Joenja Drug Information

is indicated for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older. JOENJA is a kinase inhibitor indicated for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older.

Testing

Prior to Treatment with JOENJA Verify pregnancy status in females of reproductive potential prior to initiating treatment with JOENJA .

Recommended Dosage and

Administration The recommended dosage of JOENJA in adult and pediatric patients 12 years of age and older weighing 45 kg or greater is 70 mg administered orally twice daily approximately 12 hours apart, with or without food. There is no recommended dosage for patients weighing less than 45 kg. Advise patients that if a dose is missed by more than 6 hours, wait and take the next dose at the usual time.

Advise patients that if vomiting occurs within 1 hour after taking JOENJA, take JOENJA as soon as possible. If vomiting occurs more than 1 hour after dosing, wait and take the next dose at the usual time.

Clinical Trials Experience

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 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 . 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 Adverse Reactions JOENJA N=21 n (%) Placebo N=10 n (%) 1 Dermatitis atopic: including dermatitis atopic and eczema 2 Tachycardia: including tachycardia and sinus tachycardia Headache 5 2 Sinusitis 4 0 Dermatitis atopic 1 3 0 Tachycardia 2 2 0 Diarrhea 2 0 Fatigue 2 1 Pyrexia 2 0 Back pain 2 0 Neck pain 2 0 Alopecia 2 0 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.

Postmarketing Experience

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)

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 . 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 .

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 , which may increase the risk of adverse reactions related to these substrates.

Pregnancy 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.

Pediatric Use 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 . There is no recommended dosage for pediatric patients 12 years of age and older who weigh less than 45 kg . 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.

If overdosage occurs, monitor the patient for any signs or symptoms of adverse reactions. Treatment of overdose with JOENJA consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.