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Mechanism of Action
US Drug Names
5 mg/kg/dose IV once weekly for 2 weeks as an initial therapy. For immediate sight-threatening lesions (i.e., within 1,500 microns of the fovea), give in combination with intravitreal injections of ganciclovir (2 mg/injection) or foscarnet (2.4 mg/injection). Induction therapy should be followed-up with chronic maintenance therapy (secondary prophylaxis). Guidelines suggest cidofovir as second-line induction therapy. 
NOTE: For adults and adolescents, chronic maintenance therapy is indicated for retinitis. Chronic maintenance therapy is not routinely recommended for gastrointestinal disease, pneumonitis, or CNS disease unless there is concurrent retinitis, there have already been recurrent infections, or severe disease was present initially. For infants and children, chronic maintenance therapy is indicated for retinitis, disseminated disease, CNS disease, or GI disease with relapse.
NOTE: For patients who experience progression of CMV retinitis while receiving maintenance therapy, re-induction treatment with the same drug used for maintenance followed by reinstitution of maintenance therapy is recommended. 
NOTE: The CDC does not recommend primary prophylaxis in persons living with HIV, as end-organ disease is best prevented by using antiretroviral therapy to maintain CD4 counts greater than 100 cells/mm3.
5 mg/kg/dose IV every other week as an alternative maintenance therapy after treatment of acute infection.  Treatment duration depends on the immune status of the patient. For patients who have had a sustained immune response to highly active antiretroviral therapy (i.e., CD4 counts greater than 100 cells/mm3 for 3 to 6 months), have been on CMV treatment for at least 3 to 6 months, and have no active lesions, secondary CMV retinitis prophylaxis may be discontinued after consultation with an ophthalmologist. Maintenance therapy should be restarted if subsequent CD4 counts drop to less than 100 cells/mm3, as relapse occurs most frequently in those patients whose counts decrease to less than 50 cells/mm3 after stopping treatment. However, because relapses may occur at any CD4 count, all patients who have had maintenance CMV therapy discontinued should continue to undergo regular ophthalmologic monitoring (every 3 months) for early detection of CMV relapse (as well as for immune reconstitution uveitis).
5 mg/kg/dose IV every other week as an alternative maintenance therapy after treatment of acute infection. Discontinuation of secondary prophylaxis may be considered in pediatric patients who have received at least 6 months of highly active antiretroviral therapy with a sustained increase (more than 6 months) in CD4 percentage of at least 15% (pediatric patients younger than 5 years) or CD4 count more than 100 cells/mm3 (children 6 years and older). For retinitis, the decision to discontinue secondary prophylaxis should be made in consultation with an ophthalmologist. Routine follow-up (every 3 to 6 months) with an ophthalmologist is recommended. Restart maintenance therapy if CD4 percentage is less than 15% in pediatric patients younger than 5 years or if CD4 count is less than 100 cells/mm3 in children 6 years and older.
Optimal dosing has not been established and various regimens have been reported based on transplant center-specific protocols. An induction dose of 5 mg/kg/dose IV once weekly for 2 to 3 weeks, followed by maintenance dose of 5 mg/kg/dose IV every 2 weeks until resolution or viral clearance is commonly used.  Other protocols use 5 mg/kg/dose IV once weekly or 1 mg/kg/dose IV 3 times weekly until resolution or viral clearance.    Although the 1 mg/kg 3 times weekly dose may cause less renal toxicity, it may be associated with breakthrough CMV and HSV infections and the emergence of antiviral resistance.  
Optimal dosing has not been established and various regimens have been reported based on transplant center-specific protocols. An induction dose of 5 mg/kg/dose IV once weekly for 2 to 3 weeks, followed by a maintenance dose of 5 mg/kg/dose IV every 2 weeks until resolution or viral clearance is commonly used.      Other dosing protocols use 5 mg/kg/dose IV once weekly or 1 mg/kg/dose IV 3 times weekly until resolution or viral clearance.     Although the 1 mg/kg 3 times weekly dose may cause less renal toxicity, it may be associated with breakthrough CMV and HSV infections and the emergence of antiviral resistance.  
In a placebo-controlled trial, 30 patients were treated with cidofovir 1% gel once daily or placebo. Overall 16 of 19 patients had a complete or partial response to cidofovir (9 complete responses) versus only 2 patients in the placebo group after a median of 43 days of treatment. Guidelines suggest cidofovir as an alternative regimen, but provides no further recommendations.
A review of 20 published reports involving 185 patients with adult onset recurrent respiratory papillomatosis (AORRP) and 85 patients under the age of 12 with juvenile onset recurrent respiratory papillomatosis (JORRP) found intralesional cidofovir to be an effective adjuvant therapy. Cidofovir was administered via intralesional injection at a concentration ranging from 2.5 to 15 mg/mL (mean 7.5 mg/mL). The mean number of injections administered per person was 6 (range 2 to 13 doses). The injection frequency ranged from 2 to 8 weeks, with a mean interval between injections of 26 days. The overall efficacy for AORRP was 74% complete response, 23.8% partial response, 0.6% no response, and 1.6% discontinued therapy. For JORRP, the overall efficacy was 56.5% complete response, 31.8% partial response, and 11.7% no response.
In case reports, cidofovir gel 1% to 3% used 1 to 2 times per day has led to successful resolution of this condition. In addition, patients treated with cidofovir for CMV retinitis have reported resolution of molluscum contagiosum.
5 mg/kg/dose IV once weekly for at least 21 to 28 days as an alternative. 
1% topical gel applied to lesions once daily for at least 21 to 28 days as an alternative. Alternatively, 1% topical gel applied to lesions 2 to 4 times daily for genital infections.
NOTE: Vaccinia immune globulin, VIG is the preferred treatment. Cidofovir is only available via the CDC under an investigational new drug (IND) protocol and by special request to the CDC Drug and Immunobiologics Service (404-639-3670). Cidofovir efficacy for this indication is not proven. Cidofovir is only used in vaccinia cases that fail to respond to VIG, as additional therapy in a patient severely ill (near death), or in the case that VIG supplies are exhausted.
Contact the CDC for IND protocol enrollment and product availability. 5 mg/kg IV as a one time dose infused over 60 minutes. A second dose 1 week later may be considered if clinically indicated.
Pediatric dosage is not known.
5 mg/kg/dose IV once weekly or 1 mg/kg/dose IV 3 times weekly for 2 to 4 weeks or until viral clearance and/or immune recovery.   5 mg/kg/dose IV once weekly for 2 to 3 weeks, followed by 5 mg/kg/dose IV every other week until viral clearance and/or immune recovery has also been reported.   Although the 1 mg/kg 3 times weekly dose may cause less renal toxicity, it is insufficient to treat concomitant CMV infection; if concomitant CMV infection is present, the 5 mg/kg once weekly dose is recommended.
NOTE: There is no FDA-approved treatment for monkeypox virus infections; however, the CDC holds an Expanded Access Investigational New Drug Protocol (EA-IND) that allows for cidofovir to be used to treat orthopoxviruses (including monkeypox) during an outbreak. State and territorial health authorities can contact the CDC Emergency Operations Center at 770-488-7100 for information regarding the protocol.
NOTE: Many cases of monkeypox virus infections are mild and self-limiting in the absence of specific therapy; however, the prognosis depends on multiple factors such as previous vaccination status, initial health status, concurrent illnesses, and comorbidities. Persons for whom treatment may be considered (after consultation with the CDC) include:
An EA-IND held by the CDC allows for cidofovir to be used to treat monkeypox during an outbreak. A dose is not specified; however, 5 mg/kg IV infused over 60 minutes has been used for other indications. If clinically indicated, a second dose 1 week later may be considered.  
5 mg/kg/week IV.
Safety and efficacy have not been established; however, doses up to 5 mg/kg/week IV have been used off-label.
Safety and efficacy have not been established.
No dosage adjustment required.
Adult patients (FDA-approved labeling)
CrCl more than 55 mL/minute: No dosage adjustments necessary unless SCr increases from 0.3 to 0.4 above baseline.
CrCl 55 mL/minute or less: Systemic cidofovir therapy is contraindicated; also contraindicated in patients with a SCr more than 1.5 mg/dL or a urine protein of 100 mg/dL or more (equivalent to 2+ proteinuria)
Dosage adjustments based on changes in serum creatinine (SCr):
For increases in SCr of 0.3 to 0.4 mg/dL above baseline: Decrease cidofovir dose to 3 mg/kg/dose IV.
For increases in SCr of 0.5 mg/dL or more above baseline or the development of 3+ proteinuria: Discontinue IV cidofovir.
Adult patients (alternative)†
The following dose adjustment has been used in patients receiving an initial dose of 1 mg/kg/dose IV 3 times weekly for adenovirus infection prophylaxis and treatment:
For increases in SCr of 0.3 to 0.4 mg/dL above baseline: Decrease cidofovir dose to 0.5 mg/kg/dose IV 3 times weekly.
1 mg/kg/dose IV 3 times weekly for 2 weeks, followed by the same dose every other week has been used for adenovirus infection prophylaxis and treatment in patients with renal dysfunction (serum creatinine more than 1.5 mg/dL, creatinine clearance less than 90 mL/minute/1.73 m2, and 2+ proteinuria).
Intermittent hemodialysis or Peritoneal dialysis†
Continuous renal replacement therapy (CRRT)†
Avoid use; if needed, 2 mg/kg/dose IV once weekly.
Cidofovir is an acyclic phosphonate nucleotide analog antiviral agent used for the treatment of cytomegalovirus (CMV), herpes virus infections, and adenovirus infections. Nucleotides differ chemically and pharmacologically from nucleosides (e.g., zidovudine). Nucleotides are combinations of purine or pyrimidine bases along with an attached sugar and phosphate moiety that is highly stable to serum esterase cleavage, and are the individual units that make up RNA and DNA. Unlike nucleoside analogs, cidofovir is not dependent upon intracellular activation for its antiviral activity. Other advantages of cidofovir include once-weekly dosing and activity against certain ganciclovir-, foscarnet-, and acyclovir-resistant CMV strains. Cidofovir exhibits other antiviral activity in vitro, including activity against poxviruses. Cidofovir is also available off-label via a treatment IND from the US CDC for the treatment of severe reactions to the vaccinia (smallpox) vaccine in selected circumstances. Systemic cidofovir can cause serious adverse reactions, including renal toxicity; close attention to administration protocols (concurrent probenecid and IV saline hydration) and clinical monitoring are recommended.
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
The dose-limiting adverse reaction of intravenous cidofovir is dose-dependent nephrotoxicity (i.e., renal tubular necrosis or proximal tubule cell injury). Acute renal failure (unspecified) resulting in dialysis and/or contributing to death has occurred with as few as one or two doses. Renal toxicity developed in 59% of patients receiving 5 mg/kg IV every other week and presented as more than 1+ proteinuria, serum creatinine (Scr) elevations 0.4 mg/dL or more, and decreased creatinine clearance to less than 55 ml/min. Maintenance dose reductions from 5 mg/kg to 3 mg/kg were required in 26 to 29% of patients. Renal tubular damage resulting in renal wasting syndrome and decreased serum bicarbonate leading to metabolic acidosis and Fanconi syndrome have also been noted. During clinical trials, decreases in serum bicarbonate to 16 mEq/L or less were observed in 16% of patients. Fanconi syndrome, reported in 1% of recipients, can present as glycosuria, bicarbinaturia, phosphaturia, hypophosphatemia, hypouricemia, elevated Scr, and acute renal failure. Fatal cases of metabolic acidosis in association with liver dysfunction and pancreatitis have also been reported. Other urogenital adverse events occurring in cidofovir-treated patients during clinical trials included proteinuria (50 to 88%), elevated Scr (12 to 24%), dysuria, glycosuria, hematuria, nephrolithiasis or kidney stones, nocturia, polyuria, prostatic disorders, toxic nephropathy, urethritis, urinary incontinence, and urinary retention. In an effort to reduce the potential for nephrotoxicity, intravenous prehydration with normal saline and concurrent administration of probenecid are recommended with each cidofovir infusion. Additionally, health care providers are advised to monitor serum creatinine and urine protein concentrations within 48 hour of each dose. Dose adjustment may need to be made based on changes in the patients renal function. Do not administer cidofovir with other nephrotoxic medications.
Neutropenia defined as 500 cells/mm3 or less and less than 750 cells/mm3 occurred in 24% and 43%, respectively, of patients receiving cidofovir infusions during clinical trials. Additionally, granulocyte colony stimulating factors (G-CSF) were used in 39% of cidofovir treated patients. Health care providers are advised to monitor neutrophil counts in patients during therapy. Other hematologic and lymphatic adverse events observed during clinical trials include anemia (24%), hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, lymphoma-like reactions, pancytopenia, splenomegaly, thrombocytopenia, and thrombotic thrombocytopenic purpura (TTP).
Ocular hypotonia, or a >= 50% decreased from baseline intraocular pressure, was reported in 24% of 70 patients studied during cidofovir clinical trials. Additionally, 3 patients (4%) experienced severe hypotony, defined as an intraocular pressure of 0—1 mm Hg. The risk of ocular hypotony may be increased in patients with preexisting diabetes mellitus. Iritis and uveitis were reported in 15 of 135 (11%) patients during clinical trials and during the post-marketing period. Patients who experienced iritis were more likely to have been previously treated for CMV retinitis, to be diabetic, or to be receiving protease inhibitors. The onset of iritis occurred after an average of 4.9 +/- 1.8 days after the first dose. Many patients who developed anterior uveitis were able to continue therapy while receiving concomitant topical corticosteroids with or without cycloplegic therapy. Health care providers are advised to monitor intraocular pressure and for signs and symptoms of uveitis and iritis during treatment. Other ocular adverse events observed during clinical trials include visual impairment, amblyopia, blindness, cataracts, conjunctivitis, corneal lesion, corneal opacification, diplopia, xerophthalmia, ocular pain, keratitis, miosis, refraction disorder, retinal detachment, visual field defect, and decreased visual acuity.
During clinical trials, a variety of gastrointestinal (GI) adverse events were experienced by recipients of cidofovir, including: nausea (7—69%), vomiting (7—69%), diarrhea (26%), anorexia (23%), cachexia, abdominal pain, colitis, constipation, esophagitis, dyspepsia, dysphagia, dysgeusia, fecal incontinence, flatulence, gastritis, GI bleeding, gingivitis, melena, proctitis, stomatitis, tongue discoloration, oral ulceration, dental caries, dehydration, thirst, weight gain, weight loss, and xerostomia.
Cases of infection were reported by 12—28% of cidofovir recipients during clinical trials. Specific infection sites/types included bronchitis, pharyngitis, pneumonia (9%), rhinitis, sinusitis, otitis media, otitis externa, oral candidiasis or moniliasis (18%), cholangitis, cellulitis, mastitis, urinary tract infection, herpes simplex, cryptococcosis, flu-like symptoms, and sepsis. Adverse events potentially associated with infection and reported by cidofovir-treated patients included fever (14—58%), chills (22%), increased cough (19%), increased sputum, dyspnea (8—23%), and urinary casts.
The two most commonly reported cidofovir-associated dermatologic adverse reactions during clinical trials were rash (unspecified) (30%) and alopecia (27%). Other dermatologic adverse events included injection site reaction, photosensitivity, acne vulgaris, cyst, eczema, exfoliative dermatitis, furunculosis, nail disorder, pruritus, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating, urticaria, and xeroderma.
Cidofovir therapy has been associated with hearing loss, with or without tinnitus. In some cases, symptoms were reported within 24—48 hours of the infusion and declined over time until the next dose. After discontinuation of cidofovir therapy, hearing impairment and tinnitus were lessened. Cases of otalgia and hyperacusis have also been reported.
Patients receiving cidofovir treatment during clinical trials experienced neurologic adverse events. The most commonly reported neurologic adverse events included asthenia (43%) and headache (30%). Other reported adverse reactions include malaise, migraine, abnormal dreams, acute brain syndrome, agitation, amnesia, anxiety, nervousness, confusion, cerebrovascular disorder, seizures and tremor, myoclonia, twitching, ataxia or abnormal gait, incoordination, facial paralysis, hemiplegia, delirium, dementia, depression, dizziness, drug dependence, encephalopathy, hallucinations, libido increase, insomnia, peripheral neuropathy, paresthesias, hyperesthesia, drowsiness, speech disorder, personality disorder, and vertigo.
Musculoskeletal adverse events reported by cidofovir recipients during clinical trials include back pain, neck pain, arthralgia, arthrosis, osteonecrosis, bone fractures, bone pain, leg muscle cramps, myalgia, myasthenia, hypertonia, and hypotonia.
Patients treated with cidofovir during clinical trials experienced cardiovascular adverse events including chest pain (unspecified), cardiomyopathy, heart failure, hypertension, hypotension, orthostatic hypotension with syncope, pallor, phlebitis, cardiogenic shock, sinus tachycardia, edema, facial edema, peripheral edema, and peripheral vasodilation.
Cases of hepatitis, hepatomegaly, hepatic necrosis, jaundice, and elevated hepatic enzymes have been observed in patients receiving cidofovir during clinical trials.
Metabolic adverse events that have occurred in patients receiving treatment with cidofovir during clinical trials include hypercalcemia, hypocalcemia, hyperglycemia, hypoglycemia, hyperkalemia, hypokalemia, hyperlipidemia, hypomagnesemia, hyponatremia, hypoproteinemia, increased alkaline phosphatase, and increased lactic dehydrogenase.
Respiratory adverse events occurring in recipients of cidofovir during clinical trials include respiratory alkalosis, asthma, epistaxis, hemoptysis, hiccups, hyperventilation, hypoxia, laryngeal edema, and pneumothorax.
Cidofovir has been associated with teratogenesis in animal studies involving rats and rabbits; therefore, women of childbearing age should use effective contraception during and for 1 month following treatment. Men should be advised to practice barrier contraception during and for 3 months after treatment. Men should also be informed that cidofovir has caused reduced testes weight and hypospermia in animal. This finding may correlate to human male infertility.
Antimicrobial resistance can occur during therapy with cidofovir. The frequency with which resistant viral isolates develop has not been determined. Health care providers are advised to consider viral resistance in patients who show poor clinical response or who experience recurrent retinitis.
Adverse events not discussed elsewhere in this monograph and observed in cidofovir recipients during clinical trials include allergic reactions, angioedema, hypothermia, adrenal cortex insufficiency, and accidental injury.
Cidofovir has the potential to be a carcinogen in humans and may cause a new primary malignancy. In animal studies, mammary adenocarcinomas in rates were noted.
Cidofovir is only indicated for treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS). The safe and effective use of cidofovir for treatment of other CMV infections (e.g., gastroenteritis or pneumonitis), congenital or neonatal CMV disease, or CMV disease in non-HIV-infected persons has not been established.
According to the manufacturer, cidofovir is contraindicated in patients with a known, severe probenecid hypersensitivity, sulfonamide hypersensitivity, or hypersensitivity to other sulfa-containing medications. Probenecid contains a sulfonamide side chain but does not contain the N4 aromatic amine or the N1-substituent present in sulfonamide antibiotics and thought to be responsible for hypersensitivity-type adverse reactions. The risk of cross-sensitivity in patients taking a nonantibiotic sulfonamide that have a history of sulfonamide hypersensitivity is low and has been confirmed by recent observational studies.   In general, patients with a history of hypersensitivity to any drug are predisposed to subsequent hypersensitivity reactions to other drugs. Because of this, patients with a history of sulfonamide hypersensitivity should be monitored for hypersensitivity reactions to other drugs, including cidofovir; however, treatment with a nonantibiotic sulfonamide may not need to be withheld in patients with a sulfonamide allergy as long as patients are monitored appropriately, especially if alternative therapies are not available.
Cidofovir therapy is contraindicated in patients with baseline renal disease, renal impairment, or renal failure defined as a serum creatinine concentration > 1.5 mg/dl or calculated creatinine clearance <= 55 ml/min and in those who have >= 2+ proteinuria (urine protein >= 100 mg/dl). Due to dose-dependent nephrotoxicity, renal function, including serum creatinine and urine protein, must be monitored within 48 hours of each dose of cidofovir and the dose of cidofovir modified for changes in renal function as appropriate. Proteinuria may be an early indication of nephrotoxicity. Intravenous normal saline and probenecid therapy must be given concurrently with cidofovir. In clinical trials, very high concentrations of cidofovir were found in the kidneys, and the transport into proximal tubular cells was faster than efflux into the urine, suggesting active tubular secretion. A high concentration of cidofovir in the kidney is believed to be directly related to renal toxicity, but the actual mechanism is unknown. Probenecid is used to antagonize the active tubular secretion of cidofovir in the proximal tubules. Prior foscarnet therapy has been associated with an increased risk of nephrotoxicity; these patients should be closely monitored. Cidofovir use is contraindicated in patients who are receiving agents with nephrotoxic potential. At least seven days should pass following the administration of agents with nephrotoxic potential prior to the initiation of therapy with cidofovir. These nephrotoxic drugs include amphotericin B, foscarnet, IV pentamidine, IV aminoglycosides, vancomycin, and NSAIDs.
Cidofovir therapy has been associated with neutropenia. Therefore, neutrophil counts should be monitored during cidofovir therapy.
Dehydration should be avoided prior to and during cidofovir therapy. Adequate hydration is necessary in patients receiving cidofovir in order to prevent potential nephrotoxicity. Intravenous prehydration with at least one liter of normal saline should be administered prior to each infusion of cidofovir, with additional IV normal saline administered during or after each infusion when tolerated. Special attention should be given to repletion of fluids in patients with chronic diarrhea or AIDS-related wasting because they may have intravascular volume depletion.
Direct ocular exposure of cidofovir should be avoided and intraocular administration is contraindicated. Direct injection has been associated with iritis, ocular hypotony and permanent vision impairment. Iritis is more likely to occur in patients previously treated for CMV retinitis, those having diabetes mellitus, or receiving protease inhibitors. Patients should be monitored for the development of iritis and uveitis during cidofovir therapy. In addition, intraocular pressures should be monitored during cidofovir therapy as decreases in intraocular pressure associated with decreases in visual acuity have been reported.
Although there are no adequate and well-controlled studies in pregnant women, cidofovir was embryotoxic and teratogenic in animal studies. Cidofovir was embryotoxic (reduced fetal body weights) in rats at 1.5 mg/kg/day and in rabbits at 1 mg/kg/day, doses which were also maternally toxic, following daily intravenous dosing during the period of organogenesis. The no-observable-effect levels for embryotoxicity in rats (0.5 mg/kg/day) and in rabbits (0.25 mg/kg/day) were approximately 0.04 and 0.05 times the clinical dose (5 mg/kg every other week) based on AUC, respectively. An increased incidence of fetal external, soft tissue, and skeletal anomalies (meningocele, short snout, and short maxillary bones) occurred in rabbits at the high dose (1 mg/kg/day) which was also maternally toxic. Cidofovir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
The manufacturer warns of potential male-mediated teratogenicity as cidofovir causes reduced testes weight and hypospermia in animals. These effects may also occur in humans. Men should also be warned about the potential for infertility. Men should practice barrier contraceptive methods during and for 3 months after treatment with cidofovir.
It is not known if cidofovir is excreted in human milk; however, use during breast-feeding is not recommended because of its potential for carcinogenic and other adverse effects in the infant. Additionally, cidofovir may be used to treat infections in patients with HIV and the Centers for Disease Control and Prevention (CDC) recommends that in the US, HIV-infected mothers not breast-feed their infants to avoid the risk of postnatal transmission of HIV. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a drug administered to the mother, health care providers are encouraged to report the adverse effect to the FDA. 
The manufacturer considers cidofovir to be a potential carcinogen in humans and may cause a new primary malignancy. In animal studies, mammary adenocarcinomas in rats was noted. Women should be warned about the carcinogenic potential of cidofovir and of the limited study of cidofovir in females. Women of childbearing potential should use effective contraception during and for 1 month after treatment with cidofovir. Cidofovir should be used cautiously in children in light of the risk of long-term carcinogenesis and reproductive toxicity.
The safety and efficacy of cidofovir in patients > 60 years has not been studied. Since geriatric patients commonly have reduced glomerular filtration, attention should be paid to renal function before and during therapy.
Due to the mutagenic properties of cidofovir, health care personnel should take precautions to avoid accidental exposure to cidofovir. The National Institutes of Health recommends cidofovir be prepared in a Class II laminar flow biologic safety cabinet and that personnel preparing the drug wear protective gloves and gowns. If cutaneous exposure occurs, wash and flush thoroughly with water. Excess cidofovir solution and all other materials used in the preparation and administration of this agent should be placed in a leak-proof, puncture-proof container.
Based on data from animals, cidofovir may be associated with reproductive risk. Discuss contraception requirements with the patient. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose. Men are advised to use condoms during treatment and for at least 3 months after the last dose.
Cidofovir has antiviral activity against a wide variety of DNA viruses, including cytomegalovirus (CMV) and herpesviruses. In infected cells, cidofovir inhibits viral DNA polymerase, which is responsible for replication of new viral RNA and DNA. Cidofovir is taken up intracellularly via active transport or fluid-phase endocytosis to exert its antiviral effects. Intracellularly, cidofovir is metabolized to its active diphosphate form. Cidofovir competes with deoxycytosinetriphospate (dCTP) for incorporation into viral DNA. Cidofovir is much more selective for viral DNA polymerase versus human DNA polymerase. Once two consecutive molecules of cidofovir are incorporated into the viral DNA chain, DNA production is halted. Incorporation of one cidofovir molecule slows DNA production by 31%. Viral DNA polymerase is unable to remove cidofovir diphosphate once it has been incorporated into viral DNA. The prolonged activity of cidofovir may be due to its ability to stop DNA production and the fact that viral DNA polymerase is unable to remove cidofovir diphosphate once incorporated. The mechanism of action of cidofovir in human papillomavirus (HPV) differs from CMV, since HPV utilizes host cell DNA polymerase versus viral polymerase. HPV-infected cells treated with cidofovir show cell cycle arrest in the S-phase indicating decreased DNA production. Cidofovir has also been shown to induce DNA fragmentation and Caspase-3 protease activity, which is important in the induction of apoptosis in HVP-positive cells. Cidofovir also has activity against cervical cancer cells infected with HPV. Cidofovir also inhibits ribonucleotide reductase; although, the clinical significance of this is not known.
It has also been postulated that cidofovir can accumulate in healthy cells, establishing a reservoir of drug. If the cell is invaded by a susceptible virus, cidofovir can inhibit the infection by reducing the production of new viral DNA. There are insufficient data at this time to assess the frequency and significance of resistance to cidofovir therapy following treatment in humans. Resistance to cidofovir, and cross-resistance between cidofovir, ganciclovir, and foscarnet has been observed in vitro.
Cidofovir is administered as an intravenous injection.
Intracellularly, cidofovir is metabolized via pyrimidine nucleoside monophosphate kinase to cidofovir monophosphate and is then metabolized to the diphosphate analog. The diphosphate analog is further metabolized to cidofovir monophosphate-choline. The mean elimination half-lives of the monophosphate, diphosphate, and choline metabolites are 6, 17, and > 48 hours, respectively. The choline metabolite may serve as an intracellular reservoir of cidofovir diphosphate, the active form. Cellular protection from infection with herpes simplex virus and CMV has been documented in vitro for up to 7 days following treatment with cidofovir.
Renal clearance is significantly higher than baseline creatinine clearance, suggesting that tubular secretion plays a large role in the clearance of cidofovir. At therapeutic doses of cidofovir, probenecid reduces tubular secretion so that the clearance of cidofovir is closer in magnitude to creatinine clearance. However, there is no significant change in cidofovir half-life. The administration of probenecid also results in an increase in cidofovir maximum concentration as compared to cidofovir alone.
Due to low bioavailability (5—22%), cidofovir is not administered orally.
Following intravenous administration, cidofovir distributes in total body water. Serum concentrations are proportional to dose and decline biexponentially. The plasma elimination half-life is 2.6 hours (+/- 1.2 hours).
Cidofovir clearance decreases proportionally with creatinine clearance; cidofovir is poorly eliminated in patients with a creatinine clearance <= 55 mL/min. High flux hemodialysis has been shown to reduce the serum levels of cidofovir by approximately 75%.
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