Danicopan

Q: What should I know before taking Danicopan?

5 WARNINGS AND PRECAUTIONS 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, in

Q: Is Danicopan available over the counter?

Danicopan is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

Prescription

Ticari adlar: Voydeya

Farmasötik Form

Tablet

Uygulama Yolu

ORAL

Üretici

Alexion Pharmaceuticals, Inc.

About This Medication

11 DESCRIPTION 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 C 26 H 23 BrFN 7 O 3 and its molecular weight is 580.4. Danicopan has the following structural formula: 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. Chemical Structure

Etken Maddeler

Bileşen	Güç
Danicopan	-

Endikasyonlar ve Kullanım

1 INDICATIONS AND USAGE 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.

Nasıl çalışır

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.

Dozaj ve Uygulama

2 DOSAGE AND ADMINISTRATION Start 150 mg three times a day orally, with or without food. Depending on clinical response, can increase to 200 mg three times a day. See Full Prescribing Information for instructions on dosage and administration ( 2.1 , 2.2 ). 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 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.

Side Effects Overview

6 ADVERSE REACTIONS 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.

Uyarılar ve Önlemler

5 WARNINGS AND PRECAUTIONS 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.

Kontrendikasyonlar

4 CONTRAINDICATIONS 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 ).

Farmakokinetik

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 (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. 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 [ 14 C]-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 m 2 ), 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).

Frequently Asked Questions

1 INDICATIONS AND USAGE 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 …

2 DOSAGE AND ADMINISTRATION Start 150 mg three times a day orally, with or without food. Depending on clinical response, can increase to 200 mg three times a day. See Full Prescribing Information for instructions on dosage and administration ( 2.1 , 2.2 ). 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 …

5 WARNINGS AND PRECAUTIONS 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 …

4 CONTRAINDICATIONS 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 ).

Danicopan is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

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References & Data Sources

• DailyMed — Danicopan drug label (National Library of Medicine)
• openFDA — Danicopan label data (U.S. Food & Drug Administration)
• RxNorm — RXCUI 2678957 (NLM Normalized Drug Names)
• NDC Directory — Danicopan (FDA National Drug Code)

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Veri kaynakları: DailyMed (NLM), openFDA, MFDS