Cidofovir Dihydrate

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

What Is Cidofovir Dihydrate Used For?

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...

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)] × 0.85 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,...

Side Effects (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,...

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.

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.

Pregnancy and Breastfeeding

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.

Nursing Mothers It is not known whether cidofovir is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for adverse reactions as well as the potential for tumorigenicity shown for cidofovir in animal studies, cidofovir injection should not be administered to nursing mothers. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid postnatal transmission of HIV to a child who may not yet be infected.

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.

How Supplied

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].