LENIOLISIB: 570 Adverse Event Reports & Safety Profile

Leniolisib is a kinase inhibitor. The chemical name for leniolisib phosphate is 1-[(3 S )-3-[[5,6,7,8-Tetrahydro-6-[6-methoxy-5-(trifluoromethyl)-3-pyridinyl]pyrido[4,3- d ]pyrimidin-4-yl]amino]-1-pyrrolidinyl]-1-propanone phosphate (1:1). Leniolisib phosphate has the following structural formula: The molecular formula is C 21 H 25 F 3 N 6 O 2

• H 3 PO 4 and the molecular weight is 450.47 g/mol for the free base, 548.46 g/mol for the phosphate salt. Leniolisib phosphate is a white to yellowish to yellowish-greenish powder. The aqueous solubility of leniolisib phosphate is pH dependent with decreasing solubility observed with increasing pH. JOENJA film-coated tablets are for oral administration. Each tablet contains 70 mg of leniolisib (equivalent to 85.26 mg leniolisib phosphate) with the following inactive ingredients: colloidal silicon dioxide, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The tablet filmcoating contains hydroxypropyl methylcellulose, iron oxide red, iron oxide yellow, polyethylene glycol, talc, and titanium dioxide.

Structural

Formula

AND USAGE JOENJA 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. ( 1 )

AND ADMINISTRATION Verify pregnancy status in females of reproductive potential prior to initiating treatment. ( 2.1 , 5.1 ) 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. ( 2.2 )

2.1 Testing Prior to Treatment with JOENJA Verify pregnancy status in females of reproductive potential prior to initiating treatment with JOENJA <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 ), and Use in Specific Populations ( 8.1 , 8.3 )]</span> .

2.2 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.

None. None. ( 4 )

REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Risk of Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.3) ] Most common adverse reactions (incidence > 10%) were headache, sinusitis, and atopic dermatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pharming Healthcare Inc. at 1-800-930-5221 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span> .

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 (24) 2 (20)

Sinusitis

4 (19) 0 Dermatitis atopic 1 3 (14) 0 Tachycardia 2 2 (10) 0 Diarrhea 2 (10) 0 Fatigue 2 (10) 1 (10)

Pyrexia

2 (10) 0 Back pain 2 (10) 0 Neck pain 2 (10) 0 Alopecia 2 (10) 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.

6.2 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)

AND PRECAUTIONS Embryo-Fetal Toxicity: JOENJA may cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.1 , 8.1 , 8.3 ) Vaccinations: Live, attenuated vaccinations may be less effective if administered during JOENJA treatment. ( 5.2 ) Risk of Hypersensitivty Reactions Including Anaphylaxis: Hypersensitivity reactions including anaphlyaxis have been reported in the postmarketing setting. If hypersensitivity reactions occur, discontinue JOENJA and institute appropriate therapy. ( 5.3 )

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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 ), Use in Specific Populations ( 8.1 , 8.3 )]</span> .

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 <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span>.

INTERACTIONS Strong CYP3A4 Inhibitors: Avoid concomitant use. ( 7.1 ) Strong and Moderate CYP3A4 Inducers: Avoid concomitant use. ( 7.1 ) BCRP, OATP1B1, and OATP1B3 Substrates: Avoid concomitant use. ( 7.2 )

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> , which may increase the risk of adverse reactions related to these substrates.