CIDOFOVIR DIHYDRATE

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 2.8 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 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. structure

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 from study. One patient on delayed therapy was diagnosed with CMV gastrointestinal disease. ‡ CMV retinitis progression not confirmed by retinal photography. 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.

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, 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-dose 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.

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.

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, catheter blocked, cellulitis, chest pain, chills and fever, cryptococcosis, cyst, death, face edema, flu-like syndrome, hypothermia, injection site reaction, malaise, mucous membrane disorder, neck pain, overdose, photosensitivity reaction, sarcoma, sepsis Cardiovascular System : cardiomyopathy, cardiovascular disorder, congestive heart failure, hypertension, hypotension, migraine, pallor, peripheral vascular disorder, phlebitis, postural hypotension, shock, syncope, tachycardia, vascular disorder, edema Digestive System : cholangitis, colitis, constipation, esophagitis, dyspepsia, dysphagia, fecal incontinence, flatulence, gastritis, gastrointestinal hemorrhage, gingivitis, hepatitis, hepatomegaly, hepatosplenomegaly, jaundice, abnormal liver function, liver damage, liver necrosis, melena, pancreatitis, proctitis, rectal disorder, stomatitis, aphthous stomatitis, tongue discoloration, mouth ulceration, tooth caries Endocrine System: adrenal cortex insufficiency Hemic & Lymphatic System : hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, lymphoma like reaction, pancytopenia, splenic disorder, splenomegaly, thrombocytopenia, thrombocytopenic purpura Metabolic & Nutritional System : cachexia, dehydration, edema, hypercalcemia, hyperglycemia, hyperkalemia, hyperlipemia, hypocalcemia, hypoglycemia, hypoglycemic reaction, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypoproteinemia, increased alkaline phosphatase, increased BUN, increased lactic dehydrogenase, increased SGOT, increased SGPT, peripheral edema, respiratory alkalosis, thirst, weight loss, weight gain Musculoskeletal System : arthralgia, arthrosis, bone necrosis, bone pain, joint disorder, leg cramps, myalgia, myasthenia, pathological fracture Nervous System : abnormal dreams, abnormal gait, acute brain syndrome, agitation, amnesia, anxiety, ataxia, cerebrovascular disorder, confusion, convulsion, delirium, dementia, depression, dizziness, drug dependence, dry mouth, encephalopathy, facial paralysis, hallucinations, hemiplegia, hyperesthesia, hypertonia, hypotony, incoordination, increased libido, insomnia, myoclonus, nervousness, neuropathy, paresthesia, personality disorder, somnolence, speech disorder, tremor, twitching, vasodilatation, vertigo Respiratory System : asthma, bronchitis, epistaxis, hemoptysis, hiccup, hyperventilation, hypoxia, increased sputum, larynx edema, lung disorder, pharyngitis, pneumothorax, rhinitis, sinusitis Skin & Appendages : acne, angioedema, dry skin, eczema, exfoliative dermatitis, furunculosis, herpes simplex, nail disorder, pruritus, rash, seborrhea, skin discoloration, skin disorder, skin hypertrophy, skin ulcer, sweating, urticaria Special Senses : abnormal vision, amblyopia, blindness, cataract, conjunctivitis, corneal lesion, corneal opacity, diplopia, dry eyes, ear disorder, ear pain, eye disorder, eye pain, hyperacusis, iritis, keratitis, miosis, otitis externa, otitis media, refraction disorder, retinal detachment, retinal disorder, taste perversion, tinnitus, uveitis, visual field defect, hearing loss Urogenital System : decreased creatinine clearance, dysuria, glycosuria, hematuria, kidney stone, mastitis, metorrhagia, nocturia, polyuria, prostatic disorder, toxic nephrophathy, urethritis, urinary casts, urinary incontinence, urinary retention, urinary tract infection Table 5. All Clinical Adverse Events, Laboratory Abnormalities or Intercurrent Illnesses Regardless of Severity Occurring in >15% of Patients * Patients receiving 5 mg/kg maintenance regimen in Studies 106 and 107. N = 115 * # patients (%) Any Adverse Event 115(100) Proteinuria(≥30 mg/dL) 101(88) Nausea +/- Vomiting 79(69) Fever 67(58) Neutropenia(< 750 cells/mm 3 ) 50(43) Asthenia 50(43) Headache 34(30) Rash 34(30) Infection 32(28) Alopecia 31(27) Diarrhea 30(26) Pain 29(25) Creatinine Elevation (> 1.5 mg/dL) 28(24) Anemia 28(24) Anorexia 26(23) Dyspnea 26(23) Chills 25(22) Increased Cough 22(19) Oral Moniliasis 21(18) Reporting of Adverse Reactions Malignancies or serious adverse reactions that occur in patients who have received cidofovir injection should be reported to Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.