CIDOFOVIR

Generic Name/API: cidofovir dihydrate

Manufacturer: Avet Pharmaceuticals

Dosage Forms & Strength & Pack Size:
Cidofovir Injection, USP 75 mg/mL for intravenous infusion, 375 mg in a 5 mL vial in a single-unit carton

Storage:
Cidofovir Injection, USP should be stored at 25°C (77°F); excursions permitted to 15° to
30°C (59° to 86°F).

  • INDICATION
  • IMPORTANT SAFETY INFORMATION

INDICATION
Cidofovir injection is indicated for the treatment of CMV retinitis in patients with acquired immunodeficiency syndrome (AIDS). THE SAFETY AND EFFICACY OF CIDOFOVIR
INJECTION HAVE NOT BEEN ESTABLISHED FOR TREATMENT OF OTHER CMV INFECTIONS (SUCH AS PNEUMONITIS OR GASTROENTERITIS), CONGENITAL OR NEONATAL CMV DISEASE, OR CMV DISEASE IN NON-HIV-INFECTED INDIVIDUALS.

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).
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
DOSAGE AND ADMINISTRATION).
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 Carcinogenesis, Mutagenesis, & Impairment of Fertility).
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 1 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 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 antiinflammatory agents] is contraindicated. Such agents must be discontinued at least
seven days prior to starting therapy with cidofovir injection.
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 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
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 injection 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 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.

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