AHFS Class:

• Nucleosides and Nucleotides 8:18.32

Generic Name(s):

• Cidofovir

Cidofovir, an acyclic nucleotide analog (acyclic nucleoside phosphonate), is an antiviral agent active against herpesviruses and certain other viruses.3,7,10,11,18,75,76

Treatment of Cytomegalovirus (CMV) Infection and Disease

CMV Retinitis

Cidofovir is used for the treatment of cytomegalovirus (CMV) retinitis in adults with human immunodeficiency virus (HIV) infection, including those with acquired immunodeficiency syndrome (AIDS).1,21,24,25,31,75,155 The drug is also used for the management of CMV retinitis in HIV-infected adolescents and children†.155,156 The safety and efficacy of cidofovir have not been established for the treatment of other CMV infections (e.g., pneumonitis, gastroenteritis), congenital or neonatal CMV disease, or CMV disease in individuals not infected with HIV.1

Like other antivirals, cidofovir is not a cure for CMV retinitis.1,17,21,24,25,31 Although cidofovir can induce stabilization or improvement of ocular manifestations of CMV retinitis,3,17,21,24,25,31 the retinitis may relapse and/or progress during or after discontinuance of the drug.24,25,31

Clinical Experience

Efficacy of cidofovir for the treatment of previously untreated CMV retinitis and the treatment of CMV retinitis that relapsed (progressed) despite prior therapy with other antivirals has been established in several phase 2/3 controlled trials in HIV-infected patients.1,3,21,24,31

In an open-label trial (study 106) in which previously untreated patients with peripheral CMV retinitis received either immediate or delayed (until progression) cidofovir therapy (induction with 5 mg/kg IV once weekly for 2 weeks, then maintenance therapy with 5 mg/kg IV once every other week), the median time to progression of CMV retinitis as evidenced by changes in retinal photographs was 120 or 22 days for the immediate or delayed groups, respectively.1,3,21,24 However, because of the limited number of patients in the immediate-treatment group who continued to receive cidofovir therapy over time (only 3 of 25 patients received the drug for 120 days or longer), estimates of the median time to progression are imprecise.1 For alternative indicators of retinal progression or drug discontinuance, the median times for the immediate- and delayed-treatment groups were 52 and 22 days, respectively.1 Estimates of clinical efficacy from this trial may not be directly comparable to estimates reported for other therapies.1

In an open-label, dose-response trial (study 107) in which HIV-infected patients with relapsing CMV retinitis received cidofovir 5 mg/kg IV once weekly for 2 weeks (induction) followed by either 5 or 3 mg/kg IV once every other week (maintenance therapy), the median time to CMV retinitis progression as evidenced by changes in retinal photographs was 115 or 49 days, respectively.1,31 For alternative indicators of retinal progression or drug discontinuance, the median times for the 5- and 3-mg/kg maintenance therapy groups were 49 and 35 days, respectively.1 In this trial, patients had been diagnosed with CMV retinitis approximately 290 days prior to randomization and had received a median of 3.8 prior courses of systemic antiviral therapy (ganciclovir and/or foscarnet)1,31 and 20% had received intraocular antiviral therapy active against CMV.31

Clinical Perspective

Retinitis is the most common clinical manifestation of CMV end-organ disease in HIV-infected patients.155,156 Treatment of CMV retinitis should be individualized based on consideration of factors such as tolerance to systemic medications, prior drug therapy, concomitant drugs and comorbidities, location of lesions, and the patient's immunologic and virologic status.155,156 Given the benefits of systemic therapy in preventing contralateral eye involvement, reducing CMV visceral disease, and improving survival, treatment should include systemic therapy whenever possible.155,156 CMV retinitis should be managed in consultation with an ophthalmologist.155,156

The National Institutes of Health (NIH), Centers for Disease Control and Prevention (CDC), and the HIV Medicine Association of the Infectious Diseases Society of America (IDSA) have developed guidelines for the management of opportunistic infections in adults and adolescents with HIV.155 The guidelines state that first-line therapies for the treatment of immediate sight-threatening CMV retinal lesions (i.e., within 1.5 mm of the fovea) in HIV-infected adults and adolescents include oral valganciclovir, IV ganciclovir, or IV ganciclovir induction followed by oral valganciclovir maintenance.155 While IV foscarnet and IV cidofovir are also effective treatments, these drugs are less-preferred options because of substantial toxicity, including nephrotoxicity.155

The CDC, IDSA, and the US Department of Health and Human Services (HHS) have developed guidelines for the management of opportunistic Infections in children with HIV.156 These experts state that IV ganciclovir is the drug of choice for initial treatment (induction therapy) in infants and children with HIV and acquired CMV disease, including CMV retinitis.156 Oral valganciclovir is also an option for older children, and foscarnet may be considered as an alternative drug or as an option in ganciclovir-resistant CMV infections in children with HIV.156 Cidofovir has not been studied in children with CMV disease, but can be considered for the management of CMV retinitis in HIV-infected children† when other options cannot be used.156

Mucocutaneous Herpes Simplex Virus Infections

IV cidofovir has been used for the management of mucocutaneous infections caused by acyclovir-resistant herpes simplex virus (HSV) types 1 and 2† (HSV-1 and HSV-2) in immunocompromised patients, including HIV-infected individuals.39,40,42,75,155,156

The drugs of choice for the management of orolabial lesions or initial or recurrent genital lesions caused by HSV are valacyclovir, famciclovir, and acyclovir.155,156,344 For the management of mucocutaneous lesions caused by acyclovir-resistant HSV in HIV-infected adults and adolescents, CDC, NIH, and IDSA recommend IV foscarnet as the drug of choice; IV cidofovir is one of several alternative therapies.155 These experts also recommend IV foscarnet as the drug of choice for the management of acyclovir-resistant HSV infections in HIV-infected children and state that IV cidofovir is recommended for infections caused by HSV resistant to acyclovir and foscarnet.156

Although a topical preparation of cidofovir is not commercially available in the US, the drug has been used topically† for the management of mucocutaneous HSV infections† caused by acyclovir-resistant HSV strains.43,75,78,155,156,344

Adenovirus Infections

Although safety and efficacy have not been established and data are limited, cidofovir has been used with some success for the treatment of adenovirus infections† in some immunocompromised patients (e.g., allogeneic hematopoietic stem cell transplant recipients, solid organ transplant recipients).75

Smallpox

Smallpox Vaccination Complications

Cidofovir has been used for the management of adverse reactions to vaccinia virus vaccines (smallpox vaccine)†, including eczema vaccinatum, progressive vaccinia, severe generalized vaccinia, and aberrant vaccinia infection caused by inadvertent autoinoculation.63,70 While cidofovir has antiviral activity against vaccinia virus in vitro and in animal models,55,63,64,70,77 there are limited data on the effectiveness in the treatment of vaccinia-related complications in humans.70

Vaccinia immune globulin IV (VIGIV) is considered first-line treatment for this use; antivirals may be considered as a secondary treatment after consultation with the CDC.63,70 Clinicians should contact their state or local health department or the CDC Emergency Operations Center at 770-488-7100 .63,70

Treatment of Smallpox

The role, if any, of cidofovir in the treatment of smallpox† remains to be determined.49,50,51 Cidofovir is active in vitro against poxviruses, including variola virus (the causative agent of smallpox), and has in vivo activity in mice against cowpox and vaccinia virus.53,54,55,59,60,64 Although limited in vitro and in vivo data suggest that cidofovir might prove useful in preventing smallpox infection if administered within 1-2 days after exposure, there is no evidence that the antiviral would be more effective than smallpox vaccination in this early period.50,51 Data are not available to date regarding the safety and efficacy of cidofovir for the treatment or prevention of smallpox in humans and it has been suggested that the potential usefulness of the drug for the treatment of smallpox may be limited because of the need for IV administration and potential renal toxicity.49,50 The US Working Group on Civilian Biodefense and US Army Medical Research Institute of Infectious Diseases, while acknowledging the potential activity of cidofovir against the virus, state that clinical efficacy in the treatment of smallpox has not been established for any antiviral agent to date.50,51

Mpox

Cidofovir has been used in the treatment of mpox infection†.71,74 Mpox is an orthopoxvirus closely related to the causative agent of smallpox.50,71 No specific treatments are currently available for mpox infection.71 For most patients who have an intact immune system and do not have a skin disease, supportive care and pain control are usually sufficient.71 However, additional therapy may be necessary in some patients (e.g., immunocompromised patients) with more severe manifestations.71 The CDC has issued recommendations and clinical considerations for severe manifestations of mpox infection.71,74 Drugs that have shown to be effective against other orthopoxviruses (e.g., cidofovir, tecovirimat, brincidofovir, vaccinia immune globulin intravenous [VIGIV]) have been used to treat severe mpox.71 CDC guidelines state that tecovirimat is typically the first therapy that should be considered in patients with mpox who require more than supportive care.71 Brincidofovir and VIGIV are additional therapeutics available from the Strategic National Stockpile (SNS) that can be considered in certain patients who need an additional or alternative treatment to tecovirimat; cidofovir can also be considered.71 Treatment decisions should be individualized.71 Healthcare providers may request a clinical consultation with CDC at poxvirus@cdc.gov or 770-488-7100.71

Efficacy of cidofovir for the treatment of human mpox remains to be established; however, the drug has demonstrated antiviral activity against the virus in vitro and in animal models.53,66,67,68,71,75

General

Pretreatment Screening

• Assess patient's renal function prior to initiating therapy.1 The drug is contraindicated in patients with serum creatinine concentration >1.5 mg/dL, calculated creatinine clearance ≤55 mL/minute, or urine protein concentration ≥100 mg/dL (equivalent to ≥2+ proteinuria).1

Patient Monitoring

• Monitor renal function (serum creatinine and urine protein) within 48 hours prior to each dose.1
• Monitor white blood cell counts with differential prior to each dose.1
• Monitor intraocular pressure, visual acuity, and ocular symptoms periodically.1
• Monitor for signs and symptoms of uveitis/iritis during therapy.1

Premedication and Prophylaxis

• Patients must receive adequate hydration prior to each dose of cidofovir to reduce the risk of cidofovir-induced nephrotoxicity.1 Patients should receive at least 1 L of 0.9% sodium chloride infused IV over 1-2 hours immediately before each IV infusion of cidofovir.1 For patients who can tolerate additional fluid, an additional 1 L of 0.9% sodium chloride should be administered; this second IV infusion of 0.9% sodium chloride should be initiated either concomitantly with or immediately after the cidofovir IV infusion and should be administered over 1-3 hours.1

Other General Considerations

• To reduce the risk of cidofovir-induced nephrotoxicity, a regimen of oral probenecid must be administered concomitantly with each dose of cidofovir.1,3,7
• For each dose of cidofovir, the recommended regimen of oral probenecid is 2 g given 3 hours prior to initiation of the cidofovir IV infusion, followed by 1-g doses given 2 and 8 hours after completion of the cidofovir IV infusion, for a total probenecid dose of 4 g.1
• To reduce the risk of nausea and/or vomiting associated with oral probenecid, food can be ingested prior to each probenecid dose and concomitant administration of an effective antiemetic can be considered.1 For patients who develop allergic or other hypersensitivity manifestations with probenecid, appropriate prophylactic or therapeutic use of antihistamines and/or acetaminophen can be considered.1 Because concomitant probenecid is required, cidofovir is contraindicated in patients with a history of severe hypersensitivity to probenecid or other sulfa-containing drugs since probenecid is contraindicated in such patients.1,30
• Because probenecid can affect the pharmacokinetics of many drugs, a careful assessment should be made of other drugs that the patient may be receiving.1

Administration

Cidofovir is administered by slow IV infusion using a controlled-infusion device (e.g., pump).1

Although cidofovir has been administered by intravitreal injection†,6,20,24,25,26 a preparation specifically for intravitreal administration is not commercially available in the US and the manufacturer states that direct intraocular injection of the currently available IV preparation of cidofovir (even if diluted) is contraindicated since such administration has been associated with iritis, ocular hypotony, and permanent visual impairment. 1,30

Cidofovir has been administered topically† as a gel or cream for the management of certain mucocutaneous viral infections (e.g., acyclovir-resistant herpes simplex virus [HSV] infections).43,75,78,155,156,344 Although topical preparations of cidofovir are not commercially available in the US, a topical gel containing 1% cidofovir has been prepared extemporaneously using the IV preparation of cidofovir.75,78,155,156,344

IV Infusion

Use of a standard infusion pump for IV administration of cidofovir is recommended by the manufacturer.1

Cidofovir is commercially available as an injection concentrate containing 75 mg of cidofovir per mL and must be diluted prior to IV infusion.1

Cidofovir concentrate should appear clear and colorless and should not be used if it appears discolored or contains particles.1

Caution should be exercised when preparing, administering, and discarding solutions of cidofovir according to guidelines for handling mutagenic substances.1 If cidofovir injection or a diluted solution of the drug comes in contact with the skin or mucosa, the affected area should be washed and flushed thoroughly with water.1 Partially used vials of cidofovir should be discarded.1

Dilution

For IV infusion, the appropriate dose of cidofovir concentrate for injection containing 75 mg/mL should be withdrawn from the vial and diluted in 100 mL of 0.9% sodium chloride injection in a compatible infusion container (e.g., PVC, glass, ethylene/propylene copolymer).1 The entire volume of diluted solution should then be administered by IV infusion.1

Diluted solutions of cidofovir should be administered within 24 hours of preparation and should not be refrigerated or frozen to extend the storage period beyond this 24-hour limit.1 However, if a diluted solution will not be used immediately, it may be prepared in advance and refrigerated at 2-8°C for up to 24 hours;1 the refrigerated diluted solution should be allowed to reach room temperature before administration1 and should be administered within 24 hours of initial preparation.30

Compatibility of cidofovir with Ringer's, lactated Ringer's, or bacteriostatic infusion fluids has not been evaluated.1

Rate of Administration

IV infusions of cidofovir should be given at a constant rate over 1 hour using a controlled-infusion device (e.g., pump).1

To minimize the risk of nephrotoxicity, the IV dose must not be infused over a shorter time period.1,29

Dosage

Cidofovir is commercially available as the dihydrate; dosage is expressed in terms of anhydrous drug.1

Adult Dosage

Cytomegalovirus Retinitis

For the treatment of cytomegalovirus (CMV) retinitis in HIV-infected adults with serum creatinine concentration ≤1.5 mg/dL, calculated creatinine clearance >55 mL/minute, and urine protein concentration <100 mg/dL (equivalent to less than 2+ proteinuria), the recommended dosage of cidofovir for initial treatment (induction therapy) is 5 mg/kg by IV infusion once weekly for 2 consecutive weeks.1,21,24,31,155

The recommended maintenance dosage of cidofovir is 5 mg/kg by IV infusion once every 2 weeks.1,24,155 If renal function declines during cidofovir therapy, maintenance dosage must be reduced or the drug discontinued depending on the degree of impairment.1,155 (See Renal Impairment under Dosage and Administration.)

Decisions regarding discontinuance of maintenance therapy in patients who have been treated for at least 3-6 months and have inactive CMV retinal lesions and sustained increases in CD4 cell counts as the result of antiretroviral therapy should be made in consultation with an ophthalmologist.155

Mucocutaneous Herpes Simplex Virus Infections

For the management of mucocutaneous herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) infections† known or suspected to be caused by acyclovir-resistant strains in immunocompromised individuals, including HIV-infected adults, the recommended dosage of IV cidofovir is 5 mg/kg once weekly for a treatment duration of 2-4 weeks or longer until a response is obtained.39,40,155 CDC states that a cidofovir dosage of 5 mg/kg IV once weekly may be effective for the management of acyclovir-resistant genital herpes.344

For the topical treatment† of mucocutaneous HSV infections†, including genital herpes†, caused by acyclovir-resistant HSV, an extemporaneously prepared gel containing cidofovir 1% has been applied topically once daily for 5 days.43,344 A treatment duration of 3-4 weeks or longer is recommended depending on clinical response.155,156

Pediatric Dosage

Cytomegalovirus Retinitis

If cidofovir is used as an alternative for the management of CMV retinitis in HIV-infected adolescents†, initial treatment (induction therapy) with a dosage of 5 mg/kg IV once weekly for 2 weeks has been recommended.155

After completion of initial treatment, the recommended dosage of cidofovir for maintenance therapy (secondary prophylaxis) in HIV-infected adolescents† is 5 mg/kg IV once every 2 weeks (i.e., every other week).155 If renal function declines during cidofovir therapy, dosage must be reduced or the drug discontinued depending on the degree of impairment.155

If cidofovir is used as an alternative for secondary prophylaxis in HIV-infected children†, a dosage of 5 mg/kg IV every other week has been recommended.156

Decisions regarding discontinuance of maintenance therapy of CMV retinitis in HIV-infected children who have been treated for at least 6 months and have sustained increases in CD4 counts should be made in consultation with an ophthalmologist.155

Mucocutaneous Herpes Simplex Virus Infections

For the management of mucocutaneous HSV-1 or HSV-2 infections† known or suspected to be caused by acyclovir-resistant strains in HIV-infected adolescents†, the recommended dosage of cidofovir is 5 mg/kg IV once weekly for a treatment duration of 2-4 weeks or longer until a response is obtained.155

For the topical treatment† of mucocutaneous HSV infections†, including genital herpes†, caused by acyclovir-resistant HSV, an extemporaneously prepared gel containing cidofovir 1% has been applied topically once daily for 5 days.43,344 A treatment duration of 3-4 weeks or longer is recommended depending on clinical response.155

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage recommendation for use of cidofovir in patients with hepatic impairment; the effect of hepatic impairment on the pharmacokinetics of the drug has not been evaluated to date.30

Renal Impairment

Initiation of cidofovir is contraindicated in patients with serum creatinine concentration exceeding 1.5 mg/dL, calculated creatinine clearance of 55 mL/minute or less, or urine protein concentration of 100 mg/dL or greater (equivalent to proteinuria of 2+ or greater).1

If serum creatinine concentration increases by 0.3-0.4 mg/dL above baseline during cidofovir therapy, the dose must be reduced to 3 mg/kg.1,155 If this occurs in HIV-infected adults or adolescents† receiving cidofovir for maintenance therapy (secondary prophylaxis) of CMV retinitis, dosage of the drug should be reduced to 3 mg/kg once every 2 weeks (i.e., every other week).1,155

If serum creatinine concentration increases by 0.5 mg/dL or more above baseline or if proteinuria of 3+ or greater develops, cidofovir must be discontinued.1,155

Patients who develop 2+ proteinuria in the face of a stable serum creatinine during cidofovir therapy should be observed carefully (including close monitoring of serum creatinine and urinary protein) to detect potential deterioration that would warrant dose reduction or discontinuance of the drug.29,30

Geriatric Patients

Dosage of cidofovir for geriatric patients should be selected with caution because of age-related decreases in renal function.1

Contraindications

• Initiation in patients with serum creatinine >1.5 mg/dL, calculated creatinine clearance ≤55 mL/minute, or urine protein concentration ≥100 mg/dL (equivalent to ≥2+ proteinuria).1
• Concomitant use with other nephrotoxic drugs.1 Such agents must be discontinued at least 7 days prior to starting therapy with cidofovir injection.1
• Hypersensitivity to cidofovir.1
• History of clinically severe hypersensitivity to probenecid or other sulfa-containing drugs.1
• Direct intraocular injection of the IV preparation.1

Warnings/Precautions

Warnings

Renal Effects

Dose-dependent nephrotoxicity is the major dose-limiting toxicity associated with cidofovir.1 The prescribing information of cidofovir contains a boxed warning regarding this risk.1 In clinical trials in patients with cytomegalovirus (CMV) retinitis, renal toxicity (manifested by an increase in serum creatinine concentration of 0.4 mg/dL or greater, decrease in creatinine clearance to 55 mL/minute or less, or proteinuria of 2+ or greater) occurred in 59% of patients receiving cidofovir at the recommended maintenance dosage of 5 mg/kg IV every other week.1

There have been reports of severe renal impairment in patients receiving the drug, including acute renal failure resulting in dialysis and/or contributing to death, in patients who received as few as 1 or 2 doses of cidofovir.1,29,35 In some patients, there were associated risk factors for nephrotoxicity, such as preexisting mild renal insufficiency or cidofovir administration proximal to completion of aminoglycoside therapy in a patient with preexisting normal serum creatinine concentrations.29 In some patients, renal function failed to return to baseline following discontinuance of cidofovir therapy.1

Proteinuria may be an early sign of cidofovir-induced nephrotoxicity.1 In patients who develop proteinuria during cidofovir therapy, the manufacturer recommends that IV hydration be administered and the test repeated.1 If renal function deteriorates during cidofovir therapy, dosage reduction or discontinuance of the drug may be required.1,29 Continued administration of cidofovir may lead to additional proximal tubular cell injury, which may result in glycosuria; decreases in serum phosphate, uric acid, and bicarbonate concentrations; increases in serum creatinine concentrations; and/or acute renal failure which may require dialysis.1

A diagnosis of Fanconi syndrome, manifested as multiple abnormalities of proximal renal tubular function, has been reported in 1% of patients receiving cidofovir.1

To reduce the risk of nephrotoxicity, IV hydration with 0.9% sodium chloride injection is required prior to administration of each cidofovir dose and a regimen of oral probenecid is required with each cidofovir dose.1 Volume repletion and maintenance are particularly important in patients with potential volume depletion secondary to conditions such as chronic diarrhea, poor fluid intake, or wasting related to human immunodeficiency virus (HIV) infection.29 In addition, concomitant use of cidofovir and potentially nephrotoxic drugs is contraindicated and at least 7 days should elapse between discontinuance of such drugs and administration of cidofovir.1,29

Prior to initiation of cidofovir therapy, renal function must be assessed.1 The drug is contraindicated and should not be initiated in patients with serum creatinine concentration exceeding 1.5 mg/dL, calculated creatinine clearance of 55 mL/minute or less, or urine protein concentration of 100 mg/dL or greater (equivalent to proteinuria of 2+ or greater).1 Because serum creatinine concentrations may not provide an accurate assessment of renal function in patients with severe acquired immunodeficiency deficiency syndrome (AIDS) and CMV retinitis, Cockcroft-Gault calculations should be used initially to estimate creatinine clearance more precisely when determining the eligibility of such patients to receive cidofovir;1,29 for subsequent assessments, serum creatinine and not Cockcroft-Gault calculations of creatinine clearance should be used.29,30

During cidofovir therapy, renal function (i.e., serum creatinine concentration and urine protein) must be determined within 48 hours prior to each dose of cidofovir, and the cidofovir dose should be adjusted or withheld as appropriate based on any changes in renal function.1,29

Hematologic Effects

Neutropenia may occur during cidofovir therapy.1 The prescribing information of cidofovir contains a boxed warning regarding this risk.1 In clinical trials in patients with CMV retinitis, neutropenia (500/mm³ or less) occurred in 24% of patients receiving recommended maintenance dosages of cidofovir; 39% of these patients received treatment with filgrastim (G-CSF).1

Neutrophil counts should be monitored during cidofovir therapy.1

Carcinogenic and Mutagenic Potential

Cidofovir should be considered a potential carcinogen in humans.1 The prescribing information of cidofovir contains a boxed warning regarding this risk.1 In animal studies, the drug was carcinogenic and mutagenic.1

In rats receiving cidofovir by subscapular subcutaneous injection, mammary adenocarcinomas were observed in females at dosages as low as 0.6 mg/kg once weekly (equivalent to 0.04 times the human systemic exposure achieved at recommended IV dosages); the first mass was detected after 6 doses of cidofovir.1 In another study in rats receiving IV cidofovir, mammary adenocarcinomas were observed in females and Zymbal gland carcinomas were observed in males and females at a dosage of 15 mg/kg once weekly (equivalent to 1.1 times the human systemic exposure achieved at recommended IV dosages).1

In mutagenicity studies in mice, an increase in micronucleated polychromatic erythrocytes was seen at cidofovir dosages of 2 g/kg or greater (equivalent to approximately 65 times the maximum recommended human IV dose).1 Cidofovir has induced chromosomal aberrations in human peripheral blood lymphocytes in vitro without metabolic activation, but there was no evidence of mutagenicity in microbial mutagenicity assays involving Salmonella typhimurium (Ames) and Escherichia coli in the presence and absence of metabolic activation.1

Effects on Fertility

Cidofovir has caused reduced testes weight and hypospermia in animals and it is possible that such effects could occur in humans and cause infertility.1 The prescribing information of cidofovir contains a boxed warning regarding this risk.1

Although cidofovir caused inhibition of spermatogenesis in rats and monkeys, no adverse effects on fertility or reproduction were observed in male rats receiving IV cidofovir at dosages up to 15 mg/kg once weekly (equivalent to 1.1 times the recommended human dosage) for 13 consecutive weeks.1

In female rats receiving IV cidofovir at a dosage of 1.2 mg/kg once weekly (equivalent to 0.09 times the recommended human dosages) for up to 6 weeks prior to mating and for 2 weeks after mating, decreased litter size, decreased live births per litter, and increased early resorptions per litter were observed.1 In peri- and postnatal development studies in female rats receiving subcutaneous injections of cidofovir at dosages up to 1 mg/kg daily from day 7 of gestation through day 21 postpartum (approximately 5 weeks), there were no observed adverse effects on viability, growth, behavior, sexual maturation, or reproductive capacity in the offspring.1

Women of childbearing potential and men should be advised to use an effective method of contraception during cidofovir therapy and for certain periods of time after the drug is discontinued.1

Selection and Use of Antivirals

Cidofovir is labeled by the FDA only for the treatment of CMV retinitis in patients with human immunodeficiency virus (HIV) infection, including those with AIDS.1

Safety and efficacy of the drug have not been established for the treatment of other CMV infections or for the treatment of CMV disease in individuals not infected with HIV.1

Other Warnings and Precautions

Administration Precautions

Cidofovir should be administered only by IV infusion.1 The commercially available IV preparation of the drug must not be administered by intraocular injection because iritis, ocular hypotony, and permanent visual impairment have been reported when this route was used.1,30

Patients must receive IV hydration prior to each cidofovir dose and must receive a regimen of oral probenecid concomitantly with each cidofovir dose.1

Because of the potential for nephrotoxicity, the recommended cidofovir dosage, frequency, and rate of administration must not be exceeded.1

Ophthalmologic Effects

Decreased intraocular pressure (IOP) may occur during cidofovir therapy.1 In some cases, decreased IOP has been associated with decreased visual acuity.1 Among patients in clinical trials who received IV cidofovir doses of 5 mg/kg for maintenance therapy of CMV retinitis and whose IOP was monitored, 24% experienced at least a 50% decrease in IOP from baseline and severe hypotony (i.e., IOP of 0-1 mm Hg) was reported in 3 patients.1 The risk of ocular hypotony may be increased in patients with preexisting diabetes mellitus.1

Uveitis or iritis has been reported in patients in clinical trials receiving IV cidofovir for the treatment of CMV retinitis.1 Among those receiving IV cidofovir maintenance therapy of CMV retinitis, uveitis or iritis was reported in 11%.1

Patients receiving cidofovir should receive periodic ophthalmic examinations to monitor IOP and visual acuity and to monitor for symptoms of uveitis or iritis.1,35,36

If anterior uveitis or iritis develops, appropriate therapy (e.g., topical corticosteroids with or without cycloplegic therapy) should be considered as indicated.1

Metabolic Acidosis

Decreased serum bicarbonate associated with proximal tubule injury and renal wasting syndrome (including Fanconi syndrome) has been reported in patients receiving cidofovir.1 Decreased serum bicarbonate concentration (16 mEq/L or less) has been reported in 16% of cidofovir-treated patients.1

Fatal cases of metabolic acidosis in association with liver dysfunction and pancreatitis have been reported in patients receiving cidofovir.1

Specific Populations

Pregnancy

There are no adequate and well-controlled studies to date using cidofovir in pregnant women.1 Cidofovir should be used during pregnancy only if potential benefits justify risks to the fetus.1

In animal studies, embryotoxicity (reduced fetal body weights) and maternal toxicity were observed in rats and rabbits receiving IV cidofovir at dosages of 1.5 and 1 mg/kg daily, respectively, during organogenesis.1 In rabbits receiving IV cidofovir in a dosage of 1 mg/kg daily, maternal toxicity and an increased incidence of fetal external, soft tissue, and skeletal anomalies (meningocele, short snout, and short maxillary bones) were observed.1

Women of childbearing potential should be informed that cidofovir is embryotoxic in animals and should be advised to use an effective method of contraception during and for at least 1 month after cidofovir therapy.1

Men should be advised to use a reliable method of barrier contraception during and for at least 3 months after cidofovir therapy.1

Lactation

It is not known whether cidofovir is distributed into human milk.1

Since there is a potential for adverse effects in nursing infants and because carcinogenicity has been shown in animal studies, cidofovir should not be used in breast-feeding women.1

Because of the risk of adverse effects in the infant and the risk of HIV transmission, the manufacturer states that HIV-infected women should not breast-feed infants.1

The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding.202 The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding.202 During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant.202 Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk.202 Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.202

Pediatric Use

Safety and efficacy of cidofovir have not been established in pediatric patients younger than 18 years of age.1,30

Because of the risks of potential long-term carcinogenic and reproductive toxicity, cidofovir should be used with extreme caution in children† with AIDS.1 The manufacturer states that the drug should be used in children only after careful evaluation and only when potential benefits outweigh risks.1

Some experts state that cidofovir has not been studied in children with CMV disease, but can be considered for the management of CMV retinitis in HIV-infected children† if other options cannot be used.156

Geriatric Use

Safety and efficacy of cidofovir have not been evaluated in geriatric patients older than 60 years of age.1

Because geriatric patients frequently have reduced glomerular filtration, particular attention should be paid to monitoring renal function prior to and during cidofovir therapy in this age group, and dosage should be modified in response to changes in renal function.1

Renal Impairment

Initiation of cidofovir is contraindicated in patients with serum creatinine concentration exceeding 1.5 mg/dL, calculated creatinine clearance of 55 mL/minute or less, or urine protein concentration of 100 mg/dL or greater (equivalent to proteinuria of 2+ or greater).1

Pharmacokinetic data in individuals with renal impairment (creatinine clearance as low as 11 mL/minute) indicate that cidofovir clearance decreases proportionally with creatinine clearance.1

High-flux hemodialysis reduces serum cidofovir concentrations by approximately 75%.1

Common Adverse Effects

Adverse effects reported in 15% or more of patients receiving cidofovir (with concomitant probenecid regimen) include nephrotoxicity (proteinuria, elevated serum creatinine), nausea and/or vomiting, fever, neutropenia, asthenia, headache, rash, infection, alopecia, diarrhea, pain, anemia, decreased IOP, anorexia, dyspnea, chills, increased cough, oral moniliasis, and decreased serum bicarbonate.1

Nephrotoxic Drugs

Concomitant use of cidofovir and nephrotoxic drugs (e.g., aminoglycosides [amikacin, gentamicin, tobramycin], amphotericin B, foscarnet, nonsteroidal anti-inflammatory agents, IV pentamidine, vancomycin) may increase the risk of nephrotoxicity and is contraindicated.1 Such drugs must be discontinued at least 7 days prior to initiating cidofovir therapy.1

Probenecid

Concomitant use of probenecid and cidofovir decreases renal clearance of cidofovir to a level consistent with creatinine clearance, suggesting that probenecid blocks active renal tubular secretion of cidofovir.1 This pharmacokinetic interaction is used to therapeutic advantage to reduce the risk of cidofovir-associated nephrotoxicity.1,75

Because a regimen of oral probenecid must be administered with each dose of cidofovir, drug interactions reported for probenecid must also be considered in patients receiving cidofovir.1 Probenecid interacts with the metabolism or renal tubular excretion of many drugs (e.g., acetaminophen, acyclovir, angiotensin-converting enzyme inhibitors, aminosalicylic acid, barbiturates, benzodiazepines, bumetanide, famotidine, furosemide, methotrexate, nonsteroidal anti-inflammatory agents, theophylline, zidovudine).1

Zidovudine

Although concomitant use of cidofovir (without probenecid) and zidovudine does not affect zidovudine pharmacokinetics, probenecid reduces metabolic clearance of zidovudine.1

Patients receiving zidovudine may continue taking the antiretroviral agent while receiving cidofovir therapy.1 However, on the days that the patient receives a dose of cidofovir, zidovudine should be temporarily discontinued or, alternatively, the zidovudine dosage should be reduced by 50% because the probenecid regimen used concomitantly with the cidofovir dose can increase zidovudine concentrations.1

Description

Cidofovir, an acyclic nucleotide analog of cytosine (acyclic nucleoside phosphonate), is an antiviral agent.3,7,10,11,18,75,76

Cidofovir is a prodrug and exhibits no antiviral activity until converted intracellularly to the active metabolite, cidofovir diphosphate.2,3,13,15,16,18,20,75 Unlike other nucleoside and nucleotide antivirals that require conversion within viral cells to an active metabolite (e.g., acyclovir, ganciclovir), the presence of the phosphonate group in cidofovir is believed to account for the drug's ability to become phosphorylated by cellular (host cell) enzymes to its active intracellular metabolite without initial virus-dependent phosphorylation by viral nucleoside kinases.2,3,13,15,16,18,20,75

Cidofovir is converted intracellularly by pyrimidine nucleoside monophosphate kinase to cidofovir monophosphate, which is further converted to the diphosphate and cidofovir phosphate-choline via other cellular enzymes.3,75 Cidofovir diphosphate is a viral DNA polymerase inhibitor and exerts its antiviral effects by interfering with DNA synthesis and inhibiting viral replication.1,6,10,11,13,14,16,20,75 Cidofovir diphosphate stops replication of viral DNA10,11,12,13,25,75 by competitive inhibition of viral DNA polymerase (an enzyme encoded by CMV UL54 gene),6,14,16,75 incorporation and termination of the growing viral DNA chain, and inactivation of the viral DNA polymerase.1,3,75 The inhibitory activity of cidofovir diphosphate is highly selective1,9,10,11,12,20 because of its greater affinity for viral DNA polymerases than for human DNA polymerases.1,3,5,75

The pharmacokinetics of IV cidofovir have been evaluated in patients with human immunodeficiency virus (HIV) infection when the drug was given with or without a regimen of oral probenecid.1 In patients with normal renal function, approximately 80-100% of a dose of IV cidofovir (without oral probenecid) was recovered unchanged in urine within 24 hours.1 Renal clearance of cidofovir (without oral probenecid) is greater than creatinine clearance, indicating that renal tubular secretion contributes to cidofovir elimination.1 Following IV administration of cidofovir (with oral probenecid regimen), approximately 70-85% of the dose was excreted unchanged in urine within 24 hours.1 Renal clearance of cidofovir (with oral probenecid regimen) is consistent with creatinine clearance, indicating that probenecid blocks renal tubular secretion of cidofovir.1 This effect of probenecid on the pharmacokinetics of cidofovir is used to therapeutic advantage, and a regimen of oral probenecid must be given with each dose of cidofovir.1 In vitro studies indicate that cidofovir is less than 6% bound to plasma or serum proteins.1 In one patient who received a single cidofovir dose of 5 mg/kg by IV infusion over 1 hour (with IV prehydration and concomitant oral probenecid regimen), cidofovir serum concentrations were 8.7 mcg/mL at 15 minutes after completion of the infusion and the drug was undetectable in CSF.1

Spectrum

Following intracellular conversion of cidofovir to the pharmacologically active diphosphate metabolite, the drug has in vitro1,7,11,12,15,75 and in vivo2,3,5,13,16,18,24,75 inhibitory activity against human herpes viruses, including cytomegalovirus (CMV), herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV). The drug also has in vitro activity against adenovirus,3,16,24,75 human papillomavirus (HPV),3,24,33,75 and human polyomavirus.1,2,3,7,11,13,15,16,18,24,34,75

Cidofovir has in vitro activity against poxviruses, including vaccinia virus (cowpox), monkeypox, and variola virus (the causative agent of smallpox).45,46,47,53,57,67,68,71,75,77 Studies in mice indicate that cidofovir has in vivo activity against vaccinia virus.47,48,53,54,55,56 In vivo activity against monkeypox has been demonstrated in animal models.53,66,67,68,71

Because of the drug's ability to become phosphorylated to its active metabolite without dependence on virally encoded kinases, cidofovir has been shown to exert its antiviral effect on acyclovir-resistant strains of HSV2,18 and ganciclovir-resistant strains of CMV.2,9,27 Cidofovir has been shown to exhibit greater in vitro activity against CMV than ganciclovir.3,7,9,10,12,15,16,20,27,30 In vitro and in vivo studies indicate that cidofovir diphosphate has an extended intracellular half-life,2,4,18,24,25,75 which may result in the drug's ability to exert a prolonged antiviral effect, and activation to the diphosphate by cellular rather than virally encoded enzymes as well as the extended intracellular half-life offer protection against subsequent viral infection in uninfected cells.3,7,11,14,16,24,25,30

Resistance

CMV isolates with reduced susceptibility to cidofovir have been selected in vitro in the presence of high concentrations of the drug,1 and the possibility of cidofovir-resistant CMV should be considered in patients with CMV retinitis who fail to respond to cidofovir or experience recurrent CMV retinitis progression during therapy with the drug.1,3

Some cidofovir-resistant CMV isolates selected in vitro following exposure to increasing concentrations of cidofovir have been cross-resistant to ganciclovir, but remained susceptible to foscarnet.1,75 Ganciclovir-resistant or ganciclovir- and foscarnet-resistant isolates that were cross-resistant to cidofovir have been obtained from drug-naïve patients and patients who were treated with ganciclovir with or without foscarnet.1 Although CMV strains with ganciclovir-resistance caused by mutations in DNA polymerase (UL54) are likely to be cross-resistant to cidofovir, strains with ganciclovir resistance secondary only to mutations in CMV UL97 may remain susceptible to cidofovir.1,2,3,5,9,27,31,75 Clinical isolates exhibiting high-level resistance to ganciclovir due to mutations in both CMV UL54 and UL97 have been cross-resistant to cidofovir.1 Cidofovir is active in vitro against some, but not all, CMV isolates resistant to foscarnet.1

Advice to Patients

• Advise patients that cidofovir is not a cure for CMV retinitis; they may continue to experience progression of retinitis during or following treatment.1 Regular ophthalmologic examinations are necessary.1 Other manifestations of CMV disease may also occur.1
• Advise HIV-infected patients who are receiving zidovudine to temporarily discontinue zidovudine or decrease the zidovudine dose by 50% on days cidofovir is administered because the probenecid regimen used with each cidofovir dose reduces metabolic clearance of zidovudine.1
• Inform patients that the major toxicity of cidofovir is renal impairment; dosage modifications, including reduction, interruption, and, possibly, discontinuance of the drug may be required. Stress importance of close monitoring of renal function (routine urinalysis, serum creatinine) during cidofovir therapy.1
• Stress importance of receiving IV hydration prior to each cidofovir dose and of taking the recommended regimen of oral probenecid with each cidofovir dose to minimize risk of cidofovir-associated nephrotoxicity.1
• Advise patients of the importance of completing a full course of probenecid with each cidofovir injection.1 Inform patients of possible adverse effects associated with the probenecid regimen, including headache, nausea, vomiting, and hypersensitivity reactions (e.g., rash, fever, chills, anaphylaxis).1 Advise patients that taking probenecid after a meal or concomitant use of an antiemetic may decrease nausea; antihistamines and/or acetaminophen can be used to ameliorate hypersensitivity reactions.1
• Inform patients that cidofovir has caused tumors (principally mammary adenocarcinomas) in rats and the drug should be considered a potential carcinogen in humans.1
• Inform patients that cidofovir has caused reduced testes weight and hypospermia in animals and such effects may occur in humans and cause infertility.1
• Stress importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
• Stress importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Inform women of childbearing potential that cidofovir is embryotoxic in animals and should not be used during pregnancy.1
• Advise women of childbearing potential to use effective contraception during and for 1 month after cidofovir therapy.1 Advise men to practice barrier contraceptive methods during and for 3 months after cidofovir treatment.1
• Inform patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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