Voydeya
FDA Label NDC 25682-049

VOYDEYA, a complement inhibitor, increases the risk of serious infections, especially those caused by encapsulated bacteria, such as Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type B [see Warnings and Precautions (5.1)]. Life-threatening and fatal infections with encapsulated bacteria have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early.

• Complete or update vaccination for encapsulated bacteria specifically, Neisseria meningitidis and Streptococcus pneumoniae at least 2 weeks prior to the first dose of VOYDEYA, unless the risks of delaying therapy with VOYDEYA outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against encapsulated bacteria in patients receiving a complement inhibitor. See Warnings and Precautions (5.1) for additional guidance on the management of the risk of serious infections caused by encapsulated bacteria.
• Patients receiving VOYDEYA are at increased risk for invasive disease caused by encapsulated bacteria, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious infections and evaluate immediately if infection is suspected.

Because of the risk of serious infections caused by encapsulated bacteria, VOYDEYA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the VOYDEYA REMS [see Warnings and Precautions (5.2)].

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).

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.

Starting Dose:

The recommended dosage of VOYDEYA is 150 mg three times a day administered orally.

VOYDEYA can be taken with or without food.

Dose Adjustment:

The dose can be increased to 200 mg three times a day if the patient's hemoglobin (Hgb) level has not increased by greater than 2 g/dL after 4 weeks of therapy, if the patient required a transfusion during the previous 4 weeks, or to achieve an appropriate Hgb response based on clinical judgement.

Missed Doses

A patient who misses a dose of VOYDEYA should take it as soon as they remember unless it is within 3 hours prior to their next dose, in which case the patient should skip the missed dose and take VOYDEYA at the next regularly scheduled time. Patients should not take two or more doses of VOYDEYA at the same time.

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.

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)].

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).

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).

Cardiac Electrophysiology

At a single-dose of 1200 mg that results in approximately 2 times the peak concentration achieved following 200 mg three times a day, VOYDEYA does not prolong the QTc interval to any clinically relevant extent.

Absorption

The median time to maximum drug concentration (T_max) is 3.7 hours following oral administration of 150 mg danicopan in patients with PNH.

Effect of Food

When the danicopan tablet was administered with a high-fat meal, danicopan AUC and C_max were approximately 25%, and 93% higher, respectively, compared to the fasted state. Median time to maximum drug concentration (T_max) was comparable when danicopan was administered in the fed or fasted state at approximately 3.0 and 2.5 hours, respectively.

Distribution

Plasma protein binding of danicopan is 91.5% to 94.3%. Danicopan is mainly distributed in plasma with a whole blood to plasma distribution ratio of 0.545. The apparent volume of distribution for a 75 kg person was 395 L.

Elimination

The mean half-life (t_½) is 7.9 hours. The mean apparent clearance of danicopan is 63 L/h.

Metabolism

Danicopan is extensively metabolized (96%) via oxidation, reduction, and hydrolysis pathways, with amide hydrolysis being the major pathway of elimination. Metabolism by CYP-mediated pathways is minimal.

Excretion

After a single oral administration of 150 mg [¹⁴C]-danicopan in humans, 69% of total radioactivity (danicopan plus metabolites) was excreted in feces and 25% was excreted in urine. Unchanged danicopan accounted for 3.57% and 0.48% of the dose excreted in feces and urine, respectively.

Specific Populations

No clinically significant differences in the pharmacokinetics of danicopan were observed based on sex, age (16.9 to 82 years), or race (Caucasians and Asians) based on population pharmacokinetic (PK) assessment.

Renal Impairment

Following oral administration of danicopan 200 mg in subjects with severe renal impairment (eGFR < 30 mL/min/1.73 m²), the extent of danicopan exposure (AUC_0-inf) increased by 52% as compared to subjects with normal renal function. There was no clinically meaningful change in C_max and T_max.

Hepatic Impairment

Danicopan C_max decreased by 27% and AUC_0-inf decreased by 8% in subjects with moderate hepatic impairment (Child-Pugh B). Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C).

Drug Interaction Studies

Clinical Studies

Effect of Danicopan on the Pharmacokinetics of Other Drugs:

Dedicated clinical drug interaction studies showed no clinically significant drug interactions with danicopan as an inhibitor or inducer of CYP2B6 (bupropion), CYP2C9 (warfarin), CYP2C19 (omeprazole), CYP3A4 (midazolam), and UGT1A1 and UGT2B7 (mycophenolic acid).

BCRP Substrates

Co-administration of a single oral dose of rosuvastatin 20 mg with danicopan dosed to steady state (200 mg three times a day for 4 days) resulted in increased rosuvastatin C_max and AUC_0-inf by 3.3-fold and 2.2-fold, respectively.

P-gp Substrates

Co-administration of a single oral dose of fexofenadine 180 mg with danicopan dosed to steady state (150 mg three times a day for 4 days) resulted in increased fexofenadine C_max and AUC_0-inf by 1.4-fold and 1.6-fold, respectively.

Co-administration of a single oral dose of tacrolimus 2 mg with danicopan dosed to steady state (200 mg three times a day for 5 days) resulted in increased tacrolimus C_max and AUC_0-inf by 1.1-fold and 1.5-fold, respectively.

Effect of Other Drugs on the Pharmacokinetics of Danicopan:

No clinically significant drug interactions were observed for danicopan as a victim when co-administered with antacid drugs (calcium carbonate, aluminum/magnesium hydroxide/simethicone) or a proton pump inhibitor (omeprazole).

In Vitro Studies

Non-CYP based metabolism is the predominant clearance pathway for danicopan. The minimal contribution of CYP metabolism in human hepatocytes is suggestive of a very low likelihood of danicopan as a victim of CYP-based drug-drug interactions.

Danicopan is a substrate of P-gp, but not a substrate of BCRP, Organic Anion Transporting Polypeptide 1B1 (OATP1B1), or OATP1B3. Danicopan is not an inducer of CYP1A2, CYP2B6 or CYP2C9.

Danicopan is an inhibitor of BCRP and P-gp, but not an inhibitor of transporters OATP1B1, OATP1B3, Organic Anion Transporter (OAT)1, OAT3, Organic Cation Transporter 2 (OCT2), or Multidrug And Toxin Extrusion 1 and 2K (MATE1 and MATE2-K).

Carcinogenesis

Danicopan was not carcinogenic in the 6-month carcinogenicity study in the TgRasH2 mouse model. Danicopan was not carcinogenic in the 2-year rat carcinogenicity study at exposures 15- to 23-times the exposure at the MRHD (based on AUC).

Mutagenesis

Danicopan was not genotoxic in the Ames bacterial reverse mutation assay, in vitro micronucleus assay in human peripheral blood lymphocytes, or in the in vivo micronucleus assay in rats.

Impairment of Fertility

In a rabbit study, reductions in male and female fertility and copulation/conception indices were observed at mean exposures 13-times the exposure at the MRHD (based on AUC).

Paroxysmal Nocturnal Hemoglobinuria (PNH)

The efficacy of VOYDEYA in adults with PNH and clinically significant EVH was assessed in a multiple-region, randomized, double-blind, placebo-controlled study (ALXN2040-PNH-301; NCT04469465). Clinically significant EVH was defined by anemia (hemoglobin [Hgb] ≤ 9.5 g/dL) with absolute reticulocyte count ≥ 120 × 10⁹/L with or without transfusion support. The study enrolled patients with PNH who had been treated with a stable dose of ravulizumab or eculizumab for at least the previous 6 months.

VOYDEYA was administered orally at 150 mg three times a day, escalated to 200 mg three times a day depending on the clinical response.

Patients were vaccinated against meningococcal infection prior to or at the time of initiating treatment with VOYDEYA if vaccination status within 3 years could not be verified.

Patients were randomized to VOYDEYA or placebo in a 2:1 ratio for 12 weeks in addition to background ravulizumab or eculizumab treatment. After Week 12, all patients received VOYDEYA in combination with their background ravulizumab or eculizumab treatment up to Week 24. After Week 24, patients could enter a long-term extension period and continue to receive VOYDEYA with background ravulizumab or eculizumab.

Efficacy was based on the change in Hgb level from Baseline to Week 12. Other efficacy measures included the proportion of patients with Hgb increase of ≥ 2 g/dL at Week 12 in the absence of transfusions, the proportion of patients with transfusion avoidance through Week 12, the change from Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores at Week 12, and change from Baseline in absolute reticulocyte count at Week 12. Transfusion avoidance was considered as achieved only by the patients who did not receive a transfusion and did not meet the protocol specified guidelines for transfusion from Baseline through Week 12.

A pre-specified interim analysis was performed when 63 participants reached the end (either completed or discontinued) of Week 12.

Baseline demographic and disease history characteristics were generally balanced between treatment groups.

Table 2 presents the baseline characteristics of the patients with PNH enrolled in the study.

Table 2 Baseline Characteristics in PNH Study (ALXN2040-PNH-301)

Parameter	Statistics	VOYDEYA (Add-on to ravulizumab or eculizumab) N = 42	Placebo (Add-on to ravulizumab or eculizumab) N = 21
Abbreviations: FACIT = Functional Assessment of Chronic Illness Therapy; LDH = lactate dehydrogenase; N = number of patients; pRBC = packed red blood cell; SD = standard deviation
Age (years)	Mean (SD)	55 (16)	53 (14)
	Median	58	53
	Min, max	25, 80	29, 75
Sex	n (%)
Male		19 (45.2)	7 (33.3)
Female		23 (54.8)	14 (66.7)
Race	n (%)
American Indian or Alaska Native		1 (2.4)	0
Asian		18 (42.9)	7 (33.3)
Black or African American		1 (2.4)	0
White		19 (45.2)	9 (42.9)
Other		1 (2.4)	0
Unknown		0	1 (4.8)
Not Reported		2 (4.8)	4 (19.0)
Ethnicity	n (%)
Hispanic or Latino		4 (9.5)	0
Not Hispanic or Latino		34 (81.0)	17 (81.0)
Not reported		4 (9.5)	4 (19.0)
Hemoglobin level (g/dL)	Mean (SD)	7.7 (0.9)	7.7 (1.0)
Reticulocyte count (109/L)	N	42	20
	Mean (SD)	236 (91)	241 (120)
Number of patients with pRBC/whole blood transfusions within 24 weeks prior to first dose	n (%)	38 (90)	17 (81)
pRBC/whole blood Transfusions within 24 weeks prior to first dose	Mean (SD)	2.5 (2.2)	2.6 (2.1)
LDH (U/L)	N	42	20
	Mean (SD)	299 (106)	278 (68)
FACIT-Fatigue score Fatigue-related symptoms and impacts were assessed using a patient reported outcome instrument, FACIT-Fatigue (score range from 0 to 52 with higher scores indicating less fatigue).	Mean (SD)	33 (11)	34 (11)
Background treatment with:	n (%)
Ravulizumab		27 (64.3)	10 (47.6)
Eculizumab		15 (35.7)	11 (52.4)

Efficacy was established based on demonstration of superiority of VOYDEYA in combination with ravulizumab or eculizumab compared to placebo in combination with ravulizumab or eculizumab in all efficacy measures with statistically significant results (Table 3).

Table 3 Efficacy Results for Patients with PNH (Study ALXN2040-PNH-301)

	VOYDEYA (Add-on to ravulizumab or eculizumab) (N = 42)	Placebo (Add-on to ravulizumab or eculizumab) (N = 21)
Abbreviations: CI = confidence interval; FACIT = Functional Assessment of Chronic Illness Therapy
Change in Hemoglobin Level The model included the fixed, categorical effects of treatment group, study visit, and study visit-by-treatment group interaction, as well as the fixed, continuous covariate of baseline value and the randomization stratification factor of transfusion history. An unstructured covariance matrix was used to model the within-patient errors.
Mean change from Baseline to Week 12 (g/dL)	2.9	0.5
Treatment difference	2.4 (95% CI: 1.7, 3.2)
P-value	0.0007 Statistical significance of the treatment group difference was evaluated via a re-randomization test method. The p-value for the re-randomization test was calculated as the number of re-randomized treatment group differences that were more extreme than the treatment group difference calculated under the actual randomization divided by the total number of simulated re-randomizations.
Proportion of Patients with Hemoglobin Increase of ≥ 2 g/dL in the Absence of Transfusion The proportions were compared between treatment groups using the Cochrane-Mantel-Haenszel (CMH) test stratified by randomization stratification factors of transfusion history and screening Hgb level. The p-value was from the stratified CMH test.
At Week 12 (%)	59.5	0
Treatment difference	46.9 (95% CI: 29.2, 64.7)
P-value	< 0.0001
Proportion of Patients with Transfusion Avoidance
Through 12-Week Treatment Period (%)	83.3	38.1
Treatment difference	41.7 (95% CI: 22.7, 60.8)
P-value	0.0004
Change in FACIT-Fatigue Score The model included the fixed, categorical effects of treatment group, study visit, and study visit-by-treatment group interaction, as well as the fixed, continuous covariate of baseline value and the randomization stratification factors of transfusion history and screening Hgb level. An unstructured covariance matrix was used to model the within-patient errors. Fatigue-related symptoms and impacts were assessed using a patient reported outcome instrument, FACIT-Fatigue (score range from 0 to 52 with higher scores indicating less fatigue).
Mean change from Baseline to Week 12	8.0	1.9
Treatment difference	6.1 (95% CI: 2.3, 9.9)
P-value	0.002 The p-value was for the difference of LS mean from the mixed models for repeated measures (MMRM).
Change in Absolute Reticulocyte Count
Mean change from Baseline to Week 12 (109/L)	-84	4
Treatment difference	-87 (95% CI: -118, -57)
P-value	< 0.0001

Serious Infections Caused by Encapsulated Bacteria

Advise patients of the risk of serious infection. Inform patients of the need to complete or update their vaccinations against encapsulated bacteria at least 2 weeks prior to receiving the first dose of VOYDEYA or receive antibacterial drug prophylaxis if VOYDEYA treatment must be initiated immediately and they have not previously been vaccinated. Inform patients of the requirement to be revaccinated according to ACIP recommendations for encapsulated bacteria while on VOYDEYA therapy [see Warnings and Precautions (5.1)].

Inform patients that vaccination may not prevent serious infection and to seek immediate medical attention if the following signs or symptoms occur [see Warnings and Precautions (5.1)]:

• fever with or without chills
• fever and a rash
• fever with chest pain and cough
• fever with breathlessness/fast breathing
• fever with high heart rate
• headache with nausea or vomiting
• headache and a fever
• headache with a stiff neck or stiff back
• confusion
• body aches with flu-like symptoms
• clammy skin
• eyes sensitive to light

Inform patients that they will be given a Patient Safety Card for VOYDEYA that they should carry with them at all times during and for 1 week following treatment with VOYDEYA. This card describes symptoms which, if experienced, should prompt the patient to seek immediate medical evaluation.

VOYDEYA REMS

VOYDEYA is available only through a restricted program called VOYDEYA REMS [see Warnings and Precautions (5.2)].

Inform the patient of the following notable requirements:

• Patients must receive counseling about the risk of serious infections caused by encapsulated bacteria.
• Patients must receive written educational materials about this risk.
• 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.
• Patients must be instructed to complete or update vaccines against encapsulated bacteria per ACIP recommendations as directed by the prescriber prior to treatment with VOYDEYA.
• Patients must receive antibiotics as directed by the prescriber if they are not up to date on vaccinations against encapsulated bacteria and have to start VOYDEYA right away.

Importance of Adherence to Dosing Schedule

Inform patients with PNH of the importance of taking VOYDEYA as prescribed to minimize the risk of hemolysis.

Discontinuation

Inform patients with PNH that they may develop serious hemolysis due to PNH if VOYDEYA is discontinued and that they should be monitored by their healthcare providers for at least 2 weeks following discontinuation of VOYDEYA.

Inform patients who discontinue VOYDEYA to keep the Patient Safety Card with them for 1 week after the last dose of VOYDEYA. The increased risk of serious infection may continue for a few days after the last dose of VOYDEYA.

Hepatic Enzyme Elevations

Inform patients that elevation in liver enzymes have occurred in patients treated with VOYDEYA, and liver tests will be obtained before and during VOYDEYA treatment [see Warnings and Precautions (5.3)].

Hyperlipidemia

Inform patients that VOYDEYA may increase their cholesterol and that monitoring of these parameters will be needed periodically during treatment [see Warnings and Precautions (5.4)].

Manufactured for:

Alexion Pharmaceuticals, Inc.
121 Seaport Boulevard
Boston, MA 02210 USA

This product, or its use, may be covered by one or more US patents, including US Patent No. 9,796,741 B2 in addition to others including patents pending.

VOYDEYA is a trademark of Alexion Pharmaceuticals, Inc.

© 2024 Alexion Pharmaceuticals, Inc.

Vaccinate patients against encapsulated bacteria, including Neisseria meningitidis (serogroups A, C, W, Y, and B) and Streptococcus pneumoniae according to current ACIP recommendations at least 2 weeks prior to initiation of VOYDEYA.

If urgent VOYDEYA therapy is indicated in a patient who is not up to date with vaccines for Neisseria meningitidis and Streptococcus pneumoniae according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer these vaccines as soon as possible [see Warnings and Precautions (5.1)].

Healthcare professionals who prescribe VOYDEYA must enroll in the VOYDEYA REMS [see Warnings and Precautions (5.2)].

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)].

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)].

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.

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)].

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.

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)]

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.

Clinically relevant adverse reactions in <5% of patients include increased serum triglycerides.

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.

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)].

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

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.

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)].

Serum ALT elevations occurred after treatment cessation without a taper in 2 healthy subjects who received danicopan 500 mg and 800 mg twice a day. These abnormal ALT findings were transient, with no evidence of hepatic function abnormality and resolved spontaneously. In case of overdose, elevations in liver enzymes may occur. General supportive measures are recommended. It is not known if VOYDEYA can be removed by dialysis.

Danicopan is a small molecule complement Factor D inhibitor. Its chemical name is (2S,4R)-1-{[3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl] acetyl}-N-(6-bromopyridin-2-yl)-4-fluoropyrrolidine-2-carboxamide. Its molecular formula is C₂₆H₂₃BrFN₇O₃ and its molecular weight is 580.4. Danicopan has the following structural formula:

Chemical Structure (Voydeya 01)

Danicopan is a white/off-white to pale yellow powder. In aqueous solutions, danicopan is considered slightly soluble at pH 1.2 and insoluble from pH 4 to pH 7.

Danicopan tablets are available as white to off-white, round, film-coated, immediate release tablets in strengths of 50 mg and 100 mg, intended for oral administration. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet coating components are polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

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.

Danicopan inhibits the AP of the complement system, as demonstrated by the decrease in ex vivo serum AP activity and in vivo plasma Bb concentration. Danicopan also reduces complement C3 fragment deposition on circulating red blood cells (RBCs) in PNH patients.

In patients with PNH undergoing treatment with ravulizumab or eculizumab, co-administration of VOYDEYA from 150 mg three times a day to 200 mg three times a day inhibited AP activity by >90%. Additionally, plasma Bb levels decreased by about 50% and the fraction of circulating PNH RBCs with measured C3 fragment deposition decreased by over 50%.

At the recommended dosages of 150 or 200 mg three times a day, the median systemic exposure of danicopan at steady state has a maximum plasma concentration (C_max,ss) of 535 or 665 ng/mL, respectively, and has an area under the plasma drug concentration time curve (AUC_24,ss) of 8180 or 10200 ng × h/mL, respectively.

Danicopan exposures at steady state generally increase in a dose-proportional manner from 150 mg three times a day to 200 mg three times a day. Danicopan systemic exposure reaches steady state in approximately 2 days. An approximately 2-fold accumulation of danicopan exposure is expected at steady state following thrice daily dosing compared to a single dose.

Ocular phototoxicity was observed in pigmented rats at systemic exposures 15-times and 28-times the exposure at the MRHD (based on AUC and C_max, respectively). As danicopan is expected to accumulate in the eye, a risk of developing ocular phototoxicity cannot be excluded in patients on long-term danicopan therapy who are exposed to unprotected ultraviolet radiation for extended periods of time. The clinical significance of these findings is unknown.

VOYDEYA (danicopan) tablets are available in the doses and packages listed in Table 4.

Store and dispense in the original container at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP controlled room temperature].

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

NDC 25682-043-04
Rx only

Voydeya™
(danicopan) tablets

Dispense with enclosed Medication Guide.

100 mg per tablet

Take two 100 mg tablets three times a day
(200 mg dose three times a day)

Four 7-day blister cards with 42 tablets per card (168 tablets)

Principal Display Panel (100 mg Tablet Blister Pack Carton)

NDC 25682-043-92
Rx only

Voydeya™
(danicopan) tablets

Dispense with enclosed Medication Guide.

100 mg

180 tablets
90 x 100 mg tablets per bottle

Principal Display Panel (100 mg Tablet Bottle Carton)

NDC 25682-049-04
Rx only

Voydeya™
(danicopan) tablets

Dispense with enclosed Medication Guide.

50 mg per tablet
and
100 mg per tablet

Take one 100 mg tablet and one 50 mg tablet
three times a day
(150 mg dose three times a day)

Four 7-day blister cards with 42 tablets per card (168 tablets)
21 x 50 mg per tablet
21 x 100 mg per tablet

Principal Display Panel (Kit Carton)

NDC 25682-046-92
Rx only

Voydeya™
(danicopan) tablets

Dispense with enclosed Medication Guide.

50 mg
and
100 mg

Take one 100 mg tablet and one 50 mg tablet
three times a day
(150 mg dose three times a day)

180 tablets
90 x 50 mg tablets per bottle
90 x 100 mg tablets per bottle

Principal Display Panel (Kit Carton)