PRESCRIBING INFORMATION (Great Britain)
Cabozantinib Ipsen^® (cabozantinib)

See full Summary of Product Characteristics (SmPC) before prescribing. Available at www.medicines.org.uk.

Presentation: Film-coated unscored tablets containing cabozantinib (S)-malate equivalent to 20 mg, 40 mg and 60 mg cabozantinib. Indications: Cabozantinib Ipsen monotherapy treatment of advanced renal cell carcinoma (RCC) as first line treatment of adult patients with intermediate or poor risk per IMDC criteria or adults following prior vascular endothelial growth factor (VEGF)-targeted therapy. Cabozantinib Ipsen in combination with nivolumab for the first-line treatment of advanced renal cell carcinoma in adults. Dosage: Cabozantinib presentations (tablets and capsules) are not bioequivalent and should not be used interchangeably. Therapy with Cabozantinib Ipsen should be initiated by a physician experienced in the administration of anticancer medicinal products. As monotherapy recommended dose is 60 mg orally once daily. Continue until no further clinical benefit or unacceptable toxicity. In combination with nivolumab, recommended dose is 40 mg orally once daily with nivolumab administered intravenously at either 240 mg every 2 weeks or 480 mg every 4 weeks. Continue Cabozantinib Ipsen until further disease progression or unacceptable toxicity. Continue nivolumab until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. Cabozantinib Ipsen therapy may be temporarily interrupted and/or dose reduced to manage suspected adverse reactions. The safety and efficacy of cabozantinib in children and adolescents aged <18 years has not yet been established. Please refer to the Cabozantinib Ipsen and nivolumab SmPCs for full information on dosage, dosing in special populations and dosing modifications for adverse reactions. Method of Administration: Tablets should be swallowed whole and not crushed. Patients should not eat anything for at least 2 hours before and for 1 hour after taking Cabozantinib Ipsen. Missed doses should not be taken if it is less than 12 hours before the next dose. Contraindications: Hypersensitivity to the active substance or any of the excipients. Special warnings and precautions: Monitor closely for toxicity during first 8 weeks of therapy to determine if dose modifications are warranted. Adverse reactions that generally have early onset include hypocalcaemia, hypokalaemia, thrombocytopenia, hypertension, palmar-plantar erythrodysaesthesia syndrome (PPES), proteinuria, and gastrointestinal (GI) events. Closer monitoring of overall safety is recommended for patients with mild or moderate hepatic impairment. Hepatotoxicity: Liver function tests should be performed before initiation and monitored closely during treatment. If liver function worsens and is considered related to cabozantinib treatment, dose modification should be performed as per the SmPC. Cabozantinib Ipsen is not recommended for use in patients with severe hepatic impairment. Hepatic encephalopathy: In the HCC study (CELESTIAL), hepatic encephalopathy was reported more frequently in the cabozantinib arm than the placebo arm. Patients should be monitored for signs and symptoms of hepatic encephalopathy. Perforations and fistulas: Serious GI perforations and fistulas, sometimes fatal, have been observed with cabozantinib. Patients with inflammatory bowel disease, GI tumour infiltration or complications from prior GI surgery should be evaluated prior to therapy and monitored closely; if perforation or unmanageable fistula occur, discontinue cabozantinib. Gastrointestinal disorders: Diarrhoea, nausea/vomiting, decreased appetite and stomatitis/oral pain were some of the most commonly reported GI adverse reactions. Prompt medical management, including supportive care should be instituted to prevent dehydration, electrolyte imbalances and weight loss. Dose interruption/reduction or discontinuation should be considered for persistent/recurrent GI adverse reactions. Thromboembolic events: Events of venous thromboembolism, including pulmonary embolism, and 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. Discontinue if acute myocardial infarction or other significant thromboembolic complication occurs. Haemorrhage: Patients who have a history of severe bleeding prior to treatment initiation should be carefully evaluated before initiating cabozantinib therapy. Not recommended for patients that have or are at risk of severe haemorrhage. Aneurysms and artery dissections: The use of VEGF inhibitors in patients with or without hypertension may promote the formation of aneurysm and/or artery dissection. This should carefully be considered in patients with risk factors such as hypertension or history of aneurysm. Thrombocytopenia: Platelet levels should be monitored during treatment and the dose modified according to severity of thrombocytopenia. Wound complications: Treatment should be stopped at least 28 days prior to scheduled surgery (including dental surgery or invasive dental procedures). Hypertension: 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 antihypertensive therapy. In the case of persistent hypertension despite use of anti-hypertensives interrupt treatment until controlled and resume at a reduced dose. Discontinue if persistent hypertension is severe or if hypertensive crisis occurs. Osteonecrosis: Osteonecrosis of the jaw (ONJ) has been observed with cabozantinib. An oral examination should be performed before initiation and periodically during treatment. Treatment should be held at least 28 days prior to scheduled dental surgery or invasive dental procedures, if possible. Use with caution in patients receiving agents associated with ONJ, such as bisphosphonates. If ONJ occurs, discontinue cabozantinib. PPES: Interrupt treatment if severe PPES occurs. Proteinuria: Discontinue treatment in patients who develop nephrotic syndrome. Posterior reversible encephalopathy syndrome (PRES): Discontinue in patients with PRES. QT prolongation: Use with caution in patients with a history of QT prolongation, those on antiarrhythmics or with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. Thyroid dysfunction: Thyroid function tests should be performed before initiation and monitored closely during treatment. Patients with pre-existing hypothyroidism or hyperthyroidism should be treated as per standard medical practice before treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction. Patients who develop thyroid dysfunction should be treated as per standard medical practice. Biochemical lab tests: Increased incidence of electrolyte abnormalities. Monitoring of biochemical parameters during treatment is recommended and appropriate replacement therapies should be used if required. Excipients: Do not use in patients with hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption. The product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”. Interactions: Cabozantinib is a CYP3A4 substrate. Co-administration with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice) may result in an increase in cabozantinib plasma exposure and so should be approached with caution. Coadministration with CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, St John’s Wort) may result in decreased cabozantinib plasma exposure; chronic co-administration with cabozantinib should be avoided. Cabozantinib may increase the plasma concentration of P-glycoprotein substrates (e.g. fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, talinolol, tolvaptan). MRP2 inhibitors (e.g. cyclosporine, efavirenz, emtricitabine) may increase cabozantinib plasma concentrations, so concomitant use should be approached with caution. Bile salt sequestering agents (e.g. cholestyramine and cholestagel) may impact absorption or reabsorption resulting in potentially decreased cabozantinib exposure. No dose adjustment when coadministered with gastric pH modifying agents. The effect of cabozantinib on the pharmacokinetics of warfarin has not been investigated. An interaction with warfarin may be possible. INR values should be monitored in such a combination. Women of childbearing potential/contraception in males and females: Ensure effective measures of contraception (oral contraceptive plus a barrier method) in male and female patients and their partners during therapy and for at least 4 months after treatment. Fertility: Both men and women should be advised to seek advice and consider fertility preservation before treatment. Pregnancy: Cabozantinib Ipsen should not be used during pregnancy unless the clinical condition of the woman requires treatment. Lactation: Discontinue breast-feeding during and for at least 4 months after completing treatment. Adverse reactions – Cabozantinib Ipsen monotherapy: The most common serious adverse reactions in the RCC population are pneumonia, abdominal pain, diarrhoea, nausea, hypertension, embolism, hyponatraemia, pulmonary embolism, vomiting, dehydration, fatigue, asthenia, decreased appetite, deep vein thrombosis, dizziness, hypomagnesaemia and PPES. Frequency of adverse reactions based on all grades: Very common (>1/10): anaemia, thrombocytopenia, hypothyroidism, decreased appetite, hypomagnesaemia, hypokalaemia, hypoalbuminaemia, dysgeusia, headache, dizziness, hypertension, haemorrhage, dysphonia, dyspnoea, cough, diarrhoea, nausea, vomiting, stomatitis, constipation, abdominal pain, dyspepsia,  PPES, rash, pain in extremity, fatigue, mucosal inflammation, asthenia, peripheral, weight decreased, serum ALT increased and AST increased. Common (>1/100 to <1/10): abscess, pneumonia, neutropenia, lymphopenia, dehydration, hypophosphataemia, hyponatraemia, hypocalcaemia, hyperkalaemia, hyperbilirubinemia, hyperglycaemia, hypoglycaemia, peripheral neuropathy, tinnitus, venous thrombosis,  pulmonary embolism, gastrointestinal perforation, pancreatitis, fistula, gastroesophageal reflux disease, haemorrhoids, oral pain, dry mouth, dysphagia,  hepatic encephalopathy, pruritus, alopecia, dry skin, dermatitis, acneiform, hair colour change, hyperkeratosis, erythema, muscle spasms, arthralgia, proteinuria, blood ALP increased, GGT increased, blood creatinine increased, amylase increased, lipase increased, blood cholesterol increased and blood triglycerides increased. Uncommon (>1/1000 to <1/100): convulsion, cerebrovascular accident, posterior reversible encephalopathy syndrome, acute myocardial infarction, hypertensive crisis, arterial thrombosis,  pneumothorax, glossodynia, hepatitis cholestatic,  osteonecrosis of the jaw and wound complications. Frequency not known: aneurysms and artery dissections, and cutaneous vasculitis. Adverse reactions – Cabozantinib Ipsen in combination with nivolumab: The most common serious adverse reactions in the RCC population are diarrhoea, pneumonitis, pulmonary embolism, pneumonia, hyponatremia, pyrexia, adrenal insufficiency, vomiting, dehydration. Very common (>1/10): upper respiratory tract infection, hypothyroidism, hyperthyroidism, decreased appetite, dysgeusia, dizziness, headache, hypertension, dysphonia, dyspnoea, cough, diarrhoea, vomiting, nausea, constipation, stomatitis, abdominal pain, dyspepsia, PPES, rash, pruritus, musculoskeletal pain, arthralgia, muscle spasm, proteinuria, fatigue, pyrexia, oedema, increased ALT, increased AST, hypophosphataemia, hypocalcaemia, hypomagnesaemia, hyponatraemia, hyperglycaemia, lymphopaenia, increased alkaline phosphatase, increased lipase, increased amylase, thrombocytopaenia, increased creatinine, anaemia, leucopoenia, hyperkalaemia, neutropaenia, hypercalcaemia, hypoglycaemia, hypokalaemia, increased total bilirubin, hypermagnesaemia, hypernatraemia and weight decreased. Common (>1/100 to <1/10): pneumonia, eosinophilia, hypersensitivity (including anaphylactic reaction), adrenal insufficiency, dehydration, peripheral neuropathy, tinnitus, dry eye, blurred vision, atrial fibrillation, tachycardia, thrombosis, pneumonitis, pulmonary embolism, epistaxis, pleural effusion, colitis, gastritis, oral pain, dry mouth, haemorrhoids, hepatitis, alopecia, dry skin, erythema, hair colour change, arthritis, renal failure, acute kidney injury, pain, chest pain, blood cholesterol increased and hypertriglyceridaemia. Uncommon (>1/1000 to <1/100): infusion related hypersensitivity reaction, hypophysitis, thyroiditis, encephalitis autoimmune, Guillain-Barré syndrome, myasthenic syndrome, uveitis, myocarditis, pneumothorax, pancreatitis, small intestine perforation, glossodynia, psoriasis, urticaria, myopathy, osteonecrosis of the jaw, fistula and nephritis. Frequency not known: cutaneous vasculitis. Refer to the SmPC for nivolumab prior to initiation of treatment. Selected adverse reactions: GI perforation, hepatic encephalopathy, diarrhoea, fistulas, haemorrhage, PRES, elevated liver enzymes in combination with nivolumab in RCC and hypothyroidism. Prescribers should consult the SmPCs in relation to other adverse reactions. Legal category: POM. Basic NHS cost: £5143 per bottle Package quantity: Bottles containing 30 film-coated tablets. Marketing authorisation numbers: PLGB 28247/0001, 002 and 003. Marketing authorisation holder: Ipsen Pharma, 65 quai Georges Gorse, 92100 Boulogne-Billancourt, France. Further information can be obtained from IPSEN Ltd,5th Floor, The Point, 37 North Wharf Road, London, W2 1AF. Tel: 01753 627777. Cabozantinib Ipsen^® is a registered trademark. Date of preparation of PI: July 2024. CBZ-UK-000193