VOYDEYA 100 mg

Indications

• Paroxysmal nocturnal hemoglobinuria (PNH)

Dosage

Children: Refer to the BNF for Children for specific pediatric dosing recommendations.

Adults: Refer to the BNF for specific dosing information. Generally, danicopan is administered in conjunction with other therapies for optimal management of PNH.

Mechanism of action

Danicopan reversibly binds to complement factor D, selectively inhibiting the alternative complement pathway. This inhibition prevents the formation of complement component C3 convertase (C3bBb), reducing downstream effects such as C3 fragment opsonization and the amplification of the terminal pathway, which is crucial in the pathophysiology of paroxysmal nocturnal hemoglobinuria.

Pharmacodynamics

Danicopan exerts its pharmacologic effects by selectively inhibiting the alternative pathway of the complement system. In clinical studies involving patients with PNH treated with ravulizumab or eculizumab, co-administration of danicopan at doses of 150-200 mg three times daily resulted in over 90% inhibition of alternative pathway activity. Additionally, there was approximately a 50% reduction in plasma levels of component Bb and more than 50% decrease in the fraction of circulating PNH red blood cells with C3 fragment deposition.

Pharmacokinetics

The pharmacokinetics of danicopan include absorption, distribution, metabolism, and excretion, although specific details regarding its half-life, clearance, and volume of distribution are not provided. As a targeted therapy, its pharmacokinetic profile is likely influenced by its binding to complement factor D and its role in modulating the complement cascade in patients with PNH.

Adverse effects

• Headache
• Fatigue
• Nausea
• Diarrhea
• Abdominal pain
• Dizziness
• Anemia

Interactions

• Co-administration with ravulizumab or eculizumab
• Other medications that affect the complement system

Precautions

• Monitor for signs of infection due to complement inhibition
• Use with caution in patients with a history of hypersensitivity reactions
• Regularly assess hemoglobin levels in patients with PNH

Pregnancy

There is limited data on the use of danicopan during pregnancy. It should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is unknown whether danicopan is excreted in human milk. Caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature, away from light and moisture. Do not freeze.

Formulations

• Oral tablet

Mechanism of action

The complement system is an enzyme cascade that plays a role in innate immunity. It helps defend against infection by initiating a local inflammatory response and is the system responsible for producing the terminal membrane attack complex (MAC), which causes lysis of foreign cells. In addition, the components of the complement pathway have other immune functions, including the promotion of phagocytosis, the clearance of immune complexes, and the regulation of antibody production. There are three pathways to complement activation - Lectin, Classical, and Alternative - which converge at complement component C3. Danicopan reversibly binds to complement factor D, thereby selectively inhibiting the alternative complement pathway. It prevents the formation of 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, intravascular hemolysis is mediated by the MAC, while extravascular hemolysis is facilitated by C3 fragment opsonization. Danicopan acts proximally in the alternative pathway of the complement cascade to control C3 fragment-mediated EVH, while co-administered ravulizumab or eculizumab is anticipated to maintain control over MAC-mediated IVH.

Pharmacodynamics

Danicopan exerts its pharmacologic effects by selectively inhibiting the alternative pathway (AP) of the complement system. In patients with PNH undergoing treatment with ravulizumab or eculizumab, co-administration of danicopan 150-200mg three times daily resulted in a >90% inhibition of AP activity. In addition, plasma levels of component Bb decreased by ~50% and the fraction of circulating PNH red blood cells with C3 fragment depostion decreased by >50%.