Cabometix, 60 mg 30 pcs.

The antitumor agent is a protein tyrosine kinase inhibitor.

ATX code: L01XE26.

Pharmacological properties

Pharmacodynamics:

Cabozantinib is a small molecule inhibitor of various receptor tyrosine kinases involved in tumor growth, angiogenesis, bone remodeling, drug resistance formation and metastasis formation.

The inhibitory activity of cabozantinib has been evaluated against a range of kinases, and cabozantinib has been identified as an inhibitor of MET (hepatocyte growth factor receptor) and VEGF (vascular endothelial growth factor).

In addition, cabozantinib inhibits other tyrosine kinases including GAS6 receptor (AXL), RET, ROS1, TYR03, MER, stem cell growth factor receptor (KIT), TRKB, Fms-like tyrosine kinase-3 (FLT3) and TIE-2.
In preclinical studies, cabozantinib has shown dose-dependent reduction of tumor growth, tumor regression and/or suppression of metastasis in a significant number of different tumor models.

Pharmacokinetics:

Intake

After oral administration of cabozantinib, maximum plasma concentrations (Cmax) are reached after 3-4 hours. A second peak of maximum plasma concentrations of the drug is observed 24 hours after administration of cabozantinib, which may indicate intestinal-hepatic recirculation of the drug.

Recurrent daily administration of cabozantinib at a dose of 140 mg for 19 days showed an approximately 4-5-fold increase in cabozantinib exposure (AUC, area under the pharmacokinetic “concentration-time” curve) compared to a single dose administration. Equilibrium concentrations of cabozantinib are reached at about day 15.

In healthy volunteers, a single dose of cabozantinib at 140 mg along with a high-fat meal results in a 41% and 57% increase in Cmax and AUC, respectively, compared to fasting meal. Food intake 1 hour after drug intake has no effect on the absorption of cabozantinib.

Distribution

Cabozantinib in vitro is significantly bound to human plasma proteins (≥99.7%). Calculated on the basis of a population pharmacokinetic model, the volume of distribution (VZ) is about 319 l (SE: ± 2.7%). Protein binding was not altered in patients with mild to moderate renal or hepatic impairment.

Metabolism

The metabolism of cabozantinib was evaluated in vivo. Four metabolites of the drug were determined in plasma with an exposure (AUC) 10% greater than that of the parent substance: XL184-N-oxide, XL184 amide cleavage product, XL184 monohydroxysulfate, and 6-desmethylamide sulfate cleavage product.

The exposure of unconjugated metabolites (XL184-N-oxide and XL184 amide cleavage product) with less than 1% of the activity of the parent cabozantinib is less than 10% each of the total exposure of the drug in plasma.

Cabozantinib is a substrate of the CYP3A4 isoenzyme in vitro; neutralizing antibodies to CYP3A4 inhibit the formation of the metabolite XL184-N-oxide by more than 80% in NADPH-dependent human liver microsomes. In contrast, neutralizing antibodies to CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6, and CYP2E1 had no effect on the formation of cabozantinib metabolites.

Neutralizing antibodies to CYP2C9 had minimal effect on the metabolism of cabozantinib (metabolite content was reduced by less than 20%).

Elevation

In a population pharmacokinetic analysis of cabozantinib using data collected from 318 patients with renal cell carcinoma and 63 healthy volunteers after oral doses of 60 mg, 40 mg and 20 mg, the plasma elimination half-life of cabozantinib is approximately 99 hours.

The mean clearance (CL/F) at equilibrium was 2.2 L/hour. After a single administration of radioactively labeled [14C]-cabozantinib in healthy volunteers, the level of radioactivity excreted within 48 hours was about 81% of the total radioactivity administered, of which 54% was excreted with feces and 27% with urine.

Patients with impaired renal function

. Results from a study in patients with renal impairment indicated that the Cmax and AUC0-inf of cabozantinib were 19% and 30% higher in patients with mild renal impairment (90% CI for Cmax of 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 patients with moderate renal failure compared with patients with normal renal function.

The use of cabozantinib in patients with severe renal impairment has not been studied.

Patients with impaired hepatic function

The results of the study in patients with hepatic impairment show that exposure (AUC0-inf) increased by 81% and 63% in patients with mild hepatic impairment and moderate hepatic impairment, respectively (90% CI for AUC0-inf: 121.44% to 270.34% for mild and 107.37% to 246.67% for moderate).

The use of cabozantinib in patients with severe hepatic impairment has not been studied.

Race

Population pharmacokinetic analysis showed no clinically significant differences in cabozantinib pharmacokinetics by race.

Indications

Cabomethix® is indicated for the treatment of advanced renal cell cancer:

• in adult patients with intermediate or poor prognosis who have not previously received therapy;
• in adult patients after prior therapy with anti-angiogenic drugs (VEGF-targeted therapy).

Cabometix® is intended as monotherapy for the treatment of hepatic cell cancer in adult patients after prior therapy with sorafenib.

Active ingredient

Cabozantinib

Composition

Ingredients per 1 tablet:

Active ingredient:

cabozantinib (S)-malate in terms of cabozantinib 60 mg-76.03 mg

Excipients:

Microcrystalline PH-102 cellulose 93.24 mg,

Lactose anhydrous 46.61 mg,

Hyprolose (hydroxypropyl cellulose) 7.200 mg,

croscarmellose sodium 14.40 mg,

silicon dioxide colloid (anhydrous) 0.7200 mg,

/p>

Magnesium stearate 1.800 mg, Opadray^® 03K92254 Yellow¹ 9.600 mg.

¹ Opadray^® 03K92254 Yellow Coating consists of hypromellose (E464), titanium dioxide (E171), triacetin and iron oxide yellow dye (E172).

How to take, the dosage

The therapy with Cabomethix® should be done by a physician experienced in the use of antitumor drugs.

The dosing regimen

Intravenously.

The tablets should be swallowed whole and not broken. You should refrain from eating at least 2 hours before and 1 hour after taking the drug Kabometix®.

The recommended dose of Cabomethix® is 60 mg once daily. Treatment should be continued as long as the clinical benefit of therapy is maintained or until unacceptable toxicity develops.
If adverse reactions develop, temporary discontinuation of therapy and/or reduction of the dose of Cabomethix® may be required (see Table 1).

When dose reduction is required, it is recommended that the dose be reduced first to 40 mg daily and then to 20 mg daily. Temporary discontinuation of therapy is recommended if adverse reactions of grade 3 or higher develop or if intolerable grade 2 toxicity occurs.

Dose reduction is recommended when adverse reactions are persistent, may become severe, or intolerable.

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

Table 1 Recommended dose adjustment of Cabomethix® in case of adverse reactions

Note: Toxicity grades are given according to the National Institute of Oncology General Terminology Criteria for Adverse Events, version 4.

Companion therapy

Companion medications that are potent CYP3A4 inhibitors should be used with caution, and continued use of companion medications that are potent CYP3A4 inducers should be avoided.

The choice of an alternative concomitant medication with no or minimal ability to induce or inhibit CYP3A4 should be considered.

Dosing regimen in special patient groups

Patients in the elderly (over 65 years)

Dose adjustment in patients over 65 years of age is not required.

Patients with renal impairment

Cabozantinib should be used with caution in patients with mild to moderate renal impairment. Cabozantinib is not recommended for use in patients with severe renal impairment because safety and efficacy have not been established in this population.

Patients with hepatic impairment

In patients with mild to moderate hepatic impairment, the recommended dose is 40 mg once daily. Patients should be monitored closely to check for adverse reactions.

Dose adjustment or discontinuation of treatment is possible if necessary. Cabozantinib is not recommended for use in patients with severe hepatic impairment because safety and efficacy have not been established in this population.

Patients with heart failure

Limited data are available in patients with heart failure. There are no specific dosing recommendations.

In the pediatric population

The safety and efficacy of cabozantinib in children and adolescents under 18 years of age have not been established.

Interaction

The effect of other drugs on cabozantinib.

CYP3A4 inhibitors and inducers

. Concomitant use of the potent CYP3A4 inhibitor ketoconazole (400 mg daily for 27 days) in healthy volunteers with a single administration of cabozantinib decreased cabozantinib clearance (by 29%) and increased plasma exposure to cabozantinib (AUC increased by 38%).

Caution should be exercised when concomitant use of potent CYP3A4 inhibitors (e.g., ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice) with cabozantinib.

Concomitant use of the potent CYP3A4 inducer rifampicin (600 mg daily for 31 days) in healthy volunteers with a single administration of cabozantinib increased the clearance of cabozantinib (4.3-fold) and decreased the plasma exposure of cabozantinib (AUC decreased by 77%).

Continuous co-administration of potent CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampicin, phenobarbital or herbal preparations containing St. John’s wort [Hypericum perforatum]) with cabozantinib should be avoided.

Drugs modifying the pH of gastric juice

The co-administration of the proton pump inhibitor esomeprazole (40 mg daily for 6 days) with a single dose of cabozantinib 100 mg in healthy volunteers had no clinically significant effect on the plasma exposure (AUC) of cabozantinib. Dose adjustment is not required when co-administering cabozantinib with drugs that modify gastric pH (proton pump inhibitors, H2-histamine receptor antagonists and antacids).

MRP2 inhibitors

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

Bile acid sequestrants

Bile acid salt binding agents such as colestiramine and colestagel may interact with cabozantinib and affect its absorption (or reabsorption), resulting in a potential reduction of plasma exposure. The clinical significance of this potential interaction is unknown.

The effect of cabozantinib on other drugs.

The effect of cabozantinib on the pharmacokinetics of hormonal contraceptives has not been studied. Because the contraceptive effect cannot be fully guaranteed, the use of an additional contraceptive method, such as a barrier method, is recommended.

Because of the significant binding of cabozantinib to plasma proteins, interaction with warfarin based on the mechanism of displacement from protein binding is possible. In case of their concomitant use the values of international normalized ratio (INR) should be monitored.

P-glycoprotein substrates

Cabozantinib is an inhibitor of P-glycoprotein transport activity (IC50 = 7.0 µM), but is not a substrate of P-glycoprotein. Therefore, when cabozantinib and P-glycoprotein substrates are used together, cabozantinib may increase plasma concentrations of the latter.

. Patients receiving cabozantinib should be cautioned about possible interactions when used concomitantly with P-glycoprotein substrates (e.g., fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, thalinolol, tolvaptan).

Special Instructions

Because most adverse reactions develop early in treatment, the physician should monitor the patient carefully during the first eight weeks of therapy to determine if the dose of the drug needs to be changed.

The adverse reactions that usually occur at the beginning of treatment include hypocalcemia), hypokalemia, thrombocytopenia, increased blood pressure, palpebral erythrodysesthesia syndrome, proteinuria and gastrointestinal abnormalities (abdominal pain, mucosal inflammation, constipation, diarrhea, vomiting).

In a reference clinical trial (METEOR) in patients with renal cell cancer after prior VEGF-targeted therapy, dose reduction and temporary discontinuation of therapy due to the development of adverse events occurred in 59.8% and 70% of patients receiving cabozantinib, respectively.

Dose reduction was required twice in 19.3% of patients. The median time to the first dose reduction was 55 days and to temporarily discontinue therapy was 38 days.

In a clinical trial (CABOSUN) in patients with renal cell cancer who did not receive prior treatment, dose reduction and temporary discontinuation of therapy occurred in 46% and 73% of patients receiving cabozantinib, respectively.

Perforations and fistulas

There is an increased risk of serious gastrointestinal perforations and fistulas, sometimes fatal, when taking cabozantinib.

. Patients with inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis, peritonitis, diverticulitis or appendicitis), tumor infiltration into the gastrointestinal tract or a complication from prior surgery (especially when associated with slow or incomplete wound healing) should be carefully evaluated before starting cabozantinib treatment and these patients should be closely monitored afterward for symptoms of perforation and fistula, including abscess and sepsis.

Consistent or recurrent diarrhea may be a risk factor for anal fistula. Cabozantinib therapy should be discontinued in patients with gastrointestinal perforation or fistula that cannot be adequately controlled.

Thromboembolism

Cabozantinib administration has an increased risk of venous thromboembolism, including pulmonary embolism, and arterial thromboembolism. Cabozantinib should be used with caution in patients who are at risk or have a history of such cases.

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

Bleeding

The risk of severe bleeding is increased when taking cabozantinib. Patients with a history of severe bleeding should be carefully evaluated before starting cabozantinib treatment. Cabozantinib should not be administered to patients who are at risk or have a history of severe bleeding.

Wound healing complications

There is an increased risk of wound healing complications when taking cabozantinib. Treatment with cabozantinib should be stopped at least 28 days before planned surgery, including dental surgery if possible.

The decision to resume cabozantinib therapy after surgery should be based on a clinical evaluation of the adequacy of wound healing. Cabozantinib therapy should be discontinued in patients with complications of wound healing that require medical intervention.

Hypertension

There is an increased risk of arterial hypertension when taking cabozantinib. Blood pressure should be properly controlled before starting cabozantinib therapy.

The development of arterial hypertension in all patients should be monitored during treatment with cabozantinib and treated as needed according to the standard regimen. In case of persistent increase of blood pressure, despite the use of antihypertensive agents, the dose of cabozantinib should be reduced.

Cabozantinib should be discontinued if arterial hypertension is severe and persistent despite antihypertensive therapy and reduction of the cabozantinib dose. If a hypertensive crisis develops, cabozantinib therapy should be discontinued.

Palmodontal erythrodysesthesia syndrome

The risk of palmodontal erythrodysesthesia syndrome is increased when taking cabozantinib. If severe palpebral erythrodysesthesia syndrome develops, consideration should be given to temporarily discontinuing cabozantinib therapy. When palpebral erythrodysesthesia syndrome reaches grade 1 severity, cabozantinib therapy should be resumed at a lower dose.

Proteinuria

There is an increased risk of proteinuria when taking cabozantinib. Protein in the urine should be monitored regularly during cabozantinib treatment. Cabozantinib should be stopped if patients develop nephrotic syndrome.

Posterior reversible leukoencephalopathy syndrome

The development of posterior reversible leukoencephalopathy syndrome, also known as posterior reversible encephalopathy syndrome, has been observed while taking cabozantinib. Any patient with multiple symptoms, including epileptiform seizures, headache, visual disturbances, confusion, or altered mental status should be considered for this syndrome.

Cabozantinib treatment should be withdrawn if posterior reversible leukoencephalopathic syndrome develops.

Long QT interval

Cabozantinib should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmic drugs, or in patients with existing heart disease, bradycardia, or electrolyte-water balance disturbances. Periodic monitoring of ECG and blood electrolyte concentrations (calcium, potassium and magnesium) should be performed during treatment with cabozantinib.

CYP3A4 inducers and inhibitors

Cabozantinib is a substrate for CYP3A4. Concomitant administration of cabozantinib with the potent CYP3A4 inhibitor ketoconazole resulted in increased plasma exposure of cabozantinib. Caution should be exercised when using cabozantinib with drugs that are potent CYP3A4 inhibitors.

The concomitant use of cabozantinib with the potent CYP3A4 inducer rifampicin resulted in decreased plasma exposure of cabozantinib. Long-term use of drugs that are potent inducers of CYP3A4 during treatment with cabozantinib should be avoided.

P-glycoprotein substrates

Cabozantinib is an inhibitor of glycoprotein P transport activity (IC50 = 7.0 µM), but is not a substrate of glycoprotein P. Therefore, when cabozantinib and glycoprotein P substrates are administered together, cabozantinib may increase plasma concentrations of the latter.

. Patients receiving cabozantinib should be cautioned about possible interactions when used concomitantly with glycoprotein P substrates (e.g., fexofenadine, aliskiren, ambrisentan, dabigatran etexilate, digoxin, colchicine, maraviroc, posaconazole, ranolazine, saxagliptin, sitagliptin, thalinolol, tolvaptan).

MRP2 inhibitors

The use of MRP2 inhibitors may increase plasma concentrations of cabozantinib; therefore, caution should be used with MRP2 inhibitors (e.g., cyclosporine, efavirenz, emtricitabine).

Excipients

Patients with rare hereditary diseases such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take cabozantinib.

Influence on the ability to drive, machinery

Cabozantinib has negligible effect on the ability to operate vehicles and mechanisms. Adverse reactions such as fatigue and weakness have been associated with cabozantinib. Therefore, caution should be exercised when driving or operating machinery.

Synopsis

Oval biconvex, yellow coated tablets with “XL” engraved on one side and “60” on the other side of the tablet.

Contraindications

Hypersensitivity to the active ingredient or any of the ingredients of the drug, severe renal and hepatic failure, pregnancy and breast-feeding, children under 18 years of age.

Caution

In inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis, peritonitis, diverticulitis or appendicitis); tumor infiltration into the gastrointestinal tract; complication from prior surgery (especially when associated with slow or incomplete wound healing) history of arterial thromboembolism (or in patients at risk for this condition); history of venous thromboembolism (including pulmonary embolism) (or in patients at risk for this condition); arterial hypertension; concomitant use of MRP2 inhibitors; patients with a history of QT interval prolongation; patients taking antiarrhythmic drugs; In patients with existing heart disease, bradycardia, or electrolyte-water balance disorders; in patients with mild to moderate renal insufficiency; in patients with mild to moderate hepatic insufficiency; galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

Do not prescribe in patients who are at risk or have a history of severe bleeding.
Continuous use of concomitant medications that are potent inducers of CYP3A4 should be avoided.

Side effects

The most common serious adverse reactions in the population with advanced renal cell cancer (≥1% incidence) are diarrhea, increased blood pressure, dehydration, hyponatremia, nausea, decreased appetite, embolism, weakness, hypomagnesemia, palpebral erythrodisesthesia syndrome.

. The most common adverse reactions of any category (noted in at least, 25% of patients) in the population with advanced renal cell cancer were diarrhea, increased blood pressure, weakness, and increased aspartate aminotransferase (ACT) activity, increased alanine aminotransferase (ALT) activity, nausea, decreased appetite, palpebral erythrodysesthesia syndrome, dysgeusia, decreased platelet count, stomatitis, anemia, vomiting, weight loss, dyspepsia and constipation. Increased blood pressure was more common among patients without prior treatment (67%) compared with patients after prior anti-VEGF targeting therapy (37%).

The adverse reactions are listed in Table 2 according to the Medical Dictionary for Regulatory Affairs (MedDRA) System-Organ Classes and Frequency of Reaction categories.

The frequency of adverse reactions is categorized as follows: very common (≥1/10); common (≥1/100 to < 1/10); infrequent (≥1/1000 to < 1/100), unknown (cannot be estimated from available data).

In each frequency group, adverse reactions are presented in decreasing order of severity.

Description of individual adverse reactions

Data for the following adverse reactions are from reference studies among patients with renal cell cancer who received Kabometix® 60 mg daily orally after prior VEGF-targeting therapy and who received no prior treatment.

Gastrointestinal perforation

In a study including patients with renal cell cancer after prior VEGF-targeting therapy (METEOR), gastrointestinal perforation of grade 2 or 3 severity was reported in 0.9% (3/331) of patients receiving cabozantinib. The median time to development of this adverse reaction was 10.0 weeks.

In a study including patients with previously untreated renal cell cancer (CABOSUN), gastrointestinal perforation of grade 4 and 5 severity was reported in 2.6% (2/78) of patients receiving cabozantinib.

In clinical trials there have been cases of fatal perforation.

Diarrhea

In a study including patients with renal cell cancer after prior VEGF-targeted therapy (METEOR), diarrhea was reported in 74% (245/331) of patients receiving cabozantinib; grade 3 and 4 diarrhea occurred in 11% of patients receiving cabozantinib. The median time to development of this adverse reaction was 4.9 weeks.

In a study including previously untreated renal cell cancer patients (CABOSUN), diarrhea was reported in 73% (57/78) of patients receiving cabozantinib; diarrhea of grade 3 and 4 severity occurred in 10% of patients receiving cabozantinib.

Fistulas

In a study including patients with renal cell cancer after prior VEGF-targeted therapy (METEOR), fistulas were reported in 1.2% (4/331) of patients receiving cabozantinib, including anal fistulas in 0.6% (2/331) of patients. One adverse reaction was of grade 3 severity and the others were of grade 2 severity. The median time to development of this adverse reaction was 30.3 weeks.

In a study including patients with renal cell cancer who did not receive prior treatment (CABOSUN), no cases of fistula were reported.

Bleeding

In a study including patients with renal cell cancer after prior VEGF-targeted therapy (METEOR), the incidence of severe bleeding (≥3 severity) was 2.1% (7/331 patients) among those receiving cabozantinib. The median time to development of this adverse reaction was 20.9 weeks.

In a study including patients with renal cell cancer who did not receive prior treatment with targeted drugs (CABOSUN), the incidence of severe bleeding (≥3 severity) was 5.1% (4/78 patients) among those receiving cabozantinib.

There have been cases of fatal bleeding in clinical trials.

Posterior reversible leukoencephalopathy syndrome

No cases of posterior reversible leukoencephalopathy syndrome were reported in clinical trials of cabozantinib® (METEOR, CABOSUN), but cases of this syndrome were reported in other clinical trials of cabozantinib (2/4872 patients, 0.04%).

Overdose

There is no specific antidote to cabozantinib, possible symptoms of overdose have not been established.
In case of suspected overdose, cabozantinib should be discontinued. Symptomatic therapy is indicated.

Clinical and laboratory metabolic parameters should be monitored at least once a week to detect and assess any possible changes.

Pregnancy use

Women of reproductive age/Contraception in men and women

Women of reproductive age should avoid pregnancy during treatment with cabozantinib. Female partners of men receiving cabozantinib should also avoid pregnancy. Effective contraceptive methods should be used by male and female patients and their partners during therapy and for at least 4 months after completion of therapy.

Since oral contraceptives cannot be considered “effective contraceptive methods,” they should be used in conjunction with another method, such as a barrier method.

Pregnancy

No studies of cabozantinib in pregnant women have been conducted. Animal studies have shown embryofetal and teratogenic effects. The potential risk to humans is unknown.

Breastfeeding

It is unknown whether cabozantinib and/or its metabolites are excreted with breast milk. Because of potential harm to the baby, breastfeeding should be discontinued during treatment with cabozantinib and for at least 4 months after completion of therapy.

Fertility

There are no data on the effect on fertility. Based on preclinical safety data, male and female fertility may be impaired by cabozantinib treatment. Both men and women should consult a specialist and discuss fertility preservation before starting cabozantinib treatment.