Meningitis: What It Is and How to Avoid It Watch Video

Vistide

Generic Name: Cidofovir
Class: Nucleosides and Nucleotides
VA Class: AM800
Chemical Name: (S)-[[2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]phosphonic acid dihydrate
Molecular Formula: C8H14N3O6P•2H2O
CAS Number: 149394-66-1

Warning(s)

  • Nephrotoxicity
  • The major toxicity is renal impairment.1 Acute renal failure resulting in dialysis and/or contributing to death has occurred with as few as 1 or 2 doses of cidofovir.1

  • To reduce risk of nephrotoxicity, IV prehydration with 0.9% sodium chloride prior to each cidofovir dose and concomitant probenecid must be used.1 (See Hydration and see Concomitant Probenecid under Dosage and Administration.) Renal function (serum creatinine and urine protein) must be monitored within 48 hours prior to each dose and dosage modified as appropriate based on any changes in renal function.1

  • Cidofovir is contraindicated in patients receiving other nephrotoxic drugs.1

  • Neutropenia
  • Neutropenia has been observed in association with cidofovir; neutrophil counts should be closely monitored during treatment.1

  • Other Warnings
  • The only FDA-approved indication is treatment of cytomegalovirus (CMV) retinitis in HIV-infected patients.1

  • In animal studies, cidofovir was carcinogenic, teratogenic, and caused hypospermia.1

Introduction

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

Uses for Vistide

Cytomegalovirus (CMV) Infections

Treatment of cytomegalovirus (CMV) retinitis in HIV-infected adults or adolescents.1 21 24 25 31 52 69 Cidofovir is not curative; stabilization or improvement of ocular manifestations may occur, but progression of retinitis is possible during or following treatment.1 3 17 21 23 24 25 31

Drugs of choice for initial induction and maintenance therapy of CMV retinitis are IV ganciclovir, IV ganciclovir in conjunction with oral valganciclovir, IV foscarnet, IV cidofovir, oral valganciclovir, or intravitreal fomivirsen.37 52 69

Alternative to IV ganciclovir or IV foscarnet for long-term suppressive or maintenance therapy (secondary prophylaxis) of recurrent CMV disease in HIV-infected adults or adolescents.38 69

Slideshow: Worried About Ebola? You’re More Likely to Get These 10 Serious Infections

Safety and efficacy not established for treatment of other CMV infections (e.g., pneumonitis, gastroenteritis), congenital or neonatal CMV disease, or CMV disease in individuals not infected with HIV.1

Mucocutaneous Herpes Simplex Virus (HSV) Infections

Treatment of acyclovir-resistant herpes simplex virus (HSV-1 and HSV-2) infections in immunocompromised patients, including HIV-infected adults or adolescents.39 40 42 43 69 A drug of choice.38 69

Alternative for chronic suppressive or maintenance therapy (secondary prophylaxis) against recurrence of HSV in HIV-infected adults and adolescents who have frequent or severe recurrence.38 69 Drugs of choice for secondary prophylaxis are oral acyclovir, oral famciclovir, or oral valacyclovir; IV cidofovir and IV foscarnet are alternatives for such prophylaxis if acyclovir-resistant HSV are suspected.38 69

Has been used topically for treatment of mucocutaneous HSV infections or genital herpes caused by acyclovir-resistant strains.40 43 61 69

Smallpox

Suggested for use in treatment of smallpox.49 50 51 No clinical data to date; possible benefits remain to be determined.49 50 51

Alternative for treatment of certain serious complications of smallpox vaccination, including progressive vaccinia, eczema vaccinatum, generalized vaccinia (if severe or with underlying illness), and inadvertent inoculation (if severe because of large numbers of lesions, toxicity, or pain).62 63 Safety and efficacy have not been determined and possible benefits remain to be determined.62 63

Vaccinia immune globulin (VIG) usually recommended for management of complications of smallpox vaccination; cidofovir is available from CDC under an investigational new drug (IND) protocol for patients who fail to respond to VIG and for patients who are near death and will also be available if all inventories of VIG have been exhausted.62 63

Monkeypox

Suggested for use in treatment of severe human monkeypox.65 Efficacy has not been established, but drug is active in vitro against monkeypox and has in vivo activity in animal models.53 65 66 67 68 Not indicated for prophylaxis of monkeypox.65 Clinical consultation on use of cidofovir for treatment of severe monkeypox infection can be obtained from state health departments or CDC (877-554-4625).65

Vistide Dosage and Administration

General

Hydration

  • To minimize risk of nephrotoxicity, patients must receive adequate IV prehydration with 0.9% sodium chloride prior to each cidofovir dose.1

  • Patients should receive ≥1 L of 0.9% sodium chloride infused IV over 1–2 hours immediately before each cidofovir infusion.1

  • For patients who can tolerate additional fluid, an additional 1 L of 0.9% sodium chloride should be administered; this second saline infusion should be initiated either concomitantly with or immediately after the cidofovir infusion and should be administered over 1–3 hours.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 HIV-related wasting.29

Concomitant Probenecid

  • In addition to adequate hydration, all patients must receive a regimen of concomitant oral probenecid.1 3 7 30 32 Cidofovir undergoes renal tubular secretion, suggesting that use of probenecid may reduce the risk of renal toxicity of cidofovir by decreasing its concentration within proximal tubular cells.1 4 7

  • Because concomitant use of probenecid is considered necessary, cidofovir is contraindicated in patients who cannot receive probenecid (e.g., those with a history of severe hypersensitivity to probenecid or other sulfonamide derivatives).1 30

  • The recommended dosage of probenecid to be administered concomitantly with cidofovir is 2 g orally 3 hours prior to initiation of the cidofovir infusion, followed by 1-g doses orally 2 and 8 hours after completion of the cidofovir infusion, for a total probenecid dose of 4 g.1 2 18

  • To reduce risk of nausea and/or vomiting associated with 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 should be considered.1

  • 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 Although patients receiving antiretroviral therapy can continue to receive the drugs during cidofovir therapy,1 consider possible interactions between probenecid and antiretrovirals (e.g., zidovudine).1 18 (See Specific Drugs under Interactions.)

Administration

Administer by IV infusion.1

Has been administered by intravitreal injection,6 20 24 25 26 but a preparation for intravitreal administration is not commercially available in the US.1 30 Direct intraocular injection of the IV preparation (even if diluted) is contraindicated since such administration has been associated with iritis, ocular hypotony (clinically important decreases in intraocular pressure [IOP]), and permanent visual impairment.1 30

Has been administered topically as an extemporaneously prepared gel containing cidofovir 1%.40 43 61 69

IV Infusion

To minimize the risk of nephrotoxicity, patients must receive adequate IV prehydration with 0.9% sodium chloride prior to each cidofovir dose and also should receive concomitant oral probenecid.1 (See Hydration and see Concomitant Probenecid under Dosage and Administration.)

Exercise caution should be exercised in preparing, administering, and discarding solutions of cidofovir according to guidelines for handling mutagenic substances.1 30 If cidofovir concentrate or a diluted 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.1 Partially used vials of cidofovir and diluted solutions should be discarded by high temperature incineration.1

Dilution

For IV infusion, cidofovir concentrate must be diluted in 100 mL of 0.9% sodium chloride injection in a compatible infusion container (e.g., PVC, glass, ethylene/propylene copolymer).1

Compatibility with Ringer’s, lactated Ringer’s, or bacteriostatic infusion solutions has not been established.1

Rate of Administration

IV infusions should be given over 1 hour at a constant rate via a controlled-infusion device (e.g., pump).1 To minimize risk of nephrotoxicity, the IV dose must not be infused over a shorter period.1 29

Dosage

Available as cidofovir dihydrate; dosage is expressed in terms of anhydrous drug.1

Pediatric Patients

Cytomegalovirus (CMV) Infections
CMV Retinitis in HIV-infected Adolescents
IV

Initial induction therapy: 5 mg/kg once weekly for 2 consecutive weeks.69

Maintenance therapy: 5 mg/kg once every 2 weeks (i.e., every other week).69

Prevention of Recurrence (Secondary Prophylaxis) of CMV Disease in HIV-infected Adolescents
IV

5 mg/kg once every other week.38 69 Initiate secondary prophylaxis after initial induction treatment.38 69

Consideration can be given to discontinuing secondary CMV prophylaxis in adolescents with sustained (e.g., for ≥6 months) increase in CD4+ T-cell counts to >100–150/mm3 in response to potent antiretroviral therapy.38 69

This decision should be made in consultation with an ophthalmologist and factors such as the magnitude and duration of CD4+ T-cell increase, anatomic location of the retinal lesion, vision in the contralateral eye, and feasibility of regular ophthalmic monitoring should be considered.38 69

Relapse of CMV retinitis could occur following discontinuance of secondary prophylaxis, especially in those whose CD4+ T-cell count decreases to <50/mm3; relapse has been reported rarely in those with CD4+ T-cell counts >100/mm3.38 69

Reinitiate secondary CMV prophylaxis if CD4+ T-cell count decreases to <100–150/mm3.38 69

Herpes Simplex Virus (HSV) Infections
Acyclovir-resistant HSV Infections in immunocompromised Adolescents
IV

5 mg/kg once weekly for 2–4 weeks until a response is obtained.39 40 69

Acyclovir-resistant Genital Herpes
Topical

Apply extemporaneously prepared gel containing cidofovir 1% to affected area once daily for 5 days.43 61

Adults

Cytomegalovirus (CMV) Infections
CMV Retinitis in HIV-infected Adults
IV

Initial induction therapy: 5 mg/kg once weekly for 2 consecutive weeks.1 21 24 30 31 52 69

Maintenance therapy: 5 mg/kg once every 2 weeks (i.e., every other week).1 24 52 69

Prevention of Recurrence (Secondary Prophylaxis) of CMV Disease in HIV-infected Adults
IV

5 mg/kg once every other week.38 69 Initiate secondary prophylaxis after initial induction treatment.38 69

Consideration can be given to discontinuing secondary CMV prophylaxis in adults with sustained (e.g., for ≥6 months) increase in CD4+ T-cell counts to >100–150/mm3 in response to potent antiretroviral therapy.38 69

This decision should be made in consultation with an ophthalmologist and factors such as the magnitude and duration of CD4+ T-cell increase, anatomic location of the retinal lesion, vision in the contralateral eye, and feasibility of regular ophthalmic monitoring should be considered.38 69

Relapse of CMV retinitis could occur following discontinuance of secondary prophylaxis, especially in those whose CD4+ T-cell count decreases to <50/mm3; relapse has been reported rarely in those with CD4+ T-cell counts >100/mm3.38 69

Reinitiate secondary CMV prophylaxis if CD4+ T-cell count decreases to <100–150/mm3.38 69

Herpes Simplex Virus (HSV) Infections
Acyclovir-resistant HSV Infections in immunocompromised Adults
IV

5 mg/kg once weekly for 2–4 weeks until a response is obtained.39 40 69

Acylcovir-resistant Genital Herpes
Topical

Apply extemporaneously prepared gel containing cidofovir 1% to affected area once daily for 5 days.43 61

Smallpox
Smallpox Vaccination Complications
IV

CDC has proposed a cidofovir dosage of 5 mg/kg administered once as an IV infusion over 1 hour.63 If there is no response to the initial dose, administration of a second dose 1 week later can be considered.63 If a second dose is needed, cidofovir dosage may need to be adjusted if renal function has deteriorated.63

Information on dosage and administration of cidofovir and IND materials will be provided by CDC if the drug is released for treatment of certain serious complications of smallpox vaccination.58 63

Monkeypox
IV

No specific dosage recommendations available.65 Information on appropriate dosage for severe monkeypox infection should be obtained as part of clinical consultation services provided by state health departments or CDC (877-554-4625).65

Special Populations

Renal Impairment

Contraindicated in patients with serum creatinine >1.5 mg/dL, calculated Clcr ≤55 mL/minute, or urine protein ≥100 mg/dL (equivalent to 2+ or greater).1

If serum creatinine increases by 0.5 mg/dL or more above baseline or urinary proteinuria of 3+ or greater develops, cidofovir must be discontinued.1 29 30

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 temporary discontinuance of the drug.29 30

Cytomegalovirus (CMV) Infections
CMV Retinitis in HIV-infected Adults
IV

If clinically important decreases in renal function (e.g., increase in serum creatinine to 0.3–0.4 mg/dL above baseline) occur in patients receiving cidofovir, maintenance dosage must be reduced to 3 mg/kg administered IV at the usual rate and frequency.1 29 52 Some clinicians suggest a cidofovir dosage of 2.5–4 mg/kg administered IV at the usual rate and frequency in HIV-infected patients with a Clcr 50–80 mL/minute.41

Geriatric Patients

Select dosage with caution because of age-related decreases in renal function.1 (See Renal Impairment under Dosage and Administration.)

Cautions for Vistide

Contraindications

  • Hypersensitivity to cidofovir.1

  • Serum creatinine >1.5 mg/dL, calculated Clcr ≤55 mL/minute, or urine protein ≥100 mg/dL (equivalent to 2+ or greater).1

  • Concomitant administration of other nephrotoxic drugs.1

  • History of severe hypersensitivity to probenecid or other sulfonamide derivatives.1 30

  • Direct intraocular injection of the IV preparation.1 30

Warnings/Precautions

Warnings

Nephrotoxicity

Dose-dependent nephrotoxicity is the major dose-limiting toxicity.1 Acute renal failure, resulting in dialysis and/or contributing to death, has occurred with as few as 1 or 2 doses.1 29 35 Most cases were associated with risk factors for nephrotoxicity, such as preexisting mild renal insufficiency.29

Renal function (serum creatinine and urine protein) must be monitored within 48 hours prior to each cidofovir dose and dosage modified as appropriate based on any changes in renal function.1

Proteinuria may be an early sign of cidofovir-induced nephrotoxicity.1 IV hydration should be performed and the test repeated to confirm.1

If renal function deteriorates, consider dosage reduction or discontinuance of the drug should.1 29 Continued 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, occasionally requiring dialysis.1

Occasionally, renal function may not return to baseline following discontinuance of cidofovir.1

Franconi’s syndrome can occur.

Hematologic Effects

Neutropenia (≤500/mm3) has occurred.1 WBC count and differential should be monitored prior to each cidofovir dose.1 30

Ocular Effects

Uveitis or iritis reported.1 Decreased IOP and severe hypotony reported.1 Risk of ocular hypotony may be increased in patients with preexisting diabetes mellitus.1

Periodically monitor IOP, visual acuity, and ocular symptoms during therapy.1 35 36

If anterior uveitis develops, treatment with appropriate agents (topical corticosteroids with or without cycloplegic therapy) may be indicated.35

Metabolic Acidosis

Decreased serum bicarbonate associated with proximal tubule injury and renal wasting syndrome (including Fanconi’s syndrome) has occurred.1

Metabolic acidosis in association with liver dysfunction and pancreatitis has resulted in death.1

General Precautions

Carcinogenic and Mutagenic Potential

Cidofovir should be considered a potential carcinogen in humans.1 Has caused tumors (principally mammary adenocarcinomas) in rats.1

Effects on Fertility

In animals, cidofovir has caused reduced testes weight and hypospermia.1 Possibility exists that such changes could occur in humans and cause infertility.1

Contraceptive Precautions

Women of childbearing potential should use effective contraception during and for 1 month following cidofovir treatment.1

Men should practice barrier contraceptive methods during and for 3 months after cidofovir treatment.1

Specific Populations

Pregnancy

Category C.1 (See Contraceptive Precautions under Cautions.)

Lactation

Not known whether distributed into milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1 30

Because of the risk of potential long-term carcinogenic and reproductive toxicity, use with extreme caution in children and only when potential benefits outweigh risks.1

Geriatric Use

Safety and efficacy have not been evaluated in adults >60 years of age.1

Dosage should be adjusted in response to any change in renal function that may occur during therapy.1 Because geriatric patients frequently have reduced GFR, particular attention should be paid to monitoring renal function prior to and during cidofovir therapy in this age group.1 (See Renal Impairment under Dosage and Administration.)

Renal Impairment

Contraindicated in patients with preexisting renal impairment, including serum creatinine >1.5 mg/dL, calculated Clcr ≤55 mL/minute, or urine protein ≥100 mg/dL (equivalent to 2+ or greater).1 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nephrotoxicity; neutropenia; ocular effects (decreased intraocular pressure/ocular hypotony, anterior uveitis/iritis); metabolic acidosis.1

Interactions for Vistide

Nephrotoxic Drugs

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

Specific Drugs

Drug

Interaction

Comments

Probenecid

Decreased renal clearance of cidofovir1

Used to therapeutic advantage to minimize risk of cidofovir-associated nephrotoxicity1

Zidovudine

No evidence of pharmacokinetic interactions with cidofovir;1 concomitant probenecid (used to reduce risk of cidofovir-associated nephrotoxicity) can increase zidovudine concentrations1

Temporarily discontinue zidovudine or decrease zidovudine dosage by 50% during cidofovir and concomitant probenecid therapy1

Vistide Pharmacokinetics

Absorption

Bioavailability

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

Distribution

Extent

Undetectable concentrations in CSF following IV administration.1

Not known whether distributed into milk.1

Plasma Protein Binding

<6%.1

Elimination

Metabolism

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

Elimination Route

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

Removed by hemodialysis.1

Stability

Storage

Parenteral

Concentrate for IV Infusion

20–25°C.1

Diluted solutions of cidofovir should be administered within 24 hours of preparation.1

If diluted solutions are prepared in advance, they may be refrigerated at 2–8°C but should be administered within 24 hours of preparation;1 30 the solutions should be allowed to reach room temperature before administration.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Compatibility with Ringer’s, lactated Ringer’s, or bacteriostatic infusion fluids has not been established.1

Solution Compatibilitya

Compatible

Dextrose 5% in sodium chloride 0.45%

Dextrose 5% in water

Sodium chloride 0.9%

Actions and Spectrum

  • Cidofovir is converted via cellular enzymes to the pharmacologically active diphosphate metabolite, which has in vitro and in vivo antiviral activity.1 2 3 5 7 11 12 13 15 16 18 24

  • Cidofovir diphosphate interferes with viral DNA synthesis and inhibits viral replication10 11 12 13 25 by competitive inhibition of viral DNA polymerase6 14 16 and incorporation and termination of the growing viral DNA chain.1 3 The inhibitory activity of cidofovir diphosphate is highly selective1 9 10 11 12 20 because of its greater affinity for viral DNA polymerases5 than for human DNA polymerases.1 3

  • Active against various Herpesviridae, including cytomegalovirus (CMV), herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV).1 3 16 24 33 Also active in vitro against adenovirus,3 16 24 human papillomavirus (HPV),3 24 33 and human polyomavirus.1 2 3 7 11 13 15 16 18 24 30 34

  • Has in vitro activity against poxviruses, including vaccinia virus (cowpox), monkeypox, and variola virus (the causative agent of smallpox).45 46 47 53 57 65 67 68 Also has in vivo activity against monkeypox in animal models53 65 66 67 68 and against vaccinia virus in mice.47 48 53 54 55 56

  • May be active against some ganciclovir-resistant CMV2 9 27 and some acyclovir-resistant HSV.2 18

  • CMV resistant to cidofovir can be selected in vitro.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

  • Advise HIV-infected patients receiving zidovudine to temporarily discontinue zidovudine or decrease the zidovudine dose by 50% on days cidofovir is administered.1

  • The major toxicity of cidofovir is renal impairment; dosage adjustments or discontinuance may be required.1 Importance of closely monitoring renal function (routine urinalysis, serum creatinine) during cidofovir therapy.1

  • Importance of maintaining adequate hydration and taking concomitant probenecid to minimize risk of renal impairment.1

  • Advise patients that cidofovir causes tumors (principally mammary adenocarcinomas) in animals and should be considered a potential carcinogen in humans.1

  • Advise women that only limited numbers of women were enrolled in clinical trials evaluating cidofovir.1

  • Advise patients that cidofovir caused reduced testes weight and hypospermia in animals; such changes may occur in humans and cause infertility.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Advise women of childbearing potential to use effective contraception during and for 1 month after cidofovir therapy. Men should be advised to practice barrier contraceptive methods during and for 3 months after cidofovir treatment.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

For treatment of smallpox vaccine complications, cidofovir will be distributed through the Strategic National Stockpile (formerly National Pharmaceutical Stockpile [NPS]).62 Clinicians should contact CDC Smallpox Vaccine Adverse Events Clinical Information Line at 877-554-4625 to coordinate shipment from NPS.62 Cidofovir should be expected to arrive within 12 hours of approval for release.62

Cidofovir

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, concentrate, for IV infusion only

75 mg (of anhydrous cidofovir) per mL

Vistide

Gilead

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Vistide 75MG/ML Solution (GILEAD SCIENCES): 5/$855.94 or 15/$2,397.60

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Gilead Sciences. Vistide (cidofovir) injection prescribing information. Foster City, CA; 2000 Sept.

2. Flaherty JF. Current and experimental therapeutic options for cytomegalovirus disease. Am J Health-Syst Pharm. 1996; 53(Suppl 2):S4-11.

3. Hitchcock MJM, Jaffe HS, Martin JC et al. Cidofovir, a new agent with potent anti-herpesvirus activity. Antivir Chem Chemother. 1996; 7:115-27.

4. Cundy KC, Petty BG, Flaherty J et al. Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 1995; 39:1247- 52. [IDIS 348683] [PubMed 7574510]

5. Cherrington JM, Miner R, Hitchcock MJM et al. Susceptibility of human cytomegalovirus to cidofovir is unchanged after limited in vivo exposure to various clinical regimens of drug. J Infect Dis. 1996; 173:987-92. [IDIS 362104] [PubMed 8603981]

6. Kirsch LS, Arevalo JF, Chavez de la Paz E et al. Intravitreal cidofovir (HPMPC) treatment of cytomegalovirus retinitis in patients with acquired immune deficiency syndrome. Ophthalmology. 1995; 102:533-43. [IDIS 345783] [PubMed 7724170]

7. Polis MA, Spooner KM, Baird BF et al. Anticytomegaloviral activity and safety of cidofovir in patients with human immunodeficiency virus infection and cytomegalovirus viruria. Antimicrob Agents Chemother. 1995; 39:882-6. [IDIS 345410] [PubMed 7785989]

8. Minckler D. Intravitreal cidofovir (HPMPC) treatment of cytomegalovirus retinitis in patients with acquired immune deficiency syndrome. Ophthalmology. 1995; 253:702.

9. Flores-Aguilar M, Huang J-S, Wiley CA et al. Long-acting therapy of viral retinitis with (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine. J Infect Dis. 1994; 169:642-7. [PubMed 8158041]

10. Neyts J, Snoeck R, Schols D et al. Selective inhibition of human cytomegalovirus DNA synthesis by (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine [(S)-HPMPC] and 9-(1,3- dihydroxy-2-propoxymethyl)guanine (DHPG). Virology. 1990; 179:41-50. [PubMed 2171213]

11. Neyts J, Snoeck R, Balzarini J et al. Particular characteristics of the anti-human cytomegalovirus activity of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) in vitro. Antivir Res. 1991; 16:41-52. [PubMed 1663729]

12. Snoeck R, Sakuma T, De Clercq E et al. (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, a potent and selective inhibitor of human cytomegalovirus replication. Antimicrob Agents Chemother. 1988; 32:1839-44. [PubMed 2854454]

13. Bronson JJ, Ghazzouli I, Hitchcock MJM et al. Synthesis and antiviral activity of the nucleotide analogue (S)-1-[3-hydroxy-2-(phosphonylmethoxy) propyl]cytosine. J Med Chem. 1989; 32:1457-63. [PubMed 2544723]

14. De Castro LM, Kern ER, De Clercq E et al. Phosphonylmethoxyalkyl purine and pyrimidine derivatives for the treatment of opportunistic cytomegalovirus and herpes simplex virus infections in murine AIDS. Antivir Res. 1991; 16:101-14. [PubMed 1663726]

15. De Clercq E, Sakuma T, Baba M et al. Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antivir Res. 1987; 8:261-72. [PubMed 3451698]

16. Ho H-T, Woods KL, Bronson JJ et al. Intracellular metabolism of the antiherpes agent (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine. Mol Pharmacol. 1991; 41:197- 202.

17. Polis MA, Masur H. Promising new treatments for cytomegalovirus retinitis. JAMA. 1995; 273:1457-59. [IDIS 346437] [PubMed 7723160]

18. Lalezari JP, Drew WL, Glutzer E et al. (S)-1-[3-hydroxy-2- (phosphonylmethoxy)propyl]cytosine (cidofovir): results of a phase I/II study of a novel antiviral nucleotide analogue. J Infect Dis. 1995; 171:788-96. [IDIS 346945] [PubMed 7706804]

20. Kirsch LS, Arevalo JF, De Clercq E et al. Phase I/II study of intravitreal cidofovir for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol. 1995; 119:466-76. [IDIS 345787] [PubMed 7709971]

21. Lalezari J, Stagg R, Kuppermann B et al. A phase II/III randomized study of immediate versus deferred intravenous (IV) cidofovir (CDV, HPMPC) for AIDS patients with peripheral CMV retinitis (CMV-R). Paper presented at International Conference on Ocular Infections. Jerusalem, Israel: 1995 June 18.

23. Lalezari J, Holland G, Stagg R et al. A randomized, controlled study of cidofovir (CDV) for relapsing cytomegalovirus retinitis (CMV-R) in patients with AIDS. Proceedings of ICAAC San Francisco 1995.

24. National Institutes of Health. Conference: advances in the management of AIDS- related cytomegalovirus retinitis. Ann Intern Med. 1996; 125:126-36. [IDIS 367652] [PubMed 8678367]

25. Jabs DA. Treatment of cytomegalovirus retinitis in patients with AIDS. Ann Intern Med. 1996; 125:144-5. [IDIS 367654] [PubMed 8678370]

26. Rahhal FM, Arevalo JF, Chavez de la Paz E et al. Treatment of cytomegalovirus retinitis with intravitreous cidofovir in patients with AIDS. Ann Intern Med. 1996; 125:98-103. [IDIS 367650] [PubMed 8678386]

27. Cantrill HL. Intravitreal cidofovir (HPMPC) treatment of cytomegalovirus retinitis in patients with acquired immune deficiency syndrome. Ophthalmology. 1995; 102:542.

28. Yuan LC, Samuels GJ, Visor GC. Stability of cidofovir in 9% sodium chloride injection and in 5% dextrose injection. Am J Health-Syst Pharm. 1996; 53:1939-43. [IDIS 370777] [PubMed 8862207]

29. Jaffe HS. Dear healthcare provider letter: reports of severe renal impairment. Foster City, CA: Gilead Sciences; 1996 Sept.

30. Gilead Sciences, Foster City, CA: Personal communication.

31. Lalezari JP, Holland GN, Kramer F et al. Randomized, controlled study of the safety and efficacy of intravenous cidofovir for the treatment of relapsing cytomegalovirus retinitis in patients with AIDS. J Acquir Immune Defic Syndr Hum Retrovirol. 1998; 17:339-44. [PubMed 9525435]

32. Kuppermann B, Lalezari JP, Holland GN for the Cidofovir CMV Retinitis Study Group. A randomized, controlled study of intravenous cidofovir (CDV) for treatment of relapsing CMV retinitis: final results. Paper to be presented at 1997 ARVO Conference. Abstract.

33. Alrabiah FA, Sacks SL. New antiherpesvirus agents. Drugs. 1996; 52:17-32. [PubMed 8799682]

34. Adrei G, Snoeck R, Vandeputte M et al. Activities of various compounds against murine and primate polyomaviruses. Antimicrob Agents Chemother. 1997; 41:587-93. [PubMed 9055998]

35. Safrin SF. Dear health care professional. Reinforcement of guidelines to prevent nephrotoxicity with vistide use, and reports of uveitis/iritis, hearing loss. Foster City, CA: Gilead Sciences; 1998 Aug.

36. Palau LA, Tufty GT, Pankey GA. Recurrent iritis after intravenous administration of cidofovir. Clin Infect Dis. 1997; 25:337-8. [IDIS 392223] [PubMed 9332544]

37. Whitley RS, Jacobson MA, Friedberg DN et al. Guidelines for the treatment of cytomegalovirus diseases in patients with AIDS in the era of potent antiretroviral therapy - recommendations of an international panel. Arch Intern Med. 1998; 158:957-69. [IDIS 406378] [PubMed 9588429]

38. 2001 USPHS/IDSA Guidelines for the prevention of opportunistic infections in persons with human immunodeficiency virus: US Public Health Service (USPHS) and Infectious Disease Society of America (IDSA). Nov 28, 2001. From the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website ()

39. LoPresti AE, Levine JF, Munk GB et al. Successful treatment of an acyclovir- and foscarnet-resistant herpes simplex virus type 1 lesion with intravenous cidofovir. Clin Infect Dis. 1998; 26:512-3. [IDIS 401298] [PubMed 9502489]

40. Martinez CM, Luks-Golger DB. Cidofovir use in acyclovir-resistant herpes infection. Ann Pharmacother. 1997; 31:1519-21. [IDIS 396982] [PubMed 9416391]

41. Jayasekara D, Aweeka FT, Rodriguez R et al. Antiviral therapy for HIV patients with renal insufficiency. J Acquir Immune Defic Syndr. 1999; 21:384-95. [IDIS 433126] [PubMed 10458619]

42. Balfour HH. Antiviral drugs. N Engl J Med. 1999; 340:1255-68. [IDIS 423356] [PubMed 10210711]

43. Lalezari J, Schacker T, Feinberg J et al. A randomized, double-blind, placebo-controlled trial of cidofovir gel for the treatment of acyclovir-unresponsive mucocutaneous herpes simplex virus infection in patients with AIDS. J Infect Dis. 1997; 176:892-8. [IDIS 394084] [PubMed 9333146]

44. Martin DF, Dunn JP, Davis JL et al. Use of the ganciclovir implant for the treatment of cytomegalovirus retinitis in the era of potent antiretroviral therapy: recommendations of the International AIDS Society-USA Panel. Am J Ophthalmol. 1999; 127:329-39. [IDIS 425111] [PubMed 10088745]

45. LeDuc JW, Jahrling PB. Strengthening national preparedness for smallpox: an update. Emerg Infect Dis. 2001; 7:155-7. [PubMed 11266310]

46. World Health Organization. Smallpox eradication: temporary retention of variola stocks. Report of the secretariat. Fifty-fourth world health assembly A54/16, 2001 April.

47. DeClerq E. Vaccinia virus inhibitors as a paradigm for the chemotherapy of poxvirus infection. Clin Microbiol Rev. 2001; 14:382-97. [PubMed 11292644]

48. Smee DF, Bailey KW, Wong M et al. Intranasal treatment of cowpox virus infections in mice with cidofovir. Antiviral Res. 2000; 47:171-7. [PubMed 10974369]

49. Centers for Disease Control and Prevention. Vaccinia (smallpox) vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. MMWR Recomm Rep. 2001; 50(RR-10):1-25.

50. Henderson DA, Inglesby TV, Bartlett JG et al for the Working Group on Civilian Biodefense. Smallpox as a biological weapon: medical and public health management. JAMA. 1999; 281:2427-37.

51. US Army Medical Research Institute of Infectious Disease. USAMRIID’s medical management of biologic casualties handbook. 4th ed. USAMRIID: Fort Detrick, MD; 2001 Feb.

52. Anon. Drugs for non-HIV viral infections. Med Lett Drugs Ther. 2002; 44:9-16. [PubMed 11828264]

53. De Clercq E. Cidofovir in the treatment of poxvirus infections. Antiviral Res. 2002; 55:1-13. [PubMed 12076747]

54. Bray M, Martinez M, Smee DF et al. Cidofovir protects mice against lethal aerosol or intranasal cowpox virus challenge. J Infect Dis. 2000; 181:10-9. [PubMed 10608745]

55. Smee DF, Bailey KW, Sidwell RW. Treatment of lethal vaccinia virus respiratory infections in mice with cidofovir. Antiviral Chem Chemother. 2001; 12:71-6.

56. Bray M, Martinez M, Kefauver D et al. Treatment of aerosolized cowpox virus infection in mice with aerosolized cidofovir. Antiviral Res. 2002; 54:129-42. [PubMed 12062386]

57. Snoeck R, Holy A, Dewolf-Peeters C et al. Antivaccinia activities of acyclic nucleoside phosphonate derivatives in epithelial cells and organotypic cultures. Antimicrob Agents Chemother. 2002; 46:3356-61. [PubMed 12384336]

58. Centers for Disease Control and Prevention. Smallpox vaccination clinic guide (annex 3). Atlanta, GA; 2002 Sept 23. From the CDC website ().

59. De Clercq E. Vaccinia virus inhibitors as a paradigm for the chemotherapy of poxvirus infection. Clin Microbiol Rev. 2001; 14:382-97. [PubMed 11292644]

60. Smee DF, Bailey KW, Wong M et al. Intranasal treatment of cowpox virus infections in mice with cidofovir. Antiviral Res. 2000; 47:171-7. [PubMed 10974369]

61. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep. 2006; 55(RR-11):1-95.

62. Centers for Disease Control and Prevention. Medical management of smallpox (vaccinia) vaccine adverse reactions: vaccinia immune globulin and cidofovir. From the CDC website (). Accessed 9 Apr 2003.

63. Centers for Disease Control and Prevention. Smallpox vaccination and adverse reactions: guidance for clinicians. MMWR Recomm Rep. 2003; 52(RR-4):1-28.

64. Smee DF, Bailey KW, Wong MH et al. Effects of cidofovir on the pathogenesis of a lethal vaccinia virus respiratory infection in mice. Antiviral Res. 2001; 52:55-62. [PubMed 11530188]

65. Centers for Disease Control and Prevention. Updated interim CDC guidance for use of smallpox vaccine, cidofovir, and vaccinia immune globulin (VIG) for prevention and treatment in the setting of an outbreak of monkeypox infections. 2003 Jun 25. From the CDC web site (). Accessed 2003 Sep 8.

66. Smee DF, Sidwell RW. A review of compounds exhibiting anti-orthopoxvirus activity in animal models. Antiviral Res. 2003; 57:41-52. [PubMed 12615302]

67. Huggins JW, Smee D, Martinez MJ et al. Cidofovir (HPMPC) treatment of monkeypox. Antiviral Res. 1998; 37:A73.

68. Baker RO, Bray M, Huggins JW. Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus infections. Antiviral Res. 2003; 57:13-23. [PubMed 12615299]

69. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Recomm Rep. 2004; 53(RR-15):1-112.

a. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:371-2.

Hide
(web1)