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Cidofovir

Pronunciation

(si DOF o veer)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Solution, Intravenous:

Vistide: 75 mg/mL (5 mL [DSC])

Solution, Intravenous [preservative free]:

Generic: 75 mg/mL (5 mL)

Brand Names: U.S.

  • Vistide [DSC]

Pharmacologic Category

  • Antiviral Agent

Pharmacology

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.

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%

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.

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

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: Renal Impairment

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.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Reconstitution

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Dilute dose in NS 100 mL prior to infusion.

Extemporaneously Prepared

Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

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).

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Compatibility

Stable in D51/4NS, D5W, NS.

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

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 failure, cardiomyopathy, cardiovascular disease, 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% (Limited to important or life-threatening): Hepatic failure, metabolic acidosis, pancreatitis

ALERT: U.S. 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.

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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

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 Risk Factor

C

Pregnancy Considerations

[US Boxed Warning]: Possibly carcinogenic and teratogenic based on animal data. May cause 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.

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]).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, diarrhea, lack of appetite, alopecia, vomiting, cough, or nausea. Have patient report immediately to prescriber signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), illogical thinking, black, tarry, or bloody stools, angina, tachycardia, vision changes, eye pain, eye irritation, depression, hallucinations, change in balance, burning or numbness feeling, seizures, shortness of breath, excessive weight gain, swelling of arm or leg, bloating, tremors, difficulty moving, rigidity, bruising, bleeding, loss of strength and energy, or white patches in mouth (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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