Danicopan (Monograph)

Brand name: Voydeya
Drug class: Complement Inhibitor Agents

Introduction

Danicopan is a small molecule complement factor D inhibitor.

Uses for Danicopan

Danicopan has the following uses:

Danicopan is indicated as add-on therapy to ravulizumab or eculizumab for the treatment of extravascular hemolysis (EVH) in adults with paroxysmal nocturnal hemoglobinuria (PNH).

Danicopan has not been shown to be effective as monotherapy and should only be prescribed as an add-on to ravulizumab or eculizumab.

Danicopan Dosage and Administration

General

Danicopan is available in the following dosage form(s) and strength(s):

Tablets: 50 mg and 100 mg

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• The recommended dosage of danicopan is 150 mg three times a day orally, with or without food. Dosage can increase 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.

• See Full Prescribing Information for instructions on dosage and administration.

Cautions for Danicopan

Contraindications

Initiation in patients with unresolved serious infection caused by encapsulated bacteria.

Warnings/Precautions

Serious Infections Caused by Encapsulated Bacteria

Danicopan, 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 influenzaeType B. Life-threatening and fatal infections with encapsulated bacteria have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors. The initiation of danicopan 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 danicopan, 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 danicopan. 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 danicopan 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 danicopan. The benefits and risks of treatment with danicopan, 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 danicopan in patients who are undergoing treatment for serious infections.

Danicopan is available only through a restricted program under a REMS.

Danicopan REMS

Danicopan is available only through a restricted program under a REMS called Voydeya REMS because of the risk of serious infections caused by encapsulated bacteria. Notable requirements of the danicopan 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 2 weeks prior to the first dose of danicopan.

• 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 2 weeks prior to the first dose of danicopan.

• Pharmacies that dispense danicopan must be certified in the REMS program 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 danicopan.

Further information is available by telephone: 1-888-765-4747 or online at www.VoydeyaREMS.com.

Hepatic Enzyme Increases

Hepatic enzyme elevations have been observed in patients treated with danicopan. Fourteen percent of patients receiving danicopan 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 danicopan-treated patients, and ALT elevations > 5 × ULN and ≤ 10 × ULN occurred in 5% of danicopan-treated patients.

Assess liver enzyme test results prior to the initiation of danicopan and periodically during treatment. Consider treatment interruption or discontinuation if elevations are clinically significant or if the patient becomes symptomatic. Danicopan has not been studied in patients with severe hepatic impairment.

Monitoring of PNH Manifestations After Danicopan Discontinuation

After discontinuing treatment with danicopan, closely monitor patients for at least 2 weeks after the last dose for signs and symptoms of hemolysis. If discontinuation of danicopan 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 danicopan, consider restarting treatment with danicopan if appropriate.

Hyperlipidemia

Danicopan increases total cholesterol and LDL-cholesterol. Of the 50 danicopan-treated patients who had a normal total cholesterol level at baseline in Study ALXN2040-PNH-301, 30% developed Grade 1 hypercholesterolemia. Of the 6 danicopan-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 danicopan-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 danicopan and initiate cholesterol lowering medication, if indicated.

Specific Populations

Pregnancy

There are no available data on 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 PNH in pregnancy. The use of danicopan 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.

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.

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.

Lactation

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 danicopan, and for 3-days after the last dose.

Pediatric Use

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

Geriatric Use

There were 22 patients 65 years of age and older in the clinical studies for PNH. Of the total number of danicopan-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 danicopan did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger subjects.

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 danicopan in this patient population.

Common Adverse Effects

Most frequent adverse reaction (incidence ≥10%) was headache.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Breast Cancer Resistance Protein (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.

• P-glycoprotein (P-gp) substrates: Dose adjustment might be necessary for P-gp substrates where minimal concentration changes may lead to serious adverse reactions.

Actions

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 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 co-administered ravulizumab or eculizumab is anticipated to maintain control over MAC-mediated IVH.

Advice to Patients

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

• 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 danicopan or receive antibacterial drug prophylaxis if danicopan 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 danicopan therapy.

• Inform patients that vaccination may not prevent serious infection and to seek immediate medical attention if the following signs or symptoms occur: 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; or eye sensitivity to light.

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

• Inform patients that danicopan is available only through a restricted program called Voydeya REMS. Inform patient of the notable requirements of the program.

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

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

• Inform patients that elevation in liver enzymes have occurred in patients treated with danicopan, and liver tests will be obtained before and during treatment.

• Inform patients that danicopan may increase their cholesterol and that monitoring of these parameters will be needed periodically during treatment.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Reload page with references included

Medical Disclaimer