Leaflet WAYRILZ 400mg film-coated tablets
Indicated for: cancer
Route of administration: oral
Substance: rilzabrutinib (antineoplastic agent)
This medicine may affect fertility.
Dose adjustment may be needed in liver disease.
Handle with special care.
Effective contraception is required during treatment.
Do not use this medicine while breastfeeding.
Do not use this medicine during pregnancy.
This medicine may affect the liver.
This medicine may have important interactions with other medicines.
This medicine may lower blood cell counts.
This medicine is subject to additional monitoring.
Periodic laboratory tests may be required during treatment.
Stop taking the medicine and seek urgent medical help if a severe rash occurs.
Rilzabrutinib is a medicine used in adults with persistent or chronic immune thrombocytopenia when previous treatments have not worked well enough. In this condition, the immune system destroys platelets, the blood cells that help stop bleeding. Rilzabrutinib blocks Bruton’s tyrosine kinase, an enzyme involved in immune-cell signalling, and may help raise platelet counts.
It is taken by mouth as tablets, usually twice daily, exactly as prescribed by a haematology specialist. Take it regularly and do not stop it on your own, because platelet counts may fall again and bruising or bleeding can worsen. Your doctor may adjust treatment according to blood tests, side effects, liver function and other medicines.
Common side effects include diarrhoea, nausea, headache, abdominal pain and respiratory infections, including COVID-19. Blood-test changes, liver-enzyme increases or low blood cell counts may also occur. Contact your doctor promptly for fever, repeated infections, yellow skin or eyes, dark urine, widespread bruising, nosebleeds, blood in stools or bleeding that is hard to stop.
Regular blood tests and liver monitoring are important. Tell your healthcare team about all medicines and supplements, especially antifungals, antibiotics, antivirals, acid-reducing medicines and herbal products, because interactions can change rilzabrutinib levels. People who can become pregnant should discuss effective contraception, and pregnancy should be reported immediately.
General data about WAYRILZ 400mg
- Substance: rilzabrutinib
- Commercial code: W71728001
- Concentration: 400mg
- Pharmaceutical form: film-coated tablets
- Quantity: 28
- Product type: generic
- Prescription restrictions: S - Medicines prescription reserved for use in certain specialized fields.
EMA leaflet
Leaflet WAYRILZ 400mg
Contents of the package leaflet for the medicine WAYRILZ 400mg film-coated tablets
1. NAME OF THE MEDICINAL PRODUCT
WAYRILZ 400 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 400 mg rilzabrutinib.
Excipient with known effectEach tablet contains 0.8 mg of sunset yellow FCF (E 110).
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet.
Orange tablet, capsule-shaped of 16.6 × 8.1 mm size, debossed with “P” on one side and “400” on theother side.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
WAYRILZ is indicated for the treatment of immune thrombocytopenia (ITP) in adult patients who arerefractory to other treatments (see section 5.1).
4.2 Posology and method of administration
Treatment should be initiated and remain under the supervision of a physician who is experienced inthe treatment of haematological diseases.
PosologyThe recommended dose of rilzabrutinib is 400 mg twice daily.
Use with CYP3A inhibitors or inducers and gastric acid reducing agents
Recommended use with cytochrome P450 enzyme 3A (CYP3A) inhibitors or inducers and gastric acidreducing agents are provided in Table 1 (see section 4.5).
Table 1: Use with CYP3A inhibitors or inducers and gastric acid reducing agents
Co-administered medicinal product Recommended use
CYP3A inhibitors Strong and moderate CYP3A inhibitor Avoid co-administration ofrilzabrutinib with moderate orstrong CYP3A inhibitors. Ifthese inhibitors will be usedshort-term (such as anti-infectives for up to sevendays), interrupt rilzabrutinib.
Avoid co-administration ofgrapefruit, starfruit andproducts containing thesefruits, and Seville oranges withrilzabrutinib, as these aremoderate or strong inhibitors of
CYP3A.
Weak CYP3A inhibitor No dose adjustment.
CYP3A inducers Strong and moderate CYP3A inducers Avoid co-administration ofrilzabrutinib with moderate orstrong CYP3A inducers.
Weak CYP3A inducer No dose adjustment.
Gastric acid Proton pump inhibitors (PPIs) Avoid co-administration ofreducing agents rilzabrutinib with PPIs.
H2-receptor antagonists or antacid If treatment with a gastric acidreducing agent is required,consider using a H2-receptorantagonist (H2RA) or antacid.
Take rilzabrutinib at least2 hours before taking the
H2RA or antacid.
Missed doseIf a dose of rilzabrutinib is missed, patients should take the missed dose as soon as possible on thesame day with a return to the regular schedule the following day. The missed dose and the next regularscheduled dose must be taken more than 2 hours apart. Extra tablets should not be taken to make upfor the missed dose.
DiscontinuationTreatment with rilzabrutinib should be discontinued after 12 weeks of rilzabrutinib therapy if theplatelet count does not increase to a level sufficient to avoid clinically important bleeding.
Special population
ElderlyNo dose modification is required for elderly (≥ 65 years) patients (see section 5.2).
Renal impairmentNo dose modification is required in patients with mild or moderate renal impairment. Rilzabrutinib hasnot been studied in clinical trials in patients with severe renal impairment (see section 5.2).
Hepatic impairmentNo dose modification is required in patients with mild (Child-Pugh Class A) hepatic impairment.
Rilzabrutinib has not been studied in clinical trials in patients with severe (Child-Pugh Class C)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).
Paediatric populationThe safety and efficacy of rilzabrutinib in children and adolescents below 18 years of age with ITPhave not been established. No data are available.
Method of administrationRilzabrutinib is for oral use.
The tablets can be taken at approximately the same time each day with or without food (see section5.2). In patients who experience gastrointestinal symptoms, taking rilzabrutinib with food mayimprove tolerability. Patients should be instructed to swallow the tablets whole with water. The tabletsshould not be split, crushed, or chewed in order to ensure the entire dose is delivered correctly.
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
Serious infections (including bacterial, viral, or fungal) have been reported during clinical studies (seesection 4.8). Monitor patients for signs and symptoms of infection and treat appropriately.
Women of childbearing potentialWomen of childbearing potential must use highly effective method of contraception while takingrilzabrutinib (see section 4.6). Pregnancy status of females of child-bearing potential should beverified prior to initiating treatment.
Hepatic impairmentIn 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 beevaluated at baseline and as clinically indicated during treatment with rilzabrutinib. For patients whodevelop abnormal liver tests after rilzabrutinib, continue to monitor for liver test abnormalities as wellas 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 athorough QT study, rilzabrutinib produced a shortening in the QTc interval (see section 5.1). Althoughthe underlying mechanism and safety relevance of this finding is not known, clinicians should usecaution 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).
ExcipientsSunset yellow FCF
This medicinal product contains azo colouring agent sunset yellow FCF (E 110), which may causeallergic reactions.
SodiumThis medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to sayessentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
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 rilzabrutinibplasma concentrations. Increased rilzabrutinib concentrations may increase the risk of rilzabrutinibadverse reactions.
CYP3A inhibitorsCo-administration with a strong CYP3A inhibitor (ritonavir) increased the rilzabrutinib Cmax byapproximately 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 inhibitorswill be used short term (such as anti-infectives for seven days or less), interrupt rilzabrutinib (seesection 4.2).
Avoid co-administration of grapefruit, starfruit and products containing these fruits, and Sevilleoranges 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 inexposure 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 rilzabrutinibplasma concentrations. Co-administration with a PPI decreases the plasma concentrations ofrilzabrutinib. Decreased rilzabrutinib plasma concentrations may reduce rilzabrutinib efficacy.
CYP3A inducersCo-administration with a strong CYP3A inducer (rifampicin) decreased rilzabrutinib Cmax and AUC byabout 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 wasobserved in rilzabrutinib exposure if rilzabrutinib was administered at least 2 hours prior tofamotidine.
Avoid co-administration of rilzabrutinib with PPIs. If treatment with a gastric acid reducing agent isrequired, 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 ofrilzabrutinib 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 substratesRilzabrutinib is both an in vitro inhibitor and inducer of the CYP3A4 enzyme. Co-administration of asingle 400 mg dose of rilzabrutinib with a CYP3A substrate (midazolam) increased substrate exposureby 1.7-fold in healthy subjects. When midazolam was administered 2 hours after the rilzabrutinib dosethere was increase in midazolam exposure approximately by 2.2-fold. The effect of a multiple-doseregimen of rilzabrutinib on CYP3A4 activity was not assessed in clinical trials. Caution should beexercised if co-administering rilzabrutinib with CYP3A substrates with narrow therapeutic range (e.g.
cyclosporin).
Transporter substratesRilzabrutinib 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 narrowtherapeutic range (e.g. digoxin, cyclosporin, tacrolimus) (see section 5.2).
Hormonal contraceptivesThe effect of rilzabrutinib on the plasma concentrations of hormonal contraceptives is unknown.
Therefore, women of childbearing potential should use an alternative non-hormonal or additionalhighly effective method of contraception during treatment and for at least 1 month afterdiscontinuation of rilzabrutinib (see section 4.6).
4.6 Fertility, pregnancy and lactation
Women of child-bearing potential must use highly effective contraception during rilzabrutinibtreatment and for 1 month after stopping treatment (see section 4.5 regarding potential interaction withhormonal contraceptives). Pregnancy status of females of child-bearing potential should be verifiedprior to initiating treatment.
PregnancyRilzabrutinib should not be used during pregnancy and in women of childbearing potential not usingcontraception. Based on the available nonclinical animal studies, there may be a risk to the foetus (seesection 5.3). There are no available data on rilzabrutinib use in pregnant women.
Breast-feedingThere are no available data on the presence of rilzabrutinib or its metabolites in human milk, effects onmilk production, or the breastfed infant. No conclusions can be drawn regarding whether or notrilzabrutinib is safe for use during breastfeeding. Rilzabrutinib should be used during breastfeedingonly if the potential benefits to the mother outweigh the potential risks, including those to thebreastfed child.
FertilityThere are no data on the effect of rilzabrutinib on human fertility. Effects of rilzabrutinib on male andfemale 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).
4.7 Effects on ability to drive and use machines
Rilzabrutinib may have a minor influence on the ability to drive and use machines. Mild dizziness hasbeen reported in some patients taking rilzabrutinib and should be considered when assessing apatient’s ability to drive or operate machines.
4.8 Undesirable effects
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%). Themost frequent adverse reactions resulting in discontinuation of rilzabrutinib, which occurred each in 2patients (0.7%), were diarrhoea, nausea, headache, and pneumonia.
Tabulated list of adverse reactionsUnless otherwise stated, the following frequencies of adverse reactions are based on the 284 ITP patientsexposed to rilzabrutinib in the phase 1/2 and phase 3 clinical trials (see section 5.1). The median durationof 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 termin MedDRA. The adverse reactions are ranked by frequency within each SOC, and presented in orderof 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
Frequency
MedDRA system organ
Adverse reactions (All grades)class
COVID-19 Very common
Infections and Infestations Nasopharyngitis Very common
Pneumonia* Common
Headache Very common
Nervous system disordersDizziness Common
Respiratory, thoracic, and
Cough Commonmediastinal disorders
Diarrhoea Very common
Nausea Very common
Gastrointestinal disorders Abdominal pain Very common
Vomiting Common
Dyspepsia Common
Skin and subcutaneous tissue
Rash Commondisorder
Musculoskeletal and
Arthralgia Very commonconnective tissue disorders
*Due to aspergillosis in 2 cases
Description of selected adverse reactionsInfections
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 resolvedwithin 8 days. For those that experienced an adverse reaction of infection, the median time to onsetwas 2.9 months (range: 1 day; 41.7 months). In the LUNA-3 Study double blind period, Grade 2 orhigher occurred in 17.3% and 14.5% in the rilzabrutinib group and placebo group, respectively. Grade3 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 disordersAmong 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 andresolved with median duration of 19 days for nausea, 12 days for abdominal pain, and approximately 7days for diarrhoea. For those that experienced a GI adverse reaction, the median time to onset for GIdisturbances was 4 days (range: 1 day; 12.7 months).
RashAmong patients exposed to rilzabrutinib, rash (including rash maculo-papular, rash papular, rasherythematous, 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 3.4months (range: 6 days; 57.7 months).
Other special population
ElderlyAmong 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. Inpatients below 65 years of age, 3 (1.3%) patients had serious adverse reactions of pneumonia and
COVID-19.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
There is no specific antidote for overdose with rilzabrutinib. In the event of overdose, closely monitorthe patient for any signs or symptoms of adverse reactions and appropriate symptomatic treatmentimmediately.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: not yet assigned, ATC code: not yet assigned
Mechanism of actionBruton’s tyrosine kinase (BTK) is an intracellular signalling molecule of the B-cell and innate immunecells. In B-cells, BTK signalling results in B-cell survival, proliferation, and maturation. In innateimmune cells, BTK participates in inflammatory pathways that include, toll-like receptor signalling,
Fc gamma receptor signalling, and the activation of the NLRP3 inflammasome.
Rilzabrutinib is a selective, covalent, reversible inhibitor of BTK, with a tailored residence time at
BTK to reduce off-target effects. In ITP, rilzabrutinib mediates its therapeutic effect through multi-immune modulation by inhibiting B cell activation, interruption of FcγR mediated phagocytosis, andpotentially amelioration of chronic inflammation associated with ITP.
Pharmacodynamic effectsCardiac Electrophysiology
In the “Thorough QT Study,” co-administration of 400 mg rilzabrutinib and the CYP3A inhibitor(ritonavir) resulted in plasma exposure 8 times higher than rilzabrutinib alone. Under these conditions,there was no prolongation of the mean QTc interval to any clinically relevant effect. In this samestudy, a concentration dependent shortening in the QTc interval was observed with a maximumshortening of -10.2 ms (90% CI: -12.24, -8.16) following the supratherapeutic dose (combination ofrilzabrutinib and ritonavir 100 mg)]. The shortening was smaller [-7.3 ms (90% CI: -9.33, -5.19)] atthe rilzabrutinib 400 mg twice a day dose.
Clinical efficacy and safetyThe safety and efficacy of rilzabrutinib in adult patients with primary persistent or chronic immunethrombocytopenia (ITP) was evaluated in a Phase 3, randomized, double-blind (DB), placebo-controlled, parallel-group study consisting of 24 weeks of blinded treatment, followed by an open-label (OL) period of 28 weeks and long-term extension (LTE) period during both of which all patientsreceived rilzabrutinib (LUNA 3 Study). The patients enrolled in this study did not have a sustainedresponse to either intravenous immunoglobulin (IVIg/anti-D) or corticosteroid (CS), or had adocumented intolerance or insufficient response to any appropriate course of standard-of-care ITPtherapy.
Patients were randomized 2:1 to rilzabrutinib or placebo and randomization was stratified with respectto prior splenectomy and severity of thrombocytopenia.
Concomitant ITP medicinal products [oral CS and/or thrombopoietin receptor agonist (TPO-RA)]were allowed at stable doses at least 2 weeks before the start of the study and throughout the DBperiod. Rescue therapy was permitted.
Only patients that responded during the first 12 weeks of the DB period could continue the DBtreatment until Week 24 before entering the OL period. Those who did not respond could enter the OLperiod at Week 13 or discontinue from the study. After completing the OL period, eligible patientscould continue into the LTE period.
In the LUNA 3 Study, 202 patients were randomized and treated, 133 to the rilzabrutinib group and 69to the placebo group. At baseline, the median age was 47 years (range: 18 to 80 years), 62.9% werefemale, 61.9% were Caucasian, and 31.7% Asian. Of the 202 patients, 15.8% (rilzabrutinib) and21.7% (placebo) were 65 years of age and older while 4.5% (rilzabrutinib) and 4.3% (placebo) were75 years of age and older.
At baseline, the majority (92.6%) of patients had chronic ITP, with a median time since ITP diagnosisof 7.69 years (range: 0.3, 52.2 years), and 27.7% had undergone splenectomy. The median plateletcount was 15 300/μL, with almost half (48%) less than 15 000/μL. Twenty-four (11.9%) patients hadonly one prior therapy and 178 (88.1%) patients had ≥ 2 prior therapies. The median number of priortherapies, including splenectomy, was 4 (range: 1 to 15). Prior ITP treatments varied, with the mostcommon prior therapies being CS (95.5%), TPO-RAs (68.8%), IVIg or anti-D immunoglobulins(55.4%), and anti-CD20 monoclonal antibody/rituximab (35.1%.). In addition, at baseline 65.8% ofpatients received both CS and TPO-RAs. Baseline characteristics were generally similar across bothgroups.
During the DB period, the median duration of exposure was 98 days (range: 22 to 182) and 84 days(range: 17 to 173) for the rilzabrutinib group and placebo group, respectively. The cumulative durationof treatment exposure was 44.3 participant-years and 17.9 participant years for the rilzabrutinib groupand placebo group, respectively. All rilzabrutinib treated patients received 400 mg twice a day. Inaddition, 39.8% of patients received rilzabrutinib without CS or TPO-RA, 25.6% receivedrilzabrutinib and CS, 18.8% received rilzabrutinib and TPO-RA, and 15.8% received rilzabrutinib andboth CS and TPO-RA.
During the first 12 weeks of the DB period, 85 (63.9%) patients and 22 (31.9%) patients in therilzabrutinib group and placebo group, respectively, achieved platelet count response (≥ 50 000/μL orbetween 30 000/μL and < 50 000/μL and doubled from baseline). Among the patients who respondedduring the DB period, the median time to platelet response was 15 days and 50 days for therilzabrutinib group and placebo group, respectively. Those who achieved platelet count response byweek 13 were eligible to continue the DB period. Fifty-five (41.4%) and 55 (79.7%) patients in therilzabrutinib and placebo groups, respectively, discontinued the DB period due to not achieving pre-defined criteria of platelet response and/or due to lack of response per investigator judgment. Theseindividuals were counted as treatment failure in the primary endpoint analysis.
In the LUNA 3 Study, the primary endpoint was durable platelet response. A durable platelet responsewas the achievement of a weekly platelet count ≥ 50 000/μL for at least 8 out of the last 12 weeks ofthe 24-week DB period in the absence of rescue therapy, The proportion of patients achieving durableresponse was significantly higher in the rilzabrutinib group (23.3%) compared to the placebo group(0%) during the DB period (see Table 3 for study outcomes). A numerically higher percentage ofpatients that received rilzabrutinib with concomitant CS and/or TPO-RA had durable platelet response(27.5%) compared to those taking rilzabrutinib as monotherapy (17%).
Key secondary endpoints included persistence of platelet response, onset of clinical response, use ofrescue therapy and patient reported outcome related to bleeding (see Table 3 for study outcomes).
Table 3: LUNA 3 Study outcomes during the 24-week DB period - adult ITT population
Study outcomes Statistic Rilzabrutinib Placebo400 mg twice daily (N=69)(N=133)
Durable platelet response1 n (%) 31 (23.3) 0 (0)95% CI 16.12, 30.49 0.00, 0.00
Risk difference (95% 23.1 (15.95, 30.31)
CI) vs placebop-value < 0.0001
Number of weeks withplatelet response≥ 50 000/μL or between LS4 Mean (SE) 7.18 (0.747) 0.72 (0.350)30 000/μL and < 50 000/μL2 LS Mean difference 6.46 (0.782)(SE) vs placebo95% CI 4.923, 7.990p-value < 0.0001≥ 30 000/μL3 LS Mean (SE) 6.95 (0.749) 0.64 (0.337)
LS Mean difference 6.31 (0.776)(SE) vs placebo95% CI 4.787, 7.831p-value < 0.0001
Time to first platelet Median number of 36 (22, 44) NR5response2 days to first plateletresponse (95% CI)
Hazard ratio (95% CI) 3.10 (1.948, 4.934)vs placebop-value < 0.0001
Requiring rescue therapy n (%) 44 (33.1) 40 (58)
Median number of NR5 56 (36, NR5)days to first use ofrescue therapy(95% CI)
Hazard ratio (95% CI) 0.48 (0.309, 0.733)vs placebop-value = 0.0007
Change from baseline in LS Mean (SE) -0.040 (0.0169) 0.047 (0.0226)
IBLS score6 at week 25 LS Mean difference -0.087 (0.0251)(SE) vs placebo95% CI -0.1358, -0.0373p-value = 0.00061 Defined as the proportion of participants able to achieve platelet counts ≥ 50 000/µL for ≥ two-thirds of at least 8 non-missing weekly scheduled platelet measurements during the last 12 weeks of the 24-week blinded treatment period in theabsence of rescue therapy, provided that at least 2 non-missing weekly scheduled platelet measurements are≥ 50 000/µL during the last 6 weeks of the 24-week blinded treatment period.2 Platelet count ≥ 50 000/µL or between 30 000 µL and < 50 000/µL and at least doubled from baseline in absence of rescuetherapy.3 Platelet count ≥ 30 000/µL and at least doubled from baseline in absence of rescue therapy.4 LS: Least Square5 NR: Not Reached6 The ITP Bleeding Scale (IBLS) is a bleeding assessment questionnaire, with scores ranging from 0 to 2, with higher scoresindicating higher presence of marked bleeding; average across anatomical sites.
After the DB period, 180 patients entered the OL period (115 patients from the rilzabrutinib group and65 patients from the placebo group in the DB period) with a cumulative duration of treatment exposureof 75.6 participant-years. Of these 180 patients, 115 patients completed the 28-week OL period.
In the OL period, 14/65 (21.5%) patients from the placebo group achieved a durable response afterbeing exposed to rilzabrutinib, and 10/84 (11.9%) patients in the rilzabrutinib group achieved adurable response despite not achieving durable response during the DB period.
Paediatric populationThe European Medicines Agency has deferred the obligation to submit the results of studies withrilzabrutinib in one or more subsets of the paediatric population in ITP (see section 4.2 for informationon paediatric use).
5.2 Pharmacokinetic properties
Mean Cmax (%CV) and AUC24h (%CV) at steady state were estimated to be 150 ng/mL (56%) and1 540 ng.h/mL (57.5%), respectively, for the ITP population. Accumulation, as reflected by the foldchange in maximum median concentrations, was 1.3-fold following dosing at 400 mg twice daily.
Rilzabrutinib exhibits approximately dose proportional increases in exposure over the dose range of300 mg to 600 mg.
AbsorptionThe absolute oral bioavailability of rilzabrutinib was 4.73%. The median time to peak rilzabrutinibplasma concentrations (Tmax) was 0.5 to 2.5 hours.
Effect of foodNo clinically significant differences in rilzabrutinib AUC or Cmax were observed following theadministration of a single 400 mg tablet with a high-fat meal, high-calorie meal as compared to dosingunder fasting conditions. Resulting Tmax was delayed by 1.5 hours.
DistributionVolume of distribution at terminal phase (Vz) after intravenous administration is 149 L. The in vitroplasma protein binding of rilzabrutinib is 97.5%, mainly bound to human serum albumin, and theblood-to-plasma ratio is 0.786.
MetabolismRilzabrutinib is predominantly metabolized by CYP3A enzymes.
Elimination/Excretion
Rilzabrutinib is rapidly cleared from the plasma, with a t1/2 of approximately 3 to 4 hours.
Following administration of a single 400 mg 14C-labeled rilzabrutinib dose, radioactivity waspredominantly excreted in feces (~86%) and to a lesser extent in urine (~5%) and bile (~6%).
Approximately 0.03% of rilzabrutinib is excreted unchanged in the urine.
Special populationsBased on population PK analysis, gender, body weight (range 36-140 kg), race/ethnicity and age(range 12-80 years) had no meaningful effect on rilzabrutinib PK. The PK of rilzabrutinib in Chineseand Japanese populations is similar to the Caucasian population.
Hepatic impairmentRilzabrutinib exposure increased by approximately 1.5-fold in mild hepatic impairment (Child-Pugh
Class A) and approximately 4.5-fold in moderate hepatic impairment (Child-Pugh Class B).
Rilzabrutinib has not been studied in patients with severe (Child-Pugh Class C) hepatic impairment.
Renal impairmentPatients with mild (60-90 mL/min) or moderate (30-60 mL/min) renal impairment participated inrilzabrutinib clinical trials. Population pharmacokinetic analysis suggest that mild or moderate renalimpairment do not impact rilzabrutinib exposure.
Transporter inhibition
Rilzabrutinib was shown in vitro to be a P-gp substrate, and to a lower extent potentially a substrate of
BCRP. Rilzabrutinib was not a substrate for OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, or
BSEP. Rilzabrutinib exhibited in vitro a potential to inhibit P-gp, OATP1B1, OATP1B3, and BSEP.
However, PBPK simulations suggest that rilzabrutinib does not have any relevant effect on P-gp,
BCRP, OATP1B1, and OATP1B3 substrate (see section 4.5).
Pharmacokinetic/pharmacodynamic relationshipPlasma exposure and BTK occupancy
Rilzabrutinib has a short duration of systemic exposure with a long duration of action on the target dueto its slow dissociation from BTK. At therapeutic doses in healthy participants, durable BTKoccupancy in peripheral blood mononuclear cells was observed over a 24-hour period.
5.3 Preclinical safety data
In the 6-month repeat-dose toxicology study in rats, the oesophagus (haemorrhage), duodenum(haemorrhage), stomach (haemorrhage), brain (inflammation; neutrophilic inflammation), uterus(distended, pyometra), cervix (distended uterus), vagina (distended uterus), and ovaries (distendeduterus) were identified as target organs. The no-observed-adverse-effect-level (NOAEL) was 150mg/kg/day (AUC exposure margin of 4.5-fold) for males and 50 mg/kg/day (AUC exposure margin of3.7-fold) for females. No rilzabrutinib-related changes, with the exception of the brain, were observedat the end of the 4-week recovery period. No evidence of neurodegeneration or cellular alteration inthe brain was observed.
In a 9-month repeat-dose study in dogs, the stomach (increased intraepithelial lymphocytes withmucosal atrophy) and liver (Kupffer cell pigment, Kupffer cell hypertrophy and increase in ALT and
AST) were identified as target organs. the NOAEL of this study was considered to be 30 mg/kg/day(AUC exposure margin of 0.4- to 0.5-fold). At the end of the 4-week recovery period, with theexception of Kupffer cell pigment, the liver and stomach findings had reversed.
Carcinogenicity/genotoxicity
Rilzabrutinib was not mutagenic in an in vitro bacterial reverse mutagenicity (Ames) assay, was notclastogenic in an in vitro human peripheral lymphocyte chromosomal aberration assay, nor was itclastogenic in an in vivo bone marrow micronucleus assay in rats.
Rilzabrutinib was not carcinogenic in a 6-month transgenic mouse study.
In a 2-year rat carcinogenicity study, rilzabrutinib-related thyroid adenomas and carcinomas wereobserved for male rats at 100 mg/kg/day (AUC exposure margin of 2.4-fold). The non-carcinogenicdose was considered to be 30 mg/kg/day (AUC exposure margin of 0.64-fold) for males and 5mg/kg/day (AUC exposure margin of 0.13-fold) for females. Transcriptomic analysis suggests thatthyroid tumours in rats derive from rilzabrutinib-mediated perturbation of thyroid hormonemaintenance. This nongenotoxic effect was discovered to be specific for rats with a mechanism notconsidered relevant to humans, therefore, the potential for thyroid tumours in humans is consideredlow. In this study, the non-neoplastic observation of erythrocytosis was noted for the mesentericlymph nodes.
Developmental and reproductive toxicity
In the combined male and female rat fertility study, no rilzabrutinib-related effects were observed forany reproductive parameters. The NOAEL for fertility, reproductive performance, and earlyembryonic development was considered to be 300 mg/kg/day (HED 48 mg/kg/day), the highest doseevaluated.
In definitive rat and rabbit embryo-foetal toxicity studies, no rilzabrutinib-related foetal developmentand foetal external, visceral, or skeletal malformations were observed. The embryo-foetal development
NOAELs were 300 and 100 mg/kg/day in rats and rabbits, respectively, which were the highest dosesevaluated. Exposure ratios (AUC) at the embryo-foetal NOAEL compared to human clinical exposureat 400 mg twice daily, were 11.1- and 4.5-fold, in rats and rabbits, respectively. Skeletal variations ofunknown relevance were observed at the same highest dose levels. Variations consisted in a shift inthe number of thoracic and lumbar vertebrae (rats and rabbits) and an increase in the incidence ofsupernumerary rib pairs (rats). No such variations were observed at 150 and 30 mg/kg/day (resultingin 11.9- and 0.24-fold of clinical exposure at 400 mg twice daily, respectively) in rats and rabbits,respectively. In an exploratory rat embryo-foetal range-finding study, increased post-implantation lossand incidence of early resorption, and decreased foetal weight were observed at 500 mg/kg/day (AUCexposure margin of 21.8-fold). Foetal external, visceral and skeletal changes were observed at 500mg/kg/day. No malformations were noted at ≤ 150 mg/kg/day (AUC exposure margin of 10-fold). Inan exploratory rabbit embryo-foetal range-finding study, a slight increase in the incidence of earlyresorption was observed at 150 mg/kg/day (AUC exposure margin of 5.6-fold). Foetal visceralchanges were observed at 150 mg/kg/day (AUC exposure margin of 5.6-fold).
In a pre-/postnatal developmental toxicity study investigating the effects of orally administeredrilzabrutinib, the maternal (F0) systemic toxicity NOAEL was considered to be 50 mg/kg/day (HED8.1 mg/kg/day). The NOAEL for F1 neonatal/developmental toxicity was considered to be 150mg/kg/day (HED 24.2 mg/kg/day) and the NOAELs for F1 parental system toxicity, F1 reproductivetoxicity, and F2 embryonic toxicity were considered to be 300 mg/kg/day (HED 48 mg/kg/day).
Other Toxicity Studies
Rilzabrutinib did not show any phototoxicity potential in the in vitro 3T3 neutral red uptakephototoxicity test.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline cellulose (E 460(i))
Crospovidone (Type A) (E 1202)
Sodium stearyl fumarate
Film coatingPolyvinyl alcohol (E 1203)
Macrogol (E 1521)
Titanium dioxide (E 171)
Talc (E 553b)
Sunset Yellow FCF (E 110)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years.
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
White, opaque polyvinyl chloride (PVC)/polychlorotrifluoroethylene (PCTFE)-aluminium blister packin a cardboard wallet with sun/moon symbols containing 28 film-coated tablets.
Pack sizes:Each blister wallet contains 28 film-coated tablets.
Each pack contains:
* 28 film-coated tablets
* 56 film-coated tablets (2 blister wallets of 28)
* 196 film-coated tablets (7 blister wallets of 28).
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with localrequirements. No special requirements for disposal.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu