Danicopan

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).

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).

In patients with severe renal impairment (eGFR <30 mL/min/1.73 m²), the recommended starting dose is 100 mg three times a day administered orally, approximately 8 hours apart (± 2 hours). Dose can be increased to 150 mg three times a day after a minimum of 4 weeks of treatment depending on clinical response.

Patients should be monitored for adverse events during treatment with danicopan due to higher exposure expected.

Studies have not been conducted in patients with severe (Child-Pugh Class C) hepatic impairment. Therefore, danicopan is not recommended in this patient population.

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

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.

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. As a precautionary measure, it is preferable to avoid the use of danicopan during pregnancy.

Available pharmacodynamic/toxicological data in animals have shown excretion of danicopan/metabolites in milk. A risk to the newborns/infants cannot be excluded. Danicopan 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.

Danicopan 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

The table below 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.

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.