Cidofovir dihydrate

Overdose

Two cases of cidofovir overdose have been reported. These patients received single doses of Cidofovir Dihydrate 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 Cidofovir Dihydrate 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 Dihydrate is contraindicated in patients receiving agents with nephrotoxic potential. Such agents must be discontinued at least seven days prior to starting therapy with Cidofovir Dihydrate.

Cidofovir Dihydrate is contraindicated in patients with hypersensitivity to cidofovir.

Cidofovir Dihydrate is contraindicated in patients with a history of clinically severe hypersensitivity to probenecid or other sulfa-containing medications.

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

Pharmaceutical form

Undesirable effects

1. 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 Dihydrate 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 Cidofovir Dihydrate 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 Dihydrate 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 Cidofovir Dihydrate.

In clinical trials, Cidofovir Dihydrate 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

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 Dihydrate and are listed below regardless of causal relationship to Cidofovir Dihydrate. Evaluation of these reports was difficult because of the diverse manifestations of the underlying disease and because most patients received numerous concomitant medicines.

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

cardiomyopathy, cardiovascular disorder, congestive heart failure, hypertension, hypotension, migraine, pallor, peripheral vascular disorder, phlebitis, postural hypotension, shock, syncope, tachycardia, vascular disorder, edema

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

adrenal cortex insufficiency

hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, lymphoma like reaction, pancytopenia, splenic disorder, splenomegaly, thrombocytopenia, thrombocytopenic purpura

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

arthralgia, arthrosis, bone necrosis, bone pain, joint disorder, leg cramps, myalgia, myasthenia, pathological fracture

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

asthma, bronchitis, epistaxis, hemoptysis, hiccup, hyperventilation, hypoxia, increased sputum, larynx edema, lung disorder, pharyngitis, pneumothorax, rhinitis, sinusitis

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

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

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

Malignancies or serious adverse reactions that occur in patients who have received Cidofovir Dihydrate 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.

Therapeutic indications

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

Pharmacokinetic properties

Cidofovir Dihydrate 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 Cidofovir Dihydrate 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 Cidofovir Dihydrate dose administered with concomitant probenecid was excreted as unchanged drug within 24 hr. When Cidofovir Dihydrate 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*

In vitro, cidofovir was less than 6% bound to plasma or serum proteins over the cidofovir concentration range 0.25 to 25 μg/mL. CSF concentrations of cidofovir following intravenous infusion of Cidofovir Dihydrate 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.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Dose-dependent nephrotoxicity is the major dose-limiting toxicity related to Cidofovir Dihydrate administration. Cases of acute renal failure resulting in dialysis and/or contributing to death have occurred with as few as one or two doses of Cidofovir Dihydrate. Renal function (serum creatinine and urine protein) must be monitored within 48 hours prior to each dose of Cidofovir Dihydrate. Dose adjustment or discontinuation is required for changes in renal function (serum creatinine and/or urine protein) while on therapy. Proteinuria, as measured by urinalysis in a clinical laboratory, may be an early indicator of Cidofovir Dihydrate-related nephrotoxicity. Continued administration of Cidofovir Dihydrate may lead to additional proximal tubular cell injury, which may result in glycosuria, decreases in serum phosphate, uric acid, and bicarbonate, elevations in serum creatinine, and/or acute renal failure, in some cases, resulting in the need for dialysis. Patients with these adverse events occurring concurrently and meeting a criteria of Fanconi's syndrome have been reported. Renal function that did not return to baseline after drug discontinuation has been observed in clinical studies of Cidofovir Dihydrate.

Intravenous normal saline hydration and oral probenecid must accompany each Cidofovir Dihydrate infusion. Probenecid is known to interact with the metabolism or renal tubular excretion of many drugs (see PRECAUTIONS). The safety of Cidofovir Dihydrate 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).

Initiation of therapy with Cidofovir Dihydrate 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).

Neutropenia may occur during Cidofovir Dihydrate therapy. Neutrophil count should be monitored while receiving Cidofovir Dihydrate therapy.

Decreased intraocular pressure may occur during Cidofovir Dihydrate therapy, and in some instances has been associated with decreased visual acuity. Intraocular pressure should be monitored during Cidofovir Dihydrate therapy.

Decreased serum bicarbonate associated with proximal tubule injury and renal wasting syndrome (including Fanconi's syndrome) have been reported in patients receiving Cidofovir Dihydrate (see ADVERSE REACTIONS). Cases of metabolic acidosis in association with liver dysfunction and pancreatitis resulting in death have been reported in patients receiving Cidofovir Dihydrate.

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).

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

Uveitis or iritis was reported in clinical trials and during postmarketing in patients receiving Cidofovir Dihydrate 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 Cidofovir Dihydrate therapy.

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 Cidofovir Dihydrate 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 Cidofovir Dihydrate, 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 Cidofovir Dihydrate. 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 Cidofovir Dihydrate 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.

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. Cidofovir Dihydrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether cidofovir is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for adverse reactions as well as the potential for tumorigenicity shown for cidofovir in animal studies, Cidofovir Dihydrate 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.

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

No studies of the safety or efficacy of Cidofovir Dihydrate in patients over the age of 60 have been conducted. Since elderly individuals frequently have reduced glomerular filtration, particular attention should be paid to assessing renal function before and during Cidofovir Dihydrate administration (see DOSAGE AND ADMINISTRATION).

Dosage (Posology) and method of administration

Cidofovir Dihydrate MUST NOT BE ADMINISTERED BY INTRAOCULAR INJECTION.

THE RECOMMENDED DOSAGE, FREQUENCY, OR INFUSION RATE MUST NOT BE EXCEEDED. Cidofovir Dihydrate 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 Dihydrate INFUSION.

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

The recommended maintenance dose of Cidofovir Dihydrate is 5 mg/kg body weight (given as an intravenous infusion at a constant rate over 1 hr), administered once every 2 weeks.

The maintenance dose of Cidofovir Dihydrate 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. Cidofovir Dihydrate therapy must be discontinued for an increase in serum creatinine of ≥ 0.5 mg/dL above baseline or development of ≥ 3+ proteinuria.

Cidofovir Dihydrate 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 must be administered orally with each Cidofovir Dihydrate dose. Two grams must be administered 3 hr prior to the Cidofovir Dihydrate dose and one gram administered at 2 and again at 8 hr after completion of the 1 hr Cidofovir Dihydrate 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).

Patients must receive at least one liter of 0.9% (normal) saline solution intravenously with each infusion of Cidofovir Dihydrate. The saline solution should be infused over a 1–2 hr period immediately before the Cidofovir Dihydrate 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 Dihydrate infusion or immediately afterwards, and infused over a 1 to 3 hr period.

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 Dihydrate 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 Dihydrate 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 Cidofovir Dihydrate 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 Dihydrate 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.

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 Dihydrate. 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 Dihydrate contacts the skin, wash membranes and flush thoroughly with water. Excess Cidofovir Dihydrate 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.

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.