Zidovudine with ganciclovir

Ganciclovir interacts with a number of medications, some of which are used to treat HIV or transplant patients. Ganciclovir may cause severe neutropenia when used in combination with zidovudine. Ganciclovir increases serum levels of didanosine, whereas probenecid decreases ganciclovir elimination. Nephrotoxicity may result if other nephrotoxic agents (e.g., amphotericin B, cyclosporine, NSAIDs) are administered in conjunction with ganciclovir. 

Zidovudine should be used cautiously with any other agent that causes bone marrow suppression, such as interferon-a, trimethoprim-sulfamethoxazole, dap-sone, foscarnet, flucytosine, ganciclovir, and valganci-clovir. Probenecid and interferon-p inhibit the elimination of zidovudine therefore, a dosage reduction of zidovudine is necessary when the drugs are administered concurrently. Ribavirin inhibits the phosphorylation reactions that activate zidovudine, and zidovudine similarly inhibits the activation of stavudine thus, the coadministration of zidovudine with ribavirin or stavudine is contraindicated. 

Zidovudine and ganciclovir have overlapping toxicity profiles with respect to adverse hematological effects. Severe life-threatening hematological toxicity has been reported in 82% of patients treated with a combination of zidovudine and ganciclovir (18). The combination of ganciclovir with didanosine was much better tolerated (19). 

Another study in 6 AIDS patients with CMV retinitis given zidovudine and ganciclovir found increased bone marrow toxicity but no improved efficacy over ganciclovir alone. Increased toxicity (myelotoxicity and pancytopenia) following the use of both drugs has also been reported elsewhere." ... 

Millar AB, Miller RF, Patou G, Mindel A, Marsh R, Semple SJG. Treatment of cytomegalovirus retinitis with zidovudine and ganciclovir in patients with AIDS outcome and toxicity. 

Antibodies against the virus but also amantadine and derivatives, interfere with host cell penetration. There are nucleoside analogues such as aciclovir and ganciclovir, which interfere with DNA synthesis, especially of herpes viruses. Others like zidovudine and didanosine, inhibit reverse transcriptase of retroviruses. Recently a number of non-nucleoside reverse transcriptase inhibitors was developed for the treatment of HIV infections. Foscarnet, a pyrophosphate analogue, inhibits both reverse transcriptase and DNA synthesis. Protease inhibitors, also developed for the treatment of HIV infections, are active during the fifth step of virus replication. They prevent viral replication by inhibiting the activity of HIV-1 protease, an enzyme used by the viruses to cleave nascent proteins for final assembly of new vi-rons. 

A. Ganciclovir commonly causes myelosuppression and may produce severe neutropenia when given in combination with zidovudine. Fomivirsen is most commonly associated with iritis and other ocular information rimantadine with nausea, vomiting, anorexia, and dizziness famciclovir with headache, nausea, diarrhea, and CNS effects and zanamivir with bronchospasm. 

Adverse effects Adverse effects include severe, dose-dependent neutropenia. [Note Combined treatment with zidovudine can result in additive neutropenia.] Ganciclovir is carcinogenic as well as embryotoxic and teratogenic in experimental animals. 

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS GANCICLOVIRAfALGANCIC LOVIR 1. T adverse effects with tenofovir, zidovudine and possibly didanosine, lamivudine and zalcitabine 2. Possibly 1 efficacy of ganciclovir 1. Uncertain possibly additive toxicity. Lamivudine may compete for active tubular secretion in the kidneys 2. Uncertain L bioavailability 1. Avoid if possible otherwise monitor FBC and renal function weekly. It has been suggested that the dose of zidovudine should be halved from 600 mg to 300 mg daily. Monitor for peripheral neuropathy, particularly with zalcitabine 2. Uncertain clinical significance if in doubt, consider alternative cytomegalovirus prophylaxis... 

Hochster H, Dieterich D, Bozzette S et al. Toxicity of combined ganciclovir and zidovudine for cytomegalovirus disease associated with AIDS An AIDS clinical trials group study. Ann Intern Med 1990 113 111-17. 

Analogs of naturally occurring purine bases with antileukemic, immunosuppressant, and antiviral properties include mercaptopurine, thioguanine, azathioprine, acyclovir, ganciclovir, vidara-bine, and zidovudine. Other purine analogs important in cancer therapy include pentostatin (2 -deoxycoformycin), cladribine, and fludarabine phosphate. 

Clinical uses and toxicity Ganciclovir is used for the prophylaxis and treatment of CMV retinitis and other CMV infections in immunocompromised patients. Systemic toxic effects include leukopenia, thrombocytopenia, mucositis, hepatic dysfunction, and seizures. The dmg may cause severe neutropenia when used with zidovudine or other myelosuppressive agents. 

Gaines K, Wong Jung D, Cimoch P, Lavelle J, Pollard R. Pharmacokinetic interactions with oral ganciclovir zidovudine, didanosine, probenecid. 10th Int Conf AIDS, Yokohama (J )an), 1994. Abstract p7. 

The toxicity of the zidovudine/ganciclovir combination may be simply additive, but in vitro studies with three human cell lines found synergistic cytotoxicity when both drugs were used. ... 

The interactions between ganciclovir and didanosine or zidovudine would appear to be established, but the clinical importance is uncertain. Zidovudine seems to be associated with greater toxicity than didanosine. However, there is also some evidence suggesting reduced ganciclovir efficacy in the presence of didanosine, and this requires further study. Close and careful monitoring is required if either combination is used. 

Cimoch PJ, Lavelle J, Pollard R, Griffy KG, Wong R, Tarnowsld TL, Casserella S, Jung D. Pharmacokinetics of oral ganciclovir alone and in combination with zidovudine, didanosine, and probenecid in HIV-infected subjects. J Acquir Immune Defic Syndr Hum Retroviral (1998) 17, 227-34. 

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