Renal impairment is the major toxicity of cidofovir. Cases of acute renal failure resulting in dialysis and/or contributing to death have occurred with as few as 1 or 2 doses of cidofovir. To reduce possible nephrotoxicity, IV prehydration with normal saline and administration of probenecid must be used with each cidofovir infusion. Renal function (serum creatinine and urine protein) must be monitored within 48 hours prior to each dose of cidofovir and the dose of cidofovir modified for changes in renal function as appropriate. Cidofovir is contraindicated in patients who are receiving other nephrotoxic agents.
Neutropenia has been observed in association with cidofovir treatment. Therefore, neutrophil counts should be monitored during cidofovir therapy.
Cidofovir is indicated only for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS).
In animal studies, cidofovir was carcinogenic, teratogenic and caused hypospermia.
Note: To minimize the likelihood of nephrotoxicity, unless otherwise indicated, premedicate with probenecid 2 g 3 hours prior to the cidofovir dose, then 1 g 2 hours and 8 hours after completion of the infusion. Patients should also receive 1 L of NS IV infused over 1 to 2 hours immediately prior to each cidofovir infusion. If tolerated, a second liter may be administered over 1 to 3 hours at the start of cidofovir infusion or immediately following infusion.
Adenovirus infection (treatment of disseminated, severe, or progressive disease [adjunctive agent] or preemptive therapy in hematopoietic cell transplant recipients ) (off-label use): IV: 5 mg/kg/dose once weekly or 5 mg/kg once weekly for 2 doses then 5 mg/kg once every 2 weeks or 1 mg/kg/dose 3 times weekly; with concomitant probenecid (ASBMT [Tomblyn 2009]; AST-IDCOP [Florescu 2019]; González-Vicent 2019; Lindemans 2010; Permpalung 2018).
BK virus infection (adjunctive agent) (off-label use):
Hemorrhagic cystitis, hematopoietic cell transplant recipients: Limited data available:
IV: 3 to 5 mg/kg/dose every 1 to 2 weeks with concomitant probenecid or 0.5 to 1.5 mg/kg/dose 1 to 3 times weekly without probenecid (Cesaro 2018; Coomes 2018; Schneidewind 2018).
Intravesicular: 5 mg/kg/dose (in 60 mL NS) instilled into bladder once weekly; retain for ≥1 hour (Coomes 2018; Schneidewind 2018; Tooker 2020).
Viremia or nephropathy, kidney transplant recipients: Limited data available: IV: 0.25 to 1 mg/kg/dose every 1 to 3 weeks without probenecid (AST-IDCOP [Hirsch 2019]; Keller 2003; Kuypers 2005; Vats 2003).
Cytomegalovirus (eg, treatment of invasive disease including retinitis and preemptive therapy in hematopoietic cell recipients) (alternative agent): IV:
Induction: 5 mg/kg/dose once weekly for 2 consecutive weeks, with concomitant probenecid (ASBMT [Tomblyn 2009]; AST-IDCOP [Razonable 2019]; HHS [OI adult 2021]; manufacturer's labeling).
Maintenance: 5 mg/kg/dose once every 2 weeks with concomitant probenecid (ASBMT [Tomblyn 2009]; AST-IDCOP [Razonable 2019]; HHS [OI adult 2021]; manufacturer's labeling).
Herpes simplex virus infection, acyclovir-resistant (off-label use):
IV: Mucosal infections: 5 mg/kg/dose once weekly for 3 weeks (Andrei 2007; Chen 2000; LoPresti 1998), then 5 mg/kg/dose once every 2 weeks for 3 doses (Andrei 2007); with concomitant probenecid (LoPresti 1998).
Topical (off-label route): Mucocutaneous infections: Apply cidofovir 1% gel (extemporaneously prepared by a compounding pharmacy) once daily (HHS [OI adult 2021]; Lalezari 1997; Lingappa 2007). Duration of therapy: 5 days; observe for 10 days following treatment; therapy may be repeated if necessary for up to 6 repetitive cycles (Lalezari 1997; Lingappa 2007). A prolonged duration of 21 to 28 days or longer may be required for patients with HIV (HHS [OI adult 2021]).
Manufacturer's labeling:
Renal function may be estimated using the Cockcroft-Gault formula for dosage adjustment purposes.
Preexisting renal impairment: Serum creatinine >1.5 mg/dL, CrCl ≤55 mL/minute, or urine protein ≥100 mg/dL (≥2+ proteinuria): Use is contraindicated.
Changes in renal function during therapy:
Serum creatinine increases by 0.3 to 0.4 mg/dL: Reduce dose to 3 mg/kg.
Serum creatinine increases ≥0.5 mg/dL or development of ≥3+ proteinuria: Discontinue therapy.
Alternate dosing (Brody 1999):
Note: Given significant risk of nephrotoxicity, avoid use in renal impairment (CrCl ≤55 mL/minute) unless benefit outweighs the risk. Renal function may be estimated using the Cockcroft-Gault formula for dosage adjustment purposes. Adjustment based on 5 mg/kg/dose. Induction doses should be given once weekly and maintenance doses every other week.
CrCl ≥1.3 mL/minute/kg: 5 mg/kg/dose with concomitant probenecid.
CrCl 1 to 1.2 mL/minute/kg: 4 mg/kg/dose with concomitant probenecid.
CrCl 0.8 to 0.9 mL/minute/kg: 3 mg/kg/dose with concomitant probenecid.
CrCl 0.7 mL/minute/kg: 2.5 mg/kg/dose with concomitant probenecid.
CrCl 0.5 to 0.6 mL/minute/kg: 2 mg/kg/dose with concomitant probenecid.
CrCl 0.4 mL/minute/kg: 1.5 mg/kg/dose with concomitant probenecid.
CrCl 0.2 to 0.3 mL/minute/kg: 1 mg/kg/dose with concomitant probenecid.
CrCl 0.1 mL/minute/kg: 0.5 mg/kg/dose with concomitant probenecid.
Hemodialysis: Dialyzable (~50%): Administer standard induction or maintenance dose 2 hours before hemodialysis without probenecid.
Peritoneal dialysis: Dialyzable (minimal): 0.5 mg/kg/dose without probenecid.
There are no dosage adjustments provided in the manufacturer’s labeling.
(For additional information see "Cidofovir: Pediatric drug information")
Note: Administration of cidofovir should be accompanied by concomitant oral probenecid and intravenous normal saline hydration; various regimens have been reported (Anderson 2008; Bhadri 2009; Cesaro 2005; Doan 2007; Williams 2009; Yusuf 2006)
Hydration: IV: 20 mL/kg of 0.9% sodium chloride (maximum: 1,000 mL) administered for 1 hour before cidofovir infusion and 20 mL/kg of 0.9% sodium chloride (maximum: 1,000 mL) over 1 hour during cidofovir infusion, followed by 2 hours of maintenance fluids or increase the maintenance fluid infusion rate to 3 times the maintenance rate for 1 hour before cidofovir infusion and continuing until 1 hour after, then decrease to 2 times the maintenance fluid rate for the subsequent 2 hours
Probenecid: Oral: 25 to 40 mg/kg/dose (maximum dose: 2,000 mg) administered 3 hours before cidofovir infusion and 10 to 20 mg/kg/dose (maximum dose: 1,000 mg) at 2 to 3 hours and 8 to 9 hours after cidofovir infusion or 1,000 or 1,250 mg/m2/dose administered 3 hours prior to cidofovir, followed by 500 to 1,250 mg/m2/dose 1 to 2 hours and 8 hours after completion
Adenovirus infection, posthematopoietic stem cell transplant; treatment: Limited data available; optimal dose not defined; specific regimens may vary (Bhadri 2009; Legrand 2001; Yusuf 2006): Infants, Children, and Adolescents:
Induction: IV: 5 mg/kg/dose once weekly for 2 to 3 consecutive weeks (with hydration and probenecid)
Maintenance: IV: 5 mg/kg/dose once every 2 weeks or 3 mg/kg/dose once weekly (with hydration and probenecid) until consecutive negative adenovirus samples. Note: In one study, patients requiring prolonged treatment courses were switched from 3 mg/kg/dose once weekly to 1 mg/kg/dose given 3 times/week (Bhadri 2009)
Adenovirus infection, postlung transplant; treatment: Very limited data available: Infants ≥6 months and Children <3 years: IV: 1 mg/kg/dose every other day or 3 times weekly for 4 consecutive weeks (with hydration and probenecid); dosing from a case series (n=4, age range: 0.5 to 2.6 years) (Doan 2007)
BK virus allograft nephropathy: Limited data available: Children and Adolescents: IV: Initial dose: 0.25 mg/kg/dose every 2 to 3 weeks; dose may be increased if BK virus PCR counts do not decrease 1 log fold to a maximum dose of 1 mg/kg/dose. Dosing based on reported experience from two case series of 10 renal transplant patients (ages: 5 to 21 years). The reported hydration was D51/2NS or D51/4NS for 2 hours before cidofovir and for 2 hours following the infusion; cidofovir was infused over 2 hours and no probenecid was used (Araya 2008; Araya 2010).
BK virus hemorrhagic cystitis after stem cell or bone marrow transplant: Limited data available; optimal dose not established: Children and Adolescents: IV: 5 mg/kg/dose once weekly for 2 to 4 weeks, followed by 5 mg/kg/dose every other week given with probenecid and adequate hydration until cystitis resolved is the most commonly reported dose (Cesaro 2009, Gaziev 2010, Megged 2011). Others have described lower doses of 0.5 to 1 mg/kg/dose given once weekly with or without probenecid (Cesaro 2009; Cesaro 2013; Faraci 2009).
Cytomegalovirus (CMV) infection: Limited data available. IV:
Allogeneic stem cell transplantation recipients: Treatment: Children and Adolescents: Dosing based on reported experience in 10 pediatric patients (2 to 14 years); most patients received cidofovir as second-line therapy following allogeneic stem cell transplantation (Cesaro 2005).
Induction: 5 mg/kg/dose once weekly for 2 consecutive weeks (with hydration, probenecid and antiemetic)
Maintenance: 3 to 5 mg/kg/dose once every 2 weeks for 2 to 4 doses (with hydration, probenecid, and antiemetic)
HIV-exposed/-infected patients:
CMV retinitis: Treatment: Adolescents [DHHS (adult) 2013]:
Induction: 5 mg/kg/dose once weekly for 2 consecutive weeks (with hydration and probenecid)
Maintenance: 5 mg/kg/dose every other week (with hydration and probenecid)
Secondary prophylaxis: 5 mg/kg/dose every other week (with hydration and probenecid) [DHHS (adult/pediatric) 2013]
Respiratory papillomatosis, recurrent: Limited data available: Children and Adolescents: Intralesional: 7.5 mg/mL every 2 weeks until complete remission (Naiman 2006)
Adenovirus posttransplant (Yusuf 2006): Infants ≥6 months, Children, and Adolescents: Scr >1.5 mg/dL, CrCl <90 mL/ minute/1.73 m2, and >2+ proteinuria:
Induction: IV: 1 mg/kg/dose 3 times weekly on alternate days for 2 consecutive weeks
Maintenance: IV: 1 mg/kg/dose every other week
Other uses: Infants, Children and Adolescents: There are no pediatric-specific recommendations for all uses; based on experience in adult patients, dosing adjustment suggested.
High flux hemodialysis removes ~75%
There are no dosage adjustments provided in the manufacturer's labeling.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous [preservative free]:
Generic: 75 mg/mL (5 mL)
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Generic: 75 mg/mL (5 mL)
IV: For IV infusion only. Infuse over 1 hour. Administer with concomitant probenecid. Hydrate with 1 L of NS IV over 1 to 2 hours immediately prior to cidofovir infusion. If tolerated, a second liter may be administered over a 1- to 3-hour period at the start of or immediately following cidofovir infusion.
Topical: Off-label route: An extemporaneously prepared gel may be prepared by a compounding pharmacy and applied topically for mucocutaneous infections (McElhiney 2006).
Intravesicular: Off-label route: Instill into bladder via Foley catheter over 15 minutes. If indwelling catheter is in place, clamp catheter for at least 1 hour after instillation. Remove Foley catheter after drug administration for patients who do not require indwelling catheter (Bridges 2006; Rao 2009; Tooker 2020).
Parenteral: Administer by IV infusion over 1 hour.
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.
NIOSH recommends double gloving, a protective gown, ventilated engineering controls (a class II biological safety cabinet or a compounding aseptic containment isolator), and closed system transfer devices (CSTDs) for preparation. Double gloving, a gown, and (if dosage form allows) CSTDs are required during administration (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
Cytomegalovirus retinitis: Treatment of cytomegalovirus (CMV) retinitis in patients with AIDS.
Limitations of use: Safety and efficacy have not been established for treatment of other CMV infections (eg, pneumonitis, gastroenteritis), congenital or neonatal CMV disease, or CMV disease in non-HIV infected individuals.
Adenovirus infection; BK virus infection; Cytomegalovirus, preemptive therapy in hematopoietic cell recipients; Herpes simplex virus infection, acyclovir-resistant
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Endocrine & metabolic: Decreased serum bicarbonate
Genitourinary: Proteinuria
Hematologic & oncologic: Neutropenia
Infection: Infection
Ophthalmic: Hypotony of eye (can be severe: Intraocular pressure of 0 to 1 mm Hg), iritis, uveitis
Renal: Decreased creatinine clearance, increased serum creatinine, nephrotoxicity
Miscellaneous: Fever
1% to 10%:
Endocrine & metabolic: Fanconi syndrome
Gastrointestinal: Nausea, vomiting
Respiratory: Dyspnea, pneumonia
Frequency not defined:
Renal: Acute kidney injury
Postmarketing:
Endocrine & metabolic: Metabolic acidosis
Gastrointestinal: Pancreatitis
Hepatic: Hepatic insufficiency
Hypersensitivity to cidofovir or any component of the formulation; history of clinically-severe hypersensitivity to probenecid or other sulfa-containing medications; serum creatinine >1.5 mg/dL; CrCl ≤55 mL/minute; urine protein ≥100 mg/dL (≥2+ proteinuria); use with or within 7 days of nephrotoxic agents; direct intraocular injection
Concerns related to adverse effects:
• Carcinogenic/teratogenic: [US Boxed Warning]: Possibly carcinogenic and teratogenic based on animal data. May cause hypospermia.
• Metabolic acidosis: Monitor for signs of metabolic acidosis; decreased sodium bicarbonate with proximal tubule injury and renal wasting syndrome (including Fanconi syndrome), as well as metabolic acidosis with hepatic impairment and pancreatitis (including some fatal cases) have been reported.
• Nephrotoxicity: [US Boxed Warning]: Acute renal failure resulting in dialysis and/or contributing to death has occurred with as few as 1 or 2 doses of cidofovir. Renal function (serum creatinine and urine protein) must be monitored within 48 hours prior to each dose of cidofovir and the dose of cidofovir modified as appropriate. Administration must be accompanied by oral probenecid and intravenous saline prehydration.
• Neutropenia: [US Boxed Warning]: Neutropenia has been reported; monitor neutrophil counts during therapy.
• Ocular complications: Decreased intraocular pressure, sometimes associated with decreased visual acuity, uveitis, or iritis may occur; monitor intraocular pressure for and signs of iritis/uveitis during therapy. If uveitis or iritis occurs, consider treatment with topical corticosteroids with or without topical cycloplegic agents.
Disease-related concerns:
• Renal impairment: Contraindicated in patients with a baseline serum creatinine >1.5 mg/dL, CrCl ≤55 mL/minute, or urine protein ≥100 mg/dL (≥2+ proteinuria); dosage adjustment or discontinuation of therapy may be required for changes in renal function during treatment.
Other warnings/precautions:
• Administration: For intravenous use only, not for direct intraocular injection; iritis, ocular hypotony, and permanent impairment of vision may occur.
• Appropriate use: [US Boxed Warning]: Indicated only for CMV retinitis treatment in patients with AIDS.
Administration in children warrants extreme caution due to risk of long-term carcinogenicity and reproductive toxicity. A case of invasive squamous cell cancer has been reported in a pediatric patient receiving intralesional cidofovir for severe, recurrent respiratory papillomatosis; causality not established (Lott 2009).
Inhibits MRP2
Cabozantinib: MRP2 Inhibitors may increase the serum concentration of Cabozantinib. Risk C: Monitor therapy
Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Risk X: Avoid combination
Tenofovir Products: Cidofovir may increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Cidofovir. Risk C: Monitor therapy
[US Boxed Warning]: In animal studies, cidofovir caused hypospermia.
Women of childbearing potential should use effective contraception during therapy and for 1 month following treatment. Males should use a barrier contraceptive during therapy and for 3 months following treatment.
[US Boxed Warning]: In animal studies, cidofovir was teratogenic.
The indications for treating CMV retinitis during pregnancy are the same as in nonpregnant HIV infected woman; however, systemic therapy should be avoided during the first trimester when possible. When therapy is needed to treat maternal infection, use of cidofovir is not recommended (HHS [Adult OI 2021]).
It is not known if cidofovir is present in breast milk.
Due to the potential for serious adverse reactions in the breastfeeding infant, breastfeeding is not recommended. In addition, HIV-infected mothers are discouraged from breastfeeding to decrease the potential transmission of HIV.
Serum creatinine and urine protein (at baseline and within 48 hours of each dose), WBC with differential (prior to each dose); intraocular pressure and visual acuity, signs and symptoms of uveitis/iritis; metabolic acidosis.
Cidofovir is converted to cidofovir diphosphate (the active intracellular metabolite); cidofovir diphosphate suppresses CMV replication by selective inhibition of viral DNA synthesis. Incorporation of cidofovir diphosphate into growing viral DNA chain results in viral DNA synthesis rate reduction.
The following pharmacokinetic data are based on a combination of cidofovir administered with probenecid:
Distribution: Vd: 0.41 L/kg; does not cross significantly into CSF
Protein binding: <6%
Metabolism: Minimal; phosphorylation occurs intracellularly to the active metabolite cidofovir diphosphate
Half-life elimination, plasma: ~2.6 hours; intracellular elimination half-lives of metabolites are longer (range: 24 to 87 hours) (Lea 1996)
Excretion: Urine (70% to 85% as unchanged drug)
Clearance:
Renal clearance without probenecid: 150 ± 26.9 mL/minute/1.73 m2
Renal clearance with probenecid: 98.6 ± 27.9 mL/minute/1.73 m2
Renal function impairment: Clearance decreases proportionally with CrCl.
Solution (Cidofovir Intravenous)
75 mg/mL (per mL): $177.60 - $237.29
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