Cidofovir (Vistide)
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Cidofovir (Vistide)

VISTIDE®
(cidofovir) Injection

FOR INTRAVENOUS INFUSION ONLY.
NOT FOR INTRAOCULAR INJECTION.

WARNING:

RENAL IMPAIRMENT IS THE MAJOR TOXICITY OF VISTIDE (cidofovir) . CASES OF ACUTE RENAL FAILURE RESULTING IN DIALYSIS AND/OR CONTRIBUTING TO DEATH HAVE OCCURRED WITH AS FEW AS ONE OR TWO DOSES OF VISTIDE (cidofovir) . TO REDUCE POSSIBLE NEPHROTOXICITY, INTRAVENOUS PREHYDRATION WITH NORMAL SALINE AND ADMINISTRATION OF PROBENECID MUST BE USED WITH EACH VISTIDE (cidofovir) INFUSION. RENAL FUNCTION (SERUM CREATININE AND URINE PROTEIN) MUST BE MONITORED WITHIN 48 HOURS PRIOR TO EACH DOSE OF VISTIDE (cidofovir) AND THE DOSE OF VISTIDE (cidofovir) MODIFIED FOR CHANGES IN RENAL FUNCTION AS APPROPRIATE (SEE DOSAGE AND ADMINISTRATION). VISTIDE (cidofovir) IS CONTRAINDICATED IN PATIENTS WHO ARE RECEIVING OTHER NEPHROTOXIC AGENTS.

NEUTROPENIA HAS BEEN OBSERVED IN ASSOCIATION WITH VISTIDE (cidofovir) TREATMENT. THEREFORE, NEUTROPHIL COUNTS SHOULD BE MONITORED DURING VISTIDE (cidofovir) THERAPY.

VISTIDE (cidofovir) 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).

DRUG DESCRIPTION

VISTIDE® is the brand name for cidofovir injection. 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:

VISTIDE®(cidofovir injection) Structural Formula Illustration

Cidofovir is a white crystalline powder with an aqueous solubility of ≥ 170 mg/mL at pH 6-8 and a log P (octanol/aqueous buffer, pH 7.1) value of -3.3.

VISTIDE (cidofovir) 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 with sodium hydroxide and/or hydrochloric acid and contains no preservatives. The appropriate volume of VISTIDE (cidofovir) must be removed from the single-use vial and diluted prior to administration (see DOSAGE AND ADMINISTRATION).

What are the possible side effects of cidofovir (Vistide)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any of these serious side effects:

  • urinating less than usual or not at all;
  • fever, chills, body aches, flu symptoms;
  • any change in your vision; or
  • increased thirst and urination, loss of appetite, weakness, constipation.

Less serious side effects are more likely to occur, such as:

  • nausea, vomiting, diarrhea, loss of...

Read All Potential Side Effects and See Pictures of Vistide »

What are the precautions when taking cidofovir (Vistide)?

Before using cidofovir, tell your doctor or pharmacist if you are allergic to it; or to other antivirals (e.g., ganciclovir); or to probenecid; or to other sulfa drugs (e.g., sulfamethoxazole); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe kidney disease.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: diabetes, ganciclovir eye implant, mild/moderate kidney disease.

This drug may cause vision changes. Do not drive, use machinery, or...

Read All Potential Precautions of Vistide »

Last reviewed on RxList: 8/14/2008
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

VISTIDE (cidofovir) is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS). THE SAFETY AND EFFICACY OF VISTIDE (cidofovir) 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.

DOSAGE AND ADMINISTRATION

VISTIDE (cidofovir) MUST NOT BE ADMINISTERED BY INTRAOCULAR INJECTION.

Dosage

THE RECOMMENDED DOSAGE, FREQUENCY, OR INFUSION RATE MUST NOT BE EXCEEDED. VISTIDE (cidofovir) 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 VISTIDE (cidofovir) INFUSION.

Induction Treatment

The recommended induction dose of VISTIDE (cidofovir) 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 VISTIDE (cidofovir) . CrCl (mL/min) should be calculated according to the following formula:

Creatinine clearance for males = [140-age (years)] X [body wt (kg)]
72 X [serum creatinine (mg/dL)]

Creatinine clearance for females = [140-age (years)] X [body wt (kg)] X 0.85
72 X [serum creatinine (mg/dL)]

Maintenance Treatment

The recommended maintenance dose of VISTIDE (cidofovir) 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 VISTIDE (cidofovir) Therapy: The maintenance dose of VIS-TIDE must be reduced from 5 mg/kg to 3 mg/kg for an increase in serum creatinine of 0.3 - 0.4 mg/dL above baseline. VISTIDE (cidofovir) 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: VISTIDE (cidofovir) 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 VISTIDE (cidofovir) dose. Two grams must be administered 3 hr prior to the VISTIDE (cidofovir) dose and one gram administered at 2 and again at 8 hr after completion of the 1 hr VISTIDE (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 VISTIDE (cidofovir) . The saline solution should be infused over a 1-2 hr period immediately before the VISTIDE (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 VISTIDE (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 VISTIDE (cidofovir) 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 VISTIDE (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 (2-8°C) for no more than 24 hr. Refrigerated admixtures should be allowed to equilibrate to room temperature prior to use.

The chemical stability of VISTIDE (cidofovir) 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.

VISTIDE (cidofovir) 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 VISTIDE (cidofovir) . 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 VISTIDE (cidofovir) contacts the skin, wash membranes and flush thoroughly with water. Excess VISTIDE (cidofovir) and all other materials used in the admixture preparation and administration should be placed in a leakproof, 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.

HOW SUPPLIED

VISTIDE (cidofovir injection) 75 mg/mL for intravenous infusion, is supplied as a non-preserved solution in single-use clear glass vials as follows:

NDC 61958-0101-1...............................375 mg in a 5 mL vial in a single-unit carton

VISTIDE (cidofovir) should be stored at controlled room temperature 20°-25°C (68°-77°F).

Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146-0568. Manufactured for and distributed by: Gilead Sciences, Inc. 333 Lakeside Drive Foster City, CA 94404.. September 2000. FDA Rev date: 06/26/01

Last reviewed on RxList: 8/14/2008
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

  1. Nephrotoxicity: Renal toxicity, as manifested by ≥ 2+ proteinuria, serum creati-nine elevations of ≥ 0.4 mg/dL, or decreased creatinine clearance ≤ 55 mL/min, occurred in 79 of 135 (59%) patients receiving VISTIDE (cidofovir) 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).
  2. Neutropenia: In clinical trials, at the 5 mg/kg maintenance dose, a decrease in absolute neutrophil count to ≤ 500 cells/mm3 occurred in 24% of patients. Granulocyte colony stimulating factor (GCSF) was used in 39% of patients.
  3. 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 0-1 mm Hg) has been reported in 3 patients. Risk of ocular hypotony may be increased in patients with preexisting diabetes mellitus.
  4. Anterior Uveitis/Iritis: Uveitis or iritis has been reported in clinical trials and during postmarketing in patients receiving VISTIDE (cidofovir) 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 VISTIDE (cidofovir) therapy.
  5. 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 VISTIDE (cidofovir) .

In clinical trials, VISTIDE (cidofovir) 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

  N =135a
# patients (%)
Proteinuria ( ≥ 100 mg/dL) 68 (50)
Neutropenia ( ≤ 500 cells/mm3) 33 (24)
Decreased Intraocular Pressureb 17 (24)
Decreased Serum Bicarbonate ( ≤ 16 mEq/L) 21 (16)
Fever 19 (14)
Infection 16 (12)
Creatinine Elevation ( ≥ 2.0 mg/dL) 16 (12)
Pneumonia 12 (9)
Dyspnea 11 (8)
Nausea with Vomiting 10 (7)
a Patients receiving 5 mg/kg maintenance regimen in Studies 105, 106 and 107.
b 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.

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 VISTIDE (cidofovir) and are listed below regardless of causal relationship to VISTIDE (cidofovir) . 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, lym-phadenopathy, 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, encephalopa-thy, 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

  N =115a
# patients (%)
Any Adverse Event 115 (100)
Proteinuria ( ≥ 30 mg/dL) 101 (88)
Nausea +/- Vomiting 79 (69)
Fever 67 (58)
Neutropenia (< 750 cells/mm3) 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)
a Patients receiving 5 mg/kg maintenance regimen in Studies 106 and 107.

Reporting of Adverse Reactions

Malignancies or serious adverse reactions that occur in patients who have received VISTIDE (cidofovir) should be reported to Gilead in writing to the Director of Clinical Research, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404 or by calling 1-800-GILEAD-5 (445-3235), or to FDA MedWatch 1-800-FDA-1088/fax 1-800-FDA-0178.

Read the Vistide (cidofovir) Side Effects Center for a complete guide to possible side effects »

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 VISTIDE (cidofovir) infusion.

Nephrotoxic agents: Concomitant administration of VISTIDE (cidofovir) and agents with nephrotoxic potential [e.g., intravenous aminoglycosides (e.g., tobramycin, gentamicin, and amikacin), amphotericin B, foscarnet, intravenous pentamidine, vancomycin, and non-steroidal anti-inflammatory agents] is contraindicated. Such agents must be discontinued at least seven days prior to starting therapy with VISTIDE (cidofovir) .

Last reviewed on RxList: 8/14/2008
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Nephrotoxicity: Dose-dependent nephrotoxicity is the major dose-limiting toxicity related to VISTIDE (cidofovir) 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 VISTIDE (cidofovir) . Renal function (serum creatinine and urine protein) must be monitored within 48 hours prior to each dose of VISTIDE (cidofovir) . 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 VISTIDE (cidofovir) -related nephrotoxicity. Continued administration of VISTIDE (cidofovir) 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 VISTIDE (cidofovir) .

Intravenous normal saline hydration and oral probenecid must accompany each VIS-TIDE infusion. Probenecid is known to interact with the metabolism or renal tubular excretion of many drugs (see PRECAUTIONS). The safety of VISTIDE (cidofovir) 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 antiinflammatory agents (see DOSAGE AND ADMINISTRATION).

Preexisting Renal Impairment: Initiation of therapy with VISTIDE (cidofovir) 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 VISTIDE (cidofovir) therapy. Neutrophil count should be monitored while receiving VISTIDE (cidofovir) therapy.

Decreased Intraocular Pressure/Ocular Hypotony: Decreased intraocular pressure may occur during VISTIDE (cidofovir) therapy, and in some instances has been associated with decreased visual acuity. Intraocular pressure should be monitored during VISTIDE (cidofovir) 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 VISTIDE (see ADVERSE REACTIONS). Cases of metabolic acidosis in association with liver dysfunction and pancreatitis resulting in death have been reported in patients receiving VISTIDE (cidofovir) .

PRECAUTIONS

General

Due to the potential for increased nephrotoxicity, doses greater than the recommended dose must not be administered and the frequency or rate of administration must not be exceeded (see DOSAGE AND ADMINISTRATION).

VISTIDE (cidofovir) is formulated for intravenous infusion only and must not be administered by intraocular injection. Administration of VISTIDE (cidofovir) by infusion must be accompanied by oral probenecid and intravenous saline prehydration (see DOSAGE AND ADMINISTRATION).

Uveitis/Iritis

Uveitis or iritis was reported in clinical trials and during postmarketing in patients receiving VISTIDE (cidofovir) therapy. Treatment with topical corticosteroids with or without topical cycloplegic agents should be considered. Patients should be monitored for signs and symptoms of uveitis/iritis during VISTIDE (cidofovir) therapy.

Carcinogenesis, Mutagenesis, & Impairment of Fertility

Chronic, two-year carcinogenicity studies in rats and mice have not been carried out to evaluate the carcinogenic potential of cidofovir. However, a 26-week toxicology study evaluating once weekly subscapular subcutaneous injections of cidofovir in rats was terminated at 19 weeks because of the induction, in females, of palpable masses, the first of which was detected after six doses. The masses were diagnosed as mammary adenocarcinomas which developed at doses as low as 0.6 mg/kg/week, equivalent to 0.04 times the human systemic exposure at the recommended intravenous VISTIDE (cidofovir) dose based on AUC comparisons.

In a 26-week intravenous toxicology study in which rats received 0.6, 3, or 15 mg/kg cidofovir once weekly, a significant increase in mammary adenocarcinomas in female rats as well as a significant incidence of Zymbal's gland carcinomas in male and female rats were seen at the high dose but not at the lower two doses. The high dose was equivalent to 1.1 times the human systemic exposure at the recommended dose of VISTIDE (cidofovir) , based on comparisons of AUC measurements. In light of the results of these studies, cidofovir should be considered to be a carcinogen in rats as well as a potential carcinogen in humans.

Cynomolgus monkeys received intravenous cidofovir, alone and in conjunction with concomitant oral probenecid, intravenously once weekly for 52 weeks at doses resulting in exposures of approximately 0.7 times the human systemic exposure at the recommended dose of VISTIDE (cidofovir) . No tumors were detected. However, the study was not designed as a carcinogenicity study due to the small number of animals at each dose and the short duration of treatment.

No mutagenic response was observed in microbial mutagenicity assays involving Salmonella typhimurium (Ames) and Escherichia coli in the presence and absence of metabolic activation. An increase in micronucleated polychromatic erythrocytes in vivo was seen in mice receiving ≥ 2000 mg/kg, a dosage approximately 65-fold higher than the maximum recommended clinical intravenous VISTIDE (cidofovir) dose based on body surface area estimations. Cidofovir induced chromosomal aberrations in human peripheral blood lymphocytes in vitro without metabolic activation. At the 4 cidofovir levels tested, the percentage of damaged metaphases and number of aberrations per cell increased in a concentration-dependent manner.

Studies showed that cidofovir caused inhibition of spermatogenesis in rats and monkeys. However, no adverse effects on fertility or reproduction were seen following once weekly intravenous injections of cidofovir in male rats for 13 consecutive weeks at doses up to 15 mg/kg/week (equivalent to 1.1 times the recommended human dose based on AUC comparisons). Female rats dosed intravenously once weekly at 1.2 mg/kg/week (equivalent to 0.09 times the recommended human dose based on AUC) or higher, for up to 6 weeks prior to mating and for 2 weeks post mating had decreased litter sizes and live births per litter and increased early resorptions per litter. Peri- and post-natal development studies in which female rats received subcutaneous injections of cidofovir once daily at doses up to 1.0 mg/kg/day from day 7 of gestation through day 21 postpartum (approximately 5 weeks) resulted in no adverse effects on viability, growth, behavior, sexual maturation or reproductive capacity in the offspring.

Pregnancy: Category C

Cidofovir was embryotoxic (reduced fetal body weights) in rats at 1.5 mg/kg/day and in rabbits at 1.0 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 (1.0 mg/kg/day) which was also maternally toxic. There are no adequate and well-controlled studies in pregnant women. VISTIDE (cidofovir) 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, VISTIDE (cidofovir) 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.

Pediatric Use

Safety and effectiveness in children have not been studied. The use of VISTIDE (cidofovir) in children with AIDS warrants extreme caution due to the risk of long-term carcino-genicity and reproductive toxicity. Administration of VISTIDE (cidofovir) to children should be undertaken only after careful evaluation and only if the potential benefits of treatment outweigh the risks.

Geriatric Use

No studies of the safety or efficacy of VISTIDE (cidofovir) 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 VISTIDE administration (see DOSAGE AND ADMINISTRATION).

Last reviewed on RxList: 8/14/2008
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

Two cases of cidofovir overdose have been reported. These patients received single doses of VISTIDE (cidofovir) 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.

CONTRAINDICATIONS

Initiation of therapy with VISTIDE (cidofovir) is contraindicated in patients with a serum creati-nine > 1.5 mg/dL, a calculated creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥ 2+ proteinuria).

VISTIDE (cidofovir) is contraindicated in patients receiving agents with nephrotoxic potential. Such agents must be discontinued at least seven days prior to starting therapy with VISTIDE (cidofovir)

VISTIDE (cidofovir) is contraindicated in patients with hypersensitivity to cidofovir.

VISTIDE (cidofovir) is contraindicated in patients with a history of clinically severe hypersensitiv- 102 ity to probenecid or other sulfa-containing medications.

Direct intraocular injection of VISTIDE is contraindicated; direct injection of cidofovir has been associated with iritis, ocular hypotony, and permanent impairment of vision.

Last reviewed on RxList: 8/14/2008
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

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 cid-ofovir. 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 - 2.8
HSV-1, HSV-2 12.7 - 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 7-15 µM .

There are insufficient data at this time to assess the frequency or the clinical significance of the development of resistant isolates following VISTIDE (cidofovir) 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/fos-carnet-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 poly-merase gene. The clinical significance of the development of these cross-resistant isolates is not known.

Pharmacokinetics

VISTIDE (cidofovir) 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 1.0 (n = 5), 3.0 (n = 10), 5.0 (n = 2) and 10.0 (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 VISTIDE (cidofovir) 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 3.0 (n = 12), 5.0 (n = 6), and 7.5 (n = 4) mg/kg (See Table 2). Approximately 70 to 85% of the VISTIDE (cidofovir) dose administered with concomitant probenecid was excreted as unchanged drug within 24 hr. When VISTIDE (cidofovir) 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 3.0 and 5.0 mg/kg Infusions, Without and With Probenecid*

PARAMETERS VISTIDE ADMINISTERED WITHOUT PROBENECID VISTIDE ADMINISTERED WITH PROBENECID
3 mg/kg
(n = 10)
5 mg/kg
(n = 2)
3 mg/kg
(n = 12)
5 mg/kg
(n = 6)
AUC (µg•hr/mL) 20.0 ± 2.3 28.3 25.7 ± 8.5 40.8 ± 9.0
Cmax (end of infusion) (µg/mL) 7.3 ± 1.4 11.5 9.8 ± 3.7 19.6 ± 7.2
Vdss (mL/kg) 537 ± 126
(n = 12)
410 ± 102
(n = 18)
Clearance (mL/min/1.73 m2) 179 ± 23.1
(n = 12)
148 ± 38.8
(n = 18)
Renal Clearance (mL/min/1.73 m2) 150 ± 26.9
(n = 12)
98.6 ± 27.9
(n = 11)
* See DOSAGE AND ADMINISTRATION

In vitro, cidofovir was less than 6% bound to plasma or serum proteins over the cido-fovir concentration range 0.25 to 25 µg/mL. CSF concentrations of cidofovir following intravenous infusion of VISTIDE (cidofovir) 5 mg/kg with concomitant probenecid and intravenous hydration were undetectable ( < 0.1 µg/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 µg/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 VISTIDE (cidofovir) 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.

Description Of Clinical Trials

Three phase II/III controlled trials of VISTIDE (cidofovir) 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 VISTIDE (cidofovir) (5 mg/kg once a week for 2 weeks, then 3 mg/kg every other week) or to have VISTIDE (cidofovir) 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 VISTIDE (cidofovir) (5 mg/kg once a week for 2 weeks, then 5 mg/kg every other week), immediate treatment with VISTIDE (cidofovir) (5 mg/kg once a week for 2 weeks, then 3 mg/kg every other week), or to have VISTIDE (cidofovir) 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 VISTIDE (cidofovir) (5 mg/kg once a week for 2 weeks, then 5 mg/kg every other week), or to have VISTIDE (cidofovir) 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 VISTIDE (cidofovir) 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 3a 1
  Discontinued Due to Intercurrent Illness 2b 1b
  Discontinued Based on Ophthalmological Examination 1c 1c
  No Progression at Study Completion 1 0
  Not Evaluable at Baseline 2 2
aOne patient died 2 weeks after withdrawing consent.
bTwo patients on immediate therapy were diagnosed with CMV disease and discontinued from study. One patient on delayed therapy was diagnosed with CMV gastrointestinal disease.
cCMV retinitis progression not confirmed by retinal photography.

Dose-response study of VISTIDE (cidofovir) (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.

REFERENCES

1. Ho HT, Woods KL, Bronson JJ, De Boeck H, Martin JC and Hitchcock MJM. Intracellular Metabolism of the Antiherpesvirus Agent (S)-1-[3-hydroxy-2-(phos-phonylmethoxy)propyl]cytosine. Mol Pharmacol 41:197-202, 1992.

2. Cherrington JM, Allen SJW, McKee BH, and Chen MS. Kinetic Analysis of the Interaction Between the Diphosphate of (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine, zalcitabineTP, zidovudineTP, and FIAUTP with Human DNA Polymerases b and g. Biochem Pharmacol 48:1986-1988, 1994.

3. Xiong X, Smith JL, Kim C, Huang E, and Chen MS. Kinetic Analysis of the Interaction of Cidofovir Diphosphate with Human Cytomegalovirus DNA Polymerase. Biochem Pharmacol 51:1563-1567, 1996.

4. Cherrington JM, Mulato AS, Fuller MD, Chen MS. In Vitro Selection of a Human Cytomegalovirus (HCMV) that is Resistant to Cidofovir. 35th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, CA. Abstract H117, 1995.

5. Stanat SC, Reardon JE, Erice A, Jordan MC, Drew WL, and Biron KK. Ganciclovir-Resistant Cytomegalovirus Clinical Isolates: Mode of Resistance to Ganciclovir. Antimicrob Agents Chemother 35:2191-2197, 1991.

6. Sullivan V, Biron KK, Talarico C, Stanat SC, Davis M, Pozzi M, and Coen DM. A Point Mutation in the Human Cytomegalovirus DNA Polymerase Gene Confers Resistance to Ganciclovir and phosphonylmethoxyalkyl Derivatives. Antimicrob Agents Chemother 37:19-25, 1993.

7. Tatarowicz WA, Lurain NS, and Thompson KD. A Ganciclovir-Resistant Clinical Isolate of Human Cytomegalovirus Exhibiting Cross-Resistance to other DNA Polymerase Inhibitors. J Infect Dis 166:904-907, 1992.

8. Lurain NS, Thompson KD, Holmes EW, and Read GS. Point Mutations in the DNA Polymerase Gene of Human Cytomegalovirus that Result in Resistance to Antiviral Agents. J Virol 66:7146-7152, 1992.

9. Smith IL, Cherrington JM, Jiles RE, Fuller MD, Freeman WR, Spector SA. High-level Resistance of Cytomegalovirus to Ganciclovir is Associated with Alterations in both the UL97 and DNA Polymerase Genes. J Infect Dis 176:69-77, 1997.

10. Sullivan V and Coen DM. Isolation of Foscarnet-Resistant Human Cytomegalovirus Patterns of Resistance and Sensitivity to Other Antiviral Drugs. J Infect Dis 164:781-784, 1991.

11. Snoeck R, Andrei G, and De Clercq E. Patterns of Resistance and Sensitivity to Antiviral Compounds of Drug-Resistant Strains of Human Cytomegalovirus Selected in Vitro. Eur J Clin Microbiol Infect Dis 15:574-579, 1996.

12. Baldanti F, Underwood MR, Stanat SC, Biron KK, Chou S, Sarasini A, Silini E, and Gerna G. Single Amino Acid Changes in the DNA Polymerase Confer Foscarnet Resistance and Slow-Growth Phenotype, While Mutations in the UL97-Encoded Phosphotransferase Confer Ganciclovir Resistance in Three Double-Resistant Human Cytomegalovirus Strains Recovered from Patients with AIDS. J Virol 70:1390-1395, 1996.

13. The Studies of Ocular Complications of AIDS Research Group in Collaboration with the AIDS Clinical Trials Group. Cidofovir (HPMPC) for the Treatment of Cytomegalovirus Retinitis in Patients with AIDS: the HPMPC Peripheral Cytomegalovirus Retinitis Trial. Ann Intern Med 126:264-274, 1997.

14. Lalezari JP, Stagg RJ, Kupperman BD, et al. Intravenous Cidofovir for Peripheral Cytomegalovirus Retinitis in Patients with AIDS. A Randomized, Controlled Trial. Ann Intern Med 126:257-263, 1997.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

Patients should be advised that VISTIDE (cidofovir) is not a cure for CMV retinitis, and that they may continue to experience progression of retinitis during and following treatment. Patients receiving VISTIDE (cidofovir) should be advised to have regular follow-up ophthalmologic examinations. Patients may also experience other manifestations of CMV disease despite VISTIDE (cidofovir) 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 VISTIDE (cidofovir) administration only, because probenecid reduces metabolic clearance of zidovudine.

Patients should be informed of the major toxicity of VISTIDE (cidofovir) , 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 VISTIDE (cidofovir) 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. VISTIDE (cidofovir) 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 VISTIDE (cidofovir) .

Patients should be advised that VISTIDE (cidofovir) 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 VISTIDE (cidofovir) . Men should be advised to practice barrier contraceptive methods during and for 3 months after treatment with VISTIDE (cidofovir) .

Last reviewed on RxList: 8/14/2008
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

Patients should be advised that VISTIDE (cidofovir) is not a cure for CMV retinitis, and that they may continue to experience progression of retinitis during and following treatment. Patients receiving VISTIDE (cidofovir) should be advised to have regular follow-up ophthalmologic examinations. Patients may also experience other manifestations of CMV disease despite VISTIDE (cidofovir) 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 VISTIDE (cidofovir) administration only, because probenecid reduces metabolic clearance of zidovudine.

Patients should be informed of the major toxicity of VISTIDE (cidofovir) , 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 VISTIDE (cidofovir) 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. VISTIDE (cidofovir) 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 VISTIDE (cidofovir) .

Patients should be advised that VISTIDE (cidofovir) 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 VISTIDE (cidofovir) . Men should be advised to practice barrier contraceptive methods during and for 3 months after treatment with VISTIDE (cidofovir) .

Last reviewed on RxList: 8/14/2008
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Vistide Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

CIDOFOVIR - INJECTION

(sye-DOH-foh-veer)

COMMON BRAND NAME(S): Vistide

WARNING: This medication may cause serious (possibly fatal) kidney disease. To prevent kidney problems, your doctor will usually prescribe another medication (probenecid) and direct you to receive fluids into a vein. Avoid other medications that may also damage your kidneys (see also Drug Interactions section). Tell your doctor immediately if you have any symptoms of kidney disease such as a change in the amount of urine.

This medication can lower the body's ability to fight an infection. Tell your doctor promptly if you develop any signs of an infection such as fever, chills, or persistent sore throat.

Laboratory and/or medical tests (e.g., kidney function tests, complete blood counts) should be performed before each dose to check for these side effects. Consult your doctor for more details. Keep all medical and laboratory appointments.

Cidofovir has caused tumors in laboratory animals. Although there is no information in humans, cidofovir should be considered cancer-causing (carcinogenic). See also How to Use section.

USES: This drug is used with probenecid to treat a certain viral eye infection (retinitis due to cytomegalovirus-CMV) in people with AIDS. It lowers your risk of blindness and other vision problems. Cidofovir belongs to a class of drugs known as antivirals. It works by stopping the growth of the virus.

Cidofovir is not a cure for CMV retinitis, and your disease may still worsen during and after treatment.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This medication may also be used to treat herpes simplex virus infections that have not responded to other treatment.

HOW TO USE: This medication is given into a vein as directed by your doctor, usually over 1 hour. It is usually given every 1 to 2 weeks or as directed by your doctor. This medication should not be injected into the eyes. Permanent loss of vision may occur.

Dosage is based on your medical condition, body weight, and response to treatment. You will usually receive IV fluids before your dose of cidofovir. Your doctor will also direct you to take probenecid by mouth before and after you receive cidofovir. To prevent kidney problems, drink plenty of fluids unless otherwise directed by your doctor. This is especially important if you are vomiting or having diarrhea.

If you are giving this medication to yourself at home, learn all preparation and usage instructions from your health care professional. Before using, check this product visually for particles or discoloration. If either is present, do not use the liquid. Learn how to store and discard medical supplies safely.

It is very important to use the probenecid with this medication exactly as prescribed by your doctor. Nausea and vomiting due to probenecid may be prevented by taking it after meals. Your doctor may also prescribe another medication to prevent nausea, and may direct you to take antihistamines (e.g., diphenhydramine) and/or acetaminophen to prevent allergic reactions to probenecid.

This medication works best when it is used regularly. Keep all your medical appointments. You may want to mark a calendar to help you remember.

Do not use more or less of this drug than prescribed or stop using it (or your HIV medicines) even for a short time unless directed to do so by your doctor. Doing so may cause the amount of virus to increase, make the infection more difficult to treat (resistant), or worsen side effects.

Avoid direct contact of this medicine with the skin/eyes/mouth. If contact occurs, wash thoroughly with soap and water. For eyes, rinse with a steady stream of tap water for at least 5 minutes.

Disclaimer

Vistide Consumer (continued)

SIDE EFFECTS: Nausea may occur. Headache, nausea, and vomiting may occur with probenecid use. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor right away if you have any serious side effects, including: change in the amount of urine, frothy/dark urine, bloody/pink urine, swelling, loss of appetite, unusual tiredness/sluggishness, stomach/abdominal pain, muscle loss, signs of infection (e.g., fever, persistent sore throat/cough), vision changes, new/increased eye redness or irritation, new/increased eye pain, mental/mood changes (e.g., confusion), persistent nausea/vomiting, yellowing eyes/skin.

A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any of the following symptoms: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Vistide (cidofovir) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before using cidofovir, tell your doctor or pharmacist if you are allergic to it; or to other antivirals (e.g., ganciclovir); or to probenecid; or to other sulfa drugs (e.g., sulfamethoxazole); or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: severe kidney disease.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: diabetes, ganciclovir eye implant, mild/moderate kidney disease.

This drug may cause vision changes. Do not drive, use machinery, or do any activity that requires clear vision until you are sure you can perform such activities safely. Limit alcoholic beverages.

Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, elderly people may be at a greater risk for kidney damage while using this drug.

During pregnancy, cidofovir should be used only when clearly needed. It may harm an unborn baby. Discuss the risks and benefits with your doctor. The manufacturer recommends avoiding pregnancy. To prevent pregnancy, men with female partners should use effective barrier protections (such as latex or polyurethane condoms) during all sexual activity during treatment and for at least 90 days after stopping the medication. Women should use at least 2 forms of effective birth control (such as birth control pills and condoms) during treatment and for at least 1 month after stopping the medication.

It is not known if this medication passes into breast milk. Because of the possible risks to the infant and because breast milk can transmit HIV, do not breast-feed.

Disclaimer

Vistide Consumer (continued)

DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: acyclovir, angiotensin-converting enzyme inhibitors, aminosalicylic acid, barbiturates (e.g., phenobarbital), benzodiazepines (e.g., triazolam), bumetanide, clofibrate, methotrexate, famotidine, furosemide, nonsteroidal anti-inflammatory drugs-NSAIDs (e.g., ibuprofen), theophylline, zidovudine.

If you are taking probenecid and any of the medications listed above, ask your doctor if you should temporarily stop the other medication or decrease its dosage because probenecid may affect how well those medications are removed from your body. This is very important for zidovudine.

Tell your doctor if you have had previous use of foscarnet.

Avoid taking other medications that may damage your kidneys (e.g., amphotericin B, foscarnet, pentamidine, vancomycin, aminoglycosides including tobramycin, nonsteroidal anti-inflammatory drugs-NSAIDs including ibuprofen) within 7 days before and during treatment with this medication. In some cases, serious (possibly fatal) kidney damage may occur. See also Warning section.

Check the labels on all your medicines because they may contain NSAIDs (e.g., ibuprofen, naproxen). Ask your pharmacist about using those products safely.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include: change in the amount of urine.

NOTES: Laboratory and/or medical tests (e.g., eye exams) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

To decrease your risk of spreading HIV disease to others, always use an effective barrier method (e.g., latex or polyurethane condoms/dental dams) during sexual activity. Consult your doctor or pharmacist for more details.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose of cidofovir, contact your doctor or pharmacist immediately to establish a new dosing schedule. Do not double the dose to catch up. If you miss a dose of the probenecid, tell your doctor or pharmacist immediately. You may have to reschedule your cidofovir dose.

STORAGE: Consult the product instructions and your pharmacist for storage details. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

Information last revised April 2012. Copyright(c) 2012 First Databank, Inc.

Vistide Patient Information Including Side Effects

Brand Names: Vistide

Generic Name: cidofovir (Pronunciation: si DOF o veer)

What is cidofovir (Vistide)?

Cidofovir is an antiviral medication that works by preventing certain viral cells from multiplying in your body.

Cidofovir is used to treat an eye infection called cytomegalovirus retinitis (CMV) in people who are infected with HIV (human immunodeficiency virus).

Cidofovir may also be used for purposes other than those listed in this medication guide.

What are the possible side effects of cidofovir (Vistide)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any of these serious side effects:

  • urinating less than usual or not at all;
  • fever, chills, body aches, flu symptoms;
  • any change in your vision; or
  • increased thirst and urination, loss of appetite, weakness, constipation.

Less serious side effects are more likely to occur, such as:

  • nausea, vomiting, diarrhea, loss of appetite;
  • white patches or sores inside your mouth or on your lips;
  • headache;
  • mild skin rash;
  • hair loss; or
  • cough.

Side effects other than those listed here may also occur. Talk to your doctor about any side effect that seems unusual or that is especially bothersome. You may report side effects to FDA at 1-800-FDA-1088.

Read the Vistide (cidofovir) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about cidofovir (Vistide)?

Do not receive this medication if you are allergic to cidofovir, probenecid (Benemid), or sulfa drugs, or if you have severe kidney disease.

Cidofovir may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Use an effective form of birth control while you are using cidofovir and for at least 1 month after your treatment ends.

Cidofovir can affect fertility (ability to have children) in men. If a man fathers a child while using this medication, the baby may have birth defects. Use a condom to prevent pregnancy during your treatment. Continue using condoms for at least 3 months after you stop using cidofovir.

Cidofovir must be used together with an oral (taken by mouth) medicine called probenecid (Benemid). Be sure to read the medication guide or patient instructions provided with each of your medications.

Cidofovir has caused certain types of tumors in animals. It is not known if humans would also have an increased risk of tumors. Talk with your doctor about your specific risk.

Side Effects Centers

Vistide Patient Information including How Should I Take

What should I discuss with my health care provider before receiving cidofovir (Vistide)?

Do not receive this medication if you are allergic to cidofovir, probenecid (Benemid), or sulfa drugs, or if you have severe kidney disease.

Do not receive cidofovir if you have used any of the following medications within the past 7 days:

  • pentamidine (Nebupent, Pentam);
  • tacrolimus (Prograf);
  • amphotericin B (Fungizone, AmBisome, Amphotec, Abelcet);
  • antibiotics such as capreomycin (Capastat), rifampin (Rifadin, Rimactane, Rifater), vancomycin (Vancocin, Vancoled);
  • antiviral medicines such as acyclovir (Zovirax), adefovir (Hepsera), or foscarnet (Foscavir); or
  • cancer medicine such as aldesleukin (Proleukin), carmustine (BiCNU, Gliadel), cisplatin (Platinol), ifosfamide (Ifex), oxaliplatin (Eloxatin), plicamycin (Mithracin), streptozocin (Zanosar), or tretinoin (Vesanoid).

Before using cidofovir, tell your doctor if you are allergic to any drugs, or if you have kidney disease. You may not be able to receive cidofovir, or you may need dosage adjustments or special tests during treatment.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Use an effective form of birth control while you are using cidofovir and for at least 1 month after your treatment ends.

This medication can affect fertility (ability to have children) in men. If a man fathers a child while using this medication, the baby may have birth defects. Use a condom to prevent pregnancy during your treatment. Continue using condoms for at least 3 months after you stop using cidofovir.

It is not known whether cidofovir passes into breast milk or if it could harm a nursing baby. Do not receive this medication without telling your doctor if you are breast-feeding a baby.

Cidofovir has caused certain types of tumors in animals. It is not known if humans would also have an increased risk of tumors. Talk with your doctor about your specific risk.

How is cidofovir used (Vistide)?

Cidofovir is given as an injection through a needle placed into a vein. You will receive this injection in a clinic or hospital setting. The medicine must be given slowly through an IV infusion. You may also be given an IV saline solution for 1 to 3 hours before and after you receive your cidofovir injection. This IV treatment can take up to 6 hours to complete.

To keep you from getting dehydrated, you may also be given an IV saline solution for 1 to 3 hours before and after you receive your cidofovir injection. Your IV treatment can take up to 6 hours to complete.

Cidofovir must be used together with an oral (taken by mouth) medicine called probenecid (Benemid). Be sure to read the medication guide or patient instructions provided with each of your medications.

Cidofovir and probenecid are usually given once a week for 2 weeks, and then once every 2 weeks. It is important to receive this medication for the entire length of time prescribed by your doctor. Your symptoms may get better before the infection is completely treated.

To be sure this medication is not causing harmful effects, your blood will need to be tested on a regular basis. Your kidney function may also need to be tested. Do not miss any scheduled visits to your doctor.

Side Effects Centers

Vistide Patient Information including If I Miss a Dose

What happens if I miss a dose (Vistide)?

Call your doctor if you miss an appointment to receive your cidofovir injection.

What happens if I overdose (Vistide)?

Seek emergency medical attention if you think you have received too much of this medicine.

Symptoms of a cidofovir overdose are not known.

What should I avoid while receiving cidofovir (Vistide)?

There are no restrictions on food, beverages, or activity while using cidofovir unless your doctor has told you otherwise.

What other drugs will affect cidofovir (Vistide)?

Before using cidofovir, tell your doctor if you are using any of the following drugs:

  • acetaminophen (Tylenol);
  • acyclovir (Zovirax);
  • zidovudine (Retrovir, AZT);
  • bumetanide (Bumex);
  • clofibrate (Atromid);
  • famotidine (Pepcid);
  • furosemide (Lasix);
  • methotrexate (Rheumatrex, Trexall);
  • theophylline (Elixophyllin, Respbid, Theobid, Theo-Dur, and others);
  • aspirin or other NSAIDs (non-steroidal anti-inflammatory drugs) such as ibuprofen (Motrin, Advil), naproxen (Aleve, Naprosyn), diclofenac (Voltaren), diflunisal (Dolobid), etodolac (Lodine), flurbiprofen (Ansaid), indomethacin (Indocin), ketoprofen (Orudis), ketorolac (Toradol), mefenamic acid (Ponstel), meloxicam (Mobic), nabumetone (Relafen), piroxicam (Feldene), and others;
  • an ACE inhibitor such as benazepril (Lotensin), captopril (Capoten), fosinopril (Monopril), enalapril (Vasotec), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), or trandolapril (Mavik);
  • a barbiturate such as amobarbital (Amytal), butabarbital (Butisol), mephobarbital (Mebaral), secobarbital (Seconal), or phenobarbital (Luminal, Solfoton); or
  • diazepam (Valium) or similar medicines such as alprazolam (Xanax), chlordiazepoxide (Librium), clorazepate (Tranxene), estazolam (ProSom), flurazepam (Dalmane), lorazepam (Ativan), midazolam (Versed), temazepam (Restoril), triazolam (Halcion), and others.

If you are using any of these drugs, you may not be able to receive cidofovir, or you may need dosage adjustments or special tests during treatment.

There may be other drugs not listed that can affect cidofovir. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

Where can I get more information?

Your pharmacist has information about cidofovir written for health professionals that you may read.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

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