Summary Of Exposure |
A) USES: Cidofovir is used to treat cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome (AIDS).
B) PHARMACOLOGY: Cidofovir diphosphate, the active intracellular metabolite of cidofovir, suppresses cytomegalovirus (CMV) replication by selectively inhibiting viral DNA polymerase.
C) EPIDEMIOLOGY: Overdose is rare.
D) WITH THERAPEUTIC USE
1) Nephrotoxicity has been the dose-limiting toxicity of cidofovir therapy. Acute renal failure resulting in dialysis and/or death has been reported with as few as 1 or 2 doses of intravenous cidofovir. This complication is minimized by concurrent administration of oral probenecid, prehydration with normal saline, and less frequent dosing of cidofovir. Other adverse effects with cidofovir during therapeutic use have included neutropenia, asthenia, headache, nausea, vomiting, diarrhea, ocular effects (eg, iritis, photophobia, ocular hypotony, anterior uveitis, blurred vision, and intraocular pressure changes), ototoxicity including hearing loss (with and without tinnitus), and in rare cases nephrogenic diabetes insipidus and metabolic acidosis.
E) WITH POISONING/EXPOSURE
1) Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. Two patients received unintentional single doses of cidofovir at 16.3 mg/kg and 17.4 mg/kg and developed no permanent sequelae following supportive care.
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Heent |
3.4.3) EYES
A) WITH THERAPEUTIC USE 1) Following intravitreal administration of cidofovir, reports of local side effects have included iritis, anterior uveitis, a significant decrease in intraocular pressures (IOP), and local infection in the unaffected eye (Akler et al, 1998; Cantrill, 1995) . In addition, Tseng et al (1999) reported 2 cases of iritis occurring following intravenous cidofovir (Tseng et al, 1999). 2) OCULAR HYPOTONY a) Ocular hypotony (>/= 50% decrease from baseline) was reported in 17 of 70 (24%) patients at the 5 mg/kg maintenance dose; severe hypotony (intraocular pressure of 0-1 mm Hg) has occurred in 3 patients (Prod Info VISTIDE(R) IV injection, 2000).
b) Hypotony may occur with either intravenous or intravitreal cidofovir with visual loss possible (Davis et al, 1997; Friedberg, 1997; Taskintuna et al, 1997) .
c) It may occur more frequently in patients with preexisting diabetes mellitus (Prod Info VISTIDE(R) IV injection, 2000).
d) INCIDENCE: Hypotony has occurred transiently in approximately 14% of patients treated with intravitreous cidofovir (Cantrill, 1997).
3) ANTERIOR UVEITIS a) Anterior uveitis has been reported in up to 44% of patients following intravenous and intravitreal administration of cidofovir (Akler et al, 1998; Chavez de la Paz et al, 1997; Davis et al, 1997; Kirsch et al, 1995). Recurrent iritis with spontaneous resolution was reported in one case following intravenous cidofovir (Palau et al, 1997). 1) The concomitant use of probenecid was reported in one study to significantly (from 71% to 18%) reduce the incidence of iritis (Chavez de la Paz et al, 1997).
b) Topical corticosteroids and cycloplegic agents have been used successfully to treat patients (Akler et al, 1998; Chavez de la Paz et al, 1997); however, they have no effect on decreasing the incidence of the condition (Chavez de la Paz et al, 1997). c) RISK FACTORS: In a small study, the authors suggested that the development of uveitis is unusual in patients with no previous ocular history. It is more likely to occur in patients affected by retinitis, as well as recurrent retinitis or concurrent diabetes (Labetoulle et al, 2000). d) CASE SERIES: In a clinical study of 20 patients infected with HIV, 5 (25%) patients developed anterior uveitis which developed after receiving between 2 to 13 doses of intravenous cidofovir (Skiest et al, 1999). The following risk factors were observed: prior or concurrent renal impairment (3 of 5 patients), and concurrent use of protease inhibitors (5 of 5 patients). 3.4.4) EARS
A) WITH THERAPEUTIC USE 1) Ototoxicity including hearing loss (with and without tinnitus) has been reported in 3 patients following cidofovir use. Symptoms occurred within 24 to 48 hours of administration in 2 patients and resolved with discontinuation of therapy (SF Safrin , 1998)
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Neurologic |
3.7.2) CLINICAL EFFECTS
A) HEADACHE 1) WITH THERAPEUTIC USE a) Headache was reported in 30% (n=115) of patients receiving cidofovir during clinical studies (Prod Info VISTIDE(R) IV injection, 2000).
B) ASTHENIA 1) WITH THERAPEUTIC USE a) Fourty-three percent (n=50) of 115 patients developed asthenia during a clinical study (Prod Info VISTIDE(R) IV injection, 2000).
C) CENTRAL NERVOUS SYSTEM FINDING 1) WITH THERAPEUTIC USE a) Multiple neurological symptoms (anxiety, confusion, seizure, dizziness, abnormal gait, insomnia, neuropathy, and somnolence) were observed during clinical trials with cidofovir therapy; however, NO causal relationship was determined (Prod Info VISTIDE(R) IV injection, 2000).
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Gastrointestinal |
3.8.2) CLINICAL EFFECTS
A) NAUSEA AND VOMITING 1) WITH THERAPEUTIC USE a) Nausea with vomiting occurred in 7% of patients, and symptoms were considered to be severe in patients with CMV retinitis treated with cidofovir during 3 controlled clinical trials (Prod Info VISTIDE(R) IV injection, 2000).
B) DIARRHEA 1) WITH THERAPEUTIC USE a) Diarrhea was reported in up to 26% of patients receiving cidofovir therapy (Prod Info VISTIDE(R) IV injection, 2000).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) ACUTE RENAL FAILURE SYNDROME 1) WITH THERAPEUTIC USE a) SUMMARY: The dose-limiting toxicity of cidofovir has been nephrotoxicity, (Lea & Bryson, 1996) which has been characterized by renal proximal tubular cell injury (Higgins, 1994). 1) Acute renal failure resulting in dialysis and/or death has been reported with as few as 1 or 2 doses of intravenous cidofovir (Prod Info VISTIDE(R) IV injection, 2000).
2) To avoid nephrotoxicity, the concomitant use of oral probenecid (shown to block the uptake of cidofovir by the proximal tubular cells) and intravenous saline hydration is recommended with each dose of cidofovir (Prod Info VISTIDE(R) IV injection, 2000).
b) CASE REPORT: Despite concomitant therapy with probenecid, impaired renal function was reported in 2 patients who received intravenous cidofovir (Tseng et al, 1999). Serum creatinine returned to normal in both patients within 4 months of drug cessation. c) INCIDENCE: Renal toxicity (manifested by >/=2+ proteinuria, serum creatinine elevations of >/= 0.4 mg/dL, or decreased creatinine clearance </= 55 mL/min) developed in 79 (59%) of 135 patients during a clinical trial with cidofovir at a maintenance dose of 5 mg/kg every other week (Prod Info VISTIDE(R) IV injection, 2000). 1) In 2 clinical trials, mild to moderate renal impairment occurred in 12% to 17% of patients (Skiest et al, 1999).
d) MINIMAL DOSING: As few as 1 to 2 doses of cidofovir have been associated with severe renal impairment in selected patients (ie, those with other risk factors for renal insufficiency) which necessitated dialysis or contributed to the patient's death (Anon, 1997; Anon, 1996). 1) Based on these concerns, recent labeling changes have included further contraindications to cidofovir therapy, which included concomitant nephrotoxic agents or preexisting renal disease and encouraged ongoing frequent laboratory evaluation during therapy (SF Safrin , 1998).
e) CASE SERIES: During a clinical study of 20 patients with HIV, 3 patients with the AIDS virus developed acute renal failure following 1 to 2 doses of intravenous cidofovir. Two of the three patients required hemodialysis for persistent elevated serum creatinine, despite discontinuation of therapy. One patient subsequently died from pneumonia, and the other died following clinical deterioration and patient refusal of further treatment (Skiest et al, 1999) B) RENAL TUBULAR DISORDER 1) WITH THERAPEUTIC USE a) Renal tubular injury as characterized by proteinuria, glycosuria, and decreases in serum phosphate, uric acid, and bicarbonate levels have been reported with cidofovir use (Higgins, 1994).
b) Fanconi syndrome (manifested by multiple abnormalities of proximal tubule function) developed in approximately 1% of patients (Prod Info VISTIDE(R) IV injection, 2000).
C) DIABETES INSIPIDUS 1) WITH THERAPEUTIC USE a) CASE REPORT: A 28-year-old HIV-positive male developed nephrogenic diabetes insipidus following his seventh treatment cycle with cidofovir. Studies indicated a tubular lesion, which the authors concluded was due to cidofovir therapy (Schliefer et al, 1997).
D) CASE REPORT 1) WITH THERAPEUTIC USE a) A 55-year-old HIV seropositive male with recurrent CMV retinitis developed acute renal failure associated with Fanconi syndrome after receiving 3 doses of intravenous cidofovir (Vittecoq et al, 1997). Renal biopsy results indicated interstitial fibrosis and tubular necrosis. Ongoing renal failure was documented (creatinine clearance 33 mL/min/1.73m(2)), along with proteinuria 4 months after drug therapy.
b) Despite pretreatment with intravenous fluids and concomitant probenecid therapy, a 32-year-old HIV-infected male with CMV retinitis developed severe Fanconi syndrome with hyperchloremic metabolic acidosis (pH 7.1) after chronic therapy (intermittent therapy for approximately 7 weeks) with cidofovir (Kay et al, 2000).
3.10.3) ANIMAL EFFECTS
A) ANIMAL STUDIES 1) RENAL FAILURE ACUTE a) Similar to human studies, animal data (rats and guinea pigs) have indicated that the nephrotoxic effects of cidofovir appear to be dose-dependent (Bedard et al, 1999).
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Acid-Base |
3.11.2) CLINICAL EFFECTS
A) ACIDOSIS 1) WITH THERAPEUTIC USE a) Serious metabolic acidosis occurred in less than 1% (one patient) of patients during clinical studies with cidofovir. Decreases in serum bicarbonate, to </= 16 mEq/L occurred in 16% of cidofovir-treated patients, have also been reported. The manufacturer has reported that some cases of metabolic acidosis occurring in association with liver dysfunction and pancreatitis have resulted in death in some patients (Prod Info VISTIDE(R) IV injection, 2000).
b) CASE REPORT: Hyperchloremic metabolic acidosis along with renal tubular acidosis developed in a 32-year-old HIV-positive male. Symptoms developed despite intravenous hydration (normal saline) and concomitant probenecid therapy. The patient died 11 weeks after developing nephrotoxicity from progressive pulmonary dysfunction (Kay et al, 2000).
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Hematologic |
3.13.2) CLINICAL EFFECTS
A) NEUTROPENIA 1) WITH THERAPEUTIC USE a) During maintenance therapy with cidofovir (5 mg/kg), neutropenia (less than 750 cells/mm (cubed)) was reported frequently (Lea & Bryson, 1996), and occurred in 24% of patients (Prod Info VISTIDE(R) IV injection, 2000). Neutropenia did NOT appear to be dose-dependent (Prod Info VISTIDE(R) IV injection, 2000; Higgins, 1994).
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Reproductive |
3.20.1) SUMMARY
A) Cidofovir has been classified as FDA pregnancy category C.
3.20.2) TERATOGENICITY
A) ANIMAL STUDIES 1) Embryotoxicity was reported in animals administered IV cidofovir 1 to 1.5 mg/kg/day. An increase in fetal external, soft tissue, and skeletal anomalies were also reported with the 1 mg/kg/day dose (Prod Info cidofovir intravenous injection, 2012).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) The manufacturer has classified cidofovir as FDA pregnancy category C (Prod Info cidofovir intravenous injection, 2012).
2) Use during pregnancy only if the potential maternal benefit outweighs the potential fetal risk (Prod Info cidofovir intravenous injection, 2012).
B) ANIMAL STUDIES 1) Decrease litter sizes, a decrease in live births, and increase early resorptions were reported in animals administered cidofovir at doses 0.09 times the recommended human dose or higher prior to mating and for 2 weeks after mating (Prod Info cidofovir intravenous injection, 2012).
2) No adverse effects on viability, growth, behavior, sexual maturation, or reproductive capacity were reported with administration of cidofovir up to 1 mg/kg/day in animal peri- and postnatal development studies (Prod Info cidofovir intravenous injection, 2012).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) BREAST MILK 1) It is unknown whether cidofovir is excreted in human milk. Due to the potential for adverse reactions in nursing infants, avoid use in lactating women (Prod Info cidofovir intravenous injection, 2012).
3.20.5) FERTILITY
A) ANIMAL STUDIES 1) Inhibition of spermatogenesis was reported in animals following cidofovir administration (Prod Info cidofovir intravenous injection, 2012).
2) No adverse effects on fertility or reproduction were observed with administration of cidofovir doses approximately 1.1 times the recommended human dose during animal studies (Prod Info cidofovir intravenous injection, 2012).
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Carcinogenicity |
3.21.4) ANIMAL STUDIES
A) CARCINOMA 1) Carcinomas have been reported in male and female rat studies; cidofovir may be a potential human carcinogen (Prod Info Vistide(R) Injection, cidofovir, 1999).
2) Based on this data, the manufacturer has reported that cidofovir may be a potential human carcinogen.
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