FRUZAQLA Hard capsule Ref.[111509] Active ingredients: Fruquintinib

Hypertension

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

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

Haemorrhagic events

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

Haematologic and coagulation profiles should be monitored in accordance with standard medical practices in patients at risk for bleeding, including those treated with anticoagulants or other concomitant medicinal products that increase the risk of bleeding. In the event of severe bleeding requiring immediate medical intervention, fruquintinib should be permanently discontinued (see section 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 accordance with standard medical practices. If urine dipstick proteinuria ≥2 g/24 hours is detected, dose interruptions, adjustments, or discontinuation may be necessary. Fruquintinib should be permanently discontinued in patients developing nephrotic syndrome (see section 4.2).

Palmar-plantar erythrodysaesthesia syndrome (PPES)

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 be necessary (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 also section 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 or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). In patients developing PRES, discontinuation of fruquintinib, along with control of hypertension and supportive medical management of other symptoms, are recommended.

Impaired wound healing

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

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

Arterial and venous thromboembolic events

It is recommended to avoid starting treatment with fruquintinib in patients with a history of thromboembolic events (including deep vein thrombosis and pulmonary embolism) within the past 6 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.

Excipients

Fruquintinib 1 mg capsules contain tartrazine (E102) and sunset yellow FCF (E110), which may cause allergic 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

CYP3A inducers

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

CYP3A inhibitors

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

Gastric acid lowering agents

Co-administration of fruquintinib with rabeprazole (a proton pump inhibitor) 40 mg once daily did not result in clinically meaningful changes in the AUC of fruquintinib. No dose adjustment of fruquintinib is 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 dose of 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 dose of fruquintinib decreased AUC of rosuvastatin by 19%. No dose adjustment is recommended for BCRP substrates during concomitant use with fruquintinib.

Women of childbearing potential/Contraception in females

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

Pregnancy

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 studies have shown reproductive toxicity, including foetal malformations (see section 5.3). FRUZAQLA should not be used during pregnancy unless the clinical condition of the woman requires treatment with fruquintinib.

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

Breast-feeding

The safe use of fruquintinib during breast-feeding has not been established. It is not known whether fruquintinib or its metabolites are excreted in human milk. There are no animal data on the excretion of 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.

Fertility

There are no data on the effects of fruquintinib on human fertility. Results from animal studies indicate 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 occur following administration of fruquintinib (see section 4.8).

Summary of the safety profile

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 common adverse reaction leading to treatment discontinuation is proteinuria (1.6%).

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

Tabulated list of adverse reactions

The frequencies of adverse reactions are based on pooled data from clinical studies with 911 patients with previously treated mCRC. Patients were exposed to at least 1 dose (5 mg) of fruquintinib monotherapy (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, the adverse reactions are ranked by frequency, with the most frequent reactions first. 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 frequency not known (cannot be estimated from available post-marketing data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

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

The safety data is based on all patients with mCRC who received at least 1 dose (5 mg) of fruquintinib monotherapy (5 mg once 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:
¹ Upper respiratory tract infection includes nasopharyngitis, pharyngitis, upper respiratory tract infection
² Bacterial 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 staphylococcal
³ Thrombocytopaenia includes platelet count decreased, thrombocytopaenia
⁴ Leukopenia includes leukopenia, white blood cell count decreased
⁵ Neutropenia includes neutropenia, neutrophil count decreased
⁶ Hypothyroidism includes blood thyroid stimulating hormone increased, hypothyroidism
⁷ Anorexia includes appetite decreased, weight loss
⁸ Hypertension includes blood pressure diastolic increased, blood pressure increased, diastolic hypertension, hypertension, hypertensive crisis
⁹ Dysphonia includes aphonia, dysphonia
¹⁰ Throat pain includes laryngeal discomfort, laryngeal pain, oropharyngeal discomfort, oropharyngeal pain
¹¹ Stomatitis includes aphthous ulcer, gingival ulceration, mouth ulceration, stomatitis, tongue ulceration
¹² Gastrointestinal haemorrhage includes anal haemorrhage, anastomotic haemorrhage, gastric haemorrhage, gastrointestinal haemorrhage, haematochezia, haemorrhoidal haemorrhage, intestinal haemorrhage, lower gastrointestinal haemorrhage, rectal haemorrhage, upper gastrointestinal haemorrhage
¹³ Gastrointestinal perforation includes gastric perforation, gastric ulcer perforation, gastrointestinal perforation, intestinal perforation, large intestine perforation, rectal perforation, small intestinal perforation
¹⁴ Pancreatic enzymes increased includes amylase increased, hyperamylasaemia, hyperlipasaemia, lipase increased
¹⁵ Oral pain includes gingival pain, oral pain, toothache
¹⁶ Pancreatitis includes pancreatitis, pancreatitis acute
¹⁷ Total bilirubin increased includes bilirubin conjugated increased, blood bilirubin increased, blood bilirubin unconjugated increased, hyperbilirubinaemia, jaundice, jaundice cholestatic
¹⁸ Cholecystitis includes cholecystitis, cholecystitis acute, cholecystitis infective
¹⁹ Rash includes rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic
²⁰ Musculoskeletal discomfort includes bone pain, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, neck pain, pain in extremity
²¹ Proteinuria includes albuminuria, protein urine present, proteinuria
²² Impaired wound healing includes impaired healing, wound dehiscence

Description of selected adverse reactions

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 randomised placebo-controlled studies (2012-013-00CH1; 2013-013-00CH1/FRESCO; 2019-013- GLOB1/FRESCO-2). The management guidelines for these adverse reactions are described in section 4.4.

Hypertension

Hypertension was reported in 47.4% of patients in the fruquintinib arm. Approximately half of these events occurred during the first 2 weeks after initiating treatment with fruquintinib. Grade ≥ 3 hypertension events were reported in 18.4% of patients in the fruquintinib arm. Median time to onset in fruquintinib-treated patients was 15 days (range: 1 day to 7.6 months). Three patients (0.4%) treated with fruquintinib experienced hypertensive crisis. The majority of the events recovered or resolved following 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 the placebo arm. Most haemorrhagic events in patients treated with fruquintinib were mild to moderate in severity (incidence of Grade ≥ 3 haemorrhagic events was 2.0% in the fruquintinib arm). Median time to onset in fruquintinib-treated patients was 23 days (range: 1 day to 9.8 months). Fatal haemorrhagic events were reported in 0.5% of patients in the fruquintinib arm. The incidence of haemorrhagic events leading to dose discontinuation was 1.2%. The most common haemorrhagic reactions were gastrointestinal haemorrhage (7%) and epistaxis (5.6%). The most frequently reported serious haemorrhagic event was gastrointestinal haemorrhage, which was reported in 1.5% of patients in the fruquintinib 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 GI perforation event was intestinal perforation (0.8%). The incidence of GI perforation events leading to dose discontinuation was 1.0%.

Proteinuria

Proteinuria was reported in 32.9% of the patients in the fruquintinib arm. Most proteinuria events in patients treated with fruquintinib were mild to moderate in severity (incidence of Grade ≥ 3 proteinuria events was 2.8% in the fruquintinib arm). Median time to onset in fruquintinib-treated patients was 28 days (range: 6 days to 1.3 years). Most events recovered or resolved following dose interruption or reduction. In 1.8% of patients treated with fruquintinib, proteinuria led to permanent treatment discontinuation.

Palmar-plantar erythrodysaesthesia syndrome (PPES)

Palmar-plantar erythrodysaesthesia syndrome was reported in 32.7% of patients in the fruquintinib arm. The incidence of Grade ≥ 3 PPES in the fruquintinib arm was 8.5%. The median time to onset in fruquintinib-treated patients was 20 days (range: 1 day to 7.4 months). The majority of the events recovered 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 monotherapy in clinical studies. PRES has also been reported in post-marketing experience. All the events of PRES resolved after treatment and dose discontinuation.

Hypothyroidism

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 in fruquintinib-treated patients was 56 days (range: 18 days to 1.4 years). No events led to dose reduction or discontinuation.

Infections

Infections were reported in 23.4% of the patients in the fruquintinib arm and 13.3% in the placebo arm. 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 in 4.1% 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 infection reaction was upper respiratory tract infection (5.0%). The most frequently reported serious infection was pneumonia (1.4%).

Liver function test abnormalities

Liver function test abnormalities were reported in 36.4% of the patients on the fruquintinib arm and 23.5% in the placebo arm. Most hepatobiliary disorders in patients treated with fruquintinib were mild to moderate in severity (incidence of Grade ≥ 3 liver function test abnormalities was 8.8% in the fruquintinib 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 in fruquintinib-treated patients was 28 days (range: 4 days to 12 months). Serious liver function test abnormalities were reported in 2.3% of patients and fatal liver function test abnormalities were reported in 0.3% of patients in the fruquintinib arm. Liver function test abnormalities led to dose interruption and reduction in 4.6% and 2.0% of patients, respectively, and to permanent discontinuation in 1.5% of patients.

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.