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CABOMETYX® (cabozantinib) Safety Information

CABOMETYX® (cabozantinib) Safety Information

As most events can occur early in the course of treatment, the physician should evaluate the patient closely during the first eight weeks of treatment to determine if dose modifications are warranted. Events that generally have early onset include hypocalcaemia, hypokalaemia, thrombocytopenia, hypertension, palmar-plantar erythrodysaesthesia syndrome (PPES), proteinuria, and gastrointestinal (GI) events (abdominal pain, mucosal inflammation, constipation, diarrhoea, vomiting).1

In renal cell carcinoma following prior vascular endothelial growth factor (VEGF) targeted therapy, dose reductions and dose interruptions due to an AE occurred in 59.8% and 70%, respectively, of cabozantinib-treated patients in the pivotal clinical trial (METEOR). 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 was 38 days.1

In treatment-naïve renal cell carcinoma, dose reductions and dose interruptions occurred in 46% and 73%, respectively, of cabozantinib-treated patients in the clinical trial (CABOSUN).1

In hepatocellular carcinoma following prior systemic therapy, dose reductions and dose interruptions occurred in 62% and 84%, respectively, of cabozantinib-treated patients in the clinical trial (CELESTIAL). Two dose reductions were required in 33% of patients. The median time to first dose reduction was 38 days, and to first dose interruption was 28 days. Closer monitoring is advised in patients with mild or moderate hepatic impairment.1

Hepatic effects

Abnormalities of liver function tests (increases in alanine aminotransferase [ALT], aspartate aminotransferase [AST] and bilirubin) have been frequently observed in patients treated with cabozantinib. It is recommended to perform liver function tests (ALT, AST and bilirubin) before initiation of cabozantinib treatment and to monitor closely during treatment. For patients with worsening of liver function tests considered related to cabozantinib treatment (i.e. where no alternative cause is evident), the dose modification advice in Table 1 in Section 4.2 of the SmPC should be followed.1

Cabozantinib is eliminated mainly via the hepatic route. Closer monitoring of the overall safety is recommended in patients with mild or moderate hepatic impairment (see also Sections 4.2 and 5.2 of the SmPC). A higher relative proportion of patients with moderate hepatic impairment (Child-Pugh B) developed hepatic encephalopathy with cabozantinib treatment. CABOMETYX is not recommended for use in patients with severe hepatic impairment (Child-Pugh C) as cabozantinib has not been studied in this population and exposure might be increased in these patients.1

Hepatic encephalopathy

In the hepatocellular carcinoma (HCC) study (CELESTIAL), hepatic encephalopathy was reported more frequently in the cabozantinib than the placebo arm. Cabozantinib has been associated with diarrhoea, vomiting, decreased appetite and electrolyte abnormalities. In HCC patients with compromised livers, these non-hepatic effects may be precipitating factors for the development of hepatic encephalopathy. Patients should be monitored for signs and symptoms of hepatic encephalopathy.1

Perforations and fistulas

Serious gastrointestinal (GI) perforations and fistulas, sometimes fatal, have been observed with cabozantinib. Patients who have inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis, peritonitis, diverticulitis, or appendicitis), have tumour infiltration in the GI tract, or have complications from prior GI surgery (particularly when associated with delayed or incomplete healing) should be carefully evaluated before initiating cabozantinib therapy and subsequently they should be monitored closely for symptoms of perforations and fistulas including abscesses and sepsis. Persistent or recurring diarrhoea while on treatment may be a risk factor for the development of anal fistula. Cabozantinib should be discontinued in patients who experience a GI perforation or a fistula that cannot be adequately managed.1

Gastrointestinal (GI) disorders

Diarrhoea, nausea/vomiting, decreased appetite, and stomatitis/oral pain were some of the most commonly reported GI adverse reactions (see Section 4.8 of the SmPC). Prompt medical management, including supportive care with antiemetics, antidiarrhoeals, or antacids, should be instituted to prevent dehydration, electrolyte imbalances and weight loss. Dose interruption or reduction, or permanent discontinuation of cabozantinib should be considered in case of persistent or recurrent significant GI adverse reactions (see Table 1 in Section 4.2 of the SmPC).1

Thromboembolic events

Events of venous thromboembolism, including pulmonary embolism, and events of arterial thromboembolism have been observed with cabozantinib. Cabozantinib should be used with caution in patients who are at risk for, or who have a history of, these events.1

In the HCC study (CELESTIAL), portal vein thrombosis was observed with cabozantinib, including one fatal event. Patients with a history of portal vein invasion appeared to be at higher risk of developing portal vein thrombosis.1

Cabozantinib should be discontinued in patients who develop an acute myocardial infarction or any other clinically significant thromboembolic complication.1

Haemorrhage

Severe haemorrhage, sometimes fatal, has been observed with cabozantinib. Patients who have a history of severe bleeding prior to treatment initiation should be carefully evaluated before initiating cabozantinib therapy. Cabozantinib should not be administered to patients that have or are at risk for severe haemorrhage.1

In the HCC study (CELESTIAL), fatal haemorrhagic events were reported at a higher incidence with cabozantinib than placebo. Predisposing risk factors for severe haemorrhage in the advanced HCC population may include tumour invasion of major blood vessels and the presence of underlying liver cirrhosis resulting in oesophageal varices, portal hypertension, and thrombocytopenia. The CELESTIAL study excluded patients with concomitant anticoagulation treatment or antiplatelet agents. Subjects with untreated, or incompletely treated, varices with bleeding or high risk for bleeding were also excluded from this study.1

Thrombocytopenia

In the HCC study (CELESTIAL), thrombocytopenia and decreased platelets were reported. Platelet levels should be monitored during cabozantinib treatment and the dose modified according to the severity of the thrombocytopenia (see Table 1 in Section 4.2 of the SmPC).1

Wound complications

Wound complications have been observed with cabozantinib. Cabozantinib treatment should be stopped at least 28 days prior to scheduled surgery, including dental surgery, if possible. The decision to resume cabozantinib therapy after surgery should be based on clinical judgment of adequate wound healing. Cabozantinib should be discontinued in patients with wound healing complications requiring medical intervention.1

Hypertension

Hypertension has been observed with cabozantinib. Blood pressure should be well-controlled prior to initiating cabozantinib. During treatment with cabozantinib, all patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensives, the cabozantinib dose should be reduced. Cabozantinib should be discontinued if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of cabozantinib. In case of hypertensive crisis, cabozantinib should be discontinued.1

Palmar-plantar erythrodysaesthesia syndrome

Palmar-plantar erythrodysaesthesia syndrome (PPES) has been observed with cabozantinib. When PPES is severe, interruption of treatment with cabozantinib should be considered. Cabozantinib should be restarted with a lower dose when PPES has been resolved to grade 1.1

Proteinuria

Proteinuria has been observed with cabozantinib. Urine protein should be monitored regularly during cabozantinib treatment. Cabozantinib should be discontinued in patients who develop nephrotic syndrome.1

Reversible posterior leukoencephalopathy syndrome

Reversible Posterior Leukoencephalopathy Syndrome (RPLS), also known as Posterior Reversible Encephalopathy Syndrome (PRES), has been observed with cabozantinib. This syndrome should be considered in any patient presenting with multiple symptoms, including seizures, headache, visual disturbances, confusion or altered mental function. Cabozantinib treatment should be discontinued in patients with RPLS.1

Prolongation of QT interval

Cabozantinib should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. When using cabozantinib, periodic monitoring with on-treatment ECGs and electrolytes (serum calcium, potassium, and magnesium) should be considered.1

Biochemical laboratory test abnormalities

Cabozantinib has been associated with an increased incidence of electrolyte abnormalities (including hypo- and hyperkalaemia, hypomagnesaemia, hypocalcaemia, hyponatremia). It is recommended to monitor biochemical parameters during cabozantinib treatment and to institute appropriate replacement therapy according to standard clinical practice if required. Cases of hepatic encephalopathy in HCC patients can be attributed to the development of electrolyte disturbances. Dose interruption or reduction, or permanent discontinuation of cabozantinib should be considered in case of persistent or recurrent significant abnormalities (see Table 1 in Section 4.2 of the SmPC).1

CYP3A4 inducers and inhibitors

Cabozantinib is a CYP3A4 substrate. Concurrent administration of cabozantinib with the strong CYP3A4 inhibitor ketoconazole resulted in an increase in cabozantinib plasma exposure. Caution is required when administering cabozantinib with agents that are strong CYP3A4 inhibitors. Concurrent administration of cabozantinib with the strong CYP3A4 inducer rifampicin resulted in a decrease in cabozantinib plasma exposure. Therefore chronic administration of agents that are strong CYP3A4 inducers with cabozantinib should be avoided (see Sections 4.2 and 4.5 of the SmPC).1

P-glycoprotein substrates

Cabozantinib was an inhibitor (IC50= 7.0 μM), but not a substrate, of P-glycoprotein (P-gp) transport activities in a bi-directional assay system using MDCK-MDR1 cells. Therefore, cabozantinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp. Subjects should be cautioned regarding taking a P-gp substrate (e.g., fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan) while receiving cabozantinib (see Section 4.5 of the SmPC).1

MRP2 inhibitors

Administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations. Therefore, concomitant use of MRP2 inhibitors (e.g. cyclosporine, efavirenz, emtricitabine) should be approached with caution (see Section 4.5 of the SmPC).1

Excipient related warnings

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.1

© Ipsen Group 2019 Last updated on: October 2019. This site is published by Ipsen, which is solely responsible for the content. It is intended only for healthcare professionals from the EU – excluding France. Healthcare professionals from outside the EU, as well as any non-healthcare professionals, are excluded from the intended audience. CBZ-ALL-001685

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