Truseltiq Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

RECENT MAJOR LABEL CHANGES............................................................................................ 2

PART I: HEALTH PROFESSIONAL INFORMATION ..................................................................... 4

1 INDICATIONS .............................................................................................................. 4

1.1 Pediatrics .......................................................................................................... 4

1.2 Geriatrics........................................................................................................... 4

2 CONTRAINDICATIONS ................................................................................................. 4

4 DOSAGE AND ADMINISTRATION................................................................................. 4

4.1 Dosing Considerations ....................................................................................... 4

4.2 Recommended Dose and Dosage Adjustment..................................................... 5

4.4 Administration................................................................................................... 7

4.5 Missed Dose ...................................................................................................... 7

5 OVERDOSAGE ............................................................................................................. 7

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 7

7 WARNINGS AND PRECAUTIONS .................................................................................. 8

7.1 Special Populations .......................................................................................... 11

7.1.1 Pregnant Women ....................................................................................... 11

7.1.2 Breast-feeding............................................................................................ 11

7.1.3 Pediatrics ................................................................................................... 11

7.1.4 Geriatrics ................................................................................................... 11

8 ADVERSE REACTIONS ................................................................................................ 11

8.1 Adverse Reaction Overview.............................................................................. 11

8.2 Clinical Trial Adverse Reactions ........................................................................ 12

8.2.1 Clinical Trial Adverse Reactions – Pediatrics ................................................ 14

8.3 Less Common Clinical Trial Adverse Reactions .................................................. 14

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics .......................... 15

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data ...................................................................................................... 15

9 DRUG INTERACTIONS................................................................................................ 16

9.2 Drug Interactions Overview.............................................................................. 16

9.4 Drug-Drug Interactions .................................................................................... 16

9.5 Drug-Food Interactions .................................................................................... 18

9.6 Drug-Herb Interactions .................................................................................... 18

9.7 Drug-Laboratory Test Interactions .................................................................... 18

10 CLINICAL PHARMACOLOGY ....................................................................................... 18

10.1 Mechanism of Action.................................................................................. 18

10.2 Pharmacodynamics .................................................................................... 19

10.3 Pharmacokinetics ....................................................................................... 19

11 STORAGE, STABILITY AND DISPOSAL ......................................................................... 21

12 SPECIAL HANDLING INSTRUCTIONS........................................................................... 21

PART II: SCIENTIFIC INFORMATION ...................................................................................... 21

13 PHARMACEUTICAL INFORMATION............................................................................ 21

14 CLINICAL TRIALS........................................................................................................ 22

14.1 Trial Design and Study Demographics ......................................................... 22

14.2 Study Results ............................................................................................. 23

15 MICROBIOLOGY ........................................................................................................ 23

16 NON-CLINICAL TOXICOLOGY ..................................................................................... 23

PATIENT MEDICATION INFORMATION ................................................................................. 25

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PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

TRUSELTIQ™ (infigratinib) is indicated for:

the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement.

Prior to initiation of TRUSELTIQ™ therapy, FGFR2 fusion or rearrangement should be established using a validated test.

Clinical effectiveness of TRUSELTIQ™ is based on overall response rate (ORR) and duration of response (DoR) from a single-arm Phase 2 trial in patients with specific FGFR2 rearrangements (see 14 CLINICAL TRIALS).

1.1 Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (>65 years of age): Of the 351 patients treated with TRUSELTIQ™ in clinical studies, 33% were 65 years or older and 10% were 75 years or older. No overall differences in safety and efficacy were observed between these patients and younger patients.

2 CONTRAINDICATIONS

• Infigratinib is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• A validated assay is required for the selection of patients with an FGFR2 fusion or other rearrangement.
• Avoid concomitant use with strong or moderate CYP3A4 inhibitors [see 9 DRUG INTERACTIONS].
• Avoid concomitant use with strong or moderate CYP3A4 inducers [see 9 DRUG INTERACTIONS].
• Avoid administration of proton pump inhibitors, H2-antagonists, and locally-acting antacids with TRUSELTIQ™. If coadministration of gastric acid reducing agents cannot be avoided, use an H2-receptor antagonist or locally- acting antacid and stagger administration of TRUSELTIQ™. TRUSELTIQ™ should be taken ≥2 hours before or 10 hours after administration of H2-antagonists. Locally-acting antacids should be taken at least 2 hours before or after TRUSELTIQ™ dosing. see 9 DRUG INTERACTIONS.

• TRUSELTIQ™ dose adjustment is required in patients with mild or moderate hepatic impairment

  • and in patients with mild or moderate renal impairment. (see 4 DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, special populations).

4.2 Recommended Dose and Dosage Adjustment

Recommended Dose

The recommended dose of TRUSELTIQ™ is 125 mg (one 100 mg capsule and one 25 mg capsule) orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles. Continue treatment until disease progression or unacceptable toxicity.

Dosage Adjustment

The recommended dose reductions for adverse reactions are listed in Table 1.

Table 1: Recommended Dose Reduction for TRUSELTIQ™ for Adverse Reactions

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

Table 2: Recommended Dosage Modifications for TRUSELTIQ™ Adverse Reactions

^a Severity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 4.03).

Educational material to assist healthcare professionals with the diagnosis and management of retinal pigment epithelial detachment is available through the manufacturer.

Special Populations

Pediatrics (<18 years old): Health Canada has not authorized an indication for pediatric use.

Geriatrics (≥65 years old): No dose adjustment is required in patients ≥65 years of age [see 10 CLINICAL PHARMACOLOGY, Special Populations and Conditions].

Renal Impairment: The recommended dose of TRUSELTIQ™ for patients with mild to moderate renal impairment (creatinine clearance 30 to 89 mL/min, estimated by Cockcroft-Gault) is 100 mg once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles [see 10 CLINICAL PHARMACOLOGY, Special Populations and Conditions].

TRUSELTIQ™ has not been studied in patients with severe (CrCl < 30 mL/min) renal impairment.

Hepatic Impairment: For patients with mild (total bilirubin > upper limit of normal [ULN] to 1.5 × ULN or AST > ULN) or moderate (total bilirubin >1.5 to 3 × ULN with any AST) hepatic impairment , reduce the recommended dose as follow:

• Mild Hepatic Impairment: 100 mg once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles.
• Moderate Hepatic Impairment: 75 mg once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles.

[see 10 CLINICAL PHARMACOLOGY, Special Populations and Conditions].

TRUSELTIQ™ has not been studied in patients with severe hepatic impairment per NCI-ODWG criteria (total bilirubin > 3 x ULN with any AST).

4.4 Administration

The recommended dose of TRUSELTIQ™ is 125 mg (one 100 mg capsule and one 25 mg capsule) orally once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles. Continue treatment until disease progression or unacceptable toxicity.

Capsules should be taken on an empty stomach at least 1 hour before or 2 hours after food, at approximately the same time each day. Swallow capsules whole with a large glass of water. Do not open, crush, chew, or dissolve capsules.

4.5 Missed Dose

If a dose of TRUSELTIQ™ is missed by ≥4 hours or if vomiting occurs, resume the regular daily dose schedule for TRUSELTIQ™ the next day.

5 OVERDOSAGE

There is no experience with overdose in clinical trials with TRUSELTIQ™. There is no known specific antidote for TRUSELTIQ™ overdose. In the event of suspected overdose, interrupt TRUSELTIQ™, undertake general supportive measures, and observe until clinical stabilization.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 3: Dosage Forms, Strengths, Composition and Packaging

• TRUSELTIQ™ (infigratinib) hard gelatin capsules are supplied as 25 mg, white opaque body with gray opaque cap imprinted with “INFI 25mg” on the body.

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• TRUSELTIQ™ (infigratinib) hard gelatin capsules are supplied as 100 mg, white opaque body with light orange opaque cap imprinted with “INFI 100mg” on the body.

Packaging: TRUSELTIQ™ capsules are supplied in 21-day dose pack configurations as follows:

• Blister pack for 125 mg daily dose (Contains 21 doses of 100 mg and 25 mg capsules. Dosage equal to 125 mg per day).
• Blister pack for 100 mg daily dose (Contains 21 doses of 100 mg capsules).
• Blister pack for 75 mg daily dose (Contains 21 doses of three 25 mg capsules. Dosage equal to 75 mg per day).
• Blister pack for 50 mg daily dose (Contains 21 doses of two 25 mg capsules. Dosage equal to 50 mg per day).

7 WARNINGS AND PRECAUTIONS

General

Before taking TRUSELTIQ™, patients must have confirmation of FGFR gene fusion or rearrangement by a validated test. Patients enrolled in Study CBGJ398X2204 were required to have confirmation of an FGFR2 fusion (n=88) or other rearrangement (n=20) in tumor tissues.

Table 4: FGFR2 fusions and rearrangements in patients treated with infigratinib (identified in ≥ 2 Participants)

*No partner gene identified

** This table represents FGFR2 fusions and rearrangements that were identified in ≥ 2 participants in Study CBGJ398X2204

Driving and Operating Machinery

No studies to establish the effects of TRUSELTIQ™ on the ability to drive and use machines have been conducted. However, eye disorders such as central serous retinopathy have been noted with FGFR inhibitors and with TRUSELTIQ™ treatment. If patients experience symptoms affecting their vision, it is recommended that they do not drive or use machines until the effect subsides.

Monitoring and Laboratory Tests

Serum Phosphate

Monitor for hyperphosphatemia 7-14 days after initiating TRUSELTIQ™ treatment, after the first cycle, and continue to monitor monthly thereafter. For elevated phosphate concentrations, follow dose modification guidelines in Table 2. (see 4 DOSAGE AND ADMINISTRATION, Dose Adjustment)

Ocular Testing

Perform a comprehensive ophthalmic examination including optical coherence tomography (OCT) prior to initiation of TRUSELTIQ™, at 1 month, at 3 months, and then every 3 months thereafter during treatment. Refer patients for ophthalmic evaluation urgently for onset of visual symptoms, and follow-up every 3 weeks until resolution or discontinuation of TRUSELTIQ™.

Endocrine and Metabolism

Hyperphosphatemia and Soft Tissue Mineralization

TRUSELTIQ™ can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcinosis, nonuremic calciphylaxis, vascular calcification, and myocardial calcification. Increases in phosphate levels are a pharmacodynamic effect of TRUSELTIQ™ [see 10.2 Pharmacodynamics]. Among 351 patients who received TRUSELTIQ™ across clinical trials, hyperphosphatemia was reported in 82% of patients based on laboratory values above the upper limit of normal. The median time to onset of reported hyperphosphatemia event was 8 days (range 1 to 349). Phosphate-lowering therapy was received by 83% of patients who received TRUSELTIQ™.

Among 108 patients who received TRUSELTIQ™ in CBGJ398X2204, hyperphosphatemia was reported in 89% of patients based on laboratory values above the upper limit of normal with ≥Grade 3 reactions in 13% of patients. Dose interruption occurred in 25% and none led to dose discontinuation.

Monitor for hyperphosphatemia throughout treatment. Initiate phosphate lowering therapy when serum phosphate level is >5.5 mg/dL. For serum phosphate level >7.5 mg/dL, withhold TRUSELTIQ™ and initiate phosphate lowering therapy. Withhold, dose reduce, or permanently discontinue TRUSELTIQ™ based on duration and severity of hyperphosphatemia. [see 4.2 DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment].

Hypophosphatemia

Severe hypophosphatemia may present with confusion, seizures, focal neurologic findings, heart failure, respiratory failure, muscle weakness, rhabdomyolysis, and hemolytic anemia. Among 351 patients who received TRUSELTIQ™ across clinical trials, hypophosphatemia was reported in 48 % of patients based on laboratory values below the lower limit of normal. The median time to onset of reported hypophosphatemia event was 85 days (range 1 to 610).

Among 108 patients who received TRUSELTIQ in CBGJ398X2204, hypophosphatemia was reported in 63% of patients based on laboratory values below the lower limit. Hypophosphatemia was the second most commonly reported ≥Grade 3 TEAE at 13% with SAEs occurring in 2% subjects. Dose interruption occurred in 4% and none led to dose discontinuation. Most of the reported events of hypophosphatemia recovered.

Most cases of hypophosphatemia occurred following the phosphate binder treatment (i.e., was due to unintended overcorrection of hyperphosphatemia). Monitor for hypophosphatemia throughout the treatment.

Ophthalmologic

Retinal Pigment Epithelial Detachment (RPED)

TRUSELTIQ™ can cause RPED, which may cause symptoms such as blurred vision.

Among 351 patients who received TRUSELTIQ™ across clinical trials, RPED occurred in 11% of patients, including patients with asymptomatic RPED. The median time to first onset of RPED was 26 days.

Among the 108 patients with cholangiocarcinoma enrolled in CBGJ398X2204, RPED was reported in 17% of patients. RPED led to dose interruption/reduction of infigratinib in 3.4% of patients and permanent discontinuation in 0.6% of patients.

Perform a comprehensive ophthalmic examination including optical coherence tomography (OCT) prior to initiation of TRUSELTIQ™, at 1 month, at 3 months, and then every 3 months thereafter during treatment. Refer patients for ophthalmic evaluation urgently for onset of visual symptoms, and follow-up every 3 weeks until resolution or discontinuation of TRUSELTIQ™.

Withhold TRUSELTIQ™ as recommended. Educational materials to assist healthcare professionals with the diagnosis and management of serous retinal detachment are available through the manufacturer.

See 4.2 DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment.

Dry Eye

Among 351 patients who received TRUSELTIQ™ across clinical trials, dry eye occurred in 29% of patients. Treat patients with ocular demulcents as needed.

Reproductive Health: Female and Male Potential

• Fertility

  No human data on the effect of TRUSELTIQ™ on fertility are available.

• Teratogenic Risk

  Based on findings in animal studies and its mechanism of action, TRUSELTIQ™ may cause fetal harm when administered to a pregnant woman. Oral administration of infigratinib to pregnant rats and rabbits during the period of organogenesis caused malformations, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure based on area under the curve (AUC) at the clinical dose of 125 mg.

  Advise women of reproductive potential to use effective contraception during treatment with TRUSELTIQ™ and for 1 month after the last dose. Advise men who are partnered with women of reproductive potential to use effective contraception during treatment with TRUSELTIQ™ and for

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1 month after the last dose. [see 7.1 WARNINGS AND PRECAUTIONS, Special Populations and 16 NON-CLINICAL TOXICOLOGY].

7.1 Special Populations

7.1.1 Pregnant Women

There are no available data on TRUSELTIQ™ use in pregnant women to inform a drug-associated risk.

Based on the mechanism of action and findings in animal reproduction studies, TRUSELTIQ™ can cause embryo-fetal harm or loss of pregnancy when administered to a pregnant woman [see 16 NON-CLINICAL TOXICOLOGY].

Verify pregnancy status in females of reproductive potential prior to initiating TRUSELTIQ™. TRUSELTIQ™ should not be used during pregnancy. If TRUSELTIQ™ is used during pregnancy, or if the patient becomes pregnant while taking TRUSELTIQ™, advise the patient of the potential hazard to the fetus and counsel the patient about her clinical and therapeutic options.

7.1.2 Breast-feeding

There are no data on the presence of infigratinib or its metabolites in human milk, or their effects on either the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children from TRUSELTIQ™, advise women not to breastfeed during treatment and for 1 month after the last dose.

7.1.3 Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

Of the 351 patients treated with TRUSELTIQ™ in clinical studies, 33% were 65 years or older, and 10% were 75 years or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Based on the safety database of 108 patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement, the most common adverse reactions (≥20%) in patients receiving TRUSELTIQ™ included hyperphosphatemia, nail toxicity, stomatitis, dry eye, fatigue, alopecia, palmar-plantar erythrodyesthesia syndrome, arthralgia, dysgeusia, constipation, abdominal pain, dry mouth, eyelash changes, diarrhea, dry skin, decreased appetite, vision blurred and vomiting.

Serious adverse reactions occurred in 32% of patients receiving TRUSELTIQ™. Serious adverse reactions in ≥2% of patients who received TRUSELTIQ™ included infection, anemia, pyrexia, hypercalcemia, and sepsis. Fatal adverse reactions occurred in 0.9% of patients and included sepsis.

The following adverse reactions are discussed elsewhere in the labeling:

• Hyperphosphatemia and Soft Tissue Mineralization [see 7 WARNINGS AND PRECAUTIONS]; and
• Ocular Toxicity [see 7 WARNINGS AND PRECAUTIONS].

Permanent discontinuation due to an adverse reaction occurred in 15% of patients who received TRUSELTIQ™. Adverse reactions requiring permanent discontinuation in 2% of patients were blood creatinine increased, fatigue, and subretinal fluid and calcinosis.

Dosage reductions due to an adverse reaction occurred in 60% of patients who received TRUSELTIQ™. Adverse reactions requiring dosage reductions in ≥2% of patients who received TRUSELTIQ™ included hyperphosphatemia (26%), stomatitis (12%), palmar-plantar erythrodysesthesia syndrome (8%), increased blood creatinine (4%), increased lipase (4%), hypercalcemia (3%), and onycholysis (3%).

Dosage interruptions due to an adverse reaction occurred in 64% of patients who received TRUSELTIQ™. Adverse reactions requiring dosage interruption in ≥5% of patients included hyperphosphatemia , hypercalcemia , palmar-plantar erythrodysesthesia syndrome , stomatitis , and diarrhea and blood creatinine increased.

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials, therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

The safety of TRUSELTIQ™ was evaluated in Study CBGJ398X2204, which included 108 patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement.

Patients were treated orally with TRUSELTIQ™ 125 mg once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles, until disease progression or unacceptable toxicity. The median duration of treatment was 5.52 months (range: 0.03 to 28.29 months).

Table 5 summarizes the adverse reactions in study CBGJ398X2204.

Table 5: Adverse Reactions (≥15%) in Patients Receiving TRUSELTIQ™ in Study CBGJ398X2204

8.2.1 Clinical Trial Adverse Reactions – Pediatrics

Not applicable.

8.3 Less Common Clinical Trial Adverse Reactions

The following are the less common clinical trial reactions occurring in <15% and >5% of patients receiving TRUSELTIQ™ in Study CBGJ398X2204:

Blood and lymphatic system disorders: lymphopenia, neutropenia, thrombocytopenia

Eye disorders: cataract, chorioretinopathy, subretinal fluid

Gastrointestinal disorders: abdominal pain upper, dysphagia, gastroesophageal reflux disease, oral pain

General disorders and administration site conditions: chills, non-cardiac chest pain,

Infections and Infestations: urinary tract infection

Investigations: alanine aminotransferase increased, blood alkaline phosphatase increased, weight decreased, lipase increased, blood bilirubin increased, amylase increased

Metabolism and nutrition disorders: dehydration, hyperkalemia, hypertriglyceridemia, hyperuricemia, hypokalemia, hypomagnesemia, hyponatremia

Musculoskeletal and connective tissue disorders: back pain, flank pain, muscular weakness, myalgia

Nervous system disorders: dizziness, peripheral sensory neuropathy

Psychiatric Disorders: insomnia

Respiratory, thoracic and mediastinal disorders: cough, dyspnea, oropharyngeal pain

Skin and subcutaneous tissue disorders: pruritus, rash, rash maculo-papular

8.3.1 Less Common Clinical Trial Adverse Reactions – Pediatrics

Not applicable.

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Clinical Trial Findings

Table 6: Select Laboratory Abnormalities Worsening from Baseline Reported in ≥15% of Patients in Study CBGJ398X2204

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

CYP3A4 Inhibitors

Concomitant use of a strong or moderate CYP3A4 inhibitor with TRUSELTIQ™ may increase infigratinib plasma concentrations, which may increase the incidence and severity of adverse reactions. Avoid concomitant use of strong or moderate CYP3A4 inhibitors with TRUSELTIQ™.

CYP3A4 Inducers

Concomitant use of TRUSELTIQ™ with a strong or moderate CYP3A4 inducer may decrease infigratinib plasma concentrations, which may reduce the efficacy of TRUSELTIQ™. Avoid concomitant use of strong or moderate CYP3A4 inducers with TRUSELTIQ™.

Gastric Acid Reducing Agents

The coadministration of TRUSELTIQ™ with a gastric acid reducing agent may decrease the concentration of infigratinib, which may reduce the efficacy of TRUSELTIQ™.

Proton pump inhibitors, histamine-2 (H2) receptor antagonists, and locally-acting antacids should be avoided. If coadministration of gastric acid reducing agents cannot be avoided, use an H2-antagonist or locally-acting antacid and stagger administration of TRUSELTIQ™. TRUSELTIQ™ should be taken ≥2 hours before or 10 hours after administration of H2-antagonists. Locally-acting antacids should be taken at least 2 hours before or after TRUSELTIQ™ dosing.

Drug Metabolizing Enzymes

No clinically significant differences in the pharmacokinetics of midazolam (a sensitive CYP3A4 substrate) were observed when co-administered after multiple doses of 125 mg TRUSELTIQ™.

Based on in vitro studies, infigratinib does not induce CYP1A2, CYP2B6, CYP2C9, or CYP3A4. Infigratinib, BHS697, or CQM157 do not inhibit major CYP isozymes at clinically relevant concentrations.

Drug Transporters

Based on in vitro studies, infigratinib inhibits MATE1 and BCRP. Infigratinib has a low potential to inhibit P-gp, BSEP, OCT1, OCT2 and MATE-2K at clinically relevant concentrations. Infigratinib is a substrate for P-gp and BCRP. The metabolites BHS697 and CQM157 have a low potential to inhibit OATP1B1, OATP1B3, P-gp, or BCRP at clinically relevant concentrations. The effect of these metabolites to inhibit MATE or OCT at clinically relevant concentrations is unknown.

Phosphate Binder

Based on population PK analysis, a 25% increase in infigratinib exposure (AUC) on Cycle 1 Day 1 was observed in cholangiocarcinoma patients who received phosphate binder with infigratinib on Cycle 1 Day 1. Due to limited data, the clinical relevance could not be established.

9.4 Drug-Drug Interactions

The drugs listed in Table 7 are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 7: Established or Potential Drug-Drug Interactions

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9.5 Drug-Food Interactions

Administration of infigratinib with food (either a high-fat and high-calorie meal or a low-fat and low-calorie meal) was found to increase infigratinib exposure in healthy subjects [see 10 CLINICAL PHARMACOLOGY].

Grapefruit products should be avoided during treatment with TRUSELTIQ™.

Capsules should be taken on an empty stomach at least 1 hour before or 2 hours after food [see 4 DOSAGE AND ADMINISTRATION and 10 CLINICAL PHARMACOLOGY].

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

Avoid concomitant use of St. John’s Wort, as this herb is a strong inducer of CYP3A.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Infigratinib is a small molecule kinase inhibitor that targets of FGFR with in vitro IC₅₀ values of 1.1, 1.0, and 2.0 nM and 61 nM for FGFR1, FGFR2, FGFR3 and FGFR4, respectively. The major active metabolites of TRUSELTIQ™, BHS697 and CQM157, showed similar in vitro binding activity as infigratinib towards FGFR1-3, with similar less potent activity toward FGFR4, in binding affinity studies. Infigratinib inhibited FGFR1-3 phosphorylation and signaling and decreased cell proliferation in cancer cell lines with activating FGFR amplifications, mutations, and fusions that resulted in constitutive activation of FGFR signaling. Constitutive FGFR signaling can support the proliferation and survival of malignant cells. Infigratinib exhibited anti-tumor activity in mouse and rat xenograft models of human tumors with activating FGFR2 or FGFR3 alterations, including two patient-derived xenograft models of cholangiocarcinoma that expressed FGFR2-TTC28 and FGFR2-TRA2B fusions. Infigratinib demonstrated brain-to-plasma concentration ratios (based on AUC_0-inf) of 0.682 in rats after a single oral dose.

10.2 Pharmacodynamics

Cardiac Electrophysiology

According to a pharmacokinetic-pharmacodynamic analysis of pooled data from two open-label, uncontrolled studies with a combined total of 261 patients with advanced solid tumours, of whom 170 received infigratinib at a dose of 125 mg/day for 3 weeks on and 1 week off, large mean increases from baseline (i.e., >20 msec) in the QTc interval were not predicted for the reported C_max value of 295.3 ng/mL (geometric mean C_max for the 125 mg/day dose on day 15). The QT effect of infigratinib at higher exposures, such as those associated with CYP3A inhibition, has not been studied.

Serum Phosphate

TRUSELTIQ™ increased serum phosphate levels due to FGFR inhibition. In patients, the increase in serum phosphate observed after treatment with TRUSELTIQ™ was exposure-dependent across the dose range of 20 to 150 mg once daily (0.16 to 1.2 times the recommended dose), with increased risk of hyperphosphatemia with higher exposure to TRUSELTIQ™.

10.3 Pharmacokinetics

The pharmacokinetics of TRUSELTIQ™ and its active metabolites BHS697 and CQM157 have been studied in healthy subjects and oncology patients.

The infigratinib pharmacokinetic parameters are presented following administration of the approved recommended dosage in cholangiocarcinoma patients, unless otherwise specified.

After single and repeat once daily dosing, TRUSELTIQ™ exposure (C_max and AUC) increased more than proportionally across the dose range of 5 to 150 mg (0.04 to 1.2 times the maximum recommended dose). Steady state was achieved within 15 days with once daily dosing and the mean accumulation ratio was 8- and 5-fold for C_max and AUC, respectively.

Table 8: Summary of Steady State Pharmacokinetic Parameters of Infigratinib and its Metabolites (Mean (CV%)) in Patients with Cholangiocarcinoma Receiving TRUSELTIQ™

Absorption

Median time to achieve peak plasma concentration (t_max) was 6.0 hours (range: 2 to 7 hours).

Effect of Food

Administration of infigratinib with a high-fat and high-calorie meal (800 to 1000 calories with about 50% of total caloric content from fat) or a low-calorie, low-fat meal (330 calories with about 20% of total caloric content from fat) was found to increase infigratinib exposure by approximately two-fold in healthy subjects.

Distribution:

The geometric mean (CV%) apparent volume of distribution of infigratinib was 1600 L (33%CV) at steady state.

Infigratinib protein binding was 98% in patients, primarily to alpha-1-acid glycoprotein.

Metabolism:

Infigratinib is predominantly metabolized by CYP3A4. The contribution of CYP3A4 in the total clearance of infigratinib is estimated to be 94% and to a lesser extent by FMO3 estimated to be 6% in vitro. The major drug-related moiety in plasma was unchanged infigratinib (38% of dose) in a human [¹⁴C] mass balance study, followed by two active metabolites, BHS697 and CQM157 (each at >10% of dose).

BHS697 is mainly metabolized by CYP3A4 and CQM157 is metabolized through both Phase I and Phase II biotransformation pathways.

BHS697 and CQM157 contribute about 16% to 33% and 9% to 12% of overall pharmacologic activity, respectively.

Elimination

The geometric mean (CV%) total apparent clearance (CL/F) of infigratinib at steady state was 21.77 L/h (50.6%CV). The geometric mean (CV%) terminal half-life of infigratinib at steady state was 33.5 (39%) hours.

After a single oral 125 mg dose of radiolabeled infigratinib in healthy subjects, approximately 77% of the dose was recovered in feces (3.4% as unchanged) and 7.2% in urine (1.9% as unchanged).

Special Populations and Conditions

• Geriatrics: In the population PK analysis, no clinically meaningful differences in the systemic exposure of infigratinib were observed based on age (19 to 86 years).
• Sex: In the population PK analysis, no clinically meaningful differences in the systemic exposure of infigratinib were observed based on sex.
• Ethnic Origin: In the population PK analysis, no clinically meaningful differences in the systemic exposure of infigratinib were observed based on race/ethnicity.

• Hepatic Insufficiency: Based on a hepatic impairment study, mean exposure of infigratinib increased in subjects with mild (NCI-OWDG mild) and moderate (NCI-OWDG moderate) hepatic impairment. Infigratinib exposure increased by 52% (C_max) to 108% (AUC_inf) in subjects with mild hepatic impairment and increased by 123% (C_max) to 124% (AUC_inf) in subjects with moderate

  • hepatic impairment relative to subjects with normal liver function.

BHS697 exposure decreased by 21% in C_max to increase by 15% in AUC_inf in subjects with mild hepatic impairment and increased by 34% in C_max to 29% in AUC_inf in subjects with moderate hepatic impairment relative to subjects with normal liver function. Mean exposure of the CQM157 decreased by 40% in C_max to 37% in AUC_inf in subjects with mild hepatic impairment and increased by 13% in C_max and decreased by 51% in AUC_inf in subjects with moderate hepatic impairment relative to subjects with normal liver function

The effect of severe hepatic impairment on infigratinib exposure is unknown.

• Renal Insufficiency: Based on population PK analysis, the relative potency adjusted steady state AUC of infigratinib plus its active metabolites (BHS697, CQM157) in plasma increased by 32% and 37% in patients with mild (creatinine clearance [CLcr] 60 to 89 mL/min estimated by Cockcroft-Gault) and moderate renal impairment (CLcr 30 to 59 mL/min), respectively, relative to patients with normal renal function (CLcr ≥ 90 mL/min).

  The effect of renal impairment or renal dialysis in end-stage renal disease on infigratinib exposure is unknown.

• Obesity: In the population PK analysis, no clinically meaningful differences in the systemic exposure of infigratinib were observed based on body weight (36.4 to 169.0 kg).

11 STORAGE, STABILITY AND DISPOSAL

Store TRUSELTIQ™ at 15°C to 25°C.

12 SPECIAL HANDLING INSTRUCTIONS

Not applicable.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper/Common name: Infigratinib phosphate

Chemical name: 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[4-(4-ethylpiperazin-1-yl)phenylamino]pyrimidin-4-yl}-1-methylurea phosphate (1:1)

Molecular formula and molecular mass: C₂₆H₃₁Cl₂N₇O₃·H₃PO₄ / 560.48 g/mol for the free base and 658.47 g/mol for the phosphate salt

Structural formula:

NOC/c

Physicochemical properties: Infigratinib phosphate is a white to off-white powder. It shows adequate solubility in water and 0.1N HCl. It is practically insoluble in pH 6.8 buffer and poorly soluble in common organic solvents.

14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

Table 9: Summary of Patient Demographics for Patients with Previously Treated, Unresectable, Locally Advanced or Metastatic Cholangiocarcinoma with an FGFR2 Fusion or Other Rearrangement

Study CBGJ398X2204 (NCT02150967), a multicenter, open-label, single-arm trial, evaluated the efficacy of TRUSELTIQ™ in 108 patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement, as determined in laboratory using next generation sequencing (local or central lab) (89%) or other nucleic-acid based tests (local lab) (11%). Qualifying in-frame fusions and other rearrangements were predicted to have a breakpoint within intron 17/exon 18 of the FGFR2 gene that leaves the FGFR2 kinase domain intact.

Patients received TRUSELTIQ™ as an oral monotherapy at 125 mg once daily for 21 consecutive days followed by 7 days off therapy, in 28-day cycles. TRUSELTIQ™ was administered in 28-day cycles until disease progression or unacceptable toxicity. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR), as determined by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

The median age was 53 years (range: 23 to 81 years), 62% were female, 72% were White, and 99% had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (42%) or 1 (57%). In-frame fusions and other rearrangements predicted to have breakpoint within intron 17/exon 18 of the FGFR2 gene that leaves the FGFR2 kinase domain intact were confirmed in 104 enrolled subjects (96%) with local or central laboratory Next Generation Sequencing (NGS) testing. Eighty-eight patients had in-frame FGFR2 fusions, with BICC1 the most commonly reported partner gene for FGFR2 fusions (n=27, 25%). Twenty (19%) patients had other FGFR2 rearrangements that may not be in-frame with the partner gene or the partner gene was not identifiable.

Ninety-nine percent of patients had metastatic (Stage IV) disease at the time of study entry. All patients had received at least 1 prior line of systemic therapy, 32% had 2 prior lines of therapy, and 29% had 3 or more prior lines of therapy. Ninety-nine percent of patients received prior gemcitabine-based therapy and most (88%) had progressed on their prior gemcitabine-based therapy.

14.2 Study Results

The primary endpoint (ORR assessed by BICR) was 23.1% (95% confidence interval [CI]: 15.6, 32.2) including 1 subject with a confirmed complete response (CR) and 24 subjects with confirmed partial response (PR) (Table 10). The Kaplan-Meier (K-M) estimate for median DoR assessed by BICR was 5 months (95% CI: 3.71, 9.26).

Efficacy results are summarized in Table 10. The median time to response was 3.6 months (range 1.4 to 7.4 months).

Table 10: Efficacy Results in Study CBGJ398X2204

Note: Data are according to RECIST v1.1, and complete and partial responses are confirmed.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology:

Repeat-dose studies in rats and dogs were conducted for periods > 13-weeks.

In the 13-week study in rats, the highest dose tested was 10 mg/kg/day corresponding to a lower exposure than the clinical recommended dose of 125 mg, based on AUC. Observed toxicities included effects on teeth (including incisor degeneration with degeneration of enamel, loss of ameloblast layer and fractures), bones (growth plate thickening in femur and sternum), eye (keratopathy and corneal mineralization), kidney (mineralization), nasal cavity (chondrocytes hypertrophy), tongue and hard palate (decreased epithelium thickness). Recovery (following a 6-week recovery period) was observed for most toxicities, with persisting effects on teeth and kidney and ocular mineralization. In this study, the NOAEL was considered 1 mg/kg/day.

In the 13-week dog study, at the highest dose of 10 mg/kg/day (lower than human exposure, based on AUC at the recommended dose), clinical signs included liquid feces, partially digested food and generalized thinness. Microscopic findings were observed in the sternum (growth plate thickening), in the meibomian glands (acinar atrophy and ducts dilatation), in the sebaceous glands (acinar atrophy) and skin (hyperkeratosis). All the changes were recoverable or showed ongoing recovery (sternum and meibomian glands). In this study, the NOAEL was considered 1 mg/kg/day.

Changes in appearance (longer hair, prominent backbone) and changes in plasma FGF23 levels (reversed after recovery period) were observed in both rats and dogs.

In a 26-week rat study, bone effects were observed in lumbar vertebral bodies including decreased bone strength consistent with decreases in total bone mineral density, at ≥ 1 mg/kg/day doses. Increased growth plate thickness and fractures associated with increased physeal thickness, focal mixed reaction, and bone loss were observed in a 39-week dog study, at 3 mg/kg/day.

In a 2-week repeat-dose mechanistic study investigating tissue mineralization, histopathological examination showed morphological changes in blood vessels, lungs, kidneys and bones at 20 mg/kg/day. Vascular changes included degeneration and mineralization in large blood vessels and in vessels of different organs (heart, GI-tract, kidneys and lungs). Bone changes were observed at doses >10 mg/kg/day. Reversibility or a tendency to reversibility was seen in all affected organs. Mineralization was not recoverable.

Carcinogenicity: Carcinogenicity studies have not been conducted with infigratinib.

Genotoxicity: Infigratinib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro human peripheral blood lymphocyte chromosome aberration assay. Infigratinib did not induce micronuclei in an in vivo rat bone marrow micronucleus assay. The major metabolites BHS697 and CQM157 were also not mutagenic.

Reproductive and Developmental Toxicology: Embryo-fetal development studies investigating the administration of infigratinib during the period of organogenesis were conducted in rats and rabbits. In rats, infigratinib administration resulted in an increase in embryo-fetal lethality at 10 mg/kg/day, and reductions in fetal body weights at 3 and 10 mg/kg/day. Fetal abnormalities (external, soft tissue, and skeletal) were increased at ≥1 mg/kg/day (maternal exposures < 0.1 times the recommended human dose of 125 mg, based on AUC). Once daily oral administration of infigratinib at ≥0.3 mg/kg/day to pregnant rabbits resulted in maternal toxicity and a corresponding reduction in fetal body weights (maternal exposures at all dose levels less than the human exposure (AUC) at the recommended human dose of 125 mg). Correlated with the reduction in fetal weights was a decrease in the numbers of ossification sites in some bones.

In a rat fertility study, there were no effects on mating or fertility, reproductive organ weights, or sperm motility, density, or morphology in males, and no effect on estrous cycling, mating, or fertility in females administered ≤3 mg/kg/day infigratinib. In the embryo-fetal portion of the study, a decrease in the mean number of embryos in females at 3 mg/kg/day was observed and associated with an increase in the number of nonviable embryos and in the percentage of post implantation loss. This dose corresponds to an exposure lower than human exposure, based on AUC at the clinical dose of 125 mg.