LDL-C). Of the danicopan-treated subjects who had normal total cholesterol at baseline, 30% developed grade 1 hypercholesterolemia. Of the 6 subjects with grade 1 hypercholesterolemia at baseline, a single subject experienced increased total cholesterol that worsened to grade 2. Of the subjects who had an LDL-C of 130 mg/dL or less at baseline, 13% developed LDL-C more than 130 to 160 mg/dL and 9% developed LDL-C more than 160 to 190 mg/dL. Hypertriglyceridemia was reported in less than 5% of subjects. Some subjects required cholesterol-lowering medications. Monitor serum lipid parameters periodically during danicopan treatment and initiate cholesterol lowering medication if indicated.
Vomiting was reported with danicopan in 7% of subjects during clinical trials.
Elevated hepatic enzymes have been observed with danicopan during clinical trials. Serum alanine aminotransferase (ALT) elevations were reported with danicopan in 14% of subjects. ALT elevations more than 3 times and 5 times or less the upper limit of normal (ULN) were reported in 9% of danicopan-treated subjects. ALT elevations more than 5 times and 10 times or less the ULN were reported in 5% of danicopan-treated subjects. Assess liver function test results prior to the initiation of danicopan and periodically during treatment. Consider treatment interruption or discontinuation if elevations are clinically significant or symptomatic. Permanent discontinuation of danicopan due to an adverse reaction occurred in 5% of subjects and included a single subject with elevated hepatic enzymes and a single subject with elevated ALT and aspartate aminotransferase (AST).
Serious adverse reactions reported with danicopan in 5% of subjects in clinical trials included cholecystitis, hyperbilirubinemia, and pancreatitis. Permanent discontinuation of danicopan due to an adverse reaction occurred in 5% of subjects and included a single subject with increased bilirubin and pancreatitis. No specific serious adverse reaction was reported in more than 1 patient treated with danicopan.
Danicopan use increases susceptibility to serious, life-threatening, or fatal infections caused by encapsulated bacteria, including S. pneumoniae, N. meningitidis (any serogroup, including non-groupable strains), and H. influenzae type B. Ensure persons are appropriately vaccinated. Closely monitor for early signs and symptoms of infection and evaluate immediately if infection is suspected. Instruct persons to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Serious infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of danicopan in persons who are undergoing treatment for serious infections. Danicopan dosage reduction due to an adverse reaction of COVID-19 infection occurred in a single subject during clinical trials.
Danicopan is contraindicated in persons with unresolved serious encapsulated bacteria infection, including infections caused by S. pneumoniae, N. meningitidis (any serogroup, including non-groupable strains), and H. influenzae type B. Danicopan increases the risk of serious, life-threatening, or fatal infections caused by encapsulated bacteria. Complete or update vaccination against encapsulated bacteria at least 2 weeks prior to administration of the first dose of danicopan, according to current Advisory Committee on Immunization Practices (ACIP) recommendations for persons receiving a complement inhibitor. Revaccinate considering the duration of danicopan therapy. Note that ACIP recommends an administration schedule in persons receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent danicopan therapy is indicated in persons who are not up to date with vaccines against encapsulated bacteria according to ACIP recommendations, administer these vaccines as soon as possible and provide antibacterial medication prophylaxis. The optimal durations and medication regimens for antibacterial medication prophylaxis and their efficacy have not been studied in persons receiving complement inhibitors, including danicopan. Consider the benefits and risks of treatment with danicopan in addition to the benefits and risks of antibacterial medication prophylaxis in unvaccinated or vaccinated persons against the known risks for serious infections caused by encapsulated bacteria. Closely monitor for early signs and symptoms of infection and evaluate immediately if infection is suspected. Instruct persons to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Serious infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of danicopan in persons who are undergoing treatment for serious infections. Vaccination does not eliminate the risk for infections due to these organisms, despite development of antibodies after vaccination.
If abrupt discontinuation of danicopan is necessary, continue background treatment with eculizumab or ravulizumab or consider alternative therapy. After discontinuing treatment with danicopan, closely monitor for signs and symptoms of hemolysis (e.g., a sudden decrease in hemoglobin, fatigue) for at least 2 weeks after the last dose. If hemolysis occurs after danicopan discontinuation, consider restarting treatment with danicopan if appropriate.
Ocular toxicity cannot be excluded in persons on long-term danicopan therapy who are exposed to unprotected ultraviolet (UV) radiation or sunlight (UV) exposure for extended periods. Danicopan is expected to accumulate in the eye. Ocular phototoxicity was observed in animal studies with danicopan. The clinical significance of this is unknown.
Avoid danicopan use in persons with severe hepatic disease (Child-Pugh Class C); studies have not been conducted in this population.
The use of danicopan during pregnancy or in persons planning to become pregnant may be considered after an assessment of the risks and benefits. There are no available data with danicopan use in pregnant individuals to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with untreated paroxysmal nocturnal hemoglobinuria (PNH) in pregnancy. PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriage, increased maternal mortality, and adverse fetal outcomes, including premature delivery and fetal death. Oral administration of danicopan to pregnant rabbits and rats during organogenesis at exposures 18 or 25-times, respectively, above the human exposure at the maximum recommended human dose of 200 mg 3 times daily (based on AUC) resulted in no adverse developmental effects.
Breast-feeding is not recommended during danicopan therapy and for 3 days after the last dose due to the potential for serious adverse reactions in the breast-fed child, including serious infections with encapsulated bacteria and hepatic enzyme increases. There are no data on the presence of danicopan in human milk, the effects on the breast-fed child, or the effects on milk production. Danicopan is present in animal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk.
General Dosing Information
-Vaccinate persons against encapsulated bacteria, including S. pneumoniae and N. meningitidis (serogroups A, C, W, Y, and B), at least 2 weeks prior to initiation of danicopan and according to the most current Advisory Committee on Immunization Practices (ACIP) recommendations.
--If urgent danicopan treatment is indicated in persons not up to date with vaccines for S. pneumoniae and N. meningitidis according to ACIP recommendations, administer these vaccines as soon as possible and provide antibacterial medication prophylaxis.
For the treatment of extravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) as add-on therapy to eculizumab or ravulizumab:
NOTE: Danicopan is designated as an orphan drug by the FDA for this indication.
Oral dosage:
Adults: 150 mg PO 3 times daily, initially. May increase the dose to 200 mg PO 3 times daily if hemoglobin has not increased by more than 2 g/dL after 4 weeks of therapy, if a transfusion was required during the previous 4 weeks, or to achieve an appropriate hemoglobin response based on clinical judgement.
Maximum Dosage Limits:
-Adults
600 mg/day PO.
-Geriatric
600 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
No dosage adjustment is needed for mild to moderate hepatic impairment (Child-Pugh Class A and B). Avoid use in severe hepatic impairment (Child-Pugh Class C).
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with danicopan. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Afatinib: (Moderate) If the concomitant use of danicopan and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of danicopan. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-gp substrate and danicopan is a P-gp inhibitor. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC of afatinib was 119% when coadministered with the same P-gp inhibitor, and 111% when the inhibitor was administered 6 hours after afatinib.
Alpelisib: (Major) Avoid coadministration of alpelisib with danicopan due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and danicopan is a BCRP inhibitor.
Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with danicopan is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; danicopan is a P-gp and BCRP inhibitor.
Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with danicopan is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a P-gp and BCRP substrate; danicopan is a P-gp and BCRP inhibitor.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving danicopan. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving danicopan. Concurrent use may increase betrixaban exposure resulting in an increased bleeding risk; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a P-gp substrate; danicopan is a P-gp inhibitor. Coadministration of other P-gp inhibitors increased betrixaban exposure by 2 to 3-fold.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with danicopan may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Cobimetinib: (Moderate) Monitor for an increase in cobimetinib-related adverse reactions if coadministration with danicopan is necessary. Concomitant use may increase cobimetinib exposure. In vitro, cobimetinib is a P-gp substrate; danicopan is a P-gp inhibitor.
Colchicine: (Major) Avoid concomitant use of colchicine and danicopan due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and danicopan is a P-gp inhibitor.
Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with danicopan 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 P-gp substrate and danicopan is a P-gp inhibitor.
Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with danicopan is necessary in patients with creatinine clearance (CrCl) greater than 50 mL/minute. Avoid coadministration in patients with CrCl less than 50 mL/minute when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCl less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-gp substrate and danicopan is a P-gp inhibitor.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with danicopan may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Digoxin: (Moderate) Increase monitoring of serum digoxin concentrations and watch for potential signs and symptoms of clinical toxicity when starting, adjusting, or discontinuing danicopan. Concurrent use may increase digoxin exposure. Digoxin is a P-gp substrate with a narrow therapeutic index and danicopan is a P-gp inhibitor.
Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with danicopan. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with danicopan. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Dolutegravir; Rilpivirine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with danicopan. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with danicopan may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Doxorubicin Liposomal: (Major) Avoid coadministration of danicopan with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and danicopan is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of danicopan with doxorubicin due to the risk for increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a P-gp substrate and danicopan is a P-gp inhibitor. Concurrent use of P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Edoxaban: (Major) Consider an edoxaban dosage reduction for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE) if concomitant use of danicopan is necessary. Concomitant use may increase edoxaban exposure; edoxaban is a P-gp substrate and danicopan is a P-gp inhibitor. An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with danicopan. Based on clinical experience in patients with non-valvular atrial fibrillation no dose reduction is recommended for concomitant use of danicopan. Increased concentrations of edoxaban may occur during concomitant use of danicopan; monitor for increased adverse effects of edoxaban.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with danicopan may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with danicopan may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with danicopan may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with danicopan may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with danicopan may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with danicopan may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with danicopan may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with danicopan may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with danicopan is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-gp substrate and danicopan is a P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
Ezetimibe; Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with danicopan is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; danicopan is a P-gp inhibitor.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with coadministration of glecaprevir and danicopan as increased plasma concentrations of glecaprevir may occur resulting in increased risk of glecaprevir-related adverse events. Glecaprevir is a substrate of P-gp and BCRP and danicopan is a P-gp and BCRP inhibitor. (Moderate) Monitor for an increase in pibrentasvir-related adverse effects if concomitant use of danicopan is necessary. Concomitant use may increase pibrentasvir exposure. Pibrentasvir is a substrate of P-gp and BCRP and danicopan is a P-gp and BCRP inhibitor.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with danicopan may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Lapatinib: (Moderate) Monitor for an increase in lapatinib-related adverse reactions if coadministration with danicopan is necessary. Lapatinib is a P-gp substrate and danicopan is a P-gp inhibitor. Increased plasma concentrations of lapatinib are likely.
Lefamulin: (Major) Avoid coadministration of danicopan with oral lefamulin unless the benefits outweigh the risks as concurrent use may increase lefamulin exposure and adverse effects; danicopan may be administered with intravenous lefamulin. Lefamulin is a P-gp substrate and danicopan is a P-gp inhibitor.
Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with danicopan. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and danicopan is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with danicopan. Concurrent use may increase loperamide exposure. Loperamide is a P-gp substrate and danicopan is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased loperamide plasma concentrations by 2- to 3-fold.
Lovastatin: (Moderate) Monitor for an increase in lovastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with danicopan is necessary. Concomitant use may increase lovastatin exposure. Lovastatin is a P-gp substrate; danicopan is a P-gp inhibitor.
Maraviroc: (Moderate) Monitor for an increase in maraviroc-related adverse reactions if coadministration with danicopan is necessary. Concomitant use may increase maraviroc exposure. Maraviroc is a P-gp substrate; danicopan is a P-gp inhibitor.
Mefloquine: (Moderate) Monitor for an increase in mefloquine-related adverse effects if concomitant use of danicopan is necessary. Concomitant use may increase mefloquine exposure. Mefloquine is a P-gp substrate and danicopan is a P-gp inhibitor.
Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with danicopan is necessary; decrease the dose of morphine as necessary. Morphine is a P-gp substrate and danicopan is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with danicopan is necessary; decrease the dose of morphine as necessary. Morphine is a P-gp substrate and danicopan is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Naldemedine: (Moderate) Monitor for naldemedine-related adverse reactions if coadministered with danicopan. Naldemedine plasma concentrations may increase during concomitant use. Naldemedine is a P-gp substrate; danicopan is a P-gp inhibitor.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and danicopan. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and danicopan is a P-gp inhibitor.
Pazopanib: (Major) Avoid coadministration of pazopanib and danicopan due to the potential for increased pazopanib exposure. Pazopanib is a P-gp and BCRP substrate; danicopan is a P-gp and BCRP inhibitor. Consider selection of an alternative concomitant medication with no or minimal potential to inhibit P-gp or BCRP.
Pitavastatin: (Moderate) Monitor for an increase in pitavastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with danicopan is necessary. Concomitant use may increase pitavastatin exposure. Pitavastatin is a P-gp substrate; danicopan is a P-gp inhibitor.
Posaconazole: (Moderate) Monitor for an increase in posaconazole-related adverse reactions if coadministration with danicopan is necessary. Concomitant use may increase posaconazole exposure. Posaconazole is a P-gp substrate; danicopan is a P-gp inhibitor.
Pralsetinib: (Major) Avoid concomitant use of danicopan with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a P-gp substrate and danicopan is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased the overall exposure of pralsetinib by 1.8-fold.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and danicopan due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a P-gp substrate and danicopan is a P-gp inhibitor.
Ranolazine: (Moderate) Monitor for an increase in ranolazine-related adverse reactions if coadministration with danicopan is necessary and consider a ranolazine dosage adjustment. Concomitant use may increase ranolazine exposure. Ranolazine is a P-gp substrate; danicopan is a P-gp inhibitor.
Relugolix: (Major) Avoid concomitant use of relugolix and oral danicopan. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is necessary, administer danicopan at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of danicopan is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-gp substrate and danicopan is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral danicopan. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is necessary, administer danicopan at least 6 hours after relugolix and monitor for adverse reactions. Alternatively, relugolix therapy may be interrupted for up to 14 days if a short course of danicopan is required; if treatment is interrupted for more than 7 days, resume relugolix with a 360 mg loading dose followed by 120 mg once daily. Relugolix is a P-gp substrate and danicopan is a P-gp inhibitor.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with danicopan due to increased repotrectinib exposure which may increase the risk for repotrectinib-related adverse effects. Repotrectinib is a P-gp substrate and danicopan is a P-gp inhibitor.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with danicopan is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and danicopan is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rimegepant: (Major) Avoid a second dose of rimegepant within 48 hours if coadministered with danicopan; concurrent use may increase rimegepant exposure. Rimegepant is a P-gp substrate and danicopan is a P-gp inhibitor.
Rosuvastatin: (Major) Limit the dose of rosuvastatin to 10 mg once daily and monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with danicopan. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and danicopan is a BCRP inhibitor. Coadministration with danicopan increased the overall exposure of rosuvastatin by approximately 2-fold.
Rosuvastatin; Ezetimibe: (Major) Limit the dose of rosuvastatin to 10 mg once daily and monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with danicopan. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and danicopan is a BCRP inhibitor. Coadministration with danicopan increased the overall exposure of rosuvastatin by approximately 2-fold.
Saquinavir: (Moderate) Monitor for an increase in saquinavir-related adverse reactions if coadministration with danicopan is necessary. Concomitant use may increase saquinavir exposure. Saquinavir is a P-gp substrate; danicopan is a P-gp inhibitor.
Silodosin: (Major) Avoid coadministration of silodosin and danicopan due to the potential for increased silodosin exposure. In vitro data indicate that silodosin is a P-gp substrate; danicopan is a P-gp inhibitor.
Simvastatin: (Moderate) Monitor for an increase in simvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with danicopan is necessary. Concomitant use may increase simvastatin exposure. Simvastatin is a P-gp substrate; danicopan is a P-gp inhibitor.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of danicopan. Coadministration may increase sirolimus concentrations and the risk for sirolimus-related adverse effects. Sirolimus is a P-gp substrate and danicopan is a P-gp inhibitor.
Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with danicopan is necessary. The dose of tacrolimus may need to be reduced. Coadministration with danicopan increased tacrolimus overall exposure by 1.5-fold.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of danicopan is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Temsirolimus: (Moderate) Monitor for an increase in temsirolimus-related adverse reactions if coadministration with danicopan is necessary due to the risk of increased temsirolimus exposure. Temsirolimus is a P-gp substrate and danicopan is a P-gp inhibitor. Coadministration is likely to increase plasma concentrations of temsirolimus.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with danicopan may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with danicopan may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with danicopan may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Ticagrelor: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with danicopan as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and danicopan is a P-gp inhibitor.
Tipranavir: (Moderate) Monitor for an increase in tipranavir-related adverse reactions if coadministration with danicopan is necessary. Concomitant use may increase tipranavir exposure. Tipranavir is a P-gp substrate; danicopan is a P-gp inhibitor.
Topotecan: (Major) Avoid coadministration of danicopan with oral topotecan due to increased topotecan exposure; danicopan may be administered with intravenous topotecan. Coadministration increases the risk of topotecan-related adverse reactions. Oral topotecan is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with danicopan. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with danicopan due to the potential for increased venetoclax exposure. Resume the original venetoclax dose 2 to 3 days after discontinuation of danicopan. Venetoclax is a P-gp substrate; danicopan is a P-gp inhibitor. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
Vincristine Liposomal: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of danicopan is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and danicopan is a P-gp inhibitor.
Vincristine: (Moderate) Monitor for vincristine-related adverse reactions if coadministration of danicopan is necessary as concurrent use may increase vincristine exposure. Vincristine is a P-gp substrate and danicopan is a P-gp inhibitor.
Danicopan is a small molecule complement factor D inhibitor that reversibly binds to complement factor D and selectively inhibits the alternative complement pathway. It prevents the cleavage of complement factor B into the Ba and Bb fragments which are required for the formation of the alternative pathway complement component C3 convertase (C3bBb), the generation of downstream effectors including C3 fragment opsonization, and the amplification of the terminal pathway. In paroxysmal nocturnal hemoglobinuria (PNH), intravascular hemolysis (IVH) is mediated by the terminal membrane attack complex (MAC), while extravascular hemolysis (EVH) is facilitated by C3 fragment opsonization. Danicopan acts proximally in the alternative pathway of the complement cascade to control preferentially C3 fragment-mediated EVH, while coadministered eculizumab or ravulizumab is anticipated to maintain control over MAC-mediated IVH. In those undergoing treatment with eculizumab or ravulizumab, coadministration of danicopan 150 to 200 mg PO 3 times daily inhibited alternative pathway activity by more than 90%. Additionally, Bb concentrations decreased by about 50% and the fraction of circulating PNH red blood cells with measured C3 fragment deposition decreased by over 50%.
Danicopan is administered orally. Plasma protein binding of danicopan is 91.5% to 94.3%. It is mainly distributed in plasma with a whole blood to plasma distribution ratio of 0.545. The apparent Vd for a 75 kg person is 395 L. Danicopan is extensively metabolized (96%) via oxidation, reduction, and hydrolysis pathways, with amide hydrolysis as the major pathway of elimination. Metabolism by CYP-mediated pathways is minimal. After a single oral dose of radiolabeled danicopan 150 mg, 69% of total radioactivity (danicopan plus metabolites) was excreted in the feces and 25% was excreted in the urine. Unchanged danicopan accounted for 3.57% and 0.48% of the dose excreted in the feces and urine, respectively. The mean apparent clearance of danicopan is 63 L/hour and the mean half-life of danicopan is 7.9 hours.
Affected cytochrome P450 isoenzymes and drug transporters: BCRP, P-gp
Danicopan is BCRP inhibitor and a substrate and inhibitor of P-gp. The minimal contribution of CYP metabolism of danicopan in human hepatocytes is suggestive of a very low likelihood of danicopan as a substrate of CYP-based drug-drug interactions. Dedicated clinical drug interaction studies showed no clinically significant drug interactions with danicopan as an inhibitor or inducer of CYP2B6, CYP2C9, CYP2C19, CYP3A, and UGT1A1 and UGT2B7. In vitro, danicopan is not an inducer of CYP1A2. Danicopan is not an inhibitor of transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT2, or MATE1 and MATE2-K. Danicopan is not a substrate of BCRP, OATP1B1, or OATP1B3.
-Route-Specific Pharmacokinetics
Oral Route
The median time to maximum drug concentration (Tmax) is 3.7 hours after oral administration of danicopan 150 mg in persons with paroxysmal nocturnal hemoglobinuria. Danicopan exposures at steady-state generally increase in a dose-proportional manner from 150 to 200 mg PO 3 times daily. Danicopan systemic exposure reaches steady-state in approximately 2 days. An approximately 2-fold accumulation of danicopan exposure is expected at steady-state after 3 times daily dosing compared to a single dose. At steady-state, the median danicopan maximum plasma concentration (Cmax) is 535 ng/mL and median exposure (AUC) is 8,180 ng x hour/mL at a dose of 150 mg PO 3 times daily and 665 ng/mL and 10,200 ng x hour/mL, respectively, at a dose of 200 mg PO 3 times daily. When danicopan was administered with a high-fat meal, danicopan Cmax and AUC were approximately 93% and 25% higher, respectively, compared to the fasted state. Median Tmax was comparable when danicopan was administered during in the fed or fasted state at approximately 3 and 2.5 hours, respectively.
-Special Populations
Hepatic Impairment
Danicopan Cmax decreased by 27% and AUC decreased by 8% in persons with moderate hepatic impairment (Child-Pugh Class B). Studies have not been conducted in persons with severe hepatic impairment (Child-Pugh Class C).
Renal Impairment
After oral administration of danicopan 200 mg in persons with severe renal impairment (eGFR less than 30 mL/minute/1.73 m2), the extent of danicopan exposure (AUC) increased by 52% as compared to subjects with normal renal function. There was no clinically meaningful change in Cmax and Tmax.
Geriatric
No clinically significant differences in the pharmacokinetics of danicopan were observed based on age (16.9 to 82 years).
Gender Differences
No clinically significant differences in the pharmacokinetics of danicopan were observed based on sex.
Ethnic Differences
No clinically significant differences in the pharmacokinetics of danicopan were observed based on race (Caucasians and Asians).