Cidofovir

279.19

279.19

1308068-626-2

768M1V522C

742135

DTXSID3043734

C77925

Fluffy white powder|White crystalline powder

J05AB12|J - Antiinfectives for systemic use

2933599090

146

-3.9

Solid

1.76±0.1 g/cm3(Predicted)

260 °C (decomp)

609.5ºC at 760 mmHg

322.4±34.3 °C

1.656

deionized water: ≥5mg/mL (warmed)

room temp

2.11E-17mmHg at 25°C

D20 -97.3° (c = 0.80 in water)

UV maximum (pH 2): 279 nm (E 13,000) /Monohydrate/

Ⅲ

UN 2811 6.1 / PGIII

3

25-38

36-37-45

SZ6545000

T

It is recommended that cidofovir admixtures be administered within 24 hours of preparation and that refrigeration or freezer storage not be used to extend this 24 hour limit.

P301 + P310

H301; H315

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.|Partially used vials of cidofovir and diluted solutions should be discarded by high temperature incineration.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl cidofovir, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

An overview of the pharmacology, pharmacokinetics, efficacy, side effects and dosage of cidofovir for the treatment of cytomegalovirus retinitis.[Levien T, Baker DE; Hosp Pharm 31: 1604-20 (1996)]

Due to the mutagenic potential of cidofovir, use of appropriate safety equipment is recommended for preparation, administration, and disposal of cidofovir. The National Institutes of Health recommends that cidofovir be prepared in a class II laminar flow biological safety cabinet and that personnel preparing this medication wear surgical gloves and a closed-front surgical-type gown with kint cuffs.

Caution should be exercised in preparing, administering, and discarding solutions of cidofovir according to guidelines for handling mutagenic substances. If cidofovir concentrate for injection or a dilute solution of the drug comes in contact with the skin or mucosa, the affected area should be washed immediately and thoroughly with soap and water.

Kidney damage, fall in the number of white blood cells, decreased platelets

Intravenous cidofovir therapy is associated with mild-to-moderate elevations in serum ALT levels in a proportion of patients, but the elevations are usually self-limited and do not require dose modification. Nephrotoxicity is often dose limiting, which may account for the absence of clinically significant cases of liver injury associated with cidofovir therapy. Cases of clinically apparent liver injury have been reported during cidofovir therapy, but the role of this agent has been difficult to define because most patients who receive cidofovir have severe immunodeficiency and are receiving multiple other agents, some of which are known hepatotoxins. Several instances of acute liver failure, lactic acidosis and fatty liver have been described in patients taking cidofovir, but other nucleoside analogues such as zidovudine, stavudine or didanosine were being taken concurrently.

Concomitant administration of cidofovir with potentially nephrotoxic agents (e.g., amphotericin B, aminoglycosides, foscarnet, nonsteriodal antiinflammatory agents, IV pentamidine, vancomycin) is contraindicated, and the manufacturer recommends that at least 7 days elapse between discontinuance of such drugs and administration of cidofovir.|Placement of a ganciclovir ocular implant in patients receiving IV cidofovir has resulted in profound hypotony in some patients, and some clinicians suggest that IV cidofovir not be administered within one month before or after placement of a ganciclovir ocular implant.

6%

Vitreous samples from 9 eyes of 9 patients and plasma samples from 4 patients were assayed with high-performance liquid chromatography to determine cidofovir levels. The only eye that had a detectable vitreous concentration (673.7 ng/ml) was injected with 20 ug 24 hours prior to the surgery. The remaining samples including plasma were below the detection point of the assay (100 ng/ml) and were injected between 5 and 40 days prior to sampling.

For the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS)|FDA Label|Vistide is indicated for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome (AIDS) and without renal dysfunction. Vistide should be used only when other agents are considered unsuitable.,

Cidofovir is a nucleoside analogue and antiviral agent which is used in therapy of serious cytomegalovirus infections in immunocompromised patients. Cidofovir has been associated with mild-to-moderate serum aminotransferase elevations during intravenous therapy, but has not been convincingly linked to cases of clinically apparent acute liver injury.

Antiviral Agents

Cidofovir is used for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS).|Cidofovir has been used for the management of acyclovir-resistant herpes simplex virus (HSV-1 and HSV-2) infections in immunocompromised patients.|The role, if any, of cidofovir in the treatment of smallpox remains to be determined. 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. 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 currently is no evidence that the antiviral would be more effective than vaccination in this early period.|Topical cidofovir gel eliminates virus shedding and lesions in some HIV-infected patients with acyclovir-resistant mucocutaneous HSV infections and has been use in treating anogenital warts and molluscum contagiosum in immunocompromised patients and cervical intraepithelial neoplasia in women. Intralesional cidofovir induces remission in adults or chlidren with respiratory papillomatosis.|For more Therapeutic Uses (Complete) data for CIDOFOVIR (15 total), please visit the HSDB record page.

Placement of a ganciclovir ocular implant in patients receiving IV cidofovir has resulted in profound hypotomy in some patients, and some clinicians suggest that IV cidofovir not be administered within one month before or after placement of a ganciclovir ocular implant.|.... Because evidence from clinical trials indicates that previous exposure to foscarnet may increase the risk of cidofovir-related nephrotoxicity, patients treated previously with foscarnet should receive cidofovir only when the potential benefits exceed the possible risks.|Patients should be advised that cidofovir therapy is not curative, and that progression of their retinitis is possible during or following therapy with the drug.|Safety and efficacy of cidofovir in geriatric patients older than 60 years of age have not been established. 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 doses of the drug should be modified in response to changes in renal function that occur during therapy.|For more Drug Warnings (Complete) data for CIDOFOVIR (20 total), please visit the HSDB record page.

Cidofovir is a new anti-viral drug. It is classified as a nucleotide analogue and is active against herpes cytomegalovirus (CMV) retinitis infection. Most adults are infected with CMV. Cidofovir suppresses cytomegalovirus (CMV) replication by selective inhibition of viral DNA synthesis.

Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. (See all compounds classified as Antiviral Agents.)|Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)

100%|537 ± 126 mL/kg [VISTIDE ADMINISTERED WITHOUT PROBENECID]|179 +/- 23.1 mL/min/1.73 m2 [WITHOUT PROBENECID]|Volume of distribution is 537 ml/kg without concurrent probenecid administration and 410 ml/kg with concurrent probenecid administration.|Concentrations of cidofovir were undetectable 15 minutes after the end of a 1 hour infusion in one patient who had a corresponding serum concentration of 8.7 ug/mL.|Renal (without concurrent probenecid administration): Approximately 80 to 100% of an administered cidofovir dose was recovered unchanged in the urine within 24 hours.|Cidofovir is dianionic at physiological pH and have low oral bioavailability in animals and humans. After intravenous administration to HIV-infected patients, the pharmacokinetics of /cidofovir is/ independent of dose and are consistent with preclinical data. Systemic exposure is proportional to the intravenous dose and /the drug is cleared/ by the kidney and excreted extensively as unchanged drug in the urine. Intracellular activation of a small fraction (< 10%) of the dose by cellular kinases leads to prolonged antiviral effects that are not easily predicted from conventional pharmacokinetic studies. The observed rate of elimination of cidofovir ... from the serum may not reflect the true duration of action of these drugs, since the antiviral effect is dependent on concentrations of the active phosphorylated metabolites that are present within cells. For /cidofovir/, > 90% of an iv dose is recovered unchanged in the urine over 24 hours.|This study was undertaken to evaluate the intravitreal and plasma concentrations of cidofovir (HPMPC) after intravitreal and intravenous administration in AIDS patients with cytomegalovirus retinitis. Cohort series; undiluted vitreous and blood were collected from 9 patients at the time of pars plana vitrectomy. Vitreous samples from 9 eyes of 9 patients and plasma samples from 4 patients were assayed with high-performance liquid chromatography to determine cidofovir levels. The only eye that had a detectable vitreous concentration (673.7 ng/ml) was injected with 20 microg 24 hours prior to the surgery. The remaining samples including plasma were below the detection point of the assay (100 ng/ml) and were injected between 5 and 40 days prior to sampling. The intravitreal concentration of cidofovir in humans is consistent with pharmacokinetics data in laboratory animals, and suggests that the long duration of antiviral effect (1-3 months) in clinical trials is due to a prolonged intracellular half-life in retinal tissue.

Cidofovir is converted via cellular enzymes to the pharmacologically active diphosphate metabolite ... .|This study was designed to evaluate the intraocular distribution and metabolism of the antiviral nucleotide analogs cidofovir and cyclic 1-[(S)-3-hydroxy-2-(phosphonomethoxy) propyl]cytosine (HPMPC) in New Zealand white rabbits following intravitreal administration. ...Male rabbits received either 14C-cidofovir or 14C-cyclic HPMPC by intravitreal injection into both eyes (50 micrograms/eye, 11 microCi/eye). Two animals/group were sacrificed at 24, 48, 72 or 240 hr post-dose. Ocular tissues, kidney and liver were oxidized to determine total radioactivity and metabolites were determined by HPLC. ...At 24 hr post-dose, total radioactivity was 9.96 and 5.18 micrograms-equiv/g for cidofovir and cyclic HPMPC, respectively, in vitreous and 20.9 and 3.54 micrograms-equiv/g, respectively, in retina. Although the initial vitreal clearance was 2-fold faster for the cyclic analog, the estimated terminal elimination half-lives in vitreous (42 hr) and in retina (66-77 hr) were similar for both drugs. By 240 hr post-dose, radioactivity in all ocular tissues was approx ten-fold higher for cidofovir. Radioactivity in vitreous at 240 hr after intravitreal dosing with either drug contained cidofovir, cyclic HPMPC and cidofovir-phosphocholine. ...The long retinal half-life observed presumably reflects formation of phosphorylated cidofovir within retinal cells. Cidofovir achieved a ten-fold higher level of phosphorylated drug in retina than cyclic HPMPC. Therefore, intravitreal cidofovir may be expected to suppress progression of retinitis for a longer period than an equivalent intravitreal dose of cyclic HPMPC. The intravitreal half-life of cidofovir was 20-fold longer than that of ganciclovir in the same animal model.|Pyrimidine nucleoside monophosphate kinase converts cidofovir to cidofovir monophosphate, which is further converted to the diphosphate and cidofovir phosphate-choline via other cellular enzymes.

2.4 to 3.2 hours|...Male rabbits received either 14C-cidofovir ...by intravitreal injection into both eyes (50 micrograms/eye...). ...The estimated terminal elimination half-lives /were/ in vitreous (42 hr) and in retina (66-77 hr)... .|...Levels of cidofovir in serum following iv infusion were dose proportional over the dose range of 1.0-10.0 mg/kg bw and declined biexponentially with an overall mean +/- standard deviation terminal half-life of 2.6 +/- 1.2 hr (n=25).

Cidofovir acts through the selective inhibition of viral DNA polymerase.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 polymerase alpha, beta, and gamma(1,2,3). Incorporation of cidofovir into the growing viral DNA chain results in reductions in the rate of viral DNA synthesis.|Cidofovir diphosphate exerts its antiviral effect by interfering with DNA synthesis and inhibiting viral replication. The inhibitory activity of cidofovir diphosphate is highly selective because of its greater affinity for viral DNA polymerases than for human DNA polymerases. /Cidofovir diphosphate/|Pyrimidine nucleoside monophosphate kinase converts cidofovir to cidofovir monophosphate, which is further converted to the diphosphate and cidofovir phosphate-choline via other cellular enzymes. Cidofovir diphosphate stop replication of viral DNA by competitive inhibition of viral DNA polymerase, incorporation and termination of the growing viral DNA chain, and inactivation of the viral DNA polymerase. /Cidofovir diphosphate/|Cidofovir /is an/ ... acyclic phosphonate analog of deoxynucleoside monophosphate. /This cmpd/ undergoes intracellular activation to form diphosphates that are potent inhibitors of viral DNA polymerases. Cidofovir has broad spectrum antiviral activity against herpesviruses, papillomaviruses and poxviruses.

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/|Hemodialysis and probenecid should reduce plasma concentrations in the event of an overdose.|Two cases of cidofovir overdose have been reported. These patients received single doses of /cidofovir/ 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 and vigorous iv hydration with normal saline for 3 to 5 days. Significant changes in renal function were not observed in either patient.

/HUMAN EXPOSURE STUDIES/ The major complication of cidofovir therapy is renal toxicity, which is sometimes irreversible, results in renal failure, and requires dialysis to prevent death.|/CASE REPORTS/ 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 < or =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 /cidofovir/.

1-((3-hydroxy-2-phosphonylmethoxy)propyl)cytosine

Preparations: Parenteral; for injection, concentrate, for IV infusion only; 75 mg (of anhydrous cidofovir) per mL; Vistide, Gilead Sciences|...Cream containing 1% cidofovir.

... A metabolite of cidofovir was isolated from the kidneys of rats that received a single iv bolus injection of 100 mg/kg radiolabelled cidofovir. The metabolite /isolated/ was cidofovir phosphocholine /determined/ by NMR and mass spectrometry.

Human drugs -> Vistide -> EMA Drug Category|Antivirals for systemic use -> Human pharmacotherapeutic group|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients