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Cidofovir Anhydrous
Overview
What is Cidofovir?
The chemical name of cidofovir is 1-[()-3-hydroxy-2-(phosphonomethoxy)propyl]cytosine dihydrate (HPMPC), with the molecular formula of CHNOP•2HO and a molecular weight of 315.22 (279.19 for anhydrous). The chemical structure is:
Cidofovir is a white crystalline powder with an aqueous solubility of ≥ 170 mg/mL at pH 6 to 8 and a log P (octanol/aqueous buffer, pH 7.1) value of -3.3.
Cidofovir injection 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 cidofovir injection must be removed from the single-use vial and diluted prior to administration (see ).
What does Cidofovir look like?
What are the available doses of Cidofovir?
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What should I talk to my health care provider before I take Cidofovir?
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How should I use Cidofovir?
Cidofovir is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS). THE SAFETY AND EFFICACY OF CIDOFOVIR INJECTION HAVE NOT BEEN ESTABLISHED FOR TREATMENT OF OTHER CMV INFECTIONS (SUCH AS PNEUMONITIS OR GASTROENTERITIS), CONGENITAL OR NEONATAL CMV DISEASE, OR CMV DISEASE IN NON-HIV-INFECTED INDIVIDUALS.
CIDOFOVIR INJECTION MUST NOT BE ADMINISTERED BY INTRAOCULAR INJECTION.
What interacts with Cidofovir?
Initiation of therapy with cidofovir injection is contraindicated in patients with a serum creatinine > 1.5 mg/dL, a calculated creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥ 2+ proteinuria).
Cidofovir injection is contraindicated in patients receiving agents with nephrotoxic potential. Such agents must be discontinued at least seven days prior to starting therapy with cidofovir injection.
Cidofovir injection is contraindicated in patients with hypersensitivity to cidofovir.
Cidofovir injection is contraindicated in patients with a history of clinically severe hypersensitivity to probenecid or other sulfa-containing medications.
Direct intraocular injection of cidofovir injection is contraindicated; direct injection of cidofovir has been associated with iritis, ocular hypotony, and permanent impairment of vision.
What are the warnings of Cidofovir?
Nephrotoxicity
Dose dependent nephrotoxicity is the major dose-limiting toxicity related to cidofovir injection administration. Cases of acute renal failure resulting in dialysis and/or contributing to death have occurred with as few as one or two doses of cidofovir injection. Renal function (serum creatinine and urine protein) must be monitored within 48 hours prior to each dose of cidofovir injection. Dose adjustment or discontinuation is required for changes in renal function (serum creatinine and/or urine protein) while on therapy. Proteinuria, as measured by urinalysis in a clinical laboratory, may be an early indicator of cidofovir injection-related nephrotoxicity. Continued administration of cidofovir injection may lead to additional proximal tubular cell injury, which may result in glycosuria, decreases in serum phosphate, uric acid, and bicarbonate, elevations in serum creatinine, and/or acute renal failure, in some cases, resulting in the need for dialysis. Patients with these adverse events occurring concurrently and meeting a criteria of Fanconi's syndrome have been reported. Renal function that did not return to baseline after drug discontinuation has been observed in clinical studies of cidofovir injection.
Intravenous normal saline hydration and oral probenecid must accompany each cidofovir injection infusion. Probenecid is known to interact with the metabolism or renal tubular excretion of many drugs (see ). The safety of cidofovir injection has not been evaluated in patients receiving other known potentially nephrotoxic agents, such as intravenous aminoglycosides (e.g., tobramycin, gentamicin, and amikacin), amphotericin B, foscarnet, intravenous pentamidine, vancomycin, and non-steroidal anti-inflammatory agents (see ).
Preexisting Renal Impairment
Initiation of therapy with cidofovir injection is contraindicated in patients with a baseline serum creatinine > 1.5 mg/dL, a creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥ 2+ proteinuria).
Hematological Toxicity
Neutropenia may occur during cidofovir injection therapy. Neutrophil count should be monitored while receiving cidofovir injection therapy.
Decreased Intraocular Pressure/Ocular Hypotony
Decreased intraocular pressure may occur during cidofovir injection therapy, and in some instances has been associated with decreased visual acuity. Intraocular pressure should be monitored during cidofovir injection therapy.
Metabolic Acidosis
Decreased serum bicarbonate associated with proximal tubule injury and renal wasting syndrome (including Fanconi's syndrome) have been reported in patients receiving cidofovir injection (see ). Cases of metabolic acidosis in association with liver dysfunction and pancreatitis resulting in death have been reported in patients receiving cidofovir injection.
What are the precautions of Cidofovir?
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 ).
Cidofovir injection is formulated for intravenous infusion only and must not be administered by intraocular injection. Administration of cidofovir injection by infusion must be accompanied by oral probenecid and intravenous saline prehydration (see ).
Uveitis/Iritis
Uveitis or iritis was reported in clinical trials and during postmarketing in patients receiving cidofovir injection 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 injection therapy.
Information for Patients
Patients should be advised that cidofovir injection is not a cure for CMV retinitis, and that they may continue to experience progression of retinitis during and following treatment. Patients receiving cidofovir injection should be advised to have regular follow-up ophthalmologic examinations. Patients may also experience other manifestations of CMV disease despite cidofovir injection therapy.
HIV-infected patients may continue taking antiretroviral therapy, but those taking zidovudine should be advised to temporarily discontinue zidovudine administration or decrease their zidovudine dose by 50%, on days of cidofovir injection administration only, because probenecid reduces metabolic clearance of zidovudine.
Patients should be informed of the major toxicity of cidofovir injection, namely renal impairment, and that dose modification, including reduction, interruption, and possibly discontinuation, may be required. Close monitoring of renal function (routine urinalysis and serum creatinine) while on therapy should be emphasized.
The importance of completing a full course of probenecid with each cidofovir injection dose should be emphasized. Patients should be warned of potential adverse events caused by probenecid (e.g., headache, nausea, vomiting, and hypersensitivity reactions). Hypersensitivity/allergic reactions may include rash, fever, chills and anaphylaxis. Administration of probenecid after a meal or use of antiemetics may decrease the nausea. Prophylactic or therapeutic antihistamines and/or acetaminophen can be used to ameliorate hypersensitivity reactions.
Patients should be advised that cidofovir causes tumors, primarily mammary adenocarcinomas, in rats. Cidofovir injection should be considered a potential carcinogen in humans (see ). Women should be advised of the limited enrollment of women in clinical trials of cidofovir injection.
Patients should be advised that cidofovir injection caused reduced testes weight and hypospermia in animals. Such changes may occur in humans and cause infertility. Women of childbearing potential should be advised that cidofovir is embryotoxic in animals and should not be used during pregnancy. Women of childbearing potential should be advised to use effective contraception during and for one month following treatment with cidofovir injection. Men should be advised to practice barrier contraceptive methods during and for 3 months after treatment with cidofovir injection.
Drug Interactions
Probenecid
Probenecid is known to interact with the metabolism or renal tubular excretion of many drugs (e.g., acetaminophen, acyclovir, angiotensin-converting enzyme inhibitors, aminosalicylic acid, barbiturates, benzodiazepines, bumetanide, clofibrate, methotrexate, famotidine, furosemide, nonsteroidal anti-inflammatory agents, theophylline, and zidovudine). Concomitant medications should be carefully assessed. Zidovudine should either be temporarily discontinued or decreased by 50% when coadministered with probenecid on the day of cidofovir injection infusion.
Nephrotoxic Agents
Concomitant administration of cidofovir injection and agents with nephrotoxic potential [e.g., intravenous aminoglycosides (e.g., tobramycin, gentamicin, and amikacin), amphotericin B, foscarnet, intravenous pentamidine, vancomycin, and nonsteroidal anti-inflammatory agents] is contraindicated. Such agents must be discontinued at least 7 days prior to starting therapy with cidofovir injection.
Carcinogenesis, Mutagenesis and Impairment of Fertility
Chronic, 2-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 injection 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 injection, 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 injection. 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 (Ames) and in the presence and absence of metabolic activation. An increase in micronucleated polychromatic erythrocytes was seen in mice receiving ≥ 2000 mg/kg, a dosage approximately 65-fold higher than the maximum recommended clinical intravenous cidofovir injection dose based on body surface area estimations. Cidofovir induced chromosomal aberrations in human peripheral blood lymphocytes without metabolic activation. At the four 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
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 mg/kg/day) which was also maternally toxic. There are no adequate and well controlled studies in pregnant women. Cidofovir injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether cidofovir is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for adverse reactions as well as the potential for tumorigenicity shown for cidofovir in animal studies, cidofovir injection should not be administered to nursing mothers. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid postnatal transmission of HIV to a child who may not yet be infected.
Pediatric Use
Safety and effectiveness in children have not been studied. The use of cidofovir injection in children with AIDS warrants extreme caution due to the risk of long-term carcinogenicity and reproductive toxicity. Administration of cidofovir injection to children should be undertaken only after careful evaluation and only if the potential benefits of treatment outweigh the risks.
Geriatric Use
No studies of the safety or efficacy of cidofovir injection in patients over the age of 60 have been conducted. Since elderly individuals frequently have reduced glomerular filtration, particular attention should be paid to assessing renal function before and during cidofovir injection administration (see ).
What are the side effects of Cidofovir?
In clinical trials, cidofovir injection was withdrawn due to adverse events in 39% of patients treated with 5 mg/kg every other week as maintenance therapy.
The incidence of adverse reactions reported as serious in three controlled clinical studies in patients with CMV retinitis, regardless of presumed relationship to drug, is listed in Table 4.
The most frequently reported adverse events regardless of relationship to study drugs (cidofovir or probenecid) or severity are shown in Table 5.
The following additional list of adverse events/intercurrent illnesses have been observed in clinical studies of cidofovir injection and are listed below regardless of causal relationship to cidofovir injection. Evaluation of these reports was difficult because of the diverse manifestations of the underlying disease and because most patients received numerous concomitant medicines.
Body as a Whole
Cardiovascular System
Digestive System
Endocrine System:
Hemic and Lymphatic System
Metabolic and Nutritional System
Musculoskeletal System
Nervous System
Respiratory System
Skin and Appendages
Special Senses
Urogenital System
| N = 135 | # patients (%) | |
|---|---|---|
| Proteinuria (≥ 100 mg/dL) | 68 | (50) |
| Neutropenia (≤ 500 cells/mm) | 33 | (24) |
| Decreased Intraocular Pressure | 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) | N = 115 | # patients (%) |
| Any Adverse Event | 115 | (100) |
| Proteinuria (≥ 30 mg/dL) | 101 | (88) |
| Nausea +/- Vomiting | 79 | (69) |
| Fever | 67 | (58) |
| Neutropenia (< 750 cells/mm) | 50 | (43) |
| Asthenia | 50 | (43) |
| Headache | 34 | (30) |
| Rash | 34 | (30) |
| Infection | 32 | (28) |
| Alopecia | 31 | (27) |
| Diarrhea | 30 | (26) |
| Pain | 29 | (25) |
| Creatinine Elevation (> 1.5 mg/dL) | 28 | (24) |
| Anemia | 28 | (24) |
| Anorexia | 26 | (23) |
| Dyspnea | 26 | (23) |
| Chills | 25 | (22) |
| Increased Cough | 22 | (19) |
| Oral Moniliasis | 21 | (18) |
Reporting of Adverse Reactions
To report SUSPECTED ADVERSE REACTIONS, contact Drug Safety at 1-888-875-1671 or FDA Medwatch at 1-800-FDA-1088 or www.fda.gov/medwatch.
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What should I look out for while using Cidofovir?
Initiation of therapy with cidofovir injection is contraindicated in patients with a serum creatinine > 1.5 mg/dL, a calculated creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥ 2+ proteinuria).
Cidofovir injection is contraindicated in patients receiving agents with nephrotoxic potential. Such agents must be discontinued at least seven days prior to starting therapy with cidofovir injection.
Cidofovir injection is contraindicated in patients with hypersensitivity to cidofovir.
Cidofovir injection is contraindicated in patients with a history of clinically severe hypersensitivity to probenecid or other sulfa-containing medications.
Direct intraocular injection of cidofovir injection is contraindicated; direct injection of cidofovir has been associated with iritis, ocular hypotony, and permanent impairment of vision.
What might happen if I take too much Cidofovir?
Two cases of cidofovir overdose have been reported. These patients received single doses of cidofovir injection at 16.3 mg/kg and 17.4 mg/kg, respectively, with concomitant oral probenecid and intravenous hydration. In both cases, the patients were hospitalized and received oral probenecid (one gram 3 times daily) and vigorous intravenous hydration with normal saline for 3 to 5 days. Significant changes in renal function were not observed in either patient.
How should I store and handle Cidofovir?
Cidofovir Injection, 75 mg per mL, for intravenous infusion, is available in:NDC 67457-210-055 mL (375 mg) single-use vial, packaged individually.Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Preservative FreeSterile. Non-pyrogenic.Discard unused portion.Cidofovir Injection, 75 mg per mL, for intravenous infusion, is available in:NDC 67457-210-055 mL (375 mg) single-use vial, packaged individually.Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Preservative FreeSterile. Non-pyrogenic.Discard unused portion.Cidofovir Injection, 75 mg per mL, for intravenous infusion, is available in:NDC 67457-210-055 mL (375 mg) single-use vial, packaged individually.Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Preservative FreeSterile. Non-pyrogenic.Discard unused portion.Cidofovir Injection, 75 mg per mL, for intravenous infusion, is available in:NDC 67457-210-055 mL (375 mg) single-use vial, packaged individually.Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Preservative FreeSterile. Non-pyrogenic.Discard unused portion.Cidofovir Injection, 75 mg per mL, for intravenous infusion, is available in:NDC 67457-210-055 mL (375 mg) single-use vial, packaged individually.Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Preservative FreeSterile. Non-pyrogenic.Discard unused portion.Cidofovir Injection, 75 mg per mL, for intravenous infusion, is available in:NDC 67457-210-055 mL (375 mg) single-use vial, packaged individually.Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Preservative FreeSterile. Non-pyrogenic.Discard unused portion.
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Cidofovir injection must be administered with probenecid. The pharmacokinetics of cidofovir, administered both without and with probenecid, are described below.
The pharmacokinetics of cidofovir without probenecid were evaluated in 27 HIV-infected patients with or without asymptomatic CMV infection. Dose independent pharmacokinetics were demonstrated after one hr infusions of 1 (n = 5), 3 (n = 10), 5 (n = 2) and 10 (n = 8) mg/kg (see for pharmacokinetic parameters). There was no evidence of cidofovir accumulation after 4 weeks of repeated administration of 3 mg/kg/week (n = 5) without probenecid. In patients with normal renal function, approximately 80% to 100% of the cidofovir injection dose was recovered unchanged in urine within 24 hr (n = 27). The renal clearance of cidofovir was greater than creatinine clearance, indicating renal tubular secretion contributes to the elimination of cidofovir.
The pharmacokinetics of cidofovir administered with probenecid were evaluated in 12 HIV-infected patients with or without asymptomatic CMV infection and ten patients with relapsing CMV retinitis. Dose independent pharmacokinetics were observed for cidofovir, administered with probenecid, after one hr infusions of 3 (n = 12), 5 (n = 6), and 7.5 (n = 4) mg/kg (see Table 2). Approximately 70% to 85% of the cidofovir injection dose administered with concomitant probenecid was excreted as unchanged drug within 24 hr. When cidofovir injection was administered with probenecid, the renal clearance of cidofovir was reduced to a level consistent with creatinine clearance, suggesting that probenecid blocks active renal tubular secretion of cidofovir.
In vitro
Non-Clinical Toxicology
Initiation of therapy with cidofovir injection is contraindicated in patients with a serum creatinine > 1.5 mg/dL, a calculated creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥ 2+ proteinuria).Cidofovir injection is contraindicated in patients receiving agents with nephrotoxic potential. Such agents must be discontinued at least seven days prior to starting therapy with cidofovir injection.
Cidofovir injection is contraindicated in patients with hypersensitivity to cidofovir.
Cidofovir injection is contraindicated in patients with a history of clinically severe hypersensitivity to probenecid or other sulfa-containing medications.
Direct intraocular injection of cidofovir injection is contraindicated; direct injection of cidofovir has been associated with iritis, ocular hypotony, and permanent impairment of vision.
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 ).
Cidofovir injection is formulated for intravenous infusion only and must not be administered by intraocular injection. Administration of cidofovir injection by infusion must be accompanied by oral probenecid and intravenous saline prehydration (see ).
In clinical trials, cidofovir injection was withdrawn due to adverse events in 39% of patients treated with 5 mg/kg every other week as maintenance therapy.
The incidence of adverse reactions reported as serious in three controlled clinical studies in patients with CMV retinitis, regardless of presumed relationship to drug, is listed in Table 4.
The most frequently reported adverse events regardless of relationship to study drugs (cidofovir or probenecid) or severity are shown in Table 5.
The following additional list of adverse events/intercurrent illnesses have been observed in clinical studies of cidofovir injection and are listed below regardless of causal relationship to cidofovir injection. Evaluation of these reports was difficult because of the diverse manifestations of the underlying disease and because most patients received numerous concomitant medicines.
Body as a Whole
Cardiovascular System
Digestive System
Endocrine System:
Hemic and Lymphatic System
Metabolic and Nutritional System
Musculoskeletal System
Nervous System
Respiratory System
Skin and Appendages
Special Senses
Urogenital System
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
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