Cabometyx

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KABOMETYX (CABOMETYX®)

Composition:

active substance: cabozantinib (S)-malate

1 film-coated tablet contains cabozantinib (S)-malate equivalent to 20 mg, 40 mg, or 60 mg of cabozantinib;

excipients: microcrystalline cellulose, anhydrous lactose, hydroxypropylcellulose, sodium croscarmellose, colloidal silicon dioxide (anhydrous), magnesium stearate;

film coating: Opadry Yellow (03K92254): hypromellose (HPMC) 2910 (E 464), titanium dioxide (E 171), triacetin, iron oxide yellow (E 172).

Pharmaceutical form.

Film-coated tablets.

Main physicochemical properties.

KABOMETYX, film-coated tablets, 20 mg

Yellow, round, film-coated tablets, with "XL" imprinted on one side and "20" on the other side of the tablet.

KABOMETYX, film-coated tablets, 40 mg

Yellow, triangular, film-coated tablets, with "XL" imprinted on one side and "40" on the other side of the tablet.

KABOMETYX, film-coated tablets, 60 mg

Yellow, oval, film-coated tablets, with "XL" imprinted on one side and "60" on the other side of the tablet.

Pharmacotherapeutic group.

Antineoplastic medicinal products. Protein kinase inhibitors. Cabozantinib.

ATC code L01E X07.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action

Cabozantinib is a low molecular weight tyrosine kinase inhibitor that inhibits multiple receptor tyrosine kinases (RTKs) involved in tumor growth and angiogenesis, pathological bone changes, drug resistance, and metastatic progression of cancer. In evaluation of inhibitory activity against various kinases, cabozantinib was identified as an inhibitor of the MET receptor (hepatocyte growth factor receptor) and VEGF receptors (vascular endothelial growth factor). Additionally, cabozantinib inhibits other tyrosine kinases, including the GAS6 receptor (AXL), RET, ROS1, TYRO3, MER, stem cell factor receptor (KIT), TRKB, Fms-like tyrosine kinase-3 (FLT3), and TIE-2.

Pharmacodynamic effects

Cabozantinib demonstrated dose-dependent tumor growth inhibition, tumor regression, and/or reduced metastasis in a broad range of preclinical tumor models.

Cardiac electrophysiology

An increase from baseline in the Fridericia-corrected QT interval (QTcF) of 10–15 msec was observed on day 29 (but not on day 1) after initiation of cabozantinib treatment (at a dose of 140 mg daily) in a controlled clinical trial involving patients with medullary thyroid cancer. This effect was not associated with morphological changes in the P-wave or the emergence of new cardiac rhythms. In this study, no patient receiving cabozantinib had a confirmed QTcF > 500 msec, whereas such prolongation was not confirmed with either placebo or everolimus (at a dose of 60 mg).

Clinical efficacy and safety

Clinical data in renal cell carcinoma (RCC) following prior therapy with vascular endothelial growth factor (VEGF)-targeted agents

The safety and efficacy of CABOMETYX in the treatment of renal cell carcinoma following prior VEGF-targeted therapy were evaluated in a randomized, open-label, multicenter Phase III trial (METEOR). Patients with advanced clear cell renal cell carcinoma (RCC) who had previously received at least one course of therapy with VEGF receptor tyrosine kinase inhibitors (VEGFR TKI) were randomized (1:1) to receive CABOMETYX (N = 330) or everolimus (N = 328). Patients could have received other prior therapies, including cytokines, antibodies targeting VEGF, or antibodies directed against programmed cell death-1 (PD-1) or its ligands. Patients with previously treated brain metastases were permitted. Progression-free survival was assessed by a blinded independent radiology review committee, and the primary analysis was performed in the first 375 randomized patients. Secondary endpoints included the proportion of patients achieving objective response and overall survival (OS). Tumor assessments were performed every 8 weeks for the first 12 months and then every 12 weeks thereafter.

Baseline demographic characteristics and disease features were similar between the CABOMETYX and everolimus treatment groups. The majority of patients were male (75%), with a median age of 62 years. Seventy-one percent of patients had received only one prior VEGFR TKI regimen; 41% of patients received sunitinib as their only prior VEGFR TKI. According to the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk category criteria, 46% had favorable risk (0 risk factors), 42% intermediate risk (1 risk factor), and 13% poor risk (2 or 3 risk factors). Fifty-four percent of patients had metastases in three or more organs, including lungs (63%), lymph nodes (62%), liver (29%), and bones (22%). The median duration of treatment was 7.6 months (range: 0.3–20.5) in patients receiving CABOMETYX and 4.4 months (range: 0.21–18.9) in those receiving everolimus.

A statistically significant improvement in progression-free survival was observed with CABOMETYX compared to everolimus (Figure 1 and Table 1). A planned interim analysis of overall survival conducted at the time of progression-free survival analysis did not reach the boundary for statistical significance (202 events, HR = 0.68 [95% CI: 0.51, 0.90], p = 0.006). However, a subsequent unplanned interim analysis of overall survival showed a statistically significant improvement in patients receiving CABOMETYX compared to the everolimus group (320 events, median 21.4 months vs. 16.5 months, HR = 0.66 [95% CI: 0.53, 0.83], p = 0.0003, Figure 2). Comparable results for OS were observed in a subsequent descriptive analysis of 430 events.

An exploratory analysis of progression-free survival and overall survival in the "all randomized patients who received at least one dose of study drug" population also showed consistent favorable results for CABOMETYX compared to everolimus across various subgroups based on age (<65 vs. ≥65 years), sex, MSKCC risk group (favorable, intermediate, poor), ECOG performance status (0 or 1), time from diagnosis to randomization (<1 year vs. ≥1 year), tumor MET status (high vs. low or unknown), presence of bone metastases (absent vs. present), presence of visceral metastases (absent vs. present), presence of both bone and visceral metastases (absent vs. present), number of prior VEGFR-TKI regimens (1 vs. >1), and duration of first VEGF therapy (<6 months vs. ≥6 months). Results regarding the proportion of patients achieving objective response are presented in Table 2.

Figure 1. Progression-free survival curve as assessed by independent radiological review committee in patients with advanced RCC previously treated with VEGF-targeted therapy (first 375 randomized patients) (Kaplan-Meier method, METEOR study)

Table 1

Summary of progression-free survival (PFS) results as assessed by independent radiological review committee in patients with advanced RCC previously treated with VEGF-targeted therapy (METEOR study)

1 Stratified log-rank test.

Fig. 2. Overall survival curve of patients with RCC after prior treatment with vascular endothelial growth factor (VEGF)–targeted therapies (Kaplan-Meier method, METEOR study)

Table 2

Summary of data on the number of patients with objective response according to independent radiological review committee (IRC) and investigator assessment in patients with RCC after prior treatment with vascular endothelial growth factor (VEGF)–targeted therapies

1 Chi-square test.

Clinical data on treatment of previously untreated patients with renal cell carcinoma

The safety and efficacy of CABOMECTICS in patients with previously untreated renal cell carcinoma were evaluated in a randomized, open-label, multicenter study (CABOSUN). Patients (N = 157) with previously untreated, locally advanced or metastatic clear-cell RCC were randomized (1:1) to receive CABOMECTICS (N = 79) or sunitinib (N = 78). Patients were required to have intermediate- or poor-risk disease as defined by the risk categories of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). Patients were stratified by IMDC risk group and presence of bone metastases (yes/no). Approximately 75% of patients had undergone nephrectomy prior to starting treatment.

Patients were required to have one or two of the following risk factors for intermediate risk and three or more risk factors for poor risk: time from diagnosis of RCC to systemic treatment < 1 year, hemoglobin < LLN (lower limit of normal), corrected calcium > ULN (upper limit of normal), KPS < 80%, neutrophils > ULN, platelets > ULN.

The primary endpoint was progression-free survival. Secondary efficacy endpoints included objective response rate and overall survival. Tumor assessments were performed every 12 weeks.

Baseline demographic characteristics and disease features were similar between the CABOMECTICS and sunitinib treatment groups. The majority of patients were male (78%); median age was 62 years. Distribution of patients by IMDC risk groups was as follows: 81% of patients in the intermediate-risk group (1–2 risk factors), and 19% in the poor-risk group (≥ 3 risk factors). Most patients (87%) had an ECOG performance status of 0 or 1; 13% had a score of 2. Bone metastases were present in 36% of patients.

A statistically significant improvement in progression-free survival, as assessed retrospectively by an independent review committee conducting blinded radiological review (IRC), demonstrated the advantage of CABOMECTICS over sunitinib (Figure 3, Table 3). Results of progression-free survival analyses by investigator and IRC were consistent with each other.

Patients with both positive and negative MET status showed favorable outcomes with CABOMECTICS compared to sunitinib; however, greater activity was observed in patients with positive MET status compared to those with negative MET status (HR = 0.32 (0.16, 0.63) versus 0.67 (0.37, 1.23), respectively).

Treatment with CABOMECTICS was associated with a trend toward longer survival compared to sunitinib (Table 3). This study was not powered for analysis of overall survival, and the data were immature.

Data on objective response rate are presented in Table 3.

Figure 3. Progression-free survival curve in patients with RCC who had not received prior treatment (IRC data, Kaplan-Meier method)

Table 3

Efficacy results in patients with RCC who had not received prior treatment (ITT population, CABOSUN study)

a According to the data censoring standards adopted in the EU.

b Stratification factors according to IxRS included IMDC risk categories (intermediate risk, high risk, and presence of bone metastases (yes/no)).

c Calculated based on the Cox proportional hazards model, adjusted for stratification factors according to IxRS. Hazard ratios < 1 indicate progression-free survival in favor of cabozantinib.

Clinical data in hepatocellular carcinoma (HCC)

The safety and efficacy of the medicinal product CABOMETYX were evaluated in a randomized, double-blind, placebo-controlled phase III trial (CELESTIAL). Patients (N = 707) with HCC who were refractory to curative treatment and had previously received sorafenib for advanced disease were randomized (2:1) to receive CABOMETYX (N = 470) or placebo (N = 237). Patients could have received one additional prior systemic therapy for advanced disease in addition to sorafenib. Randomization was stratified by disease etiology (hepatitis B virus [with or without hepatitis C virus], hepatitis C virus [without hepatitis B virus], or other patient category), geographic region (Asia, other regions), and presence of extrahepatic disease spread and/or macrovascular invasion (yes/no).

The primary efficacy endpoint was overall survival. Secondary efficacy endpoints were progression-free survival and objective response rate, assessed by the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Tumors were evaluated every 8 weeks. Subjects continued blinded treatment after radiological confirmation of disease progression until they experienced clinical benefit or until further systemic therapy or local liver-directed anticancer therapy was required. Crossover from placebo to cabozantinib was not permitted during the blinded treatment phase.

Baseline demographic characteristics and disease features were similar between the CABOMETYX and placebo groups and are presented below for all 707 randomized patients:

• male – 82 %;
• median patient age – 64 years;
• Caucasian – 56 %, Asian – 34 %;
• ECOG performance status 0 – 53 % or 1 – 47 %;
• Child-Pugh class A liver impairment – 99 %, class B – 1 %;
• HCC etiology included 38 % of patients with hepatitis B virus (HBV), 21 % with hepatitis C virus (HCV), and 40 % with other (neither HBV nor HCV);
• presence of macroscopic vascular invasion and/or extrahepatic disease – 78 %;
• alpha-fetoprotein (AFP) levels ≥ 400 mcg/L – 41 %;
• prior locoregional transarterial embolization or chemo-infusion procedures – 44 %;
• prior radiotherapy before cabozantinib treatment – 37 %;
• median duration of prior sorafenib treatment – 5.32 months;
• 72 % of patients received one, and 28 % received two prior systemic therapy regimens for advanced disease.

A statistically significant improvement in overall survival was demonstrated for CABOMETYX compared to placebo (Table 4, Figure 4).

Data on progression-free survival and objective response rate are presented in Table 4.

Table 4

Efficacy results in patients with HCC (ITT population, CELESTIAL study)

1 Two-sided, stratified, log-rank test, with stratification factors being disease etiology (hepatitis B virus [with or without hepatitis C virus], hepatitis C virus [without hepatitis B virus], or other category of patients), geographic region (Asia, other regions), and presence of extrahepatic disease spread and/or macrovascular invasion (yes/no) (per IVRS).

2 Calculated based on Cox proportional hazards model.

3 Investigator-assessed according to RECIST 1.1 criteria.

4 Stratified Cochran–Mantel–Haenszel (CMH) test.

Figure 4. Overall survival curve (Kaplan-Meier method, CELESTIAL study)

Figure 5. Progression-free survival curve (Kaplan-Meier method, CELESTIAL trial)

The proportion of non-protocol systemic non-radiation and locoregional liver-directed systemic anti-tumor therapy (NPACT) was 26% in the cabozantinib group and 33% in the placebo group. Patients receiving such therapies had to discontinue treatment with the study regimen. A sensitivity analysis of overall survival with censoring for NPACT provided supportive data for the results of the primary analysis: the hazard ratio (HR), adjusted for stratification factors (on IxRS), was 0.66 (95% CI: 0.52, 0.84; stratified log-rank p-value 0.0005). The Kaplan-Meier estimated median overall survival was 11.1 months in the cabozantinib group compared to 6.9 months in the placebo group, resulting in a calculated median difference of 4.2 months.

Quality of life (QoL), assessed in a disease-agnostic manner, was evaluated using the EuroQoL EQ-5D-5L questionnaire. A negative impact of CABOMETYX compared to placebo on the EQ-5D utility index score was observed during the first few weeks of treatment. After this period, only limited QoL data were available.

Pediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with CABOMETYX in all subgroups of the pediatric population for the treatment of hepatocellular carcinoma, as well as renal and ureteric carcinomas (except for nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma, and renal rhabdoid tumor) (see section "Posology and method of administration" for information on use of the medicinal product in children).

Pharmacokinetics.

Absorption

Following oral administration, peak plasma concentrations of cabozantinib are reached within 3–4 hours. Plasma concentration-time profiles show a second absorption peak approximately 24 hours after administration, suggesting that cabozantinib may undergo enterohepatic recirculation.

Repeated daily administration of cabozantinib at a dose of 140 mg for 19 days resulted in an approximately 4- to 5-fold increase in mean cabozantinib accumulation (based on the area under the pharmacokinetic concentration-time curve) compared to a single dose; steady state was reached by approximately day 15.

A high-fat meal moderately increased the maximum plasma concentration and the area under the pharmacokinetic concentration-time curve (by 41% and 57%, respectively) compared to fasting conditions in healthy volunteers receiving a single 140 mg oral dose of cabozantinib. Data on the effect of food taken 1 hour after cabozantinib administration are not available.

Bioequivalence between cabozantinib capsules and tablets could not be demonstrated after a single 140 mg dose was administered to healthy volunteers. A 19% higher maximum plasma concentration of the active substance was observed after administration of the tablet (CABOMETYX) compared to the capsule (COMETRIQ). Less than 10% difference in the area under the pharmacokinetic concentration-time curve was observed between cabozantinib tablets (CABOMETYX) and capsules (COMETRIQ).

Distribution

Cabozantinib is highly bound to human plasma proteins (≥ 99.7%). Based on pharmacokinetic parameter measurements, the volume of distribution (Vz) is approximately 212 L. Plasma protein binding was not altered in patients with mild or moderate renal or hepatic impairment.

Biotransformation

Cabozantinib is metabolized in vivo. Four metabolites were present in plasma at exposure levels (area under the pharmacokinetic concentration-time curve) greater than 10% of the parent compound: XL184-N-oxide, the amide cleavage product of XL184, monohydroxy sulfate XL184, and sulfate of the 6-desmethyl amide cleavage product. Two unconjugated metabolites (XL184-N-oxide and the amide cleavage product of XL184) have less than 1% of the original cabozantinib's kinase inhibition target activity, and each contributes less than 10% to the total drug-related exposure in plasma.

Cabozantinib is a substrate for CYP3A4 metabolism in vitro, as a neutralizing antibody to CYP3A4 inhibited the formation of the XL184-N-oxide metabolite by > 80% in NADPH-catalyzed human liver microsomal incubations. In comparison, neutralizing antibodies to CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6, and CYP2E1 had no effect on cabozantinib metabolite formation. A neutralizing antibody to CYP2C9 showed minimal effect on cabozantinib metabolite formation (i.e., reduction of < 20%).

Elimination

Following oral administration of cabozantinib at doses ranging from 20 mg to 140 mg, the mean elimination half-life in plasma, based on studies involving 1883 patients and 140 healthy volunteers, is approximately 110 hours. The mean plasma clearance (apparent clearance) is nearly 2.48 L/h after steady-state exposure. Approximately 81% of a radiolabeled dose was recovered within 48 days after administration of a single 14C-cabozantinib dose in healthy volunteers, with about 54% of the dose excreted in feces and about 27% excreted in urine.

Pharmacokinetics in special patient populations

Renal impairment

Results from a study in patients with renal impairment who received a single 60 mg dose of cabozantinib indicate that the least-squares geometric mean ratio for cabozantinib in plasma, maximum plasma concentration, and area under the pharmacokinetic concentration-time curve from 0 to infinity were 19% and 30% higher, respectively, in patients with mild renal impairment (90% CI for maximum plasma concentration: 91.60% to 155.51%; AUC from 0 to infinity: 98.79% to 171.26%) and 2% and 6–7% higher (90% CI for maximum plasma concentration: 78.64% to 133.52%; AUC from 0 to infinity: 79.61% to 140.11%) in patients with moderate renal impairment, compared to patients with normal renal function. Patients with severe renal impairment were not studied.

Hepatic impairment

Based on an integrated population pharmacokinetic analysis of cabozantinib in healthy volunteers and cancer patients (including HCC), no clinically relevant differences in mean plasma exposure to cabozantinib were observed between patients with normal hepatic function (n = 1425) and those with mild hepatic impairment (n = 558). Data in patients with moderate hepatic impairment (n = 15) according to NCI-ODWG criteria (National Cancer Institute-Organ Dysfunction Working Group) are limited. The pharmacokinetics of cabozantinib have not been evaluated in patients with severe hepatic impairment.

Race

Population pharmacokinetic analysis did not reveal clinically significant differences in cabozantinib pharmacokinetics based on patient race.

Clinical characteristics.

Indications.

Renal cell carcinoma (RCC)

CABOMETYX is indicated for the treatment of advanced renal cell carcinoma (RCC):

• in adult patients who have not received prior therapy and have intermediate or poor risk (see section "Pharmacodynamic properties");
• in adult patients following prior anti-angiogenic therapy targeting vascular endothelial growth factor (VEGF).

Hepatocellular carcinoma (HCC)

CABOMETYX is indicated as monotherapy for hepatocellular carcinoma (HCC) in adult patients previously treated with sorafenib.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on cabozantinib

Inhibitors and inducers of CYP3A4

Prior administration of ketoconazole, a strong CYP3A4 inhibitor, at a dose of 400 mg once daily for 27 days before a single dose of cabozantinib increased plasma exposure to cabozantinib by 38% (AUC) and decreased cabozantinib clearance by 29% in healthy volunteers. Strong CYP3A4 inhibitors should be used with caution (including ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice).

Prior administration of rifampicin, a strong CYP3A4 inducer, at a dose of 600 mg once daily for 31 days before a single dose of cabozantinib decreased plasma exposure to cabozantinib by 77% (AUC) and increased cabozantinib clearance by 4.3-fold in healthy volunteers. Concomitant long-term use of strong CYP3A4 inducers should be avoided (including rifampicin, carbamazepine, phenytoin, phenobarbital, or medicinal products containing St John’s wort (Hypericum perforatum)).

Gastrointestinal pH modifiers

Prior administration of esomeprazole, a proton pump inhibitor (PPI), at a dose of 40 mg once daily for 6 days before a single 100 mg dose of cabozantinib indicated no clinically significant effect on cabozantinib plasma exposure (AUC) in healthy volunteers. Dose adjustment is not recommended when cabozantinib is administered concomitantly with agents that alter gastric pH (including PPIs, H2-receptor antagonists, and antacids).

MRP2 inhibitors

In vitro data indicate that cabozantinib is a substrate of MRP2. Therefore, administration of MRP2 inhibitors may lead to increased plasma concentrations of cabozantinib.

Bile acid sequestrants

Bile acid sequestrants such as cholestyramine and cholestagel may interact with cabozantinib and affect absorption (or reabsorption), thereby reducing the administered dose, which may be detrimental (see section "Pharmacodynamics"). The clinical significance of these potential interactions is unknown.

Effect of cabozantinib on other medicinal products

The effect of cabozantinib on the pharmacokinetics of contraceptive steroids has not been studied. Since contraceptive efficacy cannot be guaranteed, an additional method of contraception, particularly a barrier method, should be used.

Due to the high degree of plasma protein binding of cabozantinib (see section "Pharmacokinetics"), interaction with warfarin is possible—displacement from plasma proteins. In such cases, international normalized ratio (INR) should be monitored.

P-glycoprotein inhibitors

Cabozantinib is an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-glycoprotein (P-gp) transport activity in a bidirectional system using cells engineered to express P-glycoprotein (MDCK-MDR1). Concomitant use of P-gp inhibitors may increase cabozantinib plasma concentrations. Patients should be advised about taking medicinal products that affect P-gp (such as fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan) during cabozantinib treatment.

Special precautions for use

Since most adverse reactions may occur at the beginning of treatment, careful monitoring is required during the first eight weeks of treatment to detect adverse reactions and increased individual sensitivity to the medicinal product, with a view to possible dose modification. Events that typically have an early onset include hypocalcemia, hypokalemia, thrombocytopenia, arterial hypertension, palmar-plantar erythrodysesthesia syndrome (PPES), proteinuria, and gastrointestinal disorders (abdominal pain, mucositis, constipation, diarrhea, vomiting).

For the management of suspected adverse reactions, a temporary interruption of treatment or dose reduction of cabozantinib may be required (see section "Dosage and administration").

In the pivotal clinical study (METEOR study), 59.8% and 70% of patients with previously treated renal cell carcinoma required dose reduction and interruption of therapy, respectively, due to adverse reactions. Two dose reductions were required in 19.3% of patients. The median time to first dose reduction was 55 days, and to first dose interruption – 38 days.

In treatment-naïve patients with renal cell carcinoma, dose reduction and therapy interruption occurred in 46% and 73% of patients, respectively, who received cabozantinib in a clinical trial (CABOSUN study).

In the treatment of hepatocellular carcinoma after prior systemic therapy, dose reduction and discontinuation of therapy occurred in 62% and 84% of patients, respectively, who received cabozantinib in a clinical trial (CELESTIAL study). Two dose reductions were required in 33% of patients. The median time to first dose reduction was 38 days, and to first dose interruption – 28 days. Patients with mild or moderate hepatic impairment should be monitored more closely.

Hepatobiliary effects

Atypical results of liver function tests (elevated levels of alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin) are frequently observed in patients receiving cabozantinib. Liver function tests (ALT, AST, bilirubin) are recommended before initiating cabozantinib treatment, and these parameters should be carefully monitored during treatment. In case of worsening liver function test results related to cabozantinib treatment (i.e., in the absence of alternative causes), dose modification recommendations as presented in Table 5 should be followed (see section "Dosage and administration").

Cabozantinib is predominantly eliminated by the liver. Patients with mild or moderate hepatic impairment should be monitored more closely for overall safety (see also sections "Special precautions for use" and "Pharmacokinetics"). Hepatic encephalopathy occurred in a relatively higher proportion of patients with moderate hepatic impairment (Child-Pugh class B). CABOMETYX is not recommended for patients with severe hepatic impairment (Child-Pugh class C), as cabozantinib has not been studied in this population and its exposure may increase in these patients.

Hepatic encephalopathy

In the HCC study (CELESTIAL study), hepatic encephalopathy was reported more frequently in the cabozantinib group than in the placebo group. Diarrhea, vomiting, decreased appetite, and electrolyte imbalance may occur during cabozantinib treatment. In patients with HCC and impaired liver function, these reactions in other systems and organs may be precursors of hepatic encephalopathy. Patients should be monitored for signs and symptoms of hepatic encephalopathy.

Perforations and fistulas

Serious gastrointestinal (GI) perforations and fistulas, including fatal cases, have been reported during treatment with cabozantinib. Patients with inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis, peritonitis, diverticulitis, or appendicitis), tumor infiltration into the GI tract, or complications from prior GI surgery (particularly when associated with delayed or incomplete wound healing) should be carefully evaluated before starting cabozantinib and monitored during treatment for signs of perforation or fistula, including abscess and sepsis. Persistent or intermittent diarrhea during treatment may be a risk factor for the development of rectal fistula. Treatment with cabozantinib should be permanently discontinued in patients who develop GI perforation or fistula that cannot be adequately managed.

Gastrointestinal (GI) disorders

Diarrhea, nausea/vomiting, decreased appetite, and stomatitis/oral pain are the most commonly reported adverse reactions affecting the GI tract (see section "Adverse reactions"). To prevent dehydration, electrolyte imbalance, and weight loss, prompt medical management should be initiated, including supportive therapy with antiemetics, antidiarrheals, and antacids. In cases of persistent or recurrent GI adverse reactions, consideration should be given to interrupting therapy, reducing the dose, or permanently discontinuing cabozantinib (see Table 5).

Thromboembolic events

Episodes of venous thromboembolism, including pulmonary embolism, and arterial thromboembolism, sometimes fatal, have been observed during treatment with cabozantinib. Cabozantinib should be administered with caution to patients at high risk of thromboembolic events or with a history of such events. In the HCC study (CELESTIAL), portal vein thrombosis was observed during cabozantinib treatment, including one fatal case. Patients with prior portal vein invasion are likely at increased risk of developing portal vein thrombosis. Cabozantinib should be discontinued in patients who experience acute myocardial infarction or any other clinically significant thromboembolic complication.

Bleeding

Cases of severe bleeding, sometimes fatal, have been reported with cabozantinib. The condition of patients with a history of severe bleeding should be carefully evaluated before initiating cabozantinib treatment.

Cabozantinib should not be administered to patients with active severe bleeding or those at risk of bleeding.

In the HCC study (CELESTIAL), fatal bleeding events were reported more frequently with cabozantinib than with placebo. Risk factors for severe bleeding in patients with advanced HCC may include tumor invasion into large blood vessels and the presence of liver cirrhosis leading to esophageal varices, portal hypertension, and thrombocytopenia. Patients receiving concomitant anticoagulant or antiplatelet therapy were not enrolled in the CELESTIAL study.

Patients with untreated or incompletely treated varices with bleeding or high risk of bleeding were also excluded from this study.

Aneurysms and arterial dissections

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or arterial dissections. This risk should be carefully considered before initiating treatment in patients with risk factors such as hypertension or a history of aneurysm.

Thrombocytopenia

In the HCC study (CELESTIAL), cases of thrombocytopenia and decreased platelet levels were reported. Platelet levels should be monitored during cabozantinib treatment, and dosing should be adjusted according to the severity of thrombocytopenia (see Table 5).

Impaired wound healing

Cases of impaired wound healing have been reported during cabozantinib treatment. It is recommended to discontinue cabozantinib therapy 28 days prior to scheduled surgery, including dental surgery or invasive dental procedures, if possible. The decision to resume cabozantinib treatment after surgical procedures should be based on clinical assessment of wound healing. Cabozantinib treatment should be discontinued in patients who develop wound healing complications requiring medical intervention.

Arterial hypertension

The use of cabozantinib has been associated with increased blood pressure and hypertensive crisis. Blood pressure should be carefully stabilized before initiating cabozantinib treatment. After starting cabozantinib, all patients should undergo regular blood pressure monitoring, and standard antihypertensive therapy should be initiated if necessary. In cases of severe or persistent hypertension uncontrolled by antihypertensive medications, the physician should consider discontinuing cabozantinib treatment until blood pressure is controlled, after which cabozantinib may be resumed at a reduced dose.

In case of hypertensive crisis, cabozantinib treatment should be discontinued.

Osteonecrosis

Cases of osteonecrosis of the jaw (ONJ) have been observed with cabozantinib use. An oral examination should be performed before starting and periodically during cabozantinib therapy. Patients should be informed about oral hygiene. Cabozantinib treatment should be discontinued at least 28 days before planned dental surgery or invasive dental procedures, if possible. Caution is advised for patients receiving agents associated with ONJ, such as bisphosphonates. Cabozantinib should be discontinued in patients who develop ONJ.

Palmar-plantar erythrodysesthesia syndrome (PPES)

Cases of palmar-plantar erythrodysesthesia syndrome (PPES) have been reported in patients receiving cabozantinib. In cases of severe PPES, discontinuation of cabozantinib treatment should be considered. In cases of onset of palmar-plantar syndrome, cabozantinib should be withheld until symptoms resolve or improve to grade 1.

Proteinuria

Cases of proteinuria have been reported during treatment with cabozantinib. Urinary protein levels should be monitored regularly during treatment. Cabozantinib should be discontinued if a patient develops nephrotic syndrome.

Reversible posterior encephalopathy syndrome (RPES)

Reversible posterior encephalopathy syndrome (RPES) has been reported in patients receiving cabozantinib. RPES may present with seizures, visual disturbances, headache, confusion, and neurological disorders. Patients with RPES should discontinue cabozantinib treatment.

QT interval prolongation

Cabozantinib should be used with caution in patients with a history of QT interval prolongation, those taking medications that may prolong the QT interval, and those with underlying cardiac conditions, bradycardia, or electrolyte imbalances. Periodic ECG monitoring and measurement of serum potassium, calcium, and magnesium concentrations are required during cabozantinib treatment.

Thyroid function disorders

All patients should undergo laboratory monitoring of thyroid function before starting the medicinal product. Patients with pre-existing hypothyroidism or hyperthyroidism should be treated according to standard medical practice before initiating cabozantinib therapy. During cabozantinib treatment, all patients should be closely monitored for signs and symptoms of thyroid dysfunction, and thyroid function should be periodically assessed. Patients who develop thyroid dysfunction should be managed according to standard medical practice, depending on the type of dysfunction identified.

Atypical blood biochemistry results

Cabozantinib use is associated with an increased frequency of electrolyte imbalances (including hypo- and hyperkalemia, hypomagnesemia, hypocalcemia, hyponatremia). Biochemical blood parameters should be monitored during cabozantinib treatment, and appropriate replacement therapy should be administered as needed according to clinical practice standards. Hepatic encephalopathy in HCC patients may be explained by electrolyte imbalances occurring during treatment. If serious laboratory parameter deviations persist or recur periodically, consideration should be given to interrupting therapy, reducing the dose, or permanently discontinuing cabozantinib (see Table 5).

CYP3A4 inhibitors and inducers

Cabozantinib is a substrate of CYP3A4. Concomitant administration of cabozantinib with the CYP3A4 inhibitor ketoconazole may lead to a marked increase in cabozantinib exposure. Particular caution is required when strong CYP3A4 inhibitors are used concomitantly with cabozantinib. Concomitant use of cabozantinib with strong CYP3A4 inducers, such as rifampicin, may reduce cabozantinib exposure and distribution. Therefore, concomitant use of agents that are strong CYP3A4 inducers with cabozantinib should be avoided (see sections "Dosage and administration" and "Interaction with other medicinal products and other forms of interaction").

P-glycoprotein substrate

Cabozantinib is an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-glycoprotein (P-gp) transport activity in a bidirectional system using cells engineered to express P-glycoprotein (MDCK–MDR1). Concomitant use of P-gp inhibitors may increase cabozantinib plasma concentrations. Patients should be advised about the use of medicinal products affecting P-gp (such as fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan) during cabozantinib treatment (see section "Interaction with medicinal products and other forms of interaction").

MRP2 inhibitors

Administration of MRP2 inhibitors may increase cabozantinib plasma concentrations. MRP2 inhibitors should be used with caution (including cyclosporine, efavirenz, emtricitabine) (see section "Interaction with medicinal products and other forms of interaction").

Warnings regarding excipients

Patients with rare hereditary galactose intolerance, complete lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

One 20 mg film-coated tablet contains 15.54 mg of lactose.

One 40 mg film-coated tablet contains 31.07 mg of lactose.

One 60 mg film-coated tablet contains 46.61 mg of lactose.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Any unused medicinal product or waste material should be disposed of in accordance with hospital practice standards.

Use during pregnancy or breastfeeding

Fertile women/contraception for men and women

Women of childbearing potential should avoid pregnancy during treatment with cabozantinib. Women whose partners are receiving cabozantinib should avoid pregnancy. Women of childbearing potential and men should use effective contraceptive methods during treatment and for 4 months after completion of treatment. Since oral contraceptives may not be considered effective contraceptive methods, additional preventive measures should be taken if they are used (see section "Interaction with medicinal products and other forms of interaction").

Pregnancy

There are no data on the use of cabozantinib in pregnant women. Animal studies have shown embryofetal and teratogenic effects. The potential risk to humans is unknown. Cabozantinib should not be used during pregnancy except in cases of urgent clinical necessity.

Breastfeeding

It is unknown whether cabozantinib or its metabolites are excreted in human breast milk. The risk to the breastfed infant cannot be excluded; therefore, breastfeeding must be discontinued during treatment with cabozantinib and for at least 4 months after the end of treatment.

Fertility

There are no data on the effect of cabozantinib on human fertility. Study results indicate that cabozantinib may have a negative effect on fertility in both men and women. Men and women should use effective contraceptive methods during treatment.

Ability to affect reaction speed when driving or operating machinery

Cabozantinib has a minor influence on the ability to drive vehicles or operate machinery. During treatment, some patients have reported adverse reactions such as fatigue and weakness. Caution should be exercised when driving or operating machinery during treatment.

Method of administration and dosage

Treatment with the medicinal product CABOMETYX should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Method of administration

CABOMETYX is intended for oral administration. Tablets should be swallowed whole, without crushing. Patients should not eat for 2 hours before and at least 1 hour after administration of CABOMETYX.

Dosage

CABOMETYX tablets and cabozantinib capsules are not bioequivalent and should not be used interchangeably (see section "Pharmacokinetics").

As monotherapy

The recommended dose of CABOMETYX for the treatment of RCC and HCC is 60 mg once daily. Treatment should continue until the patient no longer derives clinical benefit or until unacceptable toxicity occurs.

Recommended dose modifications

Suspected adverse reactions may require temporary interruption and/or reduction of the dose of CABOMETYX (see Table 5). If necessary, the dose should be reduced to 40 mg once daily, and then to 20 mg once daily.

In the event of grade 3 or higher toxicity according to CTCAE (Common Terminology Criteria for Adverse Events) or intolerable grade 2 toxicity, treatment should be temporarily withheld. Dose reduction is recommended in case of severe or intolerable manifestations of toxicity.

A missed dose should not be taken if less than 12 hours remain before the next scheduled dose.

Table 5

Recommended dose modifications of CABOMETYX and required actions in the event of adverse reactions

Note: Criteria for assessing the severity of adverse reactions according to NCI-CTCAE v4.

Concomitant Medications

Concomitant use of strong CYP3A4 inhibitors should be approached with caution, and concomitant long-term use of strong CYP3A4 inducers should be avoided (see sections "Special Warnings and Precautions for Use" and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Consider selecting an alternative concomitant medicinal product with no or minimal inhibitory activity toward the CYP3A4 isoenzyme.

Special Patient Groups

Elderly Patients

Elderly patients (≥ 65 years of age) do not require dose adjustment of cabozantinib.

Ethnicity

Dose adjustment based on patient's ethnicity is not required (see section "Pharmacokinetics").

Patients with Renal Impairment

Cabozantinib should be administered with caution to patients with mild or moderate renal impairment.

Cabozantinib is contraindicated in patients with severe renal impairment, as the safety and efficacy of cabozantinib in this patient population have not been established.

Patients with Hepatic Impairment

Dose adjustment is not required in patients with mild hepatic impairment. Since only limited data are available on the use of cabozantinib in patients with moderate hepatic impairment (Child-Pugh class B), no dosing recommendations can be provided. For these patients, monitoring of overall safety is recommended (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics"). Due to the lack of clinical experience with cabozantinib in patients with severe hepatic impairment (Child-Pugh class C), cabozantinib is not recommended for use in this patient population (see section "Pharmacokinetics").

Patients with Cardiac Impairment

Data on use in patients with cardiac impairment are limited. There are no specific dosing recommendations for this patient population.

Children

The safety and efficacy of cabozantinib in children and adolescents (< 18 years of age) have not been established. Appropriate data are lacking. Do not use in children.

Overdose

There is no specific treatment for cabozantinib overdose, and potential overdose symptoms have not been established. In case of suspected overdose, cabozantinib administration should be discontinued and supportive therapy initiated. Laboratory biochemical parameters and metabolic parameters should be monitored, at least weekly or more frequently if clinically indicated. Adverse reactions associated with overdose should be treated symptomatically.

Adverse Reactions

Summary of Safety Profile

The most common serious adverse reactions in patients with RCC (incidence ≥ 1%) are pneumonia, abdominal pain, diarrhea, nausea, arterial hypertension, embolism, hyponatremia, pulmonary embolism, vomiting, dehydration, fatigue, asthenia, decreased appetite, deep vein thrombosis, dizziness, hypomagnesemia, and palmar-plantar erythrodysesthesia syndrome (PPES).

The most common adverse reactions of any grade (observed in at least 25% of patients) in patients with RCC were diarrhea, fatigue, nausea, decreased appetite, PPES, arterial hypertension, weight decrease, vomiting, dysgeusia, constipation, and increased AST. Arterial hypertension was observed more frequently in RCC patients who had not previously received VEGF-targeted therapy (67%) compared to those who had previously received VEGF-targeted agents (37%).

The most common serious adverse reactions in patients with HCC (incidence ≥ 1%) are hepatic encephalopathy, asthenia, fatigue, PPES, diarrhea, hyponatremia, vomiting, abdominal pain, and thrombocytopenia.

The most common adverse reactions of any grade (observed in at least 25% of patients) in patients with HCC were diarrhea, decreased appetite, fatigue, nausea, PPES, arterial hypertension, and vomiting. The list of adverse reactions is presented in Table 6.

In Table 6, adverse reactions observed during clinical trials or in the post-marketing period with cabozantinib are categorized by system organ classes according to MedDRA terminology and classified by frequency based on data for all severity grades as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), and not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are listed in descending order of severity.

Table 6

Adverse Drug Reactions (ADRs) reported during clinical studies or in the post-marketing period with cabozantinib

* Description of selected adverse reactions for further characterization.

The following terms were grouped to correspond to the frequency classification:

1 Decreased hematological parameters: lymphopenia and decreased lymphocyte count; neutropenia and decreased neutrophil count; thrombocytopenia and decreased platelet count.

2 Decreased biochemical parameters: hypoproteinemia and decreased blood protein; hypoalbuminemia and decreased blood albumin; hypocalcemia and decreased blood calcium; hypoglycemia and decreased blood glucose; hypokalemia and decreased blood potassium; hypomagnesemia and decreased blood magnesium; hyponatremia and decreased blood sodium; hypophosphatemia and decreased blood phosphorus.

3 Increased biochemical parameters: increased blood cholesterol and hypercholesterolemia; hyperbilirubinemia and increased blood bilirubin; hyperglycemia and increased blood glucose; hypothyroidism and increased thyroid-stimulating hormone in blood; hyperkalemia and increased blood potassium; increased blood triglycerides and hypertriglyceridemia.

4 Abdominal pain, abdominal discomfort, upper abdominal pain, lower abdominal pain.

5 Hypertension and increased blood pressure.

6 Impaired wound healing and surgical site complications.

Description of individual adverse reactions

Data on the following reactions in patients receiving CABOMETYX at a dose of 60 mg once daily (orally) were obtained from pivotal studies in patients with RCC following VEGF-targeted therapy, treatment-naïve patients with RCC, and patients with HCC following prior systemic therapy (see section "Pharmacodynamics").

Gastrointestinal perforation

In the RCC study following VEGF-targeted agents (METEOR), grade 2 or 3 gastrointestinal perforation was reported in 0.9% of patients with renal cell carcinoma receiving cabozantinib (3 out of 331). The median time to onset of perforations was 10 weeks.

In the RCC study in treatment-naïve patients (CABOSUN), grade 4 and 5 gastrointestinal perforation was observed in 2.6% (2 out of 78) of patients receiving cabozantinib.

In the HCC study (CELESTIAL), grade 3 or 4 gastrointestinal perforation was observed in 0.9% of patients treated with cabozantinib (4 out of 467). The median time to onset of perforations was 5.9 weeks.

In the clinical development program of cabozantinib, cases of perforation with fatal outcome were reported.

Hepatic encephalopathy

In the HCC study (CELESTIAL), hepatic encephalopathy (hepatic encephalopathy, encephalopathy, hyperammonemic encephalopathy) was reported in 5.6% of patients receiving cabozantinib (26 out of 467). Grade 3–4 reactions occurred in 2.8%; one case of grade 5 (0.2%) was also reported. The median time to onset of encephalopathy was 5.9 weeks. Hepatic encephalopathy was not reported in the RCC studies (METEOR and CABOSUN).

Diarrhea

In the RCC study following prior VEGF-targeted therapy (METEOR), diarrhea was reported in 74% of patients receiving cabozantinib (245 out of 331). Grade 3–4 reactions occurred in 11%. The median time to onset of diarrhea was 4.9 weeks.

In the RCC study in treatment-naïve patients (CABOSUN), diarrhea was observed in 73% of patients receiving cabozantinib (57 out of 78). Grade 3–4 reactions occurred in 10% of cases.

In the HCC study (CELESTIAL), diarrhea was observed in 54% of patients receiving cabozantinib (251 out of 467); grade 3–4 reactions occurred in 9.9%. The median time to onset of these events was 4.1 weeks. Dose modifications, treatment interruption, and complete discontinuation due to diarrhea occurred in 84 out of 467 (18%), 69 out of 467 (15%), and 5 out of 467 (1%) patients, respectively.

Fistula

In the RCC study following prior VEGF-targeted therapy (METEOR), fistulas were observed in 1.2% (4 out of 331) of patients receiving cabozantinib, including rectal fistulas in 0.6% (2 out of 331). One case was classified as a grade 3 adverse reaction and the remainder as grade 2. The median time to onset of fistula was 30.3 weeks.

Fistulas were not observed in the RCC study in treatment-naïve patients (CABOSUN).

In the HCC study (CELESTIAL), fistulas were observed in 1.5% (7 out of 467) of patients with HCC. The median time to onset of fistula was 14 weeks.

In the clinical development program of cabozantinib, cases of fistula with fatal outcomes were reported.

Bleeding

In the RCC study following prior VEGF-targeted therapy (METEOR), the incidence of severe hemorrhagic events (grade ≥3) was 2.1% in RCC patients receiving cabozantinib (7 out of 331). The median time to onset of bleeding was 20.9 weeks.

In the RCC study in treatment-naïve patients (CABOSUN), the incidence of severe hemorrhagic events (grade ≥3) was 5.1% (4 out of 78) in RCC patients receiving cabozantinib.

In the HCC study (CELESTIAL), the incidence of severe hemorrhagic events (grade ≥3) was 7.3% in patients receiving cabozantinib (34 out of 467). The median time to onset of bleeding was 9.1 weeks.

In the clinical development program of cabozantinib, cases of bleeding with fatal outcomes were reported.

Reversible posterior leukoencephalopathy syndrome (RPLS)

No cases of RPLS were reported in the METEOR, CABOSUN, or CELESTIAL studies, but rare cases of RPLS were reported in other clinical trials (2 out of 4872 patients; 0.04%).

Hypothyroidism

In the RCC study following VEGF-targeted agents (METEOR), hypothyroidism was reported in 21% of patients (68 out of 331).

In the RCC study in treatment-naïve patients (CABOSUN), hypothyroidism was reported in 23% of patients (18 out of 78) receiving cabozantinib.

In the HCC study (CELESTIAL), hypothyroidism was reported in 8.1% of patients (38 out of 467) receiving cabozantinib, with grade 3 reactions in 0.4% (2 out of 467).

Reporting of adverse reactions

Reporting of adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life.

4 years.

Storage conditions.

The medicinal product does not require special storage conditions. Keep out of reach and sight of children.

Packaging.

20 mg: 7 film-coated tablets in a blister; 4 blisters in a cardboard box, or 30 film-coated tablets in a high-density polyethylene (HDPE) bottle with a child-resistant polypropylene closure, containing three 1 g silica gel desiccant containers and polyester fiber; 1 bottle in a cardboard box;

40 mg: 7 film-coated tablets in a blister; 4 blisters in a cardboard box, or 30 film-coated tablets in a high-density polyethylene (HDPE) bottle with a child-resistant polypropylene closure, containing three 1 g silica gel desiccant containers and polyester fiber; 1 bottle in a cardboard box;

60 mg: 7 film-coated tablets in a blister; 4 blisters in a cardboard box, or 30 film-coated tablets in a high-density polyethylene (HDPE) bottle with a child-resistant polypropylene closure, containing three 1 g silica gel desiccant containers and polyester fiber; 1 bottle in a cardboard box.

Prescription status.

Prescription only.

Manufacturers.

Rottendorf Pharma GmbH, Germany.

Patheon France.

Tjoapak Netherlands B.V.

Manufacturer addresses.

Ostenfelder Strasse 51-61, Ennigerloh, North Rhine-Westphalia, 59320, Germany.

40 Boulevard de Champert, Bourgoin-Jallieu, 38300, France.

Nieuwe Donk 9, Etten-Leur, 4879AC, Netherlands.

Marketing authorization holder.

IPSEN PHARMA.

Address of the marketing authorization holder.

70, Boulevard Victor, 75015 Paris, France