COMETRIQ Hard capsule Ref.[116727] Active ingredients: Cabozantinib

Dose reductions and dose interruptions occurred in 79% and 72%, respectively, of cabozantinib-treated patients in the pivotal clinical study. Two dose reductions were required in 41% of patients. The median time to first dose reduction was 43 days, and to first dose interruption was 33 days. Close monitoring of patients is therefore recommended during the first eight weeks of therapy (see section 4.2).

Hepatotoxicity

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 cabozantinb treatment (i.e., where no alternative cause is evident), the dose should be reduced or treatment interrupted following recommendations provided in section 4.2.

Perforations, fistulas, and intra-abdominal abscesses

Serious gastrointestinal (GI) perforations and fistulas, sometimes fatal, and intra-abdominal abscesses have been observed with cabozantinib. Patients who have had recent radiotherapy, have inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, peritonitis, or diverticulitis), have tumour infiltration of trachea, bronchi, or oesophagus, have complications from prior GI surgery (particularly when associated with delayed or incomplete healing), or have complications from prior radiation therapy to the thoracic cavity (including mediastinum) should be carefully evaluated before initiating cabozantinib therapy and subsequently they should be monitored closely for symptoms of perforations and fistulas. Non GI fistula should be ruled out as appropriate in cases of onset of mucositis after start of therapy. Cabozantinib should be discontinued in patients who experience a GI perforation or a GI or non-GI fistula.

Thromboembolic events

Events of venous thromboembolism, including pulmonary embolism and events of arterial thromboembolism, sometimes fatal, 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. Cabozantinib should be discontinued in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Haemorrhage

Severe haemorrhage, sometimes fatal, has been observed with cabozantinib. Patients who have evidence of involvement of the trachea or bronchi by tumour or a history of haemoptysis prior to treatment initiation should be carefully evaluated before initiating cabozantinib therapy. Cabozantinib should not be administered to patients with serious haemorrhage or recent haemoptysis.

Aneurysms and artery dissections

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating cabozantinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

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). 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 section 4.2).

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 or invasive dental procedures, 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.

Hypertension

Hypertension, including hypertensive crisis, has been observed with cabozantinib. Blood pressure should be well-controlled prior to initiating cabozantinib. After cabozantinib initiation blood pressure should be monitored early and regularly and treated as needed with appropriate anti-hypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensives, the cabozantinib treatment should be interrupted until blood pressure is controlled, after which cabozantinib can be resumed at a reduced dose. 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.

Cardiac Failure

Cabozantinib has been associated with an increased risk of cardiac failure. This risk may be exacerbated by common adverse drug reactions of cabozantinib (e.g. hypertension, hypothyroidism and arterial thrombotic events), which can lead to cardiac failure. Patients should be monitored for signs and symptoms of cardiac failure throughout treatment. These adverse events should be managed promptly, dose interruptions and/or adjustments should be considered if necessary (see section 4.2) and TKI therapy should be discontinued in patients who develop severe cardiac failure.

Osteonecrosis

Events of osteonecrosis of the jaw (ONJ) have been observed with cabozantinib. An oral examination should be performed prior to initiation of cabozantinib and periodically during cabozantinib therapy. Patients should be advised regarding oral hygiene practice. Cabozantinib treatment should be held at least 28 days prior to scheduled dental surgery or invasive dental procedures, if possible. Caution should be used in patients receiving agents associated with ONJ, such as bisphosphonates. Cabozantinib should be discontinued in patients who experience ONJ.

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.

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.

Posterior reversible encephalopathy syndrome

Posterior reversible encephalopathy syndrome (PRES) has been observed with cabozantinib. PRES should be considered in any patient presenting with symptoms suggestive of the diagnosis, including seizures, headache, visual disturbances, confusion or altered mental function. Cabozantinib treatment should be discontinued in patients with PRES.

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. Concomitant treatment with strong CYP3A4 inhibitors, which may increase cabozantinib plasma concentrations, should be used with caution.

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).

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.

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.

Excipient

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially "sodium-free".

Effect of other medicinal products on cabozantinib

CYP3A4 inhibitors and inducers

Administration of the strong CYP3A4 inhibitor ketoconazole (400 mg daily for 27 days) to healthy volunteers decreased cabozantinib clearance (by 29%) and increased single-dose plasma cabozantinib exposure (AUC) by 38%. Therefore, co-administration of strong CYP3A4 inhibitors (e.g., ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice) with cabozantinib should be approached with caution.

Administration of the strong CYP3A4 inducer rifampicin (600 mg daily for 31 days) to healthy volunteers increased cabozantinib clearance (4.3-fold) and decreased single-dose plasma cabozantinib exposure (AUC) by 77%. Chronic co-administration of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampicin, phenobarbital or herbal preparations containing St. John's Wort [Hypericum perforatum]) with cabozantinib should therefore be avoided.

Gastric pH modifying agents

Co-administration of proton pump inhibitor (PPI) esomeprazole (40 mg daily for 6 days) with a single dose of 100 mg cabozantinib to healthy volunteers resulted in no clinically significant effect on plasma cabozantinib exposure (AUC). No dose adjustment is indicated when gastric pH modifying agents (i.e., PPIs, H2 receptor antagonists, and antacids) are co-administered with cabozantinib.

MRP2 inhibitors

In vitro data demonstrate that cabozantinib is a substrate of MRP2. Therefore, administration of MRP2 inhibitors may result in increases in cabozantinib plasma concentrations.

Bile salt-sequestering agents

Bile salt-sequestering agents such as cholestyramine and cholestagel may interact with cabozantinib and may impact absorption (or reabsorption) resulting in potentially decreased exposure (see section 5.2). 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 investigated. As unchanged contraceptive effect may not be guaranteed, an additional contraceptive method, such as a barrier method, is recommended. Because of high plasma protein binding levels of cabozantinib (section 5.2) a plasma protein displacement interaction with warfarin may be possible. In case of such combination, INR values should be monitored.

P-glycoprotein substrates

Cabozantinib was an inhibitor (IC₅₀ = 7.0 μM), but not a substrate, of 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.

Women of childbearing potential/Contraception in males and females

Women of childbearing potential must be advised to avoid pregnancy while on cabozantinib. Female partners of male patients taking cabozantinib must also avoid pregnancy. Effective methods of contraception should be used by male and female patients and their partners during therapy, and for at least 4 months after completing therapy. Because oral contraceptives might possibly not be considered as "effective methods of contraception", they should be used together with another method, such as a barrier method (see section 4.5).

Pregnancy

There are no studies in pregnant women using cabozantinib. Studies in animals have shown embryo-foetal and teratogenic effects (see section 5.3). The potential risk for humans is unknown. Cabozantinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with cabozantinib.

Breast-feeding

It is not known whether cabozantinib and/or its metabolites are excreted in human milk. Because of the potential harm to the infant, mothers should discontinue breast-feeding during treatment with cabozantinib, and for at least 4 months after completing therapy.

Fertility

There are no data on human fertility. Based on non-clinical safety findings, male and female fertility may be compromised by treatment with cabozantinib (see section 5.3). Both men and women should be advised to seek advice and consider fertility preservation before treatment.

Cabozantinib has minor influence on the ability to drive and use machines. Adverse reactions such as fatigue and weakness have been associated with cabozantinib. Therefore, caution should be recommended when driving or operating machines.

Summary of safety profile The most common serious adverse reactions associated with cabozantinib are pneumonia, mucosal inflammation, hypocalcaemia, dysphagia, dehydration, pulmonary embolism, and hypertension. The most frequent adverse reactions of any grade (experienced by at least 20% of patients) included diarrhoea, PPES, weight decreased, decreased appetite, nausea, fatigue, dysgeusia, hair colour changes, hypertension, stomatitis, constipation, vomiting, mucosal inflammation, asthenia, and dysphonia.

The most common laboratory abnormalities were increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased alkaline phosphatase (ALP), lymphopenia, hypocalcaemia, neutropenia, thrombocytopenia, hypophosphatemia, hyperbilirubinemia, hypomagnesaemia, and hypokalaemia.

Tabulated list of adverse reactions

Adverse reactions are listed in Table 1 according to MedDRA system organ class and frequency categories. Frequencies are based on all grades and defined as very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions reported with cabozantinib:

^* See section 4.8 Description of selected adverse reactions for further characterisation.
The following terms have been combined to derive appropriate frequency categorisation:
^a Lowered haematology parameters: Lymphopenia and lymphocyte count decreased; Neutropenia and neutrophil count decreased; Thrombocytopenia and platelet count decreased.
^b Elevated haematology parameters: Eosinophil count increased and eosinophilia; Platelet count increased and thrombocytosis
^c Lowered biochemistry parameters: Hypoalbuminaemia and blood albumin decreased; Hypocalcaemia and blood calcium decreased; Hypokalaemia and blood potassium decreased; Hypomagnesaemia and blood magnesium decreased; Hypohosphatemia and blood phosphorus decreased.
^d Elevated biochemistry parameters: Hyperbilirubinaemia and blood bilirubin increased; Hypothyroidism and blood thyroid stimulating hormone increased.
^e Abdominal pain, abdominal discomfort, abdominal pain upper and abdominal pain lower
^f Hypertension and blood pressure increased.
^g Hypotension and blood pressure decreased.
^h No hypertensive crisis was reported in Cometriq clinical studies; the frequency is based on pooled cabozantinib data (including Cabometyx 60 mg tablet data).

Description of selected adverse reactions

A thyroid stimulating hormone (TSH) value above normal after first dose was observed in 57% of patients on cabozantinib versus 19% of patients on placebo (regardless of baseline values). Ninety-two percent of patients on the cabozantinib arm had a prior thyroidectomy, and 89% were taking thyroid hormones prior to first dose.

An increase from baseline in corrected QT interval by Fridericia (QTcF) of 10-15 ms on Day 29 (but not on Day 1) following initiation of cabozantinib treatment (at a dose of 140 mg qd) was observed in a controlled clinical study in cancer patients (see section 4.4). This effect was not associated with a change in cardiac wave form morphology or new rhythms. No cabozantinib-treated subjects had a QTcF >500 ms.

Please refer to section 4.4 for recommendations about the monitoring and management of the following adverse events: perforations, fistulas, and intra-abdominal abscesses; thromboembolic events; haemorrhage; aneurysms and artery dissections; gastrointestinal disorders; wound complications; hypertension; osteonecrosis; palmar-plantar erythrodysaesthesia syndrome; proteinuria; and posterior reversible encephalopathy syndrome.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.