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Cidofovir

Generic name: cidofovir systemic

Brand names: Vistide

Boxed Warning

Nephrotoxicity:

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:

Neutropenia has been observed in association with cidofovir treatment. Therefore, neutrophil counts should be monitored during cidofovir therapy.

Appropriate use:

Cidofovir is indicated only for the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS).

Carcinogenic/teratogenic:

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

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Generic: 75 mg/mL (5 mL)

Pharmacology

Mechanism of Action

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.

Pharmacokinetics/Pharmacodynamics

Distribution

Vd: 0.41 L/kg; does not cross significantly into CSF

Metabolism

Minimal; phosphorylation occurs intracellularly to the active metabolite cidofovir diphosphate

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

Half-Life Elimination

Plasma: ~2.6 hours; intracellular elimination half-lives of metabolites are longer (range: 24 to 87 hours) (Lea, 1996)

Protein Binding

<6%

Use in Specific Populations

Special Populations: Renal Function Impairment

Clearance decreases proportionally with CrCl.

Use: Labeled Indications

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.

Use: Off Label

Herpes simplex virus (HSV) infection, acyclovir-resistant:cyes

Intravenous cidofovir:

Data from case reports in immunocompromised patients (stem cell transplant recipients) suggest that intravenous cidofovir may be effective for acyclovir-resistant HSV type 1 mucosal infections Andrei 2007, Chen 2000, LoPresti 1998. A review article suggested that intravenous cidofovir be reserved for use following treatment failure with intravenous foscarnet due to concerns of cidofovir-associated toxicity Levin 2004. Additional trials may be necessary to further define the role of cidofovir in acyclovir-resistant HSV infections.

Based on the Centers for Disease Control and Prevention (CDC) sexually transmitted diseases treatment guidelines, intravenous cidofovir might be effective as an alternative agent to intravenous foscarnet for the treatment of acyclovir-resistant HSV infections, although limited evidence is available and more studies are needed.

Topical cidofovir:

Data from a small number of immunocompromised AIDS patients in a randomized, double-blind, placebo-controlled trial suggest that topical cidofovir gel (not commercially available in the US) may be beneficial for the treatment of acyclovir-resistant mucocutaneous HSV infections Lalezari 1997. Additional trials may be necessary to further define the role of topical cidofovir in this condition. Review articles suggested that for skin lesions, topical cidofovir may offer the advantage of limiting cidofovir exposure and reduce the potential for cidofovir-associated toxicity and resistance Levin 2004, Lingappa 2007.

Based on the Centers for Disease Control and Prevention (CDC) sexually transmitted diseases treatment guidelines, topical cidofovir 1 % gel might be effective as an alternative agent for the treatment of acyclovir-resistant HSV infections, although limited evidence is available and more studies are needed.

Contraindications

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

Dosage and Administration

Dosing: Adult

Cytomegalovirus (CMV) retinitis: IV:

Induction: 5 mg/kg/dose with concomitant probenecid once weekly for 2 consecutive weeks

Maintenance: 5 mg/kg/dose with concomitant probenecid once every 2 weeks

Concomitant therapy:

Probenecid: 2 g 3 hours prior to cidofovir dose, then 1 g at 2 hours and 8 hours after completion of the infusion.

Hydration: Patients should also receive 1 L of NS intravenously 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.

Herpes simplex virus (HSV) 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). Concomitant oral probenecid and hydration has been used to reduce the risk of cidofovir-associated nephrotoxicity (LoPresti 1998)

Topical (off-label route): Mucocutaneous infections: Apply cidofovir 1% gel (extemporaneously prepared by a compounding pharmacy) once daily for 5 days (CDC [Workowski 2015]; Lalezari 1997; Lingappa 2007). Observe for 10 days following treatment; therapy may be repeated if necessary for up to six repetitive cycles (Lalezari 1997)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

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/-positive 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)

Reconstitution

Dilute dose in NS 100 mL prior to infusion.

Extemporaneously Prepared

A 1% topical cidofovir gel may be prepared by using 5 mL of the 75 mg/mL cidofovir injection and combining with 32.5 mL of a propylene glycol-based jelly. Of note, propylene glycol may increase the absorption and bioavailability of cidofovir when used on abraded skin (McElhiney 2006).

Administration

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).

Storage

Store intact vials at 20°C to 25°C (68°F to 77°F). Admixtures in D51/4NS, D5W, or NS may be stored for ≤24 hours under refrigeration; however, admixtures must be administered within 24 hours of preparation.

Drug Interactions

Cabozantinib: MRP2 Inhibitors may increase the serum concentration of Cabozantinib. Monitor therapy

Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Avoid combination

Tenofovir Products: Cidofovir may increase the serum concentration of Tenofovir Products. Tenofovir Products may increase the serum concentration of Cidofovir. Monitor therapy

Adverse Reactions

Frequency not defined. *Incidence not specifically defined, but reported in the range of >10%. **Incidence not specifically defined, but reported in the range of 1% to 10%.

Cardiovascular: Cardiac disease, cardiac failure, cardiomyopathy, edema, orthostatic hypotension, shock, syncope, tachycardia

Central nervous system: Chills,* headache,* pain,* agitation, amnesia, anxiety, confusion, convulsions, dizziness, hallucination, insomnia, malaise, vertigo

Dermatologic: Alopecia,* skin rash,* skin discoloration, skin photosensitivity, urticaria

Endocrine & metabolic: Decreased serum bicarbonate,* Fanconi’s syndrome,** adrenocortical insufficiency

Gastrointestinal: Anorexia,* diarrhea,* nausea,* oral candidiasis,* vomiting,* abdominal pain, aphthous stomatitis, colitis, constipation, dysphagia, fecal incontinence, gastritis, gastrointestinal hemorrhage, gingivitis, melena, proctitis, stomatitis, tongue discoloration

Genitourinary: Nephrotoxicity,* proteinuria,* urinary incontinence

Hematologic & oncologic: Anemia,* neutropenia,* hypochromic anemia, immune thrombocytopenia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, pseudolymphoma, splenomegaly, thrombocytopenia

Hepatic: Abnormal liver function tests, hepatic disease, hepatic necrosis, hepatomegaly, hepatosplenomegaly, jaundice

Hypersensitivity: Hypersensitivity reaction

Infection: Infection,* sepsis

Local: Injection site reaction

Neuromuscular & skeletal: Weakness,* tremor

Ophthalmic: Decreased intraocular pressure,* iritis,* uveitis,* amblyopia, blindness, cataract, conjunctivitis, corneal lesion, diplopia, visual disturbance

Otic: Hearing loss

Renal: Increased serum creatinine*

Respiratory: Cough,* dyspnea,* pneumonia**

Miscellaneous: Fever*

<1%, postmarketing, and/or case reports: Hepatic failure, metabolic acidosis, pancreatitis

Warnings/Precautions

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.

Monitoring Parameters

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.

Pregnancy

Pregnancy Risk Factor

C

Pregnancy Considerations

[US Boxed Warning]: In animal studies, cidofovir was teratogenic and caused hypospermia.

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, agents other than cidofovir are recommended (DHHS [Adult OI 2014]).

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.

Patient Education

What is this drug used for?

  • It is used to treat a viral infection of the eyes in people who have AIDS.
  • It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

  • Headache
  • Diarrhea
  • Lack of appetite
  • Hair loss
  • Vomiting
  • Nausea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

  • Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain
  • Infection
  • Lactic acidosis like fast breathing, fast heartbeat, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps
  • Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting
  • Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
  • Vision changes
  • Eye pain
  • Severe eye irritation
  • Shortness of breath
  • Severe loss of strength and energy
  • Thrush
  • Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Source: Wolters Kluwer Health. Last updated January 31, 2020.