Tolebrutinib

Tolebrutinib has shown potential to inhibit the P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, and MATE1 transporters in vitro. There is a possible risk of drug-drug interactions, therefore, caution should be exercised when co-administering tolebrutinib with P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, or MATE1 sensitive substrates with a narrow therapeutic range (e.g. digoxin, cyclosporin, tacrolimus).

Co-administration of a strong CYP2C8 inhibitor (gemfibrozil 600 mg twice daily) increased tolebrutinib AUC and C_max by 8.4-fold and 5.4-fold, while M2 AUC and C_max decreased by 25-fold and 50-fold, compared to single administration of tolebrutinib under fed conditions. The clinical relevance of this interaction is uncertain. As a precaution, concomitant use of strong CYP2C8 inhibitors (e.g., gemfibrozil) or moderate CYP2C8 inhibitors (e.g., deferasirox, letermovir, selpercatinib) with tolebrutinib should be avoided. In case of known CYP2C8 poor metaboliser status of a patient, caution is to be exercised due to the potential changes in exposure to tolebrutinib and M2.

Caution should be exercised when using tolebrutinib concomitantly with anticoagulants (e.g., warfarin, heparin, apixaban, rivaroxaban, edoxaban) or antiplatelet agents (e.g., clopidogrel, ticagrelor, prasugrel) due to the risk of bleeding events. If concurrent administration cannot be avoided, increase monitoring frequency for bleeding signs and symptoms.

The safety of immunisation with live attenuated or live vaccines following tolebrutinib treatment has not been studied. However, the use of live attenuated or live vaccines may carry a risk of infections and must therefore be avoided. If live attenuated or live vaccines are needed, they should be administered at least 2 months before initiating tolebrutinib treatment. Due to its mechanism of action on B-cell function, tolebrutinib may interfere with the immune response of non-live vaccines. When possible, complete all age-appropriate non-live vaccinations according to current immunisation guidelines prior to initiating tolebrutinib treatment.

Co-administration of a strong CYP3A/2C8 inducer (rifampicin 600 mg once daily) decreased both tolebrutinib AUC and C_max by 6.2-fold, while M2 AUC and C_max decreased by 2.4-fold and 1.9-fold in healthy subjects. Moderate CYP3A/2C8 inducer efavirenz may also decrease tolebrutinib and M2 metabolite exposures. Co-administration of tolebrutinib with strong CYP3A/2C8 inducers (e.g., carbamazepine, phenytoin, rifampicin, St. John's wort) or moderate CYP3A/2C8 inducers (e.g., bosentan, efavirenz, etravirine, nafcillin) should be avoided. If a moderate or strong CYP3A/2C8 inducer must be used short-term (<2 weeks), treatment with tolebrutinib can be continued.

There is very limited data in patients with severe renal impairment, therefore, patients with severe renal impairment (<30 mL/min creatinine clearance) should be treated with tolebrutinib only if the benefit outweighs the risk and patients should be monitored closely for signs of toxicity. There are no data in patients on dialysis.

No dose adjustment is required for patients with mild hepatic impairment (Child-Pugh Class A), although caution must be exercised when initiating treatment in these patients.

The safety of concomitant use of immunosuppressants with tolebrutinib has not been studied. However, higher infection rates were observed when tolebrutinib was used concomitantly with immunosuppressants including corticosteroids. Caution should be exercised when using other immunosuppressant drugs (e.g., chronic corticosteroids, non-biologic and biologic disease-modifying antirheumatic drugs [DMARDS], mycophenolate mofetil, cyclophosphamide, azathioprine) concomitantly with tolebrutinib. Data are inconclusive as to whether concomitant steroid use for symptomatic treatment of relapses was associated with an increased risk of infections.

Atrial fibrillation/flutter were reported in patients treated with tolebrutinib. Patients with a history of cardiac arrhythmias, particularly atrial fibrillation/flutter, and those with risk factors for developing atrial fibrillation (such as heart failure or hypertension) may be at increased risk. Monitor signs and symptoms for atrial fibrillation/flutter including palpitations, dizziness, shortness of breath, or chest discomfort, and manage as appropriate.

There are limited data available from the use of tolebrutinib in pregnant women. Tolebrutinib and/or its metabolites crossed the placenta in rabbits. Animal studies with tolebrutinib do not indicate reproductive toxicity. However, there is insufficient information on embryo-foetal development regarding the active metabolite M2, therefore, a risk to the unborn child cannot be excluded. Tolebrutinib is not recommended during pregnancy and in women of childbearing potential not using contraception.

There is insufficient information on the excretion of tolebrutinib or its metabolites in human milk. A risk to breast-fed newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or to abstain/discontinue from therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

The effects of tolebrutinib on fertility in humans are unknown. Animal studies with tolebrutinib and its M2 metabolite showed no adverse effects on fertility.

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

Summary of the safety profile

The most commonly reported adverse reactions are COVID-19 (25.5%) and upper respiratory infections (16.9%). The most common serious adverse reaction is COVID-19 pneumonia (1.1%).

Tabulated list of adverse reactions

Adverse reactions reported with tolebrutinib from the clinical trials are listed below in the table below. The adverse reactions are listed by MedDRA system organ class and categories of frequency. Frequencies are defined as 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, adverse reactions are presented in the order of decreasing seriousness.

Adverse reactions:

¹ Includes multiple preferred terms.
² Pooled data from clinical studies EFC16645 (HERCULES), EFC16033 (GEMINI I) and EFC16034 (GEMINI II)
³ ALT greater than 3-fold ULN.

Description of selected adverse reactions

Drug-induced liver injury (DILI)

In the pivotal EFC16645 (HERCULES) study, ALT elevations greater than 3 x the upper limit of normal (ULN) were observed in 4.0% of patients treated with tolebrutinib and 1.6% of patients receiving placebo. Among the 754 tolebrutinib-treated patients, 0.5% experienced ALT elevations greater than 20 x ULN, and 0.3% had ALT elevations greater than 3 x ULN with concurrent bilirubin increases greater than 2 x ULN, all without alternative causes of DILI and all occurred within three months of initiating tolebrutinib treatment. In a majority of patients, patient's liver enzymes resolved spontaneously without sequelae following permanent discontinuation of tolebrutinib. One patient developed liver failure requiring a liver transplant and subsequently died due to a post-transplant complication.

Infections

In the pivotal EFC16645 (HERCULES) study, 54.4% of patients receiving tolebrutinib experienced infections with 5.2% reporting severe (Grade 3 or higher) infections compared to those treated with placebo (2.9%). The most common infection adverse reactions were COVID-19 (25.5%) and upper respiratory infections (16.9%). The majority of these patients had symptom resolution without permanent discontinuation of tolebrutinib. However, one fatal case of pneumonia (bacterial) occurred in a disabled patient in a setting of delayed care treated with tolebrutinib 60 mg for 1.8 years.

Petechiae, increased tendency to bruise, heavy menstrual bleeding, contusions

In the pivotal EFC16645 (HERCULES) study, 2.7% of tolebrutinib-treated patients experienced petechiae, compared to 0.3% of those on placebo, and 3.9% of tolebrutinib-treated patients experienced contusions, compared to 1.1% of those on placebo. Across the clinical studies EFC16645 (HERCULES), EFC16033 (GEMINI I) and EFC16034 (GEMINI II), 1.5% of tolebrutinib-treated patients showed an increased tendency to bruise, compared to 0% of those on placebo and 0.3% of those on teriflunomide, and 1.7% of tolebrutinib-treated patients experienced heavy menstrual bleeding, compared to 0.3% of those on placebo and 1% of those on teriflunomide. 1% of patients with heavy menstrual bleeding also developed mild to moderate anaemia. None of the petechiae, bruising, heavy menstrual bleeding or contusions were associated with thrombocytopenia in clinical trials. Most cases were mild. Patients on anticoagulants or anti-platelet treatments, those with significant bleeding history within 6 months prior to screening, bleeding disorders, known platelet dysfunction, platelet counts below 150 000/mcL, or major surgery within 4 weeks prior to screening were excluded from the trials.