WAYRILZ Film-coated tablet Ref.[116156] Active ingredients: Rilzabrutinib

Serious infections

Serious infections (including bacterial, viral, or fungal) have been reported during clinical studies (see section 4.8). Monitor patients for signs and symptoms of infection and treat appropriately.

Women of childbearing potential

Women of childbearing potential must use highly effective method of contraception while taking rilzabrutinib (see section 4.6). Pregnancy status of females of child-bearing potential should be verified prior to initiating treatment.

Hepatic impairment

In patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment, rilzabrutinib should not be administered (see section 5.2). Bilirubin and transaminases are to be evaluated at baseline and as clinically indicated during treatment with rilzabrutinib. For patients who develop abnormal liver tests after rilzabrutinib, continue to monitor for liver test abnormalities as well as clinical signs and symptoms as clinically indicated.

QT shortening

In the clinical trials with ITP patients, there were no clinically meaningful QTc interval changes. In a thorough QT study, rilzabrutinib produced a shortening in the QTc interval (see section 5.1). Although the underlying mechanism and safety relevance of this finding is not known, clinicians should use caution when prescribing rilzabrutinib to patients at risk for further shortening their QTc duration (e.g., Congenital Short QT Syndrome or patients with a family history of such a syndrome).

Excipients

Sunset yellow FCF

This medicinal product contains azo colouring agent sunset yellow FCF (E 110), which may cause allergic reactions.

Sodium

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

Rilzabrutinib is primarily metabolized by CYP3A.

Agents that may increase rilzabrutinib plasma concentrations

Co-administration of rilzabrutinib with a moderate or strong CYP3A inhibitor increases rilzabrutinib plasma concentrations. Increased rilzabrutinib concentrations may increase the risk of rilzabrutinib adverse reactions.

CYP3A inhibitors

Co-administration with a strong CYP3A inhibitor (ritonavir) increased the rilzabrutinib C_max by approximately 5-fold and AUC by 8-fold in healthy subjects.

Avoid co-administration of moderate or strong CYP3A inhibitors (e.g., ritonavir, clarithromycin, itraconazole, erythromycin, fluconazole, verapamil, diltiazem) with rilzabrutinib. If these inhibitors will be used short term (such as anti-infectives for seven days or less), interrupt rilzabrutinib (see section 4.2).

Avoid co-administration of grapefruit, starfruit and products containing these fruits, and Seville oranges with rilzabrutinib, as these are moderate or strong inhibitors of CYP3A.

P-glycoprotein (P-gp) inhibitors

After co-administration of rilzabrutinib with a strong P-gp inhibitor (quinidine), a modest increase in exposure to rilzabrutinib, considered not to be clinically meaningful, was observed by 12.7% for AUC, relative to rilzabrutinib alone.

Agents that may decrease rilzabrutinib plasma concentrations

Co-administration of rilzabrutinib with moderate or strong CYP3A inducers decreases rilzabrutinib plasma concentrations. Co-administration with a PPI decreases the plasma concentrations of rilzabrutinib. Decreased rilzabrutinib plasma concentrations may reduce rilzabrutinib efficacy.

CYP3A inducers

Co-administration with a strong CYP3A inducer (rifampicin) decreased rilzabrutinib C_max and AUC by about 80% in healthy subjects.

Avoid co-administration of rilzabrutinib with moderate or strong CYP3A inducers (e.g., carbamazepine, rifampicin, phenytoin) (see section 4.2).

Gastric acid reducing agents

Rilzabrutinib solubility decreases with increasing pH. Co-administration with a PPI (esomeprazole) decreased rilzabrutinib AUC by 51% in healthy subjects. Co-administration of rilzabrutinib with a H2RA (famotidine) reduced rilzabrutinib AUC by approximately 36% and no significant change was observed in rilzabrutinib exposure if rilzabrutinib was administered at least 2 hours prior to famotidine.

Avoid co-administration of rilzabrutinib with PPIs. If treatment with a gastric acid reducing agent is required, consider using a H2RA. Rilzabrutinib should be administered at least 2 hours before taking a H2RA (see section 4.2). The effect of elevating gastric pH with antacids on the pharmacokinetics of rilzabrutinib has not been studied and may be similar to that seen with famotidine (H2RA). Therefore, it is recommended to take rilzabrutinib at least 2 hours before taking the antacid.

Agents that may have their plasma concentrations altered by rilzabrutinib

CYP3A substrates

Rilzabrutinib is both an in vitro inhibitor and inducer of the CYP3A4 enzyme. Co-administration of a single 400 mg dose of rilzabrutinib with a CYP3A substrate (midazolam) increased substrate exposure by 1.7-fold in healthy subjects. When midazolam was administered 2 hours after the rilzabrutinib dose there was increase in midazolam exposure approximately by 2.2-fold. The effect of a multiple-dose regimen of rilzabrutinib on CYP3A4 activity was not assessed in clinical trials. Caution should be exercised if co-administering rilzabrutinib with CYP3A substrates with narrow therapeutic range (e.g. cyclosporin).

Transporter substrates

Rilzabrutinib has shown potential to inhibit the P-gp, BCRP, and OATP1B3 transporters in vitro. There is a possible risk of drug-drug interactions, therefore, caution should be exercised when co-administering rilzabrutinib with P-gp, BCRP, or OATP1B3 sensitive substrates with a narrow therapeutic range (e.g. digoxin, cyclosporin, tacrolimus) (see section 5.2).

Hormonal contraceptives

The effect of rilzabrutinib on the plasma concentrations of hormonal contraceptives is unknown. Therefore, women of childbearing potential should use an alternative non-hormonal or additional highly effective method of contraception during treatment and for at least 1 month after discontinuation of rilzabrutinib (see section 4.6).

Women of childbearing potential

Women of child-bearing potential must use highly effective contraception during rilzabrutinib treatment and for 1 month after stopping treatment (see section 4.5 regarding potential interaction with hormonal contraceptives). Pregnancy status of females of child-bearing potential should be verified prior to initiating treatment.

Pregnancy

Rilzabrutinib should not be used during pregnancy and in women of childbearing potential not using contraception. Based on the available nonclinical animal studies, there may be a risk to the foetus (see section 5.3). There are no available data on rilzabrutinib use in pregnant women.

Breast-feeding

There are no available data on the presence of rilzabrutinib or its metabolites in human milk, effects on milk production, or the breastfed infant. No conclusions can be drawn regarding whether or not rilzabrutinib is safe for use during breastfeeding. Rilzabrutinib should be used during breastfeeding only if the potential benefits to the mother outweigh the potential risks, including those to the breastfed child.

Fertility

There are no data on the effect of rilzabrutinib on human fertility. Effects of rilzabrutinib on male and female fertility were studied in rats at doses up to 300 mg/kg/day [Human Equivalent Dose (HED) 48 mg/kg/day]. Animal studies do not indicate any effect on fertility (see section 5.3).

Rilzabrutinib may have a minor influence on the ability to drive and use machines. Mild dizziness has been reported in some patients taking rilzabrutinib and should be considered when assessing a patient's ability to drive or operate machines.

Summary of the safety profile

The most common adverse reactions were diarrhoea (34.5%), nausea (25.4%), headache (18.3%), abdominal pain (15.8%), COVID-19 (15.5%), nasopharyngitis (11.6%), and arthralgia (11.3%). The most frequent adverse reactions resulting in discontinuation of rilzabrutinib, which occurred each in 2 patients (0.7%), were diarrhoea, nausea, headache, and pneumonia.

Tabulated list of adverse reactions

Unless otherwise stated, the following frequencies of adverse reactions are based on the 284 ITP patients exposed to rilzabrutinib in the phase ½ and phase 3 clinical trials (see section 5.1). The median duration of exposure was 6.6 months (range: <1 month to 70.8 months).

Adverse reactions are organised according to primary system organ class (SOC) for each preferred term in MedDRA. The adverse reactions are ranked by frequency within each SOC, and presented in order of decreasing seriousness. 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).

Table 2. Tabulated list of the adverse drug reactions:

^* Due to aspergillosis in 2 cases

Description of selected adverse reactions

Infections

Among patients exposed to rilzabrutinib, the most common infection adverse reactions were COVID- 19 (15.5%) and nasopharyngitis (11.6%). The majority of infections were Grade 1 or 2 and resolved within 8 days. For those that experienced an adverse reaction of infection, the median time to onset was 2.9 months (range: 1 day; 41.7 months). In the LUNA-3 Study double blind period, Grade 2 or higher occurred in 17.3% and 14.5% in the rilzabrutinib group and placebo group, respectively. Grade 3 or higher occurred in 3.8% in the rilzabrutinib group and none in the placebo group. In the LUNA-3 Study double blind period, serious grade 3 or higher adverse reaction of infection occurred in 2 (1.5%) patients in the rilzabrutinib group, including a fatal case of pneumonia due to aspergillosis and COVID-19, and none in the placebo group.

Gastrointestinal disorders

Among patients exposed to rilzabrutinib, the most common GI adverse reactions were diarrhoea (34.5%), nausea (25.4%), and abdominal pain (15.8%). Majority of GI reactions were Grade 1 and resolved with median duration of 19 days for nausea, 12 days for abdominal pain, and approximately 7 days for diarrhoea. For those that experienced a GI adverse reaction, the median time to onset for GI disturbances was 4 days (range: 1 day; 12.7 months).

Rash

Among patients exposed to rilzabrutinib, rash (including rash maculo-papular, rash papular, rash erythematous, rash pruritic, erythema, erythema nodosum, urticaria) were all non-serious. All were Grade 1 or 2. For those that experienced an adverse reaction of rash, the median time to onset was 3.4 months (range: 6 days; 57.7 months).

Other special population

Elderly

Among the patients exposed to rilzabrutinib (n=284), 51 (17.9%) patients were 65 years of age or older. In these elderly patients, 2 (3.9%) patients experienced serious adverse reactions of pneumonia. In patients below 65 years of age, 3 (1.3%) patients had serious adverse reactions of pneumonia and COVID-19.

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 national reporting system listed in Appendix V.

Not applicable.