Cidofovir Dihydrate
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Questions & Answers
Side Effects & Adverse Reactions
Nephrotoxicity
Dose-dependent nephrotoxicity is the major dose-limiting toxicity related to cidofovir injection administration. Cases of acute renal failure resulting in dialysis and/or contributing to death have occurred with as few as one or two doses of cidofovir injection. Renal function (serum creatinine and urine protein) must be monitored within 48 hours prior to each dose of cidofovir injection. Dose adjustment or discontinuation is required for changes in renal function (serum creatinine and/or urine protein) while on therapy. Proteinuria, as measured by urinalysis in a clinical laboratory, may be an early indicator of cidofovir injection -related nephrotoxicity. Continued administration of cidofovir injection may lead to additional proximal tubular cell injury, which may result in glycosuria, decreases in serum phosphate, uric acid, and bicarbonate, elevations in serum creatinine, and/or acute renal failure, in some cases, resulting in the need for dialysis. Patients with these adverse events occurring concurrently and meeting a criteria of Fanconi's syndrome have been reported. Renal function that did not return to baseline after drug discontinuation has been observed in clinical studies of cidofovir injection.
Intravenous normal saline hydration and oral probenecid must accompany each cidofovir infusion. Probenecid is known to interact with the metabolism or renal tubular excretion of many drugs (see PRECAUTIONS). The safety of cidofovir injection has not been evaluated in patients receiving other known potentially nephrotoxic agents, such as intravenous aminoglycosides (e.g., tobramycin, gentamicin, and amikacin), amphotericin B, foscarnet, intravenous pentamidine, vancomycin, and non-steroidal anti-inflammatory agents (see DOSAGE AND ADMINISTRATION).
Preexisting Renal Impairment
Initiation of therapy with cidofovir injection is contraindicated in patients with a baseline serum creatinine >1.5 mg/dL, a creatinine clearance ≤55 mL/min, or a urine protein ≥100 mg/dL (equivalent to ≥2+ proteinuria).
Hematological Toxicity
Neutropenia may occur during cidofovir injection therapy. Neutrophil count should be monitored while receiving cidofovir injection therapy.
Decreased Intraocular Pressure/Ocular Hypotony
Decreased intraocular pressure may occur during cidofovir injection therapy, and in some instances has been associated with decreased visual acuity. Intraocular pressure should be monitored during cidofovir injection therapy.
Metabolic Acidosis
Decreased serum bicarbonate associated with proximal tubule injury and renal wasting syndrome (including Fanconi's syndrome) have been reported in patients receiving cidofovir injection (see ADVERSE REACTIONS). Cases of metabolic acidosis in association with liver dysfunction and pancreatitis resulting in death have been reported in patients receiving cidofovir injection.
Legal Issues
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FDA Safety Alerts
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Manufacturer Warnings
There is currently no manufacturer warning information available for this drug.
FDA Labeling Changes
There are currently no FDA labeling changes available for this drug.
Uses
Cidofovir injection is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS). THE SAFETY AND EFFICACY OF CIDOFOVIR INJECTION HAVE NOT BEEN ESTABLISHED FOR TREATMENT OF OTHER CMV INFECTIONS (SUCH AS PNEUMONITIS OR GASTROENTERITIS), CONGENITAL OR NEONATAL CMV DISEASE, OR CMV DISEASE IN NON-HIV-INFECTED INDIVIDUALS.
DESCRIPTION OF CLINICAL TRIALS
Three phase II/III controlled trials of cidofovir injection have been conducted in HIV-infected patients with CMV retinitis.
Delayed Versus Immediate Therapy (Study 105)
In stage 1 of this open-label trial, conducted by the Studies of the Ocular Complications of AIDS (SOCA) Clinical Research Group, 29 previously untreated patients with peripheral CMV retinitis were randomized to either immediate treatment with cidofovir injection (5 mg/kg once a week for 2 weeks, then 3 mg/kg every other week) or to have cidofovir injection delayed until progression of CMV retinitis13. In stage 2 of this trial, an additional 35 previously untreated patients with peripheral CMV retinitis were randomized to either immediate treatment with cidofovir injection (5 mg/kg once a week for 2 weeks, then 5 mg/kg every other week), immediate treatment with cidofovir injection (5 mg/kg once a week for 2 weeks, then 3 mg/kg every other week), or to have cidofovir injection delayed until progression of CMV retinitis. Of the 64 patients in this study, 12 were randomized to 5 mg/kg maintenance therapy, 26 to 3 mg/kg maintenance therapy, and 26 to delayed therapy. Of the 12 patients enrolled in the 5 mg/kg maintenance group, 5 patients progressed, 5 patients discontinued therapy and 2 patients had no progression at study completion. Based on masked readings of retinal photographs, the median [95% confidence interval (CI)] time to retinitis progression was not reached (25, not reached) for the 5 mg/kg maintenance group. Median (95% CI) time to the alternative endpoint of retinitis progression or study drug discontinuation was 44 days (24, 207) for the 5 mg/kg maintenance group. Patients receiving 5 mg/kg maintenance had delayed time to retinitis progression compared to patients receiving 3 mg/kg maintenance or deferred therapy.
Delayed Versus Immediate Therapy (Study 106)
In an open-label trial, 48 previously untreated patients with peripheral CMV retinitis were randomized to either immediate treatment with cidofovir injection (5 mg/kg once a week for 2 weeks, then 5 mg/kg every other week), or to have cidofovir injection delayed until progression of CMV retinitis14. Patient baseline characteristics and disposition are shown in Table 3. Of 25 and 23 patients in the immediate and delayed groups respectively, 23 and 21 were evaluable for retinitis progression as determined by retinal photography. Based on masked readings of retinal photographs, the median [95% confidence interval (CI)] times to retinitis progression were 120 days (40, 134) and 22 days (10, 27) for the immediate and delayed therapy groups, respectively. This difference was statistically significant. However, because of the limited number of patients remaining on treatment over time (3 of 25 patients received cidofovir injection for 120 days or longer), the median time to progression for the immediate therapy group was difficult to precisely estimate. Median (95% CI) times to the alternative endpoint of retinitis progression or study drug discontinuation (including adverse events, withdrawn consent, and systemic CMV disease) were 52 days (37, 85) and 22 days (13, 27) for the immediate and delayed therapy groups, respectively.
This difference was statistically significant. Time to progression estimates from this study may not be directly comparable to estimates reported for other therapies.
Table 3. Patient Characteristics and Disposition (Study 106)
|
||
| Immediate Therapy (n = 25) |
Delayed Therapy (n = 23) |
|
| Baseline Characteristics |
||
| Age (years) | 38 |
38 |
| Sex (M/F) | 24/1 |
22/1 |
| Median CD4 Cell Count |
6 |
9 |
| Endpoints | ||
| CMV Retinitis Progression | 10 |
18 |
| Discontinued Due to Adverse Event | 6 |
0 |
| Withdrew Consent | 3* |
1 |
| Discontinued Due to Intercurrent Illness | 2† |
1† |
| Discontinued Based on Ophthalmological Examination |
1‡ |
1‡ |
| No Progression at Study Completion | 1 |
0 |
| Not Evaluable at Baseline | 2 |
2 |
Dose-response study of cidofovir injection (Study 107)
In an open-label trial, 100 patients with relapsing CMV retinitis were randomized to receive 5 mg/kg once a week for 2 weeks and then either 5 mg/kg (n = 49) or 3 mg/kg (n = 51) every other week. Enrolled patients had been diagnosed with CMV retinitis an average of 390 days prior to randomization and had received a median of 3.8 prior courses of systemic CMV therapy. Eighty four of the 100 patients were considered evaluable for progression by serial retinal photographs (43 randomized to 5 mg/kg and 41 randomized to 3 mg/kg). Twenty-six and 21 patients discontinued therapy due to either an adverse event, intercurrent illness, excluded medication, or withdrawn consent in the 5 mg/kg and 3 mg/kg groups, respectively. Thirty-eight of the 100 randomized patients had progressed according to masked assessment of serial retinal photographs (13 randomized to 5 mg/kg and 25 randomized to 3 mg/kg). Using retinal photographs, the median (95% CI) times to retinitis progression for the 5 mg/kg and 3 mg/kg groups were 115 days (70, not reached) and 49 days (35, 52), respectively. This difference was statistically significant. Similar to Study 106, the median time to retinitis progression for the 5 mg/kg group was difficult to precisely estimate due to the limited number of patients remaining on treatment over time (4 of the 49 patients in the 5 mg/kg group were treated for 115 days or longer). Median (95% CI) times to the alternative endpoint of retinitis progression or study drug discontinuation were 49 days (38, 63) and 35 days (27, 39) for the 5 mg/kg and 3 mg/kg groups, respectively. This difference was statistically significant.
History
There is currently no drug history available for this drug.
Other Information
The chemical name of cidofovir is 1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate (HPMPC), with the molecular formula of C8H14N3O6P•2H2O and a molecular weight of 315.22 (279.19 for anhydrous). The chemical structure is:
Cidofovir is a white crystalline powder with an aqueous solubility of ≥ 170 mg/mL at pH 6 to 8 and a log P (octanol/aqueous buffer, pH 7.1) value of -3.3.
Cidofovir Injection is a sterile, hypertonic aqueous solution for intravenous infusion only. The solution is clear and colorless. It is supplied in clear glass vials, each containing 375 mg of anhydrous cidofovir in 5 mL aqueous solution at a concentration of 75 mg/mL.
The formulation is pH-adjusted to 7.4 (range 7.1 to 7.7) with sodium hydroxide and/or hydrochloric acid and contains no preservatives. The appropriate volume of Cidofovir Injection must be removed from the single-use vial and diluted prior to administration (see DOSAGE AND ADMINISTRATION).
MICROBIOLOGY
Mechanism of Action
Cidofovir suppresses cytomegalovirus (CMV) replication by selective inhibition of viral DNA synthesis. Biochemical data support selective inhibition of CMV DNA polymerase by cidofovir diphosphate, the active intracellular metabolite of cidofovir. Cidofovir diphosphate inhibits herpesvirus polymerases at concentrations that are 8- to 600-fold lower than those needed to inhibit human cellular DNA polymerases alpha, beta, and gamma1, 2, 3. Incorporation of cidofovir into the growing viral DNA chain results in reductions in the rate of viral DNA synthesis.
In Vitro Susceptibility
Cidofovir is active in vitro against a variety of laboratory and clinical isolates of CMV and other herpesviruses (Table 1). Controlled clinical studies of efficacy have been limited to patients with AIDS and CMV retinitis.
Table 1. Cidofovir Inhibition of Virus Multiplication in Cell Culture
| Virus | IC50 (μM) |
| Wild-type CMV Isolates | 0.5 to 2.8 |
| HSV-1, HSV-2 | 12.7 to 31.7 |
Resistance
CMV isolates with reduced susceptibility to cidofovir have been selected in vitro in the presence of high concentrations of cidofovir4. IC50 values for selected resistant isolates ranged from 7 to 15 μM.
There are insufficient data at this time to assess the frequency or the clinical significance of the development of resistant isolates following cidofovir injection administration to patients.
The possibility of viral resistance should be considered for patients who show a poor clinical response or experience recurrent retinitis progression during therapy.
Cross Resistance
Cidofovir-resistant isolates selected in vitro following exposure to increasing concentrations of cidofovir were assessed for susceptibility to ganciclovir and foscarnet4. All were cross resistant to ganciclovir, but remained susceptible to foscarnet. Ganciclovir or ganciclovir/foscarnet-resistant isolates that are cross resistant to cidofovir have been obtained from drug naive patients and from patients following ganciclovir or ganciclovir/ foscarnet therapy. To date, the majority of ganciclovir-resistant isolates are UL97 gene product (phosphokinase) mutants and remain susceptible to cidofovir5.
Reduced susceptibility to cidofovir, however, has been reported for DNA polymerase mutants of CMV which are resistant to ganciclovir6–9. To date, all clinical isolates which exhibit high level resistance to ganciclovir, due to mutations in both the DNA polymerase and UL97 genes, have been shown to be cross resistant to cidofovir. Cidofovir is active against some, but not all, CMV isolates which are resistant to foscarnet10–12. The incidence of foscarnet-resistant isolates that are resistant to cidofovir is not known.
A few triple-drug resistant isolates have been described. Genotypic analysis of two of these triple-resistant isolates revealed several point mutations in the CMV DNA polymerase gene. The clinical significance of the development of these cross-resistant isolates is not known.
Sources
Cidofovir Dihydrate Manufacturers
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Heritage Pharmaceuticals Inc.
![Cidofovir Dihydrate Injection, Solution [Heritage Pharmaceuticals Inc.]](/wp-content/themes/bootstrap/assets/img/loading2.gif)
Cidofovir Dihydrate | Heritage Pharmaceuticals Inc.
CIDOFOVIR INJECTION MUST NOT BE ADMINISTERED BY INTRAOCULAR INJECTION.
Dosage
THE RECOMMENDED DOSAGE, FREQUENCY, OR INFUSION RATE MUST NOT BE EXCEEDED. CIDOFOVIR INJECTION MUST BE DILUTED IN 100 MILLILITERS 0.9% (NORMAL) SALINE PRIOR TO ADMINISTRATION. TO MINIMIZE POTENTIAL NEPHROTOXICITY, PROBENECID AND INTRAVENOUS SALINE PREHYDRATION MUST BE ADMINISTERED WITH EACH CIDOFOVIR INFUSION.
Induction Treatment
The recommended induction dose of cidofovir injection for patients with a serum creatinine of ≤1.5 mg/dL, a calculated creatinine clearance > 55 mL/min, and a urine protein <100 mg/dL (equivalent to < 2+ proteinuria) is 5 mg/kg body weight (given as an intravenous infusion at a constant rate over 1 hr) administered once weekly for two consecutive weeks. Because serum creatinine in patients with advanced AIDS and CMV retinitis may not provide a complete picture of the patient's underlying renal status, it is important to utilize the Cockcroft-Gault formula to more precisely estimate creatinine clearance (CrCl). As creatinine clearance is dependent on serum creatinine and patient weight, it is necessary to calculate clearance prior to initiation of cidofovir injection. CrCl (mL/min) should be calculated according to the following formula:
[140-age (years)] × [body wt (kg)]
Creatinine clearance for males = ---------------------------------------------------
72 × [serum creatinine (mg/dL)]
[140-age (years)] × [body wt (kg)] × 0.85
Creatinine clearance for females = --------------------------------------------------------------
72 × [serum creatinine (mg/dL)]
Maintenance Treatment
The recommended maintenance dose of cidofovir injection is 5 mg/kg body weight (given as an intravenous infusion at a constant rate over 1 hr), administered once every 2 weeks.
Dose Adjustment
Changes in Renal Function During cidofovir injection Therapy
The maintenance dose of cidofovir injection must be reduced from 5 mg/kg to 3 mg/kg for an increase in serum creatinine of 0.3 to 0.4 mg/dL above baseline. Cidofovir injection therapy must be discontinued for an increase in serum creatinine of ≥0.5 mg/dL above baseline or development of ≥3+ proteinuria.
Preexisting Renal Impairment
Cidofovir injection is contraindicated in patients with a serum creatinine concentration >1.5 mg/dL, a calculated creatinine clearance ≤55 mL/ min, or a urine protein ≥100 mg/dL (equivalent to ≥2+ proteinuria).
Probenecid
Probenecid must be administered orally with each cidofovir injection dose. Two grams must be administered 3 hr prior to the cidofovir injection dose and one gram administered at 2 and again at 8 hr after completion of the 1 hr cidofovir infusion (for a total of 4 grams).
Ingestion of food prior to each dose of probenecid may reduce drug-related nausea and vomiting. Administration of an antiemetic may reduce the potential for nausea associated with probenecid ingestion. In patients who develop allergic or hypersensitivity symptoms to probenecid, the use of an appropriate prophylactic or therapeutic antihistamine and/or acetaminophen should be considered (see CONTRAINDICATIONS).
Hydration
Patients must receive at least one liter of 0.9% (normal) saline solution intravenously with each infusion of cidofovir injection. The saline solution should be infused over a 1 to 2 hr period immediately before the cidofovir infusion. Patients who can tolerate the additional fluid load should receive a second liter. If administered, the second liter of saline should be initiated either at the start of the cidofovir infusion or immediately afterwards, and infused over a 1 to 3 hr period.
Method of Preparation and Administration
Inspect vials visually for particulate matter and discoloration prior to administration. If particulate matter or discoloration is observed, the vial should not be used. With a syringe, extract the appropriate volume of cidofovir injection from the vial and transfer the dose to an infusion bag containing 100 mL 0.9% (normal) saline solution. Infuse the entire volume intravenously into the patient at a constant rate over a 1 hr period. Use of a standard infusion pump for administration is recommended.
It is recommended that cidofovir infusion admixtures be administered within 24 hr of preparation and that refrigerator or freezer storage not be used to extend this 24 hr limit.
If admixtures are not intended for immediate use, they may be stored under refrigeration (2 to 8°C) for no more than 24 hr. Refrigerated admixtures should be allowed to equilibrate to room temperature prior to use.
The chemical stability of cidofovir injection admixtures was demonstrated in polyvinyl chloride composition and ethylene/propylene copolymer composition commercial infusion bags, and in glass bottles.
No data are available to support the addition of other drugs or supplements to the cidofovir admixture for concurrent administration.
Cidofovir injection is supplied in single-use vials. Partially used vials should be discarded (see Handling and Disposal).
Compatibility with Ringer's solution, Lactated Ringer's solution or bacteriostatic infusion fluids has not been evaluated.
Handling and Disposal
Due to the mutagenic properties of cidofovir, adequate precautions including the use of appropriate safety equipment are recommended for the preparation, administration, and disposal of cidofovir injection. The National Institutes of Health presently recommends that such agents be prepared in a Class II laminar flow biological safety cabinet and that personnel preparing drugs of this class wear surgical gloves and a closed front surgical-type gown with knit cuffs. If cidofovir injection contacts the skin, wash membranes and flush thoroughly with water. Excess cidofovir injection and all other materials used in the admixture preparation and administration should be placed in a leak-proof, puncture-proof container. The recommended method of disposal is high temperature incineration.
Patient Monitoring
Serum creatinine and urine protein must be monitored within 48 hours prior to each dose. White blood cell counts with differential should be monitored prior to each dose. In patients with proteinuria, intravenous hydration should be administered and the test repeated. Intraocular pressure, visual acuity and ocular symptoms should be monitored periodically.
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