Leniolisib

In vitro, leniolisib is an inhibitor of UGT1A1, and although a relevant clinical interaction is not expected, concomitant administration of leniolisib with a UGT1A1 substrate (e.g., irinotecan) should be avoided.

Leniolisib is a substrate of BCRP transporters. No interaction studies have been conducted with leniolisib and strong BCRP inhibitors. Concomitant use may result in increased leniolisib exposure, which could lead to an increased risk of adverse effects. Therefore, concomitant use of leniolisib with strong BCRP inhibitors (e.g., curcumin, cyclosporine) should be avoided.

When co-administered, leniolisib increased rosuvastatin exposure 2-fold. Avoid concomitant use of leniolisib with medicinal products that are OATP1B1, OATP1B3, and BCRP substrates (e.g., rosuvastatin, pitavastatin, letermovir).

Live, attenuated vaccinations may be less effective if administered during leniolisib treatment.

Leniolisib is an OAT3 inhibitor and may increase systemic exposure to OAT3 substrates (e.g., adefovir, baricitinib, bumetanide, cefaclor, ceftizoxime, ciprofloxacin, famotidine, furosemide, methotrexate, oseltamivir carboxylate, benzylpenicillin [penicillin G], tenofovir). When co-administered, leniolisib increased furosemide exposure 1.4-fold. Avoid concomitant use of leniolisib with medicinal products that are OAT3 substrates with a narrow therapeutic index (e.g., methotrexate).

Leniolisib is cleared primarily through oxidative metabolism (primarily hydroxylation and dealkylation) by CYP isoenzymes (predominantly CYP3A4, 95.4%). In a study of healthy adults, co-administration of leniolisib and itraconazole, a strong CYP3A4 inhibitor, resulted in a 2-fold increase in leniolisib exposure. Concomitant use of leniolisib with strong CYP3A4 inhibitors (e.g., cobicistat, danoprevir, elvitegravir, indinavir, itraconazole, ketoconazole, lopinavir, ombitasvir, paritaprevir, posaconazole, ritonavir, saquinavir, telithromycin, tipranavir, troleandomycin, voriconazole) should be avoided.

If use of strong CYP3A4 inhibitors is required, it is recommended that leniolisib be discontinued 2 days before administration of CYP3A4 inhibitor. Leniolisib may be restarted 7 days after CYP3A4 inhibitor discontinuation.

No interaction studies have been conducted with leniolisib and strong and moderate CYP3A4 inducers. Concomitant use may result in reduced leniolisib exposure and thus reduced leniolisib efficacy. Therefore, concomitant use of leniolisib with strong and moderate CYP3A4 inducers (e.g., avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampicin, St. John's Wort, bosentan, efavirenz, etravirine, modafinil, nafcillin) should be avoided.

Leniolisib has not been studied in patients with hepatic impairment. Use of leniolisib in patients with moderate to severe hepatic impairment (Child-Pugh Class B or C) is not recommended.

Leniolisib exhibits pH-dependent solubility, with lower solubility at higher pH-values. Locally acting antacids (e.g., magnesium-, aluminum-, and calcium-based antacids, sodium bicarbonate) should be taken 2 hours before or 2 hours after leniolisib administration.

No human data on the effect of leniolisib on fertility are available. Studies in animals have shown effects on the male reproductive organs.

There are no data from the use of leniolisib in pregnant women. Studies in animals have shown reproductive toxicity. Leniolisib is not recommended during pregnancy and in women of childbearing potential not using highly effective methods of contraception.

It is unknown whether leniolisib and its metabolites are excreted in human milk. Available pharmacokinetic/toxicological data in animals have shown excretion of leniolisib in milk. A risk to breastfed newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with leniolisib.

Women of childbearing potential/contraception in females

Women of childbearing potential should use highly effective methods of contraception during treatment with leniolisib and for 1 week after the last dose. Leniolisib can cause foetal harm based on findings from animal studies. Verify pregnancy status in females of reproductive potential prior to initiating treatment with leniolisib.

Fertility

No human data on the effect of leniolisib on fertility are available. Studies in animals have shown effects on the male reproductive organs.

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

Summary of safety profile

The most commonly reported adverse reactions during leniolisib treatment were headache (32%), vomiting (16%), weight increase (13%), and alopecia (11%). Based on laboratory data from the clinical studies, 33% of patients experienced a decrease in neutrophil counts.

Tabulated list of adverse reactions

The safety of leniolisib was evaluated in 38 adolescent and adult patients with APDS who participated in the placebo-controlled portion of Study 2201, and an open label safety study. Thirty-seven of 38 patients received leniolisib 70 mg orally twice daily for at least 60 weeks and 84% were exposed for 108 weeks or longer. Median duration of leniolisib treatment was approximately 4 years, and 10 patients had more than 5 years of leniolisib exposure.

The following list of adverse reactions is based on experience from clinical trials and on postmarketing experience. Adverse reactions in the following table are listed by system organ class and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), and rare (≥1/10 000 to <1/1 000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing frequency.

Adverse reactions:

^* Hypersensitivity: including itching, skin redness, hives, rash, difficulty breathing or swallowing (from post-marketing use of leniolisib)
^** Atopic dermatitis: including dermatitis atopic and eczema

Description of selected adverse reactions

Neutrophil count decreased

Seven (33%) patients receiving leniolisib developed a transient absolute neutrophil count (ANC) between 500 and 1500 cells/μL. No patients developed an ANC <500 cells/μL and there were no reports of infection associated with neutropenia. One case of Grade 3 neutrophil count decrease considered related to leniolisib was reported.

Hypersensitivity

Hypersensitivity reactions have been identified during post-marketing use of leniolisib.

Paediatric population

Thirteen patients aged 12 to 17 were treated with leniolisib in the clinical trials. Frequency, type, and severity of adverse reactions were similar to adults.