Leniolisib Phosphate (Monograph)

Brand name: Joenja
Drug class: Immunomodulatory Agents

Medically reviewed by Drugs.com on Nov 10, 2024. Written by ASHP.

[Web]

Introduction

Kinase inhibitor.

Uses for Leniolisib Phosphate

Activated Phosphoinositide 3-Kinase Delta (PI3Kδ) Syndrome

Treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adults and pediatric patients ≥12 years of age (designated an orphan drug by FDA for this use).

Leniolisib Phosphate Dosage and Administration

General

Pretreatment Screening

Verify pregnancy status in females of reproductive potential.

Administration

Oral Administration

Administer orally with or without food.

Available as tablets containing 70 mg of leniolisib.

If dose is missed by >6 hours, wait and take next dose at the usual time.

If vomiting occurs within 1 hour after taking leniolisib, take another dose as soon as possible. If vomiting occurs >1 hour after dosing, wait and take next dose at the usual time.

Dosage

Available as leniolisib phosphate; dosage expressed in terms of leniolisib.

Pediatric Patients

Activated Phosphoinositide 3-Kinase Delta (PI3Kδ) Syndrome (APDS)

Oral

Patients ≥12 years of age weighing ≥45 kg: 70 mg orally twice daily (approximately 12 hours apart).

No recommended dosage for patients weighing <45 kg.

Adults

APDS

Oral

Adults weighing ≥45 kg: 70 mg orally twice daily (approximately 12 hours apart).

No recommended dosage for patients weighing <45 kg.

Special Populations

Hepatic Impairment

Use in moderate to severe hepatic impairment not recommended.

No specific dosage recommendations for mild hepatic impairment.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

No specific dosage recommendations at this time.

Cautions for Leniolisib Phosphate

Contraindications

None.

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on findings in animal studies. Embryofetal toxicity (including malformations) demonstrated in animals.

Verify pregnancy status of patients of reproductive potential prior to starting treatment. Advise pregnant women of potential risk to a fetus. Advise females of reproductive potential to use highly effective methods of contraception during treatment and for 1 week after the last dose.

Vaccinations

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

Specific Populations

Pregnancy

May cause fetal harm based on findings from animal studies. Human data on leniolisib use during pregnancy not available. Embryofetal toxicity (including malformations) demonstrated in animals.

Verify pregnancy status in females of reproductive potential prior to initiating leniolisib. Advise pregnant women of potential risk to a fetus.

Lactation

Unknown whether leniolisib or its metabolites distribute into human milk. Effects on milk production or the breast-fed child unknown.

Advise women not to breast-feed during treatment with leniolisib and for 1 week after the last dose.

Females and Males of Reproductive Potential

May cause fetal harm.

Verify pregnancy status in females of reproductive potential prior to initiating leniolisib. Advise females of reproductive potential to use highly effective contraception during treatment with leniolisib and for 1 week after the last dose.

Pediatric Use

Safety and effectiveness of leniolisib for treatment of APDS established in pediatric patients ≥12 years of age. No recommended dosage for pediatric patients ≥12 years of age weighing <45 kg.

Safety and effectiveness not established in pediatric patients <12 years of age.

Geriatric Use

Experience in patients ≥65 years of age insufficient to determine whether they respond differently to leniolisib than younger adults.

Hepatic Impairment

Extensively (60%) metabolized by the liver; effect of hepatic impairment on pharmacokinetics of leniolisib not studied. Use in moderate to severe hepatic impairment not recommended.

Renal Impairment

Effect of renal impairment on pharmacokinetics of leniolisib not studied.

Common Adverse Effects

Most common adverse reactions (incidence >10%) reported with leniolisib include headache, sinusitis, atopic dermatitis.

Drug Interactions

Primarily metabolized by CYP3A4 with minor contributions from CYP3A5, 1A2, and 2D6.

Substrate of CYP3A4. Inhibitor of CYP1A2 in vitro.

Substrate and inhibitor of breast cancer resistance protein (BCRP); substrate of P-glycoprotein (P-gp); inhibitor of organic anion transporting polypeptide (OATP) 1B1 and 1B3 in vitro.

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 Inhibitors

Concomitant use with strong CYP3A4 inhibitors may increase leniolisib exposure.

Avoid concomitant use with strong CYP3A4 inhibitors.

CYP3A4 Inducers

Concomitant use with strong or moderate CYP3A4 inducers may reduce leniolisib exposure and reduce effectiveness of leniolisib.

Avoid concomitant use with strong and moderate CYP3A4 inducers.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP1A2 Substrates

Leniolisib inhibits CYP1A2 in a time-dependent manner in vitro.

Avoid concomitant use with drugs that are primarily metabolized by CYP1A2 and have a narrow therapeutic index.

Drugs Affected by Transport Systems

BRCP, OATP1B1, and OATP1B3 Substrates

Leniolisib inhibits BCRP, OATP1B1, and OATP1B3 in vitro; effect of leniolisib on BCRP, OATP1B1, and OATP1B3 substrates not studied clinically.

Avoid concomitant use with BCRP, OATP1B1, and OATP1B3 substrates due to possible increase in systemic exposure of these substrates.

Drugs Affecting Gastric Acidity

Leniolisib exhibits pH-dependent solubility (pH range of 1.2–4), with low solubility at higher pH values (≥5).

Acid reducing agents (e.g., histamine type 2 [H₂] receptor antagonists, proton pump inhibitors) not shown to have a clinically relevant effect on leniolisib systemic exposure.

Specific Drugs

Drug	Interaction	Comments
Efavirenz	Leniolisib AUC predicted to be decreased by 58% with efavirenz (moderate CYP3A4 inducer)	Avoid concomitant use
Erythromycin	Leniolisib AUC predicted to increase by maximum of 75% with erythromycin (moderate CYP3A4 inhibitor)
H₂ receptor antagonists	No clinically relevant effect on leniolisib systemic exposure
Itraconazole	Leniolisib exposure increased approximately 2-fold with concomitant use of itraconazole (strong CYP3A4 inhibitor)	Avoid concomitant use
Oral contraceptives (ethinyl estradiol and levonorgestrel)	Ethinyl estradiol maximum concentration and exposure increased by approximately 25–30%; no effect on maximum concentration or AUC of levonorgestrel Efficacy of combined oral contraceptive (ethinyl estradiol and levonorgestrel) not expected to be compromised by concomitant use with leniolisib
Proton pump inhibitors	No clinically relevant effect on leniolisib systemic exposure
Quinidine	No effect on leniolisib systemic exposure
Rifampin	Leniolisib AUC predicted to be decreased by 78% with rifampin (strong CYP3A4 inducer)	Avoid concomitant use

Leniolisib Phosphate Pharmacokinetics

Absorption

Bioavailability

Systemic exposure increases in a dose-proportional manner over a dosage range of 20–140 mg twice daily.

Median time to peak plasma concentration: 1 hour.

During twice daily dosing, leniolisib accumulates approximately 1.4-fold (range of 1.0–2.2) in achieving steady state.

Time to steady state: 2–3 days.

Food

Food unlikely to have a clinically meaningful effect on systemic exposure.

Distribution

Extent

Unknown whether leniolisib or its metabolites distribute into human milk.

Plasma Protein Binding

94.5%.

Elimination

Metabolism

60% metabolized in the liver.

Predominantly metabolized by CYP3A4 (95.4%), with minor contributions from CYP3A5 (3.5%), CYP1A2 (0.7%), and CYP2D6 (0.4%).

Intestinal secretion by BCRP and extrahepatic CYP1A1 cannot be excluded as excretion routes.

Elimination Route

Feces (67%) and urine (25.5%, with 6.32% as unchanged drug).

Half-life

10 hours.

Special Populations

No clinically important differences in leniolisib pharmacokinetics observed based on age.

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C); do not refrigerate.

Actions

Inhibits phosphoinositide 3-kinase delta (PI3Kδ) by blocking active binding site of PI3Kδ.
Selective for PI3Kδ over PI3Kα (28-fold), PI3Kβ (43-fold), and PI3Kγ (257-fold), as well as the broader kinome.
Reduces phosphorylated protein kinase B (pAkt) pathway activity and inhibits proliferation and activation of B and T cell subsets.
Inhibits signaling pathways that lead to increased production of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), hyperactivity of the downstream mammalian target of rapamycin/protein kinase B (mTOR/Akt) pathway, and to the dysregulation of B and T cells.
Estimated to produce time-averaged reduction of pAkt-positive B cells by approximately 80%.

Advice to Patients

Advise women to inform their clinician if they are or plan to become pregnant. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use highly effective contraceptive during treatment with leniolisib and for 1 week after the last dose.
Advise women to inform their clinician if they plan to breast-feed. Advise women not to breast-feed during treatment with leniolisib and for 1 week after the last dose.
Advise patients that leniolisib may be taken with or without food.
Advise patients that if they miss a dose by more than 6 hours, they should skip the missed dose and take the next dose as scheduled.
Advise patients that if vomiting occurs within 1 hour after taking leniolisib, they should take another dose as soon as possible.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses.
Advise patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Leniolisib is obtained through designated specialty pharmacies. Consult the Joenjawebsite ([Web]) for specific availability information.