CIDOFOVIR DIHYDRATE 375 mg/5mL Injection, Solution, 5 mL
🆔 Identity & classification
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🏷️ RxNorm drug class
This medicine belongs to the Cytomegalovirus Nucleoside Analog DNA Polymerase Inhibitor class.
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🏭 Manufacturer & labeler
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🩺 Clinical
- Cidofovir is used to treat CMV retinitis — a serious eye infection caused by a virus called cytomegalovirus — in people who have AIDS. Left untreated, CMV retinitis can lead to bli...
- No — cidofovir is given as an IV infusion, meaning it goes directly into your vein through a drip in a clinic or hospital. You won't be taking a pill at home. Each time you get cid...
- How is this medication given? Do I take it at home?
- The biggest concern with cidofovir is kidney damage — it can be serious and sometimes permanent, even after just one or two doses. That's why your kidneys are tested before every i...
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🧪 Inactive Ingredients / Excipients
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UNII QTT17582CB
A strong acid used to adjust and maintain the proper pH level in liquid medicines, ensuring stability and preventing breakdown of active ingredients.
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UNII 55X04QC32I
A strong alkaline chemical used to adjust and maintain the pH balance of liquid medicines. It helps keep the medicine stable and ensures it stays effective during storage.
2 inactive ingredients listed in the exact product block matched to this NDC.
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ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.Inactive ingredient FAQ
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💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per mL | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | $112.30 | $561.48 / 5 ml |
| Medicare drug plans payPart D · quarterly | No Part D plan price is available for this NDC in our data. | |
| Medicare Part B allowsASP · J0740 | $535.735 / J0740 unit | — |
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🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Cidofovir Dihydrate 375 mg/5mLthis 23155-0216-31 | Heritage | 5 ml | — | AP | FDA listed | — |
| Cidofovir 75 mg/mL 67457-0210-05 | Mylan | 1 vial | — | AP | FDA listed | — |
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⏳ Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
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📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 23155-0216-31 You're viewing this | 5 mL in 1 VIAL, GLASS (23155-216-31) | 2012-08-06 | Active |
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| NDC identity (package / product / labeler codes) | ✓ Available |
| Labeler | ✓ Available |
| Product & package description | ✓ Available |
| Marketing category & status | ✓ Available |
| Active ingredient / dosage form / route | ✓ Available |
| FDA label (SPL via DailyMed) | ✓ Available |
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| Inactive ingredients (structured) | ✓ Available |
| NADAC pharmacy acquisition price (CMS) | — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey. |
| Orange Book / therapeutic-equivalence data | ✓ Available |
| HCPCS J-code billing crosswalk | ✓ Available |
| Medicaid utilization (CMS SDUD) | ✓ Available |
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📄 Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING RENAL IMPAIRMENT IS THE MAJOR TOXICITY OF CIDOFOVIR INJECTION. 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. TO REDUCE POSSIBLE NEPHROTOXICITY, INTRAVENOUS 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 INJECTION AND THE DOSE OF CIDOFOVIR INJECTION MODIFIED FOR CHANGES IN RENAL FUNCTION AS APPROPRIATE (SEE ION (SERUM CREATININE AND URINE PROTEIN) MUST BE MONITORED WITHIN 48 HOURS PRIOR TO EACH DOSE OF CIDOFOVIR INJECTION AND THE DOSE OF CIDOFOVIR INJECTION MODIFIED FOR CHANGES IN RENAL FUNCTION AS APPROPRIATE (SEE DOSAGE AND ADMINISTRATION ). CIDOFOVIR INJECTION IS CONTRAINDICATED IN PATIENTS WHO ARE RECEIVING OTHER NEPHROTOXIC AGENTS.
NEUTROPENIA HAS BEEN OBSERVED IN ASSOCIATION WITH CIDOFOVIR INJECTION TREATMENT. THEREFORE, NEUTROPHIL COUNTS SHOULD BE MONITORED DURING CIDOFOVIR INJECTION THERAPY. CIDOFOVIR INJECTION IS INDICATED ONLY FOR THE TREATMENT OF CMV RETINITIS IN PATIENTS WITH ACQUIRED IMMUNODEFICIENCY SYNDROME.
IN ANIMAL STUDIES CIDOFOVIR WAS CARCINOGENIC, TERATOGENIC AND CAUSED HYPOSPERMIA (SEE CARCINOGENESIS, MUTAGENESIS, & IMPAIRMENT OF FERTILITY ).
🎯 Indications and Usage ▾
INDICATION AND USAGE 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 retinitis 13 . 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 retinitis 14 .
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) * One patient died 2 weeks after withdrawing consent. † Two patients on immediate therapy were diagnosed with CMV disease and discontinued…
⏱️ Dosage and Administration ▾
DOSAGE AND ADMINISTRATION CIDOFOVIR INJECTION, USP MUST NOT BE ADMINISTERED BY INTRAOCULAR INJECTION. Dosage THE RECOMMENDED DOSAGE, FREQUENCY, OR INFUSION RATE MUST NOT BE EXCEEDED. CIDOFOVIR INJECTION, USP 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)] ×
0.85Creatinine 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% (no…
⛔ Contraindications ▾
CONTRAINDICATIONS Initiation of therapy with cidofovir injection is contraindicated in patients with a serum creatinine >1.5 mg/dL, a calculated creatinine clearance ≤55 mL/min, or a urine protein ≥100 mg/dL (equivalent to ≥2+ proteinuria). Cidofovir injection is contraindicated in patients receiving agents with nephrotoxic potential. Such agents must be discontinued at least seven days prior to starting therapy with cidofovir injection.
Cidofovir injection is contraindicated in patients with hypersensitivity to cidofovir. Cidofovir injection is contraindicated in patients with a history of clinically severe hypersensitivity to probenecid or other sulfa-containing medications. Direct intraocular injection of cidofovir injection is contraindicated; direct injection of cidofovir has been associated with iritis, ocular hypotony, and permanent impairment of vision.
⚠️ Warnings ▾
WARNINGS 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.
🤒 Adverse Reactions ▾
ADVERSE REACTIONS Nephrotoxicity: Renal toxicity, as manifested by ≥2+ proteinuria, serum creatinine elevations of ≥0.4 mg/dL, or decreased creatinine clearance ≤55 mL/min, occurred in 79 of 135 (59%) patients receiving cidofovir injection at a maintenance dose of 5 mg/kg every other week. Maintenance dose reductions from 5 mg/kg to 3 mg/kg due to proteinuria or serum creatinine elevations were made in 12 of 41 (29%) patients who had not received prior therapy for CMV retinitis (Study 106) and in 19 of 74 (26%) patients who had received prior therapy for CMV retinitis (Study 107).
Prior foscarnet use has been associated with an increased risk of nephrotoxicity; therefore, such patients must be monitored closely (see CONTRAINDICATIONS , WARNINGS , DOSAGE AND ADMINISTRATION ). Neutropenia: In clinical trials, at the 5 mg/kg maintenance dose, a decrease in absolute neutrophil count to ≤500 cells/mm 3 occurred in 24% of patients. Granulocyte colony stimulating factor (GCSF) was used in 39% of patients.
Decreased Intraocular Pressure/Ocular Hypotony : Among the subset of patients monitored for intraocular pressure changes, a ≥50% decrease from baseline intraocular pressure was reported in 17 of 70 (24%) patients at the 5 mg/kg maintenance dose. Severe hypotony (intraocular pressure of 0 to 1 mm Hg) has been reported in 3 patients. Risk of ocular hypotony may be increased in patients with preexisting diabetes mellitus.
Anterior Uveitis/Iritis: Uveitis or iritis has been reported in clinical trials and during postmarketing in patients receiving cidofovir injection therapy. Uveitis or iritis was reported in 15 of 135 (11%) patients receiving 5 mg/kg maintenance dosing. Treatment with topical corticosteroids with or without topical cycloplegic agents may be considered.
Patients should be monitored for signs and symptoms of uveitis/iritis during cidofovir injection therapy. Metabolic Acidosis : A diagnosis of Fanconi's syndrome, as manifested by multiple abnormalities of proximal renal tubular function, was reported in 1% of patients. Decreases in serum bicarbonate to ≤16 mEq/L occurred in 16% of cidofovir-treated patients.
Cases of metabolic acidosis in association with liver dysfunction and pancreatitis resulting in death have been reported in patients receiving cidofovir injection. In clinical trials, cidofovir injection was withdrawn due to adverse events in 39% of patients treated with 5 mg/kg every other week as maintenance therapy. The incidence of adverse reactions reported as serious in three controlled clinical studies in patients with CMV retinitis, regardless of presumed relationship to drug, is listed in Table 4.
Table 4. Serious Clinical Adverse Events or Laboratory Abnormalities Occurring in > 5% of Patients * Patients receiving 5 mg/kg maintenance regimen in Studies 105, 106 and 107. † Defined as decreased intraocular pressure (IOP) to ≤50% that at baseline. Based on 70 patients receiving 5 mg/kg maintenance dosing (Studies 105, 106 and 107), for whom baseline and follow-up IOP determinations were recorded.
N = 135 * # patients (%) Proteinuria (≥100 mg/dL) 68(50) Neutropenia (≤500 cells/mm 3 ) 33(24) Decreased Intraocular Pressure † 17(24) Decreased Serum Bicarbonate (≤16 mEq/L) 21(16) Fever 19(14) Infection 16(12) Creatinine Elevation (≥2 mg/dL) 16(12) Pneumonia 12(9) Dyspnea 11(8) Nausea with Vomiting 10(7) The most frequently reported adverse events regardless of relationship to study drugs (cidofovir or probenecid) or severity are shown in Table 5. The following additional list of adverse events/intercurrent illnesses have been observed in clinical studies of cidofovir injection and are listed below regardless of causal relationship to cidofovir injection.
Evaluation of these reports was difficult because of the diverse manifestations of the underlying disease and because most patients received numerous concomitant medicines. Body as a Whole : abdominal pain, accidental injury, AIDS, allergic reaction, back pain, cat…
🔄 Drug Interactions ▾
Drug Interactions Probenecid Probenecid is known to interact with the metabolism or renal tubular excretion of many drugs (e.g., acetaminophen, acyclovir, angiotensin-converting enzyme inhibitors, aminosalicylic acid, barbiturates, benzodiazepines, bumetanide, clofibrate, methotrexate, famotidine, furosemide, nonsteroidal anti-inflammatory agents, theophylline, and zidovudine). Concomitant medications should be carefully assessed. Zidovudine should either be temporarily discontinued or decreased by 50% when coadministered with probenecid on the day of cidofovir infusion.
Nephrotoxic agents Concomitant administration of cidofovir injection and agents with nephrotoxic potential [e.g., intravenous aminoglycosides (e.g., tobramycin, gentamicin, and amikacin), amphotericin B, foscarnet, intravenous pentamidine, vancomycin, and nonsteroidal anti-inflammatory agents] is contraindicated. Such agents must be discontinued at least seven days prior to starting therapy with cidofovir injection.
🤰 Pregnancy ▾
Pregnancy Teratogenic Effects: Pregnancy Category C Cidofovir was embryotoxic (reduced fetal body weights) in rats at 1.5 mg/kg/day and in rabbits at 1 mg/kg/day, doses which were also maternally toxic, following daily intravenous dosing during the period of organogenesis. The no-observable-effect levels for embryotoxicity in rats (0.5 mg/kg/day) and in rabbits (0.25 mg/kg/day) were approximately 0.04 and 0.05 times the clinical dose (5 mg/kg every other week) based on AUC, respectively. An increased incidence of fetal external, soft tissue and skeletal anomalies (meningocele, short snout, and short maxillary bones) occurred in rabbits at the high dose (1 mg/kg/day) which was also maternally toxic.
There are no adequate and well-controlled studies in pregnant women. Cidofovir injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
🧒 Pediatric Use ▾
Pediatric Use Safety and effectiveness in children have not been studied. The use of cidofovir injection in children with AIDS warrants extreme caution due to the risk of long-term carcinogenicity and reproductive toxicity. Administration of cidofovir injection to children should be undertaken only after careful evaluation and only if the potential benefits of treatment outweigh the risks.
🧓 Geriatric Use ▾
Geriatric Use No studies of the safety or efficacy of cidofovir injection in patients over the age of 60 have been conducted. Since elderly individuals frequently have reduced glomerular filtration, particular attention should be paid to assessing renal function before and during cidofovir injection administration (see DOSAGE AND ADMINISTRATION ).
🆘 Overdosage ▾
OVERDOSAGE Two cases of cidofovir overdose have been reported. These patients received single doses of cidofovir injection at 16.3 mg/kg and 17.4 mg/kg, respectively, with concomitant oral probenecid and intravenous hydration. In both cases, the patients were hospitalized and received oral probenecid (one gram three times daily) and vigorous intravenous hydration with normal saline for 3 to 5 days.
Significant changes in renal function were not observed in either patient.
🧬 Clinical Pharmacology ▾
CLINICAL PHARMACOLOGY PHARMACOKINETICS Cidofovir injection must be administered with probenecid. The pharmacokinetics of cidofovir, administered both without and with probenecid, are described below. The pharmacokinetics of cidofovir without probenecid were evaluated in 27 HIV-infected patients with or without asymptomatic CMV infection.
Dose-independent pharmacokinetics were demonstrated after one hr infusions of 1 (n = 5), 3 (n = 10), 5 (n = 2) and 10 (n = 8) mg/kg (See Table 2 for pharmacokinetic parameters). There was no evidence of cidofovir accumulation after 4 weeks of repeated administration of 3 mg/kg/week (n = 5) without probenecid. In patients with normal renal function, approximately 80 to 100% of the cidofovir injection dose was recovered unchanged in urine within 24 hr (n = 27).
The renal clearance of cidofovir was greater than creatinine clearance, indicating renal tubular secretion contributes to the elimination of cidofovir. The pharmacokinetics of cidofovir administered with probenecid were evaluated in 12 HIV-infected patients with or without asymptomatic CMV infection and 10 patients with relapsing CMV retinitis. Dose-independent pharmacokinetics were observed for cidofovir, administered with probenecid, after one hr infusions of 3 (n = 12), 5 (n = 6), and 7.5 (n = 4) mg/kg (See Table 2).
Approximately 70 to 85% of the cidofovir injection dose administered with concomitant probenecid was excreted as unchanged drug within 24 hr. When cidofovir injection was administered with probenecid, the renal clearance of cidofovir was reduced to a level consistent with creatinine clearance, suggesting that probenecid blocks active renal tubular secretion of cidofovir. Table 2.
Cidofovir Pharmacokinetic Parameters Following 3 and 5 mg/kg Infusions, Without and With Probenecid* *See DOSAGE AND ADMINISTRATION PARAMETERS CIDOFOVIR INJECTION ADMINISTERED WITHOUT PROBENECID CIDOFOVIR INJECTION ADMINISTERED WITH PROBENECID 3 mg/kg (n = 10) 5 mg/kg (n = 2) 3 mg/kg (n = 12) 5 mg/kg (n = 6) AUC (mcg·hr/mL) 20 ± 2.3 28.3 25.7 ± 8.5 40.8 ± 9 Cmax (end of infusion) (mcg/mL) 7.3 ± 1.4 11.5 9.8 ± 3.7 19.6 ±
7.2Vdss (mL/kg) 537 ± 126 (n = 12) 410 ± 102 (n = 18) Clearance (mL/min/1.73 m 2 ) 179 ± 23.1 (n = 12) 148 ± 38.8 (n = 18) Renal Clearance (mL/min/1.73 m 2 ) 150 ± 26.9 (n = 12) 98.6 ± 27.9 (n = 11) In vitro , cidofovir was less than 6% bound to plasma or serum proteins over the cidofovir concentration range 0.25 to 25 mcg/mL. CSF concentrations of cidofovir following intravenous infusion of cidofovir injection 5 mg/kg with concomitant probenecid and intravenous hydration were undetectable (< 0.1 mcg/mL, assay detection threshold) at 15 minutes after the end of a 1 hr infusion in one patient whose corresponding serum concentration was 8.7 mcg/mL.
DRUG-DRUG INTERACTIONS Zidovudine The pharmacokinetics of zidovudine were evaluated in 10 patients receiving zidovudine alone or with intravenous cidofovir (without probenecid). There was no evidence of an effect of cidofovir on the pharmacokinetics of zidovudine. SPECIAL POPULATIONS Renal Insufficiency Pharmacokinetic data collected from subjects with creatinine clearance values as low as 11 mL/min indicate that cidofovir clearance decreases proportionally with creatinine clearance.
High-flux hemodialysis has been shown to reduce the serum levels of cidofovir by approximately 75%. Initiation of therapy with cidofovir injection is contraindicated in patients with serum creatinine >1.5 mg/dL, a calculated creatinine clearance ≤55 mL/min, or a urine protein ≥100 mg/dL (equivalent to ≥2+ proteinuria) (See CONTRAINDICATIONS ). Geriatric/Gender/Race The effects of age, gender, and race on cidofovir pharmacokinetics have not been investigated.
📦 How Supplied / Storage and Handling ▾
HOW SUPPLIED Cidofovir Injection, USP 75 mg/mL for intravenous infusion, is supplied as a non-preserved solution in single-dose clear glass vials as follows: NDC 23155-216-31 375 mg in a 5 mL vial in a single-unit carton Cidofovir Injection, USP should be stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
📋 Description ▾
DESCRIPTION The chemical name of cidofovir USP is 1-[( S )-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate (HPMPC), with the molecular formula of C 8 H 14 N 3 O 6 P• 2 H 2 O and a molecular weight of 315.22 (279.19 for anhydrous). The chemical structure is: Cidofovir USP 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, USP 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 USP 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-dose 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 gamma 1, 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 IC 50 (μM) Wild-type CMV Isolates 0.5 to
2.8HSV-1, HSV-2 12.7 to
31.7Resistance CMV isolates with reduced susceptibility to cidofovir have been selected in vitro in the presence of high concentrations of cidofovir 4 . IC 50 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 foscarnet 4 . 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 cidofovir 5 . Reduced susceptibility to cidofovir, however, has been reported for DNA polymerase mutants of CMV which are resistant to ganciclovir 6–9 .
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 foscarnet 10–12 . 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. structu…
💬 Information for Patients ▾
Information for Patients Patients should be advised that cidofovir injection is not a cure for CMV retinitis, and that they may continue to experience progression of retinitis during and following treatment. Patients receiving cidofovir injection should be advised to have regular follow-up ophthalmologic examinations. Patients may also experience other manifestations of CMV disease despite cidofovir injection therapy.
HIV-infected patients may continue taking antiretroviral therapy, but those taking zidovudine should be advised to temporarily discontinue zidovudine administration or decrease their zidovudine dose by 50%, on days of cidofovir injection administration only, because probenecid reduces metabolic clearance of zidovudine. Patients should be informed of the major toxicity of cidofovir injection, namely renal impairment, and that dose modification, including reduction, interruption, and possibly discontinuation, may be required.
Close monitoring of renal function (routine urinalysis and serum creatinine) while on therapy should be emphasized. The importance of completing a full course of probenecid with each cidofovir injection dose should be emphasized. Patients should be warned of potential adverse events caused by probenecid (e.g., headache, nausea, vomiting, and hypersensitivity reactions).
Hypersensitivity/ allergic reactions may include rash, fever, chills and anaphylaxis. Administration of probenecid after a meal or use of antiemetics may decrease the nausea. Prophylactic or therapeutic antihistamines and/or acetaminophen can be used to ameliorate hypersensitivity reactions.
Patients should be advised that cidofovir causes tumors, primarily mammary adenocarcinomas, in rats. Cidofovir injection should be considered a potential carcinogen in humans (See Carcinogenesis, Mutagenesis, & Impairment of Fertility). Women should be advised of the limited enrollment of women in clinical trials of cidofovir injection.
Patients should be advised that cidofovir injection caused reduced testes weight and hypospermia in animals. Such changes may occur in humans and cause infertility. Women of childbearing potential should be advised that cidofovir is embryotoxic in animals and should not be used during pregnancy.
Women of childbearing potential should be advised to use effective contraception during and for 1 month following treatment with cidofovir injection. Men should be advised to practice barrier contraceptive methods during and for 3 months after treatment with cidofovir injection.