Vinorelbine

Overview

Vinorelbine (Navelbine®) is a semisynthetic vinca alkaloid antineoplastic agent used in dogs and cats for the treatment of a variety of neoplastic diseases. It is commonly incorporated into chemotherapy protocols for selected solid tumors and has been investigated for use in several canine cancers, including pulmonary, mast cell, histiocytic, vascular, and urinary bladder tumors.

Compared with some other vinca alkaloids, vinorelbine appears to have a lower incidence of peripheral neurotoxicity, although myelosuppression remains a clinically important adverse effect. The drug is administered intravenously and must be given through a properly placed, freely flowing catheter because extravasation can result in significant local tissue injury.

Vinorelbine dosing is typically based on body surface area and treatment protocols are adjusted according to patient tolerance and hematologic monitoring. Because of its potential toxicity, treatment should be individualized and closely supervised throughout therapy.

Mechanism of Action (MOA): Vinorelbine binds to tubulin within the mitotic spindle, preventing microtubule formation and disrupting cell division during metaphase. This inhibition of mitosis ultimately leads to death of rapidly dividing cells. The drug also interferes with several cellular metabolic pathways, including amino acid utilization and purine synthesis.

Indications

Vinorelbine is used in dogs and cats as part of chemotherapy protocols for selected neoplastic diseases.

• Hemangiosarcoma: Used in the treatment of canine hemangiosarcoma.
• Mast cell tumors: Used for locally aggressive or metastatic cutaneous mast cell tumors in dogs.
• Pulmonary tumors: Used in the management of primary pulmonary carcinoma and bronchoalveolar carcinoma.
• Histiocytic sarcoma: May be incorporated into treatment protocols for canine histiocytic sarcoma.
• Urinary bladder carcinoma: May be used, often in combination with piroxicam, for urinary bladder carcinoma.

Dosage (Reference)

Dog

Vinorelbine is administered intravenously for the treatment of neoplastic diseases. Doses are calculated using body surface area (BSA) and should be administered through a freely flowing intravenous catheter.

Cat

Published experience in cats is limited. The recommended starting dose is administered intravenously and adjusted according to tolerance and hematologic monitoring.

Warnings & Precautions

Vinorelbine is a cytotoxic chemotherapeutic agent that can cause significant hematologic toxicity and should be administered only with appropriate patient monitoring and handling precautions.

• Pre-existing bone marrow suppression: Contraindicated in patients with granulocytopenia, thrombocytopenia, or significant anemia unless these abnormalities are associated with the disease being treated.
• Active bacterial infection: Avoid use in patients with active bacterial infections due to the risk of severe treatment-associated myelosuppression.
• Neutropenia monitoring: Delay treatment or reduce dose for low neutrophil counts. 50% dose reduction if neutrophil count 1,000–1,499 cells/mm³, delay treatment if <1,000 cells/mm³, and 25% reduction after previous fever, sepsis, or delayed treatment.
• Hepatic dysfunction: Reduce dose in liver disease. 50% reduction if bilirubin >2 mg/dL, or 75% reduction if >3 mg/dL.
• Radiation involving the liver: Use should be avoided in patients receiving radiation therapy to fields that include the liver.
• Intrathecal administration: Never administer vinorelbine intrathecally, as vinca alkaloids can cause fatal ascending paralysis when given by this route.
• Extravasation risk: Vesicant — administer through a freely flowing IV catheter. If extravasation occurs: stop infusion, aspirate, apply moderate heat (NOT ice — ice worsens vinca extravasation), and consider hyaluronidase (150 units/mL, 1–6 mL through the IV site or 0.2 mL SC/intradermally in 5 sites). Topical DMSO may also be considered. Never give SC or IM.
• Pregnancy & lactation: Teratogenic and embryotoxic in laboratory animals; may also cause aspermia in males. use milk replacer if a nursing dam requires the drug. Verify pregnancy status before treatment in sexually intact patients.
• NIOSH hazardous + owner handling: NIOSH-classified hazardous drug. Use chemotherapy-resistant PPE during preparation and administration. Advise owners to wear chemotherapy-resistant gloves when handling animal waste (urine, feces, vomit) for a few days after each treatment, and seal waste in plastic before disposal. Pregnant or nursing household members must NOT handle the drug or the animal’s waste.
• MDR1 status: Unlike vincristine and vinblastine, vinorelbine does not appear to be a significant P-glycoprotein substrate. Pre-treatment MDR1 (ABCB1-1delta) testing in herding breeds is therefore not clearly warranted before vinorelbine therapy.
• Human-data severe complications: In humans, severe and fatal complications have been reported: paralytic ileus, constipation, intestinal obstruction, necrosis, perforation, severe bronchospasm, interstitial pneumonitis, and acute respiratory distress syndrome (ARDS). Be alert to these in heavily pre-treated or compromised veterinary patients.
• Storage & handling: Store intact vials between 2–8 °C (36–46 °F) protected from light. Diluted solutions (0.5–2 mg/mL) are stable for up to 24 hours at 5–30 °C (41–86 °F). Dispose per cytotoxic-drug procedures.

Drug Interactions

Most clinically important interactions with vinorelbine involve increased drug exposure, additive myelosuppression, enhanced neurotoxicity, or immunosuppression.

• CYP3A inhibitors: Drugs that inhibit CYP3A metabolism may increase vinorelbine concentrations and the risk of toxicity.
• Azole antifungals: Agents such as itraconazole, ketoconazole, and voriconazole may increase serum vinorelbine concentrations; dose reduction may be necessary.
• Macrolide antibiotics: Macrolides (except azithromycin) may increase vinorelbine exposure and toxicity risk.
• Amiodarone, fluvoxamine, and grapefruit products: May inhibit vinorelbine metabolism and increase systemic drug concentrations.
• Myelosuppressive drugs: Concurrent use with other antineoplastic or immunosuppressive agents may result in additive bone marrow suppression.
• Immunosuppressive medications: Drugs such as azathioprine, cyclophosphamide, and corticosteroids may further increase the risk of infection.
• Neuropathy-inducing drugs: Agents such as carboplatin, dapsone, isoniazid, metronidazole, and nitrofurantoin may increase the risk of peripheral neurotoxicity.
• Heparins: Concurrent use may increase the risk of bleeding complications.
• Amphotericin B: May increase the risk of nephrotoxicity, bronchospasm, and hypotension.
• Antidiuretic hormones: Drugs such as desmopressin and vasopressin may increase the risk of water intoxication or hyponatremia.
• Ototoxic drugs: Aminoglycosides, cisplatin, and carboplatin may increase the risk of ototoxicity when used concurrently.
• Vaccines: Vinorelbine may reduce vaccine effectiveness and increase the risk of vaccine-related adverse effects.

Side Effects & Overdose

Side Effects

Myelosuppression and gastrointestinal toxicity are the most commonly reported adverse effects of vinorelbine. The frequency and severity of adverse effects may increase with repeated treatment cycles.

• Myelosuppression: Reported in 32-54% of dogs (granulocyte nadir at 7-10 days post-dose; recovery 7-14 days later). Thrombocytopenia (grade 1-2) occurred in 7% of dogs (retrospective). Vinorelbine is considered more myelosuppressive than vincristine. Bone marrow suppression may be cumulative with repeated dosing.
• Gastrointestinal toxicity: Gastroenterocolitis (nausea/vomiting/diarrhea) ; typically resolves within 24 hours. Not considered highly emetogenic.
• Peripheral neurotoxicity: May cause jaw pain, muscle pain, peripheral neuropathy, reduced reflexes, or other neurologic abnormalities.
• Ataxia: Bilateral hindlimb ataxia has been reported in dogs.
• Hepatic abnormalities: Elevated liver enzymes and hepatic dysfunction have been reported in some patients.
• Administration-site reactions: Phlebitis and erythema may occur, particularly following rapid IV administration or use of peripheral veins.
• Extravasation injury: Accidental perivascular administration may result in severe tissue irritation, cellulitis, and tissue necrosis.
• Cats: Phase I study in 19 cats reported: anemia 32%, neutropenia 21%, weight loss 16%, persistent vomiting 11%, thrombocytopenia 5.2%, and grade 4 acute renal injury 5.2%.
• Uric acid (Dalmatian risk): vinorelbine may significantly increase blood and urine uric acid concentrations — clinically significant in Dalmatians.
• Human-data severe complications: Severe complications reported in humans (rare in dogs): paralytic ileus, intestinal obstruction, necrosis/perforation, pulmonary toxicity (bronchospasm, interstitial pneumonitis, ARDS). Heightened vigilance is warranted in heavily pre-treated or compromised patients.
• More myelosuppressive than vincristine: Vinorelbine is more myelosuppressive than vincristine. Factor this into protocol choice and CBC monitoring intensity when switching among vinca alkaloids.

Overdose

Overdose is expected to cause severe manifestations of the drug’s known toxicities, particularly hematologic, gastrointestinal, and neurologic adverse effects.

• Severe myelosuppression: Marked neutropenia, thrombocytopenia, anemia, and life-threatening secondary infections may occur.
• Severe gastrointestinal toxicity: Pronounced vomiting, diarrhea, gastroenterocolitis, and ileus may develop.
• Neurotoxicity: Loss of reflexes, paresthesia-like signs, peripheral neuropathy, and other neurologic abnormalities may occur.
• SIADH-related complications: Fluid and electrolyte disturbances may develop. Management includes fluid restriction and close monitoring of fluid and electrolyte status to prevent SIADH-related complications.
• Management: Treatment is supportive and may include intensive monitoring, infection management, hematologic support, and blood product administration when clinically indicated.
• 5-fold overdose lethal in humans: Lethal threshold: in humans, death has occurred after a 5-fold overdose. Communicate exposure-distance precautions to clients with multiple animals.
• 24-hour poison consultation: For suspected or confirmed overdose, consult a 24-hour veterinary poison consultation center for case-specific guidance.

Key Notes

Practical clinical points that help optimize the use of vinorelbine in dogs and cats undergoing cancer treatment:

• Semisynthetic vinca alkaloid: Vinorelbine is a newer vinca alkaloid derivative that has demonstrated activity against a variety of solid tumors in veterinary oncology.
• Particular value in pulmonary tumors: Vinorelbine is commonly considered for canine primary pulmonary carcinoma and other pulmonary neoplasms where traditional chemotherapy options may be limited.
• Body surface area dosing: Dosages are calculated using body surface area (mg/m²) rather than body weight, as with many oncology drugs.
• Dose escalation may be possible: Some patients may tolerate gradual dose increases, allowing treatment intensity to be individualized according to response and tolerability.
• Limited feline experience: Published clinical experience in cats remains relatively limited compared with dogs, and treatment recommendations are based on a smaller evidence base.
• Flexible treatment scheduling: Administration intervals are commonly adjusted according to hematologic recovery and the overall chemotherapy protocol being followed.
• Oncology specialist involvement: Treatment planning and protocol selection are ideally performed in consultation with a veterinarian experienced in cancer chemotherapy.
• Pharmacokinetics: 90% protein-bound in dogs with terminal half-life 34.5 h (~40 h in humans); metabolized in liver by CYP3A . excreted in bile/feces (45%) with 11-18% in urine . Reaches 300-fold greater concentration in lung tissue than plasma (explains pulmonary efficacy).
• vs vincristine (myelo profile): More myelosuppressive than vincristine. When choosing between vinca alkaloids for protocol design, factor this in alongside the lower vinorelbine peripheral neurotoxicity.
• NIOSH hazardous handling: use chemotherapy-resistant gloves during preparation and administration. Advise owners to wear gloves when handling animal waste for a few days post-treatment; pregnant or nursing household members must not handle the drug or waste.