Cabozantinib-Promomed (Tablets) Instructions for Use

Marketing Authorization Holder

Promomed Rus LLC (Russia)

Manufactured By

Biokhimik, JSC (Russia)

ATC Code

L01EX07 (Cabozantinib)

Active Substance

Cabozantinib (Rec.INN registered by WHO)

Dosage Forms

	Cabozantinib-Promomed	Film-coated tablets 20 mg
		Film-coated tablets 40 mg
		Film-coated tablets 60 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription
30 pcs. – jars – cardboard packs (30 pcs.) – By prescription
5 pcs. – blister packs (6 pcs.) – cardboard packs (30 pcs.) – By prescription

Film-coated tablets

10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription
30 pcs. – jars – cardboard packs (30 pcs.) – By prescription
5 pcs. – blister packs (6 pcs.) – cardboard packs (30 pcs.) – By prescription

Film-coated tablets

10 pcs. – blister packs (3 pcs.) – cardboard packs (30 pcs.) – By prescription
30 pcs. – jars – cardboard packs (30 pcs.) – By prescription
5 pcs. – blister packs (6 pcs.) – cardboard packs (30 pcs.) – By prescription

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agents; protein kinase inhibitors; other protein kinase inhibitors

Pharmacological Action

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

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

Furthermore, Cabozantinib inhibits other tyrosine kinases including the 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 demonstrated dose-dependent tumor growth reduction, tumor regression, and/or metastasis suppression in a significant number of different tumor models.

Pharmacokinetics

After oral administration of cabozantinib, C_max in plasma is reached within 3-4 hours.

A second C_max peak in plasma is observed 24 hours after cabozantinib intake, which may indicate enterohepatic recirculation of the drug substance.

Food intake 1 hour after cabozantinib administration does not affect its absorption.

Cabozantinib in vitro is highly bound to human plasma proteins (> 99.7%).

The V_d calculated based on a population pharmacokinetic model is approximately 319 L (SE: ± 2.7 %).

Protein binding was not altered in patients with mild or moderate renal or hepatic impairment.

Cabozantinib metabolism was evaluated in vivo.

Four metabolites of cabozantinib were identified in plasma with exposure (AUC) exceeding 10% of the parent substance level: XL184-M-oxide, an amide cleavage product XL184, XL184 monohydroxy sulfate, and a 6-desmethylamide sulfate cleavage product.

The exposure of unconjugated metabolites (XL184-N-oxide and the XL184 amide cleavage product), which have activity less than 1% of the parent cabozantinib activity, each accounts for less than 10% of the total plasma exposure.

Cabozantinib is a substrate of the CYP3A4 isoenzyme in vitro; neutralizing antibodies to CYP3A4 inhibited the formation of the XL184-M-oxide metabolite by more than 80% in NADPH-dependent human liver microsomes.

In contrast, neutralizing antibodies to CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6, and CYP2E1 did not affect the formation of cabozantinib metabolites.

Neutralizing antibodies to CYP2C9 had a minimal effect on cabozantinib metabolism (metabolite content decreased by less than 20%).

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 T_1/2 of cabozantinib from plasma is about 99 hours.

The mean steady-state clearance (CL/F) was 2.2 L/h.

After a single dose of radioactively labeled [¹⁴C]-cabozantinib in healthy volunteers, the level of radioactivity excreted within 48 hours was about 81% of the total administered radioactivity, of which 54% was excreted in feces and 27% in urine.

Indications

Treatment of advanced renal cell carcinoma in adult patients with intermediate or poor prognosis, previously untreated; in adult patients after prior antiangiogenic therapy (VEGF-targeted therapy).

ICD codes

Dosage Regimen

Take orally, once daily.

The recommended starting dose is 60 mg.

Take on an empty stomach. Do not eat for at least 2 hours before and 1 hour after taking the tablet.

Swallow the tablet whole with water. Do not crush, split, or chew the tablet.

If a dose is missed, skip it if the next dose is due within 12 hours. Do not take a double dose to make up for a forgotten one.

Continue treatment as long as clinical benefit is observed and toxicity is manageable.

Dose modifications are required for management of adverse reactions.

For Grade 3 or 4 adverse reactions, interrupt therapy until resolution to Grade 1 or baseline.

Resume treatment at a reduced dose: first reduction to 40 mg; second reduction to 20 mg.

Discontinue permanently if unable to tolerate the 20 mg dose.

For severe hepatic impairment, do not administer.

No initial dose adjustment is required for elderly patients or those with mild to moderate renal or hepatic impairment.

Monitor patients closely, especially during the first 8 weeks of therapy.

Adverse Reactions

Infections and infestations : common – abscess.

Blood and lymphatic system disorders very common – anemia; common – thrombocytopenia, neutropenia; uncommon – lymphopenia.

Endocrine system disorders very common – hypothyroidism.

Metabolism and nutrition disorders very common – decreased appetite, hypomagnesemia, hypokalemia; common – dehydration, hypoalbuminemia, hypophosphatemia, hyponatremia, hypocalcemia, hyperkalemia, hyperbilirubinemia, hyperglycemia, hypoglycemia.

Nervous system disorders: very common – dysgeusia, headache, dizziness; common – peripheral sensory neuropathy; uncommon – seizures; hemorrhagic stroke.

Ear and labyrinth disorders common – tinnitus.

Cardiac disorders: very common – increased blood pressure, bleeding; common – venous thrombosis, arterial thrombosis; myocardial infarction.

Respiratory, thoracic and mediastinal disorders: very common – dysphonia, dyspnea, cough; common – pulmonary embolism.

Gastrointestinal disorders: very common – diarrhea, nausea, vomiting, stomatitis, constipation, abdominal pain, dyspepsia, upper abdominal pain; common – gastrointestinal perforation, fistula, gastroesophageal reflux disease, hemorrhoids, mouth pain, dry mouth; uncommon – pancreatitis, glossodynia.

Hepatobiliary disorders common – hepatic encephalopathy; uncommon – cholestatic hepatitis.

Skin and subcutaneous tissue disorders very common – palmar-plantar erythrodysesthesia syndrome, rash; common – pruritus, alopecia, dry skin, acneiform dermatitis, hair color changes.

Musculoskeletal and connective tissue disorders very common – pain in extremity; common – muscle spasms, arthralgia; uncommon – osteonecrosis of the jaw.

Renal and urinary disorders common – proteinuria.

General disorders and administration site conditions very common – weakness, mucosal inflammation, asthenia, peripheral edema.

Investigations: very common – weight loss, increased plasma ALT and AST activity; common – increased blood alkaline phosphatase activity, increased GGT activity, increased blood creatinine concentration, increased amylase activity, increased lipase concentration, increased blood cholesterol, decreased white blood cell count; uncommon – increased blood triglycerides.

Contraindications

Severe renal and hepatic impairment, pregnancy and breastfeeding, age under 18 years.

With caution

In inflammatory bowel diseases (e.g., Crohn’s disease, ulcerative colitis, peritonitis, diverticulitis, or appendicitis); tumor infiltration into the gastrointestinal tract; complications from previous surgery (especially when associated with slow or incomplete wound healing); history of arterial thromboembolism (or in patients at risk for such conditions); history of venous thromboembolism (including pulmonary embolism) (or in patients at risk for such conditions); arterial hypertension; when taking drugs that are strong CYP3A4 inhibitors; that are substrates of P-glycoprotein; with concurrent use of MRP2 inhibitors; in patients with a history of QT interval prolongation; in patients taking antiarrhythmic drugs; in patients with pre-existing heart disease, bradycardia, or electrolyte imbalances; in patients with mild or moderate renal impairment; in patients with mild or moderate hepatic impairment.

Use in Pregnancy and Lactation

Use is contraindicated during pregnancy and breastfeeding.

Use in Hepatic Impairment

Use is contraindicated in severe hepatic impairment.

Use in Renal Impairment

Use is contraindicated in severe renal impairment.

Pediatric Use

Use is contraindicated in children under 18 years of age.

Geriatric Use

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

Special Precautions

Since most adverse reactions develop early in treatment, the physician should closely monitor the patient during the first eight weeks of therapy to determine the need for dose adjustment of the drug.

There is an increased risk of developing serious gastrointestinal perforations and fistulas with cabozantinib use, sometimes fatal.

Patients with inflammatory bowel diseases (e.g., Crohn’s disease, ulcerative colitis, peritonitis, diverticulitis, or appendicitis), tumor infiltration into the gastrointestinal tract, or complications from previous surgery (especially when associated with slow or incomplete wound healing) should be carefully evaluated before starting treatment with cabozantinib, and such patients should subsequently be closely monitored for the development of symptoms of perforations and fistulas, including abscess and sepsis.

Persistent or recurrent diarrhea may be a risk factor for the development of an anal fistula.

Cabozantinib therapy should be discontinued in patients with gastrointestinal perforation or fistula that cannot be adequately controlled.

There is an increased risk of developing venous thromboembolism, including pulmonary embolism, and arterial thromboembolism with cabozantinib use.

Cabozantinib should be used with caution in patients who are at risk or have a history of such events.

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

There is an increased risk of severe bleeding with cabozantinib use.

There is an increased risk of wound healing complications with cabozantinib use.

Cabozantinib treatment should be discontinued at least 28 days prior to planned surgery, including dental surgery, if possible.

The decision to resume cabozantinib therapy after surgery should be based on clinical assessment of adequate wound healing.

Cabozantinib therapy should be discontinued in patients with wound healing complications requiring medical intervention.

There is an increased risk of developing arterial hypertension with cabozantinib use.

Blood pressure should be properly controlled before initiating cabozantinib therapy.

During treatment with cabozantinib, all patients should be monitored for the development of hypertension and, if necessary, treated according to standard regimen.

In case of persistent elevated blood pressure despite the use of antihypertensive agents, the dose of cabozantinib should be reduced.

Cabozantinib should be discontinued if hypertension is severe and persistent despite antihypertensive therapy and cabozantinib dose reduction.

In case of a hypertensive crisis, cabozantinib therapy should be discontinued.

If severe palmar-plantar erythrodysesthesia syndrome develops, temporary discontinuation of cabozantinib therapy should be considered.

When the palmar-plantar erythrodysesthesia syndrome reaches grade 1 severity, cabozantinib therapy should be resumed at a lower dose.

Urine protein should be regularly monitored during treatment with cabozantinib.

If patients develop nephrotic syndrome, Cabozantinib should be discontinued.

Development of posterior reversible leukoencephalopathy syndrome, also known as posterior reversible encephalopathy syndrome, has been observed with cabozantinib use.

Any patient with multiple symptoms, including epileptiform seizures, headache, visual disturbances, confusion, or altered mental status should be evaluated for the possible development of this syndrome.

Cabozantinib treatment should be discontinued upon development of posterior reversible leukoencephalopathy syndrome.

Cabozantinib should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmic drugs, or in patients with pre-existing heart disease, bradycardia, or electrolyte imbalances.

Periodic monitoring of ECG and blood electrolyte concentrations (calcium, potassium, and magnesium) should be performed during treatment with cabozantinib.

Effect on ability to drive and operate machinery

Adverse reactions such as fatigue and weakness have been associated with cabozantinib.

Therefore, caution should be exercised when driving or operating machinery.

Drug Interactions

Caution should be exercised when co-administering strong CYP3A4 inhibitors (e.g., ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice ) with cabozantinib.

Continuous co-administration of strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampicin, phenobarbital, or herbal preparations containing St. John’s wort [Hypericum perforatum]) with cabozantinib should be avoided.
In vitro data demonstrate that Cabozantinib is a substrate of MRP2.

Therefore, co-administration of cabozantinib with MRP2 inhibitors may lead to increased plasma concentrations of cabozantinib.

Bile acid sequestrant drugs, such as cholestyramine and colestagel , may interact with cabozantinib and affect its absorption (or reabsorption), leading to a potential decrease in plasma exposure.

Due to 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 simultaneous use, INR values should be monitored.

When cabozantinib is co-administered with P-glycoprotein substrates , Cabozantinib may increase their plasma concentrations.

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

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.