4.1. Therapeutic indications

Joenja is indicated for the treatment of activated phosphoinositide 3-kinase delta (P13Kδ) syndrome (APDS) in adult and paediatric patients 12 years of age and older.

4.2. Posology and method of administration

Testing prior to treatment with Joenja

Pregnancy status in females of reproductive potential should be verified prior to initiating treatment with Joenja (see sections 4.4 and 4.6).

Posology

The recommended dosage of Joenja in adult and paediatric 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.

Missed dose

If a dose is missed by more than 6 hours, patients should wait and take the next dose at the usual time.

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

Interactions

The use of Joenja is not recommended concomitantly with strong or moderate CYP3A4 inhibitors (e.g., clarithromycin, diltiazem, erythromycin, ketoconazole, ritonavir, verapamil, grapefruit juice); strong or moderate CYP3A4 inducers (e.g., carbamazepine, efavirenz, nevirapine, phenobarbital, phenytoin, rifabutin, rifampin, St. John's Wort); or CYP1A2 metabolized drugs with a narrow therapeutic index (e.g., theophylline, tizanidine) (see section 4.5).

Special populations

Elderly

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.

Paediatric population

The safety and effectiveness of Joenja have not been established in paediatric patients below the age of 12 years. There is no recommended dosage for paediatric patients 12 years of age and older who weigh less than 45 kg.

Patients with 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 (see section 5.2).

Method of administration

Oral use.

Joenja can be taken with or without meals. The tablets should be swallowed whole. The tablets should not be split, crushed, or chewed.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Embryo-foetal toxicity

Based on findings in animals, Joenja may cause foetal harm when administered to a pregnant woman. Administration of leniolisib to rats and rabbits during the period of organogenesis caused embryo-foetal toxicity including malformations at exposures that were 2 to 6 times higher than the maximum recommended human dose (MRHD) in APDS patients based on AUC comparisons. The pregnancy status of patients of reproductive potential should be verified prior to starting treatment. Pregnant women should be advised of the potential risk to a foetus. Females of reproductive potential should be advised 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 Joenja treatment.

Excipients with known effect

Lactose content

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption must not take this medicine.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Effect of other drugs on Joenja

Strong and moderate CYP3A4 inhibitors

Joenja is a substrate of CYP3A4. Leniolisib exposure was increased 2-fold when co-administered with itraconazole, a strong CYP3A4 inhibitor. Physiological based pharmacokinetic (PBPK) model-based simulations predicted a maximum increase of 75% in leniolisib AUC0-12 with erythromycin (moderate CYP3A4 inhibitor). Concomitant use of Joenja with strong and moderate CYP3A4 inhibitors (e.g., clarithromycin, cobicistat, danoprevir, dasabuvir, diltiazem, elvitegravir, erythromycin, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir, ombitasvir, paritaprevir, posaconazole, ritonavir, saquinavir, telithromycin, tipranavir, troleandomycin, verapamil, voriconazole) should be avoided.

Strong and moderate CYP3A4 inducers

Concomitant use of strong and moderate CYP3A4 inducers may result in reduced leniolisib exposure and thus reduced leniolisib efficacy. PBPK model-based simulations predicted a maximum decrease of 78% and 58% in leniolisib AUC0-12 with rifampin (strong CYP3A4 inducer) and efavirenz (moderate CYP3A4 inducer), respectively. Therefore, concomitant use of Joenja with strong and moderate CYP3A4 inducers (e.g., avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin, St. John's Wort, bosentan, efavirenz, etravirine, modafinil, nafcillin, nevirapine) should be avoided.

CYP2D6 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.

Effect of Joenja on other drugs

CYP1A2 metabolized drugs with a narrow therapeutic index

Leniolisib inhibits CYP1A2 in a time-dependent manner in vitro. Concomitant use of Joenja with drugs that are primarily metabolized by isoenzyme CYP1A2 and have a narrow therapeutic index (e.g., alosetron, caffeine, duloxetine, melatonin, ramelteon, tasimelteon, theophylline, tizanidine) should be avoided.

BCRP, OATP1B1, and OATP1B3 substrates

In vitro, leniolisib is a substrate and an inhibitor of the hepatic efflux transporter BCRP and a substrate of P-gp. Leniolisib was identified in vitro as a potential inhibitor of the hepatic uptake and efflux transporters OATP1B1/B3 and BCRP. The effect of Joenja on BCRP, OATP1B1, and OATP1B3 substrates has not been studied clinically. Due to a possible increase in systemic exposure of these substrates, concomitant use of Joenja with drugs that are BCRP, OATP1B1, and OATP1B3 substrates (e.g., rosuvastatin, pitavastatin, letermovir) should be avoided.

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.

Gastric acid reducing agents

Leniolisib exhibits pH-dependent solubility (pH range of 1.2 to 4), with low solubility at higher pH values (≥ 5). However, PK results from APDS patients did not indicate that acid reducing agents (e.g., H2-antagonists, proton pump inhibitors) have a clinically relevant effect on leniolisib systemic exposure.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/contraception in females

Women of childbearing potential should use highly effective methods of contraception during treatment with Joenja and for 1 week after the last dose. Leniolisib can cause foetal harm based on findings from animal studies. Pregnancy status in females of reproductive potential should be verified prior to initiating treatment with Joenja.

Pregnancy

There are no data from the use of leniolisib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Joenja is not recommended during pregnancy and in women of childbearing potential not using highly effective methods of contraception.

Breast-feeding

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. Available pharmacokinetic/toxicological data in animals have shown excretion of leniolisib in milk (see section 5.3). Because of the potential for serious adverse reactions from leniolisib in the breastfed child, women should be advised not to breastfeed during treatment with Joenja and for 1 week after the last dose.

4.7. Effects on ability to drive and use machines

Leniolisib has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

The safety of Joenja reflects exposure based on 38 adult and paediatric 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 60 weeks and 81% were exposed for 96 weeks or longer. Median duration of Joenja treatment was approximately 3 years, and 5 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 section 5.1. Table 1 presents 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.

Adverse reactions are listed in Table 1 by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), and rare (≥ 1/10 000 to < 1/1 000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 Adverse reactions reported by 2 or more Joenja-treated patients and more frequently than placebo

System organ class

Adverse reactions

Frequency

Infections and infestations

Sinusitis

Very common

Nervous system disorders

Headache

Very common

Cardiac disorders

Tachycardia1

Very common

Gastrointestinal disorders and administration site conditions

Diarrhoea

Very common

Skin and subcutaneous tissue disorders

Dermatitis atopic2

Alopecia

Very common

Very common

Musculoskeletal and connective tissue disorders

Back pain

Neck pain

Very common

Very common

General disorders and administration site conditions

Fatigue

Pyrexia

Very common

Very common

1Tachycardia: including tachycardia and sinus tachycardia

2Dermatitis atopic: including dermatitis atopic and eczema

Description of selected adverse reactions

Laboratory abnormalities

Seven (33%) patients receiving Joenja developed an absolute neutrophil count (ANC) between 500 and 1500 cells/microL (0.5-1.5 x 109/L). No patients developed an ANC < 500 cells/microL (0.5-1.5 x 109/L) and there were no reports of infection associated with neutropenia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: https://yellowcard.mhra.gov.uk/ or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

If overdose occurs, the patient should be monitored 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.