CABOTRES Tablets (Cabozantinib)

Table of Content

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer with a worldwide incidence of 10.1 cases per 100,000 person-years. Renal cell carcinoma (RCC) encompasses a heterogeneous group of cancers derived from renal tubular epithelial cells and is among the 10 most common cancers worldwide.

Receptor Tyrosine kinase inhibitors (RTKIs) are multitargeted agents capable of inhibiting multiple kinases in nanomole concentration and are gold standard drugs for management of unresectable advanced HCC and RCC.

Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumour growth and angiogenesis, pathologic bone remodelling, drug resistance, and metastatic progression of cancer. Cabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and VEGF (vascular endothelial growth factor) receptors. In addition, cabozantinib inhibits other tyrosine kinases including the GAS6 receptor (AXL), RET, ROS1, TYRO3, MER, the stem cell factor receptor (KIT), TRKB, Fms-like tyrosine kinase-3 (FLT3), and TIE-2.

Cabozantinib targets 3 key drivers of advance RCC and HCC tumorigenesis—MET, AXL, and VEGFR

  • In RCC and HCC tumor cells and cells of the tumor microenvironment, MET, AXL, and VEGF are overexpressed
  • These receptors are involved in normal and pathologic processes such as tumor angiogenesis, invasiveness, metastasis, and immunomodulation of the tumor microenvironment

CABOTRES Tablets are available in strengths of 20 mg /40 mg.

CABOTRES is indicated in  

RCC

CABOTRES Tablets is indicated for the treatment of advanced RCC:

  • in treatment-naïve adults with intermediate or poor risk,
  • in adults following prior VEGF-targeted therapy

HCC

CABOTRES Tablet is indicated as monotherapy for the treatment of HCC in adults who have previously been treated with sorafenib.

 

To be sold by retail on prescription of an Oncologist only.

1.Generic Name

Cabozantinib Tablets 20 mg /40 mg

2.Qualitative and Quantitative Composition

CABOTRES 20

Each film coated tablet contains:

Cabozantinib (S)-malate equivalent to

Cabozantinib.…….………20 mg

Excipients………………...q.s.

Colors: Titanium dioxide IP and Ferric oxide yellow USP-NF

CABOTRES 40

Each film coated tablet contains:

Cabozantinib (S)-malate equivalent to

Cabozantinib.…….………40 mg

Excipients………………...Q.S.

Colors: Titanium dioxide IP and Ferric oxide yellow USP-NF

3.Dosage Form & Strength

CABOTRES 20 mg /40 mg Film-coated tablets for oral use.

4.Clinical Particulars

4.1 Therapeutic Indications

Renal Cell Carcinoma (RCC)

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

  • in treatment-naïve adults with intermediate or poor risk,
  • in adults following prior vascular endothelial growth factor (VEGF)-targeted therapy

Hepatocellular Carcinoma (HCC)

CABOTRES TABLET is indicated as monotherapy for the treatment of hepatocellular carcinoma (HCC) in adults who have previously been treated with sorafenib.

4.2. Posology and Method of Administration

For RCC and HCC, the recommended dose of CABOTRES TABLETS as single agent is 60 mg once daily. Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

Management of suspected adverse drug reactions may require temporary treatment interruption and/or dose reduction of CABOTRES TABLETS therapy (see Below Table). When dose reduction is necessary, it is recommended to reduce to 40 mg daily, and then to 20 mg daily.

Dose interruptions are recommended for management of CTCAE grade 3 or greater toxicities or intolerable grade 2 toxicities. Dose reductions are recommended for events that, if persistent, could become serious or intolerable.

If a patient misses a dose, the missed dose should not be taken if it is less than 12 hours before the next dose.

Recommended CABOTRES TABLETS dose modifications for adverse reactions

Adverse reaction and severity

Treatment Modification

Grade 1 and Grade 2 adverse reactions which are tolerable and easily managed

Dose adjustment is usually not required.

Add supportive care as indicated.

Grade 2 adverse reactions which are intolerable and cannot be managed with a dose reduction or supportive care

Interrupt treatment until the adverse reaction resolves to Grade ≤1.

Add supportive care as indicated.

Consider re-initiating at a reduced dose.

Grade 3 adverse reactions (except clinically nonrelevant laboratory abnormalities)

Interrupt treatment until the adverse reaction resolves to Grade ≤1.

Add supportive care as indicated.

Re-initiate at a reduced dose.

Grade 4 adverse reactions (except clinically nonrelevant laboratory abnormalities)

Interrupt treatment.

Institute appropriate medical care.

If adverse reaction resolves to Grade ≤1, re-initiate at a reduced dose.

If adverse reaction does not resolve, permanently discontinue cabozantinib tablets.

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (NCI-CTCAE v4)

Concomitant Medicinal Products

Concomitant medicinal products that are strong inhibitors of CYP3A4 should be used with caution, and chronic use of concomitant medicinal products that are strong inducers of CYP3A4 should be avoided.

Selection of an alternative concomitant medicinal product with no or minimal potential to induce or inhibit CYP3A4 should be considered.

Special Populations

Elderly patients

No specific dose adjustment for the use of cabozantinib in older people (≥ 65 years) is recommended.

Race

No dose adjustment is necessary based on ethnicity.

Patients with Renal Impairment

Cabozantinib should be used with caution in patients with mild or moderate renal impairment.

Cabozantinib is not recommended for use in patients with severe renal impairment as safety and efficacy have not been established in this population.

Patients with Hepatic Impairment

In patients with mild hepatic impairment no dose adjustment is required. Reduce the starting dose of cabozantinib to 40 mg once daily in patients with moderate hepatic impairment (Child-Pugh B). Close monitoring of overall safety is recommended in these patients. There is no clinical experience in patients with severe hepatic impairment (Child Pugh C), so cabozantinib is not recommended for use in these patients.

Patients with Cardiac Impairment

There is limited data in patients with cardiac impairment. No specific dosing recommendations can be made.

Paediatric Population

The safety and efficacy of cabozantinib in children and adolescents aged <18 years have not yet been established. No data are available.

Dosage Modifications for Coadministration with Strong CYP3A4 Inhibitors

Reduce the daily CABOTRES TABLET dose by 20 mg (for example, from 60 mg to 40 mg daily or from 40 mg to 20 mg daily). Resume the dose that was used prior to initiating the strong CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor

Dosage Modifications for Coadministration with Strong CYP3A4 Inducers

Increase the daily CABOTRES TABLET dose by 20 mg (for example, from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated. Resume the dose that was used prior to initiating the strong CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. Do not exceed a daily dose of 80 mg

Method of Administration

CABOTRES TABLET is for oral use. The tablets should be swallowed whole and not crushed. Do not administer CABOTRES TABLET with food. Administer CABOTRES TABLET at least 1 hour before or at least 2 hours after eating.

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

As most events 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).

Management of suspected adverse reactions may require temporary interruption or dose reduction of cabozantinib therapy.

In RCC 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.

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).

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.

Hepatotoxicity

Abnormalities of liver function tests (increases in alanine aminotransferase , aspartate aminotransferase 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 above Table should be followed. Cabozantinib is eliminated mainly via the hepatic route. Closer monitoring of the overall safety is recommended in patients with mild or moderate hepatic impairment. A higher relative proportion of patients with moderate hepatic impairment (Child-Pugh B) developed hepatic encephalopathy with cabozantinib treatment. Cabozantinib tablets 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.

Hepatic Encephalopathy

In the 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.

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.

Gastrointestinal (GI) 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 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 above Table).

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.

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

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.

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.

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. Before initiating cabozantinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

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 above Table).

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.

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.

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.

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.

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.

Thyroid Dysfunction

Baseline laboratory measurement of thyroid function is recommended in all patients. Patients with pre-existing hypothyroidism or hyperthyroidism should be treated as per standard medical practice prior to the start of cabozantinib treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction during cabozantinib treatment. Thyroid function should be monitored periodically throughout treatment with cabozantinib. Patients who develop thyroid dysfunction should be treated as per standard medical practice.

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 above Table).

Embryo-Fetal Toxicity

Based on data from animal studies and its mechanism of action, cabozantinib can cause fetal harm when administered to a pregnant woman. Cabozantinib administration to pregnant animals during organogenesis resulted in embryolethality at exposures below those occurring clinically at the recommended dose, and in increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Cabozantinib and for 4 months after the last dose

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.

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 related Warnings

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

4.5 Interaction with Other Medicinal Products and Other Forms of Interaction

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 ) 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. 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 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.

4.6 Use in Special Populations (Such as Pregnant Women, Lactating Women, Paediatric Patients, Geriatric Patients etc.)

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.

Pregnant women

There are no studies in pregnant women using cabozantinib. Studies in animals have shown embryo-foetal and teratogenic effects. 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.

 Lactating Women

 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.

Females and Males of Reproductive Potential 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. Both men and women should be advised to seek advice and consider fertility preservation before treatment.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating cabozantinib.

Contraception

Cabozantinib can cause fetal harm when administered to a pregnant woman.

Females

Advise females of reproductive potential to use effective contraception during treatment with

Cabozantinib and for 4 months after the final dose.

Infertility

Females and Males

Based on findings in animals, Cabozantinib may impair fertility in females and males of

reproductive potential.

Pediatric Use

The safety and effectiveness of Cabozantinib in pediatric patients have not been established.

Geriatric Use

In CABOSUN and METEOR, 41% of 409 patients treated with cabozantinib were age 65 years and older, and 8% were 75 years and older. In CELESTIAL, 49% of 467 patients treated with cabozantinib were age 65 years and older, and 15% were 75 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Patients with Hepatic Impairment

Increased exposure to cabozantinib has been observed in patients with moderate (Child-Pugh B) hepatic impairment. Reduce the cabozantinib dose in patients with moderate hepatic impairment. Avoid cabozantinib in patients with severe hepatic impairment (Child-Pugh C), since it has not been studied in this population

Patients with Renal Impairment

No dosage adjustment is recommended in patients with mild or moderate renal impairment. There is no experience with Cabozantinib in patients with severe renal impairment.

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

Cabozantinib as monotherapy

Summary of Safety Profile

The most common serious adverse drug reactions in the RCC population (≥1% incidence) are diarrhoea, hypertension, dehydration, hyponatraemia, nausea, decreased appetite, embolism, fatigue, hypomagnesaemia and palmar-plantar erythrodysaesthesia syndrome (PPES).

The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the RCC population included diarrhoea, hypertension, fatigue, AST increased, ALT increased, nausea, decreased appetite, PPES, dysgeusia, platelet count decreased, stomatitis, anaemia, vomiting, weight decreased, dyspepsia, and constipation. Hypertension was observed more frequently in the treatment naïve RCC population (67%) compared to RCC patients following prior VEGF-targeted therapy (37%).

The most common serious adverse drug reactions in the HCC population (≥1% incidence) are hepatic encephalopathy, palmar-plantar erythrodysaesthesia syndrome, asthenia and diarrhoea.

The most frequent adverse reactions of any grade (experienced by at least 25% of patients) in the HCC population included diarrhoea, palmar-plantar erythrodysaesthesia syndrome, fatigue, decreased appetite hypertension and nausea.

Tabulated list of Adverse Reactions

Adverse reactions are listed in Table below 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.

Adverse drug reactions (ADRs) reported in clinical trials in patients treated with cabozantinib

MedDRA System Organ Class

Very Common

Common

Uncommon

Not Known

Infections and infestations

 

abscess

   

Blood and lymphatic disorders

Anaemia, thrombocytopeniaa

,neutropeniaa, lymphopeniaa

   

Endocrine disorders

hypothyroidismc

     

Metabolism and nutrition disorders

decreased appetite, hypomagnesaemiab, hypokalaemiab, hypoalbuminaemiab

dehydration, hyperglycaemiac, hypoglycaemiab hypophosphataemiab, hypoalbuminaemia, hyponatraemiab, hyperkalaemiac, hypocalcaemiab, hyperbilirubinemiac

   

Nervous system disorders

dysgeusia, headache, dizziness

peripheral neuropathy (including sensory)

convulsion

cerebrovascular accident

Ear and labyrinth disorders

 

tinnitus

   

Cardiac disorders

     

myocardial infarction

Vascular disorders

Hypertensione, haemorrhage*

deep vein thrombosis venous thrombosis

arterial thrombosis

 

aneurysms and artery dissections

Respiratory, thoracic, and mediastinal disorders

dysphonia, dyspnoea, cough

pulmonary embolism

   

Gastrointestinal disorders

Diarrhoea*, nausea, vomiting, stomatitis, constipation, abdominal paind, dyspepsia, upper abdominal pain

gastrointestinal perforation*, fistula*, gastrooesophageal reflux disease, haemorrhoids, oral pain, dry mouth, dysphagia, glossodynia

pancreatitis,

 

Hepatobiliary disorders

 

hepatic encephalopathy*

hepatitis cholestatic

 

Skin and subcutaneous tissue disorders

palmar-plantar erythrodysaesthesia syndrome, rash

pruritus, alopecia, dry skin, dermatitis acneiform, hair colour change, hyperkeratosis

   

Musculoskeletal and connective tissue disorders

pain in extremity

muscle spasms, arthralgia

osteonecrosis of the jaw

 

Renal and urinary disorders

 

proteinuria

   

General disorders and administration site conditions

fatigue, mucosal inflammation, asthenia, peripheral oedema

     

Investigations

weight decreased, serum ALT increased, AST increased,

blood ALP increased, blood creatinine increased, white blood cell count decreased, GGT increased, amylase increased, blood cholesterol increasedc, lipase increased, blood triglycerides increasedc.

   

Injury, poisoning and procedural complications

   

wound complicationsf

 

* 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 Lowered biochemistry parameters: Hypoalbuminaemia and blood albumin decreased; Hypocalcaemia and blood calcium decreased; Hypoglycaemia and blood glucose decreased; Hypokalaemia and blood potassium decreased; Hypomagnesaemia and blood magnesium decreased; Hyponatraemia and blood sodium decreased; Hypohosphataemia and blood phosphorus decreased.

c Elevated biochemistry parameters: Blood cholesterol increased and hypercholesterolaemia; Hyperbilirubinaemia and blood bilirubin increased; Hyperglycaemia and blood glucose increased; Hypothyroidism and blood thyroid stimulating hormone increased; Hyperkalaemia and blood potassium increased; Triglycerides increased and hypertriglyceridaemia.

d Abdominal pain, abdominal discomfort, abdominal pain upper and abdominal pain lower.

e Hypertension and blood pressure increased.

f Impaired healing and incision site complication.

Description of Selected Adverse Reactions

Data for the following reactions are based on patients who received Cabozantinib tablets 60 mg qd po in the pivotal studies in RCC following prior VEGF-targeted therapy and in treatment-naïve RCC and in HCC following prior systemic therapy.

Gastrointestinal (GI) Perforation

In the study in RCC following prior VEGF-targeted therapy (METEOR), GI perforations were reported in 0.9% (3/331) of cabozantinib-treated RCC patients. Events were Grade 2 or 3. Median time to onset was 10.0 weeks.

In the treatment-naïve RCC study (CABOSUN), GI perforations were reported in 2.6% (2/78) of cabozantinib-treated patients. Events were Grade 4 and 5.

In the HCC study (CELESTIAL), GI perforations were reported in 0.9% of cabozantinib-treated patients (4/467). All events were Grade 3 or 4. Median time to onset was 5.9 weeks. Fatal perforations have occurred in the cabozantinib clinical program.

Hepatic Encephalopathy

In the HCC study (CELESTIAL), hepatic encephalopathy (hepatic encephalopathy, encephalopathy, hyperammonaemic encephalopathy) was reported in 5.6% of cabozantinib-treated patients (26/467); Grade 3-4 events in 2.8%, and one (0.2%) Grade 5 event. Median time to onset was 5.9 weeks.

No cases of hepatic encephalopathy were reported in the RCC studies (METEOR and CABOSUN)

Diarrhoea

In the study in RCC following prior VEGF-targeted therapy (METEOR), diarrhoea was reported in 74% of cabozantinib-treated RCC patients (245/331); Grade 3-4 events in 11%. Median time to onset was 4.9 weeks.

In the treatment-naïve RCC study (CABOSUN), diarrhoea was reported in 73% of cabozantinib-treated patients (57/78); Grade 3-4 events in 10%.

In the HCC study (CELESTIAL), diarrhoea was reported in 54% of cabozantinib-treated patients (251/467); Grade 3- 4 events in 9.9%. Median time to onset of all events was 4.1 weeks. Diarrhoea led to dose modifications, interruptions and discontinuations in 84/467 (18%), 69/467 (15%) and 5/467 (1%) of subjects, respectively.

Fistulas

In the study in RCC following prior VEGF-targeted therapy (METEOR), fistulas were reported in 1.2% (4/331) of cabozantinib-treated patients and included anal fistulas in 0.6% (2/331) cabozantinib-treated patients. One event was Grade 3; the remainder was Grade 2. Median time to onset was 30.3 weeks.

In the treatment-naïve RCC study (CABOSUN), no cases of fistulas were reported.

In the HCC study (CELESTIAL), fistulas were reported in 1.5% (7/467) of the HCC patients. Median time to onset was 14 weeks.Fatal fistulas have occurred in the cabozantinib clinical programme.

Haemorrhage

In the study in RCC following prior VEGF-targeted therapy (METEOR), the incidence of severe haemorrhagic events (Grade ≥ 3) was 2.1% (7/331) in cabozantinib-treated RCC patients. Median time to onset was 20.9 weeks.

In the treatment-naïve RCC study (CABOSUN), the incidence of severe haemorrhagic events (Grade ≥ 3) was 5.1% (4/78) in cabozantinib-treated RCC patients.

In the HCC study (CELESTIAL), the incidence of severe haemorrhagic events (Grade ≥ 3) was 7.3% in cabozantinib-treated patients (34/467). Median time to onset was 9.1 weeks.

Fatal haemorrhages have occurred in the cabozantinib clinical program.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

No case of RPLS was reported in the METEOR, CABOSUN or CELESTIAL studies, but RPLS has been reported rarely in other clinical studies (in 2/4872 subjects; 0.04%).

Hypothyroidism

In the study in RCC following prior VEGF-targeted therapy (METEOR), the incidence of hypothyroidism was 21% (68/331).

In the treatment-naïve RCC study (CABOSUN), the incidence of hypothyroidism was 23% (18/78) in cabozantinib-treated RCC patients.

In the HCC study (CELESTIAL), the incidence of hypothyroidism was 8.1% (38/467) in cabozantinib-treated patients and Grade 3 events in 0.4% (2/467).

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.

To report any side effects, write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 18002677779. By reporting side-effects, you can help provide more information on the safety of this product.

4.9 Overdose

There is no specific treatment for cabozantinib overdose and possible symptoms of overdose have not been established.

In the event of suspected overdose, cabozantinib should be withheld and supportive care instituted. Metabolic clinical laboratory parameters should be monitored at least weekly or as deemed clinically appropriate to assess any possible changing trends. Adverse reactions associated with overdose are to be treated symptomatically.

5. Pharmacological Properties

5.1 Mechanism of Action

Cabozantinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumour growth and angiogenesis, pathologic bone remodelling, drug resistance, and metastatic progression of cancer. Cabozantinib was evaluated for its inhibitory activity against a variety of kinases and was identified as an inhibitor of MET (hepatocyte growth factor receptor protein) and VEGF (vascular endothelial growth factor) receptors. In addition, cabozantinib inhibits other tyrosine kinases including the GAS6 receptor (AXL), RET, ROS1, TYRO3, MER, the stem cell factor receptor (KIT), TRKB, Fms-like tyrosine kinase-3 (FLT3), and TIE-2.

5.2 Pharmacodynamic Properties

Cabozantinib exhibited dose-related tumour growth inhibition, tumour regression, and/or inhibited metastasis in a broad range of preclinical tumour models.

Cardiac Electrophysiology

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 medullary thyroid cancer patients. This effect was not associated with a change in cardiac wave form morphology or new rhythms. No cabozantinib-treated subjects in this study had a confirmed QTcF >500 ms, nor did any cabozantinib-treated subjects in the RCC or HCC studies (at a dose of 60 mg).

5.3 Pharmacokinetic properties

Absorption

Following oral administration of cabozantinib, peak cabozantinib plasma concentrations are reached at 3 to 4 hours post-dose. Plasma-concentration time profiles show a second absorption peak approximately 24 hours after administration, which suggests that cabozantinib may undergo enterohepatic recirculation.

Repeat daily dosing of cabozantinib at 140 mg for 19 days resulted in an approximately a 4- to 5-fold mean cabozantinib accumulation (based on AUC) compared to a single dose administration; steady state is achieved by approximately Day 15.

A high-fat meal moderately increased Cmax and AUC values (41% and 57%, respectively) relative to fasted conditions in healthy volunteers administered a single 140 mg oral cabozantinib dose. There is no information on the precise food-effect when taken 1 hour after administration of cabozantinib.

Bioequivalence could not be demonstrated between the cabozantinib capsule and tablet formulations following a single 140 mg dose in healthy subjects. A 19% increase in the Cmax of the tablet formulation compared to the capsule formulation was observed. A less than 10% difference in the AUC was observed between cabozantinib tablet and capsule formulations.

Distribution

Cabozantinib is highly protein bound in vitro in human plasma (≥ 99.7%). Based on the population-pharmacokinetic (PK) model, the volume of distribution of the central compartment (Vc/F) was estimated to be 212L.Protein binding was not altered in subjects with mild or moderately impaired renal or hepatic function.

Biotransformation

Cabozantinib was metabolized in vivo. Four metabolites were present in plasma at exposures (AUC) greater than 10% of parent: XL184-N-oxide, XL184 amide cleavage product, XL184 monohydroxy sulfate, and 6-desmethyl amide cleavage product sulfate. Two non-conjugated metabolites (XL184-N-oxide and XL184 amide cleavage product), which possess <1% of the on-target kinase inhibition potency of parent cabozantinib, each represent <10% of total drug-related plasma exposure.

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

Elimination

In a population PK analysis of cabozantinib using data collected from 1883 patients and 140 normal healthy volunteers following oral administration of a ramge of doses from 20 to 140 mg, the plasma terminal half-life of cabozantinib is approximately 110 hours. Mean clearance (CL/F) at steady-state was estimated to be 2.48 L/hr. Within a 48-day collection period after a single dose of 14C-cabozantinib in healthy volunteers, approximately 81% of the total administered radioactivity was recovered with 54% in faeces and 27% in urine.

Pharmacokinetics in Special Patient Populations

Patient with Renal Impairment

In a renal impairment study conducted with a single 60 mg dose of cabozantinib, the ratios of geometric LS mean for plasma cabozantinib, Cmax and AUC0-inf were 19% and 30% higher, for subjects with mild renal impairment (90% CI for Cmax 91.60% to 155.51%; AUC0-inf 98.79% to 171.26%) and 2% and 6-7% higher (90% CI for Cmax 78.64% to 133.52%; AUC0-inf 79.61% to 140.11%), for subjects with moderate renal impairment compared to subjects with normal renal function. Subjects with severe renal impairment have not been studied.

Patient with Hepatic Impairment

Based on an integrated population pharmacokinetic analysis of cabozantinib in healthy subjects and cancer patients (including HCC), no clinically significant difference in the mean cabozantinib plasma exposure was observed amongst subjects with normal liver function (n=1425) and mild hepatic impairment (n=558) .There is limited data in patients with moderate hepatic impairment, (n=15) as per NCI-ODWG (National Cancer Institute – Organ Dysfunction working Group) criteria. The pharmacokinetics of cabozantinib was not evaluated in patients with severe hepatic impairment.

Race

A population PK analysis did not identify clinically relevant differences in PK of cabozantinib based on race.

Drug Interaction Studies

Clinical Studies

CYP3A4 Inhibitors:

Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), with a cabozantinib capsule formulation to healthy subjects increased single-dose cabozantinib exposure (AUC0-INF) by 38%.

CYP3A4 Inducers:

Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days), with a cabozantinib capsule formulation to healthy subjects decreased single-dose cabozantinib exposure (AUC0-INF) by 77%.

CYP2C8 Substrates:

No clinically-significant effect on single-dose rosiglitazone (a CYP2C8 substrate) exposure (Cmax and AUC) was observed when co-administered with a cabozantinib capsule formulation at steady-state concentrations.

Gastric Acid Reducing Agents:

No clinically-significant effect on cabozantinib exposure (AUC) was observed following coadministration of the proton pump inhibitor (PPI) esomeprazole (40 mg daily for 6 days) with a single 100 mg dose of a cabozantinib capsule formulation to healthy subjects.

In vitro Studies

CYP Enzymes

Inhibition of CYP3A4 reduced the formation of the oxidative metabolite by > 80%. Inhibition of CYP2C9 had a minimal effect on cabozantinib metabolite formation (i.e., a <20% reduction). Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no effect on cabozantinib metabolite formation.

Although cabozantinib is an inhibitor of CYP2C8 in vitro, a clinical study of this potential interaction concluded that concurrent use did not result in a clinically relevant effect on CYP2C8 substrate exposure. Given this finding, other less sensitive substrates of pathways affected by cabozantinib in vitro (i.e., CYP2C9, CYP2C19, and CYP3A4) were not evaluated in a clinical study, because, although a clinically relevant exposure effect cannot be ruled out, it is unlikely. Cabozantinib does not inhibit CYP1A2 and CYP2D6 isozymes in vitro.

Cabozantinib is an inducer of CYP1A1 mRNA; however, the clinical relevance of this finding is unknown. Cabozantinib does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP3A4.

Transporters:

Cabozantinib is an inhibitor, but not a substrate, of P-gp transport activities and has the potential to increase concentrations of co-administered substrates of P-gp. The clinical relevance of this finding is unknown.

Cabozantinib is a substrate of MRP2 in vitro and MRP2 inhibitors have the potential to increase concentrations of cabozantinib. The clinical relevance of this finding is unknown.

6. Nonclinical Properties

6.1 Animal Toxicology or Pharmacology

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:

In rat and dog repeat-dose toxicity studies up to 6 months duration, target organs for toxicity were GI tract, bone marrow, lymphoid tissues, kidney, adrenal and reproductive tract tissues. The no observed adverse effect level (NOAEL) for these findings were below human clinical exposure levels at intended therapeutic dose.

Cabozantinib has shown no mutagenic or clastogenic potential in a standard battery of genotoxicity assays. The carcinogenic potential of cabozantinib has been evaluated in two species: rasH2 transgenic mice and Sprague-Dawley rats. In the 2-year rat carcinogenicity study, cabozantinib-related neoplastic findings consisted of an increased incidence of benign pheochromocytoma, alone or in combination with malignant pheochromocytoma/complex malignant pheochromocytoma of the adrenal medulla in both sexes at exposures well below the intended exposure in humans. The clinical relevance of the observed neoplastic lesions in rats is uncertain, but likely to be low.

Cabozantinib was not carcinogenic in the rasH2 mouse model at a slightly higher exposure than the intended human therapeutic exposure.

Fertility studies in rats have shown reduced male and female fertility. Further, hypospermatogenesis was observed in male dogs at exposure levels below human clinical exposure levels at intended therapeutic dose.

Embryo-foetal development studies were performed in rats and rabbits. In rats, cabozantinib caused post implantation loss, foetal oedema, cleft palate/lip, dermal aplasia and kinked or rudimentary tail. In rabbits, cabozantinib produced foetal soft tissue changes (reduced spleen size, small or missing intermediate lung lobe) and increased foetal incidence of total malformations. NOAEL for embryo-foetal toxicity and teratogenic findings were below human clinical exposure levels at intended therapeutic dose.

Juvenile rats (comparable to a >2 year old paediatric population) administered cabozantinib showed increased WBC parameters, decreased haematopoiesis, pubescent/immature female reproductive system (without delayed vaginal opening), tooth abnormalities, reduced bone mineral content and density, liver pigmentation and lymph node lymphoid hyperplasia. Findings in uterus/ovaries and decreased haematopoiesis appeared to be transient, while effects on bone parameters and liver pigmentation were sustained. Juvenile rats (correlating to a <2 year paediatric population) showed similar treatment-related findings, but appeared to be more sensitive to cabozantinib-related toxicity at comparable dose levels.

7. Description

Cabozantinib tablets is the (S)-malate salt of cabozantinib, a kinase inhibitor. Cabozantinib (S)-malate is described chemically as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N’-(4­fluorophenyl)cyclopropane-1,1-dicarboxamide,(2S) hydroxybutanedioate. The molecular formula is C28H24FN3O5·C4H6O5 and the molecular weight is 635.6 Daltons as malate salt. The chemical structure of cabozantinib (S)-malate salt is:

Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitor, ATC code: L01XE26.

8. Pharmaceutical Particulars

List of excipients

Tablet content

Microcrystalline cellulose, Lactose monohydrate, Croscarmellose sodium, Hypromellose, Colloidal silicon dioxide, Magnesium Stearate,

Film-coating: Opadry Yellow 3F520567

8.1 Incompatibilities

Not applicable

8.2 Shelf life

Please see manufacturing date and expiry date printed on pack. Do not use the product after the expiry date which is stated on the packaging. The expiry date refers to the last day of that month.

8.3 Packaging information

CABOTRES 20: HDPE Bottles contains 30 film-coated tablets.

CABOTRES 40: HDPE Bottles contains 30 film-coated tablets.

8.4 Storage and handling instruction

Store at temperature not exceeding 30ºC. Protect from moisture

Keep out of reach of children.

9. Patient Counselling Information

What is CABOTRES TABLET?

CABOTRES TABLET is a prescription medicine used to treat people with:

• alone to treat people with advanced kidney cancer (renal cell carcinoma), when your cancer has spread (advanced RCC), and you have not already had treatment for your advanced RCC

• Liver cancer (hepatocellular carcinoma) who have been previously treated with the medicine sorafenib. It is not known if CABOTRES TABLET is safe and effective in children.

Before you take CABOTRES TABLET, tell your doctor about all of your medical conditions, including if you:

  • have a recent history of bleeding, including coughing up or vomiting blood, or black tarry stools.
  • have had a liver problem other than liver cancer.have an open or healing wound
  • have high blood pressure
  • plan to have any surgery, dental procedure, or have had a recent surgery. You should stop taking cabozantinib tablets at least 3 weeks before planned surgery.
  • are pregnant, or plan to become pregnant. CABOTRES TABLET can harm your unborn baby.

o If you are able to become pregnant, your healthcare provider will check your pregnancy status before you start treatment with CABOTRES TABLET.

o Females who are able to become pregnant should use effective birth control (contraception) during treatment and for 4 months after your final dose of CABOTRES TABLET.

o Talk to your doctor about birth control methods that may be right for you.

o If you become pregnant or think you are pregnant, tell your doctor right away.

  • are breastfeeding or plan to breastfeed. It is not known if CABOTRES TABLET passes into your breast milk. Do not breastfeed during treatment and for 4 months after your final dose of CABOTRES TABLET.

Tell your doctor about all the medicines you take, including prescription or over-thecounter medicines, vitamins, and herbal supplements. CABOTRES TABLET and certain other medicines may affect each other causing side effects.

How should I take CABOTRES TABLET??

Take CABOTRES TABLET exactly as your doctor tells you to take it.

Do not take CABOTRES TABLET with food. Take CABOTRES TABLET at least 1 hour before or at least 2 hours after eating.

Swallow CABOTRES TABLETS whole with a full glass (at least 8 ounces) of water.

Do not crush CABOTRES TABLET tablets.

If you miss a dose and your next dose is in:

o less than 12 hours, take your next dose at the normal time. Do not make up the missed dose.

o 12 hours or more, take the missed dose as soon as you remember. Take your next dose at the normal time.

What should I avoid while taking CABOTRES TABLET?

Do not drink grapefruit juice, eat grapefruit or take supplements that contain grapefruit or St. John’s wort during treatment with CABOTRES TABLET.

What are the possible side effects of CABOTRES TABLET?

CABOTRES TABLET may cause serious side effects, including:

  • bleeding (hemorrhage). CABOTRES TABLET can cause severe bleeding that may lead to death. Tell your healthcare provider right away if you get any signs of bleeding during treatment with CABOTRES TABLET, including:
  • coughing up blood or blood clots           
  • red or black (looks like tar) stools
  • vomiting blood or if your vomit looks like Coffee-grounds
  • menstrual bleeding that is heavier than normal
  • any unusual or heavy bleeding
  • a tear in your stomach or intestinal wall (perforation) or an abnormal connection between 2 parts of your body (fistula). Tell your doctor right away if you get tenderness or pain in your stomach-area (abdomen).
  • Blood clots, stroke, heart attack, and chest pain. Get emergency help right away if you get:
    • swelling or pain in your arms or legs
    • o sudden confusion, trouble speaking or understanding
    • shortness of breath
    • feel lightheaded or faint
    • sudden trouble seeing in one or both eyes
    • sudden trouble walking
    • numbness or weakness of your face, arm or leg, especially on one side of your body
    • sweating more than usual
    • dizziness, loss of balance or coordination
    • a sudden severe headache
  • high blood pressure (hypertension). Hypertension is common with CABOTRES TABLET and sometimes can be severe. Your healthcare provider will check your blood pressure before starting CABOTRES TABLET and during treatment with CABOTRES TABLET. If needed, your healthcare provider may prescribe medicine to treat your high blood pressure.
  • diarrhea. Diarrhea is common with CABOTRES TABLET and can be severe. If needed, your healthcare provider may prescribe medicine to treat your diarrhea. Tell your healthcare provider right away, if you have frequent loose, watery bowel movements.
  • a skin problem called hand-foot skin reaction. Hand-foot skin reactions are common and can be severe. Tell your healthcare provider right away if you have rashes, redness, pain, swelling, or blisters on the palms of your hands or soles of your feet.
  • Protein in your urine and possible kidney problems. Symptoms may include swelling in your hands, arms, legs, or feet.
  • Severe jaw bone problems (osteonecrosis). Symptoms may include jaw pain, toothache, or sores on your gums. Your healthcare provider should examine your mouth before you start and during treatment with CABOTRES TABLET. Tell your dentist that you are taking CABOTRES TABLET. It is important for you to practice good mouth care during treatment with CABOTRES TABLET.
  • Wound healing problems. Wound healing problems have happened in some people who take CABOTRES TABLET. Tell your healthcare provider if you plan to have any surgery before or during treatment with CABOTRES TABLET.

o You should stop taking CABOTRES TABLET at least 3 weeks before planned surgery.

o Your healthcare provider should tell you when you may start taking CABOTRES TABLET again after surgery.

  • Reversible Posterior Leukoencephalopathy Syndrome (RPLS). A condition called reversible posterior leukoencephalopathy syndrome can happen during treatment with CABOTRES TABLET. Tell your healthcare provider right away if you have headaches, seizures, confusion, changes in vision, or problems thinking.

CABOTRES TABLET may cause fertility problems in females and males, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility.

Your doctor may change your dose, temporarily stop, or permanently stop treatment with CABOTRES TABLET if you have certain side effects.

The most common side effects of CABOTRES TABLET include:

  • tiredness
  • decreased appetite
  • nausea
  • vomiting
  • weight loss
  • constipation
  • difficulty speaking

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of CABOTRES TABLET. Call your doctor for medical advice about side effects

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.

To report any side effects, write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 18002677779. By reporting side-effects, you can help provide more information on the safety of this product

How should I store CABOTRES TABLET?

• Store at temperature not exceeding below 30ºC.  Protect from moisture. Keep out of reach of children.

General information about the safe and effective use of CABOTRES TABLET.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use CABOTRES TABLET for a condition for which it was not prescribed. Do not give CABOTRES TABLET to other people, even if they have the same symptoms you have. It may harm them. You can ask your doctor or pharmacist for information about CABOTRES TABLET that is written for health professionals.

What are the ingredients in CABOTRES TABLET?

Active ingredient: Cabozantinib (S)-malate

Inactive ingredients: Microcrystalline cellulose, Lactose monohydrate, Croscarmellose sodium ,Hypromellose ,Colloidal silicon dioxide ,Magnesium Stearate, Opadry Yellow 3F520567

Contents of the pack and other information

CABOTRES 20: HDPE Bottles contains 30 film-coated tablets.

CABOTRES 40: HDPE Bottles contains 30 film-coated tablets.

10. Details of Manufacturer

Manufactured in India by:

BDR Pharmaceuticals Int’l Pvt. Ltd.

R. S. No. 578, Near Effluent

Channel Road, Vill. Luna, Tal. Padra,

Dist. Vadodara-391 440. Gujarat.

INDIA.

Marketed By

Cipla House,

Peninsula Business Park,

Ganpatrao Kadam Marg,

Lower Parel, Mumbai - 400 013 INDIA

11. Details of Permission or Licence Number with Date

G/25/2071 issued on 13 Sept. 2021

12. Date of Revision

28 October 2021