Apvardi (Tablet kit) Instructions for Use

Marketing Authorization Holder

Alexion Europe SAS (France)

Manufactured By

Catalent CTS LLC (USA)

Quality Control Release

ALEXION PHARMA INTERNATIONAL OPERATIONS, Unlimited Company (Ireland)

ATC Code

L04AJ09 (Danicopan)

Active Substance

Danicopan (Rec.INN registered by WHO)

Dosage Forms

	Apvardi	Tablet kit, film-coated tablets, 50 mg + 100 mg
		Film-coated tablets, 100 mg: 168 or 180 pcs.

Dosage Form, Packaging, and Composition

Tablet kit, film-coated tablets

21 pcs. – blisters (8 pcs.) – cardboard packs (168 pcs.) /in the kit: 4 blisters (film-coated tablets, 50 mg – 21 pcs.); 4 blisters (film-coated tablets, 100 mg – 21 pcs.)/ – By prescription
90 pcs. – bottles (2 pcs.) – cardboard packs (180 pcs.) /in the kit: 1 bottle (film-coated tablets, 50 mg – 90 pcs.); 1 bottle (film-coated tablets, 100 mg – 90 pcs.)/ – By prescription

Film-coated tablets

42 pcs. – blisters (4 pcs.) – cardboard packs (168 pcs.) – By prescription
90 pcs. – bottles (2 pcs.) – cardboard packs (180 pcs.) – By prescription

Clinical-Pharmacological Group

Immunosuppressant

Pharmacotherapeutic Group

Immunosuppressants; complement inhibitors

Pharmacological Action

Immunosuppressant, complement inhibitor.

Complement factor D (FD) is a serine protease required for the alternative pathway (AP) of complement system activation. Factor D mediates the cleavage of complement factor B (FB) when factor B binds to activated forms of complement component 3 (C3) to form the C3-convertase – C3bBb. The C3-convertase drives activation of the next stage of the complement cascade and promotes multiple effector functions of the complement system. Factor D is present in the systemic circulation at a lower concentration than most other complement system proteins and is not an acute-phase protein.

Danicopan is a low molecular weight inhibitor that reversibly binds to factor D and acts as a potent and selective inhibitor of factor D function and, consequently, of the alternative pathway of activation. Although Danicopan blocks AP-mediated amplification of the classical pathway (CP) and lectin pathway (LP) of complement activation, these two pathways remain active, providing residual complement-dependent protection against infectious pathogens. Danicopan can inhibit AP-mediated deposition of C3 fragments on red blood cells in paroxysmal nocturnal hemoglobinuria (PNH); such deposition is a primary cause of extravascular hemolysis (EVH), which is observed in a small group of PNH patients treated with a C5 inhibitor. Maintaining C5 inhibition provides control of the life-threatening pathophysiological consequences of terminal complement activation, which is the cause of PNH.

Pharmacokinetics

Danicopan is rapidly absorbed after oral administration, with the mean time to reach C_max occurring approximately 3 hours after administration. In a human absorption, distribution, metabolism, excretion study of radioactively labeled ¹⁴C danicopan, it was found that the concentration of danicopan decreased in a biphasic manner after reaching C_max. The ratio of mean AUC_0-∞ values calculated for plasma and whole blood radioactivity levels was 0.545; based on this result, it can be assumed that the distribution of radioactively labeled ¹⁴C danicopan in blood cells is limited. After oral administration, Danicopan is extensively metabolized (96%) by oxidation, reduction, and hydrolysis, with amide hydrolysis being the primary elimination pathway. Metabolism involving cytochrome-mediated elimination mechanisms is minimal. After oral administration, the primary route of elimination is fecal excretion (approximately 69% of the administered dose compared to approximately 25% of the administered dose detected in urine). In a human absorption, distribution, metabolism, excretion study of radioactively labeled ¹⁴C danicopan, the geometric mean apparent T_1/2 was 5.75 hours. In a population pharmacokinetic analysis in PNH patients with clinically significant EVH, the estimated mean T_1/2 was 7.88 hours and ranged from 4.3 to 12.2 hours.

Indications

For the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) as add-on therapy to ravulizumab or eculizumab in the presence of persistent hemolytic anemia.

ICD codes

Dosage Regimen

Danicopan is used only as add-on therapy in combination with ravulizumab or eculizumab.

Orally for adults at an initial dose of 150 mg 3 times/day with an interval of approximately 8 hours (± 2 hours).

Depending on clinical efficacy, the dose may be increased to 200 mg 3 times/day. A dose increase is recommended if the patient’s hemoglobin level has not increased by at least 2 g/dL after 4 weeks of therapy, or if the patient received a blood transfusion within the previous 4 weeks, or to achieve the necessary clinical response.

PNH is a chronic disease, and treatment with danicopan in combination with ravulizumab or eculizumab is recommended for life, except in cases where discontinuation of danicopan is clinically indicated.

If discontinuation of danicopan is necessary, the dose should be reduced over 6 days until complete cessation according to a specific scheme.

Adverse Reactions

Nervous system disorders very common – headache.

Hepatobiliary disorders very common – increased liver enzyme activity.

Contraindications

Hypersensitivity to danicopan, pregnancy, breastfeeding period, children and adolescents under 18 years of age.

Use in Pregnancy and Lactation

Use during pregnancy is contraindicated.

During use and for 3 days after discontinuation of Danicopan, women of childbearing potential should use effective methods of contraception.

Danicopan should not be taken during breastfeeding, and breastfeeding should be initiated only 3 days after discontinuation of danicopan.

Use in Hepatic Impairment

No dose adjustment is required for patients with mild or moderate hepatic impairment. Studies in patients with severe hepatic impairment have not been conducted, therefore Danicopan is not recommended for this patient population.

Use in Renal Impairment

No dose adjustment is required for patients with renal impairment.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

No dose adjustment is required for patients aged 65 years and older.

Special Precautions

There is no experience with the use of danicopan in combination with other drugs for the treatment of PNH, except for ravulizumab and eculizumab, therefore the use of danicopan in combination with other complement inhibitors, except for ravulizumab and eculizumab, is not recommended.

Treatment with danicopan should not be initiated in patients with a Neisseria meningitidis infection that has not resolved by the time of treatment initiation; in patients without information on prophylactic vaccinations against meningococcal infection or who have not received revaccination against meningococcal infection in accordance with existing national recommendations, except when such patients receive prophylactic treatment with appropriate antibiotics for 2 weeks after vaccination.

The use of drugs that suppress the activity of the complement system increases the susceptibility of patients to meningococcal infections (Neisseria meningitidis). Patients should be vaccinated against meningococcal infection in accordance with current national recommendations before receiving the first dose of danicopan.

Patients who start treatment with danicopan less than 2 weeks after vaccination against meningococcal infection should receive prophylactic treatment with appropriate antibiotics until 2 weeks have passed since vaccination. For the prevention of meningococcal infection caused by the most common pathogenic serogroups, vaccines against Neisseria meningitidis serogroups A, C, Y, W135 are recommended. Vaccination against meningococcal infection caused by Neisseria meningitidis serogroup B is also recommended if the vaccine is available. Official recommendations for the proper use of antibacterial agents should be considered. All patients receiving Danicopan should be monitored for early signs of meningococcal infection and sepsis. If an infection is suspected, the patient’s condition should be immediately assessed and treatment with appropriate antibiotics initiated. Patients should be informed about the signs and symptoms and the actions to take to seek immediate medical attention.

It is recommended to perform liver function tests before starting treatment.

After starting treatment, regular biochemical laboratory monitoring is recommended in accordance with the standard of care for PNH. The need for temporary discontinuation or withdrawal of treatment should be considered if the increase is clinically significant or if patients develop symptoms. Studies in patients with severe hepatic impairment have not been conducted.

Effect on ability to drive vehicles and operate machinery

Danicopan is presumed to have no or negligible influence on the ability to drive vehicles and operate machinery.

Drug Interactions

Available preclinical data indicate that metabolism not mediated by the CYP450 system is the predominant pathway of danicopan clearance.

It is assumed that as a result of the interaction of danicopan with other drugs, the extent of its CYP-mediated metabolism is very low.

Concomitant administration of ravulizumab or eculizumab does not appear to affect the plasma concentration of danicopan.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.