Cidofovir

Cidofovir
	Black Box Warning
	Adult Indications & Dosage
	Pediatric Indications & Dosage
	Contraindications
	Warnings & Precautions
	Adverse Reactions
	Drug Interactions
	Use in Specific Populations
	Administration & Monitoring
	Overdosage
	Pharmacology
	Clinical Studies
	How Supplied
	Images
	Patient Counseling Information
	Precautions with Alcohol
	Brand Names
	Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]

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Black Box Warning

Warning

See full prescribing information for complete Boxed Warning.

Condition Name: Renal impairment is the major toxicity of vistide. Cases of acute renal failure resulting in dialysis and/or contributing to death have occurred with as few as one or two doses of vistide. To reduce possible nephrotoxicity, intravenous prehydration with normal saline and administration of probenecid must be used with each vistide infusion. Renal function (serum creatinine and urine protein) must be monitored within 48 hours prior to each dose of vistide and the dose of vistide modified for changes in renal function as appropriate. vistide is contraindicated in patients who are receiving other nephrotoxic agents. Neutropenia has been observed in association with vistide treatment. Therefore, neutrophil counts should be monitored during visited therapy. Vistide is indicated only for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome. In animal studies cidofovir was carcinogenic, teratogenic and caused hypospermia.

Overview

Cidofovir is an antiviral, cytosine nucleoside analog that is FDA approved for the treatment of Citomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS). The safety and efficacy of Cidofovir have not been established for treatment of other CMV infections (such as pneumonitis or gastroenteritis), congenital or neonatal CMV disease, or CMV disease in non-HIV-infected individuals.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include {{{adverseReactions}}}.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

There is limited information regarding Cidofovir FDA-Labeled Indications and Dosage (Adult) in the drug label.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Cidofovir in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Cidofovir in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Cidofovir FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Cidofovir in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Cidofovir in pediatric patients.

Contraindications

Initiation of therapy with VISTIDE is contraindicated in patients with a serum creatinine > 1.5 mg/dL, a calculated creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥ 2+ proteinuria).
VISTIDE is contraindicated in patients receiving agents with nephrotoxic potential. Such agents must be discontinued at least seven days prior to starting therapy with VISTIDE.
VISTIDE is contraindicated in patients with hypersensitivity to cidofovir.
VISTIDE is contraindicated in patients with a history of clinically severe hypersensitivity to probenecid or other sulfa-containing medications.
Direct intraocular injection of VISTIDE is contraindicated; direct injection of cidofovir has been associated with iritis, ocular hypotony, and permanent impairment of vision.

Warnings

Warning

See full prescribing information for complete Boxed Warning.

Condition Name: Renal impairment is the major toxicity of vistide. Cases of acute renal failure resulting in dialysis and/or contributing to death have occurred with as few as one or two doses of vistide. To reduce possible nephrotoxicity, intravenous prehydration with normal saline and administration of probenecid must be used with each vistide infusion. Renal function (serum creatinine and urine protein) must be monitored within 48 hours prior to each dose of vistide and the dose of vistide modified for changes in renal function as appropriate. vistide is contraindicated in patients who are receiving other nephrotoxic agents. Neutropenia has been observed in association with vistide treatment. Therefore, neutrophil counts should be monitored during visited therapy. Vistide is indicated only for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome. In animal studies cidofovir was carcinogenic, teratogenic and caused hypospermia.

Nephrotoxicity

Dose-dependent nephrotoxicity is the major dose-limiting toxicity related to VISTIDE administration. Cases of acute renal failure resulting in dialysis and/or contributing to death have occurred with as few as one or two doses of VISTIDE. Renal function (serum creatinine and urine protein) must be monitored within 48 hours prior to each dose of VISTIDE. Dose adjustment or discontinuation is required for changes in renal function (serum creatinine and/or urine protein) while on therapy. Proteinuria, as measured by urinalysis in a clinical laboratory, may be an early indicator of VISTIDE-related nephrotoxicity. Continued administration of VISTIDE may lead to additional proximal tubule cell injury, which may result in glycosuria, decreases in serum phosphate, uric acid, and bicarbonate, elevations in serum creatinine, and/or acute renal failure, in some cases, resulting in the need for dialysis. Patients with these adverse events occurring concurrently and meeting a criteria of Fanconi's syndrome have been reported. Renal function that did not return to baseline after drug discontinuation has been observed in clinical studies of VISTIDE.

Intravenous normal saline hydration and oral probenecid must accompany each VISTIDE infusion. Probenecid is known to interact with the metabolism or renal tubular excretion of many drugs. The safety of VISTIDE has not been evaluated in patients receiving other known potentially nephrotoxic agents, such as intravenous aminoglycosides (tobramycin, gentamicin, and amikacin), amphotericin B, foscarnet, intravenous pentamidine, vancomycin, and non-steroidal anti-inflammatory agents.

Preexisting Renal Impairment

Initiation of therapy with VISTIDE is contraindicated in patients with a baseline serum creatinine > 1.5 mg/dL, a creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥ 2+ proteinuria).

Hematological Toxicity

Neutropenia may occur during VISTIDE therapy. Neutrophil count should be monitored while receiving VISTIDE therapy.

Decreased Intraocular Pressure/Ocular Hypotony

Decreased intraocular pressure may occur during VISTIDE therapy, and in some instances has been associated with decreased visual acuity. Intraocular pressure should be monitored during VISTIDE therapy.

Metabolic Acidosis

Decreased serum bicarbonate associated with proximal tubule injury and renal wasting syndrome (including Fanconi's syndrome) have been reported in patients receiving VISTIDE. Cases of metabolic acidosis in association with liver dysfunction and pancreatitis resulting in death have been reported in patients receiving VISTIDE.

Adverse Reactions

Clinical Trials Experience

Nephrotoxicity

Renal toxicity, as manifested by ≥ 2+ proteinuria, serum creatinine elevations of ≥ 0.4 mg/dL, or decreased creatinine clearance ≤ 55 mL/min, occurred in 79 of 135 (59%) patients receiving VISTIDE at a maintenance dose of 5 mg/kg every other week. Maintenance dose reductions from 5 mg/kg to 3 mg/kg due to proteinuria or serum creatinine elevations were made in 12 of 41 (29%) patients who had not received prior therapy for CMV retinitis (Study 106) and in 19 of 74 (26%) patients who had received prior therapy for CMV retinitis (Study 107). Prior foscarnet use has been associated with an increased risk of nephrotoxicity; therefore, such patients must be monitored closely.

Neutropenia

In clinical trials, at the 5 mg/kg maintenance dose, a decrease in absolute neutrophil count to ≤ 500 cells/mm 3 occurred in 24% of patients. Granulocyte colony stimulating factor (GCSF) was used in 39% of patients.

Decreased Intraocular Pressure/Ocular Hypotony

Among the subset of patients monitored for intraocular pressure changes, a ≥ 50% decrease from baseline intraocular pressure was reported in 17 of 70 (24%) patients at the 5 mg/kg maintenance dose. Severe hypotony (intraocular pressure of 0–1 mm Hg) has been reported in 3 patients. Risk of ocular hypotony may be increased in patients with preexisting diabetes mellitus.

Anterior Uveitis/Iritis

Uveitis or iritis has been reported in clinical trials and during postmarketing in patients receiving VISTIDE therapy. Uveitis or iritis was reported in 15 of 135 (11%) patients receiving 5 mg/kg maintenance dosing. Treatment with topical corticosteroids with or without topical cycloplegic agents may be considered. Patients should be monitored for signs and symptoms of uveitis/iritis during VISTIDE therapy.

Metabolic Acidosis

A diagnosis of Fanconi's syndrome, as manifested by multiple abnormalities of proximal renal tubular function, was reported in 1% of patients. Decreases in serum bicarbonate to ≤ 16 mEq/L occurred in 16% of cidofovir-treated patients. Cases of metabolic acidosis in association with liver dysfunction and pancreatitis resulting in death have been reported in patients receiving VISTIDE. In clinical trials, VISTIDE was withdrawn due to adverse events in 39% of patients treated with 5 mg/kg every other week as maintenance therapy.

The incidence of adverse reactions reported as serious in three controlled clinical studies in patients with CMV retinitis, regardless of presumed relationship to drug, is listed in Table 4.

The most frequently reported adverse events regardless of relationship to study drugs (cidofovir or probenecid) or severity are shown in Table 5.

The following additional list of adverse events/intercurrent illnesses have been observed in clinical studies of VISTIDE and are listed below regardless of causal relationship to VISTIDE. Evaluation of these reports was difficult because of the diverse manifestations of the underlying disease and because most patients received numerous concomitant medicines.

Body as a Whole

Cardiovascular System

Digestive System

Endocrine System

Adrenal cortex insufficiency

Hemic & Lymphatic System

Metabolic & Nutritional System

Musculoskeletal System

Nervous System

Respiratory System

Skin & Appendages

Special Senses

Urogenital System

Postmarketing Experience

There is limited information regarding Cidofovir Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding Cidofovir Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): C Cidofovir was embryotoxic (reduced fetal body weights) in rats at 1.5 mg/kg/day and in rabbits at 1.0 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 (1.0 mg/kg/day) which was also maternally toxic. There are no adequate and well-controlled studies in pregnant women. VISTIDE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cidofovir in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Cidofovir during labor and delivery.

Nursing Mothers

It is not known whether cidofovir is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for adverse reactions as well as the potential for tumorigenicity shown for cidofovir in animal studies, VISTIDE should not be administered to nursing mothers. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid postnatal transmission of HIV to a child who may not yet be infected.

Pediatric Use

Safety and effectiveness in children have not been studied. The use of VISTIDE in children with AIDS warrants extreme caution due to the risk of long-term carcinogenicity and reproductive toxicity. Administration of VISTIDE to children should be undertaken only after careful evaluation and only if the potential benefits of treatment outweigh the risks.

Geriatic Use

No studies of the safety or efficacy of VISTIDE in patients over the age of 60 have been conducted. Since elderly individuals frequently have reduced glomerular filtration, particular attention should be paid to assessing renal function before and during VISTIDE administration

Gender

There is no FDA guidance on the use of Cidofovir with respect to specific gender populations.

Race

There is no FDA guidance on the use of Cidofovir with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Cidofovir in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Cidofovir in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Cidofovir in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Cidofovir in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Cidofovir Administration in the drug label.

Monitoring

There is limited information regarding Cidofovir Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Cidofovir and IV administrations.

Overdosage

Two cases of cidofovir overdose have been reported. These patients received single doses of VISTIDE at 16.3 mg/kg and 17.4 mg/kg, respectively, with concomitant oral probenecid and intravenous hydration. In both cases, the patients were hospitalized and received oral probenecid (one gram three times daily) and vigorous intravenous hydration with normal saline for 3 to 5 days. Significant changes in renal function were not observed in either patient.

Pharmacology


Cidofovir
Systematic (IUPAC) name
({[(S)-1-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-3-hydroxypropan-2-yl]oxy}methyl)phosphonic acid
Identifiers
CAS number	113852-37-2
ATC code	J05AB12
PubChem	60613
DrugBank	DB00369
Chemical data
Formula	Template:OrganicBox atom Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox atom Template:OrganicBox Template:OrganicBox atom Template:OrganicBox atom Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox Template:OrganicBox
Mol. mass	279.187 g/mol
SMILES	eMolecules & PubChem
Physical data
Melt. point	260 °C (500 °F)
Spec. rot	-97.3
Pharmacokinetic data
Bioavailability	complete
Protein binding	<6%
Metabolism	?
Half life	2.6 hours
Excretion	renal The above pharmacokinetic parameters are measured for cidofovir used in conjunction with probenecid.^[1]
Therapeutic considerations
Licence data	EU, US
Pregnancy cat.	D(AU) C(US)
Legal status	Prescription Only (S4)(AU) ?(CA) POM(UK) [[Prescription drug\|Template:Unicode-only]](US)
Routes	IV

Mechanism of Action

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.

Structure

The chemical name of cidofovir is 1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate (HPMPC), with the molecular formula of C8H14N3O6P•2H2O and a molecular weight of 315.22 (279.19 for anhydrous). The chemical structure is:

Pharmacodynamics

There is limited information regarding Cidofovir Pharmacodynamics in the drug label.

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. 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.

Nonclinical Toxicology

There is limited information regarding Cidofovir Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Cidofovir Clinical Studies in the drug label.

How Supplied

There is limited information regarding Cidofovir How Supplied in the drug label.

Storage

There is limited information regarding Cidofovir Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Cidofovir Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Cidofovir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Cidofovir Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Cidofovir Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

↑ Cundy, Kenneth C. "Clinical Pharmacokinetics of the Antiviral Nucleotide Analogues Cidofovir and Adefovir." Clinical Pharmacokinetics 36.2 (1999): 127-43.

Cidofovir
VISTIDE^® FDA Package Insert
Description
Clinical Pharmacology
Microbiology
Indications and Usage
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Overdosage
Clinical Studies
Dosage and Administration
How Supplied
Labels and Packages

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]

Overview

Cidofovir is an injectable antiviral medication for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. It suppresses CMV replication by selective inhibition of viral DNA synthesis.

Cidofovir demonstrated a statistically significant effect in delaying the progression of CMV retinitis lesions in newly diagnosed patients, as well as in previously treated patients who had failed other therapies. Maintenance therapy with cidofovir involves an infusion only once every two weeks, making it a convenient treatment option. Because dosing is relatively infrequent, a permanent catheter is not necessary for infusions. The major side effect of cidofovir is that it can be nephrotoxic.

US Brand Names

CIDOFOVIR^®

FDA Package Insert

Mechanism of Action

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.

References

[1] Cundy, Kenneth C. "Clinical Pharmacokinetics of the Antiviral Nucleotide Analogues Cidofovir and Adefovir." Clinical Pharmacokinetics 36.2 (1999): 127-43.

[1]