VOYDEYA Film-coated tablet Ref.[110089] Active ingredients: Danicopan

General

Danicopan must not be administered as monotherapy as the efficacy has not been established. It should only be prescribed as an add-on to ravulizumab or eculizumab.

Serious infections

Meningococcal infections

Patients receiving complement inhibitor therapy may have increased susceptibility to meningococcal infections (Neisseria meningitidis). Patients must be up to date on their meningococcal vaccines according to current national guidelines for vaccination use, prior to receiving the first dose of danicopan.

Patients who initiate treatment less than 2 weeks after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics until 2 weeks after vaccination. Patients must be vaccinated against serogroups A, C, Y, and W135 to prevent the commonly pathogenic meningococcal serogroups. Vaccination against serogroup B, where available, is also recommended. Consideration should be given to official guidance on the appropriate use of antibacterial agents.

All patients treated with danicopan should be monitored for early signs of meningococcal infection and sepsis, evaluated immediately if infection is suspected, and treated with appropriate antibiotics. Patients should be informed of these signs and symptoms and steps should be taken to seek medical care immediately.

Other serious infections

Danicopan should be administered with caution to patients with active systemic infections. Danicopan selectively blocks the activation of the complement alternative pathway; therefore, patients may have increased susceptibility to serious infections (other than Neisseria meningitidis). Prior to initiating danicopan as add-on to ravulizumab or eculizumab, it is recommended that patients initiate immunisation according to current immunisation guidelines.

Severe renal impairment

Patients with severe renal impairment that dose escalate to 150 mg three times a day should be monitored for adverse events during treatment with danicopan due to higher exposure expected in these patients.

Low body weight

Patients weighing <60 kg should be monitored for adverse events during treatment with danicopan due to higher exposure expected in these patients.

Hepatic enzymes increase

Alanine aminotransferase (ALT) elevations have been observed in clinical trials (see section 4.8). It is recommended that liver enzyme tests are performed before treatment begins. Following initiation of treatment, routine chemistry laboratory monitoring as per PNH management is recommended. Treatment interruption or discontinuation should be considered if elevations are clinically significant or if patients become symptomatic. Danicopan is not recommended in patients with severe hepatic impairment (see section 4.2).

Discontinuation

At doses higher than 200 mg three times a day, ALT elevations occurred after treatment cessation without dose tapering in healthy subjects (see section 4.9). Upon discontinuation, the dose should be tapered over 6 days (see section 4.2).

Excipients with known effect

Lactose

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially ‘sodium-free’.

Effects of danicopan on other medicinal products

P-gp substrates

Co-administration of a single oral dose of 180 mg fexofenadine, a P-gp substrate, with 150 mg three times daily doses of danicopan resulted in increased fexofenadine C_max and AUC_0-inf by 1.42-fold and 1.62-fold, respectively. The results suggest that danicopan is a mild inhibitor of P-gp. Caution may be needed in co-administering medicinal products that are known to be substrates of P-gp (such as dabigatran, digoxin, edoxaban, fexofenadine, tacrolimus).

BCRP substrates

Co-administration of a single oral dose of 20 mg rosuvastatin, a BCRP substrate, with 200 mg three times daily doses of danicopan resulted in increased rosuvastatin C_max and AUC_0-inf by 3.29-fold and 2.25-fold, respectively. This result suggests that danicopan is an inhibitor of BCRP. Caution may be needed in co-administering medicinal products that are known to be substrates of BCRP (such as rosuvastatin and sulfasalazine).

Pregnancy

There are no data from the use of danicopan in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at therapeutically relevant dose (see section 5.3). As a precautionary measure, it is preferable to avoid the use of Voydeya during pregnancy.

Breast-feeding

Available pharmacodynamic/toxicological data in animals have shown excretion of danicopan/metabolites in milk (see section 5.3). A risk to the newborns/infants cannot be excluded. Voydeya should not be used during breast-feeding and breast-feeding should not be initiated until 3 days after treatment discontinuation.

Fertility

No human data on the effect of danicopan on fertility are available. Animal studies have shown potential effects on male fertility and reproductive performance (see section 5.3).

Voydeya has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most common adverse reactions are pyrexia (25.0%), headache (19.8%), hepatic enzyme increased (11.5%), and pain in extremity (11.5%).

Tabulated list of adverse reactions

Table 1 includes adverse reactions reported in clinical trials with danicopan. Adverse reactions are listed by system organ class and preferred term using MedDRA frequency convention very common (≥1/10), common (≥1/100 to <1/10), and uncommon (≥1/1 000 to <1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Tabulated list of adverse reactions:

^a Hepatic enzyme increased includes preferred terms alanine aminotransferase increased, hepatic function abnormal, hepatic enzyme increased, and transaminases increased.

Description of selected adverse reactions

Hepatic enzyme increase

During the 12-week randomised controlled period of study ALXN2040-PNH-301 laboratory abnormalities related to elevations in ALT levels were observed in 14.0% of patients on danicopan. In danicopan-treated patients, ALT elevations >3 × the upper limit of normal (ULN) and ≤5 × ULN occurred in 8.8% of patients, and >5 × ULN and ≤10 × ULN in 5.3% of patients. All patients were asymptomatic, and all elevations were transient. Some elevations occurred in the context of haemolysis.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.