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.

2.1 Recommended Vaccination and Prophylaxis for Encapsulated Bacterial Infections

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)].

2.2 Recommended Dosage

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.

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.

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.

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

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.

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)].

8.1 Pregnancy

8.2 Lactation

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)].

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

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%.

12.3 Pharmacokinetics

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 (Cmax,ss) of 535 or 665 ng/mL, respectively, and has an area under the plasma drug concentration time curve (AUC24,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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

Ocular phototoxicity was observed in pigmented rats at systemic exposures 15-times and 28-times the exposure at the MRHD (based on AUC and Cmax, 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.

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.

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).

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].

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)].