FRUZAQLA 5mg capsules medication leaflet

FRUZAQLA 1 mg hard capsules

FRUZAQLA 5 mg hard capsules

FRUZAQLA 1 mg hard capsules

Each hard capsule contains 1 mg fruquintinib.

Each 1 mg hard capsule contains 0.0247 mg of tartrazine (E102) and 0.0004 mg of sunset yellow FCF(E110) colourants.

FRUZAQLA 5 mg hard capsules

Each hard capsule contains 5 mg fruquintinib.

Each 5 mg hard capsule contains 0.1829 mg of Allura red AC (E129) colourant.

For the full list of excipients, see section 6.1.

Hard capsule.

FRUZAQLA 1 mg hard capsules

Opaque hard gelatin capsule, size 3 (approximate length 16 mm), with a yellow cap and a white bodyimprinted with “HM013” over “1mg” in black ink.

FRUZAQLA 5 mg hard capsules

Opaque hard gelatin capsule, size 1 (approximate length 19 mm), with a red cap and a white bodyimprinted with “HM013” over “5mg” in black ink.

FRUZAQLA as monotherapy is indicated for the treatment of adult patients with metastatic colorectalcancer (mCRC) who have been previously treated with available standard therapies, includingfluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-VEGF agents, andanti-EGFR agents, and who have progressed on or are intolerant to treatment with eithertrifluridine-tipiracil or regorafenib.

FRUZAQLA should be initiated by a physician experienced in the administration of anticancertherapy.

The recommended dose of fruquintinib is 5 mg (one 5 mg capsule) once daily at approximately thesame time each day for 21 consecutive days, followed by a 7-day rest period to comprise a completecycle of 28 days.

Treatment with fruquintinib should be continued until disease progression or unacceptable toxicityoccurs.

If a dose is missed by less than 12 hours, it should be taken, and the next dose should be taken asscheduled.

If a dose is missed by more than 12 hours, it should be skipped, and the next dose should be taken asscheduled.

If a patient vomits after taking a dose, the patient should not repeat the dose on the same day butresume the usual dosing as prescribed on the following day.

Dose adjustments for adverse reactions

The dose should be modified based on safety and tolerability. Fruquintinib should be permanentlydiscontinued in patients unable to tolerate a dose of 3 mg once daily. The recommended dosereduction schedule for adverse reactions is provided in Table 1.

Table 1: Recommended FRUZAQLA dose reduction schedule

Dose reduction schedule Dose and schedule Number and strength of capsules

First dose reduction 4 mg once daily Four 1 mg capsules once daily

Second dose reduction 3 mg once daily Three 1 mg capsules once daily

The recommended dose modifications for adverse reactions are provided in Table 2.

Table 2: Recommended dose modification for FRUZAQLA for adverse reactions

Adverse reaction Severity1 Dose modification

* Withhold if Grade 3 hypertension persistsdespite initiation or modification ofantihypertensive treatment.

* If hypertension recovers to Grade 1 orbaseline, resume at a reduced dose as per

Grade 3

Hypertension Table 1.

If the patient still experiences Grade 3hypertension after taking 3 mg daily, permanentlydiscontinue.

Grade 4 Permanently discontinue.

* Withhold until bleeding fully resolves orrecovers to Grade 1.

* Resume at a reduced dose as per Table 1.

Grade 2

Haemorrhagic events

If the patient still experiences Grade 2haemorrhagic events after taking 3 mg daily,permanently discontinue.

Grade ≥ 3 Permanently discontinue.

* Withhold until proteinuria fully resolves oris < 1 g/24 hours (Grade 1).

* Resume at a reduced dose as per Table 1.

Proteinuria ≥ 2 g/24 hours If the patient still experiences ≥ 2 g/24 hoursproteinuria after taking 3 mg daily, permanentlydiscontinue.

Permanently discontinue for nephrotic syndrome.

* Withhold until liver function testabnormality recovers to Grade 1 orbaseline.

Grade 2 or 3 liver

* Resume at a reduced dose as per Table 1.function testabnormalities

If the patient still experiences Grade 2 or Grade 3liver function test abnormalities after taking 3 mgdaily, permanently discontinue.

Grade ≥ 2 elevation Permanently discontinue.

Liver function test (> 3 x ULN) of eitherabnormalities alanineaminotransferase(ALT) or aspartateaminotransferase(AST) with concurrenttotal bilirubinelevation > 2 x ULNin the absence ofcholestasis; Grade 4liver function testabnormalities

* Administer supportive treatment.

* Withhold until PPES recovers to Grade 1

Grade 2 or baseline.

* Resume at the same dose level.

Palmar-plantar

* Administer supportive treatment.

erythrodysaesthesia

* Withhold until PPES recovers to Grade 1syndrome (PPES)or baseline.

Grade 3 * Resume at a reduced dose as per Table 1.

If the patient still experiences Grade 3 PPES aftertaking 3 mg daily, permanently discontinue.

* Withhold until the reaction recovers to

Other adverse Grade 1 or baseline.

Grade 3reactions * Resume at a reduced dose as per Table 1.

If the patient still experiences Grade 3 otheradverse reactions after taking 3 mg daily,permanently discontinue.

Discontinue.

Consider resuming at a reduced dose as per

Grade 4

Table 1 if the toxicity recovers to Grade 1 orbaseline and the potential benefit outweighs therisks.

1Graded per national cancer institute common terminology criteria for adverse events, version 5.0(NCI CTCAE v5).

No dose adjustment is required for patients with mild, moderate, or severe renal impairment (seesection 5.2).

No dose adjustment is required for patients with mild or moderate hepatic impairment (seesection 5.2).

FRUZAQLA is not recommended for use in patients with severe hepatic impairment as FRUZAQLAhas not been studied in this population.

No dose adjustment is required in patients aged 65 years or above.

There is no relevant use of FRUZAQLA in the paediatric population for the indication of metastaticcolorectal cancer.

FRUZAQLA is for oral use.

The capsules can be taken with or without food and should be swallowed whole.

The capsules should not be chewed, dissolved, or opened, as the potential effects of these alterationsare unknown.

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

Hypertension, including hypertensive crisis, has been reported in patients treated with fruquintinib (seesection 4.8). Pre-existing hypertension should be monitored and adequately controlled in accordancewith standard medical practices before starting fruquintinib treatment.

Hypertension should be medically managed with antihypertensive medicinal products and adjustmentof the fruquintinib dose, if necessary (see section 4.2). Fruquintinib should be permanentlydiscontinued for hypertension that cannot be controlled with antihypertensive therapy or in patientswith hypertensive crisis.

Haemorrhagic events

Haemorrhagic events have been reported in patients treated with fruquintinib, includinggastrointestinal (GI) tract events (see section 4.8). Serious and sometimes fatal bleeding events havebeen reported in patients after treatment with fruquintinib.

Haematologic and coagulation profiles should be monitored in accordance with standard medicalpractices in patients at risk for bleeding, including those treated with anticoagulants or otherconcomitant medicinal products that increase the risk of bleeding. In the event of severe bleedingrequiring immediate medical intervention, fruquintinib should be permanently discontinued (seesection 4.2).

Gastrointestinal perforation

GI perforation events, including fatal events, have been reported in patients treated with fruquintinib(see section 4.8).

Symptoms of GI perforation should be periodically monitored during treatment with fruquintinib.

Fruquintinib should be permanently discontinued in patients developing GI perforation.

Proteinuria

Proteinuria events have occurred in patients treated with fruquintinib.

Proteinuria should be monitored before initiation and during treatment with fruquintinib in accordancewith standard medical practices. If urine dipstick proteinuria ≥ 2 g/24 hours is detected, doseinterruptions, adjustments, or discontinuation may be necessary. Fruquintinib should be permanentlydiscontinued in patients developing nephrotic syndrome (see section 4.2).

PPES is the most frequently reported dermatological adverse reaction (see section 4.8).

If Grade ≥ 2 skin reactions are detected, dose interruptions, adjustments, or discontinuation may benecessary (see section 4.2).

Posterior reversible encephalopathy syndrome (PRES)

PRES has been reported in 1 patient (0.1%) treated with fruquintinib in clinical studies (see alsosection 4.8). PRES is a rare neurologic disorder that can present with headache, seizure, lethargy,confusion, altered mental function, blindness, and other visual or neurological disturbances, with orwithout associated hypertension. A diagnosis of PRES requires confirmation by brain imaging,preferably magnetic resonance imaging (MRI). In patients developing PRES, discontinuation offruquintinib, along with control of hypertension and supportive medical management of othersymptoms, are recommended.

Impaired wound healing

Impaired wound healing has been reported in 1 patient (0.1%) treated with fruquintinib in clinicalstudies.

Patients are recommended to withhold fruquintinib for at least 2 weeks prior to surgery. Fruquintinibshould not be resumed for at least 2 weeks after surgery, as clinically indicated when there is evidenceof adequate wound healing.

Arterial and venous thromboembolic events

It is recommended to avoid starting treatment with fruquintinib in patients with a history ofthromboembolic events (including deep vein thrombosis and pulmonary embolism) within the past6 months or if they have a history of stroke and/or transient ischemic attack within the last 12 months.

If arterial thrombosis is suspected, fruquintinib should be discontinued immediately.

Fruquintinib 1 mg capsules contain tartrazine (E102) and sunset yellow FCF (E110), which may causeallergic reactions.

Fruquintinib 5 mg capsules contain Allura red AC (E129), which may cause allergic reactions.

Effects of other medicinal products on the pharmacokinetics of fruquintinib

Co-administration of fruquintinib with rifampicin (a strong CYP3A inducer) 600 mg once dailydecreased fruquintinib AUCinf by 65% and decreased Cmax by 12%. The concomitant use offruquintinib with strong and moderate CYP3A inducers should be avoided.

Co-administration of fruquintinib with itraconazole (a strong CYP3A inhibitor) 200 mg twice dailydid not result in clinically meaningful changes in the area under the concentration-time curve (AUC)and Cmax of fruquintinib. No dose adjustment of fruquintinib is needed during concomitant use with

Gastric acid lowering agents

Co-administration of fruquintinib with rabeprazole (a proton pump inhibitor) 40 mg once daily did notresult in clinically meaningful changes in the AUC of fruquintinib. No dose adjustment of fruquintinibis needed during concomitant use with gastric acid lowering agents.

Effect of fruquintinib on the pharmacokinetics of other medicinal products

Medicinal products that are substrates of P-glycoprotein (P-gp)

Co-administration of a single dose of dabigatran etexilate 150 mg (a P-gp substrate) with a single doseof fruquintinib 5 mg decreased AUC of dabigatran by 9%. No dose adjustment is recommended for

P-gp substrates during concomitant use with fruquintinib.

Medicinal products that are substrates of breast cancer resistance protein (BCRP)

Co-administration of a single 10 mg dose of rosuvastatin (a BCRP substrate) with a single 5 mg doseof fruquintinib decreased AUC of rosuvastatin by 19%. No dose adjustment is recommended for

BCRP substrates during concomitant use with fruquintinib.

Women of childbearing potential should be advised to use highly effective contraception duringtreatment and for at least 2 weeks following the last dose of fruquintinib.

There are no clinical data available on the use of fruquintinib in pregnant women.

Based on its mechanism of action, fruquintinib has the potential to cause foetal harm. Animal studieshave shown reproductive toxicity, including foetal malformations (see section 5.3). FRUZAQLAshould not be used during pregnancy unless the clinical condition of the woman requires treatmentwith fruquintinib.

If fruquintinib is used during pregnancy or if the patient becomes pregnant while on treatment, thepatient must be informed of the potential hazard to the foetus.

The safe use of fruquintinib during breast-feeding has not been established. It is not known whetherfruquintinib or its metabolites are excreted in human milk. There are no animal data on the excretionof fruquintinib in animal milk. A risk to the breast-feeding newborns/infants cannot be excluded.

Breast-feeding should be discontinued during treatment and for 2 weeks after the last dose.

There are no data on the effects of fruquintinib on human fertility. Results from animal studiesindicate that fruquintinib may impair male and female fertility (see section 5.3).

Fruquintinib has minor influence on the ability to drive and use machines. Fatigue may occurfollowing administration of fruquintinib (see section 4.8).

The most common adverse reactions are hypertension (49.3%), anorexia (35.6%), proteinuria (35.5%),

PPES (34.6%), hypothyroidism (32.4%), dysphonia (28.6%), diarrhoea (26.3%), and asthenia (24.5%).

The most common adverse reactions of Grade ≥ 3 are hypertension (19.1%) and PPES (8.3%).

The most common serious adverse reactions are gastrointestinal haemorrhage (1.5%), pneumonia(1.5%), hypertension (1.5%), and gastrointestinal perforation (1.3%).

The frequency of treatment discontinuation due to adverse reactions is 7.6%. The most commonadverse reaction leading to treatment discontinuation is proteinuria (1.6%).

The frequency of dose reduction due to adverse reactions is 20.5%. The most common adversereactions leading to dose reduction are PPES (6.4%), hypertension (3.7%), and proteinuria (3.4%).

The frequencies of adverse reactions are based on pooled data from clinical studies with 911 patientswith previously treated mCRC. Patients were exposed to at least 1 dose (5 mg) of fruquintinibmonotherapy (5 mg once daily 3 weeks on/1 week off) during a median of 3.68 months.

Adverse reactions reported in clinical studies or from post-marketing use of fruquintinib are listed in

Table 3 by MedDRA system organ class and by frequency. Within each system organ class, theadverse reactions are ranked by frequency, with the most frequent reactions first. Frequencies aredefined 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 frequency not known (cannot be estimatedfrom available post-marketing data). Within each frequency grouping, adverse reactions are presentedin the order of decreasing seriousness.

Table 3: Adverse reactions reported in patients with mCRC treated with fruquintinib (N=911)

Adverse reactions

System organ class Frequency category

All grades

Infections and

Common Upper respiratory tract infection1infestations

Bacterial infections2

Blood and lymphatic

Very common Thrombocytopaenia3system disorders

Leukopenia4

Common

Neutropenia5

Very common Hypothyroidism6

Very common Anorexia7

Metabolism andnutrition disorders

Common Hypokalaemia

Nervous system Posterior reversible encephalopathy

Uncommondisorders syndrome*

Very common Hypertension8

Not known Aortic dissection†

Respiratory, thoracic Very common Dysphonia9and mediastinal

Epistaxisdisorders Common

Throat pain10

Very common

Stomatitis11

Gastrointestinal haemorrhage12

Gastrointestinal

Gastrointestinal perforation13disorders Common

Pancreatic enzymes increased14

Oral pain15

Uncommon Pancreatitis16

Aspartate aminotransferaseincreased

Hepatobiliary Very common

Total bilirubin increased17disorders

Alanine aminotransferase increased

Uncommon Cholecystitis18

Palmar-plantar erythrodysaesthesia

Very commonsyndrome

Skin andsubcutaneous tissue Common Rash19disorders

Musculoskeletal and

Musculoskeletal discomfort20connective tissue Very common

Arthralgiadisorders

Renal and urinary

Very common Proteinuria21disorders

Asthenia

General disorders Very common

Fatigueand administrative

Common Mucosal inflammationsite conditions

Uncommon Impaired wound healing*, 22

The safety data is based on all patients with mCRC who received at least 1 dose (5 mg) of fruquintinib monotherapy (5 mgonce daily 3 weeks on/1 week off) in the following pooled studies: 2012-013-00CH1; 2013-013-00CH1/FRESCO; 2019-013-

GLOB1/FRESCO-2 including the open-label Japanese safety lead-in cohort; 2009-013-00CH1; 2012 013-00CH3; 2015-013-00US1.

*Reported in clinical studies and in the post-marketing setting.†Reported in the post-marketing setting.

The following terms represent a group of related events that describe a medical condition rather than a single event:1Upper respiratory tract infection includes nasopharyngitis, pharyngitis, upper respiratory tract infection2Bacterial infections includes asymptomatic bacteriuria, bacterial infection, bacteriuria, cellulitis, clostridium difficile colitis,clostridium difficile infection, enterobacter sepsis, escherichia urinary tract infection, folliculitis, furuncle, paronychia,pharyngitis streptococcal, streptococcal bacteraemia, urinary tract infection bacterial, urinary tract infection staphylococcal3Thrombocytopaenia includes platelet count decreased, thrombocytopaenia4Leukopenia includes leukopenia, white blood cell count decreased5Neutropenia includes neutropenia, neutrophil count decreased6Hypothyroidism includes blood thyroid stimulating hormone increased, hypothyroidism7Anorexia includes appetite decreased, weight loss8Hypertension includes blood pressure diastolic increased, blood pressure increased, diastolic hypertension, hypertension,hypertensive crisis9Dysphonia includes aphonia, dysphonia10Throat pain includes laryngeal discomfort, laryngeal pain, oropharyngeal discomfort, oropharyngeal pain11Stomatitis includes aphthous ulcer, gingival ulceration, mouth ulceration, stomatitis, tongue ulceration12Gastrointestinal haemorrhage includes anal haemorrhage, anastomotic haemorrhage, gastric haemorrhage, gastrointestinalhaemorrhage, haematochezia, haemorrhoidal haemorrhage, intestinal haemorrhage, lower gastrointestinal haemorrhage,rectal haemorrhage, upper gastrointestinal haemorrhage13Gastrointestinal perforation includes gastric perforation, gastric ulcer perforation, gastrointestinal perforation, intestinalperforation, large intestine perforation, rectal perforation, small intestinal perforation14Pancreatic enzymes increased includes amylase increased, hyperamylasaemia, hyperlipasaemia, lipase increased15Oral pain includes gingival pain, oral pain, toothache16Pancreatitis includes pancreatitis, pancreatitis acute17Total bilirubin increased includes bilirubin conjugated increased, blood bilirubin increased, blood bilirubin unconjugatedincreased, hyperbilirubinaemia, jaundice, jaundice cholestatic18Cholecystitis includes cholecystitis, cholecystitis acute, cholecystitis infective19Rash includes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic20Musculoskeletal discomfort includes bone pain, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, neckpain, pain in extremity21Proteinuria includes albuminuria, protein urine present, proteinuria22Impaired wound healing includes impaired healing, wound dehiscence

Data for the following selected adverse reactions are based on patients who received at least 1 dose(5 mg) of fruquintinib (5 mg once daily 3 weeks on/1 week off) across three randomisedplacebo-controlled studies (2012-013-00CH1; 2013-013-00CH1/FRESCO; 2019-013-

GLOB1/FRESCO-2). The management guidelines for these adverse reactions are described insection 4.4.

Hypertension was reported in 47.4% of patients in the fruquintinib arm. Approximately half of theseevents occurred during the first 2 weeks after initiating treatment with fruquintinib. Grade ≥ 3hypertension events were reported in 18.4% of patients in the fruquintinib arm. Median time to onsetin fruquintinib-treated patients was 15 days (range: 1 day to 7.6 months). Three patients (0.4%) treatedwith fruquintinib experienced hypertensive crisis. The majority of the events recovered or resolvedfollowing dose interruption or reduction, which occurred in 3.1% and 3.7% of patients, respectively.

In 0.5% of patients, hypertension led to permanent treatment discontinuation.

Haemorrhagic events

Haemorrhagic events were reported in 26.5% of patients in the fruquintinib arm and 14.6% in theplacebo arm. Most haemorrhagic events in patients treated with fruquintinib were mild to moderate inseverity (incidence of Grade ≥ 3 haemorrhagic events was 2.0% in the fruquintinib arm). Median timeto onset in fruquintinib-treated patients was 23 days (range: 1 day to 9.8 months). Fatal haemorrhagicevents were reported in 0.5% of patients in the fruquintinib arm. The incidence of haemorrhagicevents leading to dose discontinuation was 1.2%. The most common haemorrhagic reactions weregastrointestinal haemorrhage (7%) and epistaxis (5.6%). The most frequently reported serioushaemorrhagic event was gastrointestinal haemorrhage, which was reported in 1.5% of patients in thefruquintinib arm compared with 0.5% in the placebo arm.

Gastrointestinal (GI) perforation

Events of gastrointestinal perforation were reported in 1.5% of patients in the fruquintinib arm. Fatal

GI perforation was reported in 0.1% of patients treated with fruquintinib. The most common GIperforation event was intestinal perforation (0.8%). The incidence of GI perforation events leading todose discontinuation was 1.0%.

Proteinuria

Proteinuria was reported in 32.9% of the patients in the fruquintinib arm. Most proteinuria events inpatients treated with fruquintinib were mild to moderate in severity (incidence of Grade ≥ 3 proteinuriaevents was 2.8% in the fruquintinib arm). Median time to onset in fruquintinib-treated patients was28 days (range: 6 days to 1.3 years). Most events recovered or resolved following dose interruption orreduction. In 1.8% of patients treated with fruquintinib, proteinuria led to permanent treatmentdiscontinuation.

Palmar-plantar erythrodysaesthesia syndrome was reported in 32.7% of patients in the fruquintinibarm. The incidence of Grade ≥ 3 PPES in the fruquintinib arm was 8.5%. The median time to onset infruquintinib-treated patients was 20 days (range: 1 day to 7.4 months). The majority of the eventsrecovered or resolved following dose interruption or reduction, which occurred 6.4% and 6.3%,respectively. In 0.5% of patients treated for PPES led to permanent treatment discontinuation.

Posterior reversible encephalopathy syndrome (PRES)

One case (0.1%) of PRES (Grade 4) was reported in patients who received fruquintinib monotherapyin clinical studies. PRES has also been reported in post-marketing experience. All the events of PRESresolved after treatment and dose discontinuation.

Hypothyroidism was reported in 31.5% of the patients in the fruquintinib arm. The incidence of

Grade ≥ 3 thyroid dysfunction in the fruquintinib arm was low (0.3%). Median time to onset infruquintinib-treated patients was 56 days (range: 18 days to 1.4 years). No events led to dose reductionor discontinuation.

Infections were reported in 23.4% of the patients in the fruquintinib arm and 13.3% in the placeboarm. Most infection events in patients treated with fruquintinib were mild to moderate in severity(incidence of Grade ≥ 3 infections was 6% in the fruquintinib arm). Serious infections were reported in4.1% of patients and fatal infection events were reported in 1.0% of patients in the fruquintinib arm.

The incidence of infections leading to dose discontinuation was 0.9%. The most common infectionreaction was upper respiratory tract infection (5.0%). The most frequently reported serious infectionwas pneumonia (1.4%).

Liver function test abnormalities

Liver function test abnormalities were reported in 36.4% of the patients on the fruquintinib arm and23.5% in the placebo arm. Most hepatobiliary disorders in patients treated with fruquintinib were mildto moderate in severity (incidence of Grade ≥ 3 liver function test abnormalities was 8.8% in thefruquintinib arm). The most common liver function test abnormality events were AST increase(18.1%), total bilirubin increase (18.3%), and ALT increase (15.5%). Median time to onset infruquintinib-treated patients was 28 days (range: 4 days to 12 months). Serious liver function testabnormalities were reported in 2.3% of patients and fatal liver function test abnormalities werereported in 0.3% of patients in the fruquintinib arm. Liver function test abnormalities led to doseinterruption and reduction in 4.6% and 2.0% of patients, respectively, and to permanentdiscontinuation in 1.5% of patients.

Reporting 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.

The highest dose of fruquintinib studied in clinical studies was 6 mg per day.

The effects of fruquintinib overdose are unknown, and there is no known antidote for fruquintiniboverdose. In the event of an overdose, interrupt fruquintinib, general supportive measures should beundertaken and observe until clinical stabilisation.

Pharmacotherapeutic group: Antineoplastic agents, vascular endothelial growth factor receptor(VEGFR)-tyrosine kinase inhibitors, ATC code: L01EK04

Mechanism of action and pharmacodynamic effects

Fruquintinib is a selective tyrosine kinase inhibitor of VEGFR-1, -2, and -3 with antitumor effectsresulting from suppression of tumour angiogenesis.

No prolongation of heart rate-corrected QT (QTc) interval (> 10 milliseconds) was observed at therecommended dosage of fruquintinib. A concentration-QT analysis (N=205) showed no evidence of anassociation between fruquintinib plasma concentrations and changes in QTc interval from baseline.

The efficacy and safety of fruquintinib plus best supportive care (BSC) was evaluated in a randomised,placebo-controlled, double-blind, phase III study (FRESCO-2) in patients with mCRC previouslytreated with but not limited to oxaliplatin or irinotecan-based chemotherapies. The clinical efficacy offruquintinib in the FRESCO-2 study is described below.

FRESCO-2 Study

The clinical efficacy and safety of fruquintinib were evaluated in a global, randomised, double-blind,placebo-controlled, multicentre, phase III study (FRESCO-2) in 691 patients with mCRC who hadbeen previously treated with standard approved therapies including fluoropyrimidine-, oxaliplatin-,and irinotecan-based chemotherapy; an anti-VEGF biological therapy; an anti-EGFR therapy if RASwild-type, and have progressed on or had intolerance to trifluridine/tipiracil and/or regorafenib.

Patients were considered intolerant to trifluridine/tipiracil or regorafenib if they received at least1 dose of either agent and were discontinued from therapy for reasons other than progressive disease.

Patients with MSI-H or dMMR tumours were previously treated with immune checkpoint inhibitors,and patients with BRAF V600E mutant tumours were previously treated with a BRAF inhibitor, ifapproved and available in the patients’ respective country or region. Randomisation was stratified byprior therapy (trifluridine/tipiracil vs. regorafenib vs. both trifluridine/tipiracil and regorafenib), RASstatus (wild-type vs. mutant), and duration of metastatic disease (≤ 18 months vs. > 18 months).

Patients with an Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2, left ventricularfraction ≤ 50%, systolic blood pressure > 140 mm Hg or diastolic blood pressure > 90 mm Hg, urineprotein ≥ 1 g/24h, or body weight < 40 kg were excluded. The primary efficacy endpoint was overallsurvival (OS). The key secondary efficacy endpoint was progression-free survival (PFS; as assessedby the investigator using Response Evaluation Criteria in Solid Tumours [RECIST], version 1.1) andother supportive secondary endpoints included disease control rate.

In total, 691 patients were randomised (2:1) to receive fruquintinib 5 mg orally once daily (N=461)plus BSC or placebo orally once daily (N=230) plus BSC (hereafter denoted as fruquintinib andplacebo, respectively), for 21 days on therapy followed by 7 days off-therapy in a 28-day treatmentcycle.

Among the 691 randomised patients, the median age was 64 years (range: 25 to 86), with 47% ≥ 65years of age. 55.7% of patients were male, 80.9% were White, and had an ECOG performance statusof 0 (43.1%) or 1 (56.9%). Tumour RAS wild-type was reported in 36.9% of patients at study entry.

The median duration of metastatic disease of 39 months (range: 6 months to 16.1 years). The mediannumber of prior lines of therapy for metastatic disease was 4 (range: 2 to 16).

In addition to treatment with fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy, 96.4%of patients received prior anti-VEGF therapy, 38.8% received prior anti-EGFR therapy, 52.2 %received trifluridine/tipiracil, and 8.4% received regorafenib, and 39.4% received bothtrifluridine/tipiracil and regorafenib, pct. 4.6% received immunotherapy, and 2.3% received BRAFinhibitor.

In FRESCO-2, the addition of fruquintinib to BSC resulted in a statistically significant improvementin OS and PFS compared to placebo plus BSC (see Table 4 and Figure 1).

Table 4: Efficacy results from the FRESCO-2 study

Endpoint Fruquintinib Placebo(N=461) (N=230)

OS

Median in months (95% CI) 7.4 (6.7, 8.2) 4.8 (4.0, 5.8)

Hazard Ratio1 (95% CI) 0.66 (0.55, 0.80)p-value2 < 0.001

PFS3

Median in months (95% CI) 3.7 (3.5, 3.8) 1.8 (1.8, 1.9)

Hazard Ratio1 (95% CI) 0.32 (0.27 to 0.39)p-value2 < 0.001

Abbreviations: CI=confidence interval; HR=hazard ratio; N=number of patients; OS=overallsurvival; PFS=progression-free survival

The median OS and PFS were calculated using the Kaplan-Meier method.1The HR and its 95% CI were estimated using stratified Cox’s proportional hazards model(accounting for the stratification factors), in which the treatment arm is the only covariate in themodel.2p-value (2-sided) was calculated using the stratified log-rank test to account for the stratificationfactors.3Assessed by the investigator using RECIST, version 1.1.

Figure 1: Kaplan-Meier curve for overall survival in FRESCO-2 study

The European Medicines Agency has waived the obligation to submit the results of studies with

FRUZAQLA in all subsets of the paediatric population in metastatic colorectal cancer (see section 4.2for information on paediatric use).

After oral administration of fruquintinib, the median time to achieve peak plasma fruquintinibconcentration (Tmax) was approximately 2 hours. Fruquintinib showed a second absorption peakapproximately 24 hours after drug administration. Following repeat once-daily dosing, fruquintinibexposure (Cmax and AUC0-24h) increased in a dose-proportional manner across the dose range of 1 to6 mg (0.2 to 1.2 times the recommended dosage). Following administration of fruquintinib 5 mg oncedaily for 21 days with 7 days off of each 28-day cycle in patients with advanced solid tumours, steadystate of fruquintinib was achieved after 14 days, and the mean accumulation based on AUC0-24h was4-fold relative to a single dose. At the recommended dose of 5 mg of fruquintinib, the geometric mean(%CV) Cmax and AUC0-24h for fruquintinib at steady state were 300 ng/mL (28%) and 5880 ng*h/mL(29%), respectively.

Compared to the fasting state, a high-fat meal had no clinically meaningful effect on fruquintinibpharmacokinetics in healthy subjects. Fruquintinib can be administered with or without food.

The apparent volume of distribution of fruquintinib is approximately 48.5 L. Plasma protein binding offruquintinib is approximately 95% in vitro and mainly bound to human serum albumin.

Fruquintinib is metabolised by multiple enzymes, including CYP450 (CYP3A and CYP2Csubfamilies) and non-CYP450 enzyme systems. The in vivo metabolism and mass balance study of[14C] labelled fruquintinib showed that fruquintinib mainly exists in human plasma in its unchangedform, accounting for approximately 72% of total exposure in the plasma, and the CYP3A4-mediated

N-demethyl metabolite of fruquintinib account for approximately 17% of total exposure in plasma.

Other metabolic pathways include multi-site mono-oxidation, O-demethylation, N-demethylation,

O-dequinazoline ring, and amide hydrolysis. The phase II metabolites are mainly glucuronic acid andsulphuric acid conjugates of phase I products.

Cytochrome P450 enzymes

CYP3A4 was the main enzyme among the CYP isoforms involved in the metabolism of fruquintinib,with minor contributions from CYP2C8, CYP2C9 and CYP2C19. Fruquintinib is not an inhibitor of

CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A, or an inducer of CYP1A2,

CYP2B6, CYP3A at therapeutically relevant concentrations.

Transporter systems

Fruquintinib is not a substrate of P-glycoprotein (P-gp), organic anion transport protein (OATP)1B1,or OATP1B3. Fruquintinib inhibited P-glycoprotein (P-gp) and breast cancer resistance protein(BCRP) in a dose-dependent manner in vitro and demonstrated pH-dependent aqueous solubility.

Fruquintinib is not an inhibitor of OATP1B1, OATP1B3, organic anion transporter (OAT)1, OAT3,organic cation transporter (OCT)2, multidrug and toxin extrusion protein (MATE)1, or MATE2-K attherapeutically relevant concentrations.

The apparent clearance (CL/F) of fruquintinib is 14.8 mL/min at steady-state after once daily dosing inpatients with advanced solid tumours. The mean elimination half-life of fruquintinib is approximately42 hours.

Following administration of a single 5 mg radiolabelled fruquintinib in healthy subjects,approximately 60% of the dose was recovered in urine (0.5% of the dose as unchanged fruquintinib),and 30% of the dose was recovered in faeces (5% of the dose as unchanged fruquintinib).

Based on the population pharmacokinetic analyses, mild to moderate renal impairment (creatinineclearance [CrCL] 30 to 89 mL/min) had no clinically meaningful impact on fruquintinibpharmacokinetics. In a pharmacokinetic study, unbound fruquintinib AUC0-inf and Cmax were similar insubjects with moderate (CrCL 30 - 59 mL/min, N = 8) or severe (CrCL 15 - 29 mL/min, N = 8) renalimpairment as compared to subjects with normal renal function (CrCL ≥ 90 mL/min, N = 8).

No clinically meaningful differences in the pharmacokinetics of fruquintinib were observed betweenpatients with normal hepatic function and patients with mild (total bilirubin ≤ ULN with AST greaterthan ULN or total bilirubin > 1 to 1.5 times ULN with any AST) hepatic impairment based onpopulation pharmacokinetic analyses. Based on a dedicated hepatic impairment pharmacokineticstudy, following administration of a single 2 mg oral dose of fruquintinib, no clinically meaningfuldifferences in the dose-normalised AUC of fruquintinib were observed in subjects with moderate(Child Pugh B) hepatic impairment compared to subjects with normal hepatic function.

Age, body weight, gender or race

Population pharmacokinetic analyses showed that age (18 to 82 years), body weight (48 to 108 kg),gender or race had no clinically relevant impact on the pharmacokinetics of fruquintinib.

No pharmacokinetic studies were performed with fruquintinib in patients under 18 years of age.

In repeat dose and reproductive toxicity studies, toxicity was observed at fruquintinib average plasmaconcentrations below the expected human therapeutic concentrations.

In repeat dose animal toxicity studies, the main target organ effects were identified in thegastrointestinal tract, hepatobiliary system, immune system, skeletal system (femur and teeth),kidneys, hematopoietic system, and adrenal gland and appear related to the pharmacology of VEGFRinhibition and/or disruption of VEGF signalling pathway. All findings were reversible after 4 weekswithout treatment, apart from the skeletal system (broken/lost teeth).

In a fertility and early embryonic development study in rats, male and female reproductive indiceswere decreased at exposures approximately 3.2 and 0.8-fold the human AUC, respectively.

Dose-dependent increases in pre-implantation loss were observed in the same study.

In an embryo-foetal developmental study in rats, embryotoxic and teratogenic effects were observed atsubclinical exposure levels in the absence of excessive maternal toxicity, consisting of foetal external,visceral, and skeletal malformations. Malformations affected primarily the head, tail, tongue, bloodvessels, heart, thymus, and developing skeleton (notably vertebrae).

No evidence of genotoxicity was observed in in vitro and in vivo studies.

Carcinogenicity studies have not been performed with fruquintinib.

Maize starch

Cellulose, microcrystalline (E460)

Talc (E553b)

Capsule shell (1 mg hard capsules only)

Gelatin

Titanium dioxide (E171)

Tartrazine (E102)

Sunset yellow FCF (E110)

Capsule shell (5 mg hard capsules only)

Gelatin

Titanium dioxide (E171)

Allura red AC (E129)

Brilliant blue FCF (E133)

Shellac (E904)

Propylene glycol (E1520)

Potassium hydroxide

Iron oxide black (E172)

Not applicable.

2 years.

This medicinal product does not require any special temperature storage conditions.

Store in the original container in order to protect from moisture.

Keep the bottle tightly closed.

High-density polyethylene (HDPE) bottle (45 mL) with polypropylene (PP) child-resistant closure anda HDPE desiccant cartridge containing silica gel. The desiccant must be kept inside the bottle.

Each bottle contains 21 hard capsules. Each bottle is packaged in a carton.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Takeda Pharmaceuticals International AG Ireland Branch

Block 2 Miesian Plaza50-58 Baggot Street Lower

Dublin 2

D02 HW68

IrelandmedinfoEMEA@takeda.com

EU/1/24/1827/001

EU/1/24/1827/002

Date of first authorisation: 20 June 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.