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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.

Solution, Intravenous:

Vistide: 75 mg/mL (5 mL)

Solution, Intravenous [preservative free]:

Generic: 75 mg/mL (5 mL)

Brand Names: U.S.

  • Vistide

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

Dosage

Cytomegalovirus (CMV) retinitis: Adults: 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.

Dosage adjustment in 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.

Dosage adjustment in 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.

Administration

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.

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 may be stored for ≤24 hours under refrigeration; however, admixtures must be administered within 24 hours of preparation.

Drug Interactions

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

Adverse Reactions

>10%:

Central nervous system: Chills, fever, headache, pain

Dermatologic: Alopecia, rash

Gastrointestinal: Nausea, vomiting, diarrhea, anorexia

Hematologic: Anemia, neutropenia

Neuromuscular & skeletal: Weakness

Ocular: Intraocular pressure decreased, iritis, ocular hypotony, uveitis

Renal: Creatinine increased, proteinuria, renal toxicity

Respiratory: Cough, dyspnea

Miscellaneous: Infection, oral moniliasis, serum bicarbonate decreased

1% to 10%:

Renal: Fanconi syndrome

Respiratory: Pneumonia

<1%: Hepatic failure, metabolic acidosis, pancreatitis

Frequency not defined (limited to important or life-threatening reactions):

Cardiovascular: Cardiomyopathy, cardiovascular disorder, CHF, edema, orthostatic hypotension, shock, syncope, tachycardia

Central nervous system: Agitation, amnesia, anxiety, confusion, convulsion, dizziness, hallucinations, insomnia, malaise, vertigo

Dermatologic: Photosensitivity reaction, skin discoloration, urticaria

Endocrine & metabolic: Adrenal cortex insufficiency

Gastrointestinal: Abdominal pain, aphthous stomatitis, colitis, constipation, dysphagia, fecal incontinence, gastritis, GI hemorrhage, gingivitis, melena, proctitis, splenomegaly, stomatitis, tongue discoloration

Genitourinary: Urinary incontinence

Hematologic: Hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, lymphoma-like reaction, pancytopenia, thrombocytopenia, thrombocytopenic purpura

Hepatic: Hepatomegaly, hepatosplenomegaly, jaundice, liver function tests abnormal, liver damage, liver necrosis

Local: Injection site reaction

Neuromuscular & skeletal: Tremor

Ocular: Amblyopia, blindness, cataract, conjunctivitis, corneal lesion, diplopia, vision abnormal

Otic: Hearing loss

Miscellaneous: Allergic reaction, sepsis

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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