Cazanat 40 — Cabozantinib 40 mg Tablets, 30 Tablets

Cazanat 40 is formulated as film-coated tablets for oral administration.

Qualitative and Quantitative Composition per Tablet:

• • Active Ingredient: Cabozantinib (S)-malate equivalent to cabozantinib free base — 40 mg.
• • Excipients: Microcrystalline cellulose, lactose monohydrate, hydroxypropyl cellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate; film-coating components (hypromellose, titanium dioxide, triacetin, yellow iron oxide).

Packaging Configuration: Supplied in white high-density polyethylene (HDPE) bottles containing 30 tablets with child-resistant closures and tamper-evident seals. Each bottle, along with the official patient leaflet, is packaged in an outer carton displaying Natco Pharma branding, red and blue stripe design, "Cabozantinib Tablets 40 mg", "Cazanat 40", and "30 Tablets" designations.

Pharmacodynamics:
Cabozantinib is a small-molecule multi-kinase receptor tyrosine kinase inhibitor. It selectively inhibits hepatocyte growth factor receptor (MET) and vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3). Additionally, cabozantinib inhibits other oncogenic receptor tyrosine kinases including AXL, RET, ROS1, TYRO3, MER, KIT, FLT3, and TIE-2. Overexpression of MET and AXL is strongly linked to tumor invasion, metastasis, and resistance to selective VEGFR inhibitors. Dual inhibition of MET/AXL and VEGFR pathways yields synergistic anti-tumor effects.

Pharmacokinetics:

• • Absorption: Following oral administration, peak plasma concentrations occur within 2 to 5 hours. High-fat meals significantly increase Cmax and AUC, requiring administration strictly on an empty stomach.
• • Distribution: Extremely high plasma protein binding of approximately 99.7%. Volume of distribution is approximately 319 liters.
• • Metabolism: Extensively metabolized in the liver, primarily by CYP3A4 and to a lesser extent by CYP2C8. The oxidative metabolite XL184-N-oxide is the major circulating metabolite.
• • Elimination: Mean elimination half-life (T1/2) is approximately 99 hours. Approximately 54% of the dose is excreted in feces and 27% in urine as unchanged drug and metabolites.

Cazanat 40 is indicated for the treatment of adult patients with the following oncological conditions:

• • Advanced Renal Cell Carcinoma (RCC): As monotherapy in treatment-naive patients with intermediate or poor risk, or in patients previously treated with anti-angiogenic therapy (including VEGFR inhibitors) or immunotherapy.
• • Hepatocellular Carcinoma (HCC): Treatment of patients with HCC who have been previously treated with sorafenib.
• • Differentiated Thyroid Cancer (DTC): Treatment of progressive, locally advanced or metastatic DTC in patients refractory to radioactive iodine.

Treatment with Cazanat 40 should be initiated and supervised by a physician experienced in the administration of targeted anticancer therapies.

Method of Administration:
Tablets should be swallowed whole with water. Do not crush, chew, or split the tablets. Administer strictly on an empty stomach: at least 2 hours after food and at least 1 hour before eating.

Dosing Regimen:

• • Standard Daily Dose: 60 mg orally once daily (using appropriate dose combinations or 60 mg strength tablets). The 40 mg dosage strength is utilized as an initial dose in patients with impaired liver function or reduced performance status, or as a dose reduction step for toxicity management.
• • Dose Modifications for Toxicity: Management of severe adverse reactions (Grade 3/4 CTCAE) requires temporary treatment interruption. Upon resolution, resume therapy at a reduced dose (from 60 mg to 40 mg daily, or from 40 mg to 20 mg daily).

Administration of Cazanat 40 is contraindicated in:

• • Hypersensitivity: Known hypersensitivity to cabozantinib or any excipients.
• • Severe Hepatic Impairment: Severe liver function impairment (Child-Pugh Class C).
• • Severe Renal Impairment: Severe impairment of renal function.
• • Pregnancy and Lactation: Safety not established; demonstrates embryotoxic and teratogenic properties.
• • Pediatric Population: Safety and efficacy in children and adolescents under 18 years of age have not been established.

Cabozantinib is heavily metabolized by hepatic enzymes, requiring careful review of concomitant medications:

• • Strong CYP3A4 Inhibitors (ketoconazole, itraconazole, clarithromycin, grapefruit juice): Increase cabozantinib plasma exposure and toxicity risk. Avoid co-administration or reduce cabozantinib dose.
• • Strong CYP3A4 Inducers (rifampin, phenytoin, carbamazepine, St. John's Wort): Significantly decrease cabozantinib plasma concentrations, lowering clinical efficacy. Avoid co-administration.
• • P-glycoprotein Substrates: Cabozantinib inhibits P-gp and may increase plasma exposure of co-administered P-gp substrates (e.g., digoxin).

Pregnancy:
Cabozantinib is contraindicated during pregnancy. Women of childbearing potential must use effective contraception during treatment and for at least 4 months after the final dose. Male patients with female partners of childbearing potential must also use effective contraception.

Lactation:
Breastfeeding should be discontinued during Cazanat 40 therapy and for at least 4 months following the last dose.

Treatment with cabozantinib is associated with a distinct adverse reaction profile:

• • Gastrointestinal: Diarrhea, nausea, vomiting, stomatitis, anorexia, constipation, dysgeusia, risk of GI perforations and fistulas.
• • Dermatologic: Palmar-plantar erythrodysesthesia syndrome (PPE), rash, dry skin, alopecia, hair color changes.
• • Cardiovascular: Hypertension, venous and arterial thromboembolism, hemorrhage.
• • Laboratory Abnormalities: Elevated ALT, AST, alkaline phosphatase, hypophosphatemia, hypomagnesemia, hypocalcemia, neutropenia, thrombocytopenia, proteinuria.
• • General Disorders: Fatigue, asthenia, weight loss, osteonecrosis of the jaw.

Symptoms:
Overdose manifests as an amplification of known adverse reactions, particularly severe diarrhea, hypertension, severe palmar-plantar erythrodysesthesia, and hepatic toxicity.

Treatment:
There is no specific antidote. Due to high plasma protein binding, hemodialysis is ineffective. Discontinue therapy and provide supportive clinical care with vital sign monitoring.

Storage Requirements for Cazanat 40:

• 🌡️ Temperature: Store below 25 °C (77 °F).
• ☀️ Moisture Protection: Store in original HDPE bottle with cap tightly closed in a dry place. Do not remove desiccant.
• 👶 Safety: Keep out of reach of children.
• ⏳ Shelf Life: 24 months from manufacturing date. Do not use past expiration date. Prescription medicine (Rx Only).

To verify the authenticity of original Cazanat 40 produced by Natco Pharma, check the following details:

• ✅ Natco Corporate Logo: Oval blue logo containing white "NATCO" lettering located at the lower left corner of the box and bottle label.
• ✅ Package Color Design: White outer carton decorated with a Z-shaped geometric red and blue graphic ribbon.
• ✅ Product Title Typography: "Cazanat" printed in blue, accompanied by "40" in red with a red asterisk.
• ✅ Label Declarations: Clear presence of generic "Cabozantinib Tablets 40 mg" and "30 Tablets" pack size text.
• ✅ Batch Identification: Stamped Batch Number, Manufacturing Date, and Expiration Date on box flaps.