4.1. Therapeutic indications

Jaypirca as monotherapy is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) who have been previously treated with a Bruton's tyrosine kinase (BTK) inhibitor.

Jaypirca as monotherapy is indicated for the treatment of chronic lymphocytic leukaemia (CLL) in

• adult patients with treatment naïve CLL;

• adult patients with relapsed or refractory CLL who have previously not received a BTK inhibitor;

• adult patients with relapsed or refractory CLL who have previously been treated with a BTK inhibitor.

4.2. Posology and method of administration

Jaypirca therapy should be initiated and supervised by physicians experienced in the use of anticancer therapies.

Posology

The recommended dose is 200 mg pirtobrutinib once daily (QD).

Jaypirca dosing should be interrupted until recovery to Grade 1 or baseline when the patient experiences the following event:

• Grade 3 neutropenia with fever and/or infection

• Grade 4 neutropenia lasting ≥ 7 days

• Grade 3 thrombocytopenia with bleeding

• Grade 4 thrombocytopenia

• Grade 3 or 4 non‑haematologic toxicity

Asymptomatic lymphocytosis is not regarded as an adverse reaction, and patients experiencing this event should continue taking Jaypirca.

In the clinical studies, adverse events in a limited number of patients were managed by dose reduction (see section 5.1).

Treatment should be continued until disease progression or unacceptable toxicity.

Missed dose

If more than 12 hours have passed after a patient has missed a dose, the patient should be instructed to take the next dose at its scheduled time; an additional dose should not be taken. If vomiting occurs, the patient should not take an additional dose but continue with the next scheduled dose.

Special populations

Elderly

No dose adjustment is required based on age (see section 5.2).

Renal impairment

No dose adjustment is required for patients with mild, moderate or severe renal impairment. There are no data in patients on dialysis (see section 5.2).

Hepatic impairment

No dose adjustment is required for patients with mild, moderate, or severe hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of Jaypirca in children and adolescents aged less than 18 years have not been established. No data are available.

Method of administration

Jaypirca is for oral use.

The tablet should be swallowed whole with a glass of water to ensure consistent performance (patients should not chew, crush, or split tablets before swallowing) and can be taken with or without food. Patients should take the dose at approximately the same time every day.

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

Infections

Serious infections, including fatal cases, have occurred in patients treated with Jaypirca. The most frequently reported Grade 3 or higher infections were pneumonia, COVID‑19 pneumonia, COVID‑19, and sepsis. Prophylactic antimicrobial therapy should be considered in patients who are at increased risk for opportunistic infections. Based on the grade of infection and whether it occurs with neutropenia, dose interruption may be required (see section 4.2).

Haemorrhage

Bleeding events, including fatal cases, have occurred in patients treated with Jaypirca, with and without thrombocytopenia. Major bleeding events of Grade 3 or higher, including gastrointestinal bleeding and intracranial haemorrhage have been observed. Patients should be monitored for signs and symptoms of bleeding. Patients receiving anticoagulant or antiplatelet agents may be at increased risk of haemorrhage. The risks and benefits of anticoagulant or antiplatelet therapy should be considered when co‑administered with Jaypirca and consider additional monitoring for signs of bleeding. The use of Jaypirca has not been studied with warfarin or other vitamin K antagonists.

Dose interruption may be required for Grade 3 or 4 bleeding events (see section 4.2).

The benefit‑risk of withholding Jaypirca for 3 to 5 days pre- and post‑surgery should be considered depending upon the type of surgery and risk of bleeding.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia, anaemia and thrombocytopenia occurred in patients treated with Jaypirca. Complete blood counts should be monitored in patients during treatment as medically indicated. Based on the grade of cytopenia, dose interruption may be required (see section 4.2).

Atrial fibrillation/ flutter

Atrial fibrillation and atrial flutter have been observed in patients treated with Jaypirca, particularly in patients with a history of atrial fibrillation and/or multiple cardiovascular comorbidities. Signs and symptoms of atrial fibrillation and atrial flutter should be monitored in patients; obtain an electrocardiogram as medically indicated. Based on the grade of atrial fibrillation/atrial flutter, dose interruption may be required (see section 4.2).

Second primary malignancies

Second primary malignancies have commonly occurred in patients treated with Jaypirca, with the most frequent types being non‑melanoma skin cancers. Patients should be monitored for the appearance of skin cancers and advise protection from sun exposure.

Hepatotoxicity

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including Jaypirca.

Evaluate bilirubin and transaminases at baseline and throughout treatment with Jaypirca. For patients who develop abnormal liver tests after Jaypirca, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold Jaypirca. Upon confirmation of DILI, discontinue Jaypirca.

Tumour lysis syndrome

Tumour lysis syndrome (TLS) has been reported rarely with Jaypirca therapy. Patients at high risk of TLS are those with high tumour burden prior to treatment. Patients should be assessed for possible risk of TLS and closely monitored as clinically indicated.

Contraception in women of childbearing potential and males

Based on findings in animals and the genotoxicity of pirtobrutinib (see section 5.3), pirtobrutinib can cause foetal harm when administered to a pregnant woman. Women of childbearing potential should use an effective method of contraception during treatment and for 5 weeks after the last dose of Jaypirca. Men are advised to use an effective method of contraception and not father a child during treatment and for 3 months after the last dose of Jaypirca (see section 4.6).

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose‑galactose malabsorption should not take this medicinal product.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per 200 mg daily dose, that is to say essentially 'sodium‑free'.

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

Pirtobrutinib is primarily metabolised by CYP3A4, UGT1A8, and UGT1A9.

Effects of other medicinal products on the pharmacokinetics of pirtobrutinib

CYP3A inhibitors

In a clinical study, itraconazole, a strong CYP3A4 inhibitor, increased the AUC of pirtobrutinib by 48 % and did not change Cmax of pirtobrutinib. This increase in pirtobrutinib exposure is not clinically meaningful. Therefore, no dose adjustment of Jaypirca is necessary with CYP3A inhibitors.

CYP3A inducers

In a clinical study, rifampin, a strong CYP3A inducer, decreased the AUC and Cmax of pirtobrutinib by 71 % and 42 %, respectively. Though this decrease in pirtobrutinib exposure is not expected to be clinically meaningful, if possible avoid strong CYP3A inducers (e.g. rifampicin, carbamazepine, phenytoin).

Coadministration with medicinal products that are proton pump inhibitors

No clinically significant differences in pirtobrutinib pharmacokinetics were observed when administered concomitantly with omeprazole, a proton pump inhibitor.

Effects of pirtobrutinib on the pharmacokinetics of other medicinal products (increase in plasma concentration)

CYP2C8 substrates

Pirtobrutinib is a moderate inhibitor of CYP2C8. Pirtobrutinib increased the AUC and Cmax of repaglinide (a substrate of CYP2C8) by 130 % and 98 %, respectively. Therefore, since pirtobrutinib can increase the plasma concentrations of CYP2C8 substrates, caution is advised when co‑administering with CYP2C8 substrates (e.g. repaglinide, dasabuvir, selexipag, rosiglitazone, pioglitazone, and montelukast).

BCRP substrates

Pirtobrutinib is a moderate inhibitor of BCRP. Pirtobrutinib increased the AUC and Cmax of rosuvastatin (a BCRP substrate) by 140 % and 146 %, respectively. Therefore, since pirtobrutinib can increase the plasma concentrations of BCRP substrates, caution is advised when co-administering BCRP substrates (e.g. rosuvastatin). If co‑administration with narrow therapeutic index BCRP substrates (e.g. high dose methotrexate, mitoxantrone) cannot be avoided, close clinical monitoring should be considered.

P‑gp substrates

Pirtobrutinib is a weak inhibitor of P-gp. Pirtobrutinib increased the AUC and Cmax of digoxin (a P‑gp substrate) by 35 % and 55 %, respectively. Therefore, pirtobrutinib can increase the plasma concentrations of P-gp substrates. If co‑administration with narrow therapeutic index P‑gp substrates (e.g dabigatran etexilate and digoxin) cannot be avoided, close clinical monitoring should be considered.

CYP2C19 substrates

Pirtobrutinib is a weak inhibitor of CYP2C19. Pirtobrutinib increased the AUC and Cmax of omeprazole (a CYP2C19 substrate) by 56 % and 49 %, respectively. Therefore, pirtobrutinib can increase the plasma concentrations of CYP2C19 substrates. If co-administration with narrow therapeutic index CYP2C19 substrates (e.g. phenobarbital and mephenytoin) cannot be avoided, close clinical monitoring should be considered.

CYP3A substrates

Pirtobrutinib is a weak inhibitor of CYP3A. Pirtobrutinib increased the AUC and Cmax of orally administered midazolam (sensitive CYP3A substrate) by 70 % and 58 %, respectively. Pirtobrutinib did not have a clinically meaningful effect on the exposure of intravenously administered midazolam. Therefore, pirtobrutinib can increase the plasma concentrations of CYP3A substrates. If co‑administration with narrow therapeutic index CYP3A substrates (e.g alfentanil, midazolam, tacrolimus) cannot be avoided, close clinical monitoring should be considered.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Based on findings in animals and the genotoxicity of pirtobrutinib (see section 5.3), pirtobrutinib can cause foetal harm when administered to a pregnant woman. Women of childbearing potential should use an effective method of contraception during treatment and for 5 weeks after the last dose of Jaypirca. Men are advised to use an effective method of contraception and not father a child during treatment and for 3 months after the last dose of Jaypirca (see section 4.4).

Pregnancy

There are no data from the use of Jaypirca in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Jaypirca should not be used during pregnancy.

Breast‑feeding

It is unknown whether pirtobrutinib is excreted in human milk. A risk to the suckling child cannot be excluded. Breast‑feeding should be discontinued during treatment with Jaypirca and for one week after the last dose of Jaypirca.

Fertility

There are no data on the effect of pirtobrutinib on human fertility.

4.7. Effects on ability to drive and use machines

Jaypirca has a minor influence on the ability to drive and use machines. Fatigue, dizziness, and asthenia have been reported in some patients during treatment with Jaypirca and should be considered when assessing a patient's ability to drive or operate machines.

4.8. Undesirable effects

Summary of the safety profile

Of the 1153 patients treated with Jaypirca, the most common adverse reactions of any grade (in ≥20 % of patients) were neutropenia (27.4 %) and haemorrhage (20.4 %).

The most common severe (Grade ≥ 3) adverse reactions (in ≥5 % of patients) were neutropenia (22.8 %), anaemia (9.0 %), pneumonia (8.8 %), and thrombocytopenia (7.2 %).

The frequency of treatment discontinuations due to adverse reactions was 3.3 % and the most common adverse reaction leading to treatment discontinuation was pneumonia (0.8 %). The frequency of dose reductions due to adverse reactions was 4.3 % and the most common adverse reaction leading to dose reduction was neutropenia (2.4 %).

Serious adverse reactions associated with Jaypirca have occurred in 18.0 % of patients and the most common serious adverse reactions (in ≥1 % of patients) were pneumonia (8.2 %), haemorrhage (2.9 %), neutropenia (2.6 %), anaemia (2.4 %), atrial fibrillation/atrial flutter (1.1 %) and urinary tract infection (1.0 %).

Fatal adverse reactions have been observed in 0.7 % of patients for pneumonia, in 0.3 % of patients for haemorrhage and in 0.1 % of patients for urinary tract infection.

Tabulated list of adverse reactions

Table 1 lists the adverse drug reactions (ADRs) associated with Jaypirca used as a monotherapy from clinical study data and post-marketing experience. The ADRs identified from clinical trials are based on pooled data from 1153 patients treated with Jaypirca monotherapy 200 mg QD starting dose with no dose escalation in a phase 1/2 clinical study, and from patients treated with Jaypirca monotherapy 200 mg QD in phase 3 studies. Patients were treated for MCL, chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) and other non-Hodgkin lymphoma (NHL). Patients were exposed to Jaypirca for a median duration of 18 months. ADRs are listed below by MedDRA body system organ class. Frequency groups are defined by the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000), and not known (cannot be estimated from the available data). Within each frequency grouping, ADRs are presented in order of decreasing seriousness.

Table 1: ADRs of patients treated with Jaypircaa

System organ class (MedDRA)

ADR

Frequency category (%)

(All grades)

Grade ≥ 3c (%)

Infections and infestations

Pneumonia

Very common (13.9)

8.8

Upper respiratory tract infection

Very common (13.4)

0.3

Urinary tract infection

Common (9.2)

1.3

Blood and lymphatic system disorders

Neutropeniab

Very common (27.4)

22.8

Anaemiab

Very common (18.4)

9.0

Thrombocytopeniab

Very common (14.7)

7.2

Lymphocytosisb

Common (5.0)

3.2

Nervous system disorders

Headache

Very common (10.7)

0.5

Cardiac disorders

Atrial fibrillation/atrial flutter

Common (3.1)

1.6

Vascular disorders

Haemorrhageb

Very common (20.4)

2.9

Epistaxis

Common (4.2)

0.1

Haematuria

Common (4.8)

0.2

Haematoma

Common (2.4)

0.3

Conjunctival haemorrhage

Common (1.5)

0.1

Bruisingb

Very common (17.0)

0.2

Contusion

Very common (14.2)

0.1

Petechiae

Common (5.1)

0

Gastrointestinal disorders

Diarrhoea

Very common (19.5)

0.7

Nausea

Very common (13.0)

0.3

Abdominal pain

Common (7.4)

0.7

Hepatobiliary disorders

Hepatic enzyme increased

Not known

Not known

Skin and subcutaneous tissue disorders

Rashb

Very common (19.2)

1.2

Musculoskeletal and connective tissue disorders

Arthralgia

Very common (12.5)

0.8

General disorders and administration site conditions

Fatigue

Very common (17.9)

1.4

Oedema peripheral

Common (9.0)

0.3

a Frequencies are derived from Jaypirca exposure in patients with B-cell malignancies

b Includes multiple adverse reaction terms

c Severity grade assignment based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0

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: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No maximum tolerated dose was reached in the phase 1 study in which patients received repeated doses up to 300 mg once daily. In healthy volunteer studies, no dose related toxicity was observed when a maximum single dose of 900 mg was administered. Signs and symptoms of pirtobrutinib overdose have not been established and there is no specific treatment for pirtobrutinib overdose.

For patients who experience overdose, closely monitor and provide appropriate supportive treatment.