Zidovudine

Overview

Zidovudine (Retrovir®) is an antiretroviral agent used in cats as adjunctive therapy for feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) infections.

Treatment may reduce viral load and improve clinical signs in infected cats, although it may not substantially alter the natural course of disease. Drug resistance may develop during prolonged therapy and has been reported as early as 6 months after treatment initiation.

Zidovudine is well absorbed after oral administration and is widely distributed throughout the body, including the cerebrospinal fluid (CSF).

Mechanism of Action (MOA): Zidovudine is converted intracellularly to an active triphosphate metabolite that inhibits viral reverse transcriptase, interfering with viral RNA-directed DNA synthesis and producing a virustatic effect.

Zidovudine is a nucleoside reverse transcriptase inhibitor and a thymidine analogue – the same class of antiretroviral used against HIV in people. It is used in cats off-label, as no veterinary-labeled product exists.

Indications

Zidovudine is used in cats as adjunctive therapy for retroviral infections associated with feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV).

• Feline immunodeficiency virus (FIV): May reduce viral load and improve clinical signs, quality of life and immunological status; the clearest benefit is in cats with severe stomatitis or FIV-related neurological signs, and it is most effective against acute infection.
• Feline leukemia virus (FeLV): Evidence in naturally FeLV-infected cats is weak: controlled trials have not demonstrated a significant benefit, antiretroviral therapy is not routinely indicated for FeLV, and zidovudine should be used carefully or avoided in FeLV-positive cats, in which the higher doses can cause nonregenerative anemia. Where it is still tried — for example in cats with FeLV-associated neurological signs, or with refractory stomatitis when interferon has not worked — it may improve clinical signs but does not clear the virus.
• Asymptomatic infection: In FIV-positive cats that are not yet showing clinical signs, treatment may delay the onset of the clinical phase.
• Reserve zidovudine, at the dosage given above for adjunctive FIV/FeLV therapy, for cats that do not respond adequately to symptomatic and supportive treatment, as resistance may develop during therapy.

Dosage (Reference)

Cat

In cats, zidovudine is administered as adjunctive therapy for feline retroviral infections, with careful monitoring for hematologic adverse effects.

Warnings & Precautions

Zidovudine requires careful hematologic monitoring. Toxicity may occur, most commonly at the higher end of the dose range, and long-term adverse effects of lower doses have not been established.

• Contraindications: Do not use zidovudine after a previous life-threatening hypersensitivity reaction. Guidance differs for animals that are severely anemic or leukopenic: some references advise avoiding treatment, whereas another reports no animal contraindications.
• Bone marrow dysfunction: Use cautiously in patients with bone marrow dysfunction. Feline-specific guidance goes further and advises against treating cats that already have myelosuppression.
• Renal or hepatic disease: Dosage adjustment may be necessary in patients with renal or hepatic dysfunction.
• Hematologic toxicity: In people, severe anemia and neutropenia have been associated with zidovudine. In cats, severe nonregenerative anemia can develop rapidly at high doses, and leukopenia has also been reported.
• Prolonged treatment risks: In people, prolonged zidovudine use has been associated with symptomatic myopathy; lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, are included in the human product’s boxed warning.
• Injection precautions: In people, rapid infusions and bolus injections should be avoided, and zidovudine should not be administered intramuscularly.
• Hazardous drug precautions: Zidovudine is classified as a hazardous drug and protective handling precautions are recommended, although some formularies advise only normal handling precautions.
• Pregnancy and lactation: Safety in pregnancy and lactation has not been established: fetal toxicity occurred in rats and rabbits given high doses, and the drug is excreted in milk. Use only when the benefit to the queen outweighs the potential risk to the offspring.

Drug Interactions

Drug interactions with zidovudine primarily involve altered serum concentrations or increased risk of hematologic and hepatic toxicity. They are reported mainly in people or remain theoretical, and none has been reported in animals. Unless otherwise stated, concurrent use is not necessarily contraindicated; weigh the potential risks and monitor appropriately.

• Azole antifungals (e.g., fluconazole, ketoconazole): May increase zidovudine serum concentrations.
• Atovaquone: May increase serum concentrations of zidovudine.
• Doxorubicin: The two drugs may antagonize each other’s effects; avoid concurrent use.
• Interferon alfa: Increased risk of hematologic and hepatic toxicity.
• Methadone: May increase zidovudine serum concentrations.
• Myelotoxic or cytotoxic drugs: Concurrent administration may increase the risk of hematologic toxicity. The drugs named include chloramphenicol, doxorubicin, flucytosine, vincristine, vinblastine, ganciclovir, interferon alfa and ribavirin.
• Probenecid: May increase zidovudine serum concentrations.
• Rifampin: May decrease zidovudine serum concentrations.
• NSAIDs: May delay zidovudine metabolism, increasing the risk of nephrotoxicity or neutropenia.

Side Effects & Overdose

Side Effects

Hematologic toxicity is the most commonly reported adverse effect associated with zidovudine therapy in cats.

• Nonregenerative anemia: Most commonly reported adverse effect, particularly at higher doses (10–15 mg/kg).
• Reduced RBCs, PCV, and hemoglobin: Hematologic suppression may develop during treatment.
• Diarrhea: Gastrointestinal upset may occur during therapy.
• Weakness: Weakness has been reported in treated cats.
• Tolerability: In a controlled trial of 22 cats no notable adverse effects were detected, and FIV-infected cats treated for two years tolerated zidovudine well; zidovudine alone and combined with lamivudine were also well tolerated with minimal side effects. Long-term adverse effects of lower doses have not been established.
• White-cell effects: Leukopenia has also been observed in treated animals. The drug has been used infrequently in animals, so the full range of potential adverse effects has not been reported.
• Effects reported in people: In people the most likely adverse effects are granulocytopenia and gastrointestinal upset — especially nausea, vomiting and anorexia — and both frequency and severity are greater when infection is more advanced at the start of treatment.

Overdose

Veterinary information on zidovudine overdose is limited, and the reported findings come from human overdoses.

• Vomiting: In people, vomiting has been one of the most consistently reported overdose effects.
• Transient hematologic effects: In people, transient hematologic effects have been consistently reported after overdose.
• Management: For a known or suspected overdose, consult a 24-hour poison-control center that provides veterinary-specific information.
• Reported human overdoses: Human adults and children have survived oral overdoses of up to 50 g without permanent sequelae.

Key Notes

Practical clinical points that help optimize the use of zidovudine in cats:

• High oral bioavailability: Oral absorption in cats is excellent, approaching 95%.
• Rapid absorption: Peak plasma concentrations occur approximately 1 hour after oral administration; giving the dose with food may lower the peak concentration without necessarily reducing total exposure.
• Wide tissue distribution: Zidovudine distributes extensively throughout the body, including the CSF.
• Minimal plasma protein binding: Only marginally bound to plasma proteins.
• Rapid elimination: Elimination half-life in cats is approximately 1.5 hours; the drug is rapidly metabolised and excreted in the urine.
• Diluent compatibility: For subcutaneous use the injection is diluted in saline; it is also compatible with 5% dextrose and lactated Ringer’s solution.
• Antiviral dose versus safe dose: Experimental dosing at 25 mg/kg q12h IV or PO produced virus-inhibitory concentrations, but this is not the recommended clinical regimen; adverse effects are more common above 10 mg/kg q12h, and the recommended dose is 5–10 mg/kg q12h.
• Strength of the evidence: Veterinary evidence remains limited: well-controlled feline studies are scarce, and controlled studies in naturally FeLV-infected cats have generally shown limited or no lasting benefit.
• Combination with lamivudine: In naturally FIV-infected cats, zidovudine plus lamivudine produced a greater reduction in viral load than zidovudine alone, and both protocols improved the CD4:CD8 ratio.