JOENJA Film-coated tablet Ref.[116594] Active ingredients: Leniolisib

5.1 Embryo-Fetal Toxicity

Based on findings in animals, JOENJA may cause fetal harm when administered to a pregnant woman. Administration of leniolisib to rats and rabbits during the period of organogenesis caused embryo-fetal toxicity including malformations at exposures that were 2-6 times higher than the maximum recommended human dose (MRHD) in APDS patients based on AUC comparisons. Verify the pregnancy status of patients of reproductive potential prior to starting treatment. Advise pregnant women of the 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 [see Dosage and Administration (2.1), Use in Specific Populations (8.1, 8.3)].

5.2 Vaccinations

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

5.3 Risk of Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reaction(s), including anaphylaxis, have been reported in postmarketing setting. If a clinically significant hypersensitivity reaction occurs, discontinue JOENJA and institute appropriate therapy [see Adverse Reactions (6.2)].

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Risk of Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.3)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of JOENJA reflects exposure based on 38 adult and pediatric patients 12 years of age and older with activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) from the placebo-controlled portion of Study 2201 [see Clinical Studies (14)] and additional open-label clinical safety data. Thirty-seven of 38 patients received JOENJA 70 mg orally twice daily for at least 25 weeks and 66% were exposed for 96 weeks or longer. Median duration of JOENJA treatment was approximately 2 years, and 4 patients had more than 5 years of JOENJA exposure.

The data below are based on the 12-week, placebo-controlled portion of Study 2201 in which either JOENJA 70 mg (N=21) or placebo (N=10) was administered twice daily to patients with APDS. Demographics of the patients who participated in this study are summarized in Clinical Studies [see Clinical Studies (14)]. Table 1 presents the number of patients and incidence, rounded to the nearest percent, of adverse reactions that occurred in 2 or more patients treated with JOENJA and for which the incidence in patients treated with JOENJA was greater than the incidence in patients treated with placebo.

The most common adverse reactions (>10%) were headache, sinusitis, and atopic dermatitis.

Table 1. Adverse Reactions Reported by 2 or More JOENJA-Treated Patients and More Frequently than Placebo:

¹ Dermatitis atopic: including dermatitis atopic and eczema
² Tachycardia: including tachycardia and sinus tachycardia

Specific Adverse Reactions

Laboratory Abnormalities

Seven (33%) patients receiving JOENJA developed an absolute neutrophil count (ANC) between 500 and 1500 cells/microL. No patients developed an ANC < 500 cells/microL and there were no reports of infection associated with neutropenia.

Weight Increase

In the open-label clinical trial (n=37), five patients (14%) experienced weight gain. Some patients became overweight or obese.

The following adverse reactions have been identified during postapproval use of JOENJA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: hypersensitivity (anaphylaxis)

7.1 Effects of Other Drugs on JOENJA

Strong CYP3A4 Inhibitors

Concomitant use of JOENJA with strong CYP3A4 inhibitors should be avoided.

JOENJA is a substrate of CYP3A4. Leniolisib exposure was increased 2-fold when co-administered with itraconazole, a strong CYP3A4 inhibitor [see Clinical Pharmacology (12.3)].

Strong and Moderate CYP3A4 Inducers

Concomitant use of JOENJA with strong and moderate CYP3A4 inducers should be avoided.

JOENJA is a substrate of CYP3A4. Concomitant use of strong and moderate CYP3A4 inducers may result in reduced leniolisib exposure and thus reduced leniolisib efficacy [see Clinical Pharmacology (12.3)].

7.2 Effects of JOENJA on Other Drugs

BCRP, OATP1B1, and OATP1B3 Substrates

Concomitant use of JOENJA with BCRP, OATP1B1, and OATP1B3 substrates should be avoided.

JOENJA is an inhibitor of BCRP, OATP1B1, and OATP1B3 transporters. Administration of JOENJA increases exposure of BCRP, OATP1B1, and OATP1B3 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates.

Risk Summary

JOENJA can cause fetal harm based on findings from animal studies. There are no available data on JOENJA use in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

In animal reproduction studies, oral administration of leniolisib to pregnant rats and rabbits during the period of organogenesis at exposures approximately 2-6 times the MRHD on an AUC basis, produced embryofetal toxicity including malformations (see Data). Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage of clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Leniolisib was administered orally to pregnant rats at doses of 10, 30, and 120 mg/kg/day during the period of organogenesis from gestation Day 6 to Day 17. Leniolisib at a dose of 120 mg/kg/day was associated with decreased fetal body weight, visceral and skeletal variations, and external, visceral, and skeletal malformations (eye bulge, microphthalmia, anophthalmia, and reduction in orbital socket size) in the presence of maternal toxicity (decrease in body weight gain) at exposures approximately 6 times the MRHD on an AUC basis. No developmental toxicity was observed in rats at an exposure approximately 2 times the MRHD (on an AUC basis at a maternal oral dose of 30 mg/kg/day).

Leniolisib was administered orally to pregnant rabbits at doses of 10, 30, and 100 mg/kg/day during the period of organogenesis from gestation Day 7 to Day 20. Leniolisib at a dose of 100 mg/kg/day was associated with skeletal variations as well as visceral and skeletal malformations (microphthalmia and reduction in orbital socket size) in the presence of maternal toxicity (decrease in body weight gain) at exposures approximately 2 times the MRHD on an AUC basis. No developmental toxicity was observed in rabbits at an exposure approximately 0.3 times the MRHD (on an AUC basis at a maternal oral dose of 30 mg/kg/day).

In a pre- and postnatal developmental toxicity study, leniolisib was administered orally to pregnant rats at oral doses of 10, 30, and 90 mg/kg/day from gestation day 7 through postnatal day 21. Leniolisib at a dose of 90 mg/kg/day (approximately 5 times the exposure at the MRHD on an AUC basis) was associated with a slight decrease in the percentage of pups born that survived 21 days postpartum (lactation index) and decreased pup body weights were observed prior to weaning.

Risk Summary

There are no data on the presence of leniolisib or its metabolites in human milk or the effects on the breastfed infant or milk production. Leniolisib is present in rat milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions from leniolisib in the breastfed child, advise women not to breastfeed during treatment with JOENJA and for 1 week after the last dose.

Data

Animal Data

Leniolisib was present in the milk of lactating rats administered oral doses of 10, 30, and 90 mg/kg/day from gestation day 7 through postnatal day 21. Leniolisib concentrations were approximately 2- to 3-fold higher in milk than in maternal plasma. The concentration of leniolisib in animal milk does not necessarily predict the concentration of drug in human milk.

Based on findings from animal studies, JOENJA may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status in females of reproductive potential prior to initiating JOENJA.

Contraception

Females

Advise female patients of reproductive potential to use highly effective contraception during treatment with JOENJA and to continue contraception for 1 week after the last dose.

The safety and effectiveness of JOENJA for the treatment of activated phosphoinositide 3-kinase delta syndrome have been established in pediatric patients 12 years of age and older. Use of JOENJA for this indication is supported by evidence from an adequate and well-controlled study in adult and pediatric patients 12 years of age and older [see Clinical Studies (14)]. There is no recommended dosage for pediatric patients 12 years of age and older who weigh less than 45 kg [see Dosage and Administration (2.2)].

The safety and effectiveness of JOENJA have not been established in pediatric patients below the age of 12 years.

Juvenile Animal Toxicity Data

Studies were conducted with leniolisib in juvenile rats starting at postnatal day (PND) 7 (the equivalent of a human newborn) to PND 77 (the equivalent of a human adult). Death was observed in juvenile rats that received 90 mg/kg/day, approximately 2-4 times the MRHD on an AUC basis and occurred primarily during the pre-weaning period (PND 9 to PND 15). Changes in the onset of puberty (delays in males and accelerations in females) were observed in juvenile rats at equal to or greater than 30 mg/kg/day leniolisib, which is one half to equivalent to, the MRHD on an AUC basis. A no effect dose level was identified at an exposure approximately 0.2 times the MRHD on an AUC basis.

Because clinical studies of JOENJA did not include any patients 65 years of age and older, it cannot be determined whether they respond differently from younger adult patients.

Leniolisib is extensively (60%) metabolized by the liver. The effect of hepatic impairment on the pharmacokinetics of leniolisib has not been studied. The use of JOENJA in patients with moderate to severe hepatic impairment is not recommended [see Clinical Pharmacology (12.3)].