Rabacfosadine

Overview

Rabacfosadine (Tanovea®; also listed as Tanovea-CA1®) is an injectable antineoplastic agent used in dogs. It is a prodrug of the nucleotide analogue PMEG and is FDA-approved for the treatment of lymphoma in dogs; it has also been investigated in multiple myeloma.

Rabacfosadine has been evaluated in both B-cell and T-cell lymphoma and may also be used as part of combination chemotherapy protocols.

Mechanism of Action (MOA): Rabacfosadine is a prodrug of the nucleotide analogue PMEG that causes cytotoxicity in dividing cells through inhibition of DNA polymerases.

Indications

Rabacfosadine is used in dogs for the treatment of certain hematologic malignancies.

• Canine lymphoma: Used in both B-cell and T-cell lymphoma.
• Multiple myeloma: Has been investigated as a treatment option in dogs.
• Cutaneous epitheliotropic lymphoma: Reported as a single agent for cutaneous epitheliotropic (T-cell) lymphoma, with complete or partial remission in 45% of dogs (5 of 11) in one series.

Dosage (Reference)

Dog

Rabacfosadine is administered by intravenous infusion and is typically given as part of a treatment protocol for canine lymphoma or other hematologic malignancies.

Warnings & Precautions

Rabacfosadine is a potent cytotoxic drug that should be used with careful patient selection and monitoring due to the risk of serious adverse effects.

• Cytotoxic drug handling: Preparation and administration should only be performed by trained personnel experienced in handling chemotherapeutic agents.
• Bone marrow suppression: Do not use in patients with pre-existing bone marrow suppression.
• Liver dysfunction: Contraindicated in patients with liver dysfunction.
• Pulmonary disease: Do not use in patients with known pulmonary disease or in those susceptible to pulmonary fibrosis. Do not use in West Highland White Terriers, which have a genetic predisposition to pulmonary fibrosis, and use with caution in other terrier breeds.
• Hypersensitivity: Contraindicated in patients with known hypersensitivity to rabacfosadine.
• Pre-existing infection: Use with caution in patients with pre-existing infection.
• Pregnancy, lactation and breeding: Do not use in dogs that are pregnant, lactating or intended for breeding. Rabacfosadine is cytotoxic, is a likely teratogen and may affect fertility in both sexes; verify pregnancy status before administration in sexually intact patients.
• Handler protection and waste handling: Wear chemotherapy-resistant gloves, goggles and protective clothing to prepare and administer. Women who are pregnant, may become pregnant or are nursing should not handle, prepare or administer rabacfosadine. For 5 days after each treatment, avoid direct contact with the dog’s urine, feces, vomit or saliva; handle bodily waste with chemotherapy-resistant gloves, and anyone who is pregnant, attempting to conceive or nursing should not clean up the waste. Wash soiled items separately from other laundry.
• Extravasation: May cause pain and tissue damage at the injection site; avoid extravasation. If extravasation occurs, stop the infusion immediately, withdraw 3 to 5 mL of blood through the catheter to remove some of the drug, aspirate any swelling, remove the catheter, mark the area and cold-pack it for 48 to 72 hours.
• Narrow therapeutic index: Rabacfosadine has a narrow therapeutic index; calculate the dose from the exact weight of the dog and re-check the calculation before administration.

Drug Interactions

The following interactions are theoretical and may be clinically significant in patients receiving rabacfosadine. Additional monitoring may be warranted when these agents are used concurrently.

• Other cytotoxic antineoplastic agents (e.g., other antineoplastics, immunosuppressives, chloramphenicol, flucytosine, colchicine): May increase the risk of additive myelosuppression and gastrointestinal toxicity. The safety and effectiveness of rabacfosadine in combination with other chemotherapy drugs or treatment agents have not been evaluated.
• Radiation therapy: Rabacfosadine is a potent inhibitor of DNA repair and may enhance radiation-associated acute effects when administered concurrently.

Side Effects & Overdose

Side Effects

Rabacfosadine may cause hematologic, gastrointestinal, hepatic, pulmonary, dermatologic, and urinary adverse effects.

• Myelosuppression: Bone marrow suppression may occur during treatment. Neutropenia is a common adverse effect, with the nadir around seven days after treatment and recovery in almost all reported instances before the next cycle; thrombocytopenia and anemia are also reported.
• Gastrointestinal adverse effects: Diarrhea, decreased appetite and vomiting are common; haemorrhagic gastroenteritis and hematochezia have also been reported. Supportive treatment and dose reduction or delay may be used to mitigate adverse effects.
• Hepatic effects: Elevation of liver enzyme activity may occur.
• Renal effects: Azotaemia has been reported.
• Systemic effects: Fever, weight loss, and lethargy may occur during treatment.
• Dermatologic effects: Dermatological adverse reactions are common and cumulative, typically appearing from the third treatment onward as erythema and alopecia that may progress to crusting and exudate, most often over the ears and periauricular region, the dorsum, the axillae and the inguinal areas; otitis is frequent. They typically resolve with supportive therapy and dose reduction or delay, and are a dose-limiting toxicity.
• Ocular effects: Injected sclera may occur.
• Urinary effects: Urinary signs, proteinuria, and glycosuria have been reported.
• Other reported effects: Tachypnea, dyspnea, tachycardia, hypokalemia and hypophosphatemia have also been reported.

Overdose

• Dogs receiving single IV doses of 2.5 mg/kg developed moderate to severe GI signs beginning on Day 4 and resolving by Day 10; moderate to severe neutropenia and leukopenia also occurred, with a nadir between Days 6 and 9 and recovery by Day 12.
• In case of accidental overdose, aggressive supportive care measures (eg, IV fluids, antiemetics, antidiarrheals, antibiotics, ± granulocyte colony-stimulating factor) are indicated.
• At 8.2 mg/kg IV (8.2 times the label dose), dogs developed severe neutropenia, GI signs, salivation, fever, tremors and weakness, became moribund, and were found dead or euthanized by Day 7.

Key Notes

Practical points to consider when using rabacfosadine in dogs:

• Prodrug activity: Rabacfosadine is a prodrug of the nucleotide analogue PMEG.
• DNA polymerase inhibition: Its antineoplastic activity results from inhibition of DNA polymerases in dividing cells.
• Administration schedule: For the labeled single-agent regimen, treatment is administered at 21-day intervals for up to five doses; in the alternating protocol with doxorubicin it is given at weeks 0, 6 and 12.
• Combination protocols: Rabacfosadine has been used in alternating treatment protocols with doxorubicin; in one prospective study of treatment-naive dogs that protocol achieved an overall response rate of 93% and a median progression-free survival of 6.6 months.
• Monitoring: Baseline complete blood count, serum biochemistry, urinalysis and thoracic radiographs before treatment; repeat the blood count 7 days after the first dose and immediately before every subsequent dose; repeat biochemistry every 2 to 3 treatments; and repeat thoracic radiographs every 2 to 3 months or whenever respiratory signs appear.
• Pharmacokinetics: Rabacfosadine is not orally absorbed and the veterinary regimen is administered by IV infusion. The drug concentrates in lymphoid tissue and peripheral blood mononuclear cells, where PMEGpp has a terminal half-life of 68.7 hours, and it does not penetrate the central nervous system. Elimination is both fecal and renal.
• Response by immunophenotype: In one study of 60 treatment-naive dogs the overall response rate was 97% in B-cell lymphoma against 50% in T-cell lymphoma.
• Concurrent prednisone: Prednisone given alongside rabacfosadine may reduce the risk of pulmonary fibrosis: in one study the incidence of known or presumed pulmonary fibrosis was 15% in 34 dogs treated without prednisone and 4% in 25 dogs given prednisone 0.5 to 1 mg/kg daily, although the benefit is not yet established.
• Storage and stability: Store unopened vials refrigerated at 2 °C to 8 °C in the original package, protected from light. After reconstitution, store at 20 °C to 25 °C and dilute within 4 hours. Discard unused infusion solution within 24 hours of admixture and within 4 hours of attachment to the IV administration set.
• Cost and vial count: A course can be significantly more expensive than a CHOP protocol, especially in larger dogs, which may need more than one vial per treatment.