Cidofovir

Microbiology

Cidofovir suppresses cytomegalovirus (CMV) replication by selective inhibition of viral DNA synthesis. Biochemical data support selective inhibition of CMV DNA polymerase by cidofovir diphosphate, the active intracellular metabolite of cidofovir. Cidofovir diphosphate inhibits herpesvirus polymerases at concentrations that are 8- to 600-fold lower than those needed to inhibit human cellular DNA polymerases alpha, beta, and gamma1,2,3. Incorporation of cidofovir into the growing viral DNA chain results in reductions in the rate of viral DNA synthesis.

Cidofovir is active in vitro against a variety of laboratory and clinical isolates of CMV and other herpesviruses (Table 1). Controlled clinical studies of efficacy have been limited to patients with AIDS and CMV retinitis.

Table 1. Cidofovir Inhibition of Virus Multiplication in Cell Culture

CMV isolates with reduced susceptibility to cidofovir have been selected in vitro in the presence of high concentrations of cidofovir4. IC50 values for selected resistant isolates ranged from 7–15 μM. There are insufficient data at this time to assess the frequency or the clinical significance of the development of resistant isolates following VISTIDE administration to patients.

The possibility of viral resistance should be considered for patients who show a poor clinical response or experience recurrent retinitis progression during therapy.

Cidofovir-resistant isolates selected in vitro following exposure to increasing concentrations of cidofovir were assessed for susceptibility to ganciclovir and foscarnet4. All were cross resistant to ganciclovir, but remained susceptible to foscarnet. Ganciclovir- or ganciclovir/foscarnet-resistant isolates that are cross resistant to cidofovir have been obtained from drug naive patients and from patients following ganciclovir or ganciclovir/ foscarnet therapy. To date, the majority of ganciclovirresistant isolates are UL97 gene product (phosphokinase) mutants and remain susceptible to cidofovir5. Reduced susceptibility to cidofovir, however, has been reported for DNA polymerase mutants of CMV which are resistant to ganciclovir6-9. To date, all clinical isolates which exhibit high level resistance to ganciclovir, due to mutations in both the DNA polymerase and UL97 genes, have been shown to be cross resistant to cidofovir. Cidofovir is active against some, but not all, CMV isolates which are resistant to foscarnet10-12. The incidence of foscarnet-resistant isolates that are resistant to cidofovir is not known.

A few triple-drug resistant isolates have been described. Genotypic analysis of two of these tripleresistant isolates revealed several point mutations in the CMV DNA polymerase gene. The clinical significance of the development of these cross-resistant isolates is not known.

Pharmacokinetics

VISTIDE must be administered with probenecid. The pharmacokinetics of cidofovir, administered both without and with probenecid, are described below.

The pharmacokinetics of cidofovir without probenecid were evaluated in 27 HIV-infected patients with or without asymptomatic CMV infection. Dose-independent pharmacokinetics were demonstrated after one hr infusions of 1.0 (n = 5), 3.0 (n = 10), 5.0 (n = 2) and 10.0 (n = 8) mg/kg (See Table 2 for pharmacokinetic parameters). There was no evidence of cidofovir accumulation after 4 weeks of repeated administration of 3 mg/kg/week (n = 5) without probenecid. In patients with normal renal function, approximately 80 to 100% of the VISTIDE dose was recovered unchanged in urine within 24 hr (n = 27). The renal clearance of cidofovir was greater than creatinine clearance, indicating renal tubular secretion contributes to the elimination of cidofovir.

The pharmacokinetics of cidofovir administered with probenecid were evaluated in 12 HIV-infected patients with or without asymptomatic CMV infection and 10 patients with relapsing CMV retinitis. Dose-independent pharmacokinetics were observed for cidofovir, administered with probenecid, after one hr infusions of 3.0 (n = 12), 5.0 (n = 6), and 7.5 (n = 4) mg/kg (See Table 2). Approximately 70 to 85% of the VISTIDE dose administered with concomitant probenecid was excreted as unchanged drug within 24 hr. When VISTIDE was administered with probenecid, the renal clearance of cidofovir was reduced to a level consistent with creatinine clearance, suggesting that probenecid blocks active renal tubular secretion of cidofovir.

Table 2. Cidofovir Pharmacokinetic Parameters Following 3.0 and 5.0 mg/kg Infusions, Without and With Probenecid*

In vitro, cidofovir was less than 6% bound to plasma or serum proteins over the cidofovir concentration range 0.25 to 25 μg/mL. CSF concentrations of cidofovir following intravenous infusion of VISTIDE 5 mg/kg with concomitant probenecid and intravenous hydration were undetectable (< 0.1 μg/mL, assay detection threshold) at 15 minutes after the end of a 1 hr infusion in one patient whose corresponding serum concentration was 8.7 μg/mL.

Drug-Drug Interactions

The pharmacokinetics of zidovudine were evaluated in 10 patients receiving zidovudine alone or with intravenous cidofovir (without probenecid). There was no evidence of an effect of cidofovir on the pharmacokinetics of zidovudine.

Special Populations

Pharmacokinetic data collected from subjects with creatinine clearance values as low as 11 mL/min indicate that cidofovir clearance decreases proportionally with creatinine clearance.

High-flux hemodialysis has been shown to reduce the serum levels of cidofovir by approximately 75%. Initiation of therapy with VISTIDE is contraindicated in patients with serum creatinine > 1.5 mg/dL, a calculated creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥2+ proteinuria) (See CONTRAINDICATIONS).

The effects of age, gender, and race on cidofovir pharmacokinetics have not been investigated.

Clinical Studies

Description Of Clinical Trials

Three phase II/III controlled trials of VISTIDE have been conducted in HIV-infected patients with CMV retinitis.

In stage 1 of this open-label trial, conducted by the Studies of the Ocular Complications of AIDS (SOCA) Clinical Research Group, 29 previously untreated patients with peripheral CMV retinitis were randomized to either immediate treatment with VISTIDE (5 mg/kg once a week for 2 weeks, then 3 mg/kg every other week) or to have VISTIDE delayed until progression of CMV retinitis13. In stage 2 of this trial, an additional 35 previously untreated patients with peripheral CMV retinitis were randomized to either immediate treatment with VISTIDE (5 mg/kg once a week for 2 weeks, then 5 mg/kg every other week), immediate treatment with VISTIDE (5 mg/kg once a week for 2 weeks, then 3 mg/kg every other week), or to have VISTIDE delayed until progression of CMV retinitis. Of the 64 patients in this study, 12 were randomized to 5 mg/kg maintenance therapy, 26 to 3 mg/kg maintenance therapy, and 26 to delayed therapy. Of the 12 patients enrolled in the 5 mg/kg maintenance group, 5 patients progressed, 5 patients discontinued therapy and 2 patients had no progression at study completion. Based on masked readings of retinal photographs, the median [95% confidence interval (CI)] time to retinitis progression was not reached (25, not reached) for the 5 mg/kg maintenance group. Median (95% CI) time to the alternative endpoint of retinitis progression or study drug discontinuation was 44 days (24, 207) for the 5 mg/kg maintenance group. Patients receiving 5 mg/kg maintenance had delayed time to retinitis progression compared to patients receiving 3 mg/kg maintenance or deferred therapy.

In an open-label trial, 48 previously untreated patients with peripheral CMV retinitis were randomized to either immediate treatment with VISTIDE (5 mg/kg once a week for 2 weeks, then 5 mg/kg every other week), or to have VISTIDE delayed until progression of CMV retinitis14. Patient baseline characteristics and disposition are shown in Table 3. Of 25 and 23 patients in the immediate and delayed groups respectively, 23 and 21 were evaluable for retinitis progression as determined by retinal photography. Based on masked readings of retinal photographs, the median [95% confidence interval (CI)] times to retinitis progression were 120 days (40, 134) and 22 days (10, 27) for the immediate and delayed therapy groups, respectively. This difference was statistically significant. However, because of the limited number of patients remaining on treatment over time (3 of 25 patients received VISTIDE for 120 days or longer), the median time to progression for the immediate therapy group was difficult to precisely estimate. Median (95% CI) times to the alternative endpoint of retinitis progression or study drug discontinuation (including adverse events, withdrawn consent, and systemic CMV disease) were 52 days (37, 85) and 22 days (13, 27) for the immediate and delayed therapy groups, respectively. This difference was statistically significant. Time to progression estimates from this study may not be directly comparable to estimates reported for other therapies.

Table 3. Patient Characteristics and Disposition (Study 106)

In an open-label trial, 100 patients with relapsing CMV retinitis were randomized to receive 5 mg/kg once a week for 2 weeks and then either 5 mg/kg (n = 49) or 3 mg/kg (n = 51) every other week. Enrolled patients had been diagnosed with CMV retinitis an average of 390 days prior to randomization and had received a median of 3.8 prior courses of systemic CMV therapy. Eighty-four of the 100 patients were considered evaluable for progression by serial retinal photographs (43 randomized to 5 mg/kg and 41 randomized to 3 mg/kg). Twenty-six and 21 patients discontinued therapy due to either an adverse event, intercurrent illness, excluded medication, or withdrawn consent in the 5 mg/kg and 3 mg/kg groups, respectively. Thirty-eight of the 100 randomized patients had progressed according to masked assessment of serial retinal photographs (13 randomized to 5 mg/kg and 25 randomized to 3 mg/kg). Using retinal photographs, the median (95% CI) times to retinitis progression for the 5 mg/kg and 3 mg/kg groups were 115 days (70, not reached) and 49 days (35, 52), respectively. This difference was statistically significant. Similar to Study 106, the median time to retinitis progression for the 5 mg/kg group was difficult to precisely estimate due to the limited number of patients remaining on treatment over time (4 of the 49 patients in the 5 mg/kg group were treated for 115 days or longer). Median (95% CI) times to the alternative endpoint of retinitis progression or study drug discontinuation were 49 days (38, 63) and 35 days (27, 39) for the 5 mg/kg and 3 mg/kg groups, respectively. This difference was statistically significant.

REFERENCES

1. Ho HT, Woods KL, Bronson JJ, De Boeck H, Martin JC and Hitchcock MJM. Intracellular Metabolism of the Antiherpesvirus Agent (S)-1-[3-hydroxy-2-(phosphonylmethoxy) propyl]cytosine. Mol Pharmacol 41:197–202, 1992.

2. Cherrington JM, Allen SJW, McKee BH, and Chen MS. Kinetic Analysis of the Interaction Between the Diphosphate of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, zalcitabineTP, zidovudineTP, and FIAUTP with Human DNA Polymerases b and g. Biochem Pharmacol 48:1986– 1988, 1994.

3. Xiong X, Smith JL, Kim C, Huang E, and Chen MS. Kinetic Analysis of the Interaction of Cidofovir Diphosphate with Human Cytomegalovirus DNA Polymerase. Biochem Pharmacol 51:1563–1567, 1996.

4. Cherrington JM, Mulato AS, Fuller MD, Chen MS. In Vitro Selection of a Human Cytomegalovirus (HCMV) that is Resistant to Cidofovir. 35th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, CA. Abstract H117, 1995.

5. Stanat SC, Reardon JE, Erice A, Jordan MC, Drew WL, and Biron KK. Ganciclovir-Resistant Cytomegalovirus Clinical Isolates: Mode of Resistance to Ganciclovir. Antimicrob Agents Chemother 35:2191–2197, 1991.

6. Sullivan V, Biron KK, Talarico C, Stanat SC, Davis M, Pozzi M, and Coen DM. A Point Mutation in the Human Cytomegalovirus DNA Polymerase Gene Confers Resistance to Ganciclovir and phosphonylmethoxyalkyl Derivatives. Antimicrob Agents Chemother 37:19–25, 1993.

7. Tatarowicz WA, Lurain NS, and Thompson KD. A Ganciclovir-Resistant Clinical Isolate of Human Cytomegalovirus Exhibiting Cross-Resistance to other DNA Polymerase Inhibitors. J Infect Dis 166:904–907, 1992.

8. Lurain NS, Thompson KD, Holmes EW, and Read GS. Point Mutations in the DNA Polymerase Gene of Human Cytomegalovirus that Result in Resistance to Antiviral Agents. J Virol 66:7146–7152, 1992.

9. Smith IL, Cherrington JM, Jiles RE, Fuller MD, Freeman WR, Spector SA. High-level Resistance of Cytomegalovirus to Ganciclovir is Associated with Alterations in both the UL97 and DNA Polymerase Genes. J Infect Dis 176:69–77, 1997.

10. Sullivan V and Coen DM. Isolation of Foscarnet-Resistant Human Cytomegalovirus Patterns of Resistance and Sensitivity to Other Antiviral Drugs. J Infect Dis 164:781–784, 1991.

11. Snoeck R, Andrei G, and De Clercq E. Patterns of Resistance and Sensitivity to Antiviral Compounds of Drug-Resistant Strains of Human Cytomegalovirus Selected in Vitro. Eur J Clin Microbiol Infect Dis 15:574–579, 1996.

12. Baldanti F, Underwood MR, Stanat SC, Biron KK, Chou S, Sarasini A, Silini E, and Gerna G. Single Amino Acid Changes in the DNA Polymerase Confer Foscarnet Resistance and Slow-Growth Phenotype, While Mutations in the UL97-Encoded Phosphotransferase Confer Ganciclovir Resistance in Three Double-Resistant Human Cytomegalovirus Strains Recovered from Patients with AIDS. J Virol 70:1390–1395, 1996.

Cidofovir is a prescription medication used to treat cytomegaloviral (CMV) retinitis, which is a viral inflammation of the eye, in people with acquired immune deficiency syndrome (AIDS).

Cidofovir belongs to a group of drugs called antiviral agents. These work by stopping the growth of viruses that cause infections.

This medication is available in an injectable form to be given directly into a vein (IV) by a healthcare professional.

Common side effects of cidofovir include headache, diarrhea, stomach pain, constipation, sore mouth or tongue, joint and muscle pain, coughing, fever, and chills.

Cidofovir can also cause dizziness. Do not drive or operate heavy machinery until you know how cidofovir affects you.

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of cidofovir, there are no specific foods that you must exclude from your diet when receiving this medication.

If you take too much cidofovir, call your healthcare provider or local Poison Control Center or seek emergency medical attention right away.

If cidofovir is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

Do not receive this medication if you are allergic to cidofovir, probenecid (Benemid), or sulfa drugs, or if you have severe kidney disease.

Do not receive cidofovir if you have used any of the following medications within the past 7 days:

• pentamidine (Nebupent, Pentam);
• tacrolimus (Prograf);
• amphotericin B (Fungizone, AmBisome, Amphotec, Abelcet);
• antibiotics such as capreomycin (Capastat), rifampin (Rifadin, Rimactane, Rifater), vancomycin (Vancocin, Vancoled);
• antiviral medicines such as acyclovir (Zovirax), adefovir (Hepsera), or foscarnet (Foscavir); or
• cancer medicine such as aldesleukin (Proleukin), carmustine (BiCNU, Gliadel), cisplatin (Platinol), ifosfamide (Ifex), oxaliplatin (Eloxatin), plicamycin (Mithracin), streptozocin (Zanosar), or tretinoin (Vesanoid).

Before using cidofovir, tell your doctor if you are allergic to any drugs, or if you have kidney disease. You may not be able to receive cidofovir, or you may need dosage adjustments or special tests during treatment.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Use an effective form of birth control while you are using cidofovir and for at least 1 month after your treatment ends.

This medication can affect fertility (ability to have children) in men. If a man fathers a child while using this medication, the baby may have birth defects. Use a condom to prevent pregnancy during your treatment. Continue using condoms for at least 3 months after you stop using cidofovir.

It is not known whether cidofovir passes into breast milk or if it could harm a nursing baby. Do not receive this medication without telling your doctor if you are breast-feeding a baby.

Cidofovir has caused certain types of tumors in animals. It is not known if humans would also have an increased risk of tumors. Talk with your doctor about your specific risk.

You should not receive cidofovir if you are allergic to it, or if you have:

• moderate to severe kidney disease; or

• a history of severe allergic reaction to probenecid (Benemid) or sulfa drugs.

Cidofovir can harm your kidneys. This effect is increased when you also use certain other medicines. Your doctor may need to change your treatment plan if you have used any of the following drugs within the past 7 days:

• medicines to treat a bowel disorder;

• medication to prevent organ transplant rejection;

• antiviral medications;

• injectable medications to treat osteoporosis or Paget's disease of bone;

• chemotherapy;

• some pain or arthritis medicines (including aspirin, Tylenol, Advil, and Aleve); or

• any injected antibiotics.

To make sure cidofovir is safe for you, tell your doctor if you have:

• mild kidney disease;

• diabetes; or

• pancreas or liver problems.

Cidofovir has caused certain types of tumors in animals. It is not known if humans would also have an increased risk of tumors. Talk with your doctor about your specific risk.

FDA pregnancy category C. It is not known whether cidofovir will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication. Use an effective form of birth control while you are using cidofovir and for at least 1 month after your treatment ends.

This medication can affect fertility (ability to have children) in men. If a man fathers a child while using this medication, the baby may have birth defects. Use a condom to prevent pregnancy during your treatment. Continue using condoms for at least 3 months after you stop using cidofovir.

It is not known whether cidofovir passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine. Women with HIV or AIDS should not breast feed a baby. Even if your baby is born without HIV, the virus may be passed to the baby in your breast milk.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Some medicines can interact with cidofovir and should not be used at the same time. There are also some medicines that may interact with probenecid or other medications that are commonly given together with cidofovir. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using. Give a list of all your medicines to any healthcare provider who treats you.

Antiviral; purine nucleotide analog of cytosine.3 5 7 10 11 12 13 14 15 18 21 24

Nephrotoxic Drugs

Concomitant use of other nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, foscarnet, IV pentamidine, vancomycin, nonsteroidal anti-inflammatory agents) is contraindicated since it may result in increased risk of nephrotoxicity.1 Other nephrotoxic agents should be discontinued ≥7 days prior to initiating cidofovir.1

Specific Drugs

Absorption

Bioavailability

Low concentrations of cidofovir are absorbed systemically following topical application of extemporaneously prepared gel containing cidofovir 1%† to mucocutaneous HSV lesions.43

Distribution

Extent

Undetectable concentrations in CSF following IV administration.1

Not known whether distributed into milk.1

Plasma Protein Binding

<6%.1

Elimination

Metabolism

Cidofovir is converted via cellular enzymes to the pharmacologically active diphosphate metabolite.1 2 3 5 7 11 12 13 15 16 18 24

Elimination Route

When administered with the usual concomitant probenecid regimen, 70–85% of an IV cidofovir dose is eliminated unchanged in urine within 24 hours.1 If administered without probenecid, 80–100% of the IV cidofovir dose is eliminated unchanged in urine within 24 hours.1

Removed by hemodialysis.1

• It is used to treat a viral infection of the eyes in people who have AIDS.
• It may be given to you for other reasons. Talk with the doctor.

• If you have an allergy to cidofovir or any other part of cidofovir.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have kidney disease.
• If you are breast-feeding. Do not breast-feed while you take this medicine.

This is not a list of all drugs or health problems that interact with cidofovir.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Cytomegalovirus retinitis: Treatment of cytomegalovirus (CMV) retinitis in patients with AIDS.

Limitations of use: Safety and efficacy have not been established for treatment of other CMV infections (eg, pneumonitis, gastroenteritis), congenital or neonatal CMV disease, or CMV disease in non-HIV infected individuals.

Preexisting renal impairment: Serum creatinine >1.5 mg/dL, CrCl ≤55 mL/minute, or urine protein ≥100 mg/dL (≥2+ proteinuria): Use is contraindicated.

Changes in renal function during therapy:

Serum creatinine increases by 0.3 to 0.4 mg/dL: Reduce dose to 3 mg/kg.

Serum creatinine increases ≥0.5 mg/dL or development of ≥3+ proteinuria: Discontinue therapy.

Store intact vials at 20°C to 25°C (68°F to 77°F). Admixtures in D51/4NS, D5W, or NS may be stored for ≤24 hours under refrigeration; however, admixtures must be administered within 24 hours of preparation.

Concerns related to adverse effects:

• Carcinogenic/teratogenic: [US Boxed Warning]: Possibly carcinogenic and teratogenic based on animal data. May cause hypospermia.

• Metabolic acidosis: Monitor for signs of metabolic acidosis; decreased sodium bicarbonate with proximal tubule injury and renal wasting syndrome (including Fanconi syndrome), as well as metabolic acidosis with hepatic impairment and pancreatitis (including some fatal cases) have been reported.

• Nephrotoxicity: [US Boxed Warning]: Acute renal failure resulting in dialysis and/or contributing to death has occurred with as few as 1 or 2 doses of cidofovir. Renal function (serum creatinine and urine protein) must be monitored within 48 hours prior to each dose of cidofovir and the dose of cidofovir modified as appropriate. Administration must be accompanied by oral probenecid and intravenous saline prehydration.

• Neutropenia: [US Boxed Warning]: Neutropenia has been reported; monitor neutrophil counts during therapy.

• Ocular complications: Decreased intraocular pressure, sometimes associated with decreased visual acuity, uveitis, or iritis may occur; monitor intraocular pressure for and signs of iritis/uveitis during therapy. If uveitis or iritis occurs, consider treatment with topical corticosteroids with or without topical cycloplegic agents.

Disease-related concerns:

• Renal impairment: Contraindicated in patients with a baseline serum creatinine >1.5 mg/dL, CrCl ≤55 mL/minute, or urine protein ≥100 mg/dL (≥2+ proteinuria); dosage adjustment or discontinuation of therapy may be required for changes in renal function during treatment.

Other warnings/precautions:

• Administration: For intravenous use only, not for direct intraocular injection; iritis, ocular hypotony, and permanent impairment of vision may occur.

• Appropriate use: [US Boxed Warning]: Indicated only for CMV retinitis treatment in patients with AIDS.

Preexisting renal impairment:
Calculated CrCl 55 mL/min or less, serum creatinine greater than 1.5 mg/dL, or urine protein 100 mg/dL or greater (equivalent to 2+ proteinuria or greater): Contraindicated

Changes in renal function during therapy:
For increase in serum creatinine of 0.3 to 0.4 mg/dL above baseline: Maintenance dose must be reduced to 3 mg/kg.
For increase in serum creatinine of 0.5 mg/dL or greater above baseline or development of 3+ proteinuria or greater: Therapy must be discontinued.

Renal function should be monitored closely in patients who develop 2+ proteinuria and dosage reduction or interruption of cidofovir therapy should be considered.

The recommended dosage, frequency, or infusion rate must not be exceeded. Oral doses of probenecid and prehydration with IV normal saline must accompany each cidofovir infusion to minimize possible nephrotoxicity.

Direct intraocular injection of cidofovir is contraindicated; it has been associated with iritis, ocular hypotony, and permanent vision impairment.

Cidofovir is contraindicated in patients with a serum creatinine greater than 1.5 mg/dL, a calculated CrCl 55 mL/min or less, or a urine protein 100 mg/dL or greater (equivalent to 2+ proteinuria or greater). Cidofovir is contraindicated in patients who are receiving other nephrotoxic agents. Drugs with nephrotoxic potential must be stopped at least 7 days before initiating cidofovir therapy.

Because cidofovir is associated with renal toxicity, renal function, including serum creatinine concentration and urine protein, must be assessed during the 48 hour period immediately preceding each cidofovir dose. Dose modification, including reduction, interruption, and possibly discontinuation, may be required due to the major toxicity of cidofovir (i.e., renal impairment). Close monitoring of renal function (routine urinalysis and serum creatinine) during therapy should be emphasized.

Safety and effectiveness have not been studied in patients over the age of 60 years. Since elderly individuals frequently have reduced glomerular filtration, particular attention should be paid to assessing renal function before and during cidofovir administration.

Safety and effectiveness have not been established in pediatric patients (less than 18 years of age). The use of cidofovir in children with AIDS warrants extreme caution due to the risk of long-term carcinogenicity and reproductive toxicity. Administration of cidofovir to children should be undertaken only after careful evaluation and only if the potential benefits outweigh the risks.

Initiation of cidofovir is contraindicated in patients with calculated CrCl 55 mL/min or less, serum creatinine greater than 1.5 mg/dL, or urine protein 100 mg/dL or greater (equivalent to 2+ proteinuria or greater).

High-flux hemodialysis reduces serum levels of cidofovir by about 75%.