DRUG INTERACTIONS- (summary)

 • Strong CYP3A4 Inhibitors: Avoid concomitant use.

 • Strong and Moderate CYP3A4 Inducers: Avoid concomitant use.

 • CYP1A2 Metabolized Drugs with a Narrow Therapeutic Index (NTIs): Avoid concomitant use.

 • BCRP, OATP1B1, and OATP1B3 Substrates: Avoid concomitant use.

BRIEF SUMMARY-

LENIOLISIB- (Mar 2023)

Indication- To  treat activated Phosphoinated -3kinase                                                                   delta Syndrome                                                                                                                                                    

Dosage- Tablets: 70 mg leniolisib- Recommended dosage: 70 mg administered orally twice daily approximately 12 hours apart, with or without food, in adult and pediatric patients 12 years of age and older and weighing =45kg.

ADR- Most common adverse reactions (incidence >10%) were headache, sinusitis. 

CI-  None

WARNINGS- Vaccinations: Live, attenuated vaccinations may be less effective if administered during treatment

Pat Inform-  Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy..

 Advise females of reproductive potential to use highly effective contraceptive during treatment  and for 1 week after the last dose .

Lactation Advise women not to breastfeed during treatment with JOENJA and for 1 week after the last dose

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 13

Name-        JOENJA

Acive  Ingredient -  Lenoilisib

 Pharmacological clssificiation-        To  treat activated Phosphoinated -3kinase                                                                   delta Syndrome                                                                                                                                                                                                                                                        

    Date of Approval-         3/24/2023 

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                           JOENJA safely and effectively.

See full prescribing information for JOENJA. JOENJA® (leniolisib) tablets, for oral use

Initial U.S. Approval: 2023

INDICATIONS AND USAGE-

JOENJA is a kinase inhibitor indicated for the treatment of activated phosphoinositide 3-kinase delta (PI3Kd) syndrome (APDS) in adult and pediatric patients 12 years of age and older.

CONTRAINDICATIONS-

 None

WARNINGS AND PRECAUTIONS-

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

ADVERSE REACTIONS-

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

DOSAGE AND ADMINISTRATION-

 • Verify pregnancy status in females of reproductive potential prior to initiating treatment.

 • Recommended dosage: 70 mg administered orally twice daily approximately 12 hours apart, with or without food, in adult and pediatric patients 12 years of age and older and weighing =45kg.

DOSAGE FORMS AND STRENGTHS-

Tablets: 70 mg leniolisib 

Embryo-Fetal Toxicity

• Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)]

. • Advise females of reproductive potential to use highly effective contraceptive during treatment with JOENJA and for 1 week after the last dose [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with JOENJA and for 1 week after the last dose [see Use in Specific Populations (8.2)].

CLINICAL PHARMACOLOGY

1. Mechanism of Action -

Leniolisib inhibits PI3K-delta by blocking the active binding site of PI3K-delta. In cell-free isolated enzyme assays, leniolisib was selective for PI3K-delta over PI3K-alpha (28-

In cell-based assays, leniolisib reduced pAKT pathway activity and inhibited proliferation and activation of B and T cell subsets. Gain-of-function variants in the gene encoding the p110-delta catalytic subunit or loss of function variants in the gene encoding the p85-alpha regulatory subunit each cause hyperactivity of PI3K-delta. Leniolisib inhibits the signalling pathways that lead to increased production of PIP3, hyperactivity of the downstream mTOR/AKT pathway, and to the dysregulation of B and T cells.

2. Pharmacokinetics The systemic drug exposure (AUC and Cmax) of leniolisib increased dose proportionally within the studied range of doses (20 to 140 mg twice a day dosing and single doses of 10 to 400 mgt.

Food is unlikely to have a clinically meaningful effect on the systemic exposure of leniolisib during JOENJA treatment.

Distribution-

The systemic decay in leniolisib plasma concentration over time is bi-exponential, indicating a distribution delay towards peripheral tissues. The apparent terminal elimination t1/2 is approximately 10 hours. The volume of distribution of leniolisib is estimated to be

Elimination-

The mean recovery of total 14C-radioactivity following a single oral dose of 70 mg 14C-leniolisib was 92.5% (67.0% and 25.5% recovered via feces and urine, respectively) 168 hours postdose.

Unchanged leniolisib (6.32%) was the predominant drug-related material recovered in urine

Metabolism-

Leniolisib was 60% metabolized by the liver, with CYP3A4 being the most predominant enzyme involved (94.5%) in the primary oxidative metabolism of leniolisib with minor contribution from other enzymes (3.5% CYP3A5, 0.7% CYP1A2 and 0.4% CYP2D6). Intestinal secretion by BCRP as well as extrahepatic CYP1A1 cannot be excluded as excretion routes.

Specific Populations--

Pediatric Patients Following a single 70 mg oral dose of leniolisib in APDS patients, leniolisib systemic exposures were comparable between pediatric patients (12 to 17 years of age) and adults (=18 years of age), with median Tmax (ranging from 1 to 5 hours) reached approximately 3 hours post-dose in patients 12 to 17 years of age.

Patients with Hepatic Impairment-

 The effect of hepatic impairment on the pharmacokinetics of leniolisib has not been evaluated. As leniolisib is metabolized to a large extent by the liver (60%), use of JOENJA is not recommended in patients with moderate to severe hepatic impairment [see Specific Populations (8.6)].

Drug Interaction Studies -

Strong CYP3A4 Inhibitors: Leniolisib-exposure was increased approximately 2 fold when administered with itraconazole (strong CYP3A4 inhibitor). Re

 Moderate CYP3A4 Inhibitors: Physiological based pharmacokinetic (PBPK) modelbased simulations predicted a maximum increase of 75% in leniolisib AUC0-12 with erythromycin (moderate CYP3A4 inhibitor).

CYP3A4 Inducers: PBPK model-based simulations predicted a maximum decrease of 78% and 58% in leniolisib AUC0-12 with rifampin (strong CYP3A4 inducer) and efavirenz (moderate CYP3ACYP2D6 and P-gp inhibitors: Quinidine (strong P-gp and

CYP2D6 inhibitor) had no effect on leniolisib systemic exposure. Leniolisib is not a sensitive substrate of P-gp and CYP2D6.

Oral Contraceptives:

When combined with a monophasic oral contraceptive containing levonorgestrel and ethinylestradiol, leniolisib increased ethinylestradiol exposure by approximately 25 to 30% in terms of both AUC and Cmax, but did not affect the Cmax or AUC of levonorgestrel.

Efficacy of a combined oral contraceptive composed of ethinylestradiol and levonorgestrel is not expected to be compromised by concomitant use with leniolisib.

USE IN SPECIFIC POPULATIONS

1. 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.

Advise pregnant women of the potential risk to a fetus. The estimated 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 reacognized pregnancies is 2% to 4% and 15% to 20%, respectively.

2 Lactation 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.

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.

3 Females and Males of Reproductive Potential -                                                            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.

4. 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.

5. Geriatric Use-

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.

6 Hepatic Impairment-

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

 OVERDOSAGE-

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. 11 DESCRIPTION Leniolisib is a kinase inhibitor. The chemical name for leniolisib phosphate is 1-[(3S)-3- [[5,6,7,8-Tetrahydro-6-[6-methoxy-5-(trifluoromethyl)-3-pyridinyl]pyrido[4,3-d]pyrimidin4-yl]amino]-1-pyrrolidiny