Cabodx Cabozantinib

I. Drug Name

Generic Name: Cabozantinib

English Name: Cabozantinib

Brand Names: Cometriq, Cabometyx, Cabodx

Dosage form for the treatment of Medullary Thyroid Carcinoma (Capsules).

Dosage form for the treatment of Renal Cell Carcinoma and Hepatocellular Carcinoma (Tablets).

(Note: The dosage forms and strengths differ and are not interchangeable.)

Dosage Forms: Oral Capsules; Oral Film-coated Tablets

Strengths: 20 mg per capsule; 90 capsules per box

60 mg per tablet; 30 tablets per box

Manufacturer: Laos Big Bear Pharmaceutical Co., Ltd.

Regulatory Approval Numbers: 09 L1013/23; 10L1031/23

II. Pharmacological Actions

Pharmacological Classification: Multi-targeted Tyrosine Kinase Inhibitor (TKI)

Mechanism of Action: Cabozantinib exerts its anti-tumor effects by inhibiting the activity of various tyrosine kinases, primarily including:

MET, VEGFR-1, 2, 3: Inhibition of these targets blocks tumor angiogenesis, thereby cutting off the tumor's nutrient supply.

RET, KIT, AXL: Inhibition of these targets directly suppresses tumor cell proliferation, invasion, and survival.

This multi-targeted mechanism of action enables the drug to exert its effects simultaneously through two pathways: anti-angiogenesis and direct anti-tumor activity.

III. Indications

Based on the specific dosage form and regional regulatory approvals, the drug is primarily indicated for:

1.  Radioiodine-refractory Differentiated Thyroid Carcinoma (DTC):

Cabozantinib (tablets) is indicated for the treatment of adult patients with locally advanced or metastatic DTC that is refractory to radioiodine therapy and has progressed following prior VEGFR-targeted therapy.

2.  Advanced Renal Cell Carcinoma (RCC):

Cabozantinib (tablets) is indicated as a first-line treatment for adult patients with advanced RCC.

Cabozantinib (tablets) is indicated for adult patients with advanced RCC that has progressed following prior VEGFR-targeted therapy. 3.  Hepatocellular Carcinoma (HCC):

Cabozantinib (tablets) is indicated for adult patients with hepatocellular carcinoma who have previously received sorafenib therapy.

4.  Medullary Thyroid Carcinoma (MTC):

Cabozantinib (capsules) is indicated for the treatment of progressive, metastatic medullary thyroid carcinoma.

IV. Dosage and Administration

Recommended Dosage (varies by dosage form and indication):

Cabozantinib (tablets): RCC, HCC, DTC: 60 mg once daily, taken on an empty stomach (do not consume food for at least 2 hours before and at least 1 hour after taking the medication).

Cabozantinib (capsules): MTC: 140 mg (one 80 mg capsule + three 20 mg capsules) once daily, taken on an empty stomach.

Method of Administration:

Swallow the capsules/tablets whole; do not chew, crush, open the capsules, or break the tablets.

Cabozantinib tablets may be broken in exceptional circumstances, provided this is performed by a healthcare professional, and the resulting fragments must be taken within 24 hours.

If a dose is missed and more than 12 hours remain before the next scheduled dose, take the missed dose as soon as possible. Otherwise, skip the missed dose and take the next dose at the regularly scheduled time. Do not take a double dose to make up for a missed dose.

If vomiting occurs after taking the medication, do not take a replacement dose; wait until the next scheduled time to take the regular dose.

V. Contraindications

Perforation and Fistula: Contraindicated in patients with a history of tumor invasion of the gastrointestinal tract, active perforation, or fistula.

VI. Warnings and Precautions

1.  Perforation and Fistula:

Gastrointestinal perforations and fistulas, including fatal cases, may occur.

Patients should be closely monitored for relevant symptoms (e.g., severe abdominal pain, fever, nausea, vomiting, etc.) during treatment; if these occur, permanently discontinue Cabozantinib.

2.  Hemorrhage:

Severe or even fatal hemorrhage may occur.

Cabozantinib should not be used in patients with a recent history of hemorrhage or hemoptysis. In patients who experience severe hemorrhage, permanently discontinue Cabozantinib. 3.  Thromboembolic Events:

May increase the risk of venous thromboembolism (e.g., deep vein thrombosis, pulmonary embolism) and arterial thromboembolism (e.g., myocardial infarction, cerebral infarction).

Should any severe thromboembolic event occur, treatment must be suspended; once the event has resolved, treatment may be resumed at a reduced dose or permanently discontinued.

4.  Hypertension and Hypertensive Crisis:

Hypertension is a common occurrence during treatment.

Blood pressure should be monitored regularly prior to initiating treatment and throughout the treatment period. For hypertension that is not adequately controlled by standard antihypertensive medications, Cabozantinib treatment should be suspended; in the event of a hypertensive crisis, the drug must be permanently discontinued.

5.  Diarrhea:

Severe diarrhea is a common adverse effect that may lead to dehydration and renal impairment.

It should be actively managed with antidiarrheal medications (e.g., loperamide) and supportive care; the Cabozantinib dosage should be adjusted based on the severity of the diarrhea.

6.  Hand-Foot Skin Reaction (HFSR) and Cutaneous Toxicity:

May cause painful skin reactions, including blistering, hyperkeratosis, and other manifestations.

Enhanced skin care measures are required, and the dosage should be adjusted according to the severity of the reaction.

7.  Osteonecrosis of the Jaw (ONJ):

Osteonecrosis of the jaw may occur.

An oral examination should be performed prior to initiating treatment, and invasive dental procedures should be avoided during the course of treatment. If ONJ develops, treatment must be suspended, and specialized dental care should be sought.

8.  Impaired Wound Healing:

May interfere with the wound healing process.

Treatment should be suspended for at least 3 weeks prior to any elective surgery; following surgery, the decision to resume treatment should be based on the status of wound healing.

9.  Proteinuria:

May induce or exacerbate proteinuria, potentially progressing to nephrotic syndrome.

Urinary protein levels should be monitored regularly prior to initiating treatment and throughout the treatment period. Treatment should be suspended or the dosage reduced based on the severity of the proteinuria.

10. Reversible Posterior Leukoencephalopathy Syndrome (PRES):

A rare neurological disorder characterized by symptoms such as headache, seizures, lethargy, and confusion.

Should this syndrome occur, Cabozantinib treatment must be permanently discontinued.

11. Embryo-Fetal Toxicity:

Administration to pregnant women may cause harm to the fetus. Women of childbearing potential should use effective contraception during treatment and for 4 months following treatment.

VII. Adverse Reactions

Very Common (>10%) Serious and/or Major Adverse Reactions:

Gastrointestinal: Diarrhea, nausea, vomiting, abdominal pain, constipation, stomatitis, dysgeusia.

Skin and Subcutaneous Tissue: Hand-foot skin reaction (HFSR), rash, hair color changes, dry skin.

Systemic: Fatigue, asthenia, decreased appetite, weight loss.

Cardiovascular: Hypertension.

Laboratory Abnormalities: Elevated AST/ALT, thrombocytopenia, lymphocytopenia, hypocalcemia, hypophosphatemia.

VIII. Drug Interactions

Strong CYP3A Inhibitors (e.g., clarithromycin, itraconazole, ritonavir):

Co-administration significantly increases cabozantinib plasma concentrations, thereby increasing the risk of adverse reactions.

Avoid co-administration. If co-administration is unavoidable, the cabozantinib dosage should be reduced (e.g., from 60 mg to 40 mg).

Strong CYP3A Inducers (e.g., rifampin, carbamazepine, St. John's wort):

Co-administration significantly decreases cabozantinib plasma concentrations, potentially compromising efficacy.

Avoid co-administration. If co-administration is unavoidable, the cabozantinib dosage may be increased (e.g., from 60 mg to 80 mg), provided it is well-tolerated, and the patient should be closely monitored.

IX. Use in Specific Populations

Pregnant Women: May cause fetal harm. Advise pregnant women of the potential risk to the fetus.

Lactating Women: It is recommended to discontinue breastfeeding during treatment and for 4 months following the last dose.

Pediatric Patients: Safety and efficacy have not been established.

Geriatric Patients: No overall differences in safety were observed between patients aged 65 and older and younger patients; however, caution is still warranted.

Patients with Hepatic/Renal Impairment:

Hepatic Impairment: No dosage adjustment is required for patients with mild to moderate hepatic impairment. For patients with severe hepatic impairment, a reduced starting dose is recommended. Renal Impairment: No dose adjustment is required for patients with mild to moderate renal impairment. Data regarding the use of this medication in patients with severe renal impairment are limited; therefore, caution is advised.

X. Overdosage

Symptoms: An exacerbation of adverse reactions is expected, such as severe gastrointestinal reactions, bone marrow suppression, etc.

Management: Discontinue the medication immediately, initiate supportive care, and provide symptomatic treatment.

XI. Clinical Pharmacology

Pharmacokinetics: Cabozantinib is well absorbed following oral administration, reaching peak plasma concentrations approximately 2 to 5 hours after dosing. High-fat meals significantly increase its systemic exposure; therefore, the medication should be taken on an empty stomach. *In vivo*, it is primarily metabolized via the CYP3A4 pathway. Fecal excretion constitutes its primary route of elimination.

XII. Patient Counseling Information

1.  Strict Adherence to Prescribing Instructions: Pay close attention to dosage differences among different dosage forms, and ensure the medication is taken on an empty stomach.

2.  Managing Side Effects: Learn how to manage common side effects—such as diarrhea, hand-foot skin reactions, and hypertension—and report them to your physician promptly.

3.  Surgery and Dental Procedures: Inform your physician that you are taking Cabozantinib to facilitate the scheduling of any surgical or dental treatments.

4.  Contraception Requirements: Patients with reproductive potential must understand and strictly adhere to required contraceptive measures.

5.  Immediate Reporting of Warning Symptoms: Seek immediate medical attention if you experience warning symptoms such as severe abdominal pain, bloody stools, coughing up blood, severe headache, seizures, chest pain, or difficulty breathing.

In Conclusion: Please strictly follow the specific instructions provided by your attending physician and pharmacist. If you have any questions or experience any discomfort during the course of treatment, please communicate immediately with your healthcare team.

[Manufacturer Introduction]

Da Xiong Pharmaceutical is one of the officially recognized chemical pharmaceutical enterprises in Laos. Following a comprehensive two-year site selection process—conducted in the presence of investors and the Laotian Minister of Health—the factory was ultimately established in Vientiane, the capital city of Laos. Preparations for the facility began in 2020, and construction was completed in 2021. The parent company invested substantial capital to implement industrial upgrades, establishing production workshops that meet advanced international manufacturing standards. Furthermore, the facility has made significant contributions toward alleviating the shortage of medical supplies and pharmaceuticals within Laos. Over the past two years, Daewoong Pharmaceutical has sustained a trajectory of continuous innovation, prudent management, and steady expansion. With its business scope constantly broadening and its performance metrics remaining consistently strong, the company’s key economic indicators have consistently ranked at the forefront of the pharmaceutical industry within Laos. This marks the opening of a new chapter for Daewoong Pharmaceutical as it sets out to build a modern pharmaceutical group that is a leader in Laos and world-class in stature.