Danicopan

VOYDEYA is indicated as add-on therapy to ravulizumab or eculizumab for the treatment of extravascular hemolysis (EVH) in adults with paroxysmal nocturnal hemoglobinuria (PNH). VOYDEYA is a complement factor D inhibitor indicated as add-on therapy to ravulizumab or eculizumab for the treatment of extravascular hemolysis (EVH) in adults with paroxysmal nocturnal hemoglobinuria (PNH) ( 1 ). Limitations of Use VOYDEYA has not been shown to be effective as monotherapy and should only be prescribed as an add-on to ravulizumab or eculizumab. Limitations of Use VOYDEYA has not been shown to be effective as monotherapy and should only be prescribed as an add-on to ravulizumab or eculizumab.

Tablets: 50 mg and 100 mg ( 3 ) Tablets: 50 mg, white to off-white, round, film-coated, printed with "DCN" above "50" debossed on one side, plain on the other side. 100 mg, white to off-white, round film-coated, printed with "DCN" above "100" debossed on one side, plain on the other side.

VOYDEYA is contraindicated for initiation in patients with unresolved serious infection caused by encapsulated bacteria, including Neisseria meningitidis , Streptococcus pneumoniae , or Haemophilus influenzae type B [see Warnings and Precautions (5.1) ] . Initiation in patients with unresolved serious infection caused by encapsulated bacteria ( 4 ).

Hepatic Enzyme Increases: Assess liver enzymes before treatment initiation and periodically during treatment. Consider treatment interruption or discontinuation if elevations are clinically significant or if the patient becomes symptomatic ( 5.3 ). Hyperlipidemia: Monitor serum lipids periodically during treatment and initiate cholesterol-lowering medication if indicated ( 5.4 ).

5.1 Serious Infections Caused by Encapsulated Bacteria VOYDEYA, a complement inhibitor, increases a patient's susceptibility to serious, life-threatening, or fatal infections caused by encapsulated bacteria including Neisseria meningitidis (caused by any serogroup, including non-groupable strains), Streptococcus pneumoniae , and Haemophilus influenzae type B. Life-threatening and fatal infections with encapsulated bacteria have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of VOYDEYA treatment is contraindicated in patients with unresolved serious infections caused by encapsulated bacteria. Complete or update vaccination against encapsulated bacteria, specifically Neisseria meningitidis and Streptococcus pneumoniae at least 2 weeks prior to administration of the first dose of VOYDEYA, according to the current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations considering the duration of therapy with VOYDEYA. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent VOYDEYA therapy is indicated in a patient who is not up to date with vaccines against encapsulated bacteria according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including VOYDEYA. The benefits and risks of treatment with VOYDEYA, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by encapsulated bacteria. Vaccination does not eliminate the risk of serious encapsulated bacterial infections, despite development of antibodies following vaccination. Closely monitor patients for early signs and symptoms of serious infection and evaluate patients immediately if an infection is suspected. Inform patients of these signs and symptoms and instruct patients 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 VOYDEYA in patients who are undergoing treatment for serious infections. VOYDEYA is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ] . 5.2 VOYDEYA REMS VOYDEYA is available only through a restricted program under a REMS called VOYDEYA REMS, because of the risk of serious infections caused by encapsulated bacteria [see Warnings and Precautions (5.1) ] . Notable requirements of the VOYDEYA REMS include the following: Prescribers must enroll in the REMS. Prescribers must counsel patients about the risk of serious infections caused by encapsulated bacteria. Prescribers must provide patients with the REMS educational materials. Prescribers must assess patient vaccination status for vaccines against encapsulated bacteria and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of VOYDEYA. Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently, and the patient is not up to date with vaccines against encapsulated bacteria according to current ACIP recommendations at least two weeks prior to the first dose of VOYDEYA. Pharmacies that dispense VOYDEYA must be certified in the VOYDEYA REMS and must verify prescribers are certified. Patients must receive counseling from the prescriber about the need to receive vaccinations against encapsulated bacteria per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the early signs and symptoms of serious infections. Patients must be instructed to carry the Patient Safety Card with them at all times during treatment and for 1 week following the last dose of VOYDEYA. Further information is available by telephone: 1-888-765-4747 or online at www.VoydeyaREMS.com.

5.3 Hepatic Enzyme Increases Hepatic enzyme elevations have been observed in patients treated with VOYDEYA [see Adverse Reactions (6.1) ] . Fourteen percent of patients receiving VOYDEYA in Study ALXN2040-PNH-301 had elevations in serum alanine aminotransferase (ALT). ALT elevations > 3 × the upper limit of normal (ULN) and ≤ 5 × ULN occurred in 9% of VOYDEYA-treated patients, and ALT elevations > 5 × ULN and ≤ 10 × ULN occurred in 5% of VOYDEYA-treated patients. Assess liver enzyme test results prior to the initiation of VOYDEYA and periodically during treatment. Consider treatment interruption or discontinuation if elevations are clinically significant or if the patient becomes symptomatic. VOYDEYA has not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7)] .

5.4 Monitoring of PNH Manifestations After VOYDEYA Discontinuation After discontinuing treatment with VOYDEYA, closely monitor patients for at least 2 weeks after the last dose for signs and symptoms of hemolysis. If discontinuation of VOYDEYA is necessary, continue background treatment with ravulizumab or eculizumab or consider alternative therapy if necessary. The signs and symptoms of hemolysis may include a sudden decrease in hemoglobin or fatigue. If hemolysis occurs after discontinuation of VOYDEYA, consider restarting treatment with VOYDEYA if appropriate.

5.5 Hyperlipidemia VOYDEYA increases total cholesterol and LDL-cholesterol. Of the 50 VOYDEYA-treated patients who had a normal total cholesterol level at baseline in Study ALXN2040-PNH-301, 30% developed Grade 1 hypercholesterolemia. Of the 6 VOYDEYA treated patients who had Grade 1 hypercholesterolemia at baseline in Study ALXN2040-PNH-301, 1 patient experienced increased total cholesterol that worsened to Grade 2. Of the 54 VOYDEYA-treated patients who had LDL-cholesterol ≤130 mg/dL at baseline in Study ALXN2040-PNH-301, 13% developed LDL-cholesterol >130-160 mg/dL and 9% developed LDL-cholesterol >160-190 mg/dL. Some patients required cholesterol-lowering medications. Monitor serum lipid parameters periodically during treatment with VOYDEYA and initiate cholesterol lowering medication, if indicated.

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Serious Infections Caused by Encapsulated Bacteria [see Warnings and Precautions (5.1) ] Hepatic Enzyme Increases [see Warnings and Precautions (5.3) ] Hyperlipidemia [see Warnings and Precautions (5.4) ] Most frequent adverse reaction (incidence ≥10%) was headache ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Alexion Pharmaceuticals, Inc. at 1-844-259-6783 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of VOYDEYA was evaluated in 86 adults with PNH in Study ALXN2040-PNH-301 [see Clinical Studies (14) ] . Study ALXN2040-PNH-301 enrolled adults with PNH with clinically significant EVH who had been treated with a stable dose of ravulizumab or eculizumab for at least the previous 6 months. Patients were randomly assigned 2:1 to receive double-blind VOYDEYA 150 mg (n=57) or placebo (n=29) orally three times a day in addition to ravulizumab or eculizumab for 12 weeks. Patients received either US-approved or non-US-approved ravulizumab or eculizumab in the trial. Among patients who were randomized to receive VOYDEYA, 84% were exposed for at least 12 weeks. Serious adverse reactions were reported in 5% of patients who received VOYDEYA and included pancreatitis, cholecystitis, and blood bilirubin increased. No specific serious adverse reaction was reported in more than 1 patient treated with VOYDEYA. Permanent discontinuation of VOYDEYA due to an adverse reaction occurred in 5% of patients and included 1 patient with blood bilirubin increase and pancreatitis, 1 patient with hepatic enzyme increased, and 1 patient with ALT increased and aspartate aminotransferase increased. Dosage reduction due to an adverse reaction occurred in 1 patient and the adverse reaction was COVID-19. Among the 57 patients treated with VOYDEYA in Study ALXN2040-PNH-301, the most common adverse reaction (≥10%) was headache. Table 1 describes adverse reactions reported in ≥5% of patients treated with VOYDEYA and greater than placebo in the randomized, controlled period of Study ALXN2040-PNH-301. Table 1 Adverse Reactions Reported in ≥5% of VOYDEYA-Treated Patients with PNH and Greater than Placebo Adverse Reactions Common Toxicity Criteria Adverse Events (CTCAE) VOYDEYA (with ravulizumab or eculizumab) N = 57 Placebo (ravulizumab or eculizumab only) N = 29 n (%) n (%) Headache 6 (11) 3 (10) Vomiting Represents a composite of multiple, related adverse reactions 4 (7) 0 (0) Pyrexia 4 (7) 0 (0) Alanine aminotransferase increased 3 (5) 1 (3) Hypertension 3 (5) 1 (3) Pain in extremity 3 (5) 0 (0) Clinically relevant adverse reactions in <5% of patients include increased serum triglycerides.

BCRP substrates: Monitor patients more frequently for adverse reactions and consider dose reduction of the BCRP substrate drug. For rosuvastatin, the dose should not exceed 10 mg once daily ( 7.1 ). P-gp substrates: Dose adjustment might be necessary for P-gp substrates where minimal concentration changes may lead to serious adverse reactions ( 7.2 ). 7.1 BCRP Substrates Danicopan is a Breast Cancer Resistance Protein (BCRP) inhibitor. Concomitant use of VOYDEYA with a BCRP substrate increases the plasma concentrations of the BCRP substrate [see Clinical Pharmacology (12.3) ] , which may increase the risk for adverse reactions associated with the BCRP substrate. If used together, monitor patients more frequently for adverse reactions associated with the BCRP substrate, and consider dose reduction of the BCRP substrate according to its prescribing information. Rosuvastatin Danicopan significantly increased rosuvastatin exposure. The dose of rosuvastatin should not exceed 10 mg once daily when concomitantly used with VOYDEYA [see Clinical Pharmacology (12.3) ] . 7.2 P-gp Substrates Danicopan is an inhibitor of P-glycoprotein (P-gp). Concomitant administration of VOYDEYA with a P-gp substrate may increase the plasma concentration of the P-gp substrate. Dose adjustment might be necessary for P-gp substrates where minimal concentration changes may lead to serious adverse reactions [see Clinical Pharmacology (12.3) ] .

Hepatic Impairment: Avoid use in patients with severe hepatic impairment (Child-Pugh C) ( 8.6 ).

8.1 Pregnancy Risk Summary There are no available data on VOYDEYA 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 PNH in pregnancy (see Clinical Considerations ) . The use of VOYDEYA in pregnant women or women planning to become pregnant may be considered following an assessment of the risks and benefits. In animal reproduction studies, oral administration of danicopan to pregnant New Zealand White (NZW) rabbits and Wistar Hans (WH) rats during organogenesis at exposures 18 or 25-times, respectively, above the human exposure at the maximum recommended human dose (MRHD) of 200 mg three times a day (based on AUC) resulted in no adverse developmental effects (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Fetal/Neonatal Risk PNH in pregnancy is associated with adverse maternal outcomes, including worsening cytopenias, thrombotic events, infections, bleeding, miscarriages, and increased maternal mortality, and adverse fetal outcomes, including fetal death and premature delivery. Data Animal Data There were no effects on early embryonic development and fetal development in NZW rabbits (where danicopan is pharmacodynamically active) up to a mean maternal systemic exposure 18-times the exposure at the MRHD (based on AUC) or during post-natal development up to a mean maternal systemic exposure 9-times the exposure at the MRHD (based on AUC). In WH rats (where danicopan lacks pharmacodynamic activity), there were no effects on embryo-fetal development up to a mean maternal exposure 25-times the exposure at the MRHD (based on AUC).

8.2 Lactation Risk Summary There are no data on the presence of danicopan in human milk, the effects on the breastfed child, or the effect 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. Because of the potential for serious adverse reactions in the breastfed child, including serious infections with encapsulated bacteria and liver enzyme increases, advise patients not to breastfeed during treatment with VOYDEYA, and for 3-days after the last dose. Data Animal Data Danicopan was excreted into the milk of lactating rabbits following oral administration from lactation day 4 to lactation day 10, with mean milk concentrations at approximately 2 hours following dose administration 5- and 3.5-times higher than the mean maternal plasma concentrations at 50 and 250 mg/kg/day, respectively. Mean milk concentrations in dams were 19- and 43-times higher than the systemic exposure at the MRHD (based on rabbit concentration at 2 hours vs. human C max ).

8.4 Pediatric Use Safety and effectiveness of VOYDEYA for the treatment of PNH in pediatric patients have not been established.

8.5 Geriatric Use There were 22 patients 65 years of age and older in the clinical studies for PNH [see Clinical Studies (14) ] . Of the total number of VOYDEYA-treated patients in these studies, 16 (28.1%) were 65 years of age and older, and 7 (12.3%) were 75 years of age and older. Clinical studies of VOYDEYA did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

8.6 Hepatic Impairment No dose adjustment is required in patients with mild to moderate hepatic impairment (Child-Pugh Class A and B). Studies have not been conducted in patients with severe hepatic impairment, therefore, avoid use of VOYDEYA in this patient population [see Warnings and Precautions (5.3) ] .

Danicopan binds reversibly to complement Factor D and selectively inhibits the alternative complement pathway. Danicopan prevents the cleavage of complement Factor B into the Ba and Bb fragments which are required for the formation of the alternative pathway (AP) complement component C3 convertase (C3bBb), the generation of downstream effectors including C3 fragment opsonization, and the amplification of the terminal pathway. In 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 co-administered ravulizumab or eculizumab is anticipated to maintain control over MAC-mediated IVH.